RSSDI

TEXTBOOK OF
DIABETES MELLITUS
 RSSDI
TEXTBOOK OF
DIABETES MELLITUS
Third Edition

Editor-in-Chief
Hemraj B Chandalia
Executive Editor
Gumpeny Ramachandra Sridhar
Editors
Ashok Kumar Das
Sri Venkata Madhu
Viswanathan Mohan
Paturi Vishnupriya Rao

The Health Sciences Publishers

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© 2014, Research Society for the Study of Diabetes in India
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RSSDI Textbook of Diabetes Mellitus
Second Edition: 2008
Revised and Reprint: 2012
Third Edition: 2014
ISBN: 978-93-5152-090-0
Printed at:
 DEDICATION
RSSDI Textbook of Diabetes Mellitus
Third Edition

(1929 to 1998)

Prof MMS Ahuja was one of the major driving forces behind this textbook. It is unfortunate
that he passed away on July 12, 1998, when the first edition of this textbook was in its initial
stages of preparation. It took us a great deal of time to pick the threads of editorial process where
Prof Ahuja had left them and ultimately put the first edition together. Prof Ahuja was Head of
the Departments of Medicine and Endocrinology at the prestigious All India Institute of Medical
Sciences for several decades. He combined the qualities of a compassionate physician, an
inspiring teacher and an inquisitive researcher—a combination difficult to find in modern times.
He was a prolific writer and edited a highly popular series of review books entitled “Progress in
Medicine”. In the areas of diabetology, his research work covered epidemiology, ketosis resistant
diabetes in young, cardiovascular complications, nutrition and patient education. He has left his
distinctive stamp in these fields. Prof Ahuja was one of the founders of Research Society for the
Study of Diabetes in India and the major working force behind this society’s progress. He founded
and edited the ‘International Journal of Diabetes in Developing Countries’ from 1980 onwards,
until the time of his collaboration in 1991 with other editors. This textbook continues to bear
the stamp of his excellence. We, the editors of this textbook owe a great deal of gratitude to our
pioneering colleague, Prof Ahuja and pay him a respectful tribute.
 DEDICATION
RSSDI Textbook of Diabetes Mellitus
Third Edition

(1923 to 2010)

Prof BB Tripathy was a doyen among physicians and diabetologists. He was an outstanding
researcher and an astute clinician who produced some of the best epidemiological research at
a time when the field of epidemiology was in its nascent stage in India. His work was highly
signi­ficant in describing the clinical features of an atypical form of ketosis-resistant diabetes
which was associated with malnutrition. Prof Tripathy organized a landmark international
workshop “Diabetes peculiar to the Tropics” in 1995 at Cuttack. His knowledge was extensive
and encompassed the fields of medicine, biochemistry, pharmaco­logy, nutrition and epidemiology.
He was Editor-in-Chief of RSSDI Textbook of Diabetes, First and Second editions. He was the
Founder Vice President of the Research Society for Study of Diabetes in India (RSSDI) and was
connected with this organization till his demise as an Executive Patron. RSSDI is heavily indebted
to Prof Tripathy for his contributions and inspiring leadership.
 Editors

Prof (Dr) Hemraj B Chandalia MD FACP

• Director, Endocrinology, Diabetes and Metabolism, Jaslok Hospital
and Research Centre, Mumbai
• Director, Dr Chandalia’s Diabetes Endocrine Nutrition Management
and Research Centre, Mumbai
• Honorary Professor of Medicine and Diabetes, Grant Medical College
and Sir JJ Group of Hospitals, Mumbai (1971–2000)
• Patron and Past President, Research Society for the Study of Diabetes
in India
• Founding Editor, International Journal of Diabetes in Developing
Countries
• Research Interests: Glycated Hemoglobin, Lactic Acidosis, Nutrition in
Diabetes, Patient-Education, Prevention of Type 2 Diabetes.
• RSSDI Textbook—First, Second and Second Revised Edition: Executive
Editor
• RSSDI Textbook—Third Edition: Editor-in-Chief
• Chapters authored: 16, 43, 48, 53, 88, 92, 94; Section Editor: Sections
1, 2, 3, 4, 5, 9

Prof (Dr) Gumpeny Ramachandra Sridhar MD DM FACE

FRCP (Glasgow)
• Director, Endocrine and Diabetes Centre, Vishakhapatnam
• Adjunct Professor, Bioinformatics, Andhra University, College of
Engineering
• President, Research Society for the Study of Diabetes in India (2010)
• President, Endocrine Society of India (2013–2014)
• Founding Editor, Indian Journal of Endocrinology and Metabolism
(1997–2000)
• Editor-in-Chief, International Journal of Diabetes in Developing
Countries (2013 onwards)
• Research Interests: Clinical Informatics, Computational Biology and
Bioinformatics, Psychological Aspect of Diabetes
• RSSDI Textbook—Third Edition: Executive Editor
• Chapters authored: 33, 71, 81, 82, 85; Section Editor: Sections 10, 11,
12, 13, 14, 15
x RSSDI Textbook of Diabetes Mellitus

Prof (Dr) Ashok Kumar Das MD PhD FICP FAMS FACP FRCP (London)
• Senior Professor of Medicine and Endocrinology, Head Department of
Endocrinology, Jawaharlal Institute of Postgraduate Medical Education
and Research (JIPMER), Puducherry
• Past President, Association of Physicians of India
• Past President, Research Society for the Study of Diabetes in India
• Patron, Research Society for the Study of Diabetes in India
• Immediate Past Dean, Indian College of Physicians
• Research Interests: Cardiovascular Complications of Diabetes Mellitus,
Diabetic Neuropathy and Diabetic Foot, Pathogenesis of Type 1 Diabetes
Mellitus
• RSSDI Textbook—First, Second, Second Revised and Third Edition:
Editor
• RSSDI Textbook—Third Edition; Chapters authored: 14, 20, 23, 44, 58,
67, 76, 90

Prof (Dr) Sri Venkata Madhu MD DM (Endocrinology)

• Professor and Head, Department of Medicine and Head, Division of
Endocrinology and Metabolism, University College of Medical Sciences
and associated GTB Hospital, Delhi, India
• President elect, Research Society for the Study of Diabetes in India
(2014)
• Secretary, Research Society for the Study of Diabetes in India (2008–
2013)
• Research Interests: Diabetes Epidemiology, Pathogenesis of Diabetes
and its Complications, Stress and Diabetes, Postprandial Lipid
Abnormalities in relation to Diabetes and Prediabetes
• RSSDI Textbook—First, Second, Second Revised and Third Edition:
Editor
• RSSDI Textbook—Third Edition; Chapters authored: 11, 24, 52, 89
 Editors xi

Prof (Dr) Viswanathan Mohan M

 D FRCP PhD DSc FNA FACP FACE
FTWAS
• Chairman and Chief of Diabetology, Dr Mohan’s Diabetes Specialities
Centre, Chennai
• President and Director, Madras Diabetes Research Foundation
• President, Research Society for the Study of Diabetes in India (2012–
2013)
• Research Interests: Epidemiology of Diabetes and its Complications,
Genomics of Diabetes, Prevention of Diabetes
• RSSDI Textbook—Second, Second Revised and Third Edition: Editor
• RSSDI Textbook—Third Edition; Chapters authored:12, 21, 27, 28;
Section Editor: Sections 6, 7, 8

Prof (Dr) Paturi Vishnupriya Rao MD PhD

• Professor and Head, Department of Endocrinology, Diabetes and
Metabolism, Nizam’s Institute of Medical Sciences University Hospital,
Hyderabad
• Secretary, Research Society for the Study of Diabetes in India (1993–
2007)
• Cofounder, DiabetOmics Laboratories, Portland, Oregon
• Research Interests: Epidemiology of Diabetes, Genetics of Diabetes,
Biomarkers of Diabetes, Gestational Diabetes, Proteomics in Diabetes
• RSSDI Textbook—First, Second, Second Revised and Third Edition:
Editor
• RSSDI Textbook—Third Edition; Chapters authored: 6, 7, 9
 Contributors

Subrat Kumar Acharya MD DM FnA ScF ASc FN Debasis Basu MD MBA(HCS)

Professor and Head President, Diabetes Awareness and you
Department of Gastroenterology and Human Nutrition In-charge SUGAR Clinic, Apollo Gleneagles Heart Centre
All India Institute of Medical Sciences Kolkata, West Bengal, India
Teaching Block, New Delhi, India Chapters: 72, 84
Chapter: 68
Suchitra Behl MD ABIM
AK Bajaj MD (Dermatology), FICAI
Fellow, Endocrinology and Advanced Diabetes Consultant
Former Professor and Head of Dermatology Fortis C-DOC Centre of Excellence for Diabetes,
MLN Medical College
Metabolic Diseases and Endocrinology
Allahabad, Uttar Pradesh, India
Fortis Hospital
Chapter: 69
Vasant Kunj, New Delhi, India
JS Bajaj MD FRCP (Ed) FRCP (London) DM (hc Karolinska) FAMS Chapter: 49
Hon DSc (BHU) DSc (hc MGR Med Univ) DSc (hc GND Univ)
Hon DSc (Madras) Hon DSc (Punjab Univ) Anil Bhansali DM FRCP
DSc (hc Univ Health Sc Andhra)
Professor and Head, Department of Endocrinology
Former Professor of Medicine
PGIMER, Chandigarh, India
All India Institute of Medical Sciences
Chapter: 47
New Delhi, India
Chapter: 60
Sanjay Kumar Bhadada MD DM
Sarita Bajaj MD (Medicine) DM (Endocrinology AIIMS) Associate Professor, Department of Endocrinology
Director, Professor and Head PGIMER Chandigarh, India
Department of Medicine Chapter: 55
MLN Medical College
Allahabad, Uttar Pradesh, India Sudip Chatterjee MD MNAMS (Endocrinology) FRCP (London) FACP
Chapter: 69 Hon Professor of Medicine
Vivekananda Institute of Medical Sciences and
Vijayam Balaji MD Hon Secretary, Park Clinic
Director, Dr V Seshiah Diabetes Research Institute Kolkata, West Bengal, India
Dr Balaji Diabetes Care Centre Chapter: 35
Madras, Tamil Nadu, India
Chapter: 79 Swapna Chaturvedi MSc Foods and Nutrition (Delhi Univ) RD
Department of Dietetics
Samar Banerjee MD
All India Institute of Medical Sciences
President, Research Society for the Study of
New Delhi, India
Diabetes in India (RSSDI)
Chapter: 30
Professor of Medicine and Specialist Diabetes Clinic
Vivekananda Institute of Medical Sciences
Hemraj B Chandalia MD FACP
Kolkata, West Bengal, India
Chapter: 56 Director, Endocrinology Diabetes and Metabolism
Jaslok Hospital and Research Center, Mumbai
BC Bansal MD MAMS FICP FIMSA FIAMS FFGSI FIACM FICN Hon Professor of Medicine and Diabetes (Retd)
Former Professor of Neurology Grant Medical College
Medical College, Rohtak, Haryana, India Mumbai, Maharashtra, India
Chapter: 60 Chapters: 16, 43, 48, 53, 88, 92, 94
xiv RSSDI Textbook of Diabetes Mellitus

Shaival H Chandalia MBBS, Diplomate American Board in Internal Sunil Gupta MD FIAMS FIACM FICP (Diabetologist)
Medicine, Fellow Endocrinology UT Southwestern USA Director, Sunil’s Diabetes Care in Research Centre
Consultant Endocrinologist and Diabetologist Lendra Park, Ramdaspeth
Jaslok and Bhatia Hospitals, Mumbai Nagpur, Maharashtra, India
Consultant Endocrinologist and Diabetologist Chapter: 75
Dr Chandalia's Diabetes Endocrine Nutrition
Management and Research Centre Daya Kishore Hazra MD(Agra) MSc Nuclear Medicine PhD (London)
Mumbai, Maharashtra, India FNAMS FICP FICNM FIACM
Chapter: 40, 94 Emeritus Professor, SN Medical College, Agra
Chief Consultant, Boston Medical Centre
Arun R Chitale MD (Path) Diplomate of American Board of Pathology Agra, Uttar Pradesh, India
Surgical Pathologist, Surgical Pathology Center Chapter: 63
Surgical Pathologist and Electron Microscopist
Aspi J Irani MD (Pediatrics) DCH
Jaslok Hospital Research Center
Mumbai, Maharashtra, India Honorary Pediatrician: Dr Balabhai Nanavati Hospital and
Chapter: 3 Research Center, Mumbai
In-Charge: Medical Services—Juvenile Diabetes Foundation,
Maharashtra Chapter, India
Subhankar Chowdhury DTM H MD DM MRCP
Chapter: 77
Professor and Head
Department of Endocrinology Sunil M Jain MD DM (Endocrinology)
IPGME & R and SSKM Hospital Consultant Endocrinologist
Kolkata, West Bengal, India TOTALL Diabetes Hormone Institute
Chapter: 51
Indore, Madhya Pradesh, India
Chapter: 38
Ashok Kumar Das MBBS MD PhD DNB FAMS
FICP FACP FRCP Sushil Jindal MD DM (Endocrinolgy)
Senior Professor of Medicine and Head Endocrinology, Professor of Medicine, People’s College of
Jawaharlal Institute for Postgraduate Medical Sciences, Bhopal
Medical Education and Research (JIPMER) Director, Jindal Diabetes and Hormone Centre
Puducherry, India Bhopal, Madhya Pradesh, India
Chapters: 14, 20, 23, 44, 58, 67, 76, 90 Chapter: 5

Sidhartha Das MBBS(Hons) MD FICN FICP FRCP(Glasg) FRCP(Edin) Shashank R Joshi MD DM FICP FACP (USA) FACE (USA)
FRCP (Glsg & Edin)
Senior Consultant in Medicine and Diabetology
Head, Postgraduate Department of Medicine Endocrinologist, Joshi Clinic, Lilavati and Bhatia Hospital
SCB Medical College and Hospital President Elect, Association of Physicians of India (API)
Cuttack, Odisha, India Mumbai, Maharashtra, India
Chapter: 57 Chapter: 54

Sudeep K MD DNB (Endocrinology)

Mala Dharmalingam MD DM (AIIMS)
Assistant Professor and Consultant Endocrinologist
Professor and HOD, Department of Endocrinology
Endocrinology Unit, Department of Medicine
MS Ramaiah Medical College, Bengaluru
Father Muller Medical College Hospital
Director, Bangalore Endocrinology and
Mangalore, Karnataka, India
Diabetes Research Center
Chapter: 50
Bengaluru, Karnataka, India
Chapter: 29
Sanjay Kalra MD DM
Consultant, Endocrinology, Bharti Hospital and BRIDE Karnal
Prasanth G MD Internal Medicine MBBS Executive Editor, Indian J Endocrinology Metabolism
Senior Resident in Medicine Bharti Hospital
Jawaharlal Institute of Postgraduate Karnal, Haryana, India
Medical Education and Research Chapter: 74
Puducherry, India
Chapter: 67 Alok Kanungo MD PhD
Chief Consultant Diabetologist,
Leif Groop MD PhD Chairman and Managing Director
Professor of Endocrinology Kanungo Institute of Diabetes Specialities
Lund University, Malmö, Sweden Bhubaneswar, Odisha, India
Chapter: 7 Chapter: 15
 Contributors xv

Jothydev Kesavadev MD Ramchandra Dattatray Lele MBBS (OSM) DTM and H (Eng)

Chairman and Managing Director  MRCP (Edin) FRCP (London)
Jothydev’s Diabetes Research Centre FNAMS Hon DSc Hon D Litt
Trivandrum, Kerala, India Emeritus Director, Nuclear Medicine and PET CT
Chapter: 42 Department of Jaslok Hospital and Research Centre
Emeritus Professor of Medicine (for life) and Ex-Dean
Romesh Kumar Khardori MD PhD FACP FRCP(C) Grant Medical College and Sir JJ Hospitals
Mumbai, Maharashtra, India
Professor of Medicine Endocrinology and Metabolism
Chapter: 17
Director, Endocrinology Graduate Training Program
Division of Endocrinology, and Metabolism
Strelits Institute for Diabetes Endocrine and SV Madhu MD DM (Endocrinology)
Metabolic Disorders Professor and Head, Department of Medicine and
Eastern Virginia Medical School Head Division of Endocrinology and Metabolism
Norfolk, Virginia, USA UCMS-GTB Hospital Delhi, India
Chapter: 46 President Elect, Research Society for the Study of
Diabetes in India (RSSDI)
Chapter: 11, 52, 89
Ashok L Kirpalani MD (Internal Medicine) MNAMS (Nephrology)
Professor of Nephrology, Bombay Hospital
K Madhu MA PhD
Institute of Medical Sciences,
Mumbai Kidney and Blood Pressure Clinic Head, Department of Psychology, Andhra University
Indian Cancer Medical Centre Visakhapatnam, Andhra Pradesh, India
Chapter: 81
Mumbai, Maharashtra, India
Chapter: 66
Thomas Mathew MBBS MD DM
Ajay Kumar MD FRCP Assistant Professor of Medicine
St John’s Medical College
Consultant, Physician and Diabetologist
Bengaluru, Karnataka, India
Diabetes Care and Research Centre
Chapter: 67
Patna, Bihar, India
Chapter: 36
A Rosalind Marita PhD
Kalyanaraman Kumaran DM FFPH Assistant Director
Haffkine Institute for Training,
Senior Scientist, Diabetes Unit, KEM Hospital Pune, India
Research and Testing, Mumbai
Senior Lecturer, MRC Lifecourse Epidemiology Unit Formerly Director—Pharmacology Piramal Life Sciences Ltd
University of Southampton, UK Mumbai, Maharashtra, India
Chapter: 19
Chapter: 17, 18

KM Prasanna Kumar MD DM (Endo) Suresh D Mehtalia MD (Bom) FICA (USA) FICP (India)

Consultant Endocrinologist Hon Diabetologist, Asian Heart Institute, Mumbai
Centre for Diabetes and Endocrine Hon Diabetologist, Sir HN Hospital
Care and Bangalore Diabetes Hospital Mumbai, Maharashtra, India
Bengaluru, Karnataka, India Chapter: 41
Chapter: 78
Anoop Misra MBBS MD
Venkata Ranga Rao Kodali MBBS MRCP (UK) MSc  (Applied Nutrition) Chairman, Fortis-C-DOC Centre of Excellence for Diabetes
MSc (Endocrinology) FRACP
Metabolic Diseases and Endocrinology
Consultant Physician with Special interest in Director, Centre of Internal Medicine (CIM), Fortis Hospital
Endocrinology and Diabetes Vasant Kunj, New Delhi, India
Division of Medicine Geraldton Regional Hospital Chairman, National Diabetes Obesity and Cholesterol
Geraldton, Washington, USA Foundation (N-DOC), India
Chapter: 13 Chapter: 49

PS Lamba MD DM Priyanka Modi MSc

Consultant Endocrinologist Research Associate, Kanungo Institute for Diabetes
Endocrine and Diabetes Management Centre Specialities Hospital, Dumduma
Mumbai, Maharashtra, India Bhubaneswar, Odisha, India
Chapter: 4 Chapter: 15
xvi RSSDI Textbook of Diabetes Mellitus

Sonal V Modi MSc RD CDE Vijay Negalur MD

Chief Nutritionist, Dr Chandalia's Diabetes Endocrine Hon Asst Professor of Medicine
Nutrition Management and Research Centre (DENMARC) Rajeev Gandhi Medical College, Thane
Lady Ratan Tata Research Centre Diabetologist, Jupiter Hospital, Thane
Mumbai, Maharashtra, India Mumbai, Maharashtra, India
Chapter: 31
Chapter: 70

Viswanathan Mohan MD FRCP PhD DSc FNA FACP John Thomas O’Brian MD FACP FACE
FACE FTWAS
Professor of Medicine, Endocrinology and Metabolism
Chairman, Dr Mohan’s Diabetes Specialities Centre
President, Madras Diabetes Research Foundation Associate Director: Endocrinology Graduate Training Program
Chennai, Tamil Nadu, India Division of Endocrinology and Metabolism
Chapters: 12, 21, 27, 28 Eastern Virginia Medical School
W Brambleton Avenue, Norfolk, USA
Susana A Moran Chapter: 46
Emory School of Medicine Atlanta
Georgia, USA Timothy O’Connor MD FACS
Chapter: 9 Associate Clinical Professor of Surgery/Transplant Surgery
University of Illinois College of Medicine
MV Muraleedharan MD DM MRCP Peoria, Illinois, USA
Former Professor of Endocrinology Chapter: 46
Medical College
Thrissur, Andhra Pradesh, India MV Padma MD DM FAMS FNASc
Chapter: 82
Professor and Head Unit III, Neurology
All India Institute of Medical Sciences
Nutan Sham Nabar MD (Ayurveda)
New Delhi, India
Ayurvedic Consultant, Mangirish Clinic Bandra (W), Mumbai Chapter: 60
Research Associate, ICMR, Mumbai
Medical Research Centre, Kasturba Health Society NC Panda
Mumbai, Maharashtra, India
Chapter: 45 Former Professor of Biochemistry
SCB Medical College
Dukhabandhu Naik MD (Medicine) DM (Endocrinology) Cuttack, Odisha, India
Assistant Professor of Endocrinology, Chapter: 2
Diabetes and Metabolism
Christian Medical College Ramakrishna Pinjala MS FRCSED FICS
Vellore, Tamil Nadu, India Head of the Department of Vascular Surgery
Chapters: 25, 26 Nizams’s Institute of Medical Sciences
Hyderabad, Andhra Pradesh, India
Arun Nanditha MD Chapter: 61
Consultant Diabetologist
Dr A Ramachandran’s Diabetes Hospitals Kaushik Pandit MD DNB DM
Chennai, Tamil Nadu, India
Consultant Endocrinologist,
Chapter: 10
Belle Vue Clinic, Kolkata and Fortis Hospital
Praveen Namboodiri MD DM Kolkata, West Bengal, India
Chapter: 51
HOD Nephrology, Bishop Benziger Hospital, Kollam
Consultant Nephrologist, SIMS, Kollam Kizhakillam
Kerala, India Sharad P Pendsey MBBS MD
Chapter: 66 Consultant Diabetologist
Diabetes Clinic and Research Centre,
KM Venkat Narayan MD MSC MBA Dhantoli, Nagpur
Ruth and OC Hubert Chair of Global Health Managing Trustee Dream Trust, a Registered NGO
Rollins School of Public Health, EMORY University Diabetes Clinic and Research Centre
Atlanta, USA Nagpur, Maharashtra, India
Chapter: 9 Chapter: 62
 Contributors xvii

Uday K Phadke MD DNB DM(Endocrinology) FACE Sudhaker D Rao MBBS FACP FACE
Consultant in Endocrinology and Diabetes Section Head, Bone and Mineral Metabolism, and
Ruby Hall Clinic and INSTRIDE Director, Bone and Mineral Research Laboratory
Pune, Maharashtra, India Henry Ford Hospital
Chapter: 32 Detroit, Michigan, USA
Chapter: 71
Rajendra Pradeepa MSc PhD
Murlidhar S Rao MD FACP (USA) FICP
Senior Scientist and Head Research Operations
Madras Diabetes Research Foundation and Dr Mohan’s Senior Consultant Cardio-Diabetologist
Diabetes Specialities Centre Matoshree Medical Center, Court Road, Gulbarga
Chennai, Tamil Nadu, India Former Professor and HOD MR Medical College
Chapter: 64 Vithal Nagar, Gulbarga, Karnataka, India
Chapter: 59
Vijayaraghavan Prathiba MBBS DO FEDD FRCS (Glasgow)
Head of Glaucoma Department Radha Reddy MBBS
Dr Mohan’s Diabetes Specialities Centre and Fellow, Endocrinology, Diabetes and
Madras Diabetes Research Foundation Metabolism (USA)
Chennai, Tamil Nadu, India Consultant Endocrinology and
Chapter: 65 Diabetes-Claremont, USA
Chapter: 78
Vijay Panikar MD FCPS DNB
Formerly Professor of Medicine Banshi Saboo MD FICP FIACM MNAMS
KJ Somiaya Medical college Fellow—American College of Endocrinology
Department of Endocrinology and Diabetes Diabetologist and Metabolic
Lilavati Hospital Physician, Diacare—Diabetes Care and Hormone Clinic
Mumbai, Maharashtra, India Ahmedabad, Gujarat, India
Chapter: 86 Chapter: 39

P Raghupathy Rakesh K Sahay MD DM

Former Professor of Paediatrics Professor of Endocrinology
Christian Medical College Osmania Medical College and
Vellore, Tamil Nadu, India Osmania General Hospital, Hyderabad
Chapter: 23 Consultant Endocrinologist, Mediciti Hospital
Hyderabad, Andhra Pradesh, India
Paturi V Rao MD DipDiab PhD FRCP (L) FACE Chapter: 8, 34
Head, Department of Endocrinology and Metabolism
Nizam’s Institute of Medical Sciences University Rajesh G Sainani MD DNB
Hyderabad, Andhra Pradesh, India Consultant, Gastroenterologist and Hepatologist
Chapter: 6, 7, 9, 11 Jaslok Hospital and Research Centre, Bhatia Hospital
Mumbai, Maharashtra, India
Ramachandran Rajalakshmi MBBS DO FEDD PhD Chapter: 87
Head—Medical Retina, Dr Mohan’s Diabetes Specialities
Centre and Madras Diabetes Research Foundation Gurmukh S Sainani MD FRCP (Lond & Edin) Hon FRACP PhD (Poona)
Chennai, Tamil Nadu, India DSc (Poona) Hon D Lit FACC (USA) FAMS (Ind)
Chapter: 64 FACP (USA) FCCP (USA) FRSM (Lond) FAIID FIAMS
FISE FICP (Ind) FIMSA FICN FICA (USA) FICC (Ind)
Ambady Ramachandran MD PhD DSc FRCP (Lond) FIACM FGSI Hon FISC FCSI
MNAMS FICP FRCP(Edin) Director, Department of General Medicine
President, India Diabetes Research Foundation and Jaslok Hospital and Research Centre, Mumbai
Chairman and Managing Director Emeritus Professor of Medicine (for life)
Dr A Ramachandran’s Diabetes Hospitals Grant Medical College and JJ Hospital
Chennai, Tamil Nadu, India Mumbai, Maharashtra, India
Chapter: 10, 93 Chapter: 87
xviii RSSDI Textbook of Diabetes Mellitus

Carani B Sanjeevi MD MSc PhD Dhruv K Singh MD D Diab

Professor, Department of Medicine, Karolinska Institute Chief Diabetologist and Medical Director, JUST Diabetes
Head, Diabetes Autoimmunity Research Group Off New Link Road, Andheri (W)
Center for Molecular Medicine, Karolinska University Hospital Mumbai, Maharashtra, India
Stockholm, Sweden Hon Senior Visiting Lecturer, Postgraduate Medical School
Chapter: 15, 22, 91 University of Hertfordshire, UK
Chapter: 4
Krishna G Seshadri MBBS AB (IM) AB (Endo Diab Met)
Professor and Head Endocrinology, Diabetes and Gumpeny Ramachandra Sridhar MD DM FACE
Metabolism, Sri Ramachandra University FRCP
Senior Consultant, Fortis Malar Hospital Director, Endocrine and Diabetes Centre, Krishnanagar
Chennai, Tamil Nadu, India Visakhapatnam, Andhra Pradesh, India
Chapter: 80 Chapters: 33, 71, 81, 82, 85

Veeraswamy Seshiah MD Chamukuttan Snehalatha MSc DPhil DSc

Chairman—Dr V Seshiah Diabetes Research Institute, Director—Research, India Diabetes
Dr Balaji Diabetes Care Centre Research Foundation
Chennai, Tamil Nadu, India Chennai, Tamil Nadu, India
Chapter: 10
Chapter: 79

Chengjun Sun MD
Rupin Shah MS MCh (Urology)
Scientist, Department of Medicine
Consultant Andrologist and Microsurgeon
Karolonska Institute Diabetes Autoimmunity
Lilavati Hospital and Research Center, Research Group
Bhatia Hospital Center for Molecular Medicine
Mumbai, Maharashtra, India Karolinska University Hospital
Chapter: 73 Stockholm, Sweden
Chapter: 22, 91
Siddharth N Shah MD FACP
Bhatia Hospital, Saifee Hospital Nihal Thomas M
 D MNAMS DNB (Endo) FRACP (Endo)
Editor-in-Chief, Journal of Association of Physicians of India FRCP (Edin) FRCP (Glas)
Emeritus Editor—API Textbook of Medicine, IX Edition Professor and Head, Department of Endocrinology
Mumbai, Maharashtra, India Diabetes and Metabolism and Vice-Principal(Research)
Chapter: 54 Christian Medical College
Vellore, Tamil Nadu, India
Chapters: 25, 26, 50
Rekha Sharma MSc RD
Director, Nutrition and Dietetics
BB Tripathy (Deceased)
Diabetes Foundation (India)
Chapters: 6, 14, 16, 23
Former Chief Dietitian
All India Institute of Medical Sciences
Devjit Tripathy MBBS MD
New Delhi, India
Chapter: 30 Assistant Professor, University of Texas Health Science Center
San Antonio, Texas, USA
Chapters: 7, 16
Samith A Shetty MBBS MDRC
Consultant Diabetologist Ashida TS MBBS MD DNB
Dr A Ramachandran’s Diabetes Hospitals
Interventional Cardiologist, Cardiothoracic Surgeon
Chennai, Tamil Nadu, India
East Coast Hospital
Chapter: 10 Puducherry, India
Chapter: 76
Jitendra Singh MBBS MD Medicine; Fellowship Diabetes (AIIMS NDL)
MNAMS Diabetes and Endocrinology Ranjit Unnikrishnan MBBS MD (Gen Med)
Professor Diabetes and Endocrinology Vice-chairman and Consultant Diabetologist
Government Medical College Dr Mohan’s Diabetes Specialities Centre
Jammu, India Chennai, Tamil Nadu, India
Chapter: 37 Chapter: 1
 Contributors xix

Rama Ashok Vaidya MD PhD Radha Venkatesan MSc PhD

Director, Endocrine and Metabolic Executive Scientific Officer and Head
Disorder Unit, MRC-KHS, Mumbai Department of Molecular Genetics
Consulting Reproductive Endocrinologist Madras Diabetes Research Foundation
Vasudha Clinic Santacruz (W), Chennai, Tamil Nadu, India
Mumbai, Maharashtra, India Chapter: 21
Chapter: 45
Stalin Viswanathan MD
Ashok DB Vaidya MD PhD FAIM Assistant Professor, Department of Medicine
Research Director, Medical research Centre Indira Gandhi Government Post Graduate Medical Institute
Kasturba Health Society, Mumbai, Maharashtra, India Puducherry, India
Adjunct Professor, Drexel University, Philadelphia Chapter: 44
Chapter: 45
Vijay Viswanathan MD PhD FICP FRCP (London) FRCP (Glasgow)
Poovazhagi Varadarajan MD DCH Adjunct Professor
The Tamil Nadu Dr MGR Medical University
Associate Professor of Pediatrics
Head and Chief Diabetologist
Thanjavur Medical College
MV Hospital for Diabetes (P) Ltd
Chennai, Tamil Nadu, India Chennai, Tamil Nadu, India
Chapter: 27 Chapters: 63, 83

Premlata K Varthakavi MD (Internal Medicine) Chittaranjan S Yajnik MD FRCP

DNB (Endocrinology)
Director, Diabetes Unit, KEM Hospital,
TNM College and BYL Nair Charitable Hospital Pune, Maharashtra, India
Dr AL Nair road Mumbai Central Visiting Professor, Peninsula Medical School
Mumbai, Maharashtra, India Exeter, UK
Chapter: 41 Chapter: 19
 Preface to the Third Edition

It gives us great pleasure to bring to you the Third Edition of the RSSDI’s Textbook of Diabetes
Mellitus.
This textbook has held a place of pride in the diabetes world for the past decade. Conceived by
late Prof MMS Ahuja and nurtured by late Prof BB Tripathy, this book is produced by Research
Society for Study of Diabetes in India. Due to the prime position RSSDI occupies in India and
world over, the involvement of its member-academicians as authors of the book has given this
book an exalted status, which has been further vindicated by the fact that the first two editions
of the book were very well received by healthcare professionals. The book was originally intended
to present Indian data, mostly by Indian authors but has now graduated into a standard textbook
of diabetes, useful to readers of all categories and regions involved in the care of people with
diabetes. In the present edition, we requested the authors to give a balanced view of data from
all parts of the world, in addition to the Indian data. Hence, we expect the book to now find a
wider world-wide appeal.
Most authors of this book are either Indians or clinicians of Indian origin. As diabetes is highly
prevalent in India, a book originating from India holds great promise. A unique fact about the
background of the authors of this book merits attention. The majority of them are working in
the academic environment, like medical colleges or institutions of repute. In addition to their
academic work, most of them continue to practice diabetes, which makes the approach to the
subject immensely practical and outcome-oriented. The information provided is evidence-based,
yet its applicability has been examined ingeniously and clear recommendations have been
given. These authors have developed clinical approaches that are very useful and practical, at times
providing an exciting insight into future practice of diabetology. Many authors have also published
valuable research papers on the subjects on which they have agreed to write a chapter in this book.
We have introduced several new chapters in this edition in order to keep the contents abreast
of the altered pattern of diabetes and advent of new concepts and treatment modalities. A few
examples are Sleep and Type 2 Diabetes Mellitus (Chapter 20); Neonatal Diabetes (Chapter 27);
Early-onset Type 2 Diabetes (Chapter 28); Yoga and Relaxation Techniques in Diabetes Mellitus
(Chapter 33); Nutrient Blockers and Bromocriptine (Chapter 37); Insulin Pump Therapy (Chapter
39); Glycemic Management in Hospitalized Patients (Chapter 40); Continuous Glucose Monitoring
System (Chapter 42); Stem Cell Therapy in Diabetes Mellitus (Chapter 47); Vitamin D and Diabetes
Mellitus (Chapter 70); HIV in Diabetes (Chapter 74); Diabetes and Cancer (Chapter 75). The oral
anti-diabetic drugs are discussed in four chapters [Insulin Secretagogues (Chapter 34); Insulin
sensitizers: Metformin and Thiazolidinediones (Chapter 35), Incretin-Based Therapy (Chapter 36);
Nutrient Blockers and Bromocriptine (Chapter 37)].
Some chapters were found to be redundant and hence omitted while others have been
amalgamated to enhance continuity and coherence of the subject. We have thoroughly revised all
the previous chapters, incorporating literature upto the year 2013 wherever relevant. An additional
xxii RSSDI Textbook of Diabetes Mellitus

feature is listing of references for Further Reading separately from all references. This feature has
been introduced with the assumption that the book will be used both by clinical diabetologists
or physicians and research workers. The references for Further Reading are either most current
comprehensive reviews or classic research work or research work of lasting impact. These will be
highly useful to the clinicians. The exhaustive list of text-linked references will additionally be of
use to researchers.
We fervently hope that this book is received warmly by the diabetologists, physicians, diabetes
educators and researchers. In that case, we shall consider our efforts amply rewarded.
Hemraj B Chandalia
Gumpeny Ramachandra Sridhar
Ashok Kumar Das
Sri Venkata Madhu
Viswanathan Mohan
Paturi Vishnupriya Rao
 Preface to the First Edition

With explosive increase in its prevalence, diabetes mellitus, as a chronic medical disorder, is to
be reckoned on par with hypertension and atherosclerosis. A versatile disease, diabetes, in view
of its frequent clinical and epidemiological link with the other two, constitutes a health problem
of paramount concern for a very large proportion of the world population.
In the course of the last few decades, India has emerged as the country with the highest
number of patients with diabetes. In keeping with this, in India, diabetology has emerged as a
major specialty in the practice of both general medicine and endocrinology. Over the last thirty
years, several centers have adopted diabetes as a single disease specialty for the state-of-the-art
investigations and clinical care.
The idea of compiling a Textbook on Diabetes Mellitus was mooted with the above in view.
Bearing in mind the fact that there already exist a number of exclusive books on diabetes on the
global scene, this publication was planned keeping several special objectives in view. A large
number of primary care physicians as well as an increasing number of specialists are in need of
comprehensive knowledge on both basic and applied aspects of the disease. Publications from
abroad are very expensive. Prices keep on rising steeply from edition to edition. Further, beginning
from 1960s, it has been explicitly shown that problems associated with diabetes in India are in
several respects distinct from those in the West, the major source of the available publications.
Attempts to cover the special features of diabetes among diverse ethnic groups have been made
in the two editions of the International Textbook of Diabetes Mellitus. Yet, it was felt that India
needs a book of her own to cater to the needs of the burgeoning number of medical practitioners
dealing with diabetes in this country as well as to those of its neighbors in South, Mid and South
East Asia.
The Research Society for the Study of Diabetes in India (RSSDI) was founded in 1972 ostensibly
for promoting academics and research on the intricate subject of diabetes mellitus. The Society
has experienced phenomenal growth in membership and activities during the 90s of the last
century. About four and half years back, Professor MMS Ahuja, a pioneer in establishing RSSDI,
initiated a proposal for compiling a textbook on diabetes. Some of us quickly got together to
process the basics and to set the program in motion. Unfortunately, the sad demise of Professor
Ahuja in July 1998 left us high and dry. Records of the initial work were hard to trace out. It took
us close to a year to recover from the shock and reorganize the undertaking right from the start.
As is evident from the list of editors, this is a collaborative work of several persons placed at long
distances from each other. Professor PV Rao was assigned the pivotal role of keeping the records
and looking after the printing, which he has done with great alacrity in the face of numerous
difficulties in communication and coordination.
Although only a small body of basic research has originated from modern India, clinical and
epidemiological studies have been numerous. These, for sure, are of considerable importance
xxiv RSSDI Textbook of Diabetes Mellitus

for medical practitioners and patients of this country. Only a small number of these works have
been published or abstracted in the world literature and therefore most fail to hit books published
in the West. The RSSDI Textbook of Diabetes Mellitus is purported to highlight data generated
in India wherever relevant. Due scope has been provided for exposition of areas where Indian
investigators have contributed valuable original ideas such as on planning of diet with higher
carbohydrate content, use of insulin and sulfonylurea in combination, application of Yoga in the
management of diabetes, an indigenous inexpensive method for the estimation of glycohemoglobin,
identification and analysis of fibrocalculous pancreatic diabetes and malnutrition modulated
diabetes mellitus, characterization of the quite common low weight type 2 diabetes as well as
elaborate sequential study of epidemiology of diabetes in various social classes of ethnic Indians.
The scope of the textbook was proposed to be wide so as to be of service to general practitioners
as well as to broaden their academic outlook. It was scrupulously designed to target the requirements
of family physicians, academicians, clinical researchers and diabetes oriented health professionals
at large. Diabetes along with its complications is a multiorgan disease covering all subspecialities
of medicine as well as pediatrics, ophthalmology, obstetrics, surgery and orthopedics. While
keeping all these in view, the contents have been designed and presented in a classic textbook
style. Individual chapters are grouped into sections dealing with historical aspects, biochemical
basis, pathogenesis, genetics, stages and classes, epidemiology, clinical details, management,
complications and prevention. Each chapter is comprehensive and reasonably elaborate. Lists of
references are adequate and appropriate. Contributions provided by experienced professors as
well as senior and young clinical researchers from all parts of the country and some from abroad,
have enriched the contents to the best possible extent. Many of the authors happen to be devoted
members of the RSSDI.
Most notable shortcoming is the long delay of nearly three years of gestational period. Due
to multiplicity of authors and editors, there is bound to be some overlap among the chapters. A
few papers have been modified and even replaced after editorial scrutiny. Care has been taken to
refer the papers back to the authors for updating, corrections and finally for reading of the proof
copies prior to the final print.
The editors and the executives of the RSSDI are indeed thankful to various authors for devoting
a lot of time and energy for preparing their contributions. Our thanks are due to Dr Rachel Thomas-
Jacob for proofreading, the printers and numerous other persons who have helped individual
editors and Professor PV Rao in the final lap of publication of our most cherished textbook on
diabetes.
Publications on diabetes as well as CME and update sessions on the topic have been very
popular during the recent decades. Our effort to bring out a comprehensive treatise on this popular
subject, we earnestly hope, will receive fond acceptance from the readers. If this book addresses
the questions they have in their minds or if it stimulates their thinking on this subject, our purpose
would be served.
Sam GP Moses
BB Tripathy
Hemraj B Chandalia
 Acknowledgments

The editorial process has been a challenging task. My co-editors, section editors and authors have
contributed towards this effort. The authors of first and second edition also need to be thanked,
as they had laid down the foundation of the book. In most cases, they have been continued
for the chapter authored by them in the previous editions. In case the author has been changed,
the previous author’s name has been continued as a co-author especially when the contents of
the previous chapter have been utilised extensively.
A group of young physicians, diabetologists and diabetes educators deserve profuse thanks by
me; not only did they assist in copy-editing but detected important deficiencies and redundancy
in some chapters and detected a disconnect between the text and references. Dr Nikesh Jain,
Dr Puja Thadani, Dr Shaival Chandalia, Ms Niyati Likhite, Ms Vriti Srivastav and Ms Monisha
Joukani were involved at various stages of this book. They formed a cohesive team to complete
this stupendous task.
I would also like to give my heartfelt thanks to Dr Puja M Thadani for preparing the abstracts
for the e-version of the book.
I would like to thank my family members, especially my wife Leela Chandalia for gracefully
absolving me of family responsibilities during the past two years of hectic activities related to this
textbook and organisational work of the Research Society for Study of Diabetes in India.
Our publishers, starting from Shri Jitendar P Vij (Group Chairman) and all his associates,
Ms Chetna Malhotra Vohra (Senior Manager–Business Development), Ms Sheetal Arora, Sabarish
Menon and their production teams have been very patient and supportive. I appreciate their
forbearance and co-operation.
Hemraj B Chandalia
Editor-in-Chief
 Contents

SECTION 1  History of Diabetes

Section Editor: Hemraj B Chandalia
1. Landmarks in the History of Diabetes 3
Ranjit Unnikrishnan
Diabetes in the Ancient World 3; Diabetes in the Dark Ages 5; The Advent of Modern Era 5; Break-
through—the 20th Century 6; The Tiger Changes its Stripes: Transformation in the Natural History of
Diabetes and Effect on Complications 12; Advances in our Understanding of the Etiopatho­genesis
of Diabetes 13; Tight Control or No Tight Control—Changing Paradigms in Diabetes Manage-
ment 13; Diabetes Goes Global 14

SECTION 2  Physiology and Metabolism

Section Editor: Hemraj B Chandalia
2. Intermediary Metabolism and Hormonal Regulation 19
NC Panda
Major Metabolic Pathways and Control Sites 20; Stages of Extraction of Energy from Food-
stuffs 21; Recurring Motifs in Metabolic Regulations 21; Major Pathways of Metabolism and the
Principal Sites for their Control 22; Hormonal Regulation of Intermediary Metabolism 29; Fed
State 36; Fasted (Postabsorptive) State 36; Starvation 37; Prolonged Starvation 37; Diabetes
Mellitus 37

3. Morphology of Pancreatic Islets and Pathology of Pancreas in Diabetes Mellitus 42

Arun R Chitale
Normal Islets of Langerhans 42; Historical Landmarks of Clinical and Particularly Pathological Impor-
tance 44; Experimental Diabetes 44; Etiological Classification of Diabetes 44; Nature of Islet
Amyloid 46; Gestational Diabetes 46; Bronze Diabetes 46; Insulinoma 46
4. Insulin Biosynthesis and Secretion 50
Dhruv K Singh, PS Lamba
Organization of Islets of Langerhans 50; Islet Structure 51; Insulin Gene Expression and its Regu­
lation 51; Insulin Biosynthesis: Post Transcriptional Events 54; Fate of the Mature Secretory
Granule 57; Glucose and Signal Recognition 58; Regulation of Insulin Secretion 60; Molecular
Identity of the KATP Channel 61; Insulin Secretion Via KATP Channel Independent Pathways 63; 
Potentiation of Secretion by Various Agents 63; Second Messengers and the Regulation of Insulin
Secretion 65; Effector Systems for Insulin Secretion 67; Insulin Secretion and Diabetes 68
5. Biology of Insulin Action 79
Sushil Jindal
Biological Firsts about Insulin 79; Structure-Action Relationship of Insulin Molecule 79; Insulin
Receptor 80; Postreceptor Events and Downstream Signaling 81; Anti-Inflammatory and Anti-
Atherosclerotic Actions of Insulin 81
xxviii RSSDI Textbook of Diabetes Mellitus

SECTION 3  Diagnosis and Classification

Section Editor: Hemraj B Chandalia

6. Definition, Diagnosis and Classification 87

Paturi V Rao, BB Tripathy
Diagnosis 87; Screening for Diabetes 95; Classification 96; Future Consi­derations 102

7. Latent Autoimmune Diabetes in Adults 109

Devjit Tripathy, Leif Groop, Paturi V Rao
Definition: Clinical Characteristics 110; Pathogenesis 110; Genetics of Latent Autoimmune Diabetes
in Adults 111; Chronic Complications in LADA 112; LADA in the Indian Population 113; Screen-
ing for Latent Autoimmune Diabetes in Adults 113; Management of Latent Autoimmune Diabetes in
Adults 113; Newer Potential Therapies for LADA 114

8. Prediabetes 118
Rakesh K Sahay
Prevalence of Prediabetes 119; Instability of Impaired Glucose Tolerance 119; Etiology and
Pathogenesis of Impaired Glucose Tolerance 120; Clinical Implications of Impaired Glucose
Tolerance 121; Risk Factors for Deterioration to Diabetes 122; Association with Cardiovascular
Disease Mortality 123; Intervention Studies in Prediabetes 123

SECTION 4  Epidemiology
Section Editor: Hemraj B Chandalia

9. Diabetes Mellitus in Developed Countries 133

Susana A Moran, KM Venkat Narayan, Paturi V Rao
Type 1 Diabetes 134; Type 2 Diabetes 135; Global Disability-Adjusted Life Years 136; Gestational
Diabetes 137

10. Epidemiology of Diabetes in Developing Countries: The Scenario in Asia 142

Chamukuttan Snehalatha, Arun Nanditha, Samith A Shetty, Ambady Ramachandran
Scenario in South East Asia 142; Rising Prevalence of Diabetes 143; Risk Factors 145; Chronic
Complications of Diabetes 148; Diabetes in the Youth 148; Scenario in the Middle East Coun-
tries 149; Other Forms of Diabetes 149; Prevention of Diabetes 149

11. Epidemiology of Diabetes Mellitus in India 154

SV Madhu, Paturi V Rao
Type 1 Diabetes Mellitus 154; Type 2 Diabetes Mellitus 154; Factors Implicated in Causation of DM
in Asian Indians 158; Impaired Glucose Tolerance 160; Complications 161

12. Epidemiology of Complications of Diabetes 169

Viswanathan Mohan
Microvascular Complications 169; Macrovascular Complications 175; Hypertension and Diabe-
tes 177; Mortality Associated with Diabetes 177

13. Epidemiology of Diabetes in Migrant Groups 184

Venkata Ranga Rao Kodali
Overseas and Transcontinental Studies 185; Migration within India 186; Type 1 Diabetes
and Other Forms 186; Risk Factors for Diabetes in Migrants 187; Other Migrants and Special
Populations 188
 Contents xxix

SECTION 5  Etiopathogenesis of Diabetes Mellitus

Section Editor: Hemraj B Chandalia

14. Etiology of Diabetes: An Overview 193

Ashok Kumar Das, BB Tripathy
Type 1 (A) Diabetes Mellitus 194; Type 2 Diabetes Mellitus 196; Gestational Diabetes
Mellitus 197; Other Types 197

15. Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 199

Alok Kanungo, Priyanka Modi, Carani B Sanjeevi
Epidemiology 199; Pathogenesis 201; Genetics 203; Environment and Type 1 Diabetes 205; 
Autoimmunity 207; Immune Intervention Trials 208; Metabolic Alterations in Type 1
Diabetes 209

16. Pathogenesis of Type 2 Diabetes 215

Devjit Tripathy, BB Tripathy, Hemraj B Chandalia
Glucose Homeostasis 215; Insulin Resistance 216; Impaired b-Cell Function 224; The Natural
History of Type 2 Diabetes 235

17. Insulin Resistance 245

Ramchandra Dattatray Lele, A Rosalind Marita
Concept of Hormone Resistance 245; Evolution of the Concept of Insulin Resistance 247; 
Molecular Mechanisms of Insulin Resistance 250; Role of Proinsulin in Insulin Resistance 254; 
In-Vivo Measurement of Insulin Resistance 255; In-Vitro/Ex Vivo Studies on the Nature of Insu-
lin Resistance 256; Clues from Animal Models of Insulin Resistance 259; Insulin Resistance and
Endothelial Dysfunction 260; Insulin Resistance and Atherosclerosis 262; Insulin Resistance and
Obesity 264; Insulin Resistance and Hypertension 265; Essential Fatty Acids 266; Diet and
Inflammation 267

18. Endocrine and Metabolic Role of Adipose Tissue in the Pathogenesis of Diabetes 278
A Rosalind Marita
Adipokines and Their General Functions; 278 Adipokines and Insulin Resistance 280; Adipokines
and b-Cell Function 283; Adipokines and Inflammation 283; Adipokines and Cardiovascular
Disease 285

19. Fetal Programming of Type 2 Diabetes Mellitus 292

Kalyanaraman Kumaran, Chittaranjan S Yajnik
Current Strategies for Prevention of Type 2 Diabetes Mellitus 292; Programming Hypothesis and
the Developmental Origins of Health and Disease 293; Mechanisms of Nutritional Fetal Program-
ming 298; Implications for Prevention and Policy 299

20. Sleep and Type 2 Diabetes Mellitus 302

Ashok Kumar Das
Effect of Sleep on Metabolism and Hormones 303; Influence of Sleep Disturbances on the Onset of
Diabetes 303; Studies Linking Sleep Disturbances to Diabetes 306; Sleep Disturbances and Obe-
sity 306; Lose Sleep, Gain Weight: Pathophysiology 306; Role of Hunger Hormones 307; Obe-
sity, Obstructive Sleep Apnea and Diabetes: A Correlation 307; Pathophysiology of Obesity and
Insulin Resistance 308; Obstructive Sleep Apnea and Insulin Resistance: A Pathophysiological Mecha-
nism 308; Other Factors 308; Obstructive Sleep Apnea and Endocrine Dysfunction 309; Links
Between Obstructive Sleep Apnea and Cardiovascular Disorders 309; Pathophysiology: Obstructive
Sleep Apnea and Cardiovascular Disease 310
xxx RSSDI Textbook of Diabetes Mellitus

SECTION 6  Genetics and Immunology

Section Editor: Viswanathan Mohan
21. Genetics of Type 2 Diabetes 317
Venkatesan Radha, Viswanathan Mohan
Genetics of Monogenic Diabetes 318; Implications of Monogenic Diabetes Genes in Adult 320; 
Linkage Analysis 321; Candidate Gene Approach 322; Genome-Wide Association Studies 323
22. Immunologic Features of Type 1 Diabetes 331
Carani B Sanjeevi, Chengjun Sun, Alok Kanungo
Immunological Aspects of Type 1 Diabetes 332; Autoimmune Antibodies in Autoimmune Diabe-
tes 332; Cellular Immune Response and Cytokines 335; Genetic Aspects of Type 1 Diabetes 336; 
Natural History of Type 1 Diabetes 338; Environmental Factors in Type 1 Diabetes 341; Possible
Environmental Mechanisms 341; Clinical Implications and Future Direction 344; Immunological
and Genetic Studies on Different Clinical Types of Diabetes Patients from India 344; Autoimmunity and
Genetics in Indian Diabetic Patients (Type 1 and Type 2) 345

SECTION 7  Clinical Profile

Section Editor: Viswanathan Mohan
23. Clinical Features of Type 1 Diabetes Mellitus 357
Ashok Kumar Das, P Raghupathy, BB Tripathy
Classes of Type 1 Diabetes 357; Distribution 358; Etiology 358; Natural History 358; Clinical
Features 359; Type 1 Diabetes in Adults 361; Chronic Complications of Type 1 Diabetes 361; 
Other Manifestations with Type 1 Diabetes 362; Atypical Forms of Type 1 Diabetes 363
24. Clinical Features of Type 2 Diabetes Mellitus 366
SV Madhu
Types of Diabetes 366; Epidemiology 367; Natural History of Type 2 DM 367; Clinical
Features 368; Complications of Type 2 DM at Diagnosis 369; Low Body Weight Type 2 DM 370; 
Differential Diagnosis 370
25. Fibrocalculous Pancreatic Diabetes 373
Dukhabandhu Naik, Nihal Thomas
Definition and Terminology 373; Historical Background and Prevalence 374; Clinical Presenta-
tion 374; Pathology 376; Etiopathogenesis 377; Investigations 381; Complications 383; 
Criteria for Diagnosis of FCPD 385; Life Expectancy, Survival and Causes of Mortality 385; Manage-
ment 386
26. Secondary Diabetes 392
Dukhabandhu Naik, Nihal Thomas
Diseases of the Exocrine Pancreas 393; Endocrinopathies and Diabetes Mellitus 397; Syndromes
of Primary Insulin Resistance 405; Lipodystrophic Syndromes 407; Genetic Syndromes Associated
with Diabetes Mellitus 408; Viruses and Diabetes Mellitus 410; Drug Induced Diabetes 412; 
Immune Mediated Diabetes 415; Secondary Diabetes in Children 416
27. Neonatal Diabetes 426
Poovazhagi Varadarajan, Viswanathan Mohan
Classification of Neonatal Diabetes Mellitus 426; Genetic Studies of Neonatal Diabetes Mellitus in
India 430; Pathophysiology of Neonatal Diabetes Mellitus 430; Clinical Presentation and Diagnosis
of Neonatal Diabetes Mellitus 430; Case Study 433; Prognosis and Long-Term Outcome in Neona-
tal Diabetes Mellitus 434
 Contents xxxi

28. Early Onset Type 2 Diabetes 437

Viswanathan Mohan
Epidemiology 437; Pathophysiology of Early Onset T2DM 441; Risk Factors of Early Onset
T2DM 442; Criteria 446; Treatment and Management 446; Prevention of T2DM in Children 449
29. An Approach to Management of Diabetes Mellitus 455
Mala Dharmalingam
Individualization of Therapy and Treatment Goals 456; Type 2 Diabetes 456; Approach to
Management 459; Type 1 Diabetes 460

SECTION 8  Management
Section Editor: Viswanathan Mohan
30. Nutrition Management of Diabetes Mellitus 465
Rekha Sharma, Swapna Chaturvedi
Goals 465; Basic Principles for Planning Diet for Diabetics 466; Nutrition Recommenda-
tions 467; Goals of Medical Nutrition Therapy 467; Realistic Diet Prescription Strategies 469; 
Additional Nutritional Considerations to Reduce Cardiac Risk 477; Meal Planning 477
31. Nutrition Management in Special Situations 481
Sonal V Modi
Nutrition Management in Undernutrition and Obesity 481; Nutrition Management through Journey
of Life 487; Nutrition Management in Various Treatment Modalities 491; Nutrition Management in
Various Life Situations 492; Nutrition Management in Complications of Diabetes 495; Food Labe-
ling and Interpretation 505
32. Physical Activity and Exercise in Diabetes Mellitus 509
Uday K Phadke
Physiology of Fuel Metabolism in Exercise in Healthy Individuals 509; Effects of Regular Training on
Fuel Metabolism 511; Effects of Exercise in Type 1 Diabetes Mellitus 511; Effects of Exercise in Type
2 Diabetes Mellitus 512; Cardiovascular Adaptations to Exercise Training 514; Recommendations
for Exercise Therapy in Diabetes 515; Specific Considerations in Type 2 Diabetes Mellitus  515; Spe-
cial Considerations in People with Long-Term Complications of Diabetes 517; Mind Body Thera-
pies 517; Role of Exercise in Diabetes Prevention 518
33. Yoga and Relaxation Techniques in Diabetes Mellitus 521
GR Sridhar
Stress Response and Relaxation Response 521; Mind-Body Techniques 521; Yoga in Diabetes
Mellitus 522; Role of Yoga in Prevention of Diabetes 523; Biological Basis for Effectiveness of
Yoga 523; Mindfulness-Based Stress Reduction 524; Meditation and Prayer 524; Basis of
Relaxation Response 524; Stress Reduction Techniques 524
34. Insulin Secretagogues 527
Rakesh K Sahay
Role of Insulin Secretagogues in Management of Type 2 Diabetes Mellitus 527; Classification of
Insulin Secretagogues 528; Insulin Secretagogues and Cardiovascular Disease 533; Timing of Secre-
tagogue Administration 534; Comparison of Various Secretagogues 535; Newer Insulin Secreta-
gogues 535
35. Insulin Sensitizers: Metformin and Thiazolidinediones 538
Sudip Chatterjee
Metformin 538; Thiazolidinediones 541
xxxii RSSDI Textbook of Diabetes Mellitus

36. Incretin-Based Therapy 546

Ajay Kumar
Incretin Physiology 546; Development of GLP-1 Based Treatment 548; Pleiotropic Effects of
GLP-1 548; DPP-4 Inhibitors 550; Incretin Mimetics or Analogs 554; Incretin-Based Treatment
and Risk of Pancreatitis 556; Liraglutide and Risk of C-Cell Hyperplasia or Cancer 556

37. Nutrient Blockers and Bromocriptine 560

Jitendra Singh
Bromocriptine 560; a-Glucosidase Inhibitors 563; Sodium Glucose Cotransporter 2 (SGLT-2) Inhib-
itors 567; Amylin Mimetics 568; Anti-Obesity Drugs 568

38. Insulin Therapy 572

Sunil M Jain
History of Insulin Development 572; Method of Insulin Production 573; Types of Insulin 574; 
Pharmacology of Available Insulin Preparations 574; Indications for Insulin Therapy 578; Insulin
Regimens 579; Insulin Therapy in Type 2 Diabetes Mellitus 580; Insulin Therapy in Type 1 Diabetes
Mellitus 582; Practical Information on Insulin 584; Adverse Effects of Insulin 585; Continuous
Subcutaneous Insulin Infusion, Insulin Pump 586; What’s New and Future? 588

39. Insulin Pump Therapy 592

Banshi Saboo
Principles and Theory of Insulin Pump 593; The Basics of Insulin Pump Therapy 594; The
Mechanics of Insulin Pump 594; Indications and Consideration for Insulin Pump Therapy 594; 
Insulin Pump Formula 595; Operating Insulin Pump 596; Types of Insulin Pump 596; Handling
of Insulin Pump in Daily Life 597; Blood Sugar Monitoring in Insulin Pump Therapy 598; Bene­
fits of Insulin Pump Therapy 599; Proper Selection of Site and Rotation 600; Problems
Associated with Insulin Pump 601; Bolusing for Carbohydrate Containing Foods 603; Meal Bolus
Options 605; Bolus Wizard® Calculator 605; Prevention of Acute Problems 606; Training for
insulin Pump User 609; Limitations of Pump Therapy 609; Future of Insulin Pump Therapy 610

40. Glycemic Management in Hospitalized Patients 612

Shaival H Chandalia
Hyperglycemia in Hospitalized Patients: Need for Treatment 612; Insulin Versus Oral Agents in
Hospitalized Diabetics 613; Clinical Trial Evidence 614; Blood Glucose Targets in Hospitalized
Patients 616; Strategies to Achieve Blood Glucose Targets 616

41. Short-Term Monitoring of Glycemic Control 622

Suresh D Mehtalia, Premlata K Varthakavi
Evaluation at the Initial Hospital Visit 623; Monitoring Glycemic Control 623; Urine
Glucose 623; Ketones 626; Blood Glucose 627; Barriers 632; New Monitoring Device
Develop­ments 635

42. Continuous Glucose Monitoring System 639

Jothydev Kesavadev
What is Continuous Glucose Monitoring System? 639; Continuous Glucose Monitoring Techno­
logy 640; History of Continuous Glucose Monitoring 640; Clinical Utility of Continuous Glucose
Monitoring 641; Continuous Glucose Monitoring: Our Experience 642; Continuous Glucose
Monitoring: Studies from India 642; Indications for Continuous Glucose Monitoring 643; Merits of
Continuous Glucose Monitoring 644; Demerits of Continuous Glucose Monitoring 644; Limitations
of Continuous Glucose Monitoring in India 644
 Contents xxxiii

43. Monitoring Glycemic Control: Long-Term Parameters 646

Hemraj B Chandalia
Historical Aspects 646; Process of Glycation of Hemoglobin 646; Methodology to Estimate Gly­
cated Hemoglobin 647; Selection of Method and Quality Control 648; Clinical Relevance and
Application of Glycated Hemoglobin 649; Glycated Albumin and Fructosamine 653

44. Monitoring Beyond Glycemic Control 656

Ashok Kumar Das, Stalin Viswanathan
Anthropological and Physical Parameters 657; Laboratory Monitoring 658; Organ Complica-
tions: Microvascular 659; Organ Complications: Macrovascular 663; Other Complications 665; 
Monitoring in High Risk Population 666; Monitoring and Assessment of Common Comorbid
Conditions 667

45. Current Status of Indigenous Drugs and Alternative Medicine in the

Management of Diabetes Mellitus 673
Ashok DB Vaidya, Nutan Sham Nabar, Rama Ashok Vaidya
Indigenous Drugs and Medicinal Plants 674; Pharmacology and Clinical Studies of Antidiabetic
Medicinal Plants 675; Marketed Ayurvedic Formulations 681; CSIR-Nmitli Diabetes Project 683; 
Complementary and Alternative Medicine 683; Ayurvedic Prevention and Management 684; 
Dietary and Exercise Management of Diabetes 684; Indian Homeopathic Remedies 685

46. Transplantation in the Management of Diabetes Mellitus 693

Timothy O’Connor, John Thomas O’Brian, Romesh Kumar Khardori
Justification 694; Indications and Patient Selection 694; Transplant Options 695; Proce-
dure 696; Nutrition after Transplant 697; Patient and Graft Survival 697; Effects of Transplant on
Complications of Diabetes 699; Pregnancy and Pancreatic Transplant 702; Transplantation Associa­
ted Risks 703; Hyperglycemia after Pancreas Transplant 703; Islet Cell Transplant 704; Clinical
Xenotransplantation 705

47. Stem Cell Therapy in Diabetes Mellitus 710

Anil Bhansali
Animal Studies 711; Human Studies 711; Mechanism of Action 712

SECTION 9  Comorbid Conditions

Section Editor: Hemraj B Chandalia

48. Comorbid Conditions in Diabetes Mellitus 717

Hemraj B Chandalia
Definition and Significance of Comorbid Conditions 717; Tobacco Abuse 718; Obesity 719; 
Hyperuricemia 726; Hyperhomocysteinemia 726

49. Metabolic Syndrome 732

Anoop Misra, Suchitra Behl
Historical Perspective and Definition 732; Prevalence 733; Risk Factors for the Development of the
Metabolic Syndrome 734; Prevention and Control of the Metabolic Syndrome in South Asians 735

50. Diabetes and Hypertension 739

Sudeep K, Nihal Thomas
Diabetes and Hypertension 739; Defining Hypertension 739; Pathophysiology 740; Manage-
ment of Hypertension 743
xxxiv RSSDI Textbook of Diabetes Mellitus

51. Dyslipidemia in Diabetes 750

Subhankar Chowdhury, Kaushik Pandit
Lipoprotein Physiology 750; Lipoproteins and Atherosclerosis 752; Lipid Disorders in Dia­
betes 753; Screening for Dyslipidemia in Diabetes 756; Treatment of Dyslipidemia in Dia­
betes 756; Statins 759; Fibrates 761; Ezetimibe 762; Miscellaneous 763; Novel Vistas in
Lipid Modification 763; Rational Choice of Drugs 764

SECTION 10  Complications

Section Editor: Gumpeny Ramachandra Sridhar

52. Diabetes Complications: Overview 773

SV Madhu
Diabetes Exposure and Risk of Complications 773; Importance of Glycemic Control in Development
of Chronic Complications 775; Mechanisms of Diabetic Tissue Damage 776; Cellular and Molecular
Mechanisms of Hyperglycemia-Induced Cellular Damage 777; Role of Oxidative Stress in Develop-
ment of Diabetic Complications 780

53. Acute Metabolic Complications 786

Hemraj B Chandalia
Diabetic Ketoacidosis 786; Hyperglycemic Hyperosmolar Non-Ketotic State 794; Lactic Acidosis 800

54. Hypoglycemia 812

Siddharth N Shah, Shashank R Joshi
Definitions 812; Etiology 813; Pathogenesis 814; Clinical Features 814; Investigations 815; 
Differential Diagnosis 815; Course and Prognosis 815; Complications 815; Management 816

55. Acute Infections in Diabetes Mellitus 819

Sanjay Kumar Bhadada
Host Defense 820; Common Microorganisms Associated with Infections in Patients of Diabetes
Mellitus 820; Common Infections in Diabetes Mellitus 821

56. Chronic Infections and Diabetes Mellitus 828

Samar Banerjee
Immune Alterations in Diabetes 828; Secondary Factors 829; Chronic Infections 829; Hepatitis
C and Diabetes 829; Diabetes Mellitus and Tuberculosis 833; Periodontal Disease and DM 836; 
HIV Infection and Diabetes 837; Rhinocerebral Mucormycosis 840; Cholecystitis 841; Chronic
Pyelonephritis and Cystitis 841; Chronic Foot Infections 841; Fungal Infections in Diabetes 841

57. Macrovascular Disease in Diabetes: Determinants and Pathogenesis 846

Sidhartha Das
Burden of Macrovascular Disease in Diabetics 846; Distribution and Profile of Atherosclerosis in
Diabetics Versus Non-Diabetics 847; Pathogenesis and Determinants of Macrovascular Disease 848

58. Coronary Heart Disease in Diabetes 855

Ashok Kumar Das
Indian Scenario 855; Risk Factors for Coronary Artery Disease in Diabetes 857; Clinical
Features 858; Screening and Investigations 859; Management of Coronary Artery Disease in
Diabetes 860; Approach 861

59. Noncoronary Cardiac Complications in Diabetes 864

Murlidhar S Rao
Diabetic Cardiomyopathy and Heart Failure in Diabetes 865; Cardiovascular Autonomic Neuropathy
in Diabetes 869; Sudden Cardiac Death in Diabetes 872
 Contents xxxv

60. Diabetes and Cerebrovascular Disease 875

MV Padma, BC Bansal, JS Bajaj
Diabetes-Associated with Other Risk Factors for Stroke 877; Pathogenesis of Stroke and Cerebrovas-
cular Disease in Diabetes 877; Stroke Subtypes and Pattern of Vascular Disease in Diabetes 880
61. Peripheral Arterial Disease in Diabetes 888
Ramakrishna Pinjala
Incidence, Pathophysiology and Diagnosis 888; Diagnosis of Peripheral Vascular Disease in Diabe-
tes—Non-Invasive Studies 890; Special Clinical Problems in Peripheral Vascular Disease and Diabe-
tes 891; Hypertension, Peripheral Arterial Disease and Diabetes 893; Foot Ulcers and Peripheral
Vascular Disease In Diabetes—Role of Non-Invasive Studies and Angiograms for Predicting the Ampu-
tation 893; Can we Exclude Peripheral Arterial Disease in the Absence of Symptoms? 894; Can
we Exclude Peripheral Arterial Disease When There are Palpable Foot Pulses? 894; Medical Thera-
pies 895; Percutaneous Interventions and Thrombolytic Therapies for Peripheral Arterial Disease
in Diabetes 895; Surgical Therapies for Peripheral Vascular Disease in Diabetes 896; Indications
and Type of Surgical Treatment 897; Women with Diabetes and Peripheral Arterial Disease 899; 
C-Reactive Protein for Risk Assessment in Peripheral Arterial Disease with Diabetes 900; Amputations
and Survival in Patients with Peripheral Vascular Disease and Diabetes 900; Moderate and Intense
Lipid Lowering Therapy in Patients with Peripheral Arterial Disease and Diabetes 901; Therapeutic
Footwear in Peripheral Arterial Disease and Diabetes 901
62. Diabetic Foot Syndrome 905
Sharad P Pendsey
Epidemiology 906; Socio-Economics 906; Classification 906; Pathogenesis 907; Diag­
nosis 911; Management 912; Prevention 914
63. Pathogenesis of Microvascular Complications of Diabetes 918
Daya Kishore Hazra, Vijay Viswanathan
Metabolic Memory and the Pathophysiology of Diabetic Microangiopathy 918; Pathogenesis of
Diabetic Retinopathy 920; Changes in Vascular Cells 923; Mechanisms of Hyperglycemia-Induced
Damage 925; The Genetics of Diabetes and its Microangiopathic Complications 928
64. Eye Disease in Diabetes 935
Rajendra Pradeepa, Ramachandran Rajalakshmi
Mediators and Mechanisms of Ocular Damage in Diabetes 935; Extraocular Ophthalmic Manifesta-
tions of Diabetes 937; Extraretinal Ocular Manifestations of Diabetes 940
65. Diabetic Retinopathy 956
Vijayaraghavan Prathiba
Epidemiology 956; Classification and Clinical Features of Diabetic Retinopathy 957; Sight-Threat-
ening Forms of Diabetic Retinopathy 959; Major Risk Factors for Diabetic Retinopathy 960; Patho-
genesis of Diabetic Retinopathy 961; Pathogenesis of Diabetic Macular Edema 964; Pathogenesis
of Proliferative Diabetic Retinopathy 964; Clinical Diagnosis and Investigations in Diabetic Retino­
pathy 964; Management 966; Pharmacotherapy in Diabetic Retinopathy 969; Screening for
Diabetic Retinopathy 970

66. Diabetes and Kidney 975

Ashok L Kirpalani, Praveen Namboodiri
Epidemiology 975; Risk Factors for Diabetic Nephropathy 976; Predicting the Development and
Progression of Nephropathy 977; Pathology 978; Pathogenesis 980; Pathogenesis of Histologi-
cal Lesions 982; Clinical Course and Natural History 983; Management 986; Post-Transplant
Diabetes Mellitus 1002; Other Renal Manifestations in Diabetics 1002
xxxvi RSSDI Textbook of Diabetes Mellitus

67. Neurological Complications of Diabetes 1009

Ashok Kumar Das, Prasanth G, Thomas Mathew
Neurological Complications of Diabetes—An Overview 1009; Diabetic Peripheral Neuropathy 1010;
Pathogenesis 1012; Clinical Features 1015; Diagnosis 1019; Management 1021

68. Diabetes and the Gastrointestinal System 1028

Subrat Kumar Acharya
Diabetes and the Gut 1029; Epidemiology of Gastrointestinal Symptoms in Diabetes 1029; 
Diabetic Gastroparesis 1029; Diabetic Diarrhea 1031; Celiac Disease 1032; Other Gastrointes-
tinal Symptoms 1032; Anorectal Dysfunction 1032; Health-Related Quality of Life Issues 1033; 
Liver Disease and Diabetes 1033; Non-Alcoholic Fatty Liver Disease 1035; Hepatocellular Carci-
noma 1035; Gallbladder Diseases 1036; Therapeutic Modulation of Gastric Emptying 1037; Gut
Peptides 1037

69. Skin Diseases and Diabetes 1042

Sarita Bajaj, AK Bajaj
Skin Markers of Diabetes 1042; Common Skin Diseases in Diabetes 1043; Cutaneous Infec-
tions 1048; Cutaneous Complications of Diabetes Therapy 1057

70. Vitamin D and Diabetes Mellitus 1062

Vijay Negalur
Association Between Diabetes Mellitus and Vitamin D 1062; Treatment with Vitamin D and
Diabetes 1064; Vitamin D and Diabetic Complications 1064; Vitamin D and Diabetes: Future
Directions 1065

71. Bone Disease in Diabetes Mellitus 1068

Sudhaker D Rao, GR Sridhar
Pathogenesis of Bone Disease in Diabetes Mellitus 1068; Mismatch Between Bone Mineral Density
and Bone in Diabetes 1069; Bone Mineral Density in Diabetes Mellitus 1070; Fractures in Diabetes
Mellitus 1070; Screening Strategies 1071; Management of Low Bone Density and/or Osteoporosis
in the Diabetic Population 1072; Monitoring of Therapy 1072; Special Circumstances 1073

72. Musculoskeletal Complications of Diabetes 1076

Debasis Basu
Diabetic Muscle Infarction 1079; Dupuytren’s Contracture 1082; Stenosing Flexor Tenosynovi-
tis 1084; Adhesive Capsulitis 1085; Neuropathic Arthropathy 1088; Complex Regional Pain
Syndrome 1092; Carpal Tunnel Syndrome 1093; Muscle Cramps 1094; Ossification of the Poste-
rior Longitudinal Ligament of the Spine 1094; Osteopenia 1095; Diffuse Idiopathic Skeletal Hyper-
ostosis 1097; Gout 1098; Osteoarthritis 1098

73. Sexual Dysfunction in Diabetes 1107

Rupin Shah
Pathogenesis of Erectile Dysfunction in Diabetes 1107; Evaluation 1108; Therapy 1108
74. HIV in Diabetes 1113
Sanjay Kalra
Diabetes Mellitus and HIV Infection 1113; Etiopathogenesis of Diabetes and HIV Infection 1114; 
Cardiovascular Risk in Diabetes Mellitus in HIV-Infected Patients 1115; Clinical Presentation: Signs and
Symptoms 1115; Assessment and Management of Diabetes in HIV-Infected Patients 1116; Base-
line Laboratory Evaluation in HIV Patients 1116; Screening for Diabetes in HIV-Infected
Patients 1116; Antiretroviral Therapy: Modifications in Diabetes Patients 1119; NACO Antiretroviral
Therapy Guidelines 1120; Antiretroviral Therapy Associated Complications 1120; Future Pers­
pective 1123
 Contents xxxvii

75. Diabetes and Cancer 1127

Sunil Gupta
Epidemiology 1127; Total Cancer 1128; Liver Cancer 1128; Pancreatic Cancer 1128; Gastric
Cancer 1129; Colorectal Cancer 1129; Urinary Organ Cancer 1129; Breast Cancer 1129; 
Endometrial Cancer 1130; Prostate Cancer 1130; Cancer Risk in Type 1 Diabetes 1130; Pos-
sible Biologic Links Between Diabetes and Cancer Risk 1130; Hyperinsulinemia 1130; Insulin and
Insulin-Like Growth Factor Axis 1131; Hyperglycemia 1131; Inflammatory Cytokines, Diabetes, and
Cancer Risk 1132; Antidiabetic Drugs and Cancer Risk 1132
76. Impact of Glycemic Control on Complications of Diabetes Mellitus 1143
Ashok Kumar Das, Ashida TS
Pathophysiological Effects of Hyperglycemia 1143; Historical Background: Early Trials 1144; Type 1
Diabetes Mellitus (T1DM): Glycemic Control and Complications 1144; Type 2 Diabetes Mellitus: Gly-
cemic Control and Complications 1146; Effect on Individual Complications 1147; Impact of Inten-
sive Glycemic Control in the Critical Care Setting 1148; Recent Trials 1149; Recommendations for
Glycemic Control 1149; Hazards of Intensive Glycemic Control 1149

SECTION 11  Diabetes Through Life and Events

Section Editor: Gumpeny Ramachandra Sridhar

77. Special Challenges in Management of Diabetes Mellitus in Children 1155

Aspi J Irani
Etiology 1155; Clinical Presentation 1158; Diagnosis 1159; Differential Diagnosis of Diabetes in
a Child 1159; Stages of Diabetes in Childhood 1160; Day-To-Day Management 1160; Meal Plan-
ning 1164; Planned Physical Activity 1166; Therapeutic Monitoring 1166; Growth and Pubertal
Development 1170; Diabetes Related Emergencies in Children 1171; Treatment 1173; Compli-
cations 1177; Patient Education 1179; Psychosocial Aspects 1180

78. Diabetes in Elderly 1186

Radha Reddy, KM Prasanna Kumar
Demographics of Diabetes in the Elderly 1186; Carbohydrate Metabolism in the Elder-
ly 1187; Screening and Diagnosis of Diabetes 1187; Manifestations of Diabetes 1188; Common
Geriatric Syndromes Associated with Diabetes 1188; Acute Complications of Diabetes in the Elderly:
Hyperglycemic, Hyperosmolar, Non-Ketotic State and Diabetic Ketoacidosis 1188; Treatment of Dia-
betes in the Elderly 1191; Management of the Elderly Diabetic in Special Situations 1196

79. Diabetes and Pregnancy 1201

Veeraswamy Seshiah, Vijayam Balaji
Fuel Metabolism in Normal Pregnancy 1201; Pathogenesis of Glucose Intolerance Developing
during Pregnancy 1203; Fuel Metabolism in Diabetic Pregnancy 1204; Consequences of
Diabetes in the Pregnant Mother 1207; Pregestational Diabetes 1207; Gestational Diabetes
Mellitus 1207; Management 1212; Management of Gestational Diabetes Mellitus 1214; 
Monitoring Glycemic Control 1216; Follow-Up of Gestational Diabetes Mellitus 1218

80. Surgery and Diabetes 1224

Krishna G Seshadri
Factors Contributing to Adverse Surgical Outcomes in Patients with Diabetes 1224; The Metabolic
Stress Response in Surgery 1225; The Effects of Anesthesia in Diabetic Patients 1225; Type of Sur-
gery 1226; Glycemia and Surgical Outcomes 1227; Management of the Diabetic Patient Undergo-
ing Surgery 1228
xxxviii RSSDI Textbook of Diabetes Mellitus

SECTION 12  Living with Diabetes

Section Editor: Gumpeny Ramachandra Sridhar

81. Psychosocial Aspects of Diabetes 1237

GR Sridhar, K Madhu
Psychology and Diabetes—A Historical Perspective 1238; Diabetes-Care Providers 1238; Life-
style and Behavior, Perception of Life 1238; Biopsychosocial Model of Diabetes Manage-
ment 1238; Studies in Children with Type 1 Diabetes Mellitus 1244; Studies in Parents of Children
with Type 1 Diabetes 1245; Studies in Type 2 Diabetes 1245; Psychological Factors in Childhood
Diabetes 1246; Model for Living Effectively with Diabetes 1247

82. Psychiatric Problems in Diabetes 1254

MV Muraleedharan, GR Sridhar
Co-Existence of Diabetes and Psychiatric Illness 1254; Psychological Distress Caused by Screening and
Diagnosis 1255; Management of Common Mental Problems 1255; Central Obesity, Hypothalamo-
Pituitary Axis and Stress 1255; Hypothalamo-Pituitary Axis Activation and Obesity 1256; Depres-
sion and Diabetes 1256; Diabetes and Dementia 1257; Psychotic Disorders and Metabolic Syn-
drome 1257; Anti-Psychotic Drugs and Metabolic Changes 1257; Psychiatric Comorbidity in Type 1
Diabetes 1258; Coping with Stress 1259

83. Economic Aspects, Insurance, Driving and Employment Problems in Diabetes 1263
Vijay Viswanathan
Economic Aspects of Diabetes Care 1263; Cost of Diabetes Care in India 1264; Diabetes
Expenditure—The Global Scenario 1264; Impact on the Economy 1265; Insurance for a Dia­
betic 1265; Diabetes and Employment 1267; Diabetes and Driving 1268; Medical Infirmities and
Driving Restrictions Under Insurance Policies 1269

SECTION 13  Healthcare Delivery

Section Editor: Gumpeny Ramachandra Sridhar

84. Organizing a Diabetic Clinic 1275

Debasis Basu
Rationale of “Organized” Diabetes Care 1276; Components of a Diabetes Clinic 1277; How Does
Organized Diabetes Care Become Effective? 1286; Advantages of Organized Diabetes Care 1292; 
Impact of Organized Diabetes Clinic Care on Various Health Care Practices 1292; A Day at the Diabe-
tes Clinic 1293

85. Information Technology in Diabetes Management 1301

GR Sridhar, Paturi V Rao
Electronic Medical Records 1301; Linking Electronic Medical Records to Hospital Information
System 1303; Scope and Limitations of Electronic Medical Records and Hospital Information
System 1305; Accessing Medical Information 1305; Bioinformatics 1306

86. Organization of Healthcare for Diabetes 1309

Vijay Panikar
The Saint Vincent Declaration 1310; Strategies for Diabetes Management in India 1312; Problems
in India 1312
 Contents xxxix

87. Role of Primary Care Physician and Paramedical Personnel 1316

Gurmukh S Sainani, Rajesh G Sainani
Primary Care Based Models 1317; Role of Nurses and Pharmacists 1318; Two Success-
ful Models that Have been Implemented and Carefully Evaluated 1318; Lacunae in Medical
Care 1318; Role of Dietitian 1318; Self Management 1319; Patient Education 1319; Achieve-
ment of Target Goals 1319; Preventing Diabetes-Related Morbidity and Mortality in the Primary
Care Setting 1319; Impaired Glucose Tolerance and General Practitioners’ Knowledge and Percep-
tions 1320; The Prevention of Type 2 Diabetes: General Practitioner and Practice Nurse Opin-
ions 1320; Patients with Poorly Controlled Diabetes in Primary Care: Health Care Clinicians Beliefs
and Attitudes 1320; Concluding Remarks: Primary Care Setting 1320
88. Patient Education in Diabetes Care 1323
Hemraj B Chandalia
Objectives of the Patient Education 1323; Educators 1323; Targets of Education 1324; Con-
tent of Education Program 1324; Methods of Education Delivery 1326; Evaluation of Education
Program and its Outcomes 1326
89. Role of Paramedical Personnel 1329
SV Madhu
Needs of People with Diabetes 1329; Paramedical Personnel and Strict Glycemic Control 1330; Con-
cept of Self-Care and Self-Management 1330; Diabetes Health Care Teams 1331; Role of Dia-
betes Educator in Diabetes Management 1331; Role of the Nutritionist in Diabetes Manage-
ment 1333; Role of the Nursing Personnel in Diabetes Management 1333; Empowering the
Paramedical Personnel 1335
90. Diabetes in Community Setup 1337
Ashok Kumar Das
Prevalence and Trends 1337; Diagnosis of Diabetes: Community Health Perspective 1338; Health
Consequences and Economic Impact 1338; Screening 1338; Preventing Diabetes: Community-
Based Strategies 1339; Preventing Complications of Type 2 Diabetes 1340

SECTION 14  Prevention

Section Editor: Gumpeny Ramachandra Sridhar
91. Prediction and Prevention of Type 1 Diabetes Mellitus 1345
Carani B Sanjeevi, Chengjun Sun
Immune and Genetic Markers Used in Prediction of Type 1 Diabetes 1345; Prediction of Type
1 Diabetes 1346; Risk Groups Likely to Benefit from Preventive Approach 1347; Prevention
Trials 1347; Vaccine Strategies for the Prevention of Type 1 Diabetes 1348; Vaccine Delivery
Systems 1350

92. Prevention of Type 2 Diabetes 1353

Hemraj B Chandalia
Target Population 1353; Diabetes Prevention Studies 1353; Lessons from Epidemiology 1357; 
Preferred Strategy for Prevention 1357

93. Prevention of Diabetes–Indian Angle 1361

Ambady Ramachandran
Prevention of Diabetes 1361; Primary Prevention of Diabetes 1362; Indian Diabetes Prevention
Programmes 1364; Pharmacological Agents 1365; Education 1367
xl RSSDI Textbook of Diabetes Mellitus

SECTION 15  Glimpse into Future

Section Editor: Gumpeny Ramachandra Sridhar

94. A Glimpse into the Future 1373

Hemraj B Chandalia, Shaival H Chandalia
Etiopathogenesis 1373; Self-Monitoring of Blood Glucose 1376; Therapy of Diabetes 1377; 
Complications of Diabetes 1392

Appendix 1411-1418
Index 1419
Section 1

history of diabetes
Section Editor: Hemraj B Chandalia
 Chapter 1
Landmarks in the
History of Diabetes
Ranjit Unnikrishnan

History of Diabetes

Chapter Outline
♦♦ Diabetes in the Ancient World ♦♦ Advances in Our Understanding of the Etiopathogenesis
♦♦ Diabetes in the Dark Ages of Diabetes
♦♦ The Advent of Modern Era ♦♦ Tight Control or No Tight Control—Changing Paradigms in
♦♦ Breakthrough—The 20th Century Diabetes Management
♦♦ The Tiger Changes its Stripes: Transformation in the ♦♦ Diabetes Goes Global
Natural History of Diabetes and Effect on Complications

INTRODUCTION DIABETES IN THE ANCIENT WORLD

Diabetes has been known to mankind from times imme­ The first documented evidence of diabetes in human
morial. In recent decades, it has taken over the title of history comes from a remarkable papyrus discovered
“captain of the men of death” from tuberculosis and “the in Egypt in the 19th century by a German archaeologist
great mimic” from syphilis so much so that the diabetologist named George Ebers, and known ever since as the Ebers
is now considered the last of the internists, a physician papyrus in his honor. This ancient document, which has
who needs to have intimate knowledge of the working been dated to 1,552 BC by modern carbon dating tech­
of each organ of the body in order to effectively treat his niques, is 110 pages long and contains several formulae
patient. Side by side with the explosion in prevalence of and folk remedies in addition to descriptions of various
diabetes, there have been numerous exciting discoveries diseases. This papyrus describes a polyuric state, which is
in the basic science and therapeutics of diabetes which likely to have referred to diabetes, but further descriptions
have made the life of people with diabetes much more are absent.
comfortable than it was even a quarter of a century ago.
In this chapter, we will look at some of the milestones
Diabetes in Ancient India
in the history of diabetes and acquaint ourselves with In ancient India, diabetes was known as prameha (pra:
some of the outstanding men and women who have excess, meha: urine), a term used to refer to the disease
contributed to the development of this important branch even today in certain Indian languages. It is mentioned
of medicine over the course of the centuries. in the Chakradatta that Lord Shiva dictated a formulation
 4 History of Diabetes
section
1

Fig. 1.1: Charaka (left); Sushruta performing surgery (right)

Source: Life Diabetes Museum; http://www.dlife.com/files/Timeline

Flow chart 1.1: Principles of treatment of Madhumeha (diabetes) in A similar description is also given in the Sushruta Samhita
Ayurveda (1)
from the 10th century BC (Fig. 1.1).
The ancient Indian texts also recognized the existence
of two distinct types of madhumeha: (1) krisha (lean;
corresponding to type 1 diabetes) and (2) sthula (obese;
type 2 diabetes). The treatment prescribed for the latter
variety was strict diet and plenty of physical exercises
(fashionably termed lifestyle modification today) (Flow
chart 1.1). Our ancestors also appreciated the fact that
the treatment of the krisha variety was difficult, a truism
in those pre-insulin days (and indeed even today).
Thus, ancient Indian physicians were acquainted with
for the treatment of prameha to his son Lord Ganesha. the classification, etiology and treatment of diabetes as
Another view is that Ganesha himself suffered from long ago as 1,500 BC. Their texts provide a remarkably
prameha in view of his predilection for sweets and accurate picture of the disease; one would be hard-
sedentary lifestyle. This would make him the earliest pressed to find a better clinical description of diabetes in
any textbook even today.
known diabetic patient in history.1
The Charaka Samhita, dating back to 1,500 BC,
describes prameha in great detail. It recognizes 20 types
Diabetes Gets its Name
of prameha, which, if not treated, can lead to madhumeha It is generally accepted that the term diabetes, literally
(madhu: honey, meha: urine; literally sweet urine, an meaning “siphon”, was coined by Aretaeus of Cappedocia,
unambiguous description of diabetes). It was noted in reference to the polyuria characteristic of uncontrolled
that the disease could be diagnosed by detecting ants disease. He likened the disease to a “siphon”, sucking
congregating around the patient’s urine. The hereditary water out of the body through the urine. He considered
nature of the illness is also described in this ancient text. diabetes to be a rather uncommon disease characterized
 Landmarks in the History of Diabetes 5

by “melting of flesh and limbs into the urine”. He also form two diabetic patients and obtained a white cake that
noted that established patients did not live long.2 tasted exactly the same as sugar.3
Galen, who practiced in Rome in the second century The Scottish physician William Cullen divided polyuria
AD, is considered to be the foremost physician of the into two types: (1) one with sweet urine, to which he gave
Roman world. He considered diabetes to be extremely the term diabetes mellitus (mellitus: sweet), and (2) the
rare, noting that he had come across only two patients other in which the urine was tasteless, which he termed
in his entire career. Both Aretaeus and Galen were of the diabetes insipidus (insipidus: tasteless).

chapter
view that diabetes was a result of a defect in the kidney, While it was now clear that the urine of diabetic

1
a view which lingered on for more than 1,500 years. patients contained sugar, it was still not certain where this
Strangely enough, Hippocrates, considered as the Father sugar came from. The English physician John Rollo was
of Modern Medicine, was apparently unaware of dia­ of the opinion that the sugar came from the vegetables
betes, although this could reflect the extreme rarity of the in the diet. Therefore, he prescribed a strict diet for his
condition in his days. patients in which all greens were prohibited and only
foods of animal origin were allowed.4 Although patients
DIABETES IN THE DARK AGES did show improvement with this diet, its very strictness led
many of them to default, leading Rollo to lament on the
There was not much progress in the field of diabetes in
consequences of deviation. This makes him probably the
the Middle Ages, although some Arab and Chinese physi­
first person to recognize the problem of non-compliance
cians did make some clinical observations on the disease.
in diabetic patients. Nevertheless, the low-carbohydrate
The Chinese physician Chen Chhuan and the Persian
diet proposed by him remained, in its various iterations,
physician Avicenna described the complications of dia­
the mainstay of diabetes treatment for more than a century.
betes in some detail. There is also some evidence to show
The late 18th and early 19th centuries were the “golden
that diabetes was slowly becoming more common during
ages” of scientific discovery in the physical sciences.
this period, as evidenced from the frequency with which
Advances in these fields, particularly chemistry, provided
it appears in physicians’ records throughout Europe.
physicians with the tools needed to accurately diagnose
and monitor diabetes. In 1815, the French chemist Eugene
THE ADVENT OF MODERN ERA
Chevreul showed that the sugar in diabetic urine was
The modern era of diabetes can be said to have been glucose, and this was found in the 1830s to be true of
inaugurated by Theophastus Bombastus von Honnheim, the blood of diabetic patients as well. The first method
better known as Paracelsus, who led a revival of scientific to detect urine glucose was described by Trommer in
medicine in the 16th century AD. He disapproved of 1841. This was followed in rapid succession by the tests
the then popular method of “water tasting” to diagnose of Fehling, Roberts and Benedict, which remained the
diabetes and suggested that the urine should be examined mainstay of diabetes diagnosis until blood glucose
chemically instead. Toward this end, he evaporated the estimations became more widely available.
urine of a diabetic patient and obtained a white residue, Simultaneously, giant strides were being made in
which, for some reason, he mistook for salt. He therefore unraveling the pathogenesis of diabetes. Until the 19th
concluded that diabetes was due to deposition of salt-like century, it was widely believed that the seat of diabetes
material in the kidney and bladder. was the kidney. However, autopsies of diabetes patients
The first description of the sweet taste of diabetic urine failed to show any pathology in the kidneys or in any other
came from Thomas Willis (of circle of Willis fame), who organ for that matter. The initial steps in piecing together
considered diabetic urine to be as sweet as sugar or honey, the puzzle were made by the French physiologist Claude
but surprisingly failed to come to the conclusion that the Bernard in the 1840s. Until Bernard’s seminal work, it
sweetness was due to the presence of sugar. Willis also was assumed that only plants could make sugar and that
noted that diabetes was becoming increasingly common, animals could only break down substances made by plants.
possibly on account of the “good fellowship” and “guzzling It was also assumed that the blood of animals contained
down of unalloyed wine” so prevalent in his day. The no sugar except immediately after meals and in conditions
actual presence of sugar in the urine was described by like diabetes. However, Bernard found that the blood
Matthew Dobson in 1772, when he evaporated the urine of animals in the fasted state also contained sugar, even
 6 History of Diabetes

if they were not diabetic. He also correctly identified the now known as type 1 diabetes continued to be a sentence
liver to be the source of glucose in the blood and glycogen of death for most patients.
to be its immediate precursor. The discovery of the central
role of the liver in glucose metabolism led many scientists to BREAKTHROUGH—THE 20TH CENTURY
postulate that this organ could be responsible for diabetes.
The story of the discovery of insulin in 1921 is well-known
However, even these scientists agreed that this could be
throughout the world. But what is not so widely known
the case only in the older, fatter patients with diabetes, the
section

is that in the years between 1900 and 1921, at least five

so-called “diabete gras”. The cause of diabetes in young
scientists came close to isolating the elusive internal
1

thin individuals, “diabete maigre”, remained obscure.

secretion of the pancreas. With a little luck, any one of
The major breakthrough came in 1889, when the
them might have received the recognition and adulation
Lithuanian scientist Oscar Minkowski discovered that
which went to the Canadian group which eventually
removal of the pancreas in dogs caused diabetes.5 This
succeeded in isolating insulin.
focused attention on the pancreas, an organ which had
In 1905, Eugene Gley, a French scientist, ligated
hitherto been considered only as a source of digestive
the pancreatic duct of animal and after atrophy of the
enzymes. Minkowski and his colleague Josef von Mering
pancreas, extracted what was left. He found that the extract
noted that the condition of the dog was similar to that
decreased glycosuria in depancreatized dogs. However,
of a human patient with diabete maigre.
for reasons best known to himself, he did not further
It was, however, still not clear how removal of the
pursue this line of investigation and thus missed out on a
pancreas caused diabetes, or in other words, what vital
path breaking discovery. Similarly, in 1903, two Scottish
role the pancreas played in normal individuals to prevent
scientists, John Rennie and Thomas Fraser, attempted to
the development of diabetes. In 1869, a medical student in
relieve glycosuria in human patients by injecting extracts
Berlin, Paul Langerhans, had identified clusters of cells in
from fish pancreata, a proposition made attractive by the
the pancreas, distinct from the enzyme producing acinar
fact that the exocrine and endocrine components of the
cells.6 These cells were named the “islets of Langerhans”
pancreas are separate in fish. However, the injections
by Gustave Laguesse, who postulated that they might have
produced severe side effects and the experiment was
something to do with diabetes.7 abandoned.
The late 19th century saw giant strides in endocrin­ In 1906, the German physician Georg Zuelzer, in asso­
ology, the science dealing with the internal secretions of ciation with Minkowski, attempted to alleviate glycosuria
the body. Therefore, it was not surprising that scientists in humans by injecting animal pancreas extracts. Again,
soon started postulating the presence of an internal even though the extracts worked, side effects were so
secretion from the islets of Langerhans, which could severe that the investigators gave up. Other investigators
prevent the development of glycosuria and diabetes. who came tantalizingly close to piecing together the final
The hypothetical islet secretion was named “insuline” by pieces of the jigsaw were Ernest Scott and Israel Kleiner.
the Belgian scientist Jean de Meyer in 1909.8 Later, in 1919, the Romanian scientist Nicholai

Thus, by the end of the 19th century, the stepping Paulescu, in an experiment astoundingly similar to the one
stones for the next giant stride were in place. The key that would be carried out in Canada 2 years later, described
players in glucose metabolism had been identified— a pancreatic extract that cured symptoms of diabetes in
the liver, kidney and most importantly, the pancreas. depancreatized dogs.10 Unlike the earlier workers, he
Unfortunately, therapy for diabetes patients remained followed up on his studies and published a series of
rudimentary. Most patients with diabetes were treated papers in 1921, culminating in the grant of a patent for
with a combination of diets, many of which were of dubious “pancreine” in April 1922. However, he did not have the
efficacy. One diet which did show some benefit was the funds necessary to produce his extract in large quantities
Allen regime, introduced by Frederick Allen.9 This involved and his work was ignored when it came to awarding the
total elimination of carbohydrate from the diet and its Nobel Prize for the discovery of insulin.
replacement with calories derived from fat. Although this Therefore, by the end of the second decade of the
regimen provided patients with a few extra years of life, the 20th century, considerable progress had been made on
quality of life was poor and many died form malnutrition the isolation of the internal secretion of the pancreas
rather than diabetes. Meanwhile, the diagnosis of what is and its role in reducing glycosuria. However, little of this
 Landmarks in the History of Diabetes 7

chapter
1
Fig. 1.2: Frederick G Banting (right) and Charles H Best (left).
Source: University of Toronto.http://link.library.utoronto.ca/insulin/
digobject.cfm?Idno=P10103

was known to an orthopedic surgeon and part-time

physiology lecturer at the Western University, Toronto,
Frederick Grant Banting (Fig. 1.2), when he was asked
to lecture to some medical students on the physiology of
the pancreas. Preparing for his lecture, Banting chanced
to come across a report by Moses Barron in which he
described a patient whose main pancreatic duct had Fig. 1.3: John James Rickard Macleod.
Source: Bataille M Diabetes and Metabolism 2005;31(1):29-34.
been blocked by a stone, causing atrophy of the exocrine
tissue, leaving only the islets behind and in whom
diabetes did not develop. The report powerfully inspired assistant. However, it was made clear to Banting that he
Banting and he spent much of his time thinking about it, need expect no salary; indeed, only by selling his car and
until one night, suddenly waking up from sleep, he got out taking loans from his father and brothers was he able to
of bed and scribbled on a piece of paper: see the next few months through. For an assistant, he
“Diabetus. Ligate pancreatic ducts of dog. Keep dogs was offered the choice of two medical students—Charles
alive till acini degenerate leaving islets. Try to isolate the H Best and Clark Noble. The two tossed a coin to see
internal secretion of these to relieve glycosuria”.11 who should work the first half of the summer and Best
Note that the eventual discoverer of insulin got the won. By the time the second half of the summer came
spelling of diabetes wrong! around, Best had become so involved in the work that
Although Banting’s superiors at the Western University Noble agreed he should continue for the entire duration.
were supportive, they were unable to help him further as Banting and Best spent the summer of 1921 in their
the institution lacked sufficient facilities and funds. cramped lab, testing out Banting’s hypothesis. Banting
Instead, they referred him to James Macleod (Fig. 1.3), performed the pancreatectomies and made dogs develop
Professor of Physiology at Toronto University, considered diabetes. Best measured the blood and urinary glucose
to be an authority in carbohydrate metabolism. using the newly developed Benedict-Lewis method.
Banting and Macleod’s first meeting did not go well. In August 1921, they depancreatized two dogs and
Macleod was unimpressed by Banting’s rudimentary treated one with pancreatic extract, leaving the other as
knowledge of the pancreas and diabetes. However, Ban­ control. The control dog died in 4 days while the other
ting’s perseverance won through and he was able to survived and did well. However, the process of ligating
persuade Macleod to allow him the use of an old disused the pancreatic duct in dogs and waiting for atrophy of
lab within the facility, along with the services of an the exocrine tissue took close to 7 weeks. This led Banting
 8 History of Diabetes

with six others, was reported in the Canadian Medical

Association Journal in March 1922.12

Some idea of the importance of the discovery of insulin
can be gained from the fact that the scientists concerned
were awarded the Nobel Prize in 1923, less than 2 years
after the event. The prize actually went to Banting and
Macleod. Banting decided to share his prize with Best,
section

whereupon Macleod announced that he would share his

1

with Collip. There remains a considerable debate to this

day as to who among the four deserves the most credit for
the discovery of insulin. What is certain, though, is that
the discovery of insulin ranks as one of the most signi­
ficant medical achievements of modern times, changing
the lives of millions of diabetes patients for the better.
It is also of interest that no fewer than three further
Nobel Prizes have been awarded in the field of insulin
physiology in the succeeding years—to Frederick Sanger
in 1958 for the discovery of the amino acid sequence of
insulin, to Dorothy Hodgkin in 1964 for deciphering the
three-dimensional structure of insulin and to Rosalyn
Yalow in 1977 for the discovery of the radioimmunoassay
technique to measure insulin levels.

Perfecting the Miracle Drug—

Developments in Insulin Therapy
Fig. 1.4: James B Collip.
Source: Reference 1 (further reading). As described earlier, the insulin extracts prepared by
Banting and Best were far from the finished product.
to look elsewhere for a source of pancreatic extract. He Even with the best efforts of Collip, the early batches of
finally found a steady source from fetal calf pancreata, insulin varied widely in their potency and purity and
obtained from the local abattoir. Later he found that he were as capable of producing allergic reactions as they
could use adult beef pancreas just as effectively. Banting were of reducing the blood glucose. The product was also
and Best gave the name “isletin” to the active substance susceptible to rapid deterioration. This unsatisfactory state
in the extract produced by them; the name “insulin” of affairs, fortunately, did not last long.
was suggested by Macleod, harking back to de Meyer’s In January 1923, three of the discoverers of insulin,
work at the beginning of the century. Macleod, Banting and Best assigned their patent rights
Around this time, Macleod suggested the addition of to insulin to the Board of Governors of the University
Bert Collip (Fig. 1.4), a biochemist, to the team. Collip was of Toronto for the token sum of one dollar each. The
able to purify the crude extracts made by Banting and Best University then entered into a contract with Eli Lilly and
and modify it into a form more suitable for use in human Company for the commercial production of insulin. This
patients. The first patient to receive insulin injections was decision was influenced by the fact that in late 1922,
the teenaged Leonard Thompson on January 11, 1922. George Walden, Lilly’s chief chemist, had discovered the
Thompson, who at 14 years of age weighed only 29.5 kg, technique of isoelectric precipitation, which enabled the
received 15 mL of the “thick brown muck”, following manufacture of insulin with stability and purity up to
which his blood glucose fell from 440 mg/dL to 320 mg/dL. 100 times more than any of the earlier prepared extracts.
On January 23, he received a more purified form of In the meantime, August Krogh, a renowned Danish
the extract prepared by Collip, and this time his glucose scientist and Nobel laureate, happened to visit Toronto
levels fell from 520 mg/dL to 120 mg/dL. This case, along during his visit to North America to deliver a lecture at
 Landmarks in the History of Diabetes 9

Table 1.1: Landmarks in Therapy of Diabetes. The Modern Era lipoatrophy and lipohypertrophy. In 1941, the Swedish
Year Landmarks physician Jorpes found that one could prevent these
1921 Discovery of insulin
allergic reactions by using highly purified insulin obtai­
ned by multiple crystallization.15 Further work by Steiner
1922 First clinical use of insulin
demonstrated that these reactions were due to proinsulin
1926 Insulin crystallization techniques introduced
and other “contaminants”, which appeared as two addi­
1946 NPH insulin developed
tional peaks on insulin electrophoresis. Further efforts by

chapter
1955 The first sulfonylurea (carbutamide) introduced
the major insulin manufacturers led to the development
1956 Lente insulin introduced

1
of “clean” insulins (monocomponent, highly purified
1957 Introduction of the first biguanide (phenformin) and single peak) which virtually eliminated the trouble­
1963 First premixed insulin introduced some allergies.
1978 Subcutaneous insulin infusion pump (Pickup, UK) The second major issue was a direct consequence of
1982 Recombinant human insulin approved by US FDA the exploding epidemic of diabetes. By 1976, 1.5 million
1995 The first alpha glucosidase inhibitor approved by US FDA Americans were taking insulin, with an year-on-year
1996 The first rapid-acting insulin analog increment of 5%. It was projected that by the year 1992,
1997 The first thiazolidinedione the world would run out of insulin to supply all these
2000 Edmonton protocol for islet cell transplant additional patients, even if the entire beef and pork
2003 The first long-acting insulin analog approved by US FDA production of the world were diverted to insulin produc­
2005 The first GLP-1 analog tion. This meant that alternative sources of insulin had to
2006 The first DPP-4 inhibitor
be looked for urgently. Fortunately, due to developments
in biotechnology, this crisis point was never reached;
(USFDA: United States Food and Drug Administration; GLP-1: Gluca-
instead, by 1983, the first “human” insulin produced from
gon-like peptide 1; DPP-4: Dipeptidyl peptidase 4)
Escherichia coli bacteria was on the market. Within the
space of a single decade, it had displaced both porcine
Yale University. He met with Banting and Macleod and
and bovine insulin from the European market. In India,
left with an authorization from the University of Toronto
animal insulin held out for somewhat longer but is now
enabling him to introduce insulin into Scandinavia.
virtually unavailable.
By late 1923, Nordisk’s insulin production had begun
The third problem was that subcutaneous insulin the­
in Denmark.
rapy using conventional insulin, be it of animal or human
Further developments occurred in rapid succession
origin, could not precisely mimic the body’s exquisitely
(Table 1.1). In 1926, Abel succeeded in crystallizing insulin
controlled insulin secretion pattern. Regular insulin
for the first time, enabling further improvements in purity.
is not true “prandial” insulin; its slow absorption and
This, however, came at the expense of a reduction in the delayed clearance cause the blood glucose to rise too high
duration of action, necessitating up to four injections after a meal and fall too low before the next. Similarly,
per day in order to ensure stable control of sugars.13 The none of the conventional intermediate-acting insulins
problem was solved by Hans Christian Hagedorn, who are true “basal” insulins; their action does not last 24
suggested the addition of protamine (an alkaline protein hours and they have a discrete peak of action, leading to
abundant in fish sperm) in isophane (precisely balanced) nocturnal hypoglycemia when administered at dinner-
proportions to insulin.14 The resultant insulin, termed time or bed-time. The discovery of the amino acid sequ­
isophane or neutral protamine Hagedorn (NPH) insulin, ence of insulin by Sanger in 1955 stimulated research
was the first intermediate-acting insulin preparation. into developing new varieties (analogs) of insulin, which
Meanwhile, chemists at Novo (then separate from Nor­ while retaining the efficacy of conventional insulin, would
disk) solved the same problem by adding zinc crystals have more favorable pharmacokinetic profiles.
to insulin; by changing the size of the crystals, one could The first rapid-acting insulin analog to be introduced
alter the duration of action of insulin. Thus were born was insulin lispro in the mid 1990s, which was soon
the lente insulins. followed by aspart and glulisine. These molecules have
In spite of all this progress, there were still several rapid onset of action, enabling injection just before a
roadblocks to be overcome. A major issue was that meal, and rapid decay of action, reducing the risk of post­
allergic reactions were still common, as were disfiguring absorptive hypoglycemia.
 10 History of Diabetes

The first long-acting (basal) insulin analog was In 1937, Ruiz et al. serendipitously discovered the
glargine, introduced in 2003. This was followed by insulin hypoglycemic action of sulfonamide antibacterials while
detemir in 2006. These analogs have a prolonged and evaluating a new drug for the treatment of enteric fever.
peakless action, enabling once daily administration with These observations were confirmed in 1942 by Marcel
reduced risk of hypoglycemia. A very long-acting insulin Janbon, who reported hypoglycemia and seizures in
analog, insulin degludec, is ready to enter the market soon. patients administered this new sulfonamide agent.17
Concurrently, with the developments in insulin Based on these observations, Auguste Loubatieres was
section

pharmacology, insulin delivery systems also underwent able to establish that this group of drugs caused hypogly­
1

a sea change. The advent of disposable syringes obviated cemia through their direct action on pancreatic beta
the need for repeated sterilization and allowed patients cells.18,19 This marked the beginning of the sulfonylurea
more flexibility. The introduction of insulin pens enabled era. However, it was not until 1955 that the first agent
patients to inject themselves more discreetly and with in this class, carbutamide, was introduced into clinical
less pain. However, the shortcomings of subcutaneous practice by Franke and Fuchs.20 This was followed in
insulin delivery (even with the newer designer insulins) rapid succession by other agents such as tolbutamide,
in mimicking the normal pancreatic secretion of chlorpropamide, glibenclamide, glipizide, gliclazide and
glimepiride.
insulin still remained. The first continuous subcutaneous
Meanwhile, the guanidine story just refused to die
insulin infusion (CSII) pump, introduced by John Pickup
down. In 1957, the first non-toxic guanidine derivative
in 1978, was an attempt to overcome the limitations of
or biguanide, phenformin, was introduced, followed
multiple dose insulin injections by providing a constant
shortly thereafter by metformin.21 These drugs became
supply of insulin to the body, supplemented by mealtime
widely popular during the next decade, but reports of
boluses of rapid-acting insulin. The first insulin pumps
lactic acidosis led to the removal of phenformin from
were unwieldy and cumbersome affairs. Advances
the US market in the 1960s. Metformin, perhaps unfairly,
made over the last three decades have made insulin
was tarred with the same brush and did not make it to
pumps smaller, smarter and more acceptable to patients
American shores for nearly four decades. It was, however,
than ever before so much that many authorities consider widely used in the rest of the world. It was only in 1995 that
them the insulin delivery mode of choice in individuals the US market finally opened its doors to metformin, faced
with type 1 diabetes, although the cost remains prohi­ with overwhelming evidence on the safety and efficacy of
bitively high. this agent from the rest of the world. Metformin is now the
most widely prescribed oral antidiabetic agent worldwide
Completing the Armamentarium—The and is the first-line drug for type 2 diabetes according to
Development of Oral Antidiabetic Agents most of the global algorithms.
A number of new classes of antidiabetic agents were
From the mid-19th century onwards, there were sporadic
introduced during the 1990s (Table 1.1). Two of these
attempts to devise some form of oral pharmacological
classes, namely the non-sulfonylurea secretagogues (glini­
treatment of diabetes. One of the earliest candidate
des) and the alpha glucosidase inhibitors, are relatively
sources of an antidiabetic medication was goat’s rue
mild agents which have a niche role in the management
(Gallega officinalis), which has been mentioned as a of type 2 diabetes. The third drug class introduced in the
folk remedy for diabetes in different cultures over the 1990s, the thiazoloidinediones, have, however, had a
years. The active principle of this plant, guanidine, was turbulent history. The introduction of this new class of
identified in the early years of the 20th century. The first insulin sensitizers created plenty of excitement, particu­
orally active antidiabetic agent, synthalin, was a derivative larly when the initial clinical trial experiences showed
of guanidine and was introduced in 1926 by the German encouraging results not only in the treatment but also in
scientist Frank.16 Unfortunately, this agent was found to the prevention of type 2 diabetes. Indeed, the first agent
be too toxic for clinical use and was soon withdrawn from in this class, troglitazone, had the makings of a wonder
the market. Moreover, the discovery of insulin at around drug. Unfortunately, its time in the limelight was limited;
the same time cooled enthusiasm toward this line of within 4 years of its launch, it had been banned due to
research for a few years thereafter. reports of fatal hepatic toxicity. Troglitazone was never
 Landmarks in the History of Diabetes 11

marketed in India. The other two drugs in the class, agent is given by subcutaneous injection twice daily and
pioglitazone and rosiglitazone, were found to be liver is effective in reducing hyperglycemia as well as body
friendly and were widely prescribed over the last two weight. The other GLP-1 agonist available in India is
decades. However, in 2007, a meta-analysis showed an liraglutide, which can be given as a once daily injection.
increased risk of adverse coronary events in individuals Once weekly exenatide is available in the US but has
taking rosiglitazone.22 This led to a number of restrictions not been introduced in India at the time of writing.
in the use of this drug, culminating in the Drugs Controller In contrast to incretin mimetics, DPP-4 inhibitors are

chapter
General of India (DCGI) banning rosiglitazone in 2010. orally active agents which provide physiological levels of

1
With this, pioglitazone is now the only drug left in the GLP-1 to the cells. The agents currently available in India
class. It is an extremely potent antidiabetic agent, but are sitagliptin, vildagliptin, saxagliptin and linagliptin.
recent reports of bladder cancer among users of this Alogliptin is also available in some countries. These drugs
drug raise concern over its future.23 are better tolerated than GLP-1 agonists but are milder
In the first decade of the 20th century, interest has and do not produce significant weight loss.
been focused on a previously neglected aspect of carbo­ A drug class which has received much interest of late
hydrate metabolism—the gut-derived hormones or incre­ is the sodium glucose transporter 2 (SGLT2) inhibitors.
tins. Incretins are a group of peptide hormones released These agents reduce hyperglycemia by promoting glucose
from the gut in response to a meal, which have myriad loss through the urine and thereby control diabetes as
actions not only in digestion and metabolism but also in well as produce weight loss. Unfortunately, the develop­
organs far afield. The two main incretin hormones are ment of these agents has hit a roadblock due to their
glucagon-like peptide 1 (GLP-1) and glucose-dependent suspected link to bladder malignancy. The US Food and
insulinotropic peptide (GIP). Both these hormones act Drug Administration has asked for more data before the
on the pancreas, stimulating insulin release from the beta approval process can be restarted.
cells and suppressing glucagon release from the alpha
cells. They also inhibit gastric emptying and thereby A Cure for Diabetes—Still a Mirage?
induce satiety. Evidence from experimental animals also Type 1 (insulin-dependent) diabetes is a classical endo­
suggests that they may induce beta cell regeneration. crinopathy in which the main and often only patho­
In vivo, incretins have extremely short half lives since physiology is absence of insulin due to destruction of
they are rapidly degraded by the enzyme dipeptidyl pancreatic beta cells. This disorder therefore lends itself
peptidase 4 (DPP-4). to a cure if only an alternative source of beta cells could be
In type 2 diabetes, the levels of both GLP-1 and GIP provided to the patient’s body. Several approaches have
are low; however, the response to GLP-1 is maintained. been tried toward this end. The first attempts involved
This led workers to postulate that increasing the availa­ transplantation of the whole pancreas. Unfortunately,
bility of GLP-1 to the cells could help in controlling the limited availability of donor pancreata, complications
hyperglycemia in these patients. This has the advantage of involved in major surgery and the problems involved with
producing glucose-dependent insulin secretion, minimi­ immunosuppression have precluded this from gaining
zing the chances of hypoglycemia and suppressing glu­ wider acceptance. Transplantation of pancreatic islet cells
cagon levels, which none of the currently available was first attempted by Paul Lacy in 1967 and the first
antidiabetic agents are capable of doing. clinical trial was done in 1990. The introduction of the
The two strategies to improve the availability of GLP-1 Edmonton Protocol by James Shapiro in 2000 improved
to the cells are (1) to administer a GLP-1 analog which is patient responses to islet transplantation,24 but the long-
resistant to DPP-4 and (2) to inhibit the enzyme DPP-4 term efficacy of this procedure remains uncertain, with less
so that the body can make better use of endogenous than 10% of patients remaining free of insulin injections
GLP-1. The incretin mimetics act via the first mechanism 10 years after the procedure.25
whereas the DPP-4 inhibitors (incretin enhancers) utilize Recent efforts have been directed at utilizing stem
the second mechanism. cells as a source of insulin-producing beta cells in patients
The first incretin mimetic, exenatide, was developed with diabetes. This approach is currently experimental
from a protein derived form the saliva of the Gila Monster, and is limited by ethical concerns about the use of embryo­
a venomous lizard found in the US and Mexico. This nic stem cells.
 12 History of Diabetes

THE TIGER CHANGES ITS STRIPES: the lesions of diabetic microangiopathy and those of
TRANSFORMATION IN THE NATURAL atherosclerosis in the retina.33
HISTORY OF DIABETES AND Until the late 1960s there were no effective treatments
for diabetic retinopathy. Various pharmacological agents
EFFECT ON COMPLICATIONS
like rutin, Vitamin K and Vitamin C were tried with dis­
The discovery of insulin and its widespread clinical use in appointing results. In 1953, Jacob Poulsen suggested that
the early 1920s was accompanied by a wave of optimism hypophysectomy could improve retinopathy by reducing
section

bordering on euphoria among clinicians dealing with insulin resistance and improving the “metabolic hormonal
1

diabetes. In 1930, Frederick Allen confidently stated that imbalance”. Although never very popular, this procedure
diabetes had been conquered and that every diabetic continued to be performed in the 1970s for want of a better
could expect to live out his normal lifespan. However, alternative; the results were equivocal.
it soon became clear that the increased life expectancy Laser photocoagulation therapy was the brainchild of
afforded by insulin was something of a mixed blessing. the German ophthalmologist, Gerd Meyer-Schwickerath,
On the one hand, deaths from the acute complications who postulated that he might be able to stop new vessels
of diabetes, particularly diabetic ketoacidosis (DKA), from bleeding by coagulating them with heat.34 After
dwindled drastically, on the other hand, the very longe­ various trials during the 1940s, he settled on a xenon arc
vity of these patients meant that many of them could now lamp as the source of light. Although the results were
expect to develop one or other of the vascular complica­ impressive, the procedure was painful and needed up to
tions of diabetes, which were considered rarities in the 1.5 seconds to make the burn. The advent of the ruby laser
pre-insulin era. Insulin therefore had the effect of conver­ solved these problems. By the mid 1970s, the American
Diabetic Retinopathy Study (DRS) had established laser
ting diabetes from a fulminant, frequently fatal illness to a
photocoagulation as the treatment of choice for sight-
chronic lifelong disorder attended by the involvement of
threatening retinopathy. Meanwhile, in 1972, the German
various organ systems of the body.
surgeon Robert Machemer pioneered vitrectomy surgery,
Diabetic ketoacidosis (DKA) has been known to physi­
which offered a ray of hope to individuals who had lost
cians from olden days. In 1874, the German physician
vision due to intraocular bleeding from proliferative
Adolf Kussmaul described the typical labored respiration
retinopathy.
of patients with this condition.26 The peculiar fruity odor
Proteinuria has been described from the days of Rollo
of the breath in DKA was described by Watson and
and Darwin, who described the presence of coagulable
Foster independently in the 1870s.27,28 In the pre-insulin
material in the urine of diabetic patients. The first reports
era, most patients with type 1 diabetes died due to DKA.
on diabetic kidney disease were published in 1936 by
However, the starvation regime of Allen (vide supra) Paul Kimmelsteil and Clifford Wilson.35 They described
was able to bring down the mortality rate from 60% to 40%. this disease as characterized by protei­nuria, edema and
The advent of insulin therapy revolutionized the outlook a characteristic microscopic appearance of the kidney,
for DKA. Today, in most recognized centers in the world, the so called Kimmelsteil Wilson lesion (nodular inter­
the mortality rate for DKA is less than 1%.29 capillary glomerulosclerosis). These patho­logical changes

The other major hyperglycemic emergency, known as were further delineated by Bell in 1953. The development
hyperosmolar non-ketotic (HONK) state was described of the microalbuminuria assay in the 1970s has helped
by Dreschfield in 1886.30 This entity has recently been in the early detection and prevention of diabetic kidney
renamed hyperosmolar hyperglycemic state (HHS). disease. Work by Mogensen et al. has identified the risk
Much was known about chronic diabetes compli­ factors for diabetic nephropathy and elucidated the clini­
cations even in the preinsulin era. Distinctive lesions cal stages of the disease.
were described in the retinae of patients with diabetes The first description of neuropathy in diabetes is attri­
by Jaeger in 1855.31 In 1888, Nettleship described the buted to John Rollo in the 18th century.3 In 1883, Bouchard
ophthalmoscopic appearance of new vessel formation in described erectile dysfunction in poorly controlled dia­
the retina.32 In the pre-insulin era, retinopathy occurred betes.36 The first comprehensive description of the cardinal
only in older diabetic patients and was considered to features of diabetic polyneuropathy was given by Pavy
be due to atherosclerosis. This was disproved by Waite in 1885.37 Trophic ulcers and autonomic neuropathy
and Beetham, who drew clear distinction between were described by Auche in 1890.38
 Landmarks in the History of Diabetes 13

In 1868, Brigham noted that cerebral artery occlusion Eugene Opie in 1901.47 However, its clinical significance
and sudden death were more common in patients with was recognized only in the 1960s following the work of
diabetes than those without.39 In 1895, Bose reported Willy Gepts.48 The autoimmune basis of beta cell destruc­
that angina was more common in diabetes patients com­ tion in type 1 diabetes was postulated by Doniach and
pared to the general population.40 By the middle of the Bottazzo,49 while the genetic basis was established by
20th century, the relationship between coronary artery Cudworth and Woodrow.50
disease and diabetes had been proven beyond doubt
The pathogenesis of diabetic vascular complications

chapter
and many physicians started considering diabetes as a has been a subject of intense study for over a century.

1
coronary risk equivalent. Developments in molecular biology in the second half
Gangrene of the feet was known to be more common of the 20th century enabled the elucidation of the bio­
in diabetes patients from olden days; however, it was chemical pathways involved in the development of these
only in the 1920s that this was proven beyond doubt complications such as the polyol pathway, the advanced
following the work of Bell and colleagues.41-43 glycosylation end product (AGE) mechanism, the protein

Before the discovery of insulin, it was quite unusual kinase-C pathway and the hexokinase path­ way. The
for a diabetic woman to conceive. A successful completion work of Michael Brownlee in the early years of the 21st
of pregnancy was even more uncommon. As late as the century has helped to define a unified mechanism by
1950s, the outcome of pregnancy in women with dia­ which activation of these pathways can lead to diabetes
betes continued to be poor. However, work done by Pris­ complications.51
cilla White at the Joslin Clinic and Jorgen Pedersen in
Copenhagen helped in identifying good diabetes control TIGHT CONTROL OR NO TIGHT CONTROL—
as the key to a successful outcome. By the 1980s, the fetal CHANGING PARADIGMS IN DIABETES
mortality rate in diabetic pregnancies had fallen to less MANAGEMENT
than 6% in most of the Western world.
In the preinsulin era, the treatment options for insulin-
ADVANCES IN OUR UNDERSTANDING OF dependent diabetes (type 1 and advanced type 2 diabetes)
THE ETIOPATHOGENESIS OF DIABETES were limited. The main aim of treatment was to prolong
the life of the patient by avoiding episodes of acute
The widespread clinical use of insulin also helped in metabolic decompensation such as DKA. The concept of
elucidating the pathophysiology of diabetes. It was soon tight control of diabetes was unknown and since patients
found that not all patients responded in the same way rarely lived for more than few years after diagnosis, chro­
to insulin. In the 1930s, Wilhelm Falta and Harold nic complications were virtually unheard of.
Himsworth proposed that some patients were more The introduction of insulin therapy meant that diabetes
sensitive to the glucose-lowering effects of insulin than patients were now able to escape the death sentence
others.44,45 Patients in the former group were usually thin which the diagnosis would have earlier entailed. However,
and ketosis-prone (corresponding to the 19th century this development threw up other challenges to physicians
category of diabete maigre) while those in the latter group as to what the aims of treatment should be, now that
were usually obese and ketosis-resistant even without the risk of death from acute complications had receded.
insulin therapy (diabete gras). These two categories Should one try to get the glucose levels to normal, or
were variously termed as juvenile-onset and adult-onset should one just be satisfied with keeping the patient alive,
diabetes, insulin-dependent and non-insulin-dependent avoiding episodes of DKA? Elliott P Joslin of Boston,
diabetes, and finally, in the 1990s, as type 1 and type 2 considered as the Father of Modern Diabetology, was of
diabetes. The work of DeFronzo et al. in the 1970s46 led to the former persuasion. In 1935, he wrote that “the aim of
the development of the insulin clamp technique, which diabetes treatment is to keep the blood glucose levels as
has helped in relating the role of insulin resistance to close to normal as possible”.52 As obvious as this may sound
the development of type 2 diabetes. Many groups, inclu­ to modern ears, there were many like Marvin Siperstein
ding DeFronzo’s, have also looked at the role of beta cell who disagreed with Joslin, as they felt that diabetic
dysfunction in the pathogenesis of type 2 diabetes. complications may even precede diabetes. While the
In type 1 diabetes, lymphocytic infiltration of the attainment of normoglycemia was indeed a desirable aim,
islets—the so called insulitis was first described by the problem was that any attempts of tight control would
 14 History of Diabetes

invariably be accompanied by an increase in the incidence units (mmol/mol) in addition to percentage values, with
of hypoglycemia. Also, there was not enough evidence a view to switch completely to the former in the future.60
at the time to show that tight control would have any
benefits over and above those which could be attained DIABETES GOES GLOBAL
by conventional control. The debate raged on for nearly
70 years. The advocates of tight control were not helped At the beginning of the 20th century, type 2 diabetes was
by the results of the University Group Diabetes Program a disease of the better-off populations of the more
section

(UGDP) study, which showed increased mortality in advanced nations of the world. However, by the second
patients randomized to receive intensive treatment with half of the century, it had become clear that no nation
1

sulfony­ lureas compared to those given conventional or ethnic group was exempt from the disease. Countries
treatment.53 The issue was not resolved until the 1990s, like India, China and the Arab nations of the Middle East,
when the Diabetes Control and Complications Trial which experienced rapid economic growth after centuries
(DCCT) and the United Kingdom Prospective Diabetes of deprivation, found themselves at the epicenter of a
Study (UKPDS) unequi­ vocally established the benefits global epidemic, which they were ill-equipped to handle.
of tight glycemic control in preventing the development In order to tackle the burgeoning epidemic, diabetes
of chronic vascular complications in type 1 and type 2 organizations were set up in many countries, bringing
diabetes patients respectively.54-56 together physicians, paramedical staff, educators and
The conduct of these landmark studies was helped to patients under one roof. These organizations not only
a great extent by developments in clinical chemistry. The helped to improve the standards of care of individuals with
most important among these was the development of a diabetes in the respective countries, but also often acted as
robust indicator for long-term glycemic control. In 1969, powerful advocacy groups forcing through policy changes
Rahbar described the relationship between the blood for the benefit of patients with diabetes. In 1934, the
levels of an “unusual hemoglobin” called glyco­sylated British physician R D Lawrence (himself afflicted with type
hemoglobin (HbA1c) and diabetes.57,58 In 1972, Bunn et al. 1 diabetes) and the renowned author H G Wells founded
showed that the cause of the rise in HbA1c in diabetic the Diabetic Association (now known as Diabetes UK).
subjects is the increased non-enzymatic glycation of the In the United States, 28 physicians got together and
hemoglobin molecule, which was essentially irrever­ formed the American Diabetes Association in 1940.
sible.59 Koenig et al. were the first to demonstrate the The European Association for the Study of Diabetes was
relationship between HbA1c and fasting blood glucose; formed in 1965. In 1950, several diabetes associations
they also suggested that HbA1c levels might also correlate from different parts of the globe formed the International
with the mean glucose levels.55 By the 1980s, HbA1c was Diabetes Federation (IDF), which now has 200 member
being widely used in clinical practice to assess long- associations spread over seven regions. In India,
term glycemic control. However, the wide variety of the Research Society for the Study of Diabetes in India
assays available and lack of standardization remained as (RSSDI) was established in 1972 and now has more than
formidable roadblocks to its wider use. To solve this pro­ 6,000 members, and is the largest in Asia.
blem, the National Glycohemoglobin Standardization
Program (NGSP) was set up in 1996 to standardize CONCLUSION
HbA1c assays throughout the US. As a result of this pro­
gram, more than 99% of the HbA1c assays in the US, UK The story of diabetes has been a long and eventful one.
and Canada today are standardized, i.e. they are back The path is strewn with glittering achievements and
trace­able to the DCCT assay. However, in countries such exciting discoveries, but at the same time the journey
as India, the problems of standardization remain unsolved is nowhere near complete. The prospect of a cure for
to a great extent. diabetes remains as elusive today as it was a century ago.
More recently, a joint working group set up by the Many aspects of the etiopathogenesis of diabetes and its
American Diabetes Association, European Association complications await further elucidation. Nevertheless,
for the Study of Diabetes, the International Diabetes we have every reason to be grateful to the pioneers in
Federation and the International Federation of Clinical the field of diabetology whose efforts have enabled our
Chemistry (IFCC) and Laboratory Medicine has recomm­ patients to lead lives virtually indistinguishable from
ended that the HbA1c value should be reported in IFCC those of their peers without diabetes.
 Landmarks in the History of Diabetes 15

FURTHER READING 17. Janbon M, Chaptal J, Vedel A, et al. Accidents hypoglycem­

iques graves par un sulfamidothiazol (le UK 57 on 2254 RP).
1. Bliss M. The Discovery of Insulin. Chicago: University of Montpellier Med. 1942;21-22:441-4.
Chicago Press; 1982. 18. Loubatieres A. Quoted by Pyke DA. Preamble: the history of
2. Rosenfeld L. Insulin: discovery and controversy. Clin Chem. diabetes. In: Alberti KGMM, Zimmet P, Defronzo RA (Eds).
2002;48:2270-88. International Textbook of Diabetes Mellitus, 2nd edition.
3. Holleman F, Gale EA. Nice insulins, pity about the evidence. Chichester: John Wiley; 1997.
Diabetologia. 2007;50:1783-90. 19. Loubatieres A. The mechanism of action of hypoglycemic

chapter
4. Tattersall RB. Diabetes—the Biography. Oxford: Oxford sulphonamides; A concept based on investigations in ani­
University Press; 2009. mals and in man. Diabetes. 1957;6:408-17.

1
20. Franke H, Fuchs J. Ein neues antidiabetisches prin­
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Am J Med Sci. 1915;150:495-6. 30. Dreshfeld J. The Bradshaw lecture on diabetic coma. Br
10. Paulesco NC. Action de l’extrait pancreatique injecte dans Med J 1886; 2:358-363.
le sang, Chez un animal diabetique. C R Soc Biol. 1921;85: 31. Jaeger E. Beitrage Zu Pathologie des Auges, siete 33. Eien:
555-9. KK Hofund and Staatsdruckerei, 1855.
11. Bliss M. The Discovery of Insulin. Chicago: University of 32. Nettleship EN. Chronic retinitis in diabetes. Trans Ophthal
Chicago Press; 1982. pp. 45-58. Soc UK 1888;8:159-162.
12. Banting FG, Best CH, Collip JB, et al. Pancreatic Extracts 33. Waite JH, Beetham WP. The visual mechanism in diabetes
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14. Hagedorn HC. Jensen NB, Krarup NB, et al. Protamine glomeruli of the kidney. Am J Pathol. 1936;12:83-98.
insulinate. JAMA 1936;251:389-92. 36. Bouchardat A. De la glycosurie ou diabetic sucre. Geremer-
15. Jorpes JE. Recrystallized insulin for diabetic patients with Balliere. Paris, Vol. II
insulin allergy. Arch Intern Med. 1943;83:363-71. 37. Pavy FW. Introductory address to the discussion on the
16. Frank E, Nothman M, Wagner A. Uber die experimentelle clinical aspect of glycosuria. Lancet. 1885;2:1033-35.
und Klinische Wirkung des dodekamethy lindiguanids 38. Auche B. Des ulterations des nerfs peripherique chez les
(Syntholin B) Klin Wschr 1928;7:1996-2000. diabetiques. Arch Med Exp. 1890; 2:635-76.
 16 History of Diabetes

39. Brigham CB. An essay upon diabetes mellitus. Press of 52. Aragona M, Giannarelli R, Del Prato S. Intensive insulin tre­
Abner A Kingman, Boston, 1868. atment and postprandial control in Type 1 diabetes. Acta
40. Bose KC. Diabetes mellitus and its prevention. Ind Med Biomed. 2005;76:26-30.
Gaz. 1895;30:135-44. 53. University Group of Diabetes Study Program (UGDP).
41. Bell ET. Postmortem study of vascular disease in diabetics. A study of effects of hypoglycemic agents on vascular
Arch Pathol Lab Med. 1952; 53:444-55. complications in patients with adult-onset diabetes.
42. Bell ET. Incidence of gangrene of the extremities in non- Diabetes. 1970;19:747-830.
diabetic and diabetic persons. Arch Pathol Lab Med. 1950; 54. The Diabetes Control and Complications Trial Research
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49:469-73. Group. The effect of intensive treatment of diabetes on

43. Bell ET. Atherosclerotic gangrene of the lower extremities the development and progression of long-term complica­
1

in diabetic and non-diabetic persons. Am J Clin Path. 1957; tions in insulin-dependent diabetes mellitus. N Engl J Med.
28:27-36. 1993;329:977-86.
44. Falta W. Die Zuckerkrankheir. Berlin: Urban and Schwar­ 55. UK Prospective Diabetes Study Group. Intensive blood
zenberg; 1936. glucose control with sulfonylureas or insulin compared
45. Himsworth HP. Diabetes mellitus: its differentiation into with conventional treatment and risk of complications
insulin-sensitive and insulin-insensitive types. Diabet Med. in patients with type 2 diabetes (UKPDS 33). Lancet.
2011;28:1440-4. 1998;352:837-53.
46. DeFronzo RA, Tobin JD, Andres R. Glucose clamp tech­ 56. UK Prospective Diabetes Study Group. Tight blood pres­
nique: a method for quantifying insulin secretion and sure control and risk of macrovascular and microvascular
resistance. Am J Physiol. 1979;237:E214-23. complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:
47. Opie EL. On the relation of chronic interstitial pancreatitis 703-13.
to the islands of Langerhans and to diabetes mellitus. J Exp 57. Rahbar S. An abnormal hemoglobin in red cells of diabet­
Med. 1901;5:397-428. ics. Clin Chim Acta. 1968;22:296-8.
48. Gepts W. Pathologic anatomy of the pancreas in juvenile 58. Rahbar S Blumenfeld O, Ranney HM. Studies of a unusual
diabetes mellitus. Diabetes. 1965;14:619-33. hemoglobin in patients with diabetes mellitus. Biochem
49. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell Biophys Res Commun. 1969;36:838-43.
antibodies in diabetes mellitus with autoimmune polyen­ 59. Bunn HF, Haney DN, Kamin S, et al. The biosynsthesis of
docrine deficiencies. Lancet. 1974;2:1279-83. human hemoglobin A1c. Slow glycosylation of hemoglobin
50. Cudworth AG, Woodrow JC. Evidence for HL-A-linked genes in vivo. J Clin Invest. 1976;57:1652-9.
in “juvenile” diabetes mellitus. Br Med J. 1975;3:133-5. 60. ADA/EASD/IDF: Report of the ADA/EASD/IDF work­
51. Brownlee M. The pathobiology of diabetic complications: ing group of the HbA1c assay. Diabetologia. 2004;47:
a unifying mechanism. Diabetes. 2005;54:1615-25. R53-R54.
SECTION 2

PHYSIOLOGY AND METABOLISM

Section Editor: Hemraj B Chandalia
 CHAPTER 2
Intermediary Metabolism
and Hormonal Regulation
NC Panda

Intermediary Metabolism

Chapter Outline
♦♦ Major Metabolic Pathways and Control Sites ♦♦ Fed State
♦♦ Stages of Extraction of Energy from Foodstuffs ♦♦ Fasted (Post-absorptive) State
♦♦ Recurring Motifs in Metabolic Regulations ♦♦ Starvation
♦♦ Major Pathways of Metabolism and the Principal ♦♦ Prolonged Starvation
Sites for their Control ♦♦ Diabetes Mellitus
♦♦ Hormonal Regulation of Intermediary Metabolism

INTRODUCTION
The basic strategy of metabolism is to form adenosine
triphosphate (ATP) reduced nucleotides, nicotinamide
adenine dinucleotide phosphate hydrogen (NADPH),
and building blocks for biosynthesis [macromolecular
precursors such as acetyl-coenzyme A (CoA), succinyl-
CoA, ribose-5-P]. ATP is consumed in muscle contraction
and in active transport and biosynthesis. NADPH which
carries two electrons at a high potential provides reducing
power in biosynthesis of cell components from more
oxidized precursors (fatty acid synthesis). ATP and
NADPH are continuously generated and consumed. These
molecules are generated by oxidation of fuel molecules
such as glucose, fatty acids and amino acids (AAs) derived
from proximate principles of nutrition viz. carbohydrate,
fats and proteins. There are definite metabolic pathways
involved in utilization of each of these fuel molecules.
But, the pathways are not absolutely independent of one
another. There are cross links between each pathway and
the other at specific points, from which metabolites can
flow from one pathway to another. The major key functions
(crossroads) governing the flow of molecules from one
metabolic pathway to another are glucose 6-phosphate,
Fig. 2.1: Intracellular metabolic pathway
pyruvate and acetyl-CoA1,2 (Fig. 2.1).
 20 Physiology and Metabolism
SECTION
2

Fig. 2.3: Citric acid cycle in transamination and gluconeogenesis23

2. Pentose phosphate pathway, which branches from

glucose 6-phosphate and intermediate of glycolysis,
supp­lies NADPH and ribose 5-phosphate. The latter is
required for nucleic acid synthesis.
3. Triose phosphate pathway gives rise to glycerol moiety
Fig. 2.2: Citric acid (Kreb’s) cycle and oxidative phosphorylation23 required for acylglycerol (fat) formation.
4. Pyruvate and intermediates of citric acid cycle provide the
carbon skeletons for the synthesis of AAs and acetyl-CoA
MAJOR METABOLIC PATHWAYS AND is the building block for long-chain fatty acids and
CONTROL SITES2-34 cholesterol, the precursor of all steroids synthesized in
the body (Fig. 2.3).
Carbohydrate Metabolism 5. Gluconeogenesis is the process that produces glucose
Carbohydrate metabolism is centered on provision and from non-carbohydrate precursors, e.g. lactate, AAs and
fate of glucose. Glucose is metabolized to pyruvate and glycerol.
lactate in the mammalian cells by the pathway of glycolysis.
Glucose is a unique substrate because glycolysis can
Lipid Metabolism
occur in the absence of oxygen (anaerobic), where the Lipid metabolism is concerned mainly with fatty acids and
end-product is lactate. However, tissues that can utilize cholesterol. The source of long-chain fatty acids is either
oxygen (aerobic) are able to metabolize pyru­vate to acetyl- dietary lipid or de novo synthesis from acetyl-CoA derived
CoA, which can enter the citric acid cycle for complete from carbohydrate. In tissues, fatty acids may be oxidized
oxidation to CO2 and H2O, with liberation of free energy to acetyl-CoA (β-oxidation) or esterified to acylglycerols.
as ATP by the process of oxidative phosphorylation Triacylglycerol (fat) consti­ tutes body’s main caloric
(Fig. 2.2). Thus, glucose is a major fuel in many tissues. reserve. Acetyl-CoA formed by β-oxidation has several
But, it also takes part in other metabolic processes, e.g. important fates:
1. Conversion into glycogen, a storage polymer in liver and • Acetyl-CoA derived from carbohydrates is oxidized
muscle which can be reutilized during energy demands. completely to CO2 and H2O via citric acid cycle. Fatty
 Intermediary Metabolism and Hormonal Regulation 21

acids yield considerable energy both in β-oxidation small compared with that obtained from the complete
and in citric acid cycle by utilizing resulting acetyl-CoA oxidation of the acetyl unit of acetyl-CoA.
from β-oxidation reaction. 3. The third stage constitutes the citric acid cycle and
• Acetyl-CoA is required for synthesis of cholesterol and oxidative phosphorylation (Fig. 2.2). These are the
subsequently other steroids. final common metabolic pathways in oxidation of
• In liver, acetyl-CoA forms ketone bodies which serve fuel molecules. Acetyl-CoA brings the acetyl units
as alternative source of tissue fuels particularly when into this cycle where they are completely oxidized to

CHAPTER
energy is required under emergency con­ditions like CO2 and H2O. Four pairs of electrons are transferred to
NAD+ and FAD for each acetyl group that is oxidized.

2
starvation. They also serve as fuel for muscle and heart
Then, ATP is generated as electrons flow from the
to spare carbohydrates.
reduced forms of these carriers to O2 in a process called
oxidative phosphorylation. Most of ATPs generated by
Amino Acid Metabolism
degradation of foodstuffs are formed in the third stage.
Amino acid metabolism centers around protein synthesis
and transamination. The AAs are building blocks for RECURRING MOTIFS IN
protein synthesis. Some AAs must be supplied in the diet METABOLIC REGULATIONS
(the essential AAs), since they cannot be synthesized in
Even the simplest bacterial cell has the capacity for carry­
the body. The remainder, or non-essential AAs are supp­
ing out more than 1,000 interdependent reactions. It is
lied in diet and, can be synthesized from carbon skeletons
evident that this complex must be rigorously regulated.
formed as intermediates in the carbohydrate metabolism
Studies of a wide range of organisms have shown that
by transa­ mination using amino nitrogen from other
there are a number of mechanisms for the control of
surplus AAs. metabolism. The following major mechanisms can be
After deamination excess amino nitrogen is removed enumerated:
as urea and the carbon skeleton that remains after trans­
1. Enzyme levels: The amount of enzymes, as well as their
amination undergoes the following reactions: (1) oxi­
activities is controlled. The rates of synthesis and deg-
dizes to CO2 via citric acid cycle, (2) forms glucose via
radation of some regulatory enzymes are subject to
gluconeogenesis pathway and (3) forms ketone bodies.
hormonal factors.
In addition to their requirement for protein synthesis,
2. Reversible allosteric control (Fig. 2.4): The first reaction
the AAs are also the precursor of many other important
in many biosynthetic pathways is allosterically inhibited
compounds, e.g. purines, pyrimidines and hormones such
by the ultimate product of the pathway. The inhibition
as adrenaline and thyroxine.
of aspartate transcarbamylase by cytidine triphosphate
is a well-understood example of feedback inhibition.
STAGES OF EXTRACTION OF The first irreversible reaction in a pathway (commit-
ENERGY FROM FOODSTUFFS ted step) is usually an important control site. Enzymes
catalyzing committed steps are allosterically regulated,
Sir Hans Krebs3-5 discoverer of Krebs citric acid cycle has
as exemplified by phosphofructokinase in glycolysis and
described three stages in the generation of energy from
acetyl-CoA carboxylase in fatty acid synthesis.
the oxidation of foodstuffs:
3. Reversible covalent modification: Some regulating
1. In the first stage, large molecules in food are broken down
enzymes are controlled by covalent modification in
into smaller units. Proteins are hydrolyzed to 20 kinds addition to allosteric interactions. For example, the
of AAs, polysaccharides are hydrolyzed to simple sugar catalytic activity of glycogen phosphorylase is enhanced
such as glucose and fats are hydrolyzed to glycerol and by phosphorylation, whereas glycogen synthase is
fatty acids. No useful energy is generated in this stage. diminished. Covalent modification of key enzymes in
2. In the second stage, numerous molecules are degraded metabolism is the final stage of amplifying cascades.
to a few simple units that play a central role in metabo­ Consequently, metabolic pathway can be rapidly
lism. In fact, most of them—sugars, fatty acids, glycerol switched on or off by very small triggering signals, as
and several AAs—are converted to acetyl-CoA. Some shown by the action of epinephrine in stimulating the
ATPs are generated in this stage, but the amount is breakdown of glycogen.
 22 Physiology and Metabolism

4. Compartmentation: The metabolic patterns of eukary- are operating simultaneously. Each pathway must be able
otic cells are markedly affected by presence of compart- to sense the status of the others to function optimally to
ments. Glycolysis, the pentose phosphate pathway and meet the need of the organism. This is otherwise known as
fatty acid synthesis take place in the cytosol, whereas integration of metabolism in mammals.
fatty acid oxidation, citric acid cycle and oxidative
phosphorylation are carried out in mitochondria. Some MAJOR PATHWAYS OF METABOLISM AND
processes, such as gluconeogenesis and urea synthesis THE PRINCIPAL SITES FOR THEIR CONTROL
SECTION

depend on the interplay of reactions that occur in both

Glucose
2

compartments. The fate of certain molecules depends

on whether they are in cytosol or mitochondria so that Glucose after its entry inside a cell is metabolized in the
their flow across the inner mitochondrial membrane pathways like glycogenesis, glycogenolysis, glyco­ lysis,
is often regulated. For example, fatty acids transported TCA cycle, hexose monophosphate (HMP) shunt path-
into mitochondria are rapidly degraded, in contrast to way and uronic acid pathway. The major regulatory steps
fatty acids in the cytosol, which are esterified or expor­ in the above-mentioned pathways are glucose transport
ted. Long-chain fatty acids are transported into the and hexokinase (controlling glucose uptake); phospho­
mitochondrial matrix as esters of carnitine, a car- fructokinase (regulating glycolysis); phosphorylases
rier that enables these molecules to traverse the inner (regulating glycogenolysis); uridine dip­hosphate (UDP)
mitochondrial membrane. glucose-glycogen glucosyl transferases (glycogen synthe­
5. Biosynthetic and degradative pathways: It is almost a tase, regulating glycogenesis) and pyruvate dehydro­
general principle of metabolism that biosynthetic and genase (controlling pyruvate oxidation and hence entry
degradative pathways are always distinct. The separation of glucose carbon into the TCA cycle).9-12 In streamlining
is necessary for energetic reasons. For example, glyco- these events, the following steps have been considered
genesis and glycogenolysis, glycolysis and gluconeo­ essential (Fig. 2.4).
genesis and fatty acid oxidation and fatty acid synthesis • Glucose 6-phosphate stands at the metabolic crossroad
are important. for several pathways.1-12 In other words being formed
from glucose, it can be utilized for glycogen synthesis,
6. Energy status of the cell:7 Daniel Atkinson had shown that
glycolysis [Embden-Meyerhof (EM) pathway], HMP
ATP-generating pathways are inhibited by high energy
charge (excess of ATP), whereas ATP utilizing pathways shunt pathway, uronic acid pathway, or reconversion
are stimulated by a high energy charge. to glucose in liver.13-34
• Similarly, acetyl-CoA (active acetate) is the other
7. Metabolic specializations of organs:8 Despite high degree
of specialization, all the major organs in vertebrates can major crossroad in the pathway of glucose utilization.
carry out the reaction of the central metabolic pathways It can be formed from pyruvic acid1,11 which in turn
such as glycolysis, tricarboxylic acid (TCA) cycle and is obtained as the end-product of EM pathway, from
biosynthesis of lipids and proteins. However, the tuning the fatty acid cycle or from oxidative deamination of
and appropriating of central metabolic pathways differ certain ketogenic AAs. It is utilized mostly in the TCA
from one another. Each has a characteristic pattern of cycle after combining with oxaloacetic acid, which is
fuel utilization and of biosynthetic activities in keep- mostly regenerated in the TCA cycle or obtained from
ing with its specialized function in the organ. In some pyruvic acid and aspartic acid (Fig. 2.5). Active ace-
organs, particular pathways are dominant and, in some, tate normally also enters the synthetic pathways such
these operate in low profile. Definite function of the tis- as that of fatty acids, acetylcholine, cholesterol and
sues, their requirement of metabolites for the purpose ketone bodies. When so many pathways are operat-
and fuels to meet their energy needs are determining ing in which either glucose 6-phosphate or acetyl-CoA
factors for the nature of the metabolism of a particular is a substrate, it is interesting to note the principles
organ. Details in respect of different organs will be taken which govern the rate of flow of these compounds
up subsequently. into different pathways at different times. All the time,
When biochemistry of metabolism is examined, it is the flow of these compounds into different pathways
on pathway at a line, but in living systems, many pathways is not same.
 Intermediary Metabolism and Hormonal Regulation 23

CHAPTER
2

Fig. 2.4: Major pathways and regulation of glycolysis and glyconeogenesis in liver. Arrows with wavy shafts indicate allosteric effects26
 24 Physiology and Metabolism

and equilibrium considerations in the citrate synthetase

reac­ tion suggest that its concentration may depend
upon the ratio of acetyl-CoA to CoASH. The regulation of
phosphofructokinase by citrate may involve transfer of
citrate from mitochondria to cytoplasm by a mitochondrial
citrate transporting system requiring malate.29
3. A third mechanism is concerned with hormone
SECTION

action.2,9,11,13
2

Insulin may stimulate glucose uptake by activating

glucose transport and stimulate glycogen formation by
causing the conversion of glycogen synthetase D to I form.
Glycogen synthetase D (inactive and phosphorylated
form) is critically dependent on glucose 6-phosphate
concentration. The I form is independent of glucose
Fig. 2.5: Regulation of long-chain free fatty acids (FFAs) oxidation in 6-phosphate. In this regard the action of insulin is favoring
the liver. Broken chain arrows show either positive (+) or negative (–) glycogen synthesis independent of intracellular signals.
regulatory effect21
Similarly, the action of adrenaline causing glycogen
breakdown appears to involve the conversion of phosph­
orylase-b (inactive to activephosphorylase-a. This process
Rate of utilization of glucose 6-phosphate either in EM of activation requires cyclic-AMP as activator of dephos-
pathway or in that of glycogenesis will differ according to phorylase-b-kinase. This step is inhibited by ATP and
the concentration of the glucose 6-phosphate and the level glucose 6-phosphate. The processes of glycogen synthe-
of insulin and various key enzyme systems. sis and glycogen breakdown bear reciprocal relationship
Similarly, the quantity of acetyl-CoA entering the with each other. The cyclic-AMP stimulates glycogenoly-
TCA cycle or ketone body formation will depend on the sis, but inhi­bits glycogenesis. It promotes phosphorylation
concentration of acetyl-CoA and the level of various of enzyme proteins in both the reactions. During glycog-
enzymes. enolysis phosphorylation of inactive phosphorylase-b
The control systems of glucose utilization appear to activates the enzyme; hence, the process of glycogenolysis
subserve three major physiological roles involving three is stimulated. On the other hand, the same phosphoryla-
major groups of metabolites.1,2,12,27 tion reaction of glycogen synthesis I (active) converts it to
1. One set of signals may vary rates of glucose uptake, synthetase-D (inactive) form, thus inhibiting glycogenesis.
glycogen breakdown and glycolysis according to the state The process of glucose uptake, glycogen synthesis and
of ATP breakdown and synthesis. breakdown and glycolysis can be considered as a single
Lowering of phosphate potential in the adenine integrating complex unit. So also enzymes hexokinase,
nucleotide series [i.e. conversion of ATP to ADP and glycogen synthetase-D, phosphorylase-b and phospho­
5’-adenosine monophosphate (AMP)] activates the whole fructokinase act as a single complex unit. The connecting
process of conversion of glucose and glycogen to pyruvate link appears to be the concentrations of glucose 6-phosp­
and lactate by direct effects on membrane transport, hate and fructose 6-phos­phate which are held in equili­
phosphorylase system and phosphofructokinase. These brium by phospho­fructokinase.
steps are inhibited by ATP. The size of glucose monophosphate pool14 plays an
2. A second group of signals may regulate entry of glucose, important role in the central mechanisms. After the entry
glycogen synthesis and breakdown, glycolysis and pyru­ of glucose by glucose transport system, glucose utilization
vate oxidation according to the availability of alternative depends on the efficient removal of intracellular glucose
respiratory fuels such as fatty acids or ketone bodies. by hexokinase. This in turn may depend on the glucose
The major signals appear to be concentration of ratios of 6-phosphate concentration since glucose 6-phosphate
acetyl-CoA/CoASH and reduced NAD/nicotinamide is a non-competitive, allosteric inhibitor of hexokinase
adenine dinucleotide (NADH) which may regulate pyru­ and apparently major regulator of this enzyme.
vate dehydrogenase, and citrate formed from acetyl-CoA. Glucose 6-phosphate is also an inhibitor of phos­­­
Citrate is an important inhibitor of phosphofructokinase phorylase-b and an activator of glycogen synthetase-D.
 Intermediary Metabolism and Hormonal Regulation 25

CHAPTER
2
Fig. 2.6: Glucose-fatty acid cycle

Fructose 6-phosphate,6-15,18 on the other hand, is both Fig. 2.7: Glucose-fatty acid cycle in diabetes. In severe insulin defi-
a substrate for and activator of phosphofructokinase. ciency there is accelerated glycolysis and raised plasma triglycerides.
The control of this enzyme by adenine nucleotide Little of acetyl-CoA can be metabolized by the TCA cycle, remainder
is converted to ketone bodies (ketonemia) and some are excreted in
phosphate concentration or citrate leads to changes
urine (ketonuria). Since glycolysis is inhibited, the G-6-P from acceler-
in the affinity of the enzyme for fructose 6-phosphate. ated glycogenolysis is converted to glucose. This combined with acce­
Inhibition of phosphofructokinase (either with citrate or lerated gluconeogenesis results in hyperglycemia. Insulin effectively
ATP) would lead to accumulation of fructose 6-phosphate reverses this effect

and activation of the same enzyme (with lowering of

phosphate potential) which would allow it to function ADP and fructose 1, 6-diphosphate increase). Lack of
at lower concentrations of fructose 6-phosphate, thus oxygen is believed to lower ATP and raise ADP, AMP and
dragging the reactions in forward direction. phosphate, thus activating phosphofructokinase and
Inhibition of hexokinase and phosphorylase-b and phos­p horylase-b. 12 Activation of phosphofructo­ki­nase
activation of glycogen synthetase-D by glu­cose 6-phos­ raises fructose 1, 6-diphosphate and lowers fructose-6-
phate may be due to its effect on the Vmax (maximum velo­ phosphate and glucose 6-phosphate levels. The change
city of an enzyme action) of the three enzymes. In respect in glucose 6-phosphate may then activate hexokinase
to hexokinase action, inhibition by glucose 6-phosphate and also phosphory­ lase-b. Muscular contraction may
will lead to rise in blood glucose level. As inhibi-­tion by also accelerate glucose uptake, glycogen breakdown
glucose 6-phosphate only affects Vmax and not the Km and gly­colysis by activation of membrane transport, the
(Michaelis constant), i.e. substrate enzyme there may be phosphorylase system and phosphofructokinase. The
little or no compensatory increase in the rate of glucose effects on phosphorylase may be brought about through
phosphorylation when glucose accumulates. The control activation of phosphorylase-b kinase by Ca++ released
of phosphofructokinase, on the other hand appears to during contraction. Effects of Ca++ on hexokinase and
be through its effects on the Km for fructose 6-phosphate. phosphofructokinase were not detected; It is also possible
The enzyme is inhibited by ATP which raises the Km for that during muscular concentration increased concen­
fructose 6-phosphate and this inhibition is overcome trations of Ca++ may cause direct inactivation of glycogen
by fructose 6-phosphate. The rate curves for fructose synthetase (conversion of I to D form), thus inhibiting
6-phosphate are sigmoid because Km is dependent on ATP glycogenesis while glycogenolysis is going on.
concentration. Citrate increases the ATP inhibition and The oxidation of fatty acids and ketone bodies lead
further raises the Km, phosphate, ADP, AMP and fructose 1, to inhibition of glucose uptake and phos-phorylation,
6-diphosphate reverses ATP inhibition and lower the Km glycolysis and glucose oxidation in cardiac and skeletal
for fructose 6-phosphate.12,15 muscles.12 In the oxidation of glucose through Embden-
The operation of this complex can be verified from Meyerhof pathway and TCA cycle, the concept of recip­
studies of the effects of anoxia, of fatty acids and ketone rocal relationship between glucose and fatty acid meta­
bodies and of insulin in rat heart muscle. bolism is described under “glucose-fatty acid cycle”. The
Anoxia accelerates glucose phosphorylation, glycogen interrelationship between metabolism of glucose and fatty
breakdown and glycolysis and leads to a crossover bet­ acid is given in Figures 2.6 and 2.7. The essen­tial features
ween substrates and products of the phosphofructokinase are (1) the inhibitory effects of glucose metabolism on
reaction (ATP and fructose 6-phosphate decrease, the release and oxidation of fatty acids in adipose tissue
 26 Physiology and Metabolism

and (2) the restriction imposed on glucose uptake and Adipose Tissue
metabolism in muscle (also in adipose tissue) by the
release and oxidation of fatty acids from glyceride stores. Regulation of glucose utilization in adipose tissue req­
In blood transfer of fatty acids from adipose tissue (and uires specific attention to fatty acid and triglyceride
ketone bodies formed from them in liver) to muscle biosynthesis. The process of (1) fatty acid biosynthesis
inhibits uptake, breakdown and oxidation of glucose in from glucose to mitochondrial acetyl-CoA, (2) conver­
the tissue and uptake of glucose by the adipose tissue sion of-mitochondrial acetyl-CoA to extramitochondrial
SECTION

inhibits flow of free fatty acid (FFA) from adipose tissue acetyl-CoA through citrate synthase, mitochondrial citrate
to muscle (Figs 2.8 and 2.9). transport requiring malate and ATP citrate lyase and
2

The oxidation of fatty acids and ketone bodies further (3) the synthesis of long-chain fatty acetyl-CoA in the
stimulate glycogen synthesis possibly by activation of cytoplasm from acetyl-CoA and reduced NADP utilizing
glyco­gen synthetase-D. These reactions lead to crossover acetyl-CoA carboxylase and fatty acid synthetase.20 Nearly
between substrates and products of phosphofructokinase 50% of the reduced NADP required for reductive steps
(fructose 6-phosphate increases and fructose 1, 6-disphos­ in reaction (3) may be generated in HMP shunt pathway
phate decreases: ATP and ADP are little changed). The (cytoplasmic). The remainder may be formed from reduced
above metabolic effect has been known to be due to an NAD generated in glycolysis or in mitochondrial oxidation
increase in the concentration ratio of acetyl-CoA/CoASH by reactions utilizing pyruvate dehydrogenase, malate
and accumulation of citrate with consequential inhibition dehydrogenase (NAD linked) and malic enzyme (NADP
of pyruvate dehydrogenase, phosphofructokinase and linked), a mitochondrial malate transporting system and
hexokinase. extramitochondrial isocitric acid dehydrogenase system.
Insulin accelerates glucose uptake, glycolysis and Glycerol moiety required for triglyceride synthesis is
glycogen synthesis and leads to a crossover at the glucose formed from glucose and it is presumed to be formed from
transport step (intercellular glucose concentration is glycerol phosphate generated during glycolysis.
increased from an extremely low value). The hormone As in muscle, activation and inhibition by metabolites
activates membrane transport and glycogen synthetase and isoenzyme interconversions have been described in
system. Kinetic studies have shown that it increases the adipose tissue.
Vmax of transport and Km is either unchanged or possibly The properties of hexokinase and phosphofructokinase
increased. As a result of increased glucose entry, intra­ in this tissue are not very different from that of muscle.
cellular glucose concentration increases which in turn Adipose tissue phosphofructokinase may be more sen­
promotes phosphorylation of glucose. The increased sitive to activation by C-AMP. Two interconvertible forms
rate of glycolysis may be due to an increase in fructose of pyruvate kinase have been described in adipose tissue
6-phosphate concentration activating phosphofructo­ unlike muscle. Form PK-A shows sigmoid curves for
kinase. There is possibility of a direct effect of insulin phosphoenolpyruvate (PEP) with a high Km (0.6 mm) and
on pyruvate dehydrogenase, since it may restore normal is activated by fructose 1, 6-diphosphate which converts it
rates of uptake and oxidation of pyruvate in diaphragm to PK-B with a low Km for PEP (0.07 mm). The conversion
muscle in alloxan diabetes and in cardiac muscle after of PK-B to PX-A is affected by ATP or citrate.12
starvation. The recent description of inactive (phosphory­ By in-vitro experiments insulin has been shown to
lated) and active (dephosphorylated) forms of pyruvate increase membrane transport of glucose in adipose tis-
dehydrogenase in bovine kidney mitochondria may be sue. Simultaneously, conversion of glucose to glyceride,
of interest in this connection.19 Activation of glycogen glycerol and fatty acids with accompanying formation of
synthesis by insulin may involve the conversion of CO2 through HMP shunt pathway and oxidation of glu-
glycogen synthetase-D to I form as a result of inhibition of cose by TCA cycle are also enhanced. Increased rate of
glycogen synthetase kinase. glucose oxidation through HMP shunt pathway have been
Interplay of different pathways of metabolism and the attributed to the generation of NADP from reduced NADP
principal sites or their control have been discussed. Three by fatty acid biosynthesis. A major problem concerns
key crossroads: (1) glucose 6-phosphate, (2) pyruvate, and the mechanism which leads to accelerated flow between
(3) acetyl-CoA have been mentioned. pyruvate and long-chain fatty acetyl-CoA.
 Intermediary Metabolism and Hormonal Regulation 27

CHAPTER
2

Fig. 2.8: Integration of metabolism: Interconversion of the major foodstuffs

 28 Physiology and Metabolism

glucose 6-phosphatase and the activity of this enzyme is

increased in diabetes mellitus and starvation. It is also
known that hepatic glucokinase activity is diminished
after treatment with growth hormone (GH) and cortisol
which elevates plasma concentrations of glucose, insulin
and FFA.15 Elevation of plasma FFA with ingested fat and
heparin injection also lower hepatic glucokinase activity.
SECTION

It has also been shown that palmityl-CoA is a reversible

2

and competitive inhibitor of rat liver glucokinase.

Gluconeogenesis25,26,28 also needs specific mention in
relation to liver. The process converts non-carbohydrate
substances to glucose essentially through the reversal
of glycolysis. When there is lack of glucose in body,
gluconeogenesis occurs effectively to maintain the supply
Fig. 2.9: Transport of ketone bodies from liver and pathways of utiliza- of glucose. The three major steps in glycolysis which are
tion and oxidation in extrahepatic tissues irreversible by the same group of enzymes are considered
to be rate limiting. They are (1) conversion of glucose to
Since insulin increases the concentration of gly­ cerol glucose 6-phosphate and the reverse, (2) conversion of
phosphate and may suppress lipolysis, it has been fructose 6-phosphate to fructose 1, 6-diphosphate and
suggested that consequent to triglyceride formation the the reverse and (3) conversion of pyruvic acid to PEP.
tissue concentration of fatty acetyl-CoA is lowered and The last one needs specific mention as through this route
thereby acetyl-CoA carboxylase is activated. An alternate major AAs enter gluconeogenesis (lactate, alanine, serine
possibility would be, activation of acetyl-CoA carboxylase and cysteine through pyruvate and succinate fumarate,
through citrate formation.20-23 malate, glutamate, proline, aspartate, threonine and
In severe insulin deficient (alloxan diabetic) rats, valine through oxaloacetate).
glucose uptake and fatty acid biosynthesis are markedly The key enzymes of gluconeogenetic pathway are
reduced and normal rates are not restored with insulin (1) pyruvate carboxylase, (2) phosphoenolpyruvate carbo-
in-vitro though insulin treatment in-vivo is effective. xykinase (PEPCK), (3) phosphoglycerokinase, (4) trio­
sephosphate-dehydrogenase, (5) hexosedi­ phosphatase,
Liver (6) glucose 6-phosphatase and those related with con­
version of AAs. Pyruvate carboxylase is an inducible
Although glycolysis in liver is similar to that in the muscle
enzyme and is stimulated by acetyl-CoA concentration
tissue, the membrane transport system for glucose needs
inside mitochondria. Hence excess accumulation of acetyl-
specific mention. It is supposed that entry or exit of
CoA from fatty acid oxidation will promote more conversion
glucose does not restrict the uptake or output of glucose
of pyruvic acid to oxaloacetic acid. This in turn will be
by the liver. Liver cells appear to be freely permeable to
reduced to malate and come out of mitochondria and
glucose (viz. the GLUT2 transporting).26 It is not insulin
will be reoxidized to oxaloacetate with the help of malic
dependent. The phosphorylation of glucose is done by
dehydrogenase system. Oxaloacetate will be converted to
two types of enzymes: (1) glucokinase and (2) hexokinase.
PEP with the help of PEPCK. PEP will enter the reversal of
Glucokinase is inducible with nutrition or with insulin.
EM pathway. The activities of the gluconeogenetic enzymes
It is reduced in diabetes mellitus and in starvation. The
(pyruvate carboxylase, PEPCK, fructose 1, 6-diphosphatase,
hexokinase of liver has a low Km for glucose (10–40 μm),
glucose 6-phosphatase, and transaminases) are increased
catalyzes the phosphorylation of number of hexoses
in diabetes mellitus in man.27
including fructose and is inhibited non-competitively
by glucose 6-phosphate. The activity of this enzyme is
not reduced by alloxan diabetes or starvation. On the
Brain1,8,30,33
contrary, the glucokinase of liver has a high Km for glucose Glucose is virtually the sole fuel for the human brain
(10–20 mm), it has little affinity for fructose and is weakly except during prolonged starvation. The brain lacks fuel
inhibited by glucose 6-phosphate. Liver also contains stores and hence requires a continuous supply of glucose,
 Intermediary Metabolism and Hormonal Regulation 29

which enters freely at all times. It consumes about 110 g Table 2.1: Daily fuel requirements
of glucose daily. The brain accounts for some 60% of the Organ Fuel Kcal/day
utilization of glucose by the whole body in the resting Liver Amino acids fat, glucose 280
state. During starvation, ketone bodies (acetoacetate Muscle Glucose, fat 880
and β-hydroxybutyrate) partly replace glucose as fuel for Brain Glucose 480
the brain. The shift in fuel usage from glucose to ketone
bodies is critical in minimizing protein breakdown during

CHAPTER
triglyceride in liver, muscle and adipose tissue respectively.
starvation. Body protein is not strictly speaking, a fuel reservoir.

2
Protein molecules serve specific roles in maintaining
Muscle1,8,30 organ structure and function and are less expendable than
The major fuels for muscle are glucose, fatty acids and glycogen or triglyceride. On the other hand, a portion of
ketone bodies. Muscle differs from brain in having large body protein (e.g. some contractile proteins of muscle) is
store of glycogen. In fact, three-fourths of all the glycogen degraded during starvation and other periods of stress and
in the body is stored in the muscle. Glycogen is readily provides AA substrate for gluconeogenesis.
converted into glucose 6-phosphate for use within muscle Brain has a continuous need for fuel but stores almost
cells. As it lacks glucose 6-phosphatase, like liver it cannot no energy as glycogen or fat. Instead, it utilizes glucose
export glucose. Glucose is rather retained as its preferred derived from the liver either directly from glycogen or
fuel for bursts of activity. In actively contracting muscle, indirectly via gluconeogenesis. The brain does not utilize
the rate of glycolysis far exceeds that of the citric acid FFA directly. During prolonged starvation, however, it is
cycle. Much of pyruvate formed under these conditions is able to use energy derived from FFA after their conversion
reduced to lactate, which flows to liver, where it is converted to ketone bodies. Other vital organs, such as liver, heart
to glucose, through Cori’s cycle. This is a shift of metabolic and skeletal muscle also have a continuous requirement
burden of muscle to the liver. In addition, a large amount for fuels, but unlike brain, these organs can utilize fatty
of alanine is formed in active muscle by transamination acids directly to meet their energy needs.
of pyruvate. Alanine, like lactate, can be converted into Typical daily fuel requirements of liver, muscle and
glucose by liver. The metabolic pattern of resting muscle is brain of a physically active, normally fed human is given in
quite different. In resting muscle, fatty acids are the major Table 2.1.
fuel. Ketone bodies can also serve as fuel for heart muscle Energy reservoirs in humans are built up and broken
where acetoacetate is preferred to glucose. down in response to hormonal changes. The principal
Differences in the metabolic patterns of the adipose hormonal messenger is insulin. In fed state, insulin levels
tissue, liver, brain and muscle have been considered. increase, promoting glycogen synthesis (glycogenesis) in
Finally interplay between these tissues get altered and liver and muscle, lipid formation in adipocytes (lipoge­
adjusted in various adverse situations/or in the best nesis) and AA uptake and protein synthesis in most cells.
interest of the animal. In the post­-absorptive state, during starvation and in
response to many stresses, decreased insulin levels con­
HORMONAL REGULATION OF tribute to glycogen breakdown (glycogenolysis), lipid
INTERMEDIARY METABOLISM break­down (lipolysis), hepatic ketogenesis, and decreased
Humans have a constant requirement of energy. But they synthesis and increased degradation of protein. While
eat only intermittently. To cope with this problem, we insulin favors the metabolic reactions taking place during
generally ingest food in excess of the immediate caloric fed state and acts as a restraint on catabolic events, multi­
needs of our vital organs and store the extra calories in ple hormones counter the effects of insulin. Glucagon
form of hepatic and muscle glycogen, adipose tissue stimulates glycogenolysis, gluconeogenesis and ketoge­
triglyceride and to a certain extent as muscle protein. nesis in liver and it can also stimulate lipolysis in adipose
In turn during starvation and in response to various tissue.
stresses, these fuel reservoirs break down to provide Catecholamines (epinephrine) have effects similar to
energy for organ metabolism and function. those of glucagon on the liver and are key regulators of
The two principal circulating fuels in humans, glucose lipolysis in adipose tissue and glycogenolysis in muscle
and FFAs are stored intracellularly as glycogen and and other tissues. In general, the counter insulin hormones
 30 Physiology and Metabolism

Flow chart. 2.1: Metabolism effects of insulin

SECTION
2

(Solid line: Stimulation; Interrupted line: Inhibition).

Table 2.2: Cell type in islet of Langerhans Table 2.3: Metabolic effects of insulin and glucagon
Cell type Relative abundance Hormone produced Tissue Insulin Glucagon
A (or alpha) 25% Glucagon Liver ↑ Glycogen synthesis ↑ Glycogenolysis
B (or beta) 70% Insulin
↑ Glucose oxidation
C (or delta) < 5% Somatostatin
↑ Tg synthesis
F Trace Pancreatic polypeptide
↓ Glycogenolysis
or counter-regulatory hormones liberate energy from ↓ Gluconeogenesis ↑ Gluconeogenesis
fuel reservoirs by actions opposite to those of insulin ↓ Glucose output ↑ Glucose output
(Flow chart 2.1). ↓ Ketogenesis ↑ Ketogenesis
Hormonal regulation of these metabolic processes Muscle ↑ Glucose uptake
does not affect all tissues to the same extent. By and large, ↑ Glycogen synthesis
homeostasis is maintained by regulation of metabolic ↑ Glucose oxidation
activity in the liver, muscle and adipose tissues mainly ↑ Amino acid uptake
by the relative levels of insulin and glucagon. The action ↑ Protein synthesis
of these hormones on the major target tissues and the Adipocyte Lipolysis + (?)
↑ Glucose uptake
resultant effect on levels of metabolic fuels in plasma are
↑ FFA uptake
enumerated in Flow chart 2.1.
↑ Lipogenesis
The mutual antagonistic hormones, insulin and
↓ Lipolysis
glucagon are derived from beta (β) and alpha (α) cells
↓ FFA release
located in close proximity of each other in the pancreatic
Plasma ↓ Glucose, FFA, AA ↑ Glucose, ketones
islets of Langerhans (Table 2.2 and Fig. 2.10). The secre­
tory activities of these cells are regulated by the levels (AA: Amino acid; FFA: Free fatty acids; Tg: Triglyceride)
of metabolic fuels (glucose and AAs) in the plasma, the gland. Insulin secretion is an energy requiring process
impulses from autonomic nerves, other hormones such that involves the microtubule-microfilament system in
as epinephrine, GIF and somatostatin as well as by the β-cells of the islets. A number of mediators have been
influence of one on the other (paracrine effect). The release implicated in insulin release.
of insulin from β-cells following a meal is facilitated by Activity of the β-cells (insulin secretion) is principally
a number of gastrointestinal peptide hormones, GLP-1, regulated by the levels of glucose in the interstitial fluid.
glucose-dependent insulinotropic polypeptide (GIP) and There may be an 8–10-fold rise in the secretion of insulin
chole­cystokinin (CCK). The metabolic effects of insulin in response to an increase in plasma glucose from
and glucagon all given in Table 2.3. 70 mg/dL to 150 mg/dL. There is simultaneous decrease
in the secretion of glucagon from a-cell. Insulin release
Insulin in response to sharp rise of glucose in extracellular fluid
The human pancreas secretes 40–50 units of insulin daily occurs in two phases. The first rapid phase starts within
which represents about 15–20% of the hormone stored in seconds and lasts for around 10–15 minutes with peak
 Intermediary Metabolism and Hormonal Regulation 31

CHAPTER
2
Fig. 2.11: Insulin release in response to glucose in isolated β-cell

effect, which is called the incretin effect and is estimated to

be responsible for 50–70% of insulin response to glucose,
is caused mainly by two intestinal insulin stimulating
hormones, glucagon-like peptide-1 (GLP-1) and GIP.
Fig. 2.10: Schematic representation of alpha, beta and delta cells in Their contributions have been confirmed in mimicry
islet of Langerhans
experiments, in experiments with antagonists of their
actions and in experiments where the genes encoding
their receptors have been deleted. In patients with type
2 diabetes, the incretin effect is either greatly impaired
or absent and it is assumed that this could contribute
to the inability of these patients to adjust their insulin
secretion to their needs. In studies of the mechanism of the
impaired incretin effect in type 2 diabetic patients, it has
been found that the secretion of GIP is generally normal,
whereas the secretion of GLP-1 is reduced, presumably
as a consequence of the diabetic state. It might be of even
greater importance that the effect of GLP-1 is preserved
whereas the effect of GIP is severely impaired. The impaired
GIP effect seems to have a genetic background, but could
be aggravated by diabetic state. The preserved effect of
GLP-1 has inspired attempts to treat type 2 diabetes with
Fig. 2.12: Insulin release in response to IV glucose GLP-1 or its analogs. Intravenous GLP-1 administration
has been shown to be able to near-normalize both fasting
at 2–3 minutes (corresponds to stored insulin in β-cells). and postprandial glycemic concentrations in the patients,
This is followed by a phase of slow rise in insulin secretion, perhaps because the treatment compensates for both
which remains high until glucose falls to basal value impaired secretion of GLP-1 and the impaired action of
(synthesis of insulin) (Figs 2.11 and 2.12). There is a greater GLP.
β-cell response observed following oral as opposed to However, it should be noted that GLP-1 not only
intravenous glucose administration. This is known as potentiates glucose induced insulin secretion but also has
“incretin” effect. numerous other effects, all of which seem to be desirable
in the context of treating type 2 diabetic patients.
Incretins35 The actions of GLP-1 are enlisted below:
When glucose is taken orally, insulin secretion is larger • Insulin secretion
than it is when glucose is infused intravenously. This –– Potentiates glucose induced secretion
 32 Physiology and Metabolism

Insulin, a protein hormone, consists of two polypeptide

chains A and B having 21 and 30 AAs, respectively. There
exist links between two chains through disulfide bridges
at positions A7 to B7 and A20 to B19. A third disulfide
bridge occurs in A chain which connects residues 6 and 11.
The molecular mass of human insulin is 5.8 kDa.
The mechanism of action of insulin is mediated
SECTION

through insulin receptors located in most of the mam­

2

malian cells (muscle, adipose tissue) in concentration

up to 20,000 per cell. Insulin binds to the membrane
receptor and this interaction generates one or more
transmembrane signals. These signals modulate wide
variety of intra­cellular events, namely glucose transport,
protein phos­ phorylation-dephosphorylation, activation
and inhibition of enzymes and protein synthesis in
Fig. 2.13: Relationship between insulin receptor and insulin action cytoplasm and influences gene expression inside nucleus
by regulating mRNA synthesis (Fig. 2.13).
–– Enhances all steps of insulin biosynthesis Insulin deficiency or resistance to the action of insulin
–– Upregulates insulin gene expression results in diabetes mellitus. Among diabetic persons
–– Upregulates expression of genes essential for β-cell about 90% are type 2 DM non-insulin dependent diabetes
function (glucokinase, GLUT2) mellitus (NIDDM). Such patients are usually obese, have
–– Mitotic for β-cells elevated plasma insulin levels and have downregulated
–– Promotes differentiation of duct progenitor cells in insulin receptors. Most of the other 10% are insulin-
the pancreatic duct epithelium to beta cells and has dependent type 1 DM.
now been shown also to inhibit apoptosis induced A few individuals produce antibodies directed against
by cytokines or FFAs. their insulin receptors. The antibodies prevent insulin
• Inhibits glucagon secretion from binding to the receptor, so that such persons develop
• Inhibits gastrointestinal secretion and motility a syndrome of severe insulin resistance.
• Inhibits appetite and food intake. Action of insulin on metabolism can be summarized
This effect would support attempts at weight reduction as (1) It signals the fed state. (2) It stimulates storage
amongst patients with type 2 diabetes. of fuels and synthesis of proteins in a variety of ways.
The enhanced response to oral glucose has been The hormone promotes the dephosphorylation of
interpreted as an indication that absorption of glucose key interconvertible enzymes. One consequence is to
by way of the gastrointestinal tract stimulates release of stimulate glycogen synthesis in liver and muscle and to
hormones and activates other mechanisms that ultimately suppress gluconeogenesis by liver. Insulin also accelerates
enhance the sensitivity of β-cells to glucose. It has been glycolysis in liver, which in turn, increases synthesis of
demonstrated the amount of insulin secreted in response fatty acids. The entry of glucose into muscle and adipose
to IV glucose load is 26% less than that secreted in response cells is promoted by insulin. The abundance of fatty acids
to the oral glucose load. and glucose in adipose tissue results in synthesis and
Insulin secretion also rises in response to an exclusive storage of triglycerols. On the other hand, FFAs are the
protein meal as well as to IV administration of AAs such second potential mediators of insulin resistance. It now
as arginine or lysine. It is now regarded that AAs primarily seems clear that obesity is associated with increased
increase secretion of glucagon which in turn, stimulates levels of FFA, which probably are due in large measure to
insulin secretion through paracrine effect. In such a situa­ the presence of more lipolytically active intra-abdominal
tion while insulin augments AA uptake of tissues (muscle adipocytes. There are several potential consequences of
in particular) for protein synthesis, glucose lowering is increased levels of FFA, including inhibition of insulin
effectively countered by the raised levels of glucagon. stimulated glucose utilization in muscle via the “Randle
 Intermediary Metabolism and Hormonal Regulation 33

effect” and inhibition of hepatic clearance of insulin. The The elevated cyclic AMP level stimulates the conver­
improvement in the utilization of glucose that may be sion of AAs to glucose by inducing a number of enzymes
seen when FFA levels are reduced through pharmacologic involved in the gluconeogenic pathway. Principal among
means is consistent with this hypothesis, thus increasing these is PEPCK. This is opposite to the effect of insulin,
the importance of determining the basis for intra- which decreases PEPCK gene transcription and hence its
abdominal obesity and its consequences. level.
Insulin promotes uptake of neutral AAs into muscle Glucagon, on the other hand, blocks glycolysis by

CHAPTER
which helps in building up muscle protein. Indeed, lowering the level of F-2,6-BP.

2
insulin has general stimulating effect on protein synthesis. The net action of glucagon in the liver is increased
In addition, it inhibits the intracellular degradation of glucose production; since much of this glucose exists
protein. in the liver, plasma glucose concentration increases
in response to glucagon. Glucagon is a potent lipolytic
Glucagon agent. It increases adipose cell cyclic AMP levels, and this
Glucagon is an insulin antagonist. It is synthesized in activates the hormone-sensitive lipase. The increased
α cells of pancreatic islets. It is a single-chain polypeptide fatty acids can be metabolized for energy or converted to
(molecular mass 3.485 kDa) consisting of 29 AAs. Glucagon ketone bodies, acetoacetate and β-hydroxybutyrate. This
is synthesized as a much larger (about 9 kDa) proglucagon is an important aspect of metabolism in diabetes, since
precursor. Only 30–40% of immunoreactive “glucagon” glucagon levels are always increased in insulin deficiency.
in plasma is pancreatic glucagon; the rest consists of Glucagon also inhibits fatty acid synthesis by dimini­
biologically inactive large molecule. The plasma half-life shing the production of pyruvate and lowering activity of
of glucagon is short (about 5 minutes) and it is inactivated acetyl-CoA carboxylase.
in liver. Since liver is the first stop of glucagon after it is
secreted and since liver rapidly inactivates the hormone, Epinephrine and Norepinephrine
the glucagon level in portal vein is much higher than in the These catecholamine hormones are secreted by adrenal
peripheral circulation.
and sympathetic nerve endings in response to a low blood
Secretion of glucagon is inhibited by glucose. This
glucose level. Like glucagon, they stimulate the metabolism
action emphasizes the opposing metabolic roles of
of glycogen and triacylglycerols by triggering the cyclic
glucagon and insulin. It is also known that inhibition of
AMP mediated cascade. They differ from glucagon in that
glucagon secretion that accompanies insulinopenia is
their glycogenolytic effect is greater in muscle than in the
mediated through the action of somatostatin. As such,
liver.
somatostatin significantly blunts ketosis associated with
Another action of catecholamines is to inhibit the
acute insulin deficiency.
uptake of glucose by muscle. Instead fatty acids released
In general, actions of glucagon oppose those of insulin.
from adipose tissue are used as fuel. Epinephrine also
Whereas insulin promotes energy storage by stimulating
glycogenesis, lipogenesis and protein synthesis, glucagon stimulates the secretion of glucagons and inhibits
causes rapid mobilization of potential energy sources into the secretion of insulin. Thus, catecholamines increase
glucose by stimulating glycogenolysis and into fatty acids amount of glucose released into the blood by liver and
by stimulating lypolysis. Glucagon is also most potent decrease utilization of glucose by muscle.
gluconeogenic hormone, and it is ketogenic. Norepinephrine synthesis increases after acute stress.
The liver is the primary target of glucagon action. Prolonged stress accompanied by sympathetic nerve acti­
Glucagon binds to specific receptors in the hepatic cell vity results in an induction of tyrosine hydroxylase required
plasma membrane, and this activates adenylcyclase in the process of converting tyrosine to epinephrine.
through a G protein linked mechanism. The cyclic AMP A similar induction of dopamine β-hydroxylase (DBH)
generated glucagon activates phosphorylase which has been reported. Enzyme phenyl ethanolamine-N-
enhances the rate of glycogen degradation while inhibiting methyl transferase (PNMT) also plays a critical role. PNMT
glycogen synthesis and thus glycogen formation. There is induced by glucocorticoids, which reach adrenal medulla
is hormone and tissue specificity in this effect, since from the adrenal cortex through a specialized portal system,
glucagon has no effect on glycogenolysis in muscle, thus ensuring a local concentration of cortisol. PNMT cata­
whereas epinephrine is active in both muscle and liver. lyzes the conversion of norepinephrine to epinephrine.
 34 Physiology and Metabolism

The induction of these enzymes of catecholamine

biosynthesis pathway is a means of adapting to physiologic
stress and depends on neural (tyrosine hydroxylase and
DBH induction) and endocrine (PNMT induction) factors.

Somatostatin
SECTION

Somatostatin was so named because it was first isolated

from the hypothalamus as the factor that inhibited GH
2

secretion. It is a cyclic peptide synthesized as a large

somatostatin prohormone (about 11.5 kDa) in delta
cells of pancreatic islets. The rate of transcription of the
prosomatostatin gene is markedly enhanced by cyclic AMP.
The hormone is first processed into a 28 AA peptide and Fig. 2.14: Cortisol
finally into a molecule that has molecular weight of 1,640
and contains 14 AAs. All forms have biological activity.
In addition to its presence in the hypothalamus The primary action of these hormones is to promote
and pancreatic islets, somatostatin is found in many retention of Na+ and excretion of K+ and H+, particularly in
gastrointestinal tissues, where it is thought to regulate a kidney.
variety of functions and in multiple sites in central nervous Cortisol, a glucocorticoid, circulates in plasma in
system (CNS), where it may be a neurotransmitter. protein bound or free forms. The main plasma binding
Somatostatin inhibits the release of the islet cell protein is an alpha globulin called transcortin or cortico­
hormones through paracrine action. In pharmacologic steroid-binding globulin (CBG). Much smaller amounts
amounts, somatostatin significantly blunts the ketosis are also bound to albumin. Glucocorticoid hormones
associated with acute insulin deficiency. This is apparently affect basal metabolism, host defense mechanisms, blood
due to its ability to inhibit the glucagon release that pressure and response to stress. The following effects are
accompanies insulinopenia. It also decreases the delivery enlisted as under:
of nutrients from gastrointestinal tract into the circulation • Effects on intermediary metabolism
because it (i) prolongs gastric emptying, (ii) decreases –– Increase glucose production:
gastrin secretion and therefore, gastric acid production, ‚‚ By increasing the delivery of AAs (the glu­
(iii) decreases pancreatic exocrine (digestive enzyme) coneogenic substrate) from peripheral tissues
secretion, and (iv) slows glucose absorption. Little is ‚‚ By increasing the rate of gluconeogenesis by
known about the biochemical or molecular action of this increasing the amount (and activity) of several
hormone. key enzymes, and
‚‚ By permitting other metabolic reactions to ope­
Glucocorticoids36 rate at maximal rates.
–– Increase of hepatic glycogen deposition by pro­
Adrenal cortex synthesizes dozens of different steroid moting the activation of glycogen synthetase
molecules, but few of these have biologic activity. These can –– Promote lipolysis (in extremities), but can cause
be sorted into three classes of hormones, glucocorticoids, lipogenesis in other sites (face and trunk) especially
mineralocorticoids and androgens. at higher than physiologic levels.
The glucocorticoids are 21 carbon steroid with many –– Promote protein and RNA metabolism. This is an
actions, the most important of which is to promote anabolic effect at physiologic levels but can be
gluconeogenesis. Cortisol (Fig. 2.14) is the predominant catabolic in conditions and at higher than physio­
glucocorticoid in humans, and it is made in the zona logic levels.
fasciculata of adrenal cortex. Corticosterone, made in • Effects on host mechanisms
the zona fasciculata and glomerulosa, is less abundant –– Suppress the immune response. The hormones
in humans, but it is the dominant glucocorticoid in the cause a species and cell type-specific lysis of lym­
rodents. Mineralocorticoids are also 21-carbon steroid. phocytes
 Intermediary Metabolism and Hormonal Regulation 35

–– Suppress the inflammatory response:

‚‚ By decreasing the number of circulating leu­
kocytes and the migration of tissue leukocytes
‚‚ By inhibiting fibroblast proliferation, and
‚‚ By inducing lipocortins, which by inhibiting
phospholipase A, blunt the production of the
potent anti-inflammatory molecules, the pro­

CHAPTER
staglandins and leukotrienes.

2
• Other effects
–– Necessary for maintenance of normal blood pres­
sure and cardiac output
–– Required for maintenance of normal water and
electrolyte balance, perhaps by restraining ADH
release (H2O) and by increasing angiotensinogen Fig. 2.15: Human growth hormone
and Na+. These effects contribute to the effect on
blood pressure.
–– In consent with the hormones of the adrenal Carbohydrate Metabolism
medulla, allows the organism to respond to stress. Growth hormone generally antagonizes the effect of
• Glucocorticoid hormones regulate gene expression. insulin (Flow chart 2.1). Hyperglycemia after GH adminis­
Regulation of transcription requires that steroid recep­ tration is the combined result of decreased peripheral
tor complex binds to specific regions of DNA in the utilization of glucose and increased hepatic production
vicinity of the transcription initiation site and that such via gluconeogenesis. In liver, GH increases liver glycogen,
regions confer specificity to the response. probably from activation of gluconeogenesis from AAs.
Impairment of glycolysis may occur at several steps and
Growth Hormone37 the mobilization of fatty acids from triacylglycerol stores
Growth hormone is synthesized in somatotropes, a sub- may also contribute to the inhibition of glycolysis in
class of pituitary acidophilic cells; which are the most muscle. Prolonged administration of GH may result in
abundant cells in the gland. The concentration of GH in diabetes mellitus.
the pituitary is 5–15 mg/g. It is a single polypeptide with
molecular mass of about 22 kDa in all mammalian species. Lipid Metabolism
The general structure of the 191-AA human GH molecule Growth hormone promotes the release of FFAs and
is shown in Figure 2.15. Only human GH or that of higher glycerol from adipose tissue, increases circulating FFAs,
primates is active in humans. Human GH made by and causes increased oxidation of FFAs in the liver. Under
recombinant DNA techniques is available for therapeutic conditions of insulin deficiency (e.g. diabetes mellitus)
use. increased ketogenesis may occur.

Physiological and Biochemical Actions Mineral Metabolism

Protein synthesis: Growth hormone increases the transport Growth hormone or, more likely, insulin-like growth
of AAs into muscle cells and also increases protein factor 1 (IGF1) (somatomedin-c) promotes a positive
synthesis by a mechanism separate from the transport calcium, magnesium and phosphate balance and causes
+ + −
effect. Animals treated with GH show positive nitrogen the retention of Na , K and Cl . The first effect probably
balance, reflecting a generalized increase in protein relates to the action of GH in bone, where it promotes
synthesis and a decrease in plasma and urinary levels of growth of long bones at the epiphysial plates in growing
AAs and urea. This is accompanied by increased synthesis children and appositional or acral growth in adult.
of RNA and DNA in some tissues. In children, GH also increases formation of cartilage.
 36 Physiology and Metabolism

cabohydrate is stored as glycogen in liver and 300–500 g

is stored in muscle in an overnight-fasted human being.
The major form of lipid storage in human is triglyceride
and the major site for triglyceride storage is adipose
tissue. Smaller amounts can be stored in muscle, liver
and other tissues. Triglycerides are also present in the
circulation as constituents of lipoproteins. However, the
SECTION

major circulating fuels are FFA. After carbohyrate meal

2

high concentrations of insulin favor use of both glucose

and lipoprotein triglycerides for triglyceride synthesis in
adipose tissue.
As such insulin is the key hormone which is secreted
in fed state. The hormone promotes dephosphorylation
of key interconvertible enzymes. One consequence is
to stimulate glycogen synthesis in liver and muscle and
to suppress gluconeogenesis by the liver. Insulin also
accelerates glycolysis in liver which favors increase in
synthesis of fatty acids. Entry of glucose into muscle and
adipose cells is promoted by insulin. The abundance of
fatty acids and glucose in adipose tissue results in synthesis
and storage of triglycerides. Insulin promotes uptake of
neutral AAs by muscle which helps in building up muscle
protein. Indeed, insulin has a general stimulating effect on
protein synthesis. In addition, it inhibits the intracellular
degradation of proteins.

Fig. 2.16: Fuel metabolism after overnight fast (post-absorptive)

FASTED (POST-ABSORPTIVE)
STATE38 (FIG. 2.16)
Within 3–4 hours following a meal, plasma glucose grad­
Pancreatic Polypeptide ually falls to between 70 mg/dL and 100 mg/dL which
Pancreatic polypeptide (PP) a 36-AA peptide (about 4-2 has to be maintained at that level for any length of time
kDa), is a product of pancreatic F cells. Its secretion in until the next meal. This is the most vital aspect of
humans is increased by protein meal, fasting, exercise glucoregulatory mechanism as the CNS needs a supply
and acute hypoglycemia and is decreased by somatostatin of around 6 g of glucose per hour. Lowering of plasma
and intravenous glucose. The function of PP is yet to be glucose to below 60 mg/dL may be associated with serious
elucidated. disorder of the CNS functions. There has to be a reduction
of non-essential utilization of glucose such as by muscle,
FED STATE38 supply of FFA from the adipose tissue as an alternate
source of energy and a continuous release of glucose
During the first few hours after carbohydrate meal, from the liver to take care of supply of energy to different
glucose absorbed from gastrointestinal tract provides organs. These are achieved by lowering of insulin and
for the metabolic needs of the brain and other organs. rise in glucagon secretion. Yet, there is a great need for a
The absorbed glucose in excess of these needs is used basal level of plasma insulin (3–10 mg/mL) which keeps a
to rebuild fuel reservoirs in liver, muscle and fat depot. check on excessive lipolysis and consequent ketogenesis.
Under these circumstances, plasma insulin levels are high, The relative levels of secretion of insulin and gluca­
plasma glucagons levels are low, and glycogen synthesis gon following meals in diabetes mellitus is presented in
is stimulated in liver and muscle. Approximately 75 g of Table 2.4.
 Intermediary Metabolism and Hormonal Regulation 37

Table 2.4: Level of secretion of insulin and glucagon after meal and becomes the major source, as hepatic glycogen
Status Insulin Glucagon stores get depleted. Gluconeogenesis is responsible for
mU/mL pg/mL approximately 35–60% of the hepatic glucose output after
Fasting 10 150 an overnight fast (12–15 hours post-absorptive) and for
Carbohydrate meal 80 50 more than 97% of the output by 60 hours of starvation.
Protein meal 40 180 During early phases of starvation, the two principal
Mixed meal 100 50 gluconeogenic precursors are lactate and alanine.

CHAPTER
Diabetes (Fasting) <8 350 The second major group of gluconeogenic substrates
is that of AAs. Skeletal muscle is the principal reservoir

2
of AAs (alanine and glutamine) in humans. During early
STARVATION
starvation, however, the gut and liver also appear to be
With the decrease in plasma insulin levels and the increase important source of AAs entering circulation. A major
in plasma glucagon levels that accompany an overnight stimulus to protein catabolism during starvation is the
fast, fuel homeostasis shifts from energy storage to energy decrease in plasma insulin concentration. Glucagon
production. At this stage, glucose no longer enters the stimulates protein degradation in liver and glucocorticoids
circulation from the gastrointestinal tract but is derived inhibit protein synthesis in muscle and other tissues.
principally from the breakdown of liver glycogen and, via However, role of counter insulin hormones is thought to
hepatic gluconeogenesis, from lactate, AAs and glycerol. be limited as their concentrations are not dramatically
In addition, circulating FFA, derived from the hydrolysis altered during starvation. The other gluconeogenic
of adipocyte triglycerides, becomes a major source of substrate is glycerol, which is derived principally from
fuel. As such by using FFA, muscle and liver decrease hydrolysis of adipose tissue triglyceride.
their oxidation of glucose as a fuel, thereby conserving it
for the brain. In the earliest phase of starvation, i.e. the PROLONGED STARVATION (FIG. 2.17)
post-absorptive state, hepatic glycogen is a major source
With prolongation of starvation, several events occur that
of the glucose entering the circulation and remains so for
limit the need for gluconeogenesis and thereby conserve
12–24 hours. Glucagon seems to be necessary for hepatic
body protein. The first of these is an increase in the
glycogenolysis during this period. By extrapolation, 70–80 g
of glycogen in liver can provide glucose to brain and reliance of muscle and other peripheral tissues on lipid
peripheral tissues for 12–16 hours. Beyond this time derived fuels. They are initially FFA and later both FFA and
(i) muscle and other tissues begin to oxidize lipid-derived ketone bodies, acetoacetate and β-hydroxy butyrate. The
fuels in place of glucose and (ii) hepatic gluconeogenesis second is a change in the fuels used by the brain. During
replaces glycogenolysis as the principal source of glucose early starvation, the CNS continues to use glucose as its
entering the circulation. exclusive fuel. However, as starvation is prolonged, plasma
Two factors stimulate the breakdown of adipocyte levels of the ketone bodies increase to values even greater
triglyceride during starvation. First, the concentration of than that of glucose. Under these circumstances, the brain
circulating insulin diminishes and, as consequence, trigly­ increases its use of these lipid-derived fuels. In contrast to
ceride synthesis is decreased and lipolysis is enhanced. long-chain FFA, the ketone bodies are water soluble and
Second, norepinephrine is released from sympathetic cross the blood-brain barrier by specific carrier proteins.
nerve endings and directly stimulates lipolysis by raising These physiologic adaptations enhance the use of ketone
levels of cyclic AMP in adipocytes. The principal users of bodies by the brain in place of glucose and diminish the
FFA during early phases of starvation are skeletal muscle need to degrade proteins for gluconeogenesis. It is because
and liver. of these adaptations that humans of normal weight are
able to survive fasts up to 60–70 days.
Gluconeogenesis
DIABETES MELLITUS1,11,30,39
Since the brain is unable to use FFA as fuel, it must con­
tinue to use glucose during the early phases of starvation. Metabolic derangements in diabetes mellitus result
Gluconeogenesis is an important source of the glucose from relative insulin deficiency and glucagon excess.
entering the circulation even after an overnight fast Because of insulin deficiency, the entry of glucose into
 38 Physiology and Metabolism

Transport and uptake of AAs in the peripheral tissues

are also depressed in diabetes mellitus, causing an
elevated circulating level of AAs, particularly alanine
which enhances gluconeogenesis in liver. The AA break­
down during gluconeogenesis results in increased prod­
uction of urea.
Another major aberration of carbohydrate metabolism
SECTION

in diabetes mellitus is the almost complete cessation of

2

the conversion of glucose into fatty acids via acetyl-CoA.

Normally one-third of ingested glucose is converted to
fatty acids and then to triglycerides in liver and adipose
tissues. In diabetes, stored lipids are hydrolyzed by
increased lipolysis through increased action of hormone
sensitive lipase. The circulating level of FFA is increased.
Released FFA in turn inhibits fatty acid synthesis in
liver by inhibiting acetyl-CoA carboxylase, the first step in
fatty acid synthesis to form malonyl-CoA.
Resulting drop in the level of malonyl-CoA acti­
vates carnitine acyltransferase-I. Consequently, fatty
acetyl-CoA molecules are efficiently transported into the
mitochondrial matrix for oxidation to acetoacetate. Raised
level of acetyl-CoA allosterically stimulates pyruvate
carboxylase which enhances the process of gluconeo­
genesis. Acetyl-CoA that can no longer enter either the
citric acid cycle because there is insufficient oxaloacetate
for condensation step, or be used for fatty acid synthesis
is shunted to synthesis of ketone bodies or cholesterol or
Fig. 2.17: Fuel metabolism during prolonged starvation both. Ketone bodies are constituted of acetoacetic acid,
beta hydroxybutyric acid and acetone. Acetoacetic acid
cells (adipocyte and muscle) is unpaired. The excessive is first to be formed in the HMG-CoA pathway, subseq­
level of glucagon relative to insulin leads to a decrease uently acetoacetate is converted to beta hydroxybutyrate
in amount of F-2,6-BP in the liver. Hence, glycolysis is and acetone.
inhibited and gluconeogenesis stimulated (Fig. 2.18). Quantitatively, acetoacetate is the predominant ketone
Thus, blood glucose level is raised beyond physiological in blood and urine. Ketone bodies are used in skeletal
levels. Fasting blood glucose level rises up to 120 mg/dL muscle and heart for production of energy. Under normal
or above. In severe diabetes, blood glucose may remain conditions, formation of ketone bodies balances their
raised above renal threshold throughout the day. It may utilization, keeping blood level at 1 mg/dL. There is a rise in
even reach such high values (500–1,000 mg/dL) as to raise the level when production overshoots utilization. Ketone
the osmolarity of blood to dangerous levels. bodies appear in urine when serum level rises above
Glycosuria occurs in diabetes whenever blood glucose 5 mg/dL. Level of ketone bodies may rise as high as 60 times
is raised beyond renal threshold which ranges between than normal in untreated diabetes mellitus. Progressive
140 mg/dL and 200 mg/dL in normal individuals. Since loss of ketone bodies in urine depletes the alkali reserve
the maximal rates of reabsorption of glucose by renal and pH of blood may go down up to 7.0 in severe cases.
tubule (Tmax—the tubular maximum for glucose) is a Thus, gluconeogensis from the AAs and inhibition
constant, renal threshold is often expressed as Tmax which is of fatty acid synthesis from glucose indicate that the
350 mg/min. Water accompanies the excreted glucose metabolism in diabetic patient is altered to maintain a
hence there is polyuria. This leads to thirst. concentration of blood glucose. Rise in blood glucose up
 Intermediary Metabolism and Hormonal Regulation 39

CHAPTER
2
Fig. 2.18: Consequences of severe insulin deficiency

to 500 mg/dL helps in uptake of glucose by the tissues Thickening and changes in composition of basement
in conditions of severe diabetes. A striking feature of membrane of glomerular capillaries possibly lead
diabetes is the shift in fuel usage from carbohydrate to to increased permeability which may account for
fats. Glucose, more abundant than ever is spurned. proteinuria in diabetic nephropathy.
Further, diabetic state can be described literally as “starva­ There is an increase of acid mucopolysaccharide in
tion in the midst of plenty”. Constant loss of glucose in the intima of large vessels. In the diabetic aorta, there is
urine derived mostly from breakdown products acco­ increased formation of mucopolysaccharide-beta-lipo­
unts for constant hunger and loss of body weight in protein complexes which may be important in the patho­
severe diabetes. Depletion of fat from the fat depot due logy of atheroma. Increased concentrations of sorbitol
to increased breakdown and less synthesis also contri­ have been found in lens, nerve and cerebro­spinal fluid
butes to loss of body weight. (CSF) of diabetic patients, which has been implicated in
• Plasma glycoprotein level (L2-globulin) may be raised the production of diabetic cataract and neuropathy. Sor­
in diabetes. This change is more marked in diabetic bitol pathway is an alternate metabolic route for glucose
patients with degenerative vasculopathy. Analysis of in tissues endowed with the enzyme aldose reductase.
glomerular basement membrane in early diabetes Raised values for L-xylulose in blood have been detected
reveals absolute increase in glycoprotein component. in diabetes. This occurs through altered glucuronic acid
In particular, there is an increase in hydroxylysine pathway.
residues and disaccharide units. Observations reveal­ In stable diabetes, there is an increase in the concen­
ing rise in the activity of the enzyme glycosyl trans­ tration of glycosylated hemoglobin (HbA1c). Normally,
ferase lends support to alteration and excess formation HbA1c represents up to 4% of the total HbA in man. In
of basement membrane glycoprotein in diabetes. hyperglycemic states, the concentration of HbA increases
 40 Physiology and Metabolism

two to three-folds. Since glycosylation is non-enzymatic It is apparent that the regulation of metabolic flux, as
and irreversible, the rise in HbA1c persists for the life of essential as it is for life, is understood only incompletely.
the red cells. Estimation of HbA1c is helpful in assessing A study of the regulatory enzymes is complex, given the
metabolic control during the preceding 8–12 week period. maze of interconnecting pathways, multiple enzyme
Excess glycogen deposition occurs in renal tubules isoforms and their substrates. As if this is not complex
(Armanni-Ebstein lesion), liver and leukocytes in cases enough, further control of enzymes occurs at many other
with uncontrolled diabetes. Gluconeogenesis appears to levels. An interrelation occurs between fatty acids and
SECTION

be the source of the excess of glycogen. glucose homeostasis (elevated FFAs stimulate gluconeo­
2

Several types of lipoprotein abnormalities are known

genesis and inhibit glycolysis),40,41 perhaps through altered
to occur in diabetes. Among them Fredrickson’s types II,
ratio of ATP/AMP ratio.42 Therefore, the control of glucose
IV and V are more common. Depending on heredity and
flux is part of a global process, in which regulation takes
pattern of nutrition, diabetes may have greater degree
place across many enzymatic steps. Since the mechanisms
of either hypercholesterolemia (type IIb) or hypertri­
controlling glucose homeostasis in the mouse and in
glyceridemia. Eruptive xanthomas, lipemia and hepato­
megaly occur in poorly managed patients with this form humans are similar, further unravelling of this metabolic
of hyperlipidemia. In general, the ratio between alpha maze is possible by using genetically altered mice, and by
and beta lipoproteins is altered in favor of latter. All these the use of conditional gene targeting strategies.42
factors increase risk for coronary, cerebral and peripheral
atherosclerosis. FURTHER READING
High-density lipoprotein (HDL)-cholesterol level is
1. Bender DA, Mayes PA. Chapter 20. Gluconeogenesis and
somewhat higher in diabetic subjects than in controls the Control of Blood Glucose [Internet]. 29th Edition.
and the ratio of HDL-cholesterol and LDL-cholesterol is New York: McGraw-Hill, 2012 [cited 2014 Mar 21]. Available
significantly raised in diabetic patients. from http://accessmedicine.mhmedical.com/content.aspx
Insulin is required for synthesis of myelin. In dia­ ?bookid=389&Sectionid=40142496.
betes, derangement of Schwann cell function due to 2. Bender DA, Mayes PA. Chapter 18. Glycolysis and the
accumulation of fructose (sorbitol pathway) and dimi­ oxidation of Pyruvate [Internet]. 29th Edition. New York:
McGraw-Hill, 2012. Available from http://accessmedi-
nished synthesis of myelin leads to demyelination and
cine.mhmedical.com/content.aspx?bookid=389&Section
neuropathy. The metabolism of myoinositol, an important id=40142494.
component of plasma membrane phos­pholipid is distur­ 3. Botham KM, Mayes PA. Chapter 23. Biosynthesis of Fatty
bed in diabetes. Acids & Eicosanoids [Internet]. 29th Edition. New York:
In fed state, insulin is the key hormone which is McGraw-Hill, 2012. Available from http://accessmedicine.
secreted and promotes glycogen synthesis in liver and mhmedical.com/content.aspx?bookid=389&Section
muscle. It suppresses gluconeogenesis in liver. Insulin id=40142499.
also accelerates glycolysis in liver which in turn increases 4. Bender DA, Mayes PA. Chapter 19. Metabolism of Glyco-
gen [Internet]. 29th Edition. New York: McGraw-Hill, 2012.
synthesis of fatty acids and triglycerides. It helps protein
Available from http://accessmedicine.mhmedical.com/
synthesis also. content.aspx?bookid=389&Sectionid=40142495.
In overnight fasted state, metabolic adjustment occurs
at the organ levels. Muscle adopts to FA as alternate source
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2
8. Lehninger AL. Organ interrelationships in the metabolism glycolysis. Ann Rev Biochem. 1983;52:617-53.
of mammals. In: Lehninger AL (Ed). Textbook of Biochemis- 26. Bender DA, Mayes PA. Chapter 20. Gluconeogenesis &
try. New York: WH Freeman and Company; 1976. pp. 829-52. the Control of Blood Glucose [Internet]. 29th Edition. New
9. Stryer L. Pentose phosphate Pathway and gluconeogenesis. York: McGraw-Hill, 2012 [cited 2014 Mar 21]. Available from
Biochemistry, 3rd edition. New York: Freeman and Com- http://accessmedicine.mhmedical.com/content.aspx?boo
pany; 1988. pp. 427-46. kid=389&Sectionid=40142496.
10. Kat ZJ, Rognstad R. Futile cycles in the metabolism of glu- 27. Handle PJ. Pathogenesis of diabetes mellitus. In: Cerasi E,
cose. Current Top Cell Regul. 1976;10:238-87. Luft R (Eds). Nobel Symposium. Aim Quist and Wiksek,
11. Panda NC. Critical changes in proximate principles of Stockholm; 1970. p. 173.
nutrition in Diabetes Mellitus. In: Samal KC (Ed). Diabetes 28. Soling HD, William B, Kllineke J. In: Soling HD, William B
in the Indian Scene, published by Diabetic Association of (Eds). Regulation of Gluconeogenesis, New York; Academic
India, Orissa Branch, Cuttack. 1987;6:14. Press; 1971. p. 210.
12. Panda NC. Control processes in carbohydrate metabolism. 29. England PJ, Robinson BH. The permeability of rat heart
In: Kumar V (Ed). Disorders of Carbohydrate Metabolism. mitochondria to citrate. Biochem J. 1969;112:8P.
New Delhi: Arnold Heinemann Publishers (India) Private 30. Granner DK. Hormones of the pancreas and gastrointes-
Ltd.; 1974. pp. 9-18. tinal tract. In: Murray RK, Granner DA, Mayes PA (Eds).
13. Bender DA, Mayes PA. Chapter 19. Metabolism of Glyco- Harper Biochemistry, 24th edition. Stamford, CT: Appleton
gen [Internet]. 29th Edition. New York: McGraw-Hill, 2012 & Lange; 1977. pp. 581-98.
[cited 2014 Mar 21]. Available from http://accessmedi- 31. Baldwin JE, Krebs H. The evolution of metabolic cycles.
cine.mhmedical.com/content.aspx?bookid=389&Section Nature. 1981;291:381-2.
id=40142495. 32. Randle PJ. Fuel selection in animals. Biochem Soc Trans.
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1986;14:799-806.
Pathway & Other Pathways of Hexose Metabolism [Inter-
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34. Feling P. Amino acid metabolism in man. Ann Rev Bio-
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chem. 1975;44:933-55.
15. Bender DA, Mayes PA. Chapter 18. Glycolysis & the Oxi-
35. Vilsbøll T, Holst JJ. Incretins, insulin secretion and Type 2
dation of Pyruvate [Internet]. 29th Edition. New York:
diabetes mellitus. Diabetologia. 2004;47:357–66.
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Williams and Wilkins; 2000. pp. 575-87.
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37. Graner DK. Pituitary and hyothalamic hormones. In:
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pathay. Trends Biochem Sci. 1986;11:47. 38. Chipkin SR, Kelly KL, Ruderman NB. Hormone–fuel Inter-
18. Glodhammer AR, Paradies HH. Phosphofructokinase: relationships; Fed state, Starvation and Diabetes Mellitus
structure and function. Curr Top Cell Regul. 1979;15:109-41. Joslin’s Diabetes Mellitus, 13th edition. 1996. pp. 97-115.
19. Cohen P. The role of protein phosphorylation in the for- 39. Granner, Daryl K. Hormones of pancreas and gastrointes-
moral control of enzyme activity. Eur J Biochem. 1985; tinal tract. In: Murray RK, Granner DA, Mayes PA (Eds).
151:439. Harper Biochemistry, 25th edition. New York: McGraw Hill;
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complex: structure and regulation. Rev Physiol Biochem 40. Berg JM, Tymoczko JL, Stryer L. Biochemistry, 5th edition.
Pharmacol. 1983;96:123-70. New York: Freeman and Company; 2002. pp. 845-66.
21. Botham KM, Mayes PA. Chapter 23. Biosynthesis of Fatty 41. Chen X, Nayyar N, Boden G. The effects of free fatty acids
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kid=389&Sectionid=40142499. metabolic flux control. J Biol Chem. 2003;278:32485-8.
 CHAPTER 3
Morphology of Pancreatic Islets and
Pathology of Pancreas in
Diabetes Mellitus
Arun R Chitale

Pathology of Pancreas

Chapter Outline
♦ Normal Islets of Langerhans ♦ Nature of Islet Amyloid
♦ Historical Landmarks of Clinical and Particularly ♦ Gestational Diabetes
Pathological Importance ♦ Bronze Diabetes
♦ Experimental Diabetes ♦ Insulinoma
♦ Etiological Classification of Diabetes

NORMAL ISLETS OF LANGERHANS

The islets are considered as “micro-organs”, responsi-
ble for the regulation of blood glucose. There are about
1 million islets distributed throughout the pancreas in
healthy adult humans, each of which measures about
0.2 mm. The combined mass of the islets is 1–1.5 g. The islet
is separated from the surrounding exocrine pancreatic
acini by a thin fibrous connective tissue capsule, which is
continuous with fibrous connective tissue that is interwo-
ven throughout the rest of the pancreas (Figs 3.1 and 3.2).
The islet cells, like any other neuroendocrine cells, stain
positive with synaptophysin chromogranin and neuron
specific enolase on immunohistochemistry (Fig. 3.3).
There are more islets in the tail of pancreas adjacent to Fig. 3.1: Islet and exocrine pancreatic acini. A thin fibrous capsule
separating the islet from exocrine pancreatic tissue. Islet made up of
spleen. The islets are heterogeneous in their location,
small pale cuboidal cells in solid nests with central vascular strand
size, number, shape and function. Each islet forms a small
collection of a few to more than 1,000 cells.
The subject of embryological origin of neuroendocrine Pearse and challenged by others working in the field. For
cells of the gastrointestinal (GI) and respiratory system example, the experiments on the neural crest showed that
has been controversial. The hypothesis of their origin GI and pancreatic endocrine cells (islets) originate from
from migrated neural crest cells was first proposed by endoderm. This theory is supported by the fact that ablation
 Morphology of Pancreatic Islets and Pathology of Pancreas in Diabetes Mellitus 43

CHAPTER
3
Fig. 3.2: The slender fibrous capsule is continuous with fibrous Fig. 3.3: Neuroendocrine islet cells showing a strong positivity for
network that encloses pancreatic acini (Masson’s trichrome stain) chromogranin on immunohistochemistry

A B
Figs 3.4A and B: (A) Well preserved islet close to small pancreatic duct (arrow); and (B) a medium sized duct ‘D’ showing a small islet at
the end of the duct (arrows)

of neural crest did not prevent development of endocrine Hormones produced by the five different types of cells
cells in the GI tract. The current view is that the islets arise in the islets are secreted directly into the blood stream.
from undifferentiated stem cells in the pancreatic ducts In rat islet, endocrine cell subsets are distributed as
(Figs 3.4A and B). According to this theory, the cells of follows:
the islets are evaginations of the foregut, which fuse to • Alpha cells (15–20%) of islets cells secrete glucagon
form the exocrine and the endocrine pancreas. The adult • Beta cells (65–80%) secrete insulin and amylin
ductal epithelium can be seen to give rise to new islets in • Delta cells (3–10%) secrete somatostatin
cases of chronic pancreatitis, partial duct obstruction and • PP cells (3–5%) secrete pancreatic polypoid
other exocrine pancreatic diseases. This process is called • Epsilon cells (< 1%) secrete ghrelin
nesidioblastosis, which is known to occur as a congenital The distribution of various islets differs between
abnormality in newborns and infants, which gives rise to species. The rodent islets are characterized by beta cells
marked sustained intractable hypoglycemia. clustered in the core and all other endocrine cells located
 44 Physiology and Metabolism

at the periphery. On the other hand, human islets display pathogenesis of diabetes that it will not be out of place
alpha and beta cells in close relationship with each other to describe the animal model in some detail. Alloxan is a
throughout the cluster. toxic glucose analogue, which selectively destroys insulin
producing cells in the pancreas when administered to
HISTORICAL LANDMARKS OF rodents and other animal species. The alloxan compound
CLINICAL AND PARTICULARLY is structurally identical to glucose and is, therefore,
PATHOLOGICAL IMPORTANCE1 exclusively collected in beta cells. The alloxan treated
SECTION

rodents develop insulin dependent diabetes and give rise

• 1869: Paul Langerhans (age 22 years) discovered the to insulitis identical to that in T1D an autoimmune type of
2

islets during his study for a doctorate and presented the diabetes in humans.
thesis as “contributions to the microscopic anatomy of
Pancreas”. He referred to the islets as “islands of clear ETIOLOGICAL CLASSIFICATION OF
cells scattered throughout the pancreas and staining DIABETES5
differently from the surrounding tissues”.
• 1893: French histologist Laguesse reported the “spots” Type 1 (Beta cell destruction with absolute insulin defi-
in the pancreas and provisionally designate them by ciency)
the name islets of Langerhans, thereby immortalizing • Autoimmune
the name. • Idiopathic
• 1901: Eugene Opie associated diabetes with an Type 2 (May range from predominant insulin
alteration in the islets of Langerhans and proposed that resistance to a predominant secretory defect with relative
they were the source of an internal secretion. insulin deficiency).
• 1909: J de Meyer suspected the role of the islets in
diabetes mellitus (DM) and named the hypothetical Other Specific Types
secretion insulin.
• Gestational Diabetes
• 1921: Banting and Best isolated material from pancreas
The pathology of islets of type 1 and type 2 DM will be
extracts that dramatically prolonged the lives of dogs
described in detail.
who were made diabetic by removal of pancreas.
• 1922: Banting and Best treated their first human
patient, a young boy, whose life was saved by the Islets in Human Type 1 Diabetes
treatment. This was a stunning accomplishment. More than 100 years ago inflammatory infiltrate limited
• 1943: The “alloxan diabetes” was first described in to the islets was described in a diabetic child that died in
rabbits by Dunn, Sheehan and McLetchie. The islets ketoacidosis. The lesion was later described as insulitis
in this experimental model revealed insulitis similar to and is now considered pathognomonic of T1D in children
that encountered in Type 1 diabetes (T1D) in humans with recent onset of the disease.6
and the model has been used extensively in the study Type 1 diabetes is considered a disorder, whose patho-
of pathogenesis of diabetes. genesis is autoimmune in origin; a notion drawn in large
• 1960: Radioimmunoassay of insulin becomes available. part from studies of human pancreata performed as far
• 1965: Gepts reported insulitis in 68% of recent onset back as the 1960s.7 The insulin deficiency associated
cases and supported the concept of immunological with T1D is thought to be an autoimmune mediated
destruction of islets in Type 1 diabetes. selective destruction of beta cells. But there is a role for
• 1967: First pancreas transplant (Kelly and coworkers). genetic susceptibilities8 and environmental factors in
• 1976: C-peptide estimation becomes a clinical tool. the pathogenesis of T1D. The autoimmune etiology of
• 1989: First islets transplant (Lacy and coworkers). T1D has primarily been based on the identification of
• 2000: “Edmonton protocol” improved results of islet
islet cell reactive auto-antibodies in the serum of patients
transplantation.2,3
with T1D or at genetic risk for T1D as well as lymphocytic
infiltrates in the pancreatic islets of patients who died
EXPERIMENTAL DIABETES shortly after disease onset.9-12 Not all cases of T1D have
The most frequently employed experimental model is autoimmune basis and auto antibodies are not present in
the well known “Alloxan diabetes” in rodents.4 It has blood. Such cases have no known etiological agent and are
contributed so much to our understanding of the classified as “idiopathic” T1D.
 Morphology of Pancreatic Islets and Pathology of Pancreas in Diabetes Mellitus 45

CHAPTER
3
Fig. 3.5: The islet is enlarged due to marked lymphocytic infiltration Fig. 3.6: Partly hyalinized (now called Amyloid) islets in late onset
destroying endocrine cells, note residual islet cells (arrows) diabetes. Note surrounding fat and acinar pancreatic tissue
Source: CME on Endocrine Pathology, Mass General Hospital,
Boston, 1967

A number of theories based on data from human and lymphocytic infiltration limited to the islets (Fig. 3.5)
animal models to explain beta cell autoimmunity that leads and prominent in early stage disease in children.18 The
to insulin deficiency have been proposed. The theories infiltration consists predominantly of T-cells, in which
include molecular mimicry resulting from cross reactivity CD8 lymphocytes dominate, but may also contain CD4
of viral or dietary antigens with beta cell antigens and gut lymphocytes, B lymphocytes and macrophages.19 The
flora that drive deleterious immune responsiveness.13-15 cellular response is accompanied by a humoral response
Clinically, the diagnosis of T1D is based on combination that includes auto antibodies against a wide array of beta
of hyperglycemia, variable loss of C-peptide secretion and cell antigens.20 It has been found that CD8 lymphocyte
dependence on exogenous insulin for survival. The loss of population is greatly diminished or altogether vanished
C-peptide secretion and destruction of beta cells occurs from inflamed islet, when insulin positivity is lost. A total
in autoimmune T1D but not in idiopathic T1D, which of 213 cases of T1D from 10 population based studies
does not show autoimmune antibodies. Many patients were included in a meta-analysis. The combined data
with idiopathic T1D have a non-autoimmune, fulminant sets showed that insulitis occurred in 73% of young
disorder characterized by the absence of insulitis and of (< 14 years) T1D patients with a short duration (< 1 month)
diabetes-related antibodies, a remarkably abrupt onset, of the disease, in 60% of young patients with disease
and high serum pancreatic enzyme concentrations. duration of 1 month to 1 year and only in 4% of young
Immunohistologic studies of pancreatic-biopsy speci- patients with a disease duration of longer than one year.18
mens from three patients with negative circulating beta-
cell antibodies revealed T-lymphocyte–predominant infil- Islets in Type 2 Diabetes
trates in the exocrine pancreas but no insulitis and no Deposit of amyloid in the islets is the most characteristic
evidence of acute or chronic pancreatitis.16 alteration in islets of Langerhans in Type 2 diabetes and
It is important to know that test for auto antibodies was first described as far back as in 1901. For a long time
is not carried out routinely in most clinical settings and, it was named hyalinization of the islets (Fig. 3.6). By 1987
therefore, it is difficult to differentiate between type A and it was discovered that the islet amyloid is a polymerization
type B subtypes of T1D.17 product of a novel beta-cell regulatory product.21 Over
a long period of time interest in the alterations of islets
Insulitis in Human Type 1 Diabetes was rather low and it was an enigma to the pathologists,
The histopathology of T1D is defined by a decreased beta who noticed the lesions in autopsy specimens. The other
cell mass in association with insulitis, a characteristic reason for scant interest in the subject was due to the
 46 Physiology and Metabolism

fact that islet amyloid was found to be missing in rat and GESTATIONAL DIABETES
mouse models of diabetes. It is found that islet amyloid
is also encountered in non-diabetic subjects, although it Insulin resistance is a normal phenomenon emerging
has been seen uncommonly and to a lower degree.22 in the second trimester of pregnancy, which progresses
thereafter to levels seen in non-pregnant patients with
NATURE OF ISLET AMYLOID type 2 diabetes. It is thought to secure glucose supply to
the growing fetus. Women with gestational diabetes
SECTION

Initially, Congo red staining property of islet amyloid was mellitus (GDM) have an insulin resistance they cannot
found to be different from that of systemic amyloid and compensate with increased production in the β-cells
2

histochemical studies also indicated that the islet amyloid of the pancreas. The mechanism is not known. There is
is different. some question whether the condition is natural during
In 1959, fibrillary nature of amyloid was established pregnancy. Gestational diabetes is most commonly
on electron microscopic observations in the amyloid of diagnosed by screening during pregnancy. Diagnostic
diverse origin.23 Amyloid material consists of randomly tests detect inappropriately high levels of glucose in
dispersed thin fibrils of 7–9 nm thickness. Benditt blood samples. Gestational diabetes affects 3–10% of
and Eriksen showed that amyloid substances differ in pregnancies so it may be a natural phenomenon. Women
protein composition according to clinical type and it with gestational diabetes are at increased risk of developing
is best demonstrated by protein chemical methods. type 2 DM. Their offsprings are prone to develop childhood
These studies revealed that secondary systemic amyloid obesity with type 2 diabetes later in life. The most common
contained fibrillar protein AA, and AL amyloid fibril pancreatic pathology found in 85% are islet hypertrophy,
had origin from immunoglobulin light chain. Analysis increase islet cell volume, pleomorphism of β-cell nuclei
of islet amyloid revealed a novel beta cell protein called (Fig. 3.7A), eosinophilic insulitis of large islets (Fig. 3.7B),
insulin amyloid polypeptide (IAPP).24 Now this can be peri and intrainsular fibrosis.28 The hyperglycemia of
easily demonstrated by using antibody to IAPP tested by maternal diabetes promotes fetal hyperglycemia, which
immunohistochemistry.22,25 leads to hyperplasia and hypertrophy of beta cells of islets
of Langerhans.
Does Islet Amyloid have
Pathogenetic Significance? BRONZE DIABETES
Type 2 diabetes results from a combination of insulin Hemochromatosis is a disease that causes the body to store
resistance, defects in insulin secretion and hyperglu- excessive amounts of iron in the body tissues particularly
cagonemia. It is not clear whether formation of islet liver, heart and pancreas (Fig. 3.8). It is an inherited
amyloid is a pathogenetic event in the development disorder that can lead to the onset of diabetes after years
of type 2 diabetes or just participating in the final islet of iron overload, which can damage the pancreas. About
destruction. Islet amyloid is not present in all cases of 40% of those diagnosed with hemochromatosis will also
type 2 diabetes and it may also be found in elderly non- be diagnosed with diabetes at the same time. Diabetes
diabetic subjects, hence its pathogenetic role is still did not cause hemochromatosis, but hemochromatosis
controversial. Type 2 diabetes is heterogeneous in causes diabetes.  Hence, this form of diabetes is considered
human and most probably many different mechanisms “secondary” diabetes because it is caused by damage to the
operate in the pathogenesis. It is possible that deposition pancreas from excessive levels of iron. There is no insulitis
of islet amyloid acts in concert with other pathogenic and no circulating autoimmune antibodies are present.
mechanisms. Until recently there was no agreement Hemochromatosis with diabetes is often called “bronze”
about whether reduction in islet volume and beta-cell diabetes because of the presence of copper brown skin
mass occur in type 2 diabetes. Several later studies have discoloration.
shown a modest reduction of the islet cell mass in type
2 diabetes compared to age matched controls. Now it INSULINOMA
is accepted that islet amyloid deposition in human pan-
creatic islets is associated with decreased beta-cell area This is an insulin secreting benign endocrine tumor of the
and increased beta-cell apoptosis.26,27 beta cells of islets of Langerhans, giving rise to intractable
 Morphology of Pancreatic Islets and Pathology of Pancreas in Diabetes Mellitus 47

CHAPTER
3
A B
Figs 3.7A and B: (A) Hyperplastic part of islet: note enlarged pleomorphic nuclei; (B) marked eosinophilic infiltrate in the right 2/3rd of the
picture, part of islet on left lower aspect shows large hypertrophic pleomorphic nuclei
Source: CME on Endocrine Pathology, Mass General Hospital, Boston, 1967

Fig. 3.8: A case of primary hemochromatosis: heavy iron deposits (Prussian blue stain) in the islet. This patient was severely diabetic (“bronze
diabetes”)

A B
Figs 3.9A and B
 48 Physiology and Metabolism
SECTION
2

C D
Figs 3.9A to D: (A) Immunostain for insulin delineates insulinoma on right; (B) Insulin decorates beta cells in islet in the normal pancreatic
tissue; (C) Immunostain for insulin stains beta cells; and (D) Immunostain for glucagon staining alpha cells

hypoglycemia. A vast majority of insulinomas are located REFERENCES

in the pancreas and less than 2% in the duodenal wall.
1. Barnett DM, Krall LP. The history of diabetes. In: Kahn RC,
The tumors are almost equally distributed in head, body
weir G, King G, Jacobson A, Smith R, Moses A (Eds). Joslin’s
and tail of the pancreas. Determination of plasma insulin Diabetes Mellitus, 14th edition. 2005. pp. 1-18.
and proinsulin concentration by radioimmunoassay has 2. Shapiro AM, Ricordi C, Hering BJ, et al. International trial
greatly facilitated the diagnosis. Grossly, the tumor is well of the Edmonton protocol for islet transplantation. N Engl J
circumscribed or encapsulated and the malignant ones Med. 2006;355:1318-30.
appear nodular. Microscopic study shows four types of 3. Shapiro AM, Lakey JRT, Ryan EA, et al. Islet transplanta-
tion in seven patients with type 1 diabetes mellitus using a
pattern, the most common being trabecular. The cells
glucocorticoid-free immunosuppressive regimen. N Engl J
frequently show band cytology with no nuclear anaplasia. Med. 2000;343:230-8.
One of the most characteristic findings in insulinomas 4. Ahmed N. Alloxan diabetes-induced oxidative stress
is amyloid stroma. Histopathological study is required and impairment of oxidative defense system in rat brain;
mainly to confirm benignancy, which is present in 95% neuroprotective effects of Cichorium intybus. Int J Diabetes
of cases and to look for signs of malignancy such as local Metab. 2009;17:105-9.
invasion and metastasis (Figs 3.9A to D). 5. WHO Consultation Group. Definition, diagnosis and classi-
fication of diabetes mellitus and its complications, 2nd
Edition. Part 1: Diagnosis and Classification of Diabetes
FURTHER READING Mellitus. WHO/NCD/NCS/ 1999. pp. 1-59.
1. Westermark P. The pathogenesis of Amyloidosis: under- 6. Gale EMA. The discovery of type 1 diabetes. Diabetes. 2001;
standing general principles. Am J Pathol. 1998;152:1125-7. 50:217-26.
2. WHO Consultation Group. Definition, diagnosis and classi- 7. Rowe PA, Campbell-Thompson ML, Schatz DA, et al. The
fication of diabetes mellitus and its complications, 2nd pancreas in human type 1 diabetes. Semin Immunopathol.
Edition. Part 1: Diagnosis and Classification of Diabetes 2011;33:29-43.
Mellitus. WHO/NCD/NCS/ 1999. pp. 1-59. 8. Mehers KL, Gillespie KM. The genetic basis for type 1 diabe-
3. In’t Veld P. Insulitis in human type 1 diabetes: The quest for tes. Br Med Bull. 2008;88:115-29.
an elusive lesion. Islets. 2011;3:131-8. 9. Atkinson MA, Kaufman DL, Newman D, et al. Islet cell
4. Rowe PA, Campbell-Thompson ML, Schatz DA, et al. The cytoplasmic autoantibody reactivity to glutamate Decar-
pancreas in human type 1 diabetes. Semin Immunopathol. boxylase in insulin-dependent diabetes. J Clin Invest. 1993;
2011;33:29-43. 91:350-6.
 Morphology of Pancreatic Islets and Pathology of Pancreas in Diabetes Mellitus 49

10. Butler AE, Galasso R, Meier JJ, et al. Modestly increased 18. In’t Veld P. Insulitis in human type 1 diabetes: The quest for
beta cell apoptosis but no increased beta cell replication in an elusive lesion. Islets. 2011;3:131-8.
recent-onset Type 1 diabetic patients who died of diabetic 19. Wilcox A, Richardson SJ, Bone AJ, et al. Analysis of islet
ketoacidosis. Diabetologia.2007;50:2323-31. inflammation in human type 1 diabetes. Clin Exp Immunol.
11. Foulis AK, Stewart JA. The pancreas in recent onset type 1 2008;155:173-81.
(insulin dependent) diabetes mellitus: insulin content 20. Eisenbarth GS. Type 1 diabetes-a chronic autoimmune
of islets, insulitis and associated changes in the exocrine
disease. New Engl J Med. 1986;314:1360-80.
acinar tissue. Diabetologia. 1984;26:456-1.
21. Westermark P, Wernstedt C, O’brien TD, et al. Islet amyloid

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12. Gepts W. Pathologic anatomy of the pancreas in juvenile
diabetes mellitus. Diebetes.1965;14:619-33. in human diabetes 2 and adult diabetic cats contains a novel

3
13. Atkinson MA. Molecular mimicry and the pathogenesis putative polypeptide hormone. Am J Pathol. 1987;127:414-7.
of insulin-dependent diabetes :still just an attractive 22. Westermark P. Amyloid in the islets of Langerhans: Thoughts
hypothesis. Ann Med. 1997;29:393-9. and some historical aspects. Ups J Med Sc. 2011;116:81-9.
14. Roep BO, Hiemstra HS, School NC, et al. Molecular mimicry 23. Cohen AS, Calkins E. Electron microscopic observations on
in Type 1 diabetes: immune cross reactivity between a fibrous component in amyloid of diverse origins. Nature.
islet autoantigens and human cytomegalo virus but no 1959;183:1202-3.
Coxsackie’s virus. Ann N Y Acad sci. 2002;958:163-5. 24. Benditt EP, Eriksen N. Chemical classes of amyloid sub-
15. Vreugdenhill GR, Geluk A, Ottenhoff TH. Molecular stance. Am J Pathol. 1971;65:231-52.
mimicry in diabetes mellitus: the homologus domain in 25. Westermark P. The pathogenesis of Amyloidosis: under-
Cox Sachie B virus protein 2c and islet auto antigen GAD65 standing general principles. Am J Pathol. 1998;152:1125-7.
is highly conserved in the Cox Sachie B-like enteroviruses
26. Ehrlich JC, Ratner IM. Amyloidosis of the islet of Langer-
and binds to the diabetes associated HLA-DR3 molecule.
hans. A restudy of islet hyaline in diabetic and non-diabetic
Diabetologia. 1998;41:40-6.
16. Imagawa A. Hanafusa T, Miyagawa J, et al. A novel subtype individuals. Am J Pathol. 1961;38:49-59.
of type 1 diabetes mellitus characterized by a rapid onset 27. Jurgens CA, Toukatly MN, Finger CL, et al. Beta-cell Loss
and an absence of diabetes-related antibodies N Engl J and beta-cell apoptosis in human type 2 diabetes are related
Med. 2000;342:301-7. to islet amyloid deposition.. Am J Pathol. 2011;178:2632-40
17. Ize-Ludlow D, Sperling MA. The classification of diabetes 28. Wigglesworth JS, Singer DB. Textbook of fetal and perinatal
mellitus: a conceptual framework. Pediatr Clin North Am. pathology. 26. Vol. 2. Blackwell Scientific Publication; 1991.
2005;52:1533-52. pp. 1021-57.
 Chapter 4
Insulin Biosynthesis
and Secretion
Dhruv K Singh, PS Lamba

Insulin Biosynthesis

Chapter Outline

♦♦ Organization of Islets of Langerhans ♦♦ Molecular Identity of the KATP Channel

♦♦ Islet Structure ♦♦ Insulin Secretion Via KATP Channel Independent Pathways
♦♦ Insulin Gene Expression and Its Regulation ♦♦ Potentiation of Secretion by Various Agents
♦♦ Insulin Biosynthesis: Post Transcriptional Events ♦♦ Second Messengers and the Regulation of Insulin Secretion
♦♦ Fate of the Mature Secretory Granule ♦♦ Effector Systems for Insulin Secretion
♦♦ Glucose and Signal Recognition ♦♦ Insulin Secretion and Diabetes
♦♦ Regulation of Insulin Secretion

Introduction Organization of islets

Glucose homeostasis in an individual is maintained of langerhans
through a concerted co-ordination between hormonal, Anatomically, majority of the adult pancreatic mass com­
metabolic, ionic and second messenger signaling events. prises of digestive enzyme-producing exocrine (acinar)
These diverse stimuli influence the pancreatic β-cell to
cells, whereas the hormone producing endocrine cells
release appropriate amount of insulin commensurate
are scattered in small group of cells all over the pancreas.
with peripheral tissue requirements and metabolic needs
The endocrine cells are organized into micro-organs
to maintain glucose homeostasis. The β-cell is remarkably
called islets of Langerhans and represent about 1–2% of
flexible to adapt to varying insulin needs of the body in
the total pancreatic mass. Each human islet comprises of
event of insulin sensitivity and resistance in target tissues
such as liver, muscle and adipose tissue and sensing ~103 diverse cells, with the majority (~ 50–70%) of them
glucose availability in its immediate milieu.1 A breakdown being β-cells.2 Insulin and glucagon represent the most
in the chain of signaling events at any level leading to known hormones of the islets, however, several other
secretion of insulin by the β-cell puts the individual at peptides and neurotransmitters are expressed by specific
risk of developing glucose intolerance; a pathognomonic islet cell types, and some of these can modulate the islet’s
clinical feature associated with type 2 diabetes mellitus. responses to changes in the metabolic milieu. Insulin and
A close scrutiny of the molecular mechanisms governing gluca­gon play a pivotal role in regulation of fuel meta­
the regulation of insulin bio­synthesis and its secretion bolism and maintenance of normoglycemia. In normal
from the β-cell reveals the complicated nature of the subjects, insulin secretion occurs in a pulsatile manner and
entire process. displays an oscillatory pattern in the plasma, both at basal
 Insulin Biosynthesis and Secretion 51

and under stimulated conditions. The oscillatory pattern

is crucial for maintenance of normoglycemia and loss of
oscillation pattern, irrespective of the cause, may lead to
desensitization of the insulin receptors and development
of insulin resistance in the target tissues.1
Moment to moment adjustments in the availability of
insulin are crucial for normal functioning of carbohydrate,

chapter
protein and lipid metabolisms. Therefore, the β-cell has
evolved complex and sensitive mechanisms to match

4
the rate of insulin secretion to the prevailing metabolic
needs.3-5 Glucose, the principal regulator of this process,
also amplifies the actions of other insulin secretagogues.
Glucagon is a major catabolic, counter-regulatory hor­
mone, which opposes the key metabolic effects of insulin6
and makes an essential contribution to the metabolic
adaptations to stress, exercise and starvation.
Disturbances in the secretion of both insulin and
glucagon are central to major metabolic disorders. Insulin
deficiency is the hallmark of diabetes, whereas excessive
insulin secretion is responsible for conditions such as
reactive hypoglycemia, persistent hyperinsulinemic hypo­ Fig. 4.1: Vascular and cellular organization of pancreatic islets10
glycemia of infancy (PHHI) and insulinoma.7 Increased
glucagon secretion, a feature of type 2 diabetes, promotes
persistent hyperglycemia and a major factor in facilitating product, e.g. islet amyloid polypeptide (IAPP) is a β-cell
increased ketogenesis in diabetic ketoacidosis. peptide that is co-secreted with insulin and may act on the
β-cell to inhibit the release of insulin and itself.12 Paracrine
Islet structure effects are exerted on the neighboring cells rather than by
products carried by circulation, e.g. inhibition of insulin
Each islet is a complex micro-organ comprising of several and glucagon secretion by somatostatin released by
thousand cells. The core is formed by β-cells (90% of δ-cells.11,12 Plausible mechanisms of interaction are shown
total islet mass), surrounded by a mantle of somatostatin in Figure. 4.2.
containing δ-cells, which are interspersed between
glucagon producing α-cells in the tail of the pancreas
Insulin gene expression and
and pancreatic polypeptide (PP) cells in the head of the
its regulation
gland.8 This central organization of β-cell mass in the islets
is fundamental to their pulsatile insulin release, which
Structure of the Insulin Gene
is driven by the electrical burst of the β-cell membrane.9
The islets are highly vascular, being supplied by arterioles Insulin gene structure is highly specific amongst
that penetrate the mantle and reach the islet core, where species.13,14 It is located in the region p13 on the short arm
they break up into capillaries (Fig. 4.1). Within the islets, of chromosome 11, adjacent to the genes of insulin-like
blood flows centrifugally from the β-cells to the more growth factor (IGF) II and tyrosine hydroxylase.13,15,16 It is
peripherally located α-cells and then to the δ-cells8,10 and composed of three exons (expressed sequences) and is
presumably carries metabolic and hormonal information interrupted by two introns (non-coding regions), which
from the β-cells to the mantle. Islet blood flow is modulated have to be spliced out in the nucleus to produce transcrip­
in response to changes in blood glucose concentration by tionally active preproinsulin mRNA (Fig. 4.3). The
11
the autonomic innervation of the islets. insulin gene has been found to be polymorphic,mostly
Individual islet cells also influence their own activity within a hypervariable region at the 5' end extremity.17,18
and that of the adjoining cells through local paracrine A regulatory region, which is located 30 base pairs from
effects. Autocrine effects are mediated by the cell’s own the transcription initiation site, precedes the “TATA”
 52 Physiology and Metabolism
section
2

Fig. 4.4: The preproinsulin gene and mRNA.19 The gene consists of
three exons interrupted by two introns. The first intron is a 5’ untrans-
lated region and second is in the region of the C peptide. The gene is
shown with the fully spliced transcript (mRNA) below. Regions of the
mRNA encoding the different parts of the preproinsulin molecule are
as indicated below the mRNA

box (a sequence essential for transcription initiation).16

Exon I is situated in the 5' non-coding region that contains
Fig. 4.2: Potential interactions between the secretory products of the
sequences important for control of transcription; exon
major islet cell types. Black arrows indicate paracrine stimulation-inhi- II contains sequences coding for the signal peptide, the
bition. The direction of blood flow is indicated by dotted arrows11 insulin B chain and part of C peptide; exon III codes for the
rest of the C peptide, the insulin A chain and untranslated
3' sequences. The intron sequences show considerable
interspecies variation, but occupy relatively constant
positions in the gene.19,20 The primary RNA transcript is
close to 1,500 nucleotides in length. There is no evidence
of alternate splicing of the insulin gene 19 (Fig. 4.4).

Cell Specif ic Control

In mammals, insulin gene expression and insulin bio­
synthesis are restricted to the β-cells of the endocrine
pancreas, with the possible exception of the yolk sac and the
fetal liver.21,22 This tissue selectivity is conferred upon the
insulin gene by a complex interplay between upstream cis-
elements (short DNA sequences) and cellular transacting
factors (proteins) that bind to the DNA and regulate
expression.23-29 The cis-elements are broadly divisible into
promoter and enhancer elements. Promoters represent
the site of binding of the transcriptional initiation complex
composed of polymerase II and general transcription
factors such as TF IIA. The Enhancer elements modulate
the activity of the promoter either positively or negatively
by binding to various nuclear regulatory proteins.13,14,30-34
Two cis-elements, 5' to the insulin gene, regulate
(entrance) transcription of the insulin gene. There are
Fig. 4.3: Transcription of the insulin gene.20 The exons and the introns nine base pair related DNA sequences, IEB-1 and IEB-
present in the insulin gene are shown together along with the steps 2 (E boxes-with consensus sequence of CANNTG) and
involved in the formation of insulin
the repeating TAAT/ATTA sequence located between
 Insulin Biosynthesis and Secretion 53

Several negatively acting sequences have been

identified which may be responsible for muting the
insulin gene in non-β-cells. The IEB-1 box is one site of
negative regulation and can be suppressed by adenovirus
E1A gene product. A second site is situated some 3Kb
upstream of the rat insulin 1 gene. Its specific role remains
unclear, as it is functional in both β and non-β-cells.

chapter
A strong negative regulatory element has been located

4
to -270 in the human insulin gene, but again its activity is
also apparent in non-β-cells.45
The identification of regulatory regions of the insulin
gene and corresponding transacting factors represent a
major advance in our understanding of the regulation
of insulin gene expression in β-cells. These factors are
well conserved across animal species and this facilitates
transfection of foreign insulin genes into cultured animal
cells46,47 and transgenic mice48,49 and this could potentially
facilitate insulin gene transplantation into subjects with
type 1 diabetes mellitus, in future.

Acute Regulation of Insulin

Fig. 4.5: Control elements of the insulin gene. E1-E5 indicate the Biosynthesis in the β-cell
"footprints" identified as regions protected from DNAase digestion
in the rat insulin 1 gene and therefore as sites for interaction with In addition to tissue specific selective expression descri­
nuclear proteins. Elements identified as important for transcriptional
control of insulin gene expression are given above each gene. Protein
bed above, insulin gene is subject to modulation by
complexes binding to these regions are given underneath acutely acting factors, such as serum glucose concen­
tration, which is the single most important factor.
position -208 and -222 (Fig. 4.5). Trans-acting proteins Upstream regions of the insulin gene contains sequences
that bind to IEB-1 and IEB-2 regions have been identi­ responsible for conferring sensitivity to glucose.50-53 The
fied28,29,35-38 and the interactions of these and other effect of glucose seems to be dependent on its metabolism
cis-elements and trans-acting factors provide the begin­ within the β-cells. This observation is derived from the
ning of an understanding of the mechanisms underlying fact that only metabolized sugars are effective.52 However,
the tissue specific effects of gene regulation. A different there is little information on the intracellular messenger
binding protein interacts with the repeating TAAT/ systems mediating this effect. Glucose can elevate cyclic
ATTA sequence at -222 to -208, which is part of the adenosine monophosphate (cAMP) within the β-cells
homeodomain-containing protein-binding motif.39,40 and the insulin gene upstream region contains a cAMP
A complementary DNA sequence encoding this protein responsive region (CRE).54 Though CRE is a very likely
is called IsL-1.41 This protein is expressed by both α and candidate, the evidence is not very convincing as the
the β-cells and may be involved in β-cell development. glucose sensitive region (GSR) of the rat insulin gene does
The temporal and spatial pattern of its expression not contain a CRE.53 Nuclear protein factors binding to
in developing embryos implicates it as a general deter­ this region have been found both in the rat and human
minant of neuroendocrine development.42 A β-cell specific islets of Langerhans.54 The binding intensity of one com­
protein complex termed as insulin upstream factor-1 plex (C1), whose presence was highly specific to insulin
(IUF-1) that binds to the CT motifs of the human insulin producing cells, has been shown to increase in a dose
gene upstream region has been found.43 IUF-1 may dependent manner with simultaneous increase in extra­
be similar to insulin promoter factor-1 (IPF-1), a homeo­ cellular glucose concentration.53
domain containing protein, which is also found only in Sugars other than glucose and potential nutrients like
β-cells and binds to the corresponding sequence of the rat leucine, guanosine, arginine and ribose can also alter
insulin gene.44 insulin biosynthesis.55-60 Agents such as sulfonylureas and
 54 Physiology and Metabolism

diazoxide have been shown to inhibit proinsulin biosyn­

thesis,61-63 although sulfonylureas increase the secretion
of preformed insulin in the acute phase. Interferon can
have variable effects.64-66 The rate of conversion of proin­
sulin to insulin may be inhibited by interleukin-166 and
phospho-oligosaccharide (POS).67 Stimulation of proin­
sulin biosynthesis over relatively short periods may occur
section

without significant changes in levels of preproinsulin

2

mRNA.68,69 Glucose can also stimulate translation of insu­

lin mRNA directly by modulating signal recognition
peptide (SRP) mediated elongation arrest.70,71 Translation
regulation of insulin biosynthesis appears to be the domi­
nant mechanism under physiological circumstances.
Glucose remains the most important factor for genera­
tion of signals for stimulating biosynthesis of insulin and
this is linked to stimulus-secretion coupling. However, Fig. 4.6: Trafficking and processing events in the pathway of insulin
production by the pancreatic beta-cell. For clarity, some of the steps
the dose-response curve for any two stimulatory events is have been intentionally over-simplified and some critical processes
variable,55,72 suggesting involvement of other concomitant have been omitted (e.g. transcription, translation and degradation).
signals. The time course of the cessation of stimulation of The inset shows the major events involved in targeting proinsulin to
nascent granules and in the transition between proinsulin contain-
insulin biosynthesis upon glucose withdrawal is slower
ing coated granules and insulin containing granules. The trans-Golgi
than that of secretion. The lag in the rate of reduction receptor presumed to be involved in the targeting process has yet to
of insulin biosynthesis, relative to the release of insulin be identified in the b-cell
that occurs on glucose withdrawal, may be biologically
programmed to facilitate restoration of prestimulation
levels of stored insulin in the β-cell, after an extended complex.74,75,78-81 The constitutive pathway is considered
period of stimulated release.73 to be the default pathway, accepting any material in the
trans-Golgi not previously singled out for shipment to a
Insulin Biosynthesis: Post specific destination. The selection process for directing
transcriptional events prohormones to granules is not well understood.
However, there is evidence for an intimate association of
Insulin biosynthesis can occur either through constitutive proinsulin with the cisternal face of Golgi membranes,
or regulated pathways. Usually, secretory cells utilize suggesting presence of proinsulin-specific receptors on
the constitutive secretory pathway for secretion, as the cisternae.82
well as to dispatch the integral membrane proteins to Insulin is almost entirely secreted by the regulated
their appropriate destinations.74,75 Some of the highly pathway83,84 (Fig. 4.6). The first step in the post-transcrip­
differentiated secretory cell types employ the regulatory tional process is the production of preproinsulin. It is
pathway, wherein the cells can store the end-products synthesized on the rough endoplasmic reticulum (RER),
in secretory granules and release them in response to with the first 25 or so amino acids forming the signal
a secretagogue. The β-cell is equipped with both these peptide. The “pre” region of preproinsulin acts as a signal
pathways,76 but under normal circumstances it directs sequence to direct the ribosomes bearing the nascent
proinsulin almost exclusively to the regulated pathway.77 protein to the RER. This process involves interaction with
The regulated pathway involves the selective packaging of a cytosolic SRP, which causes association of the complex
prohormone into secretory granules, followed by secretion with an SRP receptor (docking protein) on the RER. SRP
(exocytosis) in response to a stimulus. is released from the complex; a step that requires guanine
Conversion of the prohormone to the active hormone nucleotide (GTP) hydrolysis and the signal sequence then
occurs in the secretory granule itself, which also serves interacts with a specific signal sequence receptor (SSR).
as the hormone storage compartment. Active selection The SSR is a transmembrane glycoprotein, which may also
of products destined for granules is understood to participate in the functional pore which is formed, and
take place in the trans-cisternae portion of the Golgi which allows transfer of the growing polypeptide chain
 Insulin Biosynthesis and Secretion 55

across the membrane and into the lumen of RER. During Secretory granule formation begins by budding from
this transfer, the signal sequence is removed by a signal the trans Golgi phase from a compartment called the
peptidase to yield intact proinsulin. Conversion occurs for trans Golgi reticulum (TGR) that contains condensing
the most part co-transitionally, such that preproinsulin secretory material. The newly formed granules are coated
itself is a very minor component of the β-cell.85 with clathrin, which is subsequently removed during
Although glucose can increase the rate of insulin granule maturation. It is in the TGR that insulin is sorted
gene transcription, this may manifest after several hours, to the regulated secretory pathway. The source of the

chapter
however, an increase in the rate of insulin biosynthesis precise signal for such exclusive sorting in the TGR is not
known, however, there have been suggestions that this

4
can occur swiftly on exposure to elevated glucose
signal may originate in the three-dimensional structure of
concentrations. This is because glucose also stimulates
the protein.96-99
the rate of translation of pre-existing insulin mRNA. This
Considerable progress has been made in the study
mechanism, which requires metabolism of glucose by
of enzymes involved in the conversion of proinsulin to
the β-cell, is exerted at three steps.70,84 In the initial stage,
insulin.83,100,101 The process occurs during the maturation
glucose increases the rate of insulin gene translation, of the secretory granules and is thought to be triggered by
followed by an increase in the rate at which initiated the relatively acidic conditions within the granules.
preproinsulin mRNA is transferred from free to membrane In the β-cells, two calcium dependent endopeptidases
bound ribosomes, which may involve alteration in have been identified in the lysed insulin granules. The
structure and activity of SRP. In the final stage, glucose type 2 endopeptidase is active at a more neutral pH
augments the peptide chain elongation process.84 and lower calcium concentrations than the type 1 endo­
peptidase. Type 1 endopeptidase cleaves proinsulin on
Processing to Insulin the C-terminal side of Arg 31, Arg 32, whereas the type
2 peptidase mainly cleaves at Lys 64, Arg 65.100 Cloning
Unlike the majority of secretory proteins found in the of putative insulin converting proteases was facilitated
lumen of the RER, proinsulin cannot be glycosylated. by discovery of a mammalian homolog of yeast protease
However, like other proteins, proinsulin is transported KEX 2, which cleaves proteins specifically at dibasic
from the transitional elements of RER to the cis-cisternae residue. Using PCR and northern blotting, two cDNA
of the Golgi complex in smooth vesicles. This transfer is sequences (PC2 and PC3) were isolated from insulinoma
energy dependent [adenosine triphosphate (ATP)],86 as cDNA libraries. Evidence has accumulated that PCS and
well as the microfilamentous-microtubular network,87-89 PC2 correspond to type 1 and 2 endopeptidases that
participation of cytosolic proteins such as N-ethylma­ process proinsulin to insulin. PC2 is the major isoform in
leimide sensitive fusion protein,90,91 G proteins92 and the β-cell. It is processed by cleavage and glycosylation in
members of the heat shock protein family.93 It is also the Golgi and is secreted from insulinoma cells in response
likely that the members of this family of proteins are also to glucose. This suggests that PC2 is a soluble protein
involved in the folding of proinsulin within the lumen of located in the β-cell secretory granule.100,101
RER.94,95 Additionally, two specific proteins, BiP (which Following proteolytic cleavage of proinsulin by endo­
helps in the folding process) and protein disulfide isome­ peptidases, basic amino acids at the junction must be
removed. This is accomplished by the carboxypeptidase
rase (which functions in disulfide bond formation) have
H, which is localized to secretory granules in a variety
been distinctly identified.90
of secretory and neural tissues including β-cells. The
The next organelle in proinsulin processing is the Golgi
C-peptide is retained within the secretory granule and
complex, where proinsulin is sorted out from proteins
is co-secreted with insulin. After an initial lag phase of
not destined for the secretory granule. Once proinsulin is approximately 15 minutes, the half-time for release of
delivered to the cis-Golgi, it is transferred from one Golgi insulin is 30–45 minutes.34,83,84 It has been demonstrated
stack to the next. Passage of proinsulin from the RER and that high glucose concentration accelerates release,102
through the Golgi occurs within transport vesicles by whereas interleukin 1 and diazoxide delay the process
repeated cycles of budding and fusion. Low molecular of insulin release.66,103
weight GTP binding proteins may be involved in this Almost 99% of newly synthesized proinsulin is
process, however, the precise molecular mechanism is destined for the secretory granule. Despite this efficient
still unclear.87 targeting, there is always a detectable level of proinsulin
 56 Physiology and Metabolism

like material in the circulation. This material consists of crystallization within the mature granule is set. Insulin
2+
intact proinsulin and conversion intermediates.42,43 The associates to form dimers and presence of Zn facilitates
major intermediate results from cleavage at the β chain/C- formation of hexamers. The histidine residue at position
2+
peptide junction,104,105 leaving the C-peptide joined by its 10 of the B chain co-ordinates the Zn ion. The zinc
C extremity to the insulin A chain. These products hexamers then pack together to form a crystal lattice.
constitute about 10% of total insulin related material in Crystallization depends upon a very high local concen­
2+
the circulation in the fasting state.12 The relative amount tration of insulin and Zn , as well as an acidic milieu, all
section

of proinsulin, intermediate and insulin in the peripheral conditions that are present within the granules.111,119-122
2

circulation reflects not only the rates of production by The dense core of the mature granule is made up of the
the pancreas, but also the rate of clearance. Proinsulin insulin crystal. C-peptide does not co-crystallize with
is cleared from the circulation much less rapidly than insulin to any significant extent, and is found as a clear
insulin (primarily because of its low affinity for the insulin halo surrounding the dense core of the granule.123,124 The
receptor), which explains its relatively higher concen­ six C-peptides, however, are thought to lie on the surface
tration at the periphery than in the portal vein. It is not of the proinsulin hexamer. This makes the proinsulin
yet clear why such relatively large amount of proinsulin hexamer more soluble, as the outlying C-peptides mask
and intermediates are released. It is plausible that these the faces involved in the assembly of insulin hexamer
proinsulin and their intermediates may have some into the crystal form. Thus, proinsulin hexamers form
hitherto unknown function or it may be so that these pro­ immature granules, with crystallization only occurring
ducts escape from the granules during insulin release. after conversion to insulin.121
One remote possibility is about presence of some degree
of secretory dysfunction in the secretory granule, which Translocation of Granules
may result in some granules releasing their contents
The role of the cytoskeletal elements, especially micro­
before conversion is complete.
tubules and microfilaments, in the intracellular translo­
cation of the insulin storage granules has been extensively
Other Constituents of the β-granule
studied. However, the precise way in which metabolic
In addition to insulin, proinsulin and the enzymes signals developed during stimulation of insulin secretion
that convert proinsulin to insulin, there are three other are translated into granule movement and exocytosis
major constituents of the β-cell granule. Chromo­granin remain unknown.
A is found in many different secretory cell types including Microtubules are formed by the polymerization of
β-cells.106-109 Proteolytic conversion results in generation of tubulin subunits (54 kDa). They were first implicated when
β-granin as well as pancreastatin, which are co-released it was discovered that colchicine and other microtubule
with insulin from the β-cell. β granin is most probably (spindle) poisons, all effectively inhibit insulin release.
released from its precursor by the proinsulin processing These agents have varying effects on the microtubule
enzymes,109 whereas generation of pancreastatin most function. Colchicine disaggregates microtubules by
likely involves a different set of enzymes.110 Pancreastatin binding to their tubulin subunits, whereas vinblastine
inhibits insulin release from the β-cell.111,112 The other causes the formation of paracrystals of microtubular
protein is amylin (IAPP), which displays considerable proteins and nocodazole produces microtubule disaggre­
structural homology with calcitonin gene related peptide gation through a different mechanism. As all these
(CGRP).113,114 Amylin is generated by proteolytic proces­ compounds inhibit glucose-stimulated insulin secretion,
sing of its high molecular weight precursor proamylin.115 the dynamic turnover of tubulin to microtubules would
The active form of amylin is amidated114 and is a major appear to be important for the mechanism of secretion,
constituent of amyloid deposits found in nearly all patients rather than the total number of polymerized microtubules
with type 2 diabetes mellitus and often in insulinoma within the β-cell.
tissue.116,117 Amylin is co-secreted with insulin.118 The localization of microtubules within the β-cells
has been studied in monolayer cultures.125 Microtubules
Mature Granules and the Insulin Crystal normally form a network radiating outwards from the
Once insulin has been formed from proinsulin, in perinuclear region, which is disrupted by prior exposure to
the setting of an acidic pH, the framework for insulin colchicine. This microtubular framework may provide the
 Insulin Biosynthesis and Secretion 57

mechanical pathway along which secretory granules move granule contents into the extracellular space, followed by
in an oriented fashion. However, it is now clear that these pinocytosis of limited regions of the plasma membrane, is
microtubules cannot provide the motive force to propel termed as exocytosis.129-131 Through this process, the total
the granules through the cytoplasm.126 Other contractile surface area of the cell is maintained, even during extensive
proteins such as actin and myosin may be involved in the exocytosis. The molecular mechanisms of exocytosis are
secretory process. far from clear, however, transportation within the secre­
Actin which is a constituent protein of the microfi­ tory pathway may be dependent upon the cytoskeletal

chapter
laments exists in two forms, a globular form of 43 kDa network of microtubules and microfilaments.132,133 Micro­

4
and a filamentous form, which associates to form micro­ tubule associated proteins (MAPs) and force-generating
filaments. Indirect evidence of the involvement of micro­ enzymes may be involved in the process.134-136 A pre-
filaments stems from the fact that cytochalasin B and assembled fusion pore, probably initiates the exocytic
phalloidin inhibit insulin secretion and also interfere event. Such a pore may form when the granule docks at
with microfilament formation. In addition, the regula­ the plasma membrane at specific sites where a putative
tion of microfilament polymerization is governed by docking protein is situated. This may function as an ion
various factors similar to those which alter rates of insulin channel that opens to facilitate the process of fusion.
secretion. Gradual dilatation of the fusion pore may occur as a conse­
Myosin light and heavy chains have also been detected quence of graded addition of lipid molecules between
in rat islets at concentrations that are considerably higher the subunits of the fusion pore.133
than those found in liver, and have been localized by In addition to facilitated fusion of the granule and the
immunofluorescence to both α-cells and β-cells. It is plasma membrane, the process of stimulation of insulin
possible that actin (microtubules), tubulin (microtubules) release also involves recruitment of granules to the plasma
and myosin may act together to transport granules. The membrane. The demonstration of granule alignment in
microtubules may act as a network along which granules proximity to the plasma membrane has led to a hypothesis
are propelled by inter-action of actin-myosin, analogous that under basal conditions, granule fusion with the
to that in the muscle. plasma membrane is inhibited by factors in the immediate
Other factors, such as kinesin and dynein could also vicinity of the inner face of the plasma membrane.20
interact with microtubules in the transport of insulin Stimulus-secretion coupling would involve the generation
secretory granules. These proteins drive organelle move­ of second messengers to override these inhibitory signals,
ment of variety of cell types, but little is known about thereby allowing for the granule fusion.
their role in insulin secretion. However, the observation The main trigger for exocytosis is an increase in the free
2+
that basal and glucose-stimulated insulin secretion is inhi­ intracellular Ca .137 A number of proteins that regulate
bited by antisense oligonucleotide suppression of β-cell neurotransmitter release in the neurons have been
kinesin heavy chain expression127 provides compelling identified in the β-cells and they appear to perform a similar
evidence that kinesins play a key role in transporting function in regulation of insulin secretion. Thus, there is
insulin secretory granules to the β-cell surface. This is compelling evidence that assembly and disintegration of
supported by the recent report that granule movement a multimeric complex of proteins (the SNARE complex)
is blocked by transfection of β-cells with a dominant nega­ is necessary for the exocytic release of insulin.138 This
tive kinesin heavy chain mutant.128 complex is made up of proteins associated with secretory
granules, the plasma membrane and soluble fusion
FATE OF THE MATURE proteins (Fig. 4.7). The secretory granules are thought to
SECRETORY GRANULE dock at the plasma membrane by the pairing of proteins
on the granule surface (v-SNAREs, e.g. synaptobrevin and
Insulin is stored in the mature secretory granule until it is
cellubrevin) with cognate proteins on the cytoplasmic
either released by exocytosis or degraded by crinophagy.
face of the target membrane (t-SNAREs, e.g. SNAP-25
and syntaxin). The docked granules will only fuse with the
Exocytosis (Insulin Release) membrane and release their contents in the presence of
Fusion of the mature granule’s membrane with the plasma elevated levels of intracellular calcium. Synaptotagmins
membrane of the β-cell, with subsequent discharge of (a class of calcium binding granule proteins), are likely to
 58 Physiology and Metabolism

per second were released, followed by a sustained second

phase with a granule release rate of 0.5–10 per second. The
first phase is ATP independent, while the second requires
ATP, probably to mobilize the granules from the reserve
pool to the readily releasable pool.141,142
There is growing evidence that newly synthesized
insulin is released in preference to older stored mate­
section

rial.140,143-147 This would imply that there is a heterogeneity

2

among secretory granules, with new granules being

recognized as such and being tagged for preferential
exocytosis. However, the immature clathrin coated
granules contain essentially proinsulin, whereas experi­
mental studies have shown preferential release of newly
synthesized insulin only. The other plausible explanation
for heterogeneity among the secretory granules could
be their source of β-cells, which are known to be
heterogenous.146 β-cell population is a mixed population,
with some cells being more dynamic than others in terms
Fig. 4.7: Likely mechanism for insulin secretory granule docking and of insulin biosynthesis148-150 and secretion.148 Thus, the
fusion.140 At stimulatory calcium concentrations secretory granules so-called preferential release of new insulin could reflect
can dock at the plasma membrane through interaction of proteins
different rates of β-cell insulin synthesis turnover. The
on the granule (v-SNAREs) with those on the plasma membrane
(t-SNAREs). Secretagogue induced elevations in the intracellular relative contribution of the secretory granule and β-cell
calcium allow granule fusion to take place, most probably through the heterogeneity towards the preferential release of new
binding of the calcium to granule associated synaptotagmins. At least insulin remains unclear, however, it is likely that β-cell
two soluble proteins (NSF and SNAP) form part of the complex and
are thought to be important for the recycling of the SNARE complexes heterogeneity may have a dominant role.146
once fusion has taken place
Crinophagy (Degradation of
Insulin Stored in β-cell)
be responsible for the calcium sensitivity of the exocytic
process.139 In addition, NSF (N-ethylmaleimide sensitive If not released, insulin is degraded in the β-cell.151,152
fusion protein) and SNAP (soluble NSF attachment Degradation is accomplished by fusion of granules with
protein) form part of the SNARE complex. NSF-associated lysosomes, an event termed as crinophagy.153 The
ATP hydrolysis is thought to be involved in recycling of the process of crinophagy may run parallel with the insulin
complex after fusion has occurred. biosynthesis and release to regulate the amount of insulin
in the β-cell at a given time.151,152 Although the factors
Secretory Granule Pools regulating crinophagy are not well understood, it has been
found that when insulin release is inhibited, degradation
Electron micrographs of pancreatic β-cells indicate
increases and vice versa.151,152,154,155 The process of insulin
that secretory granules are distributed throughout the
degradation is slow and lengthy even after its introduction
cytoplasm as well as close to the exocytic sites in the
into the lysosomes.156-158 This may be due to the stability of
vicinity of the plasma membrane. It is likely that transport
of the granules to the plasma membrane is regulated the insulin crystal in the lysosomes, which have an acidic
independently of the final secretory process, thus allowing milieu similar to that of the secretory granule. By contrast,
a reservoir of granules to accumulate underneath the both proinsulin and C-peptide are degraded rapidly
plasma membrane. It has been postulated that the fusion within the β-cell, as they do not exist in crystal form in the
of this readily releasable pool might account for the secretory granule.157-159
rapid first phase insulin secretion seen in response to a
glucose load.141 This is supported by electrophysiological
Glucose and signal Recognition
measurements in which the β-cell exocytic response of a The process of insulin release from the pancreatic β-cell
short-lived first phase, during which about 100 granules is complex and involves multiple interactions between
 Insulin Biosynthesis and Secretion 59

flux are transport into the cell and phosphorylation of

glucose (Figs 4.9A and B).
Since the glucose transport into the β-cells is rapid
and uninterrupted, it is glucose phosphorylation that
constitutes the glucose sensor, which is the primary deter­
minant of the specificity and concentration dependence
of the secretory response to sugar.20 Concen­trations of

chapter
glucose below 90 mg/dL do not have any impact on the

4
rate of insulin release and the largest increases in secretory
rates occur at extracellular glucose levels between
90 mg/dL and 306 mg/dL with half maximal stimulation
at 144 mg/dL.141 Glucose must be metabolized to induce
insulin secretion as insulin release is only evoked by
glucose and its analogues that are metabolized. Insulin
Fig. 4.8: First and second phase insulin secretion, insulin release secretion is inhibited by mannoheptulose, an inhibitor of
in-vitro from an isolated perfused pancreas, in response to increase in glucose phosphorylation.20
glucose concentration in the perfusing medium. An acute first phase,
lasting for a few minutes, is followed by a sustained second phase of
However, there has been considerable interest in
secretion which persists for the duration of the high glucose stimulus glucose transporters (GLUT), because of the possibility
that a defect in the transporters in type 2 diabetes mellitus
diverse signaling molecules with the β-cell signal trans­ could reduce its activity to levels at which it could exert
duction systems.160-162 The major signal for increased control over glycolytic flux, with major consequences for
insulin secretion is an elevation of plasma glucose. Super- glucose stimulated insulin release. Amongst the family
imposed on this primary control is an intricate network of glucose transporters, GLUT2 is the predominant
of modulatory effect of hormones and neurotransmitters. transporter in the β-cell, which incidentally, is also found
It is commonly accepted that glucose is the primary regula­ in the liver. Phosphorylation of glucose in the β-cell and in
tor of β-cell sensitivity and that it exerts multiple effects the liver is enzymatically similar.169,170
on the β-cell response. At post-prandial concentrations, Glucose is converted to glucose-6-phosphatase by
it independently increases insulin secretion. Sustained glucokinase,20,171 which suggests that substrate cycling
short-term (one hour or less) glucose stimulation results in occurs in the β-cell.172 The β-cell glucokinase has been
a biphasic secretory response characterized by a transient cloned and is distinct from the liver isoform.173 Upstream
first phase of release, and a slowly rising and sustained promoter elements similar to the CT box of the insulin
second phase response that may be 30–60 fold greater gene have been found in the glucokinase gene. These
than the pre-stimulatory release rate 163-167 (Fig. 4.8). sites bind a β-cell factor similar to IUF-1, suggesting a
The capacity of isolated islets, free from vascular or co-ordinated regulation of these two genes. The enzy­
neural modulation, to secrete insulin in this characteristic matic properties of β-cell glucokinase account for several
manner indicates that the biphasic secretion pattern is features of glucose stimulated insulin release.171,174,175
an intrinsic property of the islets themselves. It is now Thus, the enzyme phosphorylates glucose and mannose,
well established that the response to glucose is mediated which stimulate insulin secretion, but not galactose,
by metabolism of blood glucose within the β-cell.20,41 which does not. Phosphorylation is inhibited by manno­
Enhanced rates of metabolism lead to closure of ATP- heptulose, which blocks glucose induced insulin release.
+
sensitive K channels (KATP channels).168 The resulting Glucokinase is controlled by a specific regulatory
depolarization evokes the opening of voltage dependent protein, which in the liver, is controlled by fructose-1-
2+
Ca channels through which Ca2+ ions enter to trigger phosphatase.176 The receptor protein has been found in
insulin secretion (Figs 4.9 and 4.13). In order to vary the islets of Langerhans177 but its significance has not
the rate of glucose metabolism in response to change in been established. The potential importance of glucokinase
blood glucose over the physiological range, the rate- has been highlighted in maturity onset diabetes of young
limiting step for glucose metabolism must have a K for (MODY-2), which has been linked to the mutation of
m
glucose in a millimolar range. The initial steps in glucose this gene. However, there is less information about β-cell
metabolism capable of exerting control of the overall glucose-6-phosphatase.
 60 Physiology and Metabolism
section
2

A B
Figs 4.9A and B: Model for insulin secretion. (A) Resting: At low extracellular glucose levels (< 3 mmol/L), K channels are open and their
169
ATP
activity sets their resting potential of the pancreatic β-cell at a hyperpolarized level of approximately 70 mV. Diazoxide opens the K channel,
ATP
which hyperpolarizes the β-cell and inhibits insulin secretion, even in the presence of glucose; (B) Active: Glucose metabolism, possibly by
changes in intracellular adenine nucleotide concentrations, induces K channel closure. This leads to membrane depolarization; opening of
+ 2+ ATP
voltage-gated Ca channels and an increase in cytosolic Ca that triggers the exocytosis of insulin. Sulfonylureas block the K channel and
ATP
initiate the same chain of events, even when glucose is absent.
(ADP: Adenosine diphosphate; ATP: Adenoine triphosphate; KATP: ATP-sensitive potassium channels).

The pituitary cell line, AtT20ins, has been stably trans­ Regulation of Insulin secretion
fected with proinsulin cDNA and it secretes insulin in
response to agents that activate protein kinase A (PKA).178 Time-dependent Potentiation
AtT20ins cells express glucokinase, but do not secrete In addition to stimulating a biphasic insulin secretory
insulin in response to glucose. Glucose-induced insulin response, glucose also indirectly regulates the release
secretion was obtained from this cell line after transfection of insulin at different glycemic levels. For example, at
with GLUT2 cDNA, although maximal secretion occurred glucose levels greater than 104 mg/dL, acetylcholine
with glucose levels far below the physiological range. This and cholecystokinin (CCK)180,181 are potent stimulators
was attributed to the fact that relative levels of hexokinase for insulin secretion, but at hypoglycemic levels, they
and glucokinase levels are different in these cells as fail to activate insulin exocytosis from the β-cell. This
compared to the β-cells. If this view is correct, it implies “permissive effect” of glucose results from glucose
that the level of glucokinase is very significant for β-cell metabolism and adequate ATP to support a secretory
function. Further, immunological studies have indicated response.160 The fact that other nutrient secretagogues
that are metabolized, supply the gene permissive signals,
that individual β-cells show marked heterogeneity in
supports the concept.182 Glucose stimulation of the
expression of glucokinase.179 Since there is evidence that
β-cell also sensitizes it to subsequent stimulation by a
glucose stimulated insulin release also shows hetero­
variety of agonists163,183,184 such as acetylcholine185 CCK,186
geneity between β-cells, it is plausible that stimulation of
α-ketoisocaproate,187 glyceraldehydes188 monomethyl­
secretion with increasing glucose loads may involve pro­ succinate,182 methylpyruvate189 and protein kinase
gressive recruitment of β-cells to an active state. It has C(PKC) activator tetradecanoylphorbol acetate.190,191 This
been suggested that low glucokinase expressing cells response is induced by prior short-term stimulation with
could conversely respond to low glucose concentration, glucose and manifests itself as heightened release of
whereas those with high glucokinase concentration might insulin during subsequent stimulation. Termed “time-
only be activated at higher glucose levels. dependent potentiation” (TDP) these phenomena can
 Insulin Biosynthesis and Secretion 61

be induced by agonists. TDP may play a particularly closure. However, the mechanism does not involve
important role in cephalic phase of insulin secretion, β-cell metabolism. Rather, sulfonylurea binds directly to
whereas vagally derived acetylcholine maybe responsible membrane receptors to cause closure of K channels.205
ATP
for its induction.192,193 Mobilization of intracellular calcium may also be of
importance for sustained insulin secretion. The liberation
Time-dependent Suppression of of Ca2+ from intracellular stores by 1,4,5-triphosphate (IP )
3
Insulin Release has been documented.137,206 Cyclic ADP-ribose can also be

chapter
Glucose is responsible for acutely regulating insulin formed in β-cells and lead to mobilization of stored Ca2+.207

4
secretion. However, sustained stimulation with high Additionally, activation of PLC and protein kinase C also
glucose blunts the β-cell response and leads to a fall in play a role in glucose mediated insulin release.169,208-211
insulin secretion. This phenomenon is termed as the third Measurement of Ca2+ in single β-cell has revealed
phase of insulin secretion,194,195 and β-cell desensitization that individual β-cells show heterogeneous patterns of
is an inevitable consequence of sustained high glucose oscillation of Ca2+.212,213 It is likely that these correspond to
exposure. This process has also been referred as “time- the slow wave oscillations of membrane potential since
dependent suppression (TDS)” of insulin release196 and they are synchronized with β-cell electrical activity.213
may be analogous to β-cell glucotoxicity.197-199 The capacity Since the effect of glucose is to increase the duration of
to induce TDS is not confined to glucose alone and can the Ca+ transients and reduce the intervals between them
be induced by sustained exposure to agonists such as rather than increase their amplitude, the Ca2+ signal to the
CCK,195 glucosamine,200 carbachol201 and forskolin.202 secretory systems may be frequently modulated.
What suppressed islets have in common, is their inability
to respond in terms of increase in both phospholipase MOLECULAR IDENTITY OF
C (PLC) mediated phosphoinositol (PI) hydrolysis and THE KATP CHANNEL
insulin secretion, when subsequently challenged by high
The KATP channel is formed by two types of subunits: a
glucose.196 Secretory failure is not the result of insulin pore forming subunit Kir6.X and a regulatory subunit, the
depletion, since desensitized islet cells contain large sulfonylurea receptor (SUR), which co-assembles with
quantities of insulin 201,203 and they will respond to an a 4:4 stoichiometry.214-216 Two Kir6.X genes have been
agonist, which bypasses the lesion in the PLC activation. described, Kir6.1 and Kir6.2.217-219 Likewise, two genes
encoding sulfonylurea receptors SUR 1 and SUR 2, have
Control of Calcium Level: ATP been cloned and further diversity is created by alternative
Sensitive K+ Channels splicing of SUR 2.220-222 Co-expression of Kir6.2 and SUR 1
in both mammalian cells and in xenopus oocytes results in
The relative importance of extracellular and intracellular
KATP currents with properties identical to the native beta-
calcium as source of elevation of free cytosolic Ca2+
cell KATP channel.217,218,223
concentration varies between cell types. In the β-cell, the +
Kir6.2 is a member of the inward rectifying K family
influx of extracellular Ca2+ ions is of prime importance for
and has two transmembrane domains (TMDs), linked by a
the control of Ca2+.131 Influx occurs through voltage
pore loop and cytosolic amino acid carboxy terminals
dependent Ca2+ channels, which are opened on depolari­ (Fig. 4.6). The specific sequence for ATP binding is not
zation of plasma membrane. The resting membrane yet clear, though studies suggest that ATP interacts with
potential of approximately 80 mV is determined primarily this subunit (Kir6.2) to close the channel.224,225 The SUR
by the activity of KATP channels, whose opening can be units belong to the ABC-transporter super family,222 which
modulated by intracellular ATP.168,204 Depolarization is includes the cystic fibrosis gene product and multidrug-
evoked by closure of K channels. Physiologically, this resistance p-glycoprotein. These proteins are characterized
ATP
occurs in response to an increase in blood glucose and by multiple TMDs and two intracellular nucleotide-binding
involves an increased rate of metabolism of the sugar and domains (NBDs), which contain consensus sequences
consequent elevation of the intracellular ATP:ADP ratio. for nucleotide-binding and hydrolysis68,69,226 (Figs 4.9A
The sulfonylureas such as glibenclamide and glinides and B). SUR is thought to possess 17 TMDs arranged in
(repaglinide) also elicit insulin secretion via KATP channel three groups of 5 + 6 + 6 226–228 (Figs 4.10A and B and 4.11).
 62 Physiology and Metabolism
section
2

A B
Figs 4.10A and B: The KATP channel is composed of two types of subunits, Kir6.2 and SUR229. (A) Hydropathy analysis suggests that Kir6.2 has
two TMDs whereas SUR1 has multiple TMDs and two cytosolic nucleotide binding domains (NBDs), each of which contains a Walker A (WA)
and a Walker B (WB) motif. These motifs are involved in the activation of the K channel by MgADP. The estimated molecular weight of Kir6.2
ATP
is 43 kDa and that of SUR1 is 177 kDa; (B) The K channel is an octameric complex of four pore forming Kir6.2 subunits and four regulatory
ATP
SUR subunits

and is likely to form the pore of the K channel in

ATP
all these tissues.217,218 Both Kir6.1 and Kir6.2 have been
postulated to serve as the pore of the smooth muscle
KATP channel,221,230 and it has been shown Kir6.1 and
+
Kir6.2 form ATP sensitive K ATP channels with different
properties.231 There is evidence that SUR 1 serves as the
regulatory subunit of the KATP channel in beta-cells
and some types of neurons,229,232 SUR 2A in cardiac and
skeletal muscles 229,233 and SUR 2B in smooth muscles.222,230
In contrast to most other members of the Kir channel
family, Kir6.2 does not form functional channels in
absence of SUR.217,218 SUR functions as a chaperone
protein to facilitate the surface expression of Kir6.2.214,234
Kir6.2 is the primary site where the ATP causes K
ATP
channel inhibition.224,235-237
Both oleoyl CoA and PIP reduce the ATP sensitivity
2
of the K channel by interacting with Kir6.2, since
ATP
both agents are active when this subunit is expressed in
Fig. 4.11: The β-cell K channel is a complex of two different pro- absence of SUR.238,239 The SUR is very important for the
ATP
teins; Kir6.2 and SUR1. These assemble 4:4 stoichiometry. S, sulfony- metabolic regulation of the K channel as it confers
lurea binding site (Ashcroft FM). Recent advances in our understand- ATP

ing of SUR and ATP-sensitive K channels in the pancreatic beta-cell.

sensitivity to the stimulatory effect of the Mg ATP and Mg
Source: In Marshall SM, Home PD, Rizza RR (Eds). The Diabetes GDP.240-244 The effects of these nucleotides are mediated
Annual. Elsevier Science BV: 1998. pp.1-18. through interaction with NBD’s of SUR. Mutations
in the NBDs that abolish the stimulatory effect of
Mg-nucleotides also prevent K channel activation by
ATP
Electrophysiological studies have shown that different the metabolic inhibition in intact cells.243-245 This suggests
combination of Kir and SUR subunits account for the that a key physiological role of SUR is to mediate the
diverse properties of K channels. Kir6.2 is strongly metabolic regulation of channel activity in addition
ATP
expressed in β-cells, heart, brain and skeletal muscle to its ability as a sulfonylurea binding site. In summary,
 Insulin Biosynthesis and Secretion 63

Mg ADP interacts with K channels at two sites: one Flow chart 4.1: Factors contributing to the regulation of islet cell
ATP
secretion.14
that induces channel inhibition (now known to be Kir6.2)
and one that causes channel activation (on SUR). The
overall action of Mg ADP therefore will be a balance of
these two effects because ATP interacts with both stimu­
latory and inhibitory sites. 241 The relative contributions
of the adenine nucleo­tides to K channel regulation in

chapter
ATP
the intact β-cell remains to be elucidated.
Persistent hyperinsulinemic hypoglycemia of in­

4
fancy is a rare recessively inherited disorder of glucose
homeostasis that is characterized by unregulated insulin
secretion and profound hypoglycemia. Linkage analysis
studies of families with PHHI indicate that the gene
responsible maps to chromosome 11p 14-15.1.246-249
Subsequently, it was discovered that genes for both K
ATP
channel subunits are clustered in the same region and
more than 12 different mutations in SUR 1 and 2, and
Kir6.2 have now been reported to cause the disease. Two
types of mutations have been described. Class I mutation
leads to total loss of functional activity of K channel,250
ATP
whereas class II mutation leads to total loss of functional
activity of the Mg ADP to enhance the inhibitory effect of
ATP.246,251,252 Both classes of mutations result in continuous
depolarization of the β-cell even at low glucose levels,
2+ (CCK: Cholecystokinin; GIP: Gastric inhibitory polypeptide; GLP:
thereby resulting in a high Ca concentration, which Glucagon-like peptide; GRP: Gastrin releasing polypeptide; IAPP:
explains the constitutive insulin secretion characteristic Islet amyloid polypeptide; NPY: Neuropeptide Y; PACAP: Pituitary
of PHHI.251 adenylate cyclase activating polypeptide; SRIF: Somatostatin release
inhibiting factor; VIP: Vasoactive intestinal peptide).

Insulin secretion via KATP

channel independent pathways in type 2 diabetes and that the identification of novel
therapeutic strategies targeted at this pathway maybe
Since the early reports linking K channel closure to the beneficial in restoring β-cell function in type 2 diabetes
ATP
exocytic release of insulin, it has now become apparent patients.254
that β-cell also possess a K channel independent
ATP
stimulus-secretion coupling pathway. This is termed Potentiation of secretion
as the amplifying pathway to distinguish it from the
by various agents
triggering pathway that is activated by K channel
ATP
closure.245 Studies in which β-cell calcium is elevated A large number of hormones and neurotransmitters are
by depolarization and KATP channel maintained in an involved in the modulation of insulin release. The cephalic
open state by diazoxide have indicated that glucose, at phase of insulin release, initiated when food is ingested,
concentrations as low as 18 to 108 mg/dL, is still capable is due to acetylcholine released from the parasympathetic
of stimulating insulin secretion.204,253 The independent nerves terminating in the islets of Langerhans. Stimulation
mechanism of insulin secretion by glucose in a KATP of sympathetic nerves inhibits insulin release mediated
channel is not yet understood. However, it is clear by adrenaline and probably galanin, a mechanism
that glucose must be metabolized and that there is responsible for maintaining euglycemia during exercise
compelling evidence that adenine nucleotides are or in response to stress. Flow chart 4.1 shows factors
involved (39 Pick), while it has been established that contributing to the regulation of islet cell secretion.
activation of protein kinases A and C is not required. Insulin secretagogues can be divided into initiators
The KATP-independent amplifying pathway is impaired and potentiators. The former are capable of secreting
 64 Physiology and Metabolism

insulin on their own and include nutrients such as glucose, Table 4.1: Intracellular signaling mechanisms through which insu-
and drugs such as sulfonylureas. These substances act by lin secretion is regulated
inhibiting K channel activity. Whereas nutrients must ATP-sensitive potassium channels
ATP
be metabolized to effect channel closure, the drugs bind Closure (stimulates secretion) glucose, leucine, sulfonylureas,
directly to the channel and block its activity. Potentiators glinides
of insulin secretion include a number of hormones [such Opening (inhibits secretion)
as glucagon, glucagon-like peptide (GLP)-1], transmitters
Norepinephrine (noradrenaline), galanin, insulin, diazoxide
section

(such as acetylcholine) and amino acid, arginine. These

Intracellular calcium
agents amplify insulin secretion induced by an initiator,
2

but cannot elicit insulin secretion by themselves because (Increased cytosolic calcium stimulates insulin secretion through
activation of CaMK II/direct effects on exocytosis)
they do not close K channels and are only able to exert
ATP
their effects after an initiator secretagogue has effected K Entry of extracellular calcium
ATP
channel inhibition. Agents that open K channels such 
All agonists that close K channels cause calcium influx
ATP
ATP
as diazoxide, produce inhibition of insulin release. Thus, through voltage operated channels Calcium ionophores

the K channel has a key role to play in the regulation of Calcium mobilization from endoplasmic reticulum
ATP
insulin secretion from the pancreas.229 Cholecystokinin acetylcholine arginine vasopressin (AVP)
Cyclic AMP
Amino Acids 
(Increased cyclic AMP potentiates insulin secretion through
activation of protein kinase A)
Several amino acids are effective insulin secretagogues.
Most require glucose, but some, e.g. lysine, leucine and Adenylate cyclase activation

arginine, can stimulate insulin secretion in absence Glucagon

of glucose. Leucine enters the islets by a sodium- Glucagon-like-peptide 1 (GLP-1)
Pituitary adenylate cyclase activating polypeptide (PACP)
independent transport system and stimulates a biphasic
Phosphodiesterase inhibition
insulin release. The effects of leucine on insulin secretion,
Isobutylmethylxanthine (IBMX)
β-cell membrane potential and ion fluxes are similar to,
but lesser than, those of glucose.255 Thus, metabolism Diacylglycerol (DAG)
of leucine within β-cells decreases the potassium (Increased stearate/arachidonate DAG potentiates insulin secretion
permeability, causing depolarization and activation of the through activation of DAG sensitive PKC isoforms)

L-type calcium channels through which calcium enters Phospholipase C activation (Stearate/arachidonate rich)
the β-cells and initiates insulin secretion. Leucine is also Cholecystokinin acetylcholine AVP
able to activate the amplifying pathway of insulin secretion Synthesis de novo (Palmitate rich)
in a K channel independent manner, as described for Glucose
ATP
glucose. The charged amino acids, lysine and arginine,
(ATP: Adenosine triphosphate; KATP: ATP-sensitive potassium; AMP:
cross the β-cell plasma membrane via a transport system Adenosine monophosphate; PKC: Protein kinase C).
specific for cationic amino acids. It is generally believed
that the accumulation of these positively charged
(PACP). Secretion is inhibited by insulin, somatostatin,
molecules directly depolarize the β-cell membrane
epinephrine (adrenaline), norepinephrine (noradrena­
leading to calcium influx.141
line), and galanin. In many cases, it is not clear whether
the effects are physiological or pharmacological. The
Hormones and Neurotransmitters autonomic innervation plays a key role, with the parasym­
Hormones may affect the secretion of insulin either by pathetic input potentiating insulin secretion through the
autocrine/paracrine manner or by reaching the β-cells action of acetylcholine at the M muscarinic receptors and
3
via circulation. Cholinergic, adrenergic and peptidergic the sympathetic system inhibiting secretion through the
neurons, which innervate the islets, can modulate insulin effects of norepinephrine at α receptors.
2
secretion. Specific receptor proteins located on the All of the above factors are coupled to the process
β-cell plasma membrane mediate hormonal and neuro­ of insulin secretion through various intracellular signa­
transmitter regulation of insulin secretion. ling pathways discussed below. The signaling systems
Secretagogues include glucagon, acetylcholine, CCK through which secretagogues and inhibitors operate are
and pituitary adenylate cyclase activating polype­ ptide summarized in Table 4.1.141
 Insulin Biosynthesis and Secretion 65

Amylin and the β-cell islets indicating that other abnormalities must also be
present for the formation of islet amyloid in type 2 diabetes
Amylin or islet amyloid peptide is normally co-expressed
mellitus.
and co-secreted with insulin β-cells and forms amyloid
fibrils, especially in islets of type 2 diabetes subjects.
Second messengers and the
Insulin and amylin genes contain similar cell specific
promoter elements that bind with the same β-cell nuclear regulation of insulin secretion

chapter
protein complexes.256 Amylin is secreted in amounts 1–2% The role of K channel has been discussed above.
ATP
of that of insulin. Sequence divergence in a specific region Pathways downstream of K channel closure consists of

4
ATP
of amylin explains the difference between species in forms release of the key second messenger system responsible
of amyloid fibrils.257 Whether amylin can modify insulin for regulating insulin secretory response.
secretion remains controversial, though physiological
doses of amylin has been shown to inhibit insulin secretion
Calcium
in experimental models.258
Although amyloid deposition is a characteristic feature Calcium is essential for the initiation of insulin secretion
of type 2 diabetes mellitus, there is no evidence for its by glucose. Conditions that elevate intracellular calcium
overproduction, nor any defects in the amylin gene on usually stimulate insulin release.260 Studies with permea­
chromosome 12. The precise role of amyloid deposition bilized islets, in which intracellular calcium concentration
in type 2 diabetes mellitus remains to be established. A can be regulated, have shown calcium stimulation in the
model to study this was a transgenic mouse containing insulin secretory process (Fig. 4.12).261
a rat-insulin 1-promoter-human amylin–fusion gene.259 An electrochemical gradient is maintained between
Expression of human amylin was localized to islets of the β-cell extracellular space and cytoplasm by plasma
Langerhans, anterior pituitary and the brain in transgenic membrane associated calcium extruding systems and
animals. Blood amylin levels were elevated fivefold, by calcium sequestration within intracellular organelles.
while fasting glucose levels remained normal. However, The major route through which calcium is elevated
amyloid deposits were not detected in the transgenic within the β-cells is by influx of extracellular calcium

Fig. 4.12: Calcium handling within the b-cell. The cytosolic calcium concentration can be increased either by mobilizing calcium ion from the
endoplasmic reticulum and other intracellular organelles, or by depolarizing the cell membrane when extracellular calcium ions enter the b-cell
through voltage gated L-type calcium channels
 66 Physiology and Metabolism

through voltage dependent L-type calcium channels Flow chart 4.2: Role of inositol phospholipid products in the regu-
that are opened following β-cell depolarization. Each lation of insulin secretion.141 Some receptor agonists (e.g. acetylcho-
line, cholecystokinin) bind to cell surface receptors that are coupled to
β-cell contains less than 500 L-type channels and a rapid phospholipase C (PLC) through the heterotrimeric GTP binding protein
exocytotic rate of up to 650 granules per second may be Gq. PLC hydrolyses PIP2 an integral component of the membrane, to
reached by secretory granules located adjacent to these generate inositol 1,4,5-triphosphate (IPs) and diacylglycerol (DAG).
channels.262 Several channels associate with individual IPs mobilizes calcium from the endoplasmic reticulum and DAG acti-
vates protein kinase C (PKC), both of which enhance insulin secretion
secretory granules to couple calcium channel activity with
section

insulin release.262
2

Cyclic Adenosine Monophosphate

Glucagon stimulates insulin secretion has been known
for decades, however involvement of cyclic AMP in β-cell
signaling mechanism has been revealed recently.263 The
islet cyclic AMP concentration is approximately 6 µmol/L,
which reflects a balance between its synthesis following
adenylate cyclase activation and its breakdown by cyclic
nucleotide phosphodiesterases. Agents known to activate
adenylate cyclase (e.g. glucagon, GLP-1, PACP) cause
both an increase in cyclic AMP levels and a potentiation of
glucose stimulated insulin secretion. However, elevations
in cyclic AMP are ineffective at substimulatory glucose
concentrations, so it is generally believed that cyclic
AMP acts as a potentiator rather than a primary trigger of
β-cell secretory function. Adenylate cyclase activity can
be inhibited through binding of inhibitory agents such
as norepinephrine, somatostatin and galanin to β-cell
receptors.

Inositol Phospholipid Metabolites Diacylglycerol

A variety of receptor operated non-nutrient, secretagogues Both glucose and agonists that act at cell surface receptors
such as acetylcholine, CCK, arginine vasopressin (AVP), elevate DAG levels in β-cells. However, while DAG forma­
activate β-cell PLC via a heterotrimeric G protein (Gq) tion in response to receptor agonists is a consequence of
leading to generation of inositol 1,4,5-triphosphate (IP ) PLC mediated PIP hydrolysis, this pathway appears to
3 2
and diacylglycerol (DAG). Both of these can serve second contribute little to the glucose-induced increase in β-cell
messenger functions in β-cells (Flow chart 4.2). DAG mass. Thus, cholinergic agonist generated DAG is
predominantly of a stearoyl-arachidonoyl configuration
Inositol 1, 4, 5-Triphosphate
(consistent with it being a product of PIP hydrolysis),
2
In vitro β-cell IP levels rise quickly following exposure while the DAG in glucose stimulated islets contains mainly
3
to cholinergic muscarinic agonists and this is rapidly palmitic acid, indicating that it is produced de novo.265
followed by mobilization of intracellular calcium, required The different fatty acid species of DAG produced by
for the onset of insulin secretion.264 Although the genera­ receptor agonists and glucose might provide a means of
tion of IP and mobilization of calcium are early events, differential control of PKC activity by these stimuli.
3
calcium mobilization is not sufficient to initiate exocytosis.
The significance of IP generation during glucose stimula­
3 Arachidonic Acid
tion of insulin secretion is not clear. It is likely that it
plays little more than a modulatory role amplifying The major pathway of arachidonic acid (AA) generation
the elevations of cytosolic calcium concentration induced in islets is via deacylation of membrane protein phospho­
by calcium influx. lipids by phospholipase A (PLA ). Several species of
2 2
 Insulin Biosynthesis and Secretion 67

EFFECTOR SYSTEMS FOR

INSULIN SECRETION
The second messengers that are generated in response
to agonists binding to cell surface receptors or following
nutrient metabolism transduces extracellular signals into
a secretory response through a number of intracellular

chapter
effector systems. Serine/threonine protein kinases are

4
the most well studied of these systems and are discussed
below.268

Calcium/Calmodulin-dependent
Protein Kinases
Fig. 4.13: Possible roles of arachidonic acid (AA) and its derivatives Calcium/calmodulin-dependent protein kinases (CaMKs)
on insulin secretion.140 AA is cleaved from membrane phospholip- are dependent on calcium and binding protein calmo­
ids by cytosolic phospholipase A which is activated by increased dulin, for their activation. CaMK II transduces elevations
2
cytosolic calcium concentrations. AA stimulates insulin secretion
in intracellular calcium into an insulin secretory response.
in-vitro in absence of glucose and calcium, and may directly facilitate
granule fusion. AA is metabolized by cyclooxygenase and lipoxyge-
These have shown that the effects of insulin secretagogues
nase enzymes in β-cells, but the importance of the products in regula- on elevations in calcium correlate well with increased
tion of insulin secretion has not been established. (HETES: Hydroxyei- CaMK II activity both in-vitro and in-situ; experimental
cosatetraenoic acids). elevations in β-cell calcium stimulate phosphorylation
and insulin secretion; and that CaMK inhibitors
inhibit insulin secretion. It is proposed that CaMK II is
PLA have been identified in β-cells, but the cytosolic responsible for the initiation of insulin secretion in
2
PLA (cPLA ), which is activated by concentrations response to glucose and other nutrients and for enhancing
2 2
nutrient induced secretion in response to receptor agonists
of calcium is most likely to be of importance in β-cell
that elevate intracellular calcium.268
function. AA is capable of stimulating in a glucose and
calcium-independent manner and it has been implicated
Protein Kinase A
in facilitating fusion of secretory granule with plasma
membrane.266 Recent studies in which cPLA expression The effects of cyclic AMP is exerted through the activation
was inhibited in β-cells have indicated that this enzyme of PKA agents that elevate β-cell cyclic AMP rather
plays a role in the maintenance of insulin secretory than initiate insulin secretion, suggesting that PKA is a
granule stores, but it is not required for the initiation of potentiator rather than a primary trigger. Much of the
insulin secretion.267 work on the role of PKA in the insulin secretory process
Arachidonic acid is metabolized in islets by the has been performed using PKA inhibitors and cyclic AMP
cyclooxygenase (COX) pathway to produce prostaglandins antagonists.268 These studies have indicated that PKA acts
and thromboxane, and by the lipooxygenase (LOX) to couple receptor agonist induced elevations in cyclic
pathway to produce hydroperoxyeicosatetraenoic acids AMP to the potentiation of nutrient induced insulin
(HPETES), hydroxyeicosatetraenoic acids (HETES) and secretion.268 However, glucose still stimulates insulin
ultimately leukotrines (Fig. 4.13). The exact role and mode secretion following blockade of PKA activity, indicating
of action of AA derivatives in islet cell function remains that this kinase is not required for the secretory response
unclear since their involvement in insulin secretion has to this nutrient. 141
been investigated largely using COX and LOX inhibitors of
poor specificity. In general it appears that prostaglandins, Protein Kinase C
particularly PGE inhibit while LOX products enhance Protein kinase C isoforms are classified into three groups:
2
glucose stimulated insulin secretion. calcium and DAG sensitive (conventional); calcium
 68 Physiology and Metabolism

work to date has yielded much information about the

basic biology of the β-cell and provides an important
basis for further understanding of the pathophysiology of
type 2 diabetes, and for the development of novel drugs
to stimulate insulin secretion. In addition, improved
understanding of the signal transduction mechanisms
in native β-cells will be pivotal in designing strategies to
section

develop β-cell replacements for therapy of type 1 diabetes.

2

INSULIN SECRETION AND DIABETES

One of the major defects seen in type 2 diabetes mellitus
is faulty proinsulin processing. In type 2 diabetes
mellitus, there is an elevated ratio of proinsulin, insulin
Fig. 4.14: Overview of second messenger and effector systems split products and related peptides in comparison to
involved in the regulation of insulin secretion. 141 Glucose and other insulin.272-277 It has also been noted in some patients with
nutrients stimulate insulin secretion through increases in intra­cellular recent onset type 1 diabetes mellitus 278-280 or their non-
calcium consequent to KATP channel closure and calcium influx via
voltage operated calcium channels (VOCC). Increased calcium
diabetic twin281 or siblings.282 This abnormality has also
activates cytosolic phospholipase Az (cPLAz) and calcium/calmodulin been demonstrated in patients with thyrotoxicosis,283
dependent kinase II (CaMK II). Nutrients stimulate insulin secretion hypokalemia,284 hyperinsulinemic hypoglycemic subjects
through CaMK II induced protein phosphorylation, but arachidonic acid without known insulinoma,285 and in patients with cystic
(AA) generation through cPLAz activation is not required. Receptor
agonists coupled to PLC [e.g. acetylcholine (ACh), cholecystokinin fibrosis with impaired glucose tolerance.286 It is interesting
(CCK) and arginine vasopressin (AVP) can activate CaMK 11 through to note that abnormal proinsulin-insulin ratios can be
inositol 1,4,5-triphosphate (IP3) mediated mobilization of intracellular restored fully or partially by improving the glycemic
calcium, and they can also activate some isoforms of protein kinase C
(PKC) through DAG generation and IP3 induced increases in calcium.
status.287-289
Other classes of receptor agonists that activate adenylate cyclase The reasons for this abnormality are not established.
(e.g. PACP), glucagon and glucagon-like peptide-1 (GLP-1)] poten- So far there is no evidence that the constitutive pathway
tiate insulin secretion through cyclic AMP induced activation of PKA may be involved in this process.290-292 The possible mecha­
(KATP: ATP–sensitive potasium channels; PACAP: Pituitary adenylate
cyclase activating polypeptide; DAG: Diacylglycerol; AVP: Acetylcho- nisms may be either due to a defect in conversion of
line arginine vasopressin). proinsulin per se or that the insulin granule turnover
is so rapid that a significant amount of proinsulin is
released before it can be converted. According to the
independent and DAG sensitive (novel); and calcium and
former explanation, the conversion system itself is at fault.
DAG independent (atypical). β-cells contain conventional,
This implies that not only should the amount of unpro­
atypical and novel isoforms.269 The presence of a variety of
cessed proinsulin that leaves the β-cell be increased,
differentially regulated isoforms in β-cells makes it difficult
but any other proprotein cleaved in the β-cell should
to define a role for the PKC family in the regulation of
also be elevated. Amylin is such a protein and indeed
insulin secretion.
proamylin has been detected in amyloid deposits.293-295
The conventional and the novel isoforms can be
The second explanation is based on increased turnover
depleted in β-cells by prolonged exposure to pharma­
cological DAG analogs (phorbol esters). Under conditions of the secretory granules leading to reduced residence
where DAG sensitive isoforms are depleted, islets still show time of some proinsulin molecules within the granules
normal insulin secretory profiles to glucose, but secretion before release. This would lead to insufficient time for full
in response to receptor agonists is reduced 270 or absent.271 conversion of proinsulin. This may occur in type 2 diabetes
Conventional and novel PKC isoforms are not required mellitus under conditions of increased insulin demand
for glucose stimulated insulin secretion, but the use of caused by insulin resistance, in the background of partially
inhibitors that inhibit all the isoforms of PKC suggests that depleted β-cell population.
atypical PKC isoforms may play a role in β-cell secretory Secretory response to glucose in some β-cell lines
response to nutrients. occurs in conjunction with altered β-cell glucose trans­
Some of the key pathways involved in β-cell stimulus porters. In HITT15 β-cells, there is diminished β-cell
secretion coupling are shown in Figure 4.14. Published glucose transporter activity, which results in glucose
 Insulin Biosynthesis and Secretion 69

transport becoming the rate-limiting step for glucose secretory processes is far from perfect. However, some
utilization. Thus, in this cell line, the glucose transporter light is being shed on the probable mechanisms of the
serves as glucose sensor.296 In RINmSF cells, there is secretory defects in type 2 diabetes mellitus and currently
population. expression of GLUT1 instead of GLUT2.296 the hypothesis that defective β-cell metabolism leads to the
inability of K channels to close in response to changes in
ATP
Research plasma glucose, is gaining strength. A large body of work
still remains to be done, but the future holds promise to

chapter
At the molecular level, since SU induced insulin release
is not impaired, events subsequent to closing of diabetes unravel the mysteries and perhaps help millions of people

4
mellitus indeed have significant defects in the β-cell K with diabetes.
ATP
channels are likely to function normally. Thus, the most The maintenance of glucose homeostasis depends
likely sites for defects are in glucose metabolism itself or upon a well-orchestrated series of hormonal, metabolic,
in the coupling of the process to the K closure. Defects ionic and second messenger signaling events. The islet
ATP
in the glucokinase gene linking to MODY-2 have been β-cell is specially adapted for the synthesis of prepro­
discussed above, but are not a common cause of this insulin, processing of this through proteolytic cleavage
disease. Absent or altered secretory response to glucose to insulin, storage of insulin in membrane limited vesicles
in some β-cell lines occurs in conjunction with altered and the secretion of insulin in response to specific stimuli.
β-cell glucose transporters. In HITT15 β-cells, there is Insulin secretion occurs in a pulsatile fashion and displays
diminished β-cell glucose transporter activity, which an oscillatory pattern in the plasma, both at basal and
results in glucose transport becoming the rate-limiting under stimulation conditions. The oscillatory pattern is
step for glucose utilization. Thus, in this cell line, the crucial for maintenance of normoglycemia and loss of
glucose transporter serves as glucose sensor.296 In RINmSF oscillation pattern, irrespective of the cause, may lead to
cells, there is population, expression of GLUT1 instead of desensitization of the insulin receptors and development
GLUT2.296 Research is in progress to determine if some of insulin resistance in the target tissues.
subsets of type 2 diabetes mellitus indeed have significant The preproinsulin gene is located on the short arm of
defects in the glucose transporter. chromosome 11. Gene transcription following specific
Further work is also done on enzymes involved in stimuli yields preproinsulin, which is cleaved in the
the glucose-6-phosphatase system. One possibility to be endoplasmic reticulum by protease activity to yield pro­
explored is whether an increase in glucokinase/glucose- insulin. This is packaged in vesicles and is transported
6-phosphatase step could result in diabetic β-cells failing to the Golgi apparatus. The proinsulin is converted to
to increase cellular ATP levels in response to increasing insulin at this site and in the maturing secretory vesicles by
glucose concentrations. Hepatic glucose cycling is known proteolytic removal of C peptide. Insulin co-precipitates
to be increased in type 2 diabetes mellitus. However, this with zinc ions to form microcrystals within the secretory
effect has not been shown in the pancreatic β-cells so far.297 granule.
Whether alterations in the β-cell K channel protein(s) Increase in the extracellular glucose concentration
ATP
account for a failure to respond to nutrient secretagogues stimulate proinsulin biosynthesis but not the rate of its
currently is still not clear. conversion to insulin. Insulin together with C peptide is
released from the β-cell by exocytosis. Secretory granules
SUMMARY are transported to the β-cell surface plasma membrane,
where its membrane fuses and the contents are released.
Significant progress has been made in the understanding Translocation of granules to the cell membrane involves
of the β-cell function. In general, the broad details of the cytoskeleton and microtubules composed of polyme­
insulin biosynthesis, secretion and the glucose sensing rized tubulin subunits, which provide the mechanical
system are well established. However, large lacunae in framework, while actin, myosin and other motor proteins
our knowledge concerning the molecular details still provide the motive force.
remain. Complexities of cell specific and acute control of This regulated pathway, with complete cleavage of
insulin gene expression are just beginning to unfold. The proinsulin to insulin, normally carries 95% of the insulin
biochemical details targeting the insulin to the secretory produced by the β-cell. In certain pathological states
granules still remain sketchy and our knowledge of the such as type 2 diabetes and insulinoma, an alternative
 70 Physiology and Metabolism

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section

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lation of insulin secretion by glucose. Diabetes. 2000;49: calcium. Physiol Rev. 1981;61:914-73.
1751-60. 261. Jones PM, Persaud SJ, Howell SL. Time-course of Ca2+-indu­
246. Thomas PM, Cote GJ, Hallman DM, et al. Homozygosity ced insulin secretion from perifused, electrically permea-
mapping, to chromosome 11p, of the gene for familial per- bilised islets of Langerhans: effects of cAMP and a phorbol
sistent hyperinsulinemic hypoglycemia of infancy. Am J ester. Biochem Biophys Res Commun. 1989;162:998-1003.
Hum Genet. 1995;56:416-21. 262. Barg S, et al. Fast exocytosis with few Ca(2+) channels
247. Thomas PM, Cote GJ, Wohllk N, et al. Mutations in
in insulin-secreting mouse pancreatic B cells. Biophys J.
the sulfonylurea receptor gene in familial persistent 2001;81:3308-23.
hyperinsulinemic hypoglycemia of infancy. Science. 1995; 263. Samols E, Marri G, Marks V. Promotion of Insulin Secretion
68:426-9. by Glucagon. Lancet. 1965;2:415-6.
 78 Physiology and Metabolism

264. Wollheim CB, Biden TJ. Second messenger function of 281. Heaton DA, Millward BA, Gray IP, et al. Increased proin-
inositol 1,4,5-trisphosphate. Early changes in inositol sulin levels as an early indicator of B-cell dysfunction in
phosphates, cytosolic Ca2+, and insulin release in carbamyl­ non-diabetic twins of type 1 (insulin-dependent) diabetic
choline-stimulated RINm5F cells. J Biol Chem. 1986;261: patients. Diabetologia. 1988;31:182-4.
8314-9. 282. Hartling SG, Lindgren F, Dahlqvist G, et al. Elevated proin-
265. Peter-Riesch B, Fathi M, Schlegel W, et al. Glucose and sulin in healthy siblings of IDDM patients independent of
carbachol generate 1,2-diacylglycerols by different mecha- HLA identity. Diabetes. 1989;38:1271-4.
nisms in pancreatic islets. J Clin Invest 1988;81:1154-61. 283. Sestoft L, Heding LG. Hypersecretion of proinsulin in thyro-
section

266. Jones PM, Persaud SJ. Arachidonic acid as a second mes- toxicosis. Diabetologia. 1981;21:103-7.
senger in glucose-induced insulin secretion from pancre- 284. Gorden P, Sherman BM, Simopoulos AP. Glucose intoler-
2

atic beta-cells. J Endocrinol. 1993;137:7-14. ance with hypokalemia: an increased proportion of circu-
267. Persaud SJ, Roderigo-Milne HM, Squires PE, et al. A key lating proinsulin-like component. J Clin Endocrinol Metab.
role for beta-cell cytosolic phospholipase A(2) in the main- 1972;34:235-40.
tenance of insulin stores but not in the initiation of insulin 285. Duckworth WC, Kitabchi AE. Hyperproinsulinemia in

secretion. Diabetes. 2002;51:98-104. hypoglycemic subjects. Horm Metab Res. 1972;4:133-5.
268. Jones PM, Persaud SJ. Protein kinases, protein phos­
286. Hartling SG, Garne S, Binder C, et al. Proinsulin, insulin,
phorylation, and the regulation of insulin secretion from and C-peptide in cystic fibrosis after an oral glucose toler-
pancreatic beta-cells. Endocr Rev. 1998;19:429-61. ance test. Diabetes Res. 1988;7:165-9.
269. Tian YM, Urquidi V, Ashcroft SJ. Protein kinase C in beta- 287. Kanazawa Y, Awata T, Shibasaki Y, et al. Alteration of beta-
cells: expression of multiple isoforms and involvement in cell function in different diabetic states. Exp Clin Endo-
cholinergic stimulation of insulin secretion. Mol Cell Endo- crinol. 1984;84:346-51.
crinol. 1996;119:185-193. 288. Glaser B, , Leibovich G, Nesher R, et al. Improved beta-
270. Persaud SJ, Jones PM, Howell SL. Activation of protein cell function after intensive insulin treatment in severe
kinase C is essential for sustained insulin secretion in non-insulin-dependent diabetes. Acta Endocrinol
response to cholinergic stimulation. Biochim Biophys Acta.
(Copenh). 1988;118:365-73.
1991;1091:120-2.
289. Yoshioka N, Kuzuya T, Matsuda A, et al. Effects of dietary
271. Karlsson S, Ahrén, B. Cholecystokinin-stimulated insulin
treatment on serum insulin and proinsulin response in
secretion and protein kinase C in rat pancreatic islets. Acta
newly diagnosed NIDDM. Diabetes. 1989;38:262-6.
Physiol Scand. 1991;142:397-403.
290. Nagi DK, Hendra TJ, Ryle AJ, et al. The relationships of
272. Duckworth WC, Kitabchi AE. Direct measurement of

concentrations of insulin, intact proinsulin and 32-33
plasma proinsulin in normal and diabetic subjects. Am J
split proinsulin with cardiovascular risk factors in type 2
Med. 1972;53:418-27.
(non-insulin-dependent) diabetic subjects. Diabetologia.
273. Gorden P, Hendricks CM, Roth J. Circulating proinsulin-like
1990;33:532-7.
component in man: increased proportion in hypoinsuline-
291. Deacon CF, Schleser-Mohr S, Ballmann M, et al.

mic states. Diabetologia. 1974;10:469-74.
274. Mako ME, Starr JI, Rubenstein AH. Circulating proinsulin Preferential release of proinsulin relative to insulin in
in patients with maturity onset diabetes. Am J Med. 1977; non-insulin-dependent diabetes mellitus. Acta Endocrinol
63:865-9. (Copenh). 1988;119:549-54.
275. Ward WK, LaCava EC, Paquette TL, et al. Disproportion- 292. Temple RC, Carrington CA, Luzio SD, et al. Insulin defi-
ate elevation of immunoreactive proinsulin in type 2 (non- ciency in non-insulin-dependent diabetes. Lancet. 1989;1:
insulin-dependent) diabetes mellitus and in experimental 293-5.
insulin resistance. Diabetologia. 1987;30:698-702. 293. Clark A, Matthews DR, Naylor BA, et al. Pancreatic islet
276. Yoshioka N, Kuzuya T, Matsuda A, et al. Serum proinsulin amyloid and elevated proinsulin secretion in familial
levels at fasting and after oral glucose load in patients with maturity-onset diabetes. Diabetes Res. 1987;4:51-5.
type 2 (non-insulin-dependent) diabetes mellitus. Dia­ 294. Westermark P, Engström U, Westermark GT, et al. Islet
betologia. 1988;31:355-60. amyloid polypeptide (IAPP) and pro-IAPP immunoreactiv-
277. Hampton SM, Beyzavi K, Teale D, et al. A direct assay for ity in human islets of Langerhans. Diabetes Res Clin Pract.
proinsulin in plasma and its applications in hypoglycae- 1989;7:219-26.
mia. Clin Endocrinol (Oxf ). 1988;29:9-16. 295. Porte Jr D, Kahn SE. Hyperproinsulinemia and amyloid in
278. Ludvigsson J, Heding L. Abnormal proinsulin/C-peptide NIDDM. Clues to etiology of islet beta-cell dysfunction?
ratio in juvenile diabetes. Acta Diabetol Lat. 1982;19:351-8. Diabetes. 1989;38:1333-6.
279. Heding LG, Ludvigsson J, Kasperska-Czyzykowa T. B-cell 296. Thorens B, Weir GC, Leahy JL, et al. Reduced expression of
secretion in non-diabetics and insulin-dependent dia­ the liver/beta-cell glucose transporter isoform in glucose-
betics. Acta Med Scand Suppl. 1981;656:5-9. insensitive pancreatic beta cells of diabetic rats. Proc Natl
280. Snorgaard O, Hartling SG, Binder C. Proinsulin and C-pep- Acad Sci USA. 1990;87:6492-6.
tide at onset and during 12 months cyclosporin treatment 297. Efendić S, Wajngot A, Vranić M.. Increased activity of the
of type 1 (insulin-dependent) diabetes mellitus. Diabetolo- glucose cycle in the liver: early characteristic of type 2
gia. 1990;33:36-42. diabetes. Proc Natl Acad Sci USA. 1985;82:2965-9.
 Chapter 5
Biology of Insulin Action
Sushil Jindal

Biology of Insulin Action

Chapter Outline
♦♦ Biological Firsts about Insulin ♦♦ Post-receptor Events and Downstream Signaling
♦♦ Structure-Action Relationship of Insulin Molecule ♦♦ Anti-Inflammatory and Anti-Atherosclerotic Actions of
♦♦ Insulin Receptor Insulin

INTRODUCTION scientists. Apart from being pivotal in many Nobel Prize

winning researches, insulin is also associated with many
The importance of understanding the mechanism of biological firsts:
action of insulin is not limited to satisfying the intellectual • Insulin was the first protein whose complete amino
curiosities of cell biologists. It provides important steps in acid sequence was determined1
unraveling the pathogenesis of type 2 diabetes mellitus • Insulin was the first substance for which radioim­
and its complications. munoassay (RIA) was developed2
Insulin is an evolutionarily ancient hormone. Insulin- • Insulin was the first hormone whose 3D crystal
like gene family is identified in invertebrate species, where structure was solved3
the main function of insulin-like peptide hormones is • Insulin gene was among the first to be cloned by
regulation of tissue growth and development. However, recombinant DNA technology.4
in vertebrates, the mitogenic growth functions were
taken over by insulin-like growth factors (IGF-1, IGF-2). STRUCTURE-ACTION RELATIONSHIP OF
A structurally similar but diversified molecule, insulin INSULIN MOLECULE
evolved primarily to regulate metabolic functions and to
provide substrates to tissues for energy generation and Among vertebrate animals the structure of insulin
growth. Insulin became the primary hormone involved molecule seems to have been kept surprisingly stable
in glucose homeostasis in mammals. It acts on cells to during evolution. Hagfish, considered to be evolutionarily
regulate glucose, protein and fat metabolism by modifying the most ancient vertebrate, has 61% amino acid analogy
the activity of a variety of enzymes and transport systems. between its insulin and human insulin. The evolutionary
divergence between humans and hagfish is more than 400
BIOLOGICAL FIRSTS ABOUT INSULIN million years, yet the key amino acid sequences involved
in receptor binding are maintained.
Right from its discovery by Banting and Best, insulin Majority of known vertebrate insulins are composed
generated immense interest in biologists and medical of two polypeptide chains linked to each other by two
 80 Physiology and Metabolism
section
2

Fig. 5.1: Amino acid sequences of A and B chains of insulin and variations in different species and analogs

disulfide bonds. The A and B chains have 21 and 30 amino INSULIN RECEPTOR
acids, respectively (Fig. 5.1).
The key amino acid sequences, which are evolutionarily Like most peptide hormones, insulin also has cell surface
highly conserved are also important in receptor binding receptors. Such receptors have two important functions:
and any mutation or modification in these sites generally 1. To bind the hormone molecules present in extra-cellular
diminish or abolish the receptor binding and biological space with high affinity and specificity.
activity of the molecule. There is almost perfect correlation 2. To produce a transmembrane signal that modifies the
between binding affinity and biological action of the intracellular metabolism and initiates the actions of the
molecule, i.e. structural requirements for binding include hormone.
requirements for biological action also. This also means Actions of a hormone can vary from cell to cell and also
that there is no competitive antagonist of insulin action at in the same cell by presence or absence of other hormones
the receptor level. and substrates. Insulin responsiveness of any given tissue
Additions and alterations in amino acids at non- depends on presence of insulin receptors and their density
conserved positions and in positions not involved in on the surface of its cells. Insulin receptor density varies
binding with receptor can change the polymerization from cell to cell. There are only 40 insulin receptors on a
properties of insulin molecules. This has become the circulating erythrocyte while an adipocyte or a hepatocyte
basis for development of analogues of insulin with altered may have more than 200,000 insulin receptors on its
pharmacokinetics, by genetic engineering and recom­ surface. One important action of insulin is to regulate the
binant DNA technology, to suit the clinical requirements. entry of glucose into the cell. Those tissues with very few
 Biology of Insulin Action 81

POST-RECEPTOR EVENTS AND

DOWNSTREAM SIGNALING
Insulin binding at alpha subunits activates tyrosine
kinases in beta subunits leading to rapid auto-phospho­
rylation at multiple sites. It is more likely that the post­
receptor signaling involves recruitment of intracellular

chapter
signaling molecules collec­tively known as insulin recep­
tor substrates (IRS). There are nine such recognized IRS

5
molecules which carry out different metabolic and growth
promoting functions of insulin by series of phospho­
rylation and dephosphorylation reactions. Complicated
intracellular post-receptor events are now being unrave­
led. The IRS, their downstream pathways and final meta­
bolic effects are now more clearly being recognized. For
Fig. 5.2: Insulin receptor-Insulin binding and signal transduction inside example, phosphatidylinositol-3-kinase (PI3-kinase) path­
the cell way stimulates translocation of glucose transporters
(GLUT-4) to cell surface. GLUT-4 is responsible for glu­
cose uptake in skeletal muscle and adipose tissue. The
or no insulin receptors allow the glucose to diffuse inside
other insulin receptor signaling pathways are involved
the cytoplasm, along the concentration gradient. These
in stimulating glycogen synthesis, protein synthesis,
tissues, like nerve, vascular endothelium and renal parenc­
lipogenesis and regulation of various genes (Fig. 5.3).
hyma, are most vulnerable to prolonged hyperglycemic
The distribution of various IRS proteins in different
insults leading to the classical complications of diabetes.
tissues varies and hence the effects of insulin are different in
Insulin receptor belongs to a family of receptors called
different tissues. Defects in these post-receptor pathways
tyrosine kinases. Other receptors in this family are IGF-1
are postulated to be responsible for the insulin resistant
receptor and insulin receptor related (IRR) receptor. While
states and type-2 diabetes mellitus. Certain cytokines like
IGF-1 receptor is involved in growth regulation, the ligand
tumor necrosis factor (TNF)-alpha and cellular substrates
and functions of IRR receptor are not clear. Both insulin
like free fatty acids can interfere in these pathways and
and IGF-1 bind with their receptors with high degree of
may contribute to development of insulin resistance.
specificity, but at higher concentrations both have cross
reactivity with each other’s receptors. When developing
ANTI-INFLAMMATORY AND ANTI-
the analogues of insulin, the cross reactivity with IGF-1
ATHEROSCLEROTIC ACTIONS OF INSULIN
receptor becomes an important issue because greater
IGF-1 activity increases risk of developing neoplasia. Many earlier studies suggested that hyperinsulinemia
Acanthosis nigricans is a clinical marker of insulin is linked to increased cardiovascular events and athero­
resistance. This is a velvety pigmented overgrowth of sclerosis.5,6 The link between insulin resistance and
epidermis seen on the nape of neck. This is supposed to be cardiovascular events was also thought to be due to
due to high plasma concentration of insulin cross reacting hyperinsulinemia. In vitro studies showed vascular
with dermal IGF-1 receptors. smooth muscle proliferation with insulin, a marker
Insulin receptor is a tetrameric protein. It has two of atherogenecity.7,8 But in these experiments, insulin
alpha subunits which are protruding out of the cell concentrations used were far greater than ever seen in
membrane and are joined by a disulfide bond. Two patients. At these concentrations insulin can cross react
beta subunits are transmembrane and intrude into the with IGF-1 receptors and activate mitogen activated
cytoplasm. The two extracellular alpha subunits provide protein (MAP) kinase system. But no study has ever
two binding sites, which recognize and bind with insulin demonstrated increased MAP kinase activity in insulin
molecules. The beta subunits are catalytically active and resistance states in humans.
initiate cascade of metabolic activity inside the cell, after The oxidative stress and inflammation are the integral
insulin binds with alpha subunits (Fig. 5.2). part of atherosclerosis. Insulin has been shown to have
 82 Physiology and Metabolism
section
2

Fig. 5.3: Post-receptor signaling pathways

an anti-inflammatory effect in human mononuclear cell but the lack of insulin action in insulin resistant tissues,
in vivo and human aortic endothelial cells in vitro.9,10 A which is responsible for the pro-inflammatory and athero­
low dose insulin infusion suppresses nuclear factor kappa genic state. It is more likely that the genetic background,
B (NFkB), increases inhibitor kB (IkB) and suppresses increased glucose, associated lipid abnormalities and
reactive oxygen species (ROS) generation. Insulin also hypertension are responsible for accelerated athero­
suppresses the soluble intercellular adhesion molecule- sclerosis in insulin resistant states rather than the hyper­
1(sICAM) and MCP-1.11 Insulin has been shown to insulinemia. In type 2 diabetes mellitus, with advancing
inhibit genetic expression of matrix metalloproteins and duration of disease and progressive decline in beta cell
plasminogen activator inhibitor-1 (PAI-1), leading to an reserve, most patients become insulin deficient in later
anti-thrombotic effect.12,13 part of disease. This is the time they are most vulnerable to
Insulin also exerts a vasodilatory effect on arteries, cardiovascular disease. This argument again supports the
veins and capillary beds14,15 This is achieved by inducing view that it is not the insulin but the lack of insulin or its
nitric oxide synthase in endothelial cells.16-20 All these action which is cause of cardiovascular disease.
properties strongly suggest anti-inflammatory and anti- If insulin has anti-inflammatory and anti-athero­
atherogenic actions of insulin. sclerotic properties, can they be put to clinical use?
Then why there is an epidemiological link between In Diabetes and Insulin Glucose Infusion in Acute
insulin resistance, hyperinsulinemia and cardiovascular Myocardial Infarction (DIGAMI) study21 and Esudios
disease? It seems that it is not the hyperinsulinemia Cardiologicos Latinoamerica (ECLA) study22 continuous
 Biology of Insulin Action 83

insulin infusion in acute myocardial infarction markedly as IRS. Each of these have specific pathways leading to
improved the outcomes. In her famous study on a specific actions of insulin. The types of molecules in IRS
series of 1,500 patients in surgical ICU, van den Berghe and their density vary in different cells and hence the
reported23 dramatic improvement in outcomes with actions of insulin vary in different cells. Certain substances
insulin infusion. In this study, the mortality was reduced like free fatty acids and TNF-alpha can interfere in these
by half in intensively treated group with insulin infusion to signaling pathways and may be responsible for insulin
maintain the blood glucose of less than 110 as compared resistance.

chapter
to conventionally treated group with blood glucose of Insulin resistance is linked with increased cardio­

5
153 mg/dL. The intensively treated group also showed vascular risk. Insulin resistance is also associated with
significant reduction of C-reactive protein (CRP). In day to hyperinsulinemia. Based on these facts it is simple to
day clinical practice one can see remarkable improvement derive a conclusion that there is an association between
in wound dynamics after starting insulin in a patient of inulin and atherosclerosis. Furthermore, there are epide­
bad diabetic foot, which extends much beyond glycemic miological studies linking hyperinsulinemia to increased
control. cardiovascular events. But to the contrary, scientific
data show that insulin has anti-atherosclerotic, anti-
SUMMARY thrombotic and vasodilatory actions on vascular bed.
Atherosclerosis is considered a low grade inflammation of
Biologically, insulin is an ancient hormone. Insulin-like
vasculature. Experimental evidence suggests that insulin
peptide hormones were involved in regulation of growth
also has an anti-inflammatory action. This fact has been
and development in invertebrate animals. Insulin evolved
tested in clinical use. In DIGAMI study, insulin infusion in
into a major regulator hormone of carbohydrate, fat and
acute myocardial infarction remarkably improved the
protein metabolism in vertebrates. outcomes. While treating patients in surgical ICU, van den
The structure of insulin molecule has strikingly Berghe et al. showed that insulin infusion to keep blood
remained stable during evolution. Almost all vertebrate glucose less than 110, can bring down mortality by half.
insulins are comprised of two chains, A and B, joined
together by two disulfide bonds. A-chain consists of Further Reading
21 amino acids and B-chain has 30 amino acids. Key
1. Le Roith D and Zick Y.Recent Advances in Our Understand-
amino acid sequences are conserved over millions of ing of Insulin Action and Insulin Resistance. Diabetic Care.
years of evolution. The non-conserved amino acids can 2001;24:588-97.
be manipulated through genetic engineering to make 2. Dandona P, Aljada A, Mohanty P. The anti-inflammatory
synthetic analogues of insulin, retaining biological activity and potential anti-atherogenic effect of insulin: a new para-
digm. Diabetologia, 2002:45:924-30.
but with different degree of polymerization and pharma­
3. Dandona P, Aljada A, O’donnell A, et al. Insulin Is an
cokinetic properties. Anti-inflammatory and Anti-atherosclerotic Hormone.
Insulin specific cell surface receptors are widely spread Metab Syndr Relat Disord. 2004;2:137-42.
all over in various tissues of the body. The receptor density
varies from tissue to tissue and determines the insulin REFERENCES
responsiveness of a given tissue. Insulin receptor binds 1. Ryle A, Sanger F, Smith L, et al. The disulfide bonds of insu-
specifically to insulin molecule but there is some cross- lin. Biochem J. 1955;60:541-56.
reactivity with IGF-1 at higher concentrations. 2. Yalow RS, Berson SA. Immunoassay of endogenous plasma
insulin in man. J Clin Invest. 1960;39:1157-75.
Insulin receptor is a tetrameric protein consisting of
3. Adams M, Blundell T, Hodgkin D, et al. Structure of
two alpha and two beta subunits. The alpha subunits pro­ rhombohedral 2-zinc insulin crystals. Nature. 1969;224:
trude outside and are involved in identifying and binding 491-5.
insulin molecules. The beta subunits are trans-membrane 4. Ullrich A, Shine J, Chirgwin J, et al. Rat insulin genes: Con-
and intrude into the cytoplasm. After binding of insulin struction of plasmids on the coding sequences. Science.
1977;196:1313-9.
to alpha subunits, the beta subunits undergo a cascade of 5. Fontbonne AM, Eschwege EM. Insulin and cardiovas-
autophosphorylation and dephosphorylation reactions. cular disease. Paris Prospective Study. Diabetes Care.
These reactions involve many catalytic molecules known 1991;14:461-9.
 84 Physiology and Metabolism

6. Després JP, Lamarche B, Mauriège P, et al. Hyper-insuline- 14. Chaudhuri A, Kanjwal Y, Mohanty P, et al. Insulin induced
mia as an independent risk factor for ischemic heart dis- vasodilatation of internal carotid artery. Metabolism.
ease. N Eng J Med. 1996;334:952-7. 1999;48:1470-3.
7. Stout RW, Bierman EL, Ross R. Effect of insulin on the pro- 15. Grover A, Padginton C, Wilson MF, et al. Insulin attenuates
liferation of cultured primate arterial smooth muscle cells. norepinephrine-induced venoconstriction. An ultrasono-
Circ Res. 1975;36:319-27. graphic study. Hypertension. 1995;25:779-84.
8. Huang B, Dreyer T, Heidt M, et al. Insulin and local growth 16. Scherrer U, Randin D, Vollenweider P, et al. Nitric oxide
factor PDGF induce intimal hyperplasia in bypass graft release accounts for insulin’s vascular effects in humans.
section

culture models of saphenous vein and internal mammary J Clin Invest. 1994;94:2511-5.
artery. Eur J Cardiothorac Surg. 2002;21:1002-8. 17. Zeng G, Quon MJ. Insulin-stimulated production of nitric
2

9. Aljada A, Ghanim H, Saadeh R, et al. Insulin inhibits oxide is inhibited by wortmannin. Direct measurement in
NFKappaB and MCP-1 expression in human aortic endo­ vascular endothelial cells. J Clin Invest. 1996;98:894-8.
thelial cells. J Clin Ednocrinol Metab. 2001;86:450-3. 18. Aljada A, Dandona P. Effect of insulin on human aortic
10. Aljada A, Saadeh R, Assian E, et al. Insulin inhibits expres- endothelial nitric oxide synthase. Metabolism. 2000;49:
sion of intracellular adhesion molecule -1 by human aortic 147-50.
endothelial cells through stimulation of nitric oxide. J Clin 19. Guo JP, Murohara T, Buerke M, et al. Direct measurement
Ednocrinol Metab. 2000;85:2572-5. of nitric oxide release from vascularendothelial cells. J Appl
11. Dandona P, Aljada A, Mohanti P, et al. Insulin inhibits Physiol. 1996;81:774-9.
intracellular nuclear factor kappaB and stimulates Ikap- 20. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediat-
paB in mononuclear cells in obese subjects: evidence for ed skeletal muscle vasodilation is nitric oxide dependent. A
anti-inflammatory effect? J Clin Ednocrinol Metab. 2001;86: novel action of insulin to increase nitric oxide release. J Clin
3257-65. Invest. 1994;94:1172-9.
12. Ghanim H, Mohanti P, Aljada A, et al. Insulin reduces pro- 21. Malmberg K, Ryden L, Hamsten A, et al. Mortality predic-
inflammatory transcription factor, activation protein-1 tionin diabetic patients with myocardial infarction: expe-
(AP-1), inmononuclear cells (MNC) and plasma matrix riences from the DIGAMI study. Cardiovasc Res. 1997;34:
metalloproteinase-9 (MMP-9) concentration. Diabetes. 248-53.
2001;50:A408. 22. Diaz R, Paolasso EA, Piegas LS, et al. Metabolic modulation
13. Aljada A, Ghanim H, Mohanti P, et al. Insulin inhibits of acute myocardial infarction. The ECLA (EstudiosCardio-
the pro-inflammatory transcription factor early growth logicosLatinoamerica) Collaborative Group Circulation.
response gene-1 (Egr-1) expression in mononuclear cells 1998;98:2227-34.
(MNC) and reduces plasma tissue factor (TF) and plasmi- 23. van den Berghe G, Wouters P, Weekers F, et al. Inten-
nogen activator inhibitor-1 (PAI-1) concentrations. J Clin sive insulin therapy in critically ill patients. N Engl J Med.
Ednocrinol Metab. 2002;87:1419-22. 2001;345:1359-67.
Section 3

diagnosis
and
classification
Section Editor: Hemraj B Chandalia
 Chapter 6
Definition, Diagnosis
and Classification
Paturi V Rao, BB Tripathy

Diagnosis and Classification

Chapter Outline

♦♦ Diagnosis ♦♦ Classification
♦♦ Screening for Diabetes ♦♦ Future Considerations

DEFINITION limits) with or without glucosuria and a tendency to

develop ketoacidosis. Polyuria, polydipsia, asthenia and
It is customary to enunciate the definition of each disease weight loss, the cardinal symptoms of severe hyper­glyce­
dealt within textbooks. The practice is useful as the atten­ mia, may not be present in a proportion of cases. There is
tion of the reader is focused to the core characteristics of an increased susceptibility to bacterial and fungal infec­
the disorder before he/she proceeds to comprehend the
tion. In course of time, prolonged hyperglycemia and
details. At one time, it was considered difficult to define
associated metabolic aberrations result in tissue toxicity
diabetes1 to any degree of precision as the diagnostic
manifested as accelerated atherosclerosis, renoretinal
criteria were so much more arbitrary. The problem still
microangiopathy and neuropathy leading to a variety of
remains and to add to it, the widely acknowledged dictum
vascular, neurological and focal complications.
is that diabetes mellitus is to be regarded as a syndrome
rather than a single disease. Primarily diabetes evolves from interaction of genetic
The definition may be abridged as brief as in (1) or and environmental factors resulting in autoimmune des­
more comprehensive as in (2). truction of the b-cells or progressive deterioration in b-cell
1. Brief: Diabetes mellitus is a heterogeneous chronic capacity on the face of gross defects in insulin action.
metabolic disorder principally characterized by persis­ Diabetes also occurs in association with some well-defined
tent hyperglycemia resulting from defects in insulin genetic syndromes and acquired disorders of the pancreas
action and/or insulin secretion. and the endocrine apparatus.
2. Comprehensive: Diabetes mellitus comprizes of a
group of chronic metabolic disorders involving the DIAGNOSIS
principal metabolic fuels, carbohydrates, fats as well as
proteins. The disorder results from absolute or relative Introduction
deficiency in insulin secretion often along with defect Diagnosis of diabetes is for life. It entails certain lifestyle
in insulin action. and social restraints as well as mounting therapeutic
The syndrome of diabetes mellitus is characterized obligations. All these are compounded with problems
by chronic hyperglycemia (blood glucose above defined of employment and insurance. Hence, there is need for
 88 Diagnosis and Classification

extreme care in conclusively establishing diagnosis of O’toluidine and Ferricyanide methods.14 These were
diabetes mellitus. On the other hand, any delay in the in common use until enzymatic (glucose oxidase and
process would raise the risk of tissue damage and long- hexokinase) procedures were widely available and more
term complications. autoanalyzers were pressed into service.
Difference in the glucose content of arterial (capillary)
History and Development and venous blood, possibly first appreciated by Hagedorn
(1921)15 were subsequently worked out, among others,
For over two millennia following discovery, diagnosis of
section

by Mosenthal and Barry,13 Goldberg and Luft.16 It is

diabetes was based on passing of large volume of urine,
3

since known that arteriovenous (AV) differences may be

hence the labels of “Bahumutra” and “pissing evil”. Next
negligible at fasting, but widen appreciably in the post­
to the inscriptions in the Egyptian papyrus (1550 BC) and prandial periods. Compared to venous, arterial (capillary)
immaculate description of polyuria by ancient Indian blood may be higher by 25−40 mg at 1 hour and 8−15 mg
physicians (600−400 BC) were the graphic observations at 2 hours following a glucose load. Samples of arteriolized
of Demetrius of Apamea (200 BC) that the excessive capillary blood collected randomly up to certain periods
water drinking and profuse urination in the disorder after meals have a higher content of glucose compared
appeared “as if passing through a siphon”. Corroborated to venous glucose.
by Celsus in the first century AD, this led to the genesis of Preferences for estimation of glucose in plasma
the term “Diabetes”2 that has so far stood the test of time. instead of whole blood were evinced since the later half
Sweetness of urine that attracted insects was documented of the seventh decade.17,18 It was realized that plasma
by the ancient discoverers of Madhumeha in India (rain of glucose would very closely reflect the concentration of the
honey). Yet, it was unknown in Europe until Thomas Willis metabolite in extracellular fluid. Further values of glucose
(1674) rediscovered the sweet taste that he attributed to in whole blood are influenced by hematocrit (a variable)
excess of sulphur and other chemicals.3 It was for Mathew because of lower water content of the formed elements.
Dobson (1776)4 to recognize sugar in the dried residue of The process of glycolysis is largely stalled when plasma is
urine and to observe that plasma of patients of diabetes promptly separated following collection of blood. Plasma
also tasted sweet. The sugar in urine was identified as is more convenient for use in autoanalyzers. Serum has the
glucose by 1835 while the presence of glucose in blood was same advantages, but to preserve glucose content, speed
established some years later.5 Although initially reported of coagulation needs to be stepped up. Plasma (serum)
by Rollo,6 Claude Bernard was the first to establish correla­ glucose measures 14−15% higher than that of whole blood.
tion between glycosuria and excess sugar (glucose) in Benedict's reagent provides a quantitative test for
reducing sugars along with qualitative test. It can be
blood which he considered to be released from raised
used to test for the presence of glucose in urine. This test,
glycogen stores in the liver in response to neurogenic
widely known as Benedict's test, remains in use in certain
stimuli.7 Estimation of blood glucose in normal persons
parts of the world. Clinitest that does not require a burner,
was difficult at that period of time. Biochemical procedures
may be less sensitive but is more specific for reducing
for testing of reducing substances in urine and estimation
sugars. Lactosuria (during late pregnancy and lactation)
of glucose in small samples of blood were developed by
and much rarer fructosuria and galactosuria require to
the second decade of the twentieth century.8-10 Glucose be differentiated when the above tests are used. Since
tolerance test (GTT) was first conceived by Hofmeisten availability of glucose oxidase impregnated test strips
(1889).11 Subsequently, Alien undertook analysis of crude (clinistix), urine testing has been simplified and made
data from GTT available till 1913.12 The test was practised more specific. By and by, ketostix, albustix, diastix (glucose
more extensively following availability of more convenient and ketone), uristix (glucose and albumin) and multistix
laboratory methods later in the decade.9,10 Refinements have been available for self-monitoring and laboratory use
in the procedures for estimation13 of “true” glucose in with reasonable accuracy.
blood in exclusion of other reducing substances such Rapid estimation of blood glucose by dextrostix
as glutathione, ergothionine and creatinine that account came into vogue in the late 60s. Improvements in range,
for variable proportions of glucose estimated by Folin accuracy, convenience and record keeping (memory) are
and Wu procedure was achieved by Somogyi-Nelson, continuing till date. Today, bed side tests by paramedics
 Definition, Diagnosis and Classification 89

and self-monitoring provide reasonably accurate results with corticosteroid therapy. When glucose is present in
for hospital screening and monitoring of control. Most urine all the time even at the fasting state (plasma glucose
brands estimate (capillary) whole blood, while few others of 80 mg/dL), the condition is (true) renal glycosuria
provide plasma glucose. It is felt that venous plasma (ikshumeha: Sushruta). On the other hand, when gluco­
glucose is still the best for epidemiological screening and suria is noted during early postprandial periods and after
for first diagnosis of impaired glucose tolerance (IGT) or glucose load (while 2-hour values of blood glucose do not
diabetes mellitus in the absence of frank symptoms.18 exceed 140 mg/dL)—the possibilities are that of alimentary

chapter
glycosuria, as 30–60 minute postprandial blood glucose
Current Status

6
values rise above 180 mg/dL. It may occur at lower glucose
level (100–160 mg/dL) in cases with low renal threshold
Laboratory tests available for the diagnosis and manage­
(pseudo-renal glycosuria). The latter is possibly more
ment of diabetes will be discussed in later chapters. Basic
tests for diagnosis of the disease have been mentioned likely to be associated with diabetes and therefore needs
in the following paragraphs. Diagnosis of diabetes can more careful follow-up.19 In the past, in population surveys
never be established without estimation of blood/plasma following glucose load, glycosuria has been noted in 3–4%
glucose. Yet, urinalysis may also be extremely useful in of subjects while diabetes was diagnosed in 1–2%.20,21 Thus,
providing indications for its diagnosis, facilitating control glycosuria in fasting state has relatively high specificity
and treating some of its complications. albeit low sensitivity for the diagnosis of diabetes.
Urine glucose has been shown to be a very poor
Urinalysis indicator of levels of plasma glucose particularly in
patients with type 1 diabetes [insulin dependent diabetes
Urine examination is called for routinely in most clinical mellitus (IDDM)] with wild swings in glycemic status.
situations. Finding of sugar in urine during routine test In stable diabetes with standard renal threshold, semi-
offers the first clue for detection of diabetes in a number of quantitative assessment of urine glucose, several times
instances. Test for ketones in urine is essential at diagnosis during a day, may be utilized for assessment of control
and whenever fasting plasma glucose (FPG) exceeds between periodic tests for plasma glucose and glycated
240 mg/dL. Additional tests for protein, leucocytes, red hemoglobin. Estimation of 24-hour urinary glucose has
cells and bacteriuria are equally important at periodic been used as a useful indicator of control in case of type
follow up. Hence the prevailing trend, to overlook 1 diabetes. In conclusion, urinalysis is essential both at
examinations of urine initially and at each follow-up, diagnosis and follow-up of diabetic status. A positive urine
cannot be encouraged. Normally, a small amount of glucose test for glucose still remains the single most common
(30–150 mg/dL) is excreted in urine. Tests for sugar in indicator for the diagnosis of diabetes.22 Although absence
urine (Benedict’s, Clinitest) are usually positive at levels of or presence of glucose in urine cannot be solely depended
300 mg/dL or above. Other reducing substances are on for the exclusion, diagnosis or assessment of control
lactose, fructose, galactose, large amounts of ascorbic of diabetes—the utility of urinary findings may not be
acid and glucoronic acid (in conjugation with salicylates ignored in any of these situations.
or other drugs) may reduce Benedict’s reagent as does
glucose. Testape, clinistix, diastix, uristix, combistix, Blood and Plasma Glucose
multistix and the like are specific for glucose as reaction is
mediated by the enzyme glucose oxidase. High levels of blood/plasma glucose is diagnostic of
Glycosuria is not uncommon without hyperglycemia. diabetes, but “exactly beyond how much is too much
Renal tubular capacity to reabsorb glucose may be vari­ in different situations” has so far remained open to
able. Further the completeness of the process depends controversy. Tests are carried out as FPG or random blood
on the load as determined by the glomerular filtration glucose (RBG) at any part of the day irrespective of food
rate (GFR) and on levels of plasma glucose. The so called intake or following carbohydrate (glucose) loads. GTT has
renal threshold may physiologically vary from 140 mg to been utilized as the gold standard for diagnosis of early
230 mg with a median of 180 mg/dL. It may rise to 300 mg diabetes. In most populations, values of plasma glucose
in case of substantial drop in GFR. Low renal threshold have a continuous (unimodal) distribution. Cut-off points
is more common at younger age, during pregnancy and for abnormality have to be rather arbitrary and subject to
 90 Diagnosis and Classification

Table 6.1: Diagnosis of diabetes: interpretation of oral glucose tolerance test

Glucose load Sample Maximum Normal values (mg/dL)
(Venous) fasting 1 hour 1½ hours 2 hours 3 hours
Mosenthal and Barry 100 g Blood 100 150 — 100 —
(1950)23
Fajans and Conn (1959)24 1.75 g/kg Blood — 160 — 140 120
Plasma — 185 — 160 140
section

United States Public Health 100 g Blood 110 170 120 110 —
3

Services (USPHS) Plasma 125 195 140 125 —

Wikersen25
British Diabetes 50 g Blood — 160 110 — —
Association26 Plasma — 180 130 — —
University Group 30 g/sqm Blood Sum of values 500 mg or greater
Diabetes Study Body Plasma Sum of values 600 mg or greater
Programme27 Surface

Table 6.2: Criteria for diagnosis of diabetes and impaired glucose tolerance (IGT): National Diabetes Data Group (NDDG) (1979),28 World
Health Organization (WHO) (1980)29 in non-pregnant adults. Glucose load-75g, values-mg/dL (mmol/L)
Fasting whole Plasma 2-hour postglucose capillary Whole blood Plasma Capillary blood
blood
Diabetes > 120 (6.7) 140 (7.8) 120 (6.7) 180 (10.0) 200 (11.1) 200 (11.1)
NDDG at either > 180 (10.0) 200 (11.1) 200 (11.1)
½ hour 1 or 1½ hour
IGT < 120 (6.7) 140 (7.8) 120 (6.7) 120–179 140–199 140–199
(6.7–10) (7.8–11.1) (7.8–11.1)

variations (Table 6.1). Two standard deviations or three National Diabetes Data Group (1979), and
standard errors of measurement (SEM) above the mean World Health Organization (1980)
values obtained from sizeable samples of normal subjects,
as adopted by Fajans and Conn,24 appears to be one of the Fasting Glucose
more logical methods for fixing the dividing line between Overnight fasting for 8–14 hours is considered desirable.
the non-diabetic and the diabetic glucose tolerance. Yet,
In case of exigency, 4 hours after a modest meal may
follow-up of subjects diagnosed to have diabetes based
be taken as fasting but is far from ideal. In the past,
on any of the above standards, contrary to expectation,
upper limit for true blood glucose at fasting has been stated
often reverted to normal. Further many of them would
to be 110 mg/dL (plasma glucose 125 mg/dL) by various
not develop any evidence of microvascular complications
authors but the diagnostic value for diabetes was not
even after 10 years of diagnosis.
clearly spelt out either by Fajans and Conn,24 United States
More recent criteria adopted by the National Diabetes
Data Group (NDDG) of United States of America (USA)28 (US) Public Health Service (USPHS)25 or the University
and the World Health Organization (WHO)29 (1979, 1980) Group Diabetes Program (UGDP)27 (Table 6.1). Frank
have been based on plasma levels corresponding to diabetes was usually diagnosed at 130 mg/dL up to 1979,
appearance of diabetes specific microangiopathy. Further when NDDG28 and the WHO Expert Committee (1980)29
skewed and bimodal distribution of plasma glucose recommended diagnosis of diabetes at 120 mg/dL (6.7
values in high prevalence population groups such as Pima mmol/L) and 140 mg/dL (7.8 mmol/L) of fasting venous
Indians, Nauru Micronesians,30 South African Indians whole blood and plasma glucose respectively. These
and Mexican Americans31 have provided indication for recommendations were widely accepted and followed
the dividing zone between the normal and the abnormal. until recently (Table 6.2).
Such values are much less likely to revert to normal on Increasing awareness of a sustained stage of pre­
long term follow-up. diabetes in the natural history of diabetes and the
 Definition, Diagnosis and Classification 91

prospect of fruitful intervention particularly for primary data analysts have recommended need for oral glucose
prevention, in the context of high prevalence of type 2 tolerance tests (OGTT) in subjects with FPG of 100 mg/dL
diabetes, has led to greater attention to impaired fasting (5.55 mmol/L).
glucose/glycemia (IFG) along with IGT. American Dia­ The attempt to increase the sensitivity of fasting
betes Association (ADA) Expert Committee (1997)32 glucose value (by lowering limit to 100 mg/dL) to match
conceived IFG under the shadow of IGT and defined it IGT in predicting progress to diabetes, leads to an increase
as fasting glucose of 110–125 mg/dL (6.1–6.9 mmol/L). in the number reckoned to have IFG by 2.6 times covering

chapter
The lower limit of 110 mg/dL was adopted based on the 24.1% of the USA population. The increase is by 4.6-fold

6
contemporary acceptance of 109 mg/dL as the upper rise among younger people between 20 years and 49 years
limit in case of normal glucose regulation. No attention of age. Another analysis reveals the rise of number with
was paid to the aspect of homology with the criteria for IFG to be from 10% to 35% of the adult population by the
IGT, the other method of looking at prediabetes. In the new standards.40 Yet, there may not be any clinical benefit
meantime, analysis of individual and population data from this change. Glycated hemoglobin (HbA1c) figures
revealed gross lack of equivalence between the criteria do not appear to be affected.41 Around 94% of persons
set for IFG and IGT. A high proportion of individuals with with FPG between 100 mg and 109 mg have HbA1c values
IGT, even diabetics diagnosed by 2-hour postglucose within normal limits. Only in 0.045%, the levels may be
(PG) standards, are found to have FPG below 110 mg/dL. as high as 7.1% indicating negligible effect on incidence
In the Diabetes Epidemiology: Collaborative Analysis of microvascular complications.40 On the other hand,
of Diagnostic Criteria in Europe (DECODE) study, 18% the stigma of IFG may create problems in the fields of
subjects with fasting glucose of ~110 mg/dL had their insurance and employment. In contradiction, it has been
diabetes diagnosed by 2-hour PG criteria.33 Analysis of stated that the identification of a larger proportion of
eight large population studies by Unwin et al. revealed people with IFG is consistent with the raising epidemic
IFG alone in 23%, compared to IGT alone in 60% while of type 2 diabetes in USA and a number of developing
only 16% had both.34 Findings such as the above called for countries. This may lead to adoption of more aggressive
revision of criteria in order to set-up homology between prophylactic measures in order to delay or prevent
IFG and IGT. progression to diabetes.40,42 As such measures are not yet
A large population study revealed fasting value of based on evidence, it is imperative to undertake large
106 mg/dL as the 95th percentile, which may be indicative studies-like Diabetes Prevention Program (DPP)43 among
of the upper limit of normal.35,36 An elegant Pima subjects with IFG. A proportion of DPP subjects had
Indian study by Gabir et al. calculated the fasting value fasting levels between 95 mg/dL and 109 mg/dL. Among
of 102.6 mg/dL as equivalent to levels diagnostic of IGT controls, 6.4% were projected to develop diabetes in next
in marking out similar proportion of people having 12 years—while among study subjects, those managed
glucose problems (dysglycemia).37 Similar data have been with lifestyle changes (diet and exercise regime) only 2.9%
obtained from analysis of receiver operator characteristic were considered vulnerable to develop diabetes after a
(ROC) curves in four large population studies. The ability longer follow-up period of 24 years, on average. But, these
of base line levels of FPG to later prediction of diabetes at impressive results may not be applicable to IFG, as all DPP
fasting level more than 126 mg/dL or 2-hour PG of more study subjects had IGT in the first place.40
than 200 mg/dL close to 100% sensitivity and specificity Analysis of data from National Health and Nutrition
was realized at 103 mg/dL in a Dutch population, 97 mg/dL Examination Survey (NHANES) III study reveals that
in case of Pima Indians, 94 mg/dL in Mauritius and 94 mg/ among subjects with FPG between 100 mg/dL and
dL from the San Antonio Study.38 110 mg/dL, 98% have one or more features of metabolic
Based on such information, the Expert Committee syndrome such as dyslipidemia (76.8%), hypertension
constituted by ADA set 99 mg/dL (5.5 mmol/L) as the (40%), unfavorable body mass index (BMI) (50.9%) and all
upper limit of normal fasting glucose and 100–125 mg/dL three in 21%. Although any of these would call for caution,
(5.6–6.9 mmol/L) as criterion for impaired fasting glyce­ the added stigma of IFG may provide further warning
mia (glucose) (IFG). By this, the lower limit of IFG has sign for seeking medical advice and to adopt lifestyle
been brought down from 110 mg/dL to 100 mg/dL. By and modification measures. A more compelling evidence has
by, the WHO Consultation (1999)39 as well as DECODE come out from a meta-analysis of 20 published studies
 92 Diagnosis and Classification

Table 6.3: Criteria for classes of plasma glucose abnormalities: for diagnosis of diabetes early from the third decade of
American Diabetes Association (ADA) 1997,32 World Health Organi- the twentieth century. For over 50 years, the procedures
zation (WHO) 199939 and diagnostic criteria adopted by different investigating
Fasting 2-hour postglucose mmol/L (mg/dL) centers were far from uniform. The glucose load used was
Normal < 6.1 (110) < 7.8 (140) 50 g in Europe, Great Britain and their erstwhile colonies,
Diabetes > 7.0 (126) >11.1 (200) while it was 100 g in most countries across the Atlantic. A few
IFG 6.1–6.9 (110–125) — epidemiology groups used 75 g glucose as a compromise
section

IGT — 7.8–11.0 (140–199) before the end of the eighth decade. Samples for testing
were collected variably every half-hour for 2 hours or
3

Glucose: mmol/L (mg/dL)

IFG: Impaired fasting glycemia (glucose) hourly for 3 hours. Diagnostic values differed depending
Modified to 5.6–6.9 mmol/L (100–125 mg/dL) on one or the other recommendation shown in Table 6.1.
ADA (2003)38 This created difficulties in the comparison of epidemiologic
(IGT: Impaired glucose tolerance) or even clinical data reported from different centers.
Yeoman services were rendered by the NDDG
involving 95,783 persons, among whom 3,707 manifested followed by the WHO Expert Committee by thorough
cardiovascular (CV) events in course of a 12.4 years of survey of contemporary literature and formulation of
follow-up. Results reveal that persons having FPG close recommendations on procedures and diagnostic criteria
to 110 mg/dL had a 1.33 times higher risk for developing with regard to GTT for universal adoption. The simplified
CV disease (CVD) compared to those with 75 mg/dL.44 version of these early recommendations has been ever
Overall, it may be argued that the lowering of FPG criterion since followed all over the World in clinical practice,
for IFG has been an objective to achieve homology with epidemiologic and other research. Borderline values were
IGT without looking for substantial evidence in its favor. spelt out and the term IGT was introduced to replace old
Yet, it is expected in knowledgeable circles that the terminology on the preclinical stages of diabetes. Thus
ADA recommendations may be endorsed by the WHO the stigma of “diabetes” was removed from such groups
Committee sooner or later. Criteria for diagnosis of of subjects where there was no certainty of progression to
diabetes and related glycemic abnormalities are presented frank diabetes in reasonable period of time. The glucose
in Table 6.3. load was fixed as 75 g anhydrous glucose or its equivalent
for adults of all ages and body weight and 1.75 g/kg for
Random Blood Glucose children up to a maximum of 75 g. Table 6.2 presents
recommendation on OGTT criteria for diagnosis of
Samples for test may be collected at any time of the day diabetes and IGT.
irrespective of prandial status. Prior to 1980, venous whole
blood level of 160 mg/dL was taken as upper limit in most American Diabetes Association (1997), World
places including the Joslin Clinic. Later, in the presence of Health Organization (1998–99)
typical symptoms, a sole plasma or capillary blood glucose In course of the decade following the final recommen­
of 200 mg/dL or venous whole blood of 180 mg/dL is dation of the WHO in 1985,45 a plethora of clinical and
accepted as diagnostic of diabetes. In the absence of frank epidemiological data called for a revision of recommen­
symptoms, a second test is needed to confirm the diagnosis. ded diagnostic criteria. The outstanding issues were:
In case the screening test is by capillary blood glucose, two • A gross discrepancy in homology or equivalence
further tests using venous plasma are needed for confir­ between the fasting and 2-hour PG criteria for diagnosis
mation of diagnosis in subjects who are asymptomatic. of diabetes.
This applies to fasting, random as well as 2-hour PG tests. • Emergence of new epidemiologic data, indicating
These cut off points first suggested by NDDG28 in 1979 sharp rise in incidence of microvascular lesions
have been accepted by the WHO Study Group.29 (retinopathy) at lower levels of fasting plasma glucose.
The lack of equivalence between diagnostic FPG
Glucose Tolerance Test criterion of 140 mg/dL (7.8 mmol/L) and 2-hour PG value
Standard GTT (SGTT) and OGTT, its modifications and of 200 mg/dL (11.1 mmol/L) was evident in most studies.
1 or 2 hours PG blood/plasma sugar estimations have been One outstanding revelation emerged from analysis of data
regularly utilized in clinical and epidemiologic studies generated by NHANES in USA. It was found that while
 Definition, Diagnosis and Classification 93

in nearly all cases with values of more than 140 mg/dL recommend the use of fasting glucose alone for both
at fas­ting, the 2-hour PG levels were up to or above clinical and epidemiological evaluations except in case
200 mg/dL, only 25% among the latter (with 2-hour PG of pregnant women. On the other hand, the WHO expert
levels > 200 mg/dL) had fasting values up to 140 mg/dL. Committee39 decided to retain use of OGTT for borderline
Thus, 140 mg/dL46 at fasting indicated a relatively greater cases in clinical practice and particularly in epidemiology
degree, of metabolic abnormalities than 2-hour PG value of surveys because of its greater sensitivity and as fasting
200 mg/dL. In course of search for the equivalent fasting state cannot be ensured particularly in field studies.

chapter
value for 2-hour PG value of 200 mg, it was located at 126 Keeping the above in view, the diagnostic cut off point

6
mg/dL in contingency tables constructed from epidemio­ for plasma glucose was fixed at 126 mg/dL (7.0 mmol/L)
logic data from 13 pacific populations. The number diag­ in place of 140 mg/dL (7.8 mmol/L) while that for 2-hour
nosed to have diabetes at cut off point of 126 mg/dL, at PG was retained at 200 mg/dL (11.1 mmol/L) in view of
fasting was found to be nearly the same as determined the appropriateness of the basis on which this value was
with 2-hour PG values of 200 mg/dL.47 adopted in the past (Table 6.2). WHO Committee (1999)39
Population studies from Pima Indians,48 among Egyp­ recommends the use of OGTT wherever fasting values lie
tians49 and analysis of NHANES III32,50 data revealed that between 100 mg/dL and 125 mg/dL (5.6–6.9 mmol/L). As
a sharp rise in the incidence of retinopathy occurred at diabetes should not be diagnosed from a single glucose
fasting levels of 117 and 123 mg/dL. Furthermore points of value in the absence of characteristic symptoms both
intersection in the bimodal distribution of plasma glucose fasting and OGTT values are preferred for diagnosis of
in high prevalence groups fall approximately at 129 mg/dL early diabetes.
for fasting and 207 mg/dL in case of 2-hour PG values.51 In addition to defining plasma glucose values for
With regards to macrovascular manifestation analysis of diagnosis of diabetes, the Committee specified two states
data on peripheral vascular disease among Pima Indians,52 where the values fall between those found in subjects
incidence of coronary disease in Paris Prospective Study53 with normal glucose regulation and those diagnosed to
and Baltimore Longitudinal Study32 indicate threshold have diabetes. Because of enhanced risk of progression
for rise in incidence appeared around 120–125 mg/dL at to diabetes and development of vascular lesions, 2-hour
fasting and at 140 mg of 2-hour PG plasma glucose. By PG values between 140 mg/dL and 199 mg/dL (7.8–11
then available data suggested that the threshold for rise mmol/L) have been designated as IGT by NDDG (1979)28
in incidence of retinopathy may fall between fasting levels and WHO (1980)29 in their recommendations. These
between 117 mg/dL and 125 mg/dL and 2-hour PG levels recommendations have been ratified by both ADA32 and
of 195–207 mg/dL.51 WHO.39 On similar grounds, fasting values higher than
Raised fasting blood plasma glucose has all along been those seen in individuals with perfect glucose regulation
regarded to have high degree of specificity for diagnosis. but lower than the cut-off point for diagnosis of diabetes
On the other hand, for over a century the sensitivity of the were designated as IFG. The upper limit of normal was
fasting parameter has been widely questioned. This has taken as 109 mg in consideration of data from Paris
led to introduction of tests for carbohydrate tolerance, Prospective Study57 and observations that there was
particularly the OGTT. For long, OGTT has been practised decline in first phase insulin secretion following IV glucose
as the gold standard for early diagnosis of evolving diabetes. beyond this level.58 This led the Committee to adopt
In course of time, the reproducibility of results from this fasting values between 110 mg/dL and 125 mg/dL (6.1–7
procedure has also been observed to be inconsistent. By mmol/L) as IFG, a term suggested by Charles et al. in 1991
1970,54 the authenticity of OGTT as the most dependable (Table 6.3).
diagnostic tool has been challenged. In the USA, OGTT The recommendations of the ADA and the WHO vary
was seldom used in clinical practice55 as this procedure more widely in case of gestational diabetes mellitus (GDM).
was considered to be cumbersome and time consuming. ADA recommends and American physicians adhere to
Furthermore, it has been observed that the reproduci­ method set by O’Sullivan and Mahan59 from their original
bility of fasting glucose is distinctly better than that of work on diabetes in pregnancy evaluating 752 pregnant
2-hour PG values when repeated after 2–6 weeks. The women and subsequent follow-up of 1,013 women for
coefficient of variation has been estimated to be 6.4 for 10 years. The procedure involved 3-hour GTT with 100 g
repeat fasting glucose values compared to 16.7 for PP of oral glucose. The diagnostic levels were recommended
values.56 On these grounds, ADA Expert Committee49 as blood glucose values estimated by Somogyi-Nelson
 94 Diagnosis and Classification

Table 6.4: American Diabetes Association (ADA) criteria for Table 6.5: Comparative prevalence of diabetes among those iden-
diagnosis of gestational diabetes mellitus59 tified singly as impaired glucose tolerance (IGT), impaired fasting
OGTT (100 g) Plasma (mg/dL) Glucose (mmol/L) glucose/glycemia (IFG) or both assessed by five outstanding studies

Fasting 95 5.3 Glucose level mmol/L Prevalence %

1 hour 180 10.0 148 233 361 437 537

2 hours 155 8.6 2-hour PG only 11.1 (200 mg/dL) 6.7 3.5 5.9 7.5 14.4

3 hours 140 7.8 Fasting only 7.0 (126 mg/dL) 4.8 3.9 4.0 6.4 12.35
section

Fasting and 2-hour PG both 8.0 5.8 7.2 9.2 15.3

Note: Two or more values must be met or exceeded for diagnosis
3

of GDM.
(OGTT: Oral glucose tolerance tests). (PG: Postglucose).

method. Modified to plasma glucose by glucose oxidase highest figures were obtained in all studies when both
technique, the figures adopted by ADA (1997)32 stand as were recorded. Thus, any one of the tests alone missed
follows (Table 6.4). a substantial number of subjects, at risk for developing
On the other hand, WHO Consultation39 recommends complications and needing medical care. In another
use of 75 g OGTT with limit of FPG targeted at 126 mg/dL population analysis of 20,000 persons, it has been
(7.0 mmol/L) and 2-hour plasma glucose at 140 mg/dL observed that, among diabetic subjects diagnosed by
(7.8 mmol/L). WHO criteria are more sensitive and detects 2-hour PG values of 200 mg/dL—more than 50% had FPG
more subjects with diagnosis of GDM. But, there are no less than 126 mg/dL. Scanning data from eight population
comparable long-term follow-up data on adverse fetal studies, Unwin et al.34 estimated that diagnosis of diabetes
effects or maternal risk for development of diabetes. In was made in 23% based on fasting and 60% from 2-hour
view of much greater simplicity and popularity of WHO PG values each considered alone, while only 16% had
recommendation and its popularity, a large National abnormal fasting and 2-hour PG values.
Institutes of Health (NIH) funded multinational study has Furthermore, calculations from NHANES III reveal
been launched aiming to cover 25,000 pregnant women that, among newly diagnosed diabetics, 14% fulfilled
from 16 diverse geographical locations to assess validity of fasting and 41% 2-hour PG values, and the rest met both
the system. the criteria.60 The 2-hour PG value is more sensitive to
Evaluation of the new recommendations by ADA detect diabetes than fasting alone while both tests would
(1997)33 and WHO (1999)40 individually and in comparison establish diabetes in a larger number of subjects.
to each other started soon after the publications of these The clinical implications of fasting hyperglycemia
reports. Comparison was particularly made in the field of (ADA)32 compared to raised 2-hour PG values (WHO)4
epidemiology (prevalence studies) where sensitivity and have been looked for in a number of studies. Testing FPG
specificity of the criteria were estimated. Criteria for IFG alone is empowered to detect IFG while OGTT is needed to
and IGT were also evaluated on predictability for prog­ identify IGT. Comparisons of the predictive values of these
ression to diabetes and microvascular or macrovascular two states broadly establish that IGT is more sensitive
manifestations. Data from five large epidemiologic studies in predicting progression to diabetes, development of
were analyzed for prevalence figures estimated by the CV complications and increase in mortality. In a longi­
ADA recommended FPG values and by 2-hour PG values tudinal population-based study to test the ability of IFG
as per WHO Consultation. Results from reanalysis of and IGT for predicting development of diabetes in
data generated by (1) NHANES III (USA),60 (2) DECODE Mauritius, Shaw et al. observed that IFG values predicted
(Europe),33 (3) Diabetes Epidemiology: Collaborative progression to type 2 diabetes in 26% of subjects, and a
Analysis of Diagnostic Criteria in Asia (DECODA) (Asia)61 further 35% could be identified by prior presence of IGT.62
(4) Pacific and Indian Ocean island (Mauritius)37 and A Pima Indian study tested 2,443 subjects having either
(5) PimaIndians37 are summarized in (Table 6.5). IGT, IFG or both; the cumulative number progressing
It is clear that, except in the DECODE where data from to diabetes was 19.9%, 31.0% and 41.2%, respectively.
several nations obtained over decades were collated, The predictive value of fasting glucose of 6.1–6.9 mmol/L
prevalence of diabetes was found to be 1–2% higher by (110–125 mg/dL) was higher than that of IGT between
2-hour PG test than by fasting criteria alone, while the 7.8 mmol/L and 9.2 mmol/L (140–167 mg) but similar to
 Definition, Diagnosis and Classification 95

2-hour PG values between 9.3 mmol/L and 11 mmol/L WHO Committee39 appreciated the value of HbA1c that
(167–200 mg/dL) indicating lack of equivalence and need offered almost equal sensitivity and specificity as plasma
for performing both tests for diagnosis and predictions.37 glucose for assessment of the diabetes status and to pre­
The same group of workers observed that predictive power dict development of vascular complications. Yet, it was
for microvascular manifestations of IFG among Pima considered inappropriate and impracticable as by then
Indians was 4–7% and that of IGT was 1.6%—while in procedures for measurement of HbA1c lacked standardi­
diabetics diagnosed either by fasting value or 2-hour PG zation and it was not widely available in large parts of

chapter
level, it was similar (19.2% vs 20.0%) after a follow-up the World.
period of 10 years. There was no increase in risk of morta­ The question of utility of HbA1c in diagnosing diabetes

6
lity either with IFG or IGT in Pima Indians while that and prediabetes, and its possible advantages have been
risk was much higher among subjects diagnosed with discussed in the Committee. One obvious disadva­ntage is
diabetes by either criterion.63 Thus, FPG marked out that several unrelated conditions such as hemoglobino­
smaller number of people with risk of diabetes and its pathies, hemolytic anemias, uremia, pregnancy and blood
complications in Pima Indians, and it appears to predict transfusion may alter the values of HbA1c. Further,
higher risk levels compared to IGT as far as microvascular although methodology for its estimation has been stand­
complications are concerned. ardized in laboratories within USA and a few other
On the other hand, 7-year follow-up study (1990–1997) countries, this procedure has not been available in many
in Japan revealed IGT to be a greater risk factor for CV other parts of the World. Hence, the adoption of HbA1c as
mortality. At the end of the study, cumulative survival a diagnostic parameter was deferred for future conside­
rates from cardiovascular disease was significantly lower ration.38 ADA recommends that this test should be
for subjects with IGT (0.962) and diabetes (0.954), respec­ performed in a laboratory using a method that is National
tively, when compared to subjects with NGT (0.988).64 Glycohemoglobin Standardization Program (NGSP)
In a DECODE report, isolated 2-hour PG hyperglycemia certified and standardized to the Diabetes Control and
(IPH) was found to be common (33%) among the elderly Complications Trial (DCCT) assay. Diabetes is diagnosed
with mortality risk similar to diabetes.65 Results from at HbA1c level more than or equal to 6.5%, and HbA1c
Framingham Offspring Study revealed a 40% higher rela­ between 5.7% and 6.4% is indicative of preclinical diabetes.
tive risk (RR) for CVD with 2-hour PG hyperglycemia
than with fasting glucose,66 thus emphasizing the need
SCREENING FOR DIABETES
for 2-hour PG test for detection of additional cases with
increased risk for CV events. In the context of raging epidemic of type 2 diabetes all
With the above in view, it may be concluded that IGT over the World, health authorities have prevention pro­
determined by OGTT (2-hour PG plasma glucose) has grams at the top of their concerns. Recent observations
higher sensitivity to detect more individuals with risk of on success of intervention efforts in subjects with IGT
developing diabetes, its macrovascular complications have raised the need for early detection of prediabetic
and mortality, and it is therefore a desirable adjunct to states of IFG and IGT. As screening of the entire adult
estimation of FPG. It appears that fasting and 2-hour PG population is extremely difficult and may not be cost
values identify different aspects of glucose homeostasis. effective, the consensus is to screen subjects at high risk
In the DECODE Study more than 50% of those diagnosed for the disorder.67-69 Criteria for selection of such subjects
as diabetic with abnormal 2-hour PG values had normal are listed as follows in Table 6.6.
fasting values and vice versa.65 It is hypothesized that Although the currently prescribed IFG criterion of
while abnormal fasting values may be due to lower insulin 100–125 mg/dL may be sensitive and have lesser variabi­
secretion, isolated IGT possibly indicates greater role of lity for confirmation, OGTT with determination of 2-hour
insulin resistance.39 PP value may be of real value for confident adoption of any
preventive programs. Dual testing, it is felt, may be more
Glycated Hemoglobin comprehensive as it has been suggested that fasting and
The feasibility of adopting parameters other than plasma 2-hour PG abnormalities may represent different facets of
glucose values for diagnosis of diabetes has been consi­ glucose metabolism.39 As such, assessment of both values
dered from time to time. In this context, HbA1c has may be more appropriate for screening of select subjects
been considered as the prime choice. Both ADA32 and as per indications listed above. In conclusion, it may be
 96 Diagnosis and Classification

Table 6.6: Risk factors for Type 2 Diabetes of diabetes mellitus as a syndrome rather than a single
• Persons over 45 years age, 35 years for South Asians disease.72 Lawrence73 classified diabetes as type 1 or juve­
• Those with obesity, especially central obesity nile diabetes with absolute insulin deficiency and type 2
• South Asians abroad, native Americans, Mexican or MOD with relative deficiency of insulin (Table 6.7).
• Americans In addition, another rare, clinically distinct form of the
• Persons with any microvascular, coronary, cerebral or periph-
disorder, “lipoatrophic diabetes” was brought to notice
eral vascular disease
around the middle of the fifth decade.74 Thus by 1955,
• People with dyslipidemia, hypertension
section

• Women with history of gestational diabetes mellitus (GDM) or primarily three types of diabetes were recognized in
3

birth of large babies United Kingdom (UK) and the western World.75
• Women with polycystic ovary disease Diabetes occurring in association with calcific panc­
reatic disease and hemochromatosis has been deciphered
from 178876 and 1865,77 respectively. Gluco­suria, abnormal
opined that the ADA (2003)41 recommended criteria for
glucose tolerance or diabetes have been described in
diagnosis of diabetes and prediabetes appear appropriate
patients with diseases of the endocrine glands such as
except for the negative attitude for OGTT. Extensive
acromegaly,78 hyperthyroidism79 and Cushing syndrome80
screening for diabetes and prediabetes must be the order
during the first few decades of the present century. Several
of the day in view of the rising epidemic of type 2 diabetes
stages in the development of diabetes were discerned with
and consequent increase in CV and renal mortality and
extensive use of the GTT and follow-up studies in course of
neuropathic morbidity. OGTT with estimation of 2-hour
PG plasma glucose is simple, universally available and the 50s and early 60s of the twentieth century.
can identify IGT, a state of great clinical significance. The term “Prediabetes”81 (preferably “potential dia­
betes”) was applied to subjects with strong family history,
such as diabetes in both parents and diabetes in the
CLASSIFICATION
identical twins as well as in women with very poor obstetric
Hyperglycemia, the sine qua non of diabetes mellitus, may history and those giving birth to large babies. Abnormal
occur in a variety of situations from a number of related GTT during periods of stress and cortisone primed GTT82
and unrelated pathophysiologic aberrations. As a widely were classed as “latent” or “latent chemical” diabetes.
heterogeneous disorder, diabetes inevitably has distinctly Subjects with abnormal GTT, but normal fasting blood
divergent modes of clinical presentation, course and glucose were diagnosed to have chemical or subclinical
therapeutic responses. diabetes.1,83 Clinical or overt diabetes was diagnosed
Differences in clinical picture of patients passing in the presence of frank symptoms and/or raised fasting
large volume of sweet (honey) urine (madhumeha) that blood glucose.1 This system of staging of diabetes remai­
attracted ants was appreciated in the antiquity by Charak ned popular throughout the seventh and eighth decades
and Sushruta (600–400 BC). Some were observed to be of the last century.
lean and languishing from severe polyuria, thirst and Observations on two hitherto unknown clinical types
dehydration, while others were characterized by stout of diabetes were brought to light from tropical developing
built, gluttony and indolence. These distinctions were countries during the 50s. Hugh-Jones described occur­
next documented by the French physicians Bouchardat rence of severe diabetes in some lean young subjects
and Lancereaux70 who classified the patients as diabete in Jamaica who did not develop ketosis and required
maigre (small, lean) and diabete gras (large, fat). By the high doses of insulin for control (J type)84 while Zuidema
early decades of the twentieth century, these classes detected diffuse pancreatic disease with calcification in
were distinguished as juvenile onset diabetes (JOD) or malnourished young subjects with diabetes85 (Table 6.7).
growth onset, ketosis prone, brittle diabetes on one hand The need for a generally acceptable appropriate system
and maturity onset diabetes (MOD), adult onset, ketosis of classification became more and more imperative with
resistant, stable or lipoplethoric diabetes, on the other. discovery of insulin, assessment of insulin sensitivity,
Difference in the pathophysiology of these two major advent of oral hypoglycemic agents, radio-immuno­
types was first perceived by Himsworth who characterized assay of plasma insulin and availability of information on
one as insulin sensitive and the other as insulin insensitive follow-up studies of abnormal GTT during pregnancy and
diabetes mellitus.71 Further, he was the first to speak other situations. An effort in this direction was initiated by
 Definition, Diagnosis and Classification 97

Table 6.7: Classification of diabetes mellitus: Historical background and current development
A. Historical Background
I. Major Classes Class I Class II
(600–400 BC) Charak and Sushruta Severe, lean, thirsty, dehydrated (genetic) Obese, indolent, fond of sweet and fatty
food (gluttony)
1875 Bauchardat Young, severe Older, obese

chapter
1880 Lancereaux (French) Diabete maigre (small, lean) Diabete gras (large, fat)
1910–1920 Juvenile onset diabetes (JOD), Ketosis prone, Brittle Maturity onset onset diabetes (MOD)

6
stable, ketosis resistant, lipoplethoric
1936 Himsworth Insulin sensitive Insulin insensitive
1951 Lawrence Type 1: Absolute insulin deficiency Type 2: Relative insulin deficiency

II. Other Classes

1946–1951 Lawrence Lipoatrophic diabetes
1955 Hugh-Jones J-type diabetes, ketosis resistant diabetes in the young
(KRYD)
1955–1959 Zuidema (Z-type) Pancreatic calcification and diabetes in malnourished
young subjects
1961–1964 O’Sullivan Glucose intolerance during pregnancy, gestational
diabetes
1974–76 Maturity onset diabetes in young (MODY) Mason type
Taltersall and Fajans
B. Current Development
I. Major Classes
1979–1980 NDDG, WHO Insulin-dependent diabetes mellitus (IDDM) Non-insulin-dependent diabetes mellitus
(NIDDM)
1985 WHO IDDM NIDDM
1997 ADA and WHO 1998–1999 Type 1 Type 2
(Type 1 and Type 2 not synonymous with IDDM,
NIDDM)
II. Other Classes
1979–1980 NDDG and Gestational diabetes mellitus (GDM)
WHO 1995, 1999, Criteria modified
1985 WHO • Malnutrition-related diabetes mellitus (MRDM)
• Fibrocalculous pancreatic diabetes (FCPD)
• Protein-deficient pancreatic diabetes (PDPD)
1987 (Cuttack) Protein-deficient diabetes melltus (PDDM) to replace
PDPD
1995 (Cuttack) Malnutrition-modulated diabetes mellitus (MMDM) to
replace PDDM
FCPD due to fibrocalculous pancreatopathy to be
classed under “pancreatic diseases”.
ADA 1997 Monogenetic defect in β-cell function: phenotype-
MODY
WHO1998 Deletion of MRDM. Shifting of FCPD to “diseases of
exocrine pancreas” section
WHO 1999 May be MMDM in place of PDDM for which more
studies are needed

(NDDG: National Diabetes Data Group (USA); ADA: American Diabetes Association; WHO: World Health Organization).
 98 Diagnosis and Classification

WHO in1965.86 Unfortunately, the Expert Committee felt Table 6.8: Classification of diabetes mellitus and allied categories
that it was “obviously possible to define diabetes types of glucose intolerance (WHO 1985)45
according to the period of life when the disease begins A. Diabetes mellitus (DM) clinical classes
and becomes manifest”. Contemporary and subsequent Insulin-dependent diabetes (Can be considered
observations indicated that the classification principally same as type 1)*

based on age at onset, was untenable and unsuitable Non-insulin-dependent diabetes mellitus (Can be considered
(NIDDM) same as type 2)*
for general use. Further, their unqualified emphasis on
section

a. Non-obese
protective role of undernutrition was controversial and
b. Obese
3

open to question.
c. Lean (low body weight)**
Malnutrition-related diabetes
Current Status mellitus (MRDM)
The next collective effort on formulation of criteria for Other types of diabetes associated with
diagnosis and classification of diabetes were made by the certain conditions and syndromes.
NDDG of USA toward the end of the eighth decade and 1. Pancreatic disease
a comprehensive report was brought out in 1979.28 Next 2. Disease of hormonal etiology
year the WHO Expert Committee on diabetes mellitus 3. Drug-induced or chemical-induced
conditions
virtually reiterated the same recommendations except for
4. Abnormalities of insulin or its recep-
modifications in the diagnostic criteria for IGT and GDM.29
tors
A WHO Study Group set-up to finalize these interim
5. Certain genetic syndromes
recommendations brought out a “Revised Classification”
6. Miscellaneous
in 1985.45 This classification of diabetes mellitus by WHO
Impaired glucose tolerance (IGT)
is aimed at devising a system based on simple, readily
a. Non-obese
obtainable clinical and biological data. The classes were
b. Obese
meant to be easily definable and mutually exclusive at
c. Lean (low body weight)**
the point, although follow-up might alter the status at
d. Associated with certain conditions
subsequent times. The terminology was required to be and syndromes
precise and descriptive of the phenotypic expression of Gestational diabetes mellitus (GDM)
the disorder. It was considered imperative to include all B. Statistical risk classes (subjects with
possible forms of diabetes mellitus on a global perspective. normal glucose tolerance but substantially
The WHO classification (1985)45 has been widely accep­ increased risk of developing diabetes)

ted internationally and the terms employed have been Previous abnormality of glucose
tolerance
incorporated in the WHO International Nomen­clature of
Potential abnormality of glucose toler-
Diseases (1991) and the 10th revision of the International
ance
Classification of Disease (1992). This classification with
*Recommended by WHO Study Group
minor supplements is reproduced in Table 6.8. Problem
**Additions by the author
with the prevailing system is that it is based on a combi­
nation of clinical and etiological background designed to
2. Malnutrition-related diabetes mellitus (MRDM) as a
be useful for purposes of manage­ment and epidemiology. major clinical class with two divisions: (1) fibrocalculous
Further, there has been scope for controversy in at least pancreatic diabetes (FCPD) and (2) protein-deficient
three more areas: pancreatic diabetes has been questioned as hypo­
1. Although “type 1” and “type 2” are not identical with thetical and unrealistic particularly by those who have
insulin-dependent diabetes mellitus (IDDM) and non- hardly any opportunity to come across such clinical
IDDM (NIDDM) their omission from the table with material in the areas of their activity.87 Technical objec­
the recommendation for continued use of the terms as tions have been validly raised to the use of the term
synonymous32 irrespective of the pathogenetic consid­ “protein-deficient pancreatic diabetes”, for patients
eration have raised confusing problems for teaching who do not have any evidence of diffuse pancreatic
and research personnel. pathology. Hence by 1987–1988, the term was modified
 Definition, Diagnosis and Classification 99

to “protein deficient diabetes mellitus (PDDM)”. 88 view, in 1995 the ADA set-up an Expert Committee and
FCPD was classified as a form of MRDM as it was most the WHO a Consultation Group. The report of the former
commonly seen in places of deficient dietary intake with was published in 199732 and a provisional report of the
an excessive consumption of cassava or yam as in Kerala latter in 1998. All forms of diabetes pass through the stages
and Nigeria. Further, most patients of FCPD attending of IGT before progressing to clinical or overt diabetes
charitable hospitals appeared to be undernourished. (Table 6.8). This system of staging has been retained as
But FCPD also occurs in many areas where cassava, yam such, except for modification in criteria for FPG. In

chapter
or sorghum are not consumed in significant amounts addition to IGT, with 2-hour PG plasma glucose values

6
as well as in a good number of patients with normal intermediate between normal and diabetes (140–199
nutritional status.89,90 As diabetes in these patients occurs mg/dL), a new class “IFG” with fasting plasma glucose
in association with diffuse pancreatic disease (tropical values covering 110–125 mg/dL was introduced in view
calcific pancreatitis/fibrocalculous pancreatopathy), of the potential of such levels to raise the risk of vascular
FCPD has to be reckoned as a form of secondary dia­ complication (Table 6.3).32,39 The values have been revised
betes. Hence, its placement in the same slot with PDDM to 100–125 mg/dL by ADA in 2003.38
next to IDDM and NIDDM that are regarded as primary
With the sole objective to classify the ubiquitous and
appears incongruous. most commonly prevalent clinical forms of diabetes exclu­
To sort out these controversies, an International Work­ sively on the basis of etiopathogenesis, the committees
shop was convened in October 1995, at Cuttack (India) have done away with the terms IDDM and NIDDM while
where there was scope to exhibit adequate number of retaining type 1 and type 2. Patients with diabetes that
patients classified as either PDDM or FCPD. Following results from extensive destruction of β-cells and tend to
discussions, it was generally felt that although fetal be prone to ketoacidosis are classed as type 1. In a large
and early life malnutrition was potentially diabetogenic majority of such patients, the β-cell destruction can be
and can obviously modify clinical expression of diabe­ attributed to autoimmune process (type 1a), while in the
tes, protein deficiency by itself was unlikely to give rise case of some, the mechanism cannot be identified with
to severe diabetes, as proposed in PDDM. Hence this certainty (Type 1b. Idiopathic). The most common major
form of diabetes, reported fairly commonly in certain form of diabetes termed as type 2 results basically from
tropical areas, was by consensus termed as “malnu­ impairment of insulin action (insulin resistance) along
trition-modulated diabetes mellitus (MMDM)”. It was with defects in insulin secretion.
agreed upon to distinguish FCPD as a special form of Taking a plea from the “consensus statement” formu­
pancreatogenous diabetes that was to find a place in lated by the International Workshop (1995)83,93 held at
the section dealing with “other types of diabetes associ­ Cuttack, the Committee has dispensed with the common
ated with certain conditions and syndromes”.91,92 term MRDM. Further as recommended therein, “FCPD”
3. The third point of controversy was regarding criteria resulting from fibrocalculous pancreatopathy has been
for diagnosis of GDM. While the ADA32 continues to shifted to the class of diabetes associated with “diseases of
recommend the O’sullivan and Mahan criteria based the exocrine pancreas”.32,94 While the ADA has remained
on 3-hour GTT following 100 gm of glucose load, 59 silent or non-commital on PDDM, the WHO Consultation
WHO consultation (1985)45 and the most recent ones group has stated that PDDM “may be considered as
since 199939 recommend use of 75 g glucose load and malnutrition modulated or modified form of diabetes
plasma glucose measurements at 2-hour. Pregnant mellitus for which more studies are needed”39 as possibly
women who meet the WHO criteria for diabetes mellitus for any other type of diabetes. As already mentioned,
or IGT are to be classified as having GDM. the WHO Consultation Group has recommended the
As already stated the 1985 WHO45 classification was recognition of IGT (in addition to diabetes) as GDM when
based partly on therapeutic requirement (IDDM, NIDDM) detected first time during pregnancy.39
while the rest (MRDM, GDM, “other types of diabetes Total omission of the terms IDDM and NIDDM appears
associated with”) on etiology. With progress in knowledge premature. The basis of classification of diabetes should
on etiology and pathogenesis, it was keenly felt that time preferably be clinic-etiopathological rather than simply
was ripe for a revised classification that would be useful etiological particularly as the etiology of the primary
for current clinical and epidemiological research as forms of diabetes is thus far only partially understood.
well as for the therapeutic management. With these in A relatively young person with diabetes, in the absence
100 Diagnosis and Classification

of ketosis, may belong to type 1, type 2, monogenic [maturity cell-related antibodies predicted graded and variable islet
onset diabetes in young (MODY)] or latent autoimmune cell dysfunction due to autoimmune β-cytopathy, short
diabetes in adults (LADA) category. To sort this out, even of subtotal destruction. Antibody testing was found to be
plasma insulin and C-peptide values may not suffice. useful for prediction of early insulin requirement (rather
Autoimmune status, genetic and clamp studies may be than insulin dependence) in subjects with onset below
required for final classification. These are not widely 45 years of age.98
available even in the more advanced countries. By remai­ It has been suggested that the term LADA may be
section

ning somewhat callous to the needs of the clinician, the applied to patients with type 2 diabetes with onset at
3

ADA Committee has been alluded to have performed or after 35 years of age and positive for GAD antibody
an imperfect academic exercise. “For whom then, if not titers more than 30 IU/mL. Below this serum level, the
clinicians and patients, was the classification created?”93 GAD positivity may be transient. Assigning a new term
appears to be a pertinent question. LADA and not combining it with type 1 class signifying its
The natural history in the development of type 1 and insulin-dependence may be less misleading and clinically
type 2 diabetes may be very variable. Destruction or gross more relevant. An earlier suggestion for distinction
dysfunction of β-cells due to autoimmunity or occasionally of this diabetes as a type 1 and ½ half or type IVa may
to other causes may progress rapidly or in stages to variable also be applicable to LADA as it may be reckoned as a
extents leading to clinical expression of type 1 diabetes. A separate type of diabetes in which β-cell deficiency due
similar situation is also well-known in case of the type 2 to autoimmunity and not insulin resistance plays a major
variety. The confusing state of affairs continue following role in the pathogenesis of diabetes. The topic has been
reports published by ADA32 and the current classification updated and discussed in greater detail in a subsequent
strategies as encountered in Europe and North America.95 Chapter 7. The prevalence of islet cell antibodies (ICA)-
The main impulse to do away with the terms IDDM related autoantibodies is around 9–10% among type 2
and NIDDM was based possibly on the discovery of LADA patients in Western Europe.98 Whereas, ICA512 or GAD
that may be pathogenetically akin to type 1 but clinically antibody was detected in around 45% of type 2 patients
manifest as NIDDM or type 2. It was construed that from Cuttack in Eastern India. Suprisingly, the former
practically all these subjects would sooner or later develop (ICA512), known to be associated with rapid destruction of
absolute insulin deficiency and insulin dependence. In β-cells in the West was also more common among patients
course of time, this has been observed not to be so. In a in Cuttack.99
10-year follow-up, only16% of glutamate decarboxylase The need for an updated clinico-pathologic classifi­
(GAD) antibody positive patients presenting as type cation continues to remain a paramount need for
2 diabetes developed absolute insulin deficiency.96 A clinical practice and epidemiological documentation.
larger and comparative study on clinical and genetic An exclusive etiological classification has to wait until
characteristics of type 2 diabetes positive for GAD adequate progress is made so that the basic cause can be
antibody revealed that the situation was more frequent determined by means applicable to a large proportion of
among patients with onset at or below 45 years age than clinicians around the world.
among those above that age (20 vs 8%).97 Further, while Keeping the above in view, a modified system of ADA
high risk genotypes were found to be far less common classification is given in Table 6.9. Those relating to type
than in type 1 diabetes, the incidence was significantly 1 and type 2 diabetes are based on the points discussed
higher in those with onset below 35 years than in the rest. above. LADA with prevalence of over 10–20% of adults
Moreover, the younger GAD antibody positive patients with diabetes all over the World has earlier been
revealed a relatively lower insulin and C-peptide response incorporated at category III of the classification. But, it
to glucose and glucagon and a less frequent association does not find a place in the current classification, as it was
with features of the metabolic syndrome compared to not considered a separate class of diabetes. Major portions
those with onset above 45 years of age. The latter group of the rest of the ADA classification are basically non-
of patients may continue to behave as typical type 2 controversial and self-explanatory, and hence they have
diabetes all the way. In a 6-year follow-up study of 3,672 been incorporated as such in Table 6.9. Some changes
subjects from the United Kingdom Prospective Diabetes have been considered necessary in order to differentiate
Study (UKPDS), it was observed that presence of islet the conditions where diabetes mellitus appears as the
 Definition, Diagnosis and Classification 101

Table 6.9: Clinical classes of diabetes mellitus: etiologic classification, American Diabetes Association (ADA), 2013100
I. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
A. Immune mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect
with insulin resistance)
III. Other specific types

chapter
A. Genetic defects of β-cell function
1. Maturity onset diabetes in young (MODY) 3 [Chromosome 12, hepatocyte nuclear factor 1α (HNF-1α)]

6
2. MODY 1 (Chromosome 20, HNF-4α)
3. MODY 2 (Chromosome 7, glucokinase)
4. Other very rare forms of MODY (e.g. MODY 4: Chromosome 13, insulin promoter factor-1; MODY 6: Chromosome 2, NeuroD1;
MODY 7: Chromosome 9, carboxyl ester lipase)
5. Transient neonatal diabetes (most commonly ZAC/HYAMI imprinting defect on 6q24)
6. Permanent neonatal diabetes (most commonly KCNJ11 gene encoding Kir6.2 subunit of β-cell adenosine triphosphate-sensitive
potassium (KATP) channel)
7. Mitochondrial deoxyribonucleic acid (DNA)
8. Others
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipoatrophic diabetes
5. Others
C. Diseases of the exocrine pancreas
1. Pancreatitis
2. Trauma/pancreatectomy
3. Neoplasia
4. Cystic fibrosis
5. Hemochromatosis
6. Fibrocalculous pancreatopathy
7. Others
D. Endocrinopathies
1. Acromegaly
2. Cushing’s syndrome
3. Glucagonoma
4. Pheochromocytoma
5. Hyperthyroidism
6. Somatostatinoma
7. Aldosteronoma
8. Others
E. Drug or chemical induced
1. Vacor
2. Pentamidine
3. Nicotinic acid
4. Glucocorticoids
5. Thyroid hormone
6. Diazoxide
7. β-adrenergic agonists
8. Thiazides
9. Dilantin
10. γ-Interferon
11. Others
Contd....
102 Diagnosis and Classification

Contd....
F. Infections
1. Congenital rubella
2. Cytomegalovirus
3. Others
G. Uncommon forms of immune-mediated diabetes
1. “Stiff-man” syndrome
2. Anti-insulin receptor antibodies
section

3. Others
3

H. Other genetic syndromes sometimes associated with diabetes

1. Down syndrome
2. Klinefelter syndrome
3. Turner syndrome
4. Wolfram syndrome
5. Friedreich ataxia
6. Huntington chorea
7. Laurence-Moon-Biedl syndrome
8. Myotonic dystrophy
9. Porphyria
10. Prader-Willi syndrome
11. Others
IV. Gestational diabetes mellitus
Note: Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself,
classify the patient.

sole or predominant manifestation (primary) from others considered a single pathologic entity that exhibited a
where diabetes is associated with certain known disorders. spectrum of symptoms, with a few subtle differences
In that context, MMDM and FCPD, previously placed between two putative classes (Table 6.7). The subsequent
together under the head of MRDM have been considered adoption of guidelines from the ADA and the WHO
as pancreatitis or pancreatopathy placed under a section defining two types of diabetes-based on the extremes of
including exocrine pancreatic disease (Table 6.9). clinical presentation (juvenile, insulin-sensitive vs adult,
insulin-resistant) ignored the complete spectrum of dis­
FUTURE CONSIDERATIONS ease presentation. Thus, new categories such as type 1½
double diabetes and LADA evolved to describe the range
The classical distinctions of type 1 and type 2 diabetes of symptoms seen in patients103-105.Several commentators
are becoming blurred, with a greater emphasis on the have argued that it is now appropriate to return to the
consideration of diabetes as a spectrum that encompasses more nuanced concept of diabetes as a complex disease
the extremes of classical type 1 and type 2 diabetes, but entity that may have a wide range of presentations.106,107
which captures the significant number of individuals who The definition of prediabetes-based upon IGT
fall between these historical classifications. The incidence assessed by an OGTT was introduced many years ago.
of both type 1 and type 2 diabetes is increasing, with Subsequently, the classification of IFG was introduced
pediatric patients now presenting with features typical to provide a less complicated and expensive parameter.
of type 2 rather than type 1, reflecting the mixed nature IFG and IGT are now thought to actually reflect different
of many cases of diabetes. While the emphasis has been aspects of the development of insulin resistance in type
centered on the obesity epidemic and the associated 2 diabetes, with differing underlying pathologies.108-110
increase in metabolic syndrome and type 2 diabetes, Specifically, IGT is associated with peripheral insulin
the incidence of type 1 diabetes is also increasing due to resistance and loss of first-phase insulin secretion and
increased obesity.101,102 second-phase insulin secretion, while IFG is associated
It is not generally appreciated that the current with hepatic insulin resistance and absence of first-phase
classification scheme for diabetes is a relatively recent insulin secretion. These distinctions in location of insulin
phenomenon. Prior to the 1970–1980, diabetes was resistance and extent of β-cell dysfunction are consistently
 Definition, Diagnosis and Classification 103

seen in Native American,111 Mexican-American,112 and major autoantigen in type 1 diabetes that, with IAA, GAD
adult113 and adolescent114 Caucasian populations, and not and IA-2α, permits detection of 98% of patients at disease
in many other World populations. onset124 and to facilitate diagnosis of type 1 diabetes in non-
The current ADA guidelines for diagnosis of diabetes pediatric patients under 40 years of age125 and adult-onset
and prediabetes115 are based largely upon the notion that autoimmune diabetes/LADA.126,127 Thus, a comprehensive
there is a threshold FPG concentration above which the autoantibody panel based upon current knowledge would
risk of diabetes-specific microvascular complications include IAA, GAD, IA-2α and ZnT8. Relevant parameters

chapter
(specifically retinopathy) is significantly increased. In would include the number of positive autoantibody

6
other words, the strong chance of developing retinopathy species, further stratified by affinity or epitope specificity.
is equated with the presence of clinically defined type The main pediatric population for autoantibody scree­
2 diabetes. It has been recently noted that there were ning is children with suspected type 1 diabetes and their
significant problems with the population-based studies siblings, since most newly diagnosed type 1 diabetes
upon which the current diagnostic criteria are based,116 patients have at least one autoantibody124 and that the risk
including small sample size, inadequate knowledge of for development of type 1 diabetes is related to number
the glycemic history of the participants and the inherently of autoantibodies present, with any one denoting a
poor reproducibility of OGTTs. A more recent study, based 27-fold increase in risk.128,129 Additionally, recent studies
upon more carefully controlled analyses, has raised issues have shown that children or adolescents can present with
about the adequacy of the retinopathy assessments in putative type 2 diabetes, but actually have an autoimmune
these earlier studies, and by relying on newer population component that is only discernable by autoantibody
studies, has concluded that there is no clear inflection point screening, and who may require different therapeutic
in the relationship between FPG and risk of retinopathy.117 strategies.130,131 Autoantibody screening would also be
By extension, these considerations also affect the desirable for specific adult groups, such as those with
utility of IFG and IGT as classifications for prediabetes. In features of classical type 1 diabetes, patients suspected
other words, if there is no clear transition from prediabetes of having autoimmune/LADA-type disease and patients
to diabetes in the spectrum of FPG levels, then what are with type 2 diabetes in whom autoantibodies would
the parameters that can accurately define prediabetes or, predict more rapid progression to insulin deficiency.
perhaps more correctly, risk for developing diabetes as In view of the alarming public health status of
defined by a particular diabetic complication? This diabetes Worldwide, improved detection techniques
problem is illustrated by the recent report that patients and biomarkers are urgently needed across the entire
with a diagnosis of isolated IFG, considered to be a cate­ spectrum of diabetes initiation and progression. Since
gory with normal muscle insulin sensitivity, in fact exhibit 70% of individuals with prediabetes will progress to frank
a wide range of insulin resistance;118 thus, currently accep­ diabetes132 and 7% of newly diagnosed type 2 diabetes
ted classifications of prediabetes are potentially much patients in the US have been diabetic for approximately
less definitive and therefore, less useful than previously 4–7 years before diagnosis,133 the ability to ascertain
thought. those individuals at risk for the development of clinically
As described above, the assessment of diabetes-related apparent diabetes is critical to effectively focus potentially
autoimmunity will be an important aspect of new diagno­ limited clinical resources. In particular, it is desirable to
stic approaches. Specific autoantibodies that are thought screen and start treating glucose-intolerant individuals as
to indirectly reflect the T cell-mediated β-cell destruction early as possible, since, even before the onset of diabetes,
that results in type 1 diabetes include antibodies to vascular lesions gradually develop with deterioration
insulin [insulin autoantibodies (IAA)], GAD65 and protein of glucose tolerance. Data from the recent Whitehall II
tyrosine phosphatase-like antigen (IA-2α),119-123 and are study demonstrate that changes in the rate of change
detectable in prediabetic individuals. The number of of glycemia and insulin sensitivity and secretion are
autoantibody species and their affinity and epitope speci­ evident 3–6 years before diagnosed type 2 diabetes;134
ficity can be related to disease risk. IAA, GAD and IA-2α thus, other biomarkers may provide robust assessment
autoantibodies are routinely measured with standard of prediabetes and type 2 risk. Additionally, since β-cell
approaches such as radioimmunoassay (RIA) or enzyme- function is already compromised by the time that overt
linked immunosorbent assay (ELISA). More recently, the alterations in glucose homeostasis such as IGT or IFG
cation efflux transporter ZnT8 has been identified as a are evident, timely intervention is important to maintain
104 Diagnosis and Classification

residual insulin secretory capacity. The effectiveness of of OGTTs, and the potentially distinct pathologies of IGF
early intervention and lifestyle modification or medication and IFG raise serious questions about the adequacy and
has been demonstrated by the DPP and the UKPDS and relevance of current diagnostic criteria for diabetes and
verified by subsequent analyses.43,135-138 prediabetes. A separate, but related issue is the consistency
of plasma glucose measurements themselves.141 Thus, the
SUMMARY prediabetic state is clearly more complex than previously
appreciated, while the means of assessing prediabetes
section

The public health and health care systems in India and

as well as overt diabetes are fraught with both technical
Worldwide are seriously threatened and overwhelmed by
3

and patient-variability issues. Resolution of this situation

the twin epidemics of obesity and diabetes. The effective
screening, diagnosis and treatment of diabetes urgently will be facilitated by the discovery of new biomarkers
requires the accurate determination of disease category for diabetes risk, progression and monitoring.
and the attendant prediction of disease progression,
development of complications and response to various Further Reading
therapies. 1. University Group Diabetes Study Program (UGDP). A study
It is generally accepted that classical type 1 diabetes, of the effects of hypoglycemic agents on vascular complica­
also known as juvenile, autoimmune, or IDDM is tions in patients with adult onset diabetes: 1. Design, meth­
characterized by an early age of onset and the progressive ods and baseline results. Diabetes 1970;19:747-84.
loss of insulin secretory capacity due to β-cell destruction. 2. National Diabetes Data Group. Classification and diagnosis
of diabetes mellitus and other categories of glucose intoler­
This form of diabetes is generally distinguished from
ance. Diabetes. 1979;28:1039-57.
classical type 2 diabetes also known as adult-onset or 3. Tripathy BB, Samal KC. Protein-deficient diabetes mellitus
NIDDM. Type 2 diabetes is characterized by progressive (PDDM) in India. Int J Diab Dev Countries. 1993;13:3-13.
hyperinsulinemia, peripheral insulin resistance and β-cell 4. Engelgau MM, Thompson TJ, Herman WH, et al. Compari­
insufficiency. The principal molecular basis for type 1 son of fasting and 2-hour glucose and HBA1c level for diag­
diabetes is islet destruction caused by an autoimmune nosing diabetes, diagnostic criteria and performance revis­
response, although a specific precipitating antigen has ited. Diabetes Care. 1997;20:785-91.
yet to be identified.139 Type 2 diabetes, on the other hand, 5. Kanungo A, Shtauvera A, Samal K, et al. Antibodies to ICA
512 and GAD 65 in patients with NIDDM from Eastern
is a more complex disorder that involves both insulin
India. Diabetologia. 1997;40:164.
resistance and β-cell dysfunction. It is currently felt that 6. DECODE Study (Diabetes Epidemiology: Collaborative
clinically apparent type 2 diabetes is manifested only when Analysis of Diagnostic Criteria in Europe). Consequences
β-cell secretory capacity is insufficient to maintain a level of the new diagnostic criteria for diabetes in older men and
of hyperinsulinemia sufficient to overcome peripheral women. Diabetes Care. 1999:22:1667-71.
insulin resistance.140 7. Tabak AG, Jokela M, Akbaraly TN, et al. Trajectories of
The ramifications of this for accurate diagnosis glycaemia, insulin sensitivity, and insulin secretion before
diagnosis of type 2 diabetes: an analysis from the Whitehall
include the presence of autoantibodies in putative type
II study. Lancet. 2009;373:2215-21.
2 diabetes patients and aspects of insulin resistance in
putative type 1 diabetes patients. The application of novel
biomarkers to more accurately stage at-risk individuals
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autoantibodies as predictors of type 1 diabetes in the diabe­ 141. Gambino R. Glucose: a simple molecule that is not simple
tes prevention trial-type 1. Diabetes Care. 2009;32:2269-74. to quantify. Clin Chem. 2007;53:2040-1.
 Chapter 7
Latent Autoimmune
Diabetes in Adults
Devjit Tripathy, Leif Groop, Paturi V Rao

Latent Autoimmune DM in Adults

Chapter Outline
♦♦ Definition: Clinical Characteristics ♦♦ Lada in the Indian Population
♦♦ Pathogenesis ♦♦ Screening for Latent Autoimmune Diabetes in Adults
♦♦ Genetics of Latent Autoimmune Diabetes in Adults ♦♦ Management of Latent Autoimmune Diabetes in Adults
♦♦ Chronic Complications in LADA ♦♦ Newer Potential Therapies for Lada

INTRODUCTION phenotype, about 25% of patients who develop type 1

diabetes are diagnosed after the age of 35 years.5,6 The
The recent classification of diabetes is an attempt to clas­
presence or absence of markers of autoimmunity is
sify diabetes based on the etiology rather than clinical
one way of differentiating between immune-mediated
type. However, diabetes is a far more heterogeneous
and non-immune mediated pathogenesis of diabetes.
disease than type 1 and type 2 categorization that the
Irvine et al. first reported the presence of islet cell auto-
current classification implies.1-3 In clinical practice, pati­
antibodies (ICAs) in patients with type 2 diabetes and
ents with diabetes are classified according to the clinical
phenotype, e.g. the age of onset, body mass index and that it was associated with a higher probability of insulin
insulin requirement. Type 1 diabetes is due to insulin requirement in the future.7 Subsequently prospective
deficiency resulting from autoimmune β-cell destruction studies in subjects with adult onset diabetes showed
and characterized by the presence of autoantibodies to that those with ICA had lower C-peptide levels and more
islet cell cytoplasm (ICA), glutamic acid decarboxylase frequently required insulin than those without ICA.8-10
65 (GAD) and/or to the intracytoplasmic domain of It was Tuomi et al. who first described that presence of
the tyrosine phosphatase-like protein IA-2. Type 2 or GAD antibody was associated with more severe insulin
adult onset diabetes is considered to be due to a non- deficiency in patients diagnosed with type 2 diabetes
autoimmune process. Clinicians face considerable and suggested the name Latent Autoimmune Diabetes
dilemma in differentiating between the different types of in Adults (LADA).11,12 Subsequently, some have also
diabetes.4 While primary failure of oral hypoglycemic called this form of diabetes as Slowly Progressing Insulin
agents is observed in significant number of patients Dependent Diabetes Mellitus (SPIDDM),13 1½ diabetes14
with type 2 diabetes suggesting a type 1 diabetes, like or youth onset diabetes of maturity.
110 Diagnosis and Classification

DEFINITION: CLINICAL CHARACTERISTICS older (> 50 years) type 2 diabetic subjects.34 A cross-
sectional and comparative study of LADA patients, ascer­
The term LADA was introduced to define adult diabetics tained from the Non-Insulin Requiring Autoimmune
(age of onset > 35 years), initially non-insulin requiring Diabetes (NIRAD) Study from Italy and those diagnosed
(in first 6 months) but with immune markers of type 1 in Korean National Diabetes Program, found a very
diabetes, that often progress to insulin dependency.15,16 similar prevalence of LADA in the two populations (4.4%
Unlike type 1 diabetic patients, newly diagnosed LADA in Italy and 4.4% in Korea). While the age at onset of
section

patients usually maintain good metabolic control with LADA and hemoglobin A1c (HbA1c) values were similar,
diet or oral hypoglycemic agents. However, with time a there was a significantly higher BMI in Caucasians, and
3

significantly greater proportion of LADA subjects require higher HDL (but not total) cholesterol levels. By contrast,
insulin treatment for metabolic control. Compared to triglyceride levels were significantly higher in Asians.
patients with type 2 diabetes, LADA patients have more Despite a difference in prevalence of type 1 diabetes,
severe β-cell dysfunction as shown by low fasting and LADA prevalence is remarkably similar between these
stimulated C-peptide concentrations.10,11,16,17 The other two different ethnicities.34,35 However, metabolic features
striking feature of LADA subjects is that they have a lower differ substantially between the two ethnicities. It is
prevalence of features of the metabolic syndrome.18,19 apparent that a significantly higher preva­ lence (10%
LADA subjects have lower body mass index (BMI), waist- vs 4%) is observed when GADab is measured in a popula­
hip ratio (WHR), lower frequency of hypertension, higher tion-based sample compared to when measured in a clinic
HDL cholesterol and lower triglyceride concen­ trations based sample.
compared to the type 2 subjects of same age and disease
duration.16,20-22 At diagnosis, both ICA and GADab predict PATHOGENESIS
future insulin dependency16,23 but GADab appear to be Immunology
better predictors than ICA.16 The tendency of ICA to dec­
line and disappear with increasing disease duration24 The hallmark of LADA is the presence of GAD65 auto­
and the relative stability and persistence of GADab make antibodies (GAD65Ab) in adult diabetic subjects not
them preferred immune markers for diagnosing LADA requiring insulin therapy at the time of clinical diag­
nosis.16 The presence of GAD65Ab in LADA subjects is
subjects.16,25-28 To differentiate LADA from type 1 and
highly predictive for the future development of insulin
type 2 diabetes, the Immunology of Diabetes Society has
requirement, but not all GAD65Ab-positive LADA sub­
proposed three main criteria: adult age of onset (> 30 years
jects will require insulin therapy at follow up. Higher
of age), presence of at least one circulating autoantibody
GADab titres have been associated with lower residual
(GAD, ICA, IAA or IA-2) and insulin independence for the
β-cell function suggesting a direct role of GADab in
first 6 months after diagnosis.29
the pathogenesis of β-cell destruction.16,36 In fact,

The prevalence of LADA varies between 10–20% of
Lohmann et al. showed that the combination of ICA and
diabetics in different populations.12,16,23,30 The largest study
GAD antibodies and high titer of GAD antibodies were
on the prevalence of GADab in patients with adult onset characteristic of patients with severe insulin deficiency
diabetes comes from the UKPDS study which showed and had clinical features of type 1 diabetes mellitus. It
a prevalence of 10% in newly diagnosed diabetics in the was proposed that they be called LADA-type 1 diabetes.
age group of 25–65 years.23 In the Scandinavian countries Those with single antibody positivity and low titer
where approximately 3% of the population has known antibodies (LADA-type 2) resembled more the clinical
diabetes, 15% of them have type 1 whereas 85% are consi­ and metabolic phenotype of type 2 diabetes patients.
dered to have type 2 diabetes.2 Of the patients diagnosed Also, the antibody to different epitopes of GAD65 has
as type 2 diabetes, about 10% have GAD antibodies been reported to vary between subjects with LADA
(LADA).18,31 A recent study from Seattle reported the and type 1 diabetes.20,37,38 Falorni et al.38 demonstrated
preva­lence being 16% in all newly diagnosed subjects with the occurrence of autoantibodies to both the middle
type 2 diabetes.32 In a study in Chinese subjects, 16% (GAD65-MAb) and the COOH-terminal (GAD65-CAb)
of patients diagnosed as type 2 diabetes had GADab.33 region of the autoantigen. However, only the presence of
A recent study from Italy showed a prevalence of 4% in GAD65-CAb was associated with high risk of progression
 Latent Autoimmune Diabetes in Adults 111

Table 7.1: Clinical features of latent autoimmune diabetes in adults at all ages. The frequency of the protective DQB*0602
Types Clinical features was more common in LADA than in young onset type 1
LADA • Age of onset > 35 years diabetes.18 A recent study from Hungary reported incr­
• Non-insulin requiring for at least first 6 months after eased prevalence of HLA-DQB1*0201/*0302, DR4, DR3,
onset but often requiring insulin later
and DR3/DR4 genotypes and DR4-DQB1*0302 and DR3/
LADA 1 • Higher titers of GAD
DR4-DQB1*0302 haplotypes in patients with LADA and
• Lower C-peptide, lower BMI, ketosis prone
type 1 diabetes as compared with the general population,20

chapter
LADA 2 • Lower titers of GAD
• Less ketosis, dyslipidemia, prone though no differences in risk alleles and frequency of

7
(LADA: Latent autoimmune diabetes in adults; GAD: Glutamic acid haplotypes were observed between the LADA and adult
decarboxylase; BMI: Body mass index). onset type 1 diabetic subjects.
Sanjeevi et al. recently demonstrated that the poly­
towards insulin requirement and low C-peptide values morphic alleles of MHC class I chain related A (MICA)
at follow-up, while the exclusive presence of GAD65- gene influences the risk for type 1 diabetes and that allele
MAb identified a subgroup of LADA subjects with clinical 5 of MICA was significantly associated with type 1 diabetes
and metabolic characteristics indistinguishable from only in the age group 1–25 years at diagnosis while allele
patients with typical type 2 diabetes. More recently, 5.1 of MICA was associated with LADA, more than 25 years
the cation efflux transporter ZnT8 has been identified age at onset.47,48 They thereby suggested the existence of
as a major autoantigen in type 1 diabetes. Antibodies distinct genetic markers for childhood/young-onset type
to insulin (IAA),GAD, and IA-2β, permit detection of 1 diabetes and for LADA, namely MICA5 and MICA5.1,
98% of patients at disease onset39,40 and facilitate diagnosis
respectively. The killer immunoglobulin-like receptor
of type 1 diabetes in non-pediatric patients under 4041
(KIR) genes and HLA-C ligand genotyping showed that in
and differentiate adult-onset autoimmune diabetes
86 Indian patients with LADA, KIRs 2DL5 and 3DL1 were
(LADA)42 (Table 7.1)..
associated with susceptibility and KIRs 2DS1 and 2DS3
with protection, which was specific to Indian ethnicity.49
GENETICS OF LATENT AUTOIMMUNE
Taken together, available data suggest that LADA
DIABETES IN ADULTS and early-onset type 1 diabetes differ in genetic predis­
Approximately, 40% of familial aggregation in classical position.50 While type 2 diabetes is characterized by
type 1 diabetes has been attributed to the HLA genes, in insulin resistance and pancreatic β-cell defect, type 1
particular the class II genes DQ and DR.43,44 Type 1 diabetes diabetes results primarily from β-cell defect. Studies on
is positively associated with HLA DR4-DQ8 and/or DR3- insulin sensitivity and insulin secretion in LADA are
DQ2 while DR15-DQ6 (B*0602) is negatively associated. relatively few and restricted to Scandinavian populations.
The prevalence of DR3/DR4 and DQB1*0201/*0302 is Although several studies have reported lower C-peptide
reported to be age-related in childhood onset type 1 levels in LADA subjects, it is not clear whether it was a
diabetic patients. In Caucasians and Asians in general, it consequence or the cause of more severe hyper­
has been observed that type 2 diabetic patients have an glycemia.9,23,51,52 In a study of a large number of subjects
increase in type 1 susceptibility human leukocyte antigen with GADab no difference in insulin secretion measured
(HLA) genes, (particularly those with younger age at as first phase insulin secretion during an intravenous
onset), lower BMI, antibodies to GAD or ICA and have a glucose tolerance test (IVGTT) was observed between
relatively higher incidence of insulin deficiency.9,11,45,46 subjects with and without GADab, neither in the predia­
Studies in LADA subjects are, however, rare. It has been betic nor in the diabetic state.22 To study whether anti­
suggested that the typical HLA predisposition to type 1 bodies to glutamic acid decarboxylase (GADab) were asso­
diabetes is less marked in LADA. The frequency of the ciated with subclinical beta-cell damage and impaired
type 1 associated HLADQB1* 0201/*0302 genotype was insulin secretion, Lethagen et al.19 studied C peptide,
less common in Finnish LADA patients than in type 1 and glucagon response to glucose and arginine at three
diabetic patients whereas the frequency of DQB*0302/X blood glucose concentrations (fasting, 250 mg/dL, > 450
did not differ between LADA and type 1 diabetes mg/dL) in non-diabetic patients with autoimmune
suggesting that DQB*0302 (DR4) predisposes to diabetes thyroiditis with and without GADab. The acute insulin
112 Diagnosis and Classification

Table 7.2: Antibody status and genetics of latent autoimmune diabetes in adults
Antibody status Genetics
LADA • Type 1: ICA + GAD antibodies (GADab) or high titres of GADab
• Type 2: Single antibody positivity in low titres HLA predisposition less marked
DQB-0302(DR4) gene → predisposes to LADA
Genetic markers • MICA 5.1 → LADA
• MICA 5 → Type 1 diabetes (childhood/young onset)
section

GAD 65-CAb • High risk towards progression to insulin dependency (type 1 diabetes)
3

GAD65-MAb • Clinical and metabolic characteristics similar as in type 2 diabetes

(LADA: Latent autoimmune diabetes in adults; ICA: Islet cell antigen; GAD: Glutamic acid decarboxylase; HLA: Human leukocyte antigen; MICA:
MHC class I chain related A)

response to arginine was lower in GADab+ than in GADab Insulin resistance is an early and possibly inherited
thyroiditis subjects at glucose concen­tration of 250 and feature of first-degree relatives of patients with common
> 450 mg/dL. GADab positivity was thus associated with type 2 diabetes. In contrast, normal insulin sensitivity has
a decreased insulin secretion capacity in non-diabetic been reported in offspring of LADA patients.53 The insulin
subjects with thyroiditis, which suggests that GADab resistance observed in the LADA patients could thus
positivity could be a marker of subclinical insulitis. represent secondary insulin resistance as a consequence
Vauhkonen et al. in a study of offspring of LADA subjects of elevated glucose and/or NEFA levels.54 Despite these
showed that the insulin secretion measured as early putative etiologic differences, the course of deterioration
insulin response during an IVGTT and hyperglycemic in insulin secretion seems to be similar and is accom­
clamp were lower than in control subjects though no diffe­ panied by a similar defect in insulin action in LADA and
rence was observed in insulin sensitivity,53 they thereby type 2 diabetes.22 This could imply that means to improve
concluded that insulin deficiency observed in LADA insulin sensitivity could have the same effect in both
subjects could be partly familial (Table 7.2). groups. It remains to be shown whether insulin resistance
The causes leading to impaired β-cell function most in LADA and type 2 diabetes really has different causes and
likely differ between subjects with LADA and type 2 whether the different risks of cardiovascular complica­
diabetes; while autoimmune destruction of the β-cells tions are related to intrinsic differences in the cause of
is most likely operative in LADA patients, toxic effects of insulin resistance or to different exposure times to insulin
elevated glucose, free fatty acids and amylin in addition resistance.
to unknown factors are considered in the pathogenesis of
β-cell dysfunction in type 2 diabetes.54-58 CHRONIC COMPLICATIONS IN LADA

Groop et al. in 199131 first showed that there was no There are epidemiological differences in the evolution of
difference in insulin sensitivity measured by euglycemic chronic complications of diabetes between type 1 and
clamp between subjects with late onset autoimmune type 2 diabetic patients. About 30% of subjects with type
diabetes and type 2 diabetes. Subsequently in another 2 diabetes have some evidence of chronic complications
study from the same group using hyperinsulinemic eugly­ at the presentation of diabetes.59 Since LADA is a type of
cemic clamps, there was no difference in insulin sensitivity diabetes intermediate between type 2 and type 1 diabetes,
between GADab positive or subjects from families with it can be hypothesized that the complication rates will
type 2 diabetes, neither in the pre diabetic nor in the dia­ also be intermediate between the two subgroups. Studies
betic state.22 Despite a similar degree of insulin resistance, in different populations have shown differing results.
the type 2 diabetic subjects showed more features of the In a Finnish study in the Botnia region, the prevalence
insulin resistance syndrome than the LADA patients, i.e. of complications was compared between subjects with
higher WHR, blood pressure and triglycerides.16,22 The type 1 diabetes, patients with GAD antibodies and age at
dissociation between insulin resistance and features of onset of diabetes more than 35 years (LADA) and GADab-
the insulin resistance syndrome in LADA is intriguing. negative-type 2 diabetic patients.21 The prevalence of
 Latent Autoimmune Diabetes in Adults 113

retinopathy (51% vs 56%), neuropathy (29% vs 27%), and treatment (unpublished). The clinical relevance of GADab
microalbuminuria (27% vs 29%) did not differ between in preclinical diabetes and whether it predicts progression
the groups. Subject with type 1 diabetes had lower preva­ to diabetes and insulin dependency remains to be studied.
lence of neuropathy (13%) and higher prevalence of retino­ South Asians living in UK, were reported to have higher
pathy (76%) compared with the other groups. Neither prevalence of autoimmunity associated with diabetes, as
the prevalence of coronary heart disease (CHD) (56% vs 27% of newly diagnosed type 2 diabetics had higher titres
58%) nor cardiovascular mortality (7.4% vs 12.4%) differed of GAD antibodies.66 But in 2007, in a large study for the

chapter
significantly between the LADA and type 2 diabetic pati­ prevalence of LADA among South Asian population in

7
ents. Furthermore, the authors also showed that glycemic UK, autoantibodies were detected in only 13 of 500 (2.6%)
control was associated with CHD in the LADA group but individuals with type 2 diabetes.67 Thus, there is hetero­
not in the type 2 diabetic group. This could be related to geneity in the prevalence of autoantibodies in Asian
the lower prevalence of the metabolic syndrome seen in Indians with adult onset diabetes. A major contributor to
the LADA subjects. this discrepancy is whether antibodies have been mea­
In an Australian population, the prevalence of retino­ sured in a population-based sample (diluted with mild
pathy was higher in LADA subjects than in GAD-ve type incidence cases of diabetes) or a clinic-based sample
2 diabetic subjects.60 However, the GADab+ve group also (mostly consisting of more advanced cases of diabetes).
had poor glycemic control. A recent study from Germany It is now apparent that LADA is a distinct and hetero­
showed that LADA subjects had less neuropathy than geneous entity that represents a significant proportion up
type 2 diabetic patients in the early stages of the disease, to 10% of adults with diabetes in India.68
thus being more similar to classical type 1 diabetes in
which neuropathy develops rather late.61 SCREENING FOR LATENT
AUTOIMMUNE DIABETES IN ADULTS
LADA IN THE INDIAN POPULATION
Measurement of GADab in adults diagnosed with type 2
Kanungo et al. from Eastern India measured GAD65 and
diabetes is a prerequisite to identify subjects with LADA.
IA-2 autoantibodies in 210 patients clinically diagnosed
Data from several studies have now clearly shown that
as type 2 diabetes and reported that the frequency of
presence of GADab is a predictor of future insulin require­
GAD65 was not significantly different between patients
ment.23,69 However, in countries, like India with limited
and controls (7% vs 2%).62 In contrast to the situation in
resources, all type 2 diabetic patients are not tested for
Caucasians IA-2 was the predominant autoantibody seen
GADab, and the decision to start a patient on insulin is
in 36% of younger Eastern Indian type 2 diabetic patients.
mostly made on clinical grounds. The prevention of prog­
Islet Cell antibody (ICA-12) was also more frequently
ression of microvascular and macrovascular complica­
associated with non-DR3/non-DR4 patients with LADA in
tions, as in type 1 and type 2 diabetes, clearly depends on
Northern India.63 A study of lean diabetics from Southern
the glycemic control and the control of cardiovascular risk
India showed that they had a higher prevalence of GADab,
factors. However, if resources permit, measuring GADab
more severe diabetes and were distinct from type 1 diabetic
is helpful in predicting future insulin requirements.
patients.64 It was possible that these with GADab were
classified as LADA. But many lean diabetics in Eastern
MANAGEMENT OF LATENT
India are GADab negative with good β-cell function, and
AUTOIMMUNE DIABETES IN ADULTS
considered are phenotype variants of type 2 diabetes.65

In a large study from Hyderabad, dried blood spots In the absence of definite guidelines for treatment of
(DBS), collected from 175 adults with preclinical diabetes LADA, we would recommend the standard approach to
and 143 with newly ascertained type 2 diabetes, were tested any patient with type 2 diabetes, that is starting with a
for autoimmunity. The prevalence of GAD65ab positivity trial of oral hypoglycemic agents, like sulfonylureas,
(> 30 IU/mL) was 5%, similar in preclinical as well as in metformin and thiazolidinediones followed by insulin.
new type 2 diabetes. In a nearby rural population, GADab It may be worthwhile to start insulin early, as it will
tests done on DBS revealed GADab positivity in 5% of 157 provide β-cell rest rather than allowing β-cell exhaustion
preclinical diabetics, and 9% of 125 adult diabetics on by sulfonylureas, although data supporting early use of
114 Diagnosis and Classification

Table 7.3: Treatment of latent autoimmune diabetes in adults considered. The new approach is using a peptide Diapep
Treatment Recommendations 277, the heat shock protein 60 (Hsp60)-derived peptide,
Diet Obese patients benefit from calorie to stop progression towards beta cell destruction.74 The
restriction strategy underlying the Diapep 277 approach in LADA
Sulfonylureas Not first-line therapy is that of antigen specific suppression. Hsp60-specific
Insulin Early insulin therapy is recommended
autoimmunity precedes the onset of clinical hypergly­
Insulin sensitizers Beneficial in treating metabolic syndrome
cemia in the NOD mouse and the low-dose streptozotocin
section

Metformin not yet studied

Incretin-based therapy Not yet studied
(STZ) model. The diabetogenic T-cells recognize a hsp60
3

Immune modulation DiaPep277—Safety and tolerability peptide epitope corresponding to the positions 437–460,
proved called p277. The peptide Diapep 277 is fully cross-reactive
GAD65 (Diamyd)—Safety reported with the original p277 and has the same biological activity.
In recent-onset type 1 patients (children and adults), data
insulin are partly conclusive. Newer experimental agents has shown that stimulated C-peptide can be preserved
are now being tried (Table 7.3). at 1 year after diagnosis compared to control patients. In
Italy, therapy with Diapep 277 was more efficacious in
NEWER POTENTIAL THERAPIES FOR LADA terms of C-peptide preservation in 70 adults with recent-
onset type 1 diabetes with lower risk HLA class II genotypes
Since the disease process in LADA is similar to that of who are characterized by less extended destruction of
type 1 diabetes, several therapies have been attempted pancreatic β-cells. Similar effects can be expected in
to prevent the ongoing destruction of β-cells in patients LADA, as these Italian subjects with type 1 diabetes aged
with LADA. Although the results of numerous trials in 28.8 ± 8.8 years, with BMI (normal 23 ± 3.12 kg/m2) and
prevention of type 1 diabetes, including the recently preserved C-peptide (0.41 ± 0.23 mmol/L) are pheno­
concluded DPT-1, have been inconclusive,70 prevention typically akin to LADA.75
of progression towards full exhaustion of beta cells and Finally, GAD65 vaccination (Diamyd) has been tested
consequent dependency on insulin could be ideally app­ as a mean to retard progression of β-cell destruction
lied to LADA patients. It needs to be pointed that the in subjects with LADA. A phase II trial with 5 years of
nega­tive results from the DPT-1 may not necessarily follow-up of LADA patients has recently been completed
be extrapolated to the LADA subjects, as autoimmune in Malmö Sweden and the preliminary data showed that
destruction of the islets is less aggressive or have a different insulin production normalized for glucose concentration
course in the adults. increased significantly in diabetics treated with GAD
Initial results in GADab +ve type 2 diabetic subjects compared to placebo suggesting that the autoimmune
from Japan showed promising results with small daily damage to the β-cells is halted or stopped.76 Some of these
doses of insulin71 and encouraging results were also seen efforts also included interfering with the cytokines that are
in a recent multicenter study in the Japanese subjects.72 implicated in the inflammatory process, which include
GADab positive patients were randomly divided into tumor necrosis factor-α and interleukin-1β, among others.
two groups: one group received insulin (Ins group), the
A patient diagnosed with LADA was treated successfully
other a sulfonylurea (SU group). Among subjects with
with etanercept, a tumor necrosis factor-α blocker for
a high GADab titer, 64.3% of the SU group, but only
more than 11 years, emphasizing the availability of newer
12.5% of the Ins group, became insulin dependent over therapies to alter the natural progression of LADA.77
4 years. This suggests that small doses of insulin effectively
prevent β-cell failure in LADA subjects. In a prospective, CONCLUSION
3-year intervention study in LADA patients in Sweden, a
significant beneficial effect of early insulin treatment on the Latent autoimmune diabetes in adults is diagnosed by
preservation of β-cell function could not be demonstrated, presence of GADab in patients with age of onset of diabetes
but level of HbA1c after 36 months was better preserved in greater than 30 years and who do not require insulin in
the insulin treated.73 the first 6 months of diagnosis. LADA differs from type 2
Despite the priority of treatment of hyperglycemia, diabetes in terms of more severe β-cell dysfunction, less
treating the underlying pathogenesis in LADA is being features of the metabolic syndrome and earlier insulin
 Latent Autoimmune Diabetes in Adults 115

requirement. Chronic complications in LADA are similar 7. Irvine WJ, Sawers JS, Feek CM, et al. The value of islet cell
to that seen in type 2 diabetes. Management of LADA antibody in predicting secondary failure of oral hypo­
involves similar therapeutic approaches as in type 2 dia­ glycaemic agent therapy in Diabetes mellitus. J Clin Lab
Immunol. 1979;2:23-6.
betes, but with a much greater propensity of insulin
8 Groop L, Groop PH, Koskimies S. Treatment failures in
requirement. Several newer promising therapeutic trials patients with type 2 (non-insulin dependent) diabetes. Dia­
are currently being conducted to preserve β-cell function betologia. 1988;31:186-7.
in LADA. 9 Groop, L, Miettinen, A, Groop, PH, et al. Organ-specific

chapter
autoimmunity and HLA-DR antigens as markers for beta-
cell destruction in patients with type II diabetes. Diabetes.

7
Further Reading
1988;37:99-103.
1. Groop LC, Bottazzo GF, Doniach D. Islet cell antibodies 10. Groop LC, Bottazzo GF, Doniach D. Islet cell antibodies
identify latent type I diabetes in patients aged 35-75 years at identify latent type I diabetes in patients aged 35-75 years at
diagnosis. Diabetes. 1986;35:237-41. diagnosis. Diabetes. 1986;35:237-41.
2. Palmer, JP. What is the best way to predict IDDM? Lancet. 11. Tuomi T, Groop LC, Zimmet PZ, et al. Antibodies to
1994;343:1377-8. glutamic acid decarboxylase reveal latent autoimmune dia­
3. Turner R, Stratton I, Horton V, et al. UKPDS 25: autoanti­ betes mellitus in adults with a non insulin-dependent onset
bodies to islet-cell cytoplasm and glutamic acid decarboxy­ of disease. Diabetes 1993;42:359-62.
lase for prediction of insulin requirement in type 2 diabetes. 12. Zimmet PZ, Tuomi T, Mackay IR, et al. Latent autoimmune
UK Prospective Diabetes Study Group. Lancet. 1997;350: diabetes mellitus in adults (LADA): the role of antibodies to
1288-93. glutamic acid decarboxylase in diagnosis and prediction of
4. Tripathy D, Carlsson AL, Lehto M, et al. Insulin secretion insulin dependency. Diabet Med. 1994;11:299-303.
and insulin sensitivity in diabetic subgroups: studies in 13. Kobayashi T. Subtype of insulin-dependent diabetes
the prediabetic and diabetic state. Diabetologia. 2000;43: mellitus (IDDM) in Japan: slowly progressive IDDM—the
1476-83. clinical characteristics and pathogenesis of the syndrome.
5. Sanjeevi, CB, Gambelunghe, G, Falorni, A, et al. Genetics Diabetes Res Clin Pract. 1994;24 Suppl:S95-9.
of latent autoimmune diabetes in adults. Ann N Y Acad Sci. 14. Juneja R, Palmer JP. Type 1½ diabetes: myth or reality?
2002;958:107-11. Autoimmunity. 1999;29:65-83.
6. Hosszúfalusi N, Vatay A, Rajczy K, et al. Similar genetic 15. Vatay A, Rajczy K, Pozsonyi E, et al. Differences in the
features and different islet cell autoantibody pattern of genetic background of latent autoimmune diabetes in
latent autoimmune diabetes in adults (LADA) compared adults (LADA) and type 1 diabetes mellitus. Immunol Lett.
with adult-onset type 1 diabetes with rapid progression. 2002;84:109-15.
Diabetes Care. 2003;26:452-7. 16. Lehto, M, Bitzén PO, Isomaa, B, et al. Mutation in the
HNF-4alpha gene affects insulin secretion and triglyceride
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6. Lorenzen T, Pociot F, Hougaard P, et al. Long-term risk 21. Isomaa B, Almgren P, Henricsson M, et al. Chronic com­
of IDDM in first-degree relatives of patients with IDDM. plications in patients with slowly progressing autoimmune
Diabetologia. 1994;37:321-7. type 1 diabetes (LADA). Diabetes Care. 1999;22:1347-53.
116 Diagnosis and Classification

22. Tripathy D, Carlsson AL, Lehto M, et al. Insulin secretion 38. Falorni, A. Immunologic and genetic aspects of latent
and insulin sensitivity in diabetic subgroups: studies in autoimmune diabetes in the adult. Minerva Endocrinol.
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1476-83. 39. Wentzlau JM, Juhl K, Yu L, et al. The cation efflux transporter
23. Turner R, Stratton I, Horton V, et al. UKPDS 25: autoanti­ ZnT8 (Slc30A8) is a major autoantigen in human type 1
bodies to islet-cell cytoplasm and glutamic acid decarboxy­ diabetes. Proc Nat Acad Sci USA. 2007;104:17040-5.
lase for prediction of insulin requirement in type 2 diabetes. 40. Vermeulen I, Weets I, Asanghanwa M, et al. Contribution
UK Prospective Diabetes Study Group. Lancet. 1997;350: of antibodies against IA-2β and zinc transporter 8 to
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24. Palmer, JP. What is the best way to predict IDDM? Lancet.
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3

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41. Kawasaki E, Nakamura K, Kuriya G, et al. Autoantibodies
25. Kobayashi T, Nakanishi K, Okubo M, et al. GAD antibo­
dies seldom disappear in sloly progressive IDDM. Diabetes to insulin, insulinoma-associated antigen-2, and zinc
Care. 1996;19:1031. transporter 8 improve the prediction of early insulin
26. Tuomi T, Björses P, Falorni A, et al. Antibodies to glutamic requirement in adult-onset autoimmune diabetes. J Clin
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patients with autoimmune polyendocrine syndrome type I. 42. Lampasona V, Petrone A, Tiberti C, et al. Zinc transporter
J Clin Endocrinol Metab. 1996;81:1488-94. 8 antibodies complement GAD and IA-2 antibodies in
27. Christie MR, Daneman D, Champagne P, et al. Persistence the identification and characterization of adult-onset
of serum antibodies to 64,000-Mr islet cell protein after autoimmune diabetes: Non Insulin Requiring Autoimmune
onset of type I diabetes. Diabetes. 1990;39:653-6. Diabetes (NIRAD) 4. Diabetes Care. 2010;33:104-8.
28. Marner B, Agner T, Binder C, et al. Increased reduction in 43. Davies JL, Kawaguchi Y, Bennett ST, et al. A genome wide
fasting C-peptide is associated with islet cell antibodies in search for human type 1 diabetes susceptibility genes.
type 1 (insulin-dependent) diabetic patients. Diabetologia. Nature. 1994;371:130-6.
1985;28:875-80. 44. Redondo MJ, Fain PR, Eisenbarth GS. Genetics of type 1A
29. Gale EA. Latent autoimmune diabetes in adults: a guide for diabetes. Recent Prog Horm Res 2001;56:69-89.
the perplexed. Diabetologia. 2005;48:2195-9. 45. Horton V, Stratton I, Bottazzo GF, et al. Genetic hetero­
30. Zhou Z, Ouyang L, Peng J, et al. Diagnostic role of antibodies
geneity of autoimmune diabetes: age of presentation in
to glutamic acid decarboxylase in latent autoimmune dia­
adults is influenced by HLA DRB1 and DQB1 genotypes
betes mellitus in adults. Chin Med J (Engl). 1999;112:554-7.
(UKPDS 43). UK Prospective Diabetes Study (UKPDS)
31. Groop LC, Eriksson J, Ekstrand A, et al. Metabolic
characteristics of autoimmune diabetes mellitus in adults. Group. Diabetologia. 1999;42:608-16.
Diabetologia. 1991;34:46-51. 46. Kobayashi T, Tamemoto K, Nakanishi K, et al. Immuno­
32. Juneja R, Hirsch IB, Naik RG, et al. Islet cell antibodies genetic and clinical characterization of slowly progressive
and glutamic acid decarboxylase antibodies, but not the IDDM. Diabetes Care. 1993;16:780-8.
clinical phenotype, help to identify type 1(1/2) diabetes 47. Sanjeevi, CB, Gambelunghe, G, Falorni, A, et al. Genetics
in patients presenting with type 2 diabetes. Metabolism. of latent autoimmune diabetes in adults. Ann N Y Acad Sci.
2001;50:1008-13. 2002;958:107-11.
33. Thai AC, Ng WY, Loke KY, et al. Anti-GAD antibodies in 48. Törn C, Gupta M, Nikitina Zake L, et al. Heterozygosity
Chinese patients with youth and adult onset IDDM and for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are
NIDDM. Diabetologia. 1997;40:1425-30. independent genetic risk factors for latent autoimmune
34. Petrone A, Park Y, Genovese S, et al. for the NIRAD Study diabetes in adults. Hum Immunol. 2003;64:902-9.
Group and the Korean National Diabetes Program. Similar­ 49. Shastry A, Sedimbi SK, Rajalingam R, et al. Different KIRs
ities and differences between Caucasian and Asian LADA. confer susceptibility and protection to adults with latent
Diabetologia. 2008;51:S155. autoimmune diabetes in Latvian and Asian Indian popula­
35. Guglielmi C, Palermo A, Pozzilli P. Latent autoimmune dia­ tions. Ann N Y Acad Sci. 2008;1150:133-8.
betes in the adults (LADA) in Asia: from pathogenesis and
50. Li H, Lindholm E, Almgren P, et al. Possible human leuko­
epidemiology to therapy. Diabetes Metab Res Rev. 2012;
cyte antigen-mediated genetic interaction between type
28:40-6.
1 and type 2 Diabetes. J Clin Endocrinol Metab. 2001;86:
36. Lohmann T, Kellner K, Verlohren HJ, et al. Titre and com­
bination of ICA and autoantibodies to glutamic acid decar­ 574-82.
boxylase discriminate two clinically distinct types of latent 51. Gottsäter A, Landin-Olsson M, Lernmark A, etal. Gluta­
autoimmune diabetes in adults (LADA). Diabetologia. mate decarboxylase antibody levels predict rate of beta-cell
2001;44:1005-10. decline in adult-onset diabetes. Diabetes Res Clin Pract.
37. Kobayashi, T, Tanaka, S, Okubo, M, et al. Unique epitopes 1995;27:133-40.
of glutamic acid decarboxylase autoantibodies in slowly 52. Zimmet P. Antibodies to glutamic acid decarboxylase in the
progressive type 1 diabetes. J Clin Endocrinol Metab. 2003; prediction of insulin dependency. Diabetes Res Clin Pract.
88:4768-75. 1996;34 Suppl:S125-31.
 Latent Autoimmune Diabetes in Adults 117

53. Vauhkonen I, Niskanen L, Knip M, et al. Impaired insu­ weight type 2 diabetes mellitus. Metab Syndr Relat Disord.
lin secretion in non-diabetic offspring of probands with 2007;5:136-41.
latent autoimmune diabetes mellitus in adults. Diabetolo­ 66. Tica V, Hanif MW, Andersson A, et al. Frequency of latent
gia. 2000;43:69-78. autoimmune diabetes in adults in Asian patients diagnosed
54. Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, as type 2 diabetes in Birmingham, United Kingdom. Ann N
free Fatty acids, and ectopic fat in pathogenesis of type Y Acad Sci. 2003;1005:356-8.
2 diabetes mellitus: peroxisomal proliferator-activated 67. Britten AC, Jones K, Törn C, et  al. Latent autoimmune
receptor agonists provide a rational therapeutic approach. diabetes in adults in a South Asian population of the UK.

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J Clin Endocrinol Metab. 2004;89:463-78. Diabetes Care. 2007;30:3088-90.
68. Brahmkshatriya PP, Mehta AA, Saboo BD, et al. Character­

7
55. Gastaldelli A, Ferrannini, E, Miyazaki, Y, et al. Beta cell
dysfunction and glucose intolerance: results from the San istics and Prevalence of Latent Autoimmune Diabetes in
Antonio metabolism (SAM) study. Diabetologia. 2004;47: Adults (LADA). ISRN Pharmacol. 2012;2012:580202.
31-9. 69. Littorin B, Sundkvist G, Hagopian W, et al. Islet cell and
56. Brownlee M. A radical explanation for glucose induced beta glutamic acid decarboxylase antibodies present at diag­
cell dysfunction. J Clin Invest. 2003;112:1788-90. nosis of diabetes predict the need for insulin treatment. A
57. Storgaard H, Jensen, CB, Vaag AA, et al. Insulin secretion cohort study in young adults whose disease was initially
labeled as type 2 or unclassifiable diabetes. Diabetes Care.
after short- and long-term low-grade free fatty acid infusion
1999;22:409-12.
in men with increased risk of developing type 2 diabetes.
70. Diabetes Prevention Trial—Type 1 Diabetes Study Group.
Metabolism 2003;52:885-94.
Effects of insulin in relatives of patients with type 1 diabetes
58. Kashyap S, Belfort R, Gastaldelli A, et al. A sustained
mellitus. N Engl J Med. 2002;346:1685-91.
increase in plasma free fatty acids impairs insulin secretion
71. Kobayashi T, Nakanishi K, Murase T, et al. Small dos­
in non-diabetic subjects genetically predisposed to develop
es of subcutaneous insulin as a strategy for preventing
type 2 diabetes. Diabetes. 2003;52:2461-74.
slowly progressive beta-cell failure in islet cell antibody-
59. UK Prospective Diabetes Study (UKPDS). IX: Relationships
positive patients with clinical features of NIDDM. Diabetes.
of urinary albumin and Nacetyl glucosaminidase to glycae­ 1996;45:622-6.
mia and hypertension at diagnosis of type 2 (non-insulin- 72. Maruyama T, Shimada A, Kanatsuka A, et al. Multicenter
dependent) diabetes mellitus and after 3 months diet ther­ prevention trial of slowly progressive type 1 diabetes
apy. Diabetologia. 1993;36:835-42. with small dose of insulin (the Tokyo study): preliminary
60. Balme M, McAllister I, Davis WA, et al. Retinopathy in latent report. Ann N Y Acad Sci. 2003;1005:362-9.
autoimmune diabetes of adults: the Fremantle Diabetes 73. Thunander M, Thorgeirsson H, Törn C, et al. β-cell func­
Study. Diabet Med. 2002;19:602-5. tion and metabolic control in latent autoimmune diabtes
61. Baum, P, Hermann, W, Verlohren, HJ, et al. Diabetic neu­ in adults with early insulin versus conventional treatment:
ropathy in patients with “latent autoimmune diabetes of a 3-year follow-up. Eur J Endocrinol. 2011;164:239-45.
the adults” (LADA) compared with patients with type 1 and 74. Raz I, Elias D, Avron A, et al. Beta-cell function in new-onset
type 2 diabetes. J Neurol. 2003;250:682-7. type 1 diabetes and immunomodulation with a heat-shock
62. Kanungo, A and Sanjeevi, CB. IA-2 autoantibodies are pre­ protein peptide (DiaPep277): a randomised, double-blind,
dominant in latent autoimmune diabetes in adults patients phase II trial. Lancet. 2001;358:1749-53.
from eastern India. Ann N Y Acad Sci. 2003;1005:390-4. 75. Buzzetti R, Cernea S, Petrone A, DiaPep Trialists Group,
63. Gupta M, Tandon N, Shtauvere-Brameus A, et al. ICA12 et al. C-peptide response and HLA genotypes in subjects
autoantibodies are associated with non-DR3/non-DR4 in with recent-onset type 1 diabetes after immunotherapy with
patients with latent autoimmune diabetes in adults from DiaPep277: an exploratory study. Diabetes. 2011;60:3067-72.
northern India.Ann N Y Acad Sci. 2002;958:329-32. 76. Agardh CD, Lynch KF, Palmér M, et al. GAD65 vaccina­
64. Mohan V, Vijayaprabha R, Rema M, et al. Clinical profile tion: 5 years of follow-up in a randomised dose-escalating
of lean NIDDM in South India. Diabetes Res Clin Pract. study in adult-onset autoimmune diabetes. Diabetologia.
1997;38:101-8. 2009;52:1363-8.
65. Das S, Bhoi SK, Baliarsinha AK, et al. Autoimmunity, insulin 77. Montes VN, Hirsch IB. Treatment of LADA with etanercept.
resistance and Beta cell function in subjects with low body Diabetes Care. 2012;35:e36.
 Chapter 8
Prediabetes

Rakesh K Sahay

Prediabetes

Chapter Outline
♦♦ Prevalence of Prediabetes ♦♦ Clinical Implications of Impaired Glucose Tolerance
♦♦ Instability of Impaired Glucose Tolerance ♦♦ Risk Factors for Deterioration to Diabetes
♦♦ Etiology and Pathogenesis of Impaired Glucose ♦♦ Association with Cardiovascular Disease Mortality
Tolerance ♦♦ Intervention Studies in Prediabetes

INTRODUCTION viewed as clinical entities, but rather as risk factors for

diabetes as well as cardiovascular disease (CVD). Similarly,
Prediabetes is defined by blood glucose concentrations a glycated hemoglobin (HbA1c) in the range of 5.7–6.4%
higher than normal, but lower than established thresholds also defines individuals with prediabetes and confers a
for diagnosis of diabetes. Prediabetes is also known as
significantly higher risk for the future development of
intermediate hyperglycemia, a state in which the risk of
diabetes and CVD. IFG and IGT are associated with obesity
developing diabetes is increased. The Expert Committee
(especially abdominal or visceral obesity), hypertension
on Diagnosis and Classification of Diabetes Mellitus in
and dyslipidemia with high triglycerides and/or low high-
1997 and 20031,2 recognized this intermediate group of
density lipoprotein (HDL) cholesterol.3
individuals whose glucose levels, although not meeting
The relationship of HbA1c to the risk of subsequent
criteria for diabetes, are however too high to be considered
normal. These persons were defined as having impaired development of diabetes has also been studied in several
fasting glucose (IFG) [fasting plasma glucose (FPG) levels large prospective studies which have analyzed the HbA1c
100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L)] or values in the intermediate range. These studies have
impaired glucose tolerance (IGT) [2-h values in the oral demonstrated a strong, continuous association between
glucose tolerance test (OGTT) of 140 mg/dL (7.8 mmol/L) HbA1c values and subsequent diabetes. In a systematic
to 199 mg/dL (11.0 mmol/L)]. However, the World Health review of 44,203 individuals from 16 cohort studies with an
Organization (WHO) and a number of other diabetes average follow-up of 5.6 years (range 2.8–12 years), those
organizations define the cut-off for IFG at 110 mg/dL with an A1c between 5.5% and 6.0% had a substantially
(6.1 mmol/L). increased risk of diabetes with 5-year incidences ranging
Prediabetes is a high-risk state not only for developing from 9% to 25%. While, an A1c range of 6.0–6.5% had a
diabetes, but also the associated cardiovascular compli­ 5-year risk of developing diabetes between 25% and 50%
cations. These categories of IFG and IGT should not be and relative risk (RR) 20 times higher compared with an
 Prediabetes 119

HbA1c of 5.0%.3 In another community based study of rural population in subjects more than 60 years of age, the
non-diabetic individuals of a mixed racial descent, the prevalence rates of IGT were 12.4% in urban and 14.9% in
baseline HbA1c was a stronger predictor of subsequent rural areas. In the same population, the prevalence rates
diabetes and cardiovascular events than was fasting of diabetes were significantly higher in urban population
glucose.4 Other analyses also suggest that an HbA1c of (23.7%) compared to (9.9%) the rural. In this population,
5.7% is associated with diabetes risk similar to that in the age was strongly associated with IGT. In a previous
high-risk participants in the Diabetes Prevention Program survey, the prevalence of IGT in Madras in 1988–1989 and

chapter
(DPP).5 Based on these data therefore, it is reasonable 1994–1995 was 8.7% and 9.1% respectively, while those

8
to consider an HbA1c range of 5.7–6.4% as identifying of diabetes had risen from 8.2% to 11.6% during the
individuals with prediabetes. As is the case for individuals same period. These findings would suggest the impact of
found to have IFG and IGT, individuals with an HbA1c urbanization on the rising rates of diabetes in India. Data
of 5.7–6.4% should be informed of their increased from a large number of subjects from six metropolitan
risk for diabetes as well as CVD and counseled about cities in India in 2000 showed that age standardized
effective strategies to lower their risks. As with glucose prevalence of IFG, IGT and new diabetics was 8.7%, 8.1%
measurements, the continuum of risk is curvilinear, so that and 13.9%, respectively.
as A1c rises, the risk of diabetes rises disproportionately.3 In the recent Indian Council of Medical Research-
Accordingly, interventions should be most intensive and INdia DIABetes (ICMR-INDIAB) study, the data from
follow-up particularly vigilant for those with A1c above the first phase of the study shows prevalence rates of
6.0%, who should be considered to be at very high risk. prediabetes (IFG and/or IGT) as 8.3%, 12.8%, 8.1% and
14.6% in Tamil Nadu, Maharashtra, Jharkhand and
PREVALENCE OF PREDIABETES Chandigarh, respectively. Based on this data it can be
estimated that, Maharashtra will have 9.2 million indivi­
The prevalence rates for prediabetes have been increasing
duals with prediabetes, Tamil Nadu will have 3.9 million
steadily in the past few decades. The standardization
with prediabetes Jharkhand will have 1.5 million with
of criteria for diagnosis of diabetes in 1985 enabled
prediabetes and Chandigarh will have 0.13 million with
comparison of prevalence of IGT in different populations.
prediabetes. Projections for the whole of India would be
While in certain racial groups, the prevalence of IGT
77.2 million people with prediabetes.13
is low; in others, it is extremely high. In general, the
prevalence rates of IGT follow the rates of diabetes in
INSTABILITY OF IMPAIRED
these populations.6 However, in some populations with
GLUCOSE TOLERANCE
low rates of diabetes, the prevalence of IGT is significantly
high, suggesting that diabetes may be expected to rise in Although IGT has become established as a category of
near future.7 The prevalence rates of IGT in United States abnormality in glucose metabolism and considerable
of America (USA) were found to be 6.4% in people aged epidemiological data have accumulated, there remain
20–44 years compared to a prevalence of 22% in those some problems with categorization of individuals as
aged 65–74 years,8 suggesting a strong association with IGT. Firstly, there is up to 40% variation in 2-hour plasma
age. Data from the Hoorn study in Holland showed that glucose concentrations, most of which is biological. Seco­
10.3% of subjects aged 50–75 years had IGT while 8.4% ndly, to apply cut-off values to a continuously distributed
had diabetes. In the island of Fiji, the prevalence rates variable with such large variability creates further diffi­
of diabetes among Indians aged 20 years or over were culties. This is a problem in defining IGT as there is a
found to be high, but there were no significant differences narrow 2-hour plasma glucose range of 3.3 mmol/L
among urban and rural populations. Similarly, high rates (7.8–11.0) which separates normal glucose tolerance
of IGT have been reported from people of Indian origin in (NGT) from type 2 diabetes. Subjects who have IGT on
Mauritius, where rate of IGT among men with mean age of one occasion may not have it when tested on another
42 years was 14% and in women with similar age structure, day. Those who test normal, on the second test have been
the prevalence was 20.9%.9 classified by some as having “transient IGT”, compared to
People of India and migrant Indian populations show those who have IGT on repeat testing “persistent IGT”.14
high rates of IGT.10–12 In a survey conducted in urban and Data from Pima Indians have shown that subjects with
120 Diagnosis and Classification

transient IGT also have increased risk of future diabetes assays for insulin.28,29 Snehlata and colleagues found
although it would appear to be less than that seen in those hyperinsulinemia and differences in insulin response to
with persistent IGT.14 These data suggest that transient OGTT among urban and rural Asians,30 which are most
IGT at least in some populations represent an earlier stage likely to be due to differences in diet and physical activity.
in the progression from NGT to more serious category of Most conventional insulin immunoassays, based on
glucose intolerance.14–16 Furthermore, even those labeled polyclonal antibodies, also cross-react with insulin
as “persistent IGT” do not always develop diabetes over a precursor molecules such as intact proinsulin and its
section

long period of follow-up and some even revert to NGT. In split products and make interpretation of these results
124 Pima Indians with persistent IGT, after an average
3

somewhat difficult.31
follow-up of 5.0 years, 75 (60%) had developed diabetes, However, even when highly specific assays are used to
34 (27%) continued to have IGT and 15 (12%) had measure insulin, subjects with IGT showed postprandial
reverted to NGT. The corresponding rates in subjects hyperinsulinemia both in Asian and Caucasian, sugges­
with transient IGT were 44%, 35% and 21%, respectively, ting underlying insulin resistance.32 In addition to the
after similar length of follow-up. In this study, severity of above, the ratio of proinsulin-like molecules to total
glucose intolerance, higher fasting insulin and low insulin insulin-like molecules was similar among Asian and
response predicted diabetes in people with IGT.14 Caucasian subjects with IGT.32 Recent studies from India
have confirmed that using specific assays, subjects with
ETIOLOGY AND PATHOGENESIS OF IGT show postprandial hyperinsulinemia and the proin­
IMPAIRED GLUCOSE TOLERANCE sulin to insulin ratio was similar among subjects with
Both insulin resistance and impaired β-cell function play NGT and IGT.33 Data comparing Asians, Whites and
a role in the development of type 2 diabetes, although the Pima Indians showed that fasting insulin levels in Asian
relative roles of these two has been debated for a number subjects from United Kingdom (UK) were intermediate
of years.17-21 However, type 2 diabetes is a heterogeneous between European subjects who have a lower prevalence
disease and the relative contribution of insulin resistance of diabetes and Pima Indians, who have an extremely
and β-cell dysfunction varies among populations and high prevalence. These findings suggest greater insulin
among subjects within the same population.22 resistance in Asians and Pima Indians compared to
Prediabetes represents an intermediate stage of glu­ Whites.34 On the other hand, in non-diabetic subjects
cose intolerance, with likelihood that most people who from these three populations, the ratio of insulin to proin­
develop type 2 diabetes generally pass through a stage sulin-like molecules was similar suggesting that these
of abnormal glucose tolerance. Although there remains subjects respond in similar fashion to compensate for
a debate about the underlying primary nature of the underlying insulin resistance.
defect, data support the view that subjects with IGT have In the past, the state of β-cell function in subjects with
impaired insulin action, i.e. their insulin stimulated IGT remained somewhat unclear; however, recent studies
glucose uptake is less than those with NGT.22,23 However, suggest that impaired insulin secretion is a ubiquitous
these subjects, maintain plasma glucose concentrations feature. Davies et al. showed the presence of β-cell
at levels lower than those seen in manifest diabetes by dysfunction with low insulin response during intravenous
compensatory hyperinsulinemia. It is only when the ailing glucose tolerance test (IVGTT).16 Using specific assays
pancreas can no longer adequately compensate for degree for insulin, we showed that when insulin secretion is
of insulin resistance that insulin deficiency ensues and measured as a ratio of increment in insulin to increment
overt diabetes develops.18 in glucose during OGTT, subjects with IGT showed
Studies done during mid-eighties, using hyperin­ diminished ratio in both Asian and Caucasian subjects
sulinemic clamps, showed that Asian subjects were more suggesting impaired insulin secretion.32 An elegant study
insulin resistant than Whites, despite being younger.23 by Mitrakou and colleagues showed that postprandial
Several studies have also confirmed compensatory hyperglycemia and hyperinsulinemia in subjects with IGT
hyperinsulinemia in subjects with IGT,14,24-27 both during is due to defective first phase insulin secretion with distur­
fasting and post-prandial state compared to those with bed insulin/glucagon ratio.34 Longitudinal data from
NGT. Similarly, hyperinsulinemia was demonstrated in Pima Indians confirms that the transition from NGT to IGT
Asian non-diabetic individuals, using immunoreactive is characterized by initial hyperinsulinemia and further
 Prediabetes 121

decline in insulin secretion leads to development of frank CLINICAL IMPLICATIONS OF

hyperglycemia.27 It is clear that IGT, like-type 2 diabetes, is IMPAIRED GLUCOSE TOLERANCE
a heterogeneous condition35 with differential contribution
from insulin insensitivity and β-cell dysfunction. A study Conversion to Diabetes
by Byrne et al. has confirmed presence of both insulin Impaired glucose tolerance is neither a disease nor a
insensitivity and β-cell dysfunction in subjects with IGT.36 syndrome. It has a certain predictive ability and data have
It would appear that the prevalence of IGT in people shown consistently that subjects who have IGT are at an

chapter
of developing nations including Indians, both at home increased risk of diabetes.15 The risk of subsequent diabetes

8
and overseas, is high and is likely to rise further. The is manifold higher which depends upon some other risk
pathogenesis of IGT suggests underlying insulin resistance factors as well. The conversion rates of diabetes in subjects
and degree of β-cell dysfunction. Indeed, the underlying with glucose intolerance vary among populations. In
pathogenesis of IGT is similar among different ethnic subjects of European origin, the conversion rates are
groups.37 Genetic factors clearly play a role in determining approximately 2% per year and up to 6% per year in Pima
predisposition to glucose intolerance,38,39 which may be Indians. A study from Hoorn, alluded to earlier has shown
more important in Asian Indians, but are at present high conversion rates in subjects of European origin,
unidentified and hence unmodifiable. Data support that which may be partly due to the older age structure, in the
there is a major contribution of environmental factors study population.9 In Indian populations, the only long­
such as physical inactivity, dietary practices, obesity and itudinal data showed that in 107 subjects with IGT after
fat distribution, all of which are potentially modifiable.40 2–8 years follow-up, 32% of subjects still had IGT, 32%
The debate has been whether the different predia­ had reverted to NGT and 36% had developed diabetes.42
betic states namely isolated-IFG (i-IFG), isolated-IGT In Asians from South Africa, the conversion rates were
(i-IGT) and combined IFG/IGT differ in terms of the high at 12.6%43 but low at 2.0% in Hindu population from
mechanisms and potential etiological factors leading to rural Tanzania.44
their development. The pathophysiology of i-IFG seems
to include the following key defects: reduced hepatic Comparison of Impaired Glucose Tolerance
insulin sensitivity, stationary β-cell dysfunction and/or with Impaired Fasting Glucose
chronic low β-cell mass, altered glucagon-like peptide-1 Data from populations in Mauritius show that when old
secretion and inappropriately elevated glucagon secre­ WHO criteria are applied to subjects with IFG, about 30%
tion. Conversely, the prediabetic state i-IGT is charac­ have IGT, and another 30% have type 2 diabetes based
terized by reduced peripheral insulin sensitivity, near on cut-off value of 11.1 mmol/L after an OGTT.45 This
normal hepatic insulin sensitivity, progressive loss of has been confirmed in a number of recently published
β-cell function, reduced secretion of glucose-dependent studies from different populations.46–49 Furthermore, IGT
insulinotropic polypeptide and inappropriately elevated has been shown to have a higher sensitivity than IFG for
glucagon secretion. Individuals developing combined predicting progression to diabetes over a 5-year follow-up.
IFG/IGT exhibit severe defects in both peripheral and The sensitivity, specificity and positive predictive values
hepatic insulin sensitivity as well as a progressive loss were 26, 94 and 29% for IFG and 50, 84 and 24% for IGT,
of β-cell function. The etiologies of i-IFG and i-IGT also respectively.49 In Japanese, IFG is associated with similar
seem to differ, with i-IFG being predominantly related to rates of hypertension, as seen in subjects with IGT,50 while
genetic factors, smoking and male sex, while i-IGT is others report IGT and not IFG to be risk factor for CVD.
predominantly related to physical inactivity, unhealthy Whatever may be the future risk of diabetes in subjects
diet and short stature. Since the transition from the with IGT or IFG, IGT appears to be somewhat better at
prediabetic states to overt type 2 diabetes is characterized defining future risk of CVD than can be done by IFG,49,50
by a non-reversible vicious cycle that includes severe although more data are needed to be certain about this.
deleterious effects on glucose metabolism, there are good Recently published data from India, FPG of 7.0 mmol
reasons to use the well-established etiological and path­ when used to diagnose diabetes had a sensitivity of 83%
ophysiological differences in i-IFG, i-IGT and IFG/IGT and the prevalence of diabetes using fasting glucose alone
to design individualized preventive strategies.41 was 4.3% compared to 5.3% using WHO criteria.51 In this
122 Diagnosis and Classification

study rates of IFG were not given, but identification of IFG and gain in weight. In the Israeli study by Modan et al.
had only 50% sensitivity for diagnosing IGT. In addition, a baseline BMI of more than 23 conferred a high-risk
the prevalence of cardiovascular risk factors were similar of IGT, which increased dramatically once BMI was
irrespective of whether a cut-off of 7.0 or 7.8 mmol/L was exceeded 27. However, there remain inconsistencies in
used to diagnose diabetes. In a study published from South this relationship, as in Australian aborigines, BMI showed
Asian Indians in UK, the prevalence of IFG was 19% and positive association only in men.55 In various studies,
that of diabetes using new American Diabetes Association a strong family history is a risk factor for IGT.38–40 In the
section

(ADA) criteria was 21.4% in subjects aged 25–64 years.52 Unites States (US) data, up to 30% of subjects had a family
3

In this population, the prevalence of IGT was 18.7% and history of type 2 diabetes compared to only 20 in those
that of diabetes 20.1% using old WHO criteria. In this study with NGT.8 In a study from Mauritius, family history of
when subjects with IFG were reclassified by WHO criteria, diabetes was present in approximately 20% of men and
53% had NGT, 37% had IGT and 8.4% had diabetes, which women with glucose intolerance.56 Data from India,
are in agreement with other published data. Recent data in adult offspring of two diabetic parents showed that
from six cities showed IFG rates of 8.7%, which were visceral adiposity seemed to precede glucose intolerance
similar to that of IGT 8.1%. Among subjects with IFG in in women only. In this population, β-cell dysfunction
this study, only 4% had diabetes, 27% had IGT applying as measured by low early insulin response was not asso­
2-hour criteria. Subjects with IFG were older and had ciated with IGT.57 The authors suggested that in those who
worse anthropometric characteristics in comparison with have a strong genetic predisposition to diabetes; abdo­
NGT. IFG was more common in women and its prevalence minal adiposity may not be an important prerequisite
did not increase with age. for the development of IGT.
Future studies may address the exact predictive Studies have shown physical inactivity to be a strong
ability of IFG in defining risk of subsequent diabetes, risk factor for IGT.56,58 In Maltese population, the risk of
CVD and mortality. However, IFG only requires a single future diabetes in subjects who fell in the highest tertile of
fasting glucose value for diagnosis, compared to IGT, physical activity was lower at 5.2% compared to 16.5% in
which requires an OGTT. Therefore, the use of new those in the lowest tertile of physical activity.59 In Indian
ADA criteria is a simple and more attractive option as it population from Mauritius, physical inactivity was strongly
does not necessitate an OGTT, particularly taking into associated with IGT and was an independent determinant
account the direct and indirect cost and the logistics of of insulin resistance and β-cell function both in men and
performing an OGTT. FPG measurement is also less time women.60
consuming, easier to perform and is a less expensive It is likely that most people who develop type 2 diabetes
test than OGTT, which is a consideration in developing go through a variable period of glucose intolerance before
countries. Therefore, it offers more scope and possibility developing overt diabetes. On the contrary, not all sub­
to detect undiagnosed diabetes and people at future risk jects with IGT progress to develop diabetes as some revert
of diabetes.37 Secondly, due to less variation of FPG than to NGT or stay as IGT.42 It is, therefore, important to know
2-hour glucose classification into a category of IFG may which particular risk factors will predict future diabetes
represent a more stable condition than IGT. Nevertheless, in subjects with IGT. By far, the most consistent of risk
it is likely that IFG and IGT, although defined by different factors, determining the progression to overt diabetes,
criteria, represent a continuum of glucose intolerance remains the severity of 2-hour glucose following OGTT.
severity.53–54 Data from Pima Indians, Japanese and Caucasian popula­
tions have confirmed the same.60,61 Study by Kadowaki
RISK FACTORS FOR et al. showed that the risk of future diabetes in subjects
with IGT increased progressively with worsening fasting
DETERIORATION TO DIABETES
and 2-hour post-prandial glucose concentrations within
In cross-sectional surveys, age, body mass index (BMI), the cutoff value used to define IGT. They showed that
a positive family history of diabetes, hypertension, and among subjects with IGT the rate of worsening to diabetes
high plasma triglyceride have been associated with IGT. was linearly and strongly related to increasing baseline
The major focus of attention as a risk factor for develo­ 2-hour plasma glucose concentrations. The rate of
ping IGT and type 2 diabetes has been body weight deterioration in those with 2-hour glucose of less than
 Prediabetes 123

7.8 was 3.4%, while those with 2-hour value between that does IGT causally relate to CVD? Or are they
7.8 mmol/L and 11.0 mmol/L, the rate rose stepwise to a usual manifestation of a common underlying defect?75,76
16.1%. More importantly, in the same study, subjects who There is no doubt that the cardiovascular risk factors are
had a FPG less than 6.1 mmol/L, current level to define elevated long before development of diabetes, as was
normal fasting glucose (NFG), only 13% worsened to shown in San-Antonio study.77 Subjects in this study had
diabetes compared to 45% in those whose initial fasting high blood pressure, higher LDL-cholesterol, plasma
glucose was 6.6 mmol/L still within the IFG limits.62 triglycerides, and low HDL-cholesterol. Rancho Bernado’s

chapter
Therefore, the risk of diabetes in subjects with IGT can study subjects who subsequently developed diabetes, had

8
be more clearly assessed by measuring fasting glucose as higher blood pressures and triglycerides at baseline.78
well.14,24,62 These studies support the contention that insulin resis­
Another risk factor, which has been consistently shown tance along with associated hyperinsulinemia is a com­
to be predictive of progression to diabetes, is a low early mon underlying defect, a constituent of metabolic synd­
insulin response during an OGTT.22,24 High proinsulin rome that manifests itself much prior to development of
levels indicative of β-cell dysfunction also predict future overt diabetes.75
diabetes in these subjects.63,64 These findings have been Role of vitamin D: Vitamin D receptors (VDRs) are
confirmed in some migrant populations also.65 Both expressed in more than 30 different tissues, including
obesity and weight gain predict future development of pancreatic islet and skeletal muscle cells, and serum
diabetes in subjects with IGT.66 This relationship, however, vitamin D concentrations may exert modulating effects on
is abolished when adjusted for plasma glucose and raised both insulin secretion and insulin action.79 Vitamin D may
insulin concentrations, suggesting that obesity operates also be involved in systemic inflammation processes, and
through underlying insulin resistance.66 improve insulin sensitivity and promote β-cell survival
by directly modulating the effect of cytokines.79 It has
ASSOCIATION WITH CARDIOVASCULAR been shown that higher serum 25 (OH)D concentrations
predict a reduced risk of type 2 diabetes in individuals
DISEASE MORTALITY
with prediabetes, but not NGT. However, there is a need
In the Paris Prospective Study, subjects with IGT showed for data from interventional studies measuring the effect
mortality rates very similar to those with newly diagnosed of vitamin D supplementation.
diabetes, suggesting the serious nature of this condition.67,68
Similar findings were observed from the Whitehall study INTERVENTION STUDIES IN PREDIABETES
in London, where subjects with IGT had higher mortality69
As prediabetes is a strong risk factor for diabetes and CVD,
likewise from Helsinki policemen study.70 Data from
Helsinki study confirmed that the risk of subsequent it is logical to see if intervention to modify known risk
mortality was dependent upon levels of fasting glucose, factors, will slow or reduce development of overt diabetes
as subjects who had IGT but lower fasting glucose had and reduce cardiovascular risk.80 This is of extreme
mortality rates similar to subjects with NGT. However, in importance, especially in developing countries where the
study from Kupio in Finland, there was no such contribu­ prevalence rates of diabetes are likely to double over the
tion of fasting glucose to increase in mortality. Why next 10–20 years, and will have enormous socioeconomic
subjects with IGT should have high mortality is precisely implications.81 In reducing the risk of diabetes in subjects
unknown, but may be due to the association of IGT with with IGT, different strategies can be adopted.82 Lifestyle
additional cardiovascular risk factors. Whether hyper­ interventions with diet and physical activity are attractive
glycemia in itself is associated with excess cardiovascular and may impact on other disease conditions such as
mortality remains arguable, however, there are emerging hypertension and CVD,79 but are difficult to sustain over
data to support this contention.71–73 longer time periods. Pharmacological agents which target
There are a number of studies showing a positive fundamental underlying pathogenetic mechanisms such
association between IGT and CVD risk factors74 similar to as insulin resistance and β-cell dysfunction can be used to
what is seen in subjects with newly diagnosed type 2 reduce the risk of developing type 2 diabetes.82,83
diabetes, and may explain the association between Early studies of interventions in subjects with IGT
asymptomatic hyperglycemia after OGTT and CVD mor­ were performed as early as 1970s and produced varied
tality. The intriguing and unanswered question remains results.84–89 However, more recent studies using lifestyle
124 Diagnosis and Classification

interventions have provided consistent and encouraging • The risk of diabetes was reduced despite fairly modest
results.90–92 A study by Eriksson and Lindgarde showed that reduction in body weight (approximately 2 kg).
an outpatient exercise program can be maintained success­ • The increase in physical activity was modest but was
fully for up to 6 years. This was a non-randomized study of sustained over the time span of the study.
primary prevention of type 2 diabetes, which also included • The effects were similar in obese and non-obese
41 patients with known type 2 diabetes and 161 subjects subjects.
with IGT. In 28% of subjects with diabetes, the glucose The results of this intervention trial cannot be genera­
section

tolerance had returned to normal, 26% of subjects reverted lized to other racial groups and need to be replicated in
3

to IGT and 46% were still classified as diabetic. In subjects other racial groups with a high risk of type 2 diabetes.
who had IGT at baseline, 69% had NGT and 21% still had The results of a recently published study from Finland,
IGT, 11% had developed diabetes compared to 21% in have been extremely encouraging.93 In this study, the
the control group, despite fairly modest amount of weight authors studied 522 subjects (172 men, 350 women).
loss.90 The most valid and encouraging conclusion of this These were middle-aged subjects with mean age of 55
study was the demonstration that outpatient based exercise and with mean BMI of 31 kg/m2. Intervention in control
program was successfully maintained for up to 5 years. group consisted of verbal and written instructions about
The overall mortality in the whole cohort was 3.3% diet and exercise at baseline. The intervention group
(230 of 6,956 subjects) with an annual mortality figure of was given individualized dietary counseling aimed at
0.5%. The RR of death in the treatment cohort with lifestyle reducing weight, total fat and saturated fat intake and
interventions (5 of 222 subjects) was 0.67, and was not increased intake of fiber. This intervention was given as
statistically significant from the control group. However, face-to-face sessions with dietician and seven times during
no cases of acute myocardial infarction occurred among first year and three monthly thereafter. Physical activity
those who continued with the treatment protocol for a counseling was also individually designed and included
period of 6 years, which is reassuring. The cumulative both aerobic (endurance) and resistance training. Incre­
mortality in subjects with IGT and type 2 diabetes who ased walking along with routine daily activities was
participated in the program was 3.2% which was signi­ encouraged. Some supervised activities were provided to
ficantly less than those with known diabetes (mortality train people. An OGTT was given annually on all subjects.
11.9%). Clearly, only a limited conclusion can be drawn If abnormal, diabetes was confirmed by a second test.
from this non-randomized study, nevertheless physical After an average follow-up of 3.2 years, subjects in the
activity appears to be safe over a long-term period and may intervention group lost 4.2 kg of weight compared to 0.8 kg
potentially have benefits in terms of lowering mortality. in the control group at year 1 and 3.5 kg and 0.8 kg at year
The 12-year follow-up data from the same study showed 2, respectively. The cumulative incidence of diabetes in
that in subjects with IGT, lifestyle interventions with diet the intervention group was 11% [95% confidence interval
and exercise, achieved mortality rates similar to those (CI) 6–15] compared to 23% (95% CI 17–29) in the control
with NGT. group. Thus, lifestyle intervention resulted in a total risk
The Da Qing study from China was a population-based reduction of 58%, which was highly significant. The redu­
randomized study. 576 subjects with IGT were randomized ced incidence of diabetes was related to modification
to four groups (control, diet alone, exercise alone or both) of lifestyle. To interpret data in another way, 22 subjects
and were followed for an average period of 5.6 years. The with IGT will need to be treated for 1 year (or 5 subjects
incidence of diabetes was reduced in all three intervention for 5 years) in this way to prevent one case of diabetes.
groups and to an equal extent with 50% reduction in the The DPP recruited 3,234 subjects at high risk of
incidence of diabetes. Some general points of interest type 2 diabetes. Eligibility criteria included age more than
emerging from this first properly randomized and 25 years, overweight and IGT as defined by WHO criteria.
controlled intervention study are as follows:92 This study included 68% women, while 45% of sub­
• Lifestyle interventions in the form of diet and physical jects were non-Caucasian (African American, His­panic,
activity for up to 6 years significantly reduced the American Indians, and Asian Americans). The mean
development of diabetes. age was 51 years and BMI was 34 kg/m2. Subjects were
• The effects of diet or exercise were similar, i.e. both randomized to intensive lifestyle interventions (n = 1,979),
reduced the risk of diabetes. placebo (n = 1,082) and metformin (MET) 850 mg twice
 Prediabetes 125

daily (n = 1,073). Intervention consisted of a goal to lose In the Indian Diabetes Prevention Program 531 (421
7% of weight and at least 150 minutes of exercise per men 110 women) subjects with IGT (mean age 45.9 +/– 5.7
week. The participants in the intensive exercise program years, BMI 25.8 +/– 3.5 kg/m2)) were randomized to four
met case study managers on one-to-one basis 16 times groups. Group 1 was the control, Group 2 was given advice
during the first 6 months and monthly thereafter. Primary on LSM, Group 3 was treated with MET and Group 4 was
outcome was diabetes based on results of an OGTT. given LSM plus MET. After a median follow-up period of
The results of this study confirmed that type 2 diabetes 30 months, cumulative incidences of diabetes were 55.0%,

chapter
could be prevented by lifestyle modifications (LSMs) and 39.3%, 40.5% and 39.5% in Groups 1–4, respectively. The

8
by pharmacological interventions. The risk of diabetes RR reduction was 28.5% with LSM (95% CI 20.5–37.3,
was reduced by both lifestyle changes in the form of diet p = 0.018), 26.4% with MET (95% CI 19.1–35.1, p = 0.029)
and exercise and also by MET treatment. After an average and 28.2% with LSM + MET (95% CI 20.3–37.0, p = 0.022),
follow-up of 2.8 years the incidence of diabetes was 11.0, as compared with the control group. The number needed
7.8, 4.8 cases per 100 person years of follow-up in placebo, to treat to prevent one incident case of diabetes was 6.4
MET and lifestyle interventions, respectively. The lifestyle for LSM, 6.9 for MET and 6.5 for LSM + MET. This study
intervention reduced diabetes incidence by 58% while therefore showed that LSM and MET significantly reduced
MET did so by 38% compared to placebo treatment. The the incidence of diabetes in Indians with IGT; there was no
results of this trial were similar in men, women and in all added benefit from combining them.100
racial and ethnic groups. Moreover, lifestyle interventions The cost effectiveness of interventions used in these
were equally effective in younger and older individuals.94 studies has been assessed in French, German and
Other studies to prevent diabetes in populations at UK set up,101 and was found to be higher for lifestyle
high risk including studies using pharmacological inter­ interventions than for MET. Therefore, one might argue
ventions are worth considering. In a Study to Prevent-Non­ that pharmacological interventions would appear to be a
insulin-Dependent Diabetes Mellitus (STOP-NIDDM), more attractive option for preventing diabetes. However,
acarbose was evaluated in a placebo-controlled trial, in lifestyle interventions have the potential to exert impact
subjects with IGT.95 After a mean follow-up of 3.3 years, the on multiple disease states. Diabetes prevention is a major
absolute risk reduction was 9% in acarbose group and RR public health issue in populations with high prevalence
was reduced by 36% when diabetes was confirmed with a of type 2 diabetes, such as Asian Indians, as the rate of
second OGTT. In addition, there was a significant reversion incidence of diabetes is projected to double over the next
from IGT to NGT. In the Troglitazone in the Prevention 20 years.81 It remains for the health policy makers to make
of Diabetes (TRIPOD) study, 236 Hispanic women with this a public health issue and institute urgent intervention
gestational diabetes were randomized to troglitazone, trials. However, it needs to be appreciated that lifestyle
which is now withdrawn from the market. After a follow-up interventions in different racial groups may be particularly
of 2.5 years, the incidence of diabetes was 12.3 and 5.4% challenging,102 suggesting that when intervening with
in control and intervention group giving a RR reduction of lifestyle measures, different strategies may need to be
56%, in progression to diabetes.96 The results of XENical in adopted in different racial groups. In a study reported from
the prevention of Diabetes in Obese Subjects (XENDOS) Tanzania in people of Hindu religion, simple dietary advice
trial have shown that orlistat and lifestyle intervention to eat less and exercise more in the form of walking for
reduced risk of diabetes by 37% compared to lifestyle 30 minutes per day, resulted in protection from progres­
alone. Other major consideration was that orlistat group sion to diabetes.103 In most studies of lifestyle interventions,
had significant reduction in cardiovascular risk factors. there was a tendency toward a reduction in risk factors for
These results underscore the fact that obesity prevention, CVD such as total and LDL-cholesterol, triglyceride and a
with whatever measures, is needed to reduce diabetes and decrease in systolic and diastolic blood pressure.
cardiovascular risk.97 Other drugs especially angiotensin- There would appear to be a greater urgency to develop
converting enzyme inhibitors (ACEI) appear to be strategies to prevent type 2 diabetes, given that diabetes
promising in preventing new onset diabetes in a number seems to be appearing at a younger age even in children
of studies such as Heart Outcomes Prevention Evaluation and adolescents. On the other hand, for the results of
(HOPE) and Losartan Intervention For Endpoint reduction clinical trials to prevent diabetes to be meaningful, the
in hypertension (LIFE) trials.98,99 results need to be generalized and the methods need
126 Diagnosis and Classification

to be affordable, acceptable and practical so as to be The following facts have been fully documented:
easily implemented. It is quite clear that the intensity of • Impaired glucose tolerance is a strong risk factor for
intervention in the trials is unaffordable even in the rich future development of diabetes in all populations.
countries. However, the risk of future diabetes can be defined
equally well with measuring FPG, which is cheaper
CONCLUSION and easier to perform than an OGTT.
It is clear that people with IGT and IFG are a group of high- • Impaired glucose tolerance is associated with the
section

risk individuals for development of diabetes and ischemic metabolic syndrome and high rates of CVD. Insulin
3

heart disease. These categories of glucose abnormalities resistance is likely to be the underlying mechanism for
are frequently associated with obesity, hypertension and the association of IGT with CVD.
dyslipidemia, which may be instrumental in increasing • In subjects with IGT and IFG, environmental factors
the risk of ischemic heart disease. In India, diabetes and play an important role in subsequent deterioration to
IGT are common and the prevalence is continually on diabetes while both are potentially modifiable; IGT has
the rise. Considering the intricate relationship of glucose been proven to do so.
intolerance with CVD, as seen in migrant Indian popula­ • Randomized intervention studies have confirmed that
tions, emphasis has to be laid on strategies to identify these it is possible to prevent and delay the onset of diabetes
high-risk individuals and intervention. However, taking in different racial groups using lifestyle interventions
into account the extremely high rates of diabetes in Indian and pharmacological interventions.
subjects, it may be justifiable to screen for asymptomatic • Only a modest weight loss and a modest increase in
diabetes and to plan intervention with lifestyle changes, physical activity, sustained over longer periods, are
even in those found to have IFG or IGT. Screening based needed to reduce risk of type 2 diabetes.
on fasting glucose alone may be appropriate for those
at high risk, in view of limited resources. Those who are Further reading
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to advice these individuals about the benefits of lifestyle Diabetes Mellitus. Report of the Expert Committee on the
changes incorporating dietary modifications and increase Diagnosis and Classification of Diabetes Mellitus. Diabetes
in physical activity. In addition, we need to manage Care. 1997;20:1183-97.
2. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention
hypertension, dyslipidemia and cigarette smoking to
of type 2 diabetes mellitus by changes in lifestyle among
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The results of the Diabetes Prevention Study (DPS) 3. Ramachandran A, Snehalatha C, Satyavani K, et al. Impai­
from Finland, DPP from the USA and the Indian DPP have red fasting glucose and impaired glucose tolerance in
shown that lifestyle interventions and metformin treat­ urban population in India. Diab Med. 2003;20:220-4.
4. Ramachandran A, Snehalatha C, Mary S, et al. The Indian
ment were both successful in preventing type 2 diabetes Diabetes Prevention Programme shows that lifestyle modi-
in those at high risk. The strength of these studies showed fication and metformin prevent type 2 diabetes in Asian
consistency in that only a modest weight loss was required Indian subjects with impaired glucose tolerance (IDPP-1).
to reduce the risk of incident diabetes as long as it was Diabetologia. 2006;49:289-97.
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impaired glucose tolerance: does it matter for preven- lence of non-insulin dependent diabetes and impaired glu-
tion and treatment of type 2 diabetes? Diabetologia 2009; cose tolerance in Indian, Creole and Chinese Mauritians.
52:1714-23. Diabetes. 1990;39:390-6.
42. Ramachandran A, Snehalatha C, Naik RA, et al. Significance 57. Ramachandran A, Snehalatha C, Mohan V, et al. Decreased
of impaired glucose tolerance in an Asian Indian popula- insulin sensitivity in offspring whose both parents have
tion: a follow-up study. Diabetes Res Clin Pract. 1986;2: type 2 diabetes. Diabet Med. 1990;7:331-4.
173-8. 58. Kriska AM, LaPorte RE, Pettitt DJ, et al. The associa-
43. Motala AA, Omar MA, Gouws E. High risk of progression tion of physical activity with obesity, fat distribution and
to NIDDM in South African Indians with impaired glucose glucose intolerance in Pima Indians. Diabetologia. 1993;36:
tolerance. Diabetes. 1993;42:556-63. 863-9.
44. Swai AB, McLarty DG, Sherrif F, et al. Diabetes and impaired 59. Dowse GK, Qin H, Collins VR, et al. Determinants of
glucose tolerance in an Asian community in Tanzania. Dia- estimated insulin resistance and β-cell function in Indian,
betes Res Clin Pract. 1990;8:227-34. Creole and Chinese Mauritians. Diabetes Res Clin Pract.
45. Shaw JE, Zimmet PZ, de Courten M, et al. Impaired fasting glu- 1990;10:265-79.
cose or impaired glucose tolerance. What best predict future 60. Keen H, Jarrett RJ, McCartney P. The 10-year follow-up of
diabetes in Mauritius? Diabetes Care 1999;22:399-402. Bedford survey (1962-1972): glucose tolerance and diabe-
46. Gómez-Pérez FJ, Aguilar-Salinas CA, López-Alvarenga tes. Diabetologia. 1982;22:73-8.
JC, et al. Lack of agreement between the World Health 61. Sasaki A, Suzuki T, Horiuchi N. Development of diabetes
Organization category of impaired glucose tolerance and in Japanese subjects with impaired glucose tolerance: a
the American Diabetes Association category of impaired sevenyear follow-up study. Diabetologia. 1982;22:154-7.
fasting glucose. Diabetes Care. 1998;21:1886-8. 62. Kadowaki T, Miyaki Y, Hagura R, et al. Risk factors for wors-
47. De Vegt F, Dekker JM, Stehouwer CDA, et al. The 1997
ening to diabetes in subjects with impaired glucose toler-
American Diabetes Association criteria versus the
ance. Diabetologia. 1984;26:44-9.
1985 World Health Organization criteria for the diagnosis
63. Inoue I, Takahashi K, Katayama S, et al. A higher proinsu-
of abnormal glucose tolerance. Diabetes Care. 1998;21:
lin response to glucose loading predicts deteriorating fast-
1686-90.
ing plasma glucose and worsening to diabetes in subjects
48. Harris MI, Eastman RC, Cowie CC, et al. Comparison of
diabetes diagnostic categories in the US population accord- with impaired glucose tolerance. Diabet Med. 1996;13:
ing to 1997 American Diabetes Association and 1980-1985 330-6.
World Health Organization diagnostic criteria. Diabetes 64. Nijpels G, Popp-Snijders C, Kostense PJ, et al. Fasting
Care. 1997;20:1859-62. proinsulin and 2-h post-load glucose levels predict the
49. Shaw JE, Hodge AM, de Courten M, et al. Isolated post-chal- conversion to NIDDM in subjects with impaired glucose
lenge hyperglycaemia confirmed as a risk factor for mortal- tolerance: the Hoorn Study. Diabetologia. 1996;39:113-8.
ity. Diabetologia. 1999;42:1050-4. 65. Kahn SE, Leonetti DL, Prigeon RL, et al. Proinsulin
50. Suematsu C, Hayashi T, Fujii S, et al. Impaired fasting glu- levels predict the development of non-insulin-dependent
cose and the risk of hypertension in Japanese men between diabetes in Japanese-American men. Diabet Med. 1996;13:
the 1980s and the 1990s. Diabetes Care. 1999;22:228-32. S63-6.
 Prediabetes 129

66. Harris MI, Hadden WC, Knowler WC, et al. Prevalence 82. Knowler WC, Narayan KM, Hanson RL, et al. Perspective in
of diabetes and impaired glucose tolerance and plasma diabetes. Preventing non-insulin-dependent diabetes. Dia-
glucose levels in US population aged 20-74 years. Diabetes. betes. 1995;44:483-8.
1987;36:523-34. 83. Bourn DM. The potential for lifestyle changes to influence
67. Eschwege E, Richard JL, Thibult N, et al. Coronary heart the progression of impaired glucose tolerance to nonin-
disease mortality in relation with diabetes, blood glucose sulin-dependent diabetes mellitus. Diab Med. 1996;13:
and plasma insulin levels: the Paris Prospective Study, ten 938-45.
years later. Horm Metab Res. 1985;17:41-6. 84. Fajans SS, Conn JW. Tolbutamide-induced improvement in

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68. Fontbonne A, Thibult N, Eschwège E, et al. Body fat dis- carbohydrate tolerance of young people with mild diabetes
tribution and coronary heart disease mortality in subjects mellitus. Diabetes. 1960;9:83-8.

8
with impaired glucose tolerance or diabetes mellitus: the 85. Engelhardt HT, Vecchio TJ. The long-term effect of tolbuta-
mide on glucose tolerance in adults, asymptomatic, latent
Paris Prospective Study, 15-year follow-up. Diabetologia.
diabetes. Metabolism. 1965;14:885-90.
1992;35:464-8.
86. Belknap BH, Bagdade JD, Amaral JAP, et al. Plasma lipids
69. Fuller JH, Shipley MJ, Rose G, et al. Coronary artery disease
and mild glucose intolerance. A double blind study of the
and impaired glucose tolerance. The Whitehall study. Lan-
effect of tolbutamide and placebo in mild adult diabetic
cet. 1980;1:1373-6.
outpatients. Excerpta Med Intl Congr Ser. 1967;149:171-6.
70. Stengård JH, Tuomilehto J, Pekkanen J, et al. Diabetes mel- 87. Jarrett RJ, Keen H, Fuller JH, et al. Treatment of borderline
litus, impaired glucose tolerance and mortality among diabetes: controlled trial using carbohydrate restriction
elderly men: the Finnish cohort of seven countries study. and phenformin. Br Med J. 1977;2:861-5.
Diabetologia. 1992;35:760-5. 88. Page RC, Harnden KE, Walravens NK, et al. Healthy living
71. Barrett-Connor E. Dose hyperglycemia really causes coro- and sulphonylurea therapy have different effects on glucose
nary artery disease? Diabetes Care. 1997;20:1620-3. tolerance and risk of cardiovascular disease in subjects with
72. Yarnell JW, Pickering JE, Elwood PC, et al. Does nondia- impaired glucose tolerance. Q J Med. 1993;86:145-54.
betic hyperglycemia predict future IHD? Evidence from 89. Sartor G, Scherstén B, Carlström S, et al. Ten-year follow-up
the Caerphilly and Speedwell studies. J Clin Epidemiol. of subjects with impaired glucose tolerance. Prevention
1994;47:383-8. of diabetes by tolbutamide and diet regulation. Diabetes.
73. Pan WH, Cedres LB, Lui K, et al. Relationship of diabe- 1980;29:41-9.
tes and asymptomatic hyperglycemia to risk of coronary 90. Eriksson KF, Lindgärde F. Prevention of type 2 (non-insulin
artery disease in men and women. Am J Epidemiol. 1986; dependent) diabetes mellitus by diet and physical exer-
123:504-16. cise: the six-year Malmo feasibility study. Diabetologia.
74. Laws A, Marcus EB, Groves JS, et al. Lipids and lipopro- 1991;34:891-8.
teins as risk factors for coronary artery disease in men with 91. Eriksson KF, Lindgärde F. No excess 12-year mortality in
impaired glucose tolerance: the Honolulu Heart Program. men with impaired glucose tolerance who participated in
J Inter Med. 1993;234:471-8. Malmo preventive trail with diet and exercise. Diabetologia.
75. Stern MP. Diabetes and cardiovascular disease: the “com- 1998;41:1010-7.
mon soil” hypothesis. Diabetes. 1995;44:369-74. 92. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in
76. Jarrett RJ. Cardiovascular risk associated with impaired glu- preventing NIDDM in people with impaired glucose toler-
cose tolerance. Diabet Med. 1996;13:S15-9. ance. Diabetes Care. 1997;20:537-44.
77. Haffner SM, Stern MP, Hazuda HP, et al. Cardiovascular 93. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention
risk factors in confirmed prediabetic individuals. Does the of type 2 diabetes mellitus by changes in lifestyle among
clock for coronary heart disease start ticking before the subjects with impaired glucose tolerance. N Engl J Med.
onset of clinical diabetes? JAMA. 1990;263:2893-8. 2001;344:1343-50.
78. McPhillips JB, Barrett-Connor E, Wingard DL. Cardiovas- 94. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction
cular disease risk factors prior to the diagnosis of impaired in the incidence of type 2 diabetes with lifestyle interven-
glucose tolerance and non-insulin-dependent diabetes tion or metformin. N Engl J Med. 2002;346:393-403.
mellitus in a community of older adults. Am J Epidemiol. 95. Chiasson JL, Josse RG, Gomis R, et al, Acarbose for preven-
1990;131:443-53. tion of type 2 diabetes mellitus: the STOP-NIDDM ran-
79. Deleskog A, Hilding A, Brismar K, et al. Low serum domised trial. Lancet. 2002;359:2072-7.
25-hydroxyvitamin D level predicts progression to type 96. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of
2 diabetes in individuals with prediabetes but not with nor- pancreatic β-cell function and prevention of type 2 diabetes
mal glucose tolerance. Diabetologia. 2012;55:1668-78. by pharmacological treatment of insulin resistance in high-
80. Bennett PH. Impaired glucose tolerance: a target for inter- risk Hispanic women. Diabetes. 2002;51:2796-803.
vention? Arteriosclerosis. 1985;5:315-7. 97. Torgerson JS, Boldrin MN, Hauptman J, et al. XENical in
81. King H, Rewers M, WHO Ad Hoc Reporting Group. Global the prevention of Diabetes in Obese Subjects (XENDOS)
estimates for the prevalence of diabetes mellitus and study: a randomized study of orlistat as an adjunct to life-
impaired glucose tolerance in adults. Diabetes Care. style changes for the prevention of type 2 diabetes in obese
1993;16:157-77. patients. Diabetes Care. 2004;27:155-61.
130 Diagnosis and Classification

98. Heart Outcomes Prevention Evaluation (HOPE) Study 101. Palmer AJ, Roze S, Valentine WJ, et al. Intensive lifestyle
Investigators. Effects of ramipril on cardiovascular and changes or metformin in patients with impaired glucose
microvascular outcomes in people with diabetes mellitus: tolerance: modeling the long-term implications of the dia-
results of the HOPE study and MICRO-HOPE substudy. betes prevention program in Australia, France, Germany,
Lancet. 2000;355:253-9. Switzerland and the United Kingdom. Clin Ther. 2004;
99. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular mor- 26:304-21.
bidity and mortality in patients with diabetes in the lor-
102. Narayan KM, Hoskin M, Kozak D, et al. Randomized clini-
sartan intervention for endpoint reduction in hypertension
cal trial of lifestyle interventions in Pima Indians: a pilot
section

study (LIFE): a randomized trial against atenolol. Lancet.

2002;359:1004-10. study. Diabet Med. 1998;15:66-72.
3

100. Ramachandran A, Snehalatha C, Mary S, et al. The Indian 103. Ramaya KL, Swai AB, Alberti KG, et al. Lifestyle changes
Diabetes Prevention Programme shows that lifestyle modi- decrease rates of glucose intolerance and cardiovascular
fication and metformin prevent type 2 diabetes in Asian (CVD) risk factors: a 6-year intervention study: diagnosis
Indian subjects with impaired glucose tolerance (IDPP-1). and classification in a high-risk Hindu Indian subcommu-
Diabetologia. 2006;49:289-97. nity. Diabetologia. 1992;35:A60.
Section 4

EPIDEMIOLOGY
Section Editor: Hemraj B Chandalia
 Chapter 9
Diabetes Mellitus in
Developed Countries
Susana A Moran, KM Venkat Narayan, Paturi V Rao

DM in Developed Countries

Chapter Outline

♦♦ Type 1 Diabetes ♦♦ Global Disability-Adjusted Life Years

♦♦ Type 2 Diabetes ♦♦ Gestational Diabetes

INTRODUCTION is any degree of glucose intolerance during pregnancy.

After pregnancy ends, glucose control usually returns to
The burden of diabetes mellitus is increasing worldwide normal (Report of the Committee on the Diagnosis and
in both the developing and developed world. The burden Classifications of Diabetes Mellitus 1997).4
of diabetes has been linked to growing urbanization and
The estimated number of people with diabetes world­
population aging. Diabetes affects persons of all ages
wide is expected to increase from 366 million in 2011 to
and ethnic groups. The disease reduces both a person’s
522 million in 2030, at an average annual growth of 2.7%,
quality of life and life expectancy and imposes a large
which is 1.7 times the annual growth of the total world
economic burden on the health care system and on
adult population. Forty-eight percent of the anticipated
families,1 [American Diabetes Association (ADA) 2003].2
absolute global increase of 186 million people with
The etiology and prevalence of diabetes and the inter-
diabetes is projected to occur in India and China alone.5
ethnic and inter-country differences are associated with
environmental and genetic factors. This chapter will review With the increase of an aging population in developed
the epidemiology of diabetes in developed countries.3 countries, the biggest impact will be on people older than
There are three principal forms of diabetes: (1) type 1; 65 years of age. Among the population of adults older
(2) type 2; and (3) gestational diabetes mellitus (GDM). than 20 years of age, the diabetes prevalence was higher
Type 1 diabetes, formerly referred as insulin-dependent (6.3%) in the developed compared to the developing world
diabetes mellitus or juvenile-onset diabetes, develops (4.1%) in the year 2000. Although the developing world
when the pancreatic β-cells are no longer capable of will experience the fastest increase in numbers of people
producing insulin after being destroyed by the body’s with diabetes, the prevalence rate will continue to rise at
immune system. Type 2 diabetes, which represents the 8.4% in developed countries until 2030 compared to the
majority (90–95%) of cases of diabetes, formerly referred 6.0% rate of rise for developing countries. The United States
to as non-insulin-dependent diabetes and maturity- (US), Japan, and Italy were among the top 10 countries
onset diabetes, is a disorder of insulin resistance, which with the highest number of people with diabetes in 2011,
obstructs cells from using insulin properly. Lastly, GDM each of the three are developed countries.
134 Epidemiology

Table 9.1: Estimates and projections of type 1 diabetes prevalence will reach 50.1 per 100,000 person years.10 In Europe, the
in developed countries—1994 to 2010 (in thousands) incidence in adults was one-third or less of the total inci­
Country Population 1994 2010 dence in children aged 15–29 years.11 In the UK, among
United States 258,542 1,480 1,858 15–29 year olds, an annual incidence rate of 0.2% was
Canada 27,479 203 223 found and among 0–14 year olds the annual rate was
United Kingdom 58,033 262 536 5.9%.12,13 These three investigators found patterns in
France 57,275 306 328 most populations in incidence rates of type 1 diabetes to
section

Italy 57,772 293 320

be highest among children between 10 years to 14 years
4

of age.11-13
Australia 17,942 97 135
The increase of type 1 diabetes began a steadily
New Zealand 3,408 13 27
upward incline around the mid 1960s.14 Established regis­
Singapore 2,863 11 16
tries around Western countries contributed to gathering
Source: Modified from Amos et al. 7
data in incidence of type 1 diabetes. The EURODIAB
collaborative group used the population-based registries
TYPE 1 DIABETES to determine incidence in European children. They found
northern Europe with the highest incidence of type 1
The number of people with type 1 diabetes in industria­ diabetes and southern and eastern Europe with the
lized countries appears to be increasing steadily. Accor­ lowest.15 Conversely, between 1988 and 1999, an incidence
ding to the International Diabetes Federation (IDF), the rate of 16.5% per 100,000 person/year was seen in Spain,
European region has an estimated 1.27 million people which is in the same incidence rate range with northern
with type 1 diabetes, the North American region follows European countries, 14.3–16.4%.16 In a comprehensive
a close second with approximately 1.04 million people sample population to evaluate the global pattern in type 1
(International Diabetes Federation 2005).6 diabetes, between 1990–1994, Europid populations were
more likely to have higher incidence rates, specifically
Prevalence Finland (36.5 per 100,000/year). Incidence rates ranged
Prevalence estimates and projections for type 1 diabetes widely within regions in Italy, the highest in Sardinia
reported by Amos et al. (Table 9.1) suggest that from (36.8 per 100,000/year) to the lowest in Lombardia
1995 to 2010, North America and Europe saw an upward (7.2 per 100,000/year).8 Overall, the annual rate of increase
trend in type 1 diabetes. The United States, Canada and in incidence of type 1 diabetes from the EURODIAB coho­
Australia, were projected to experience increases, while rts is 3.4%.17 France found an annual increase in incidence
United Kingdom, France, Italy, and Singapore maintained rate of 4.9% over an extended 19-year period from 1980
stability throughout the projected years.7 Children under to 1998 among children aged 15 years and younger.18
the age of 14 are disproportionately affected by type 1 In New Zealand, an annual incidence rate averaging
diabetes compared to adults.8 17.9 per 100,000 persons/year under the age of 15 years
between 1999 and 2000 were at risk of type 1 diabetes.
Incidence A 1.55 per 100,000 persons/year incidence rate ratio
between South Islanders and North Islanders of children
To determine if the incidence of type 1 diabetes is increasing and adolescents aged 15 years and younger was found.
globally, Onkamo et al.9 reviewed studies in developed Since the South Island of New Zealand has a higher
countries and found an increase of 3.0% per year, higher Caucasian population, the variation is attributed to
in Caucasoid populations than others. Finland has the ethnic differences.19 Furthermore, the prevalence of type 1
highest incidence rate of type 1 diabetes in children diabetes in New Zealand was three to four times higher
aged 14 years or younger. During the time period 1967 to in European New Zealanders than non-European
1996, the incidence rate was 37 per 100,000 person years. New Zealanders. This result furthers the evidence that varia­
In addition, the age of diagnosis has become younger; tion is due to the growing multi-ethnic population in this
the median age at diagnosis has come down to 8 years country.20
in 1996. If the incidence trend continues at a linear rate, Studies have found positive associations between some
then by 2010, it is projected that the incidence of type 1 viruses and diabetes autoantibodies.21 Socio-economic
diabetes among Finnish children aged 14 years or younger conditions are another risk factor contributing in the
 Diabetes Mellitus in Developed Countries 135

increased incidence in type 1 diabetes in Europe. Over diabetes was due to environmental or genetic factors,
an 18-year observation period of 1983 to 2000, children a study compared the incidence in Finland with that of
in Sweden experienced an incidence increase in the latter a neighboring region, Russian Karelia. HLA-DQ allele
half of the observation for both genders. However, Lith­ combinations, genetically linked to type 1 diabetes,
uania’s (geographically close to Sweden) rise in incidence between children in Russian Karelia and in Finland were
of type 1 diabetes was first observed in the last 4 years, not significantly different. Thus, the results suggested that
1997 to 2000, with an annual average increase in incidence the difference may be related to environmental factors.24

chapter
of 1.5% for boys and 3.1% for girls. The difference was Obesity is established as a risk factor for type 2 diabetes,

9
associated with socio-economic changes between the two but there is evidence that obesity may also contribute to
countries.22 the development of type 1 diabetes in children under the
age of 15 years.25 Children of higher weight and greater
Risk Factors height were associated with an increased risk of develo­
Genetic and environmental factors are linked to the ping type 1 diabetes.25
development of type 1 diabetes. Type 1 diabetes is most
likely a polygenic disease and a number of potential TYPE 2 DIABETES
risk factors have been implicated including dietary,
breastfeeding, initiation of bovine milk, infectious agents
Prevalence
(e.g. Enterovirus, Rotavirus, and rubella), chemicals Prevalence of type 2 diabetes in developed countries
and toxins but the results have been inconclusive.23 is shown in Table 9.2. In the majority of the studies, the
To determine whether Finland’s high incidence of type 1 prevalence of diabetes increased with age. Based on the

Table 9.2: Diabetes prevalence of cohorts in developed countries24-31

Country Cohort/Year Age Groups Prevalence (%)
Male Female
United States NHANES III/ 1988–1994 20–39 1.1 1.1
40–49 3.3 4.4
50–59 9.6 6.6
60–74 11.8 13.3
Australia The Australian Diabetes, Obesity and Lifestyle Survey/1999–2000 25–34 0.5 0.2
35–44 1.3 1.1
45–54 3.3 2.9
55–64 8.3 4.7
65–74 10.3 7.8
50–59 2.2 1.4
Netherlands Hoorn/1989–1992 60–69 3.8 5.0
70–74 4.0 8.1
Italy Health District of Cremona/1990 45–54 4.5 3.2
55–64 11.6 7.5
65–74 9.3 10.9
Japan Funagata/1990–1992 40–49 2.4 3.1
50–59 4.9 6.6
60–69 12.7 13.5
United Kingdom Newcastle/1993–1994 25–34 0.0 0.5
35–44 0.5 1.5
45–54 4.0 3.5
55–64 4.5 5.0
Spain Catalonia/ 1994–995 30–49 1.6 1.1
50–69 9.6 8.5
70–89 15.3 18.1
Canada Canadian Community Health Survey/2000–2001 18–44 1.2 1.3
45–64 6.7 5.3
65–74 14.7 11.3
136 Epidemiology

Table 9.3: Top 10 countries for diabetes prevalence in 2011 and as Risk Factors
predicted in 2030
The development of type 2 diabetes is associated with
2011 2030
the interaction of genetic and environmental factors.
Crude Adjusted Crude Adjusted
Mutations and polymorphisms of genes are linked with
Country prevalence prevalence prevalence prevalence
monogenic and polygenic forms of type 2 diabetes.
Kiribati 24.9 25.3 27.7 28.3
Nevertheless, only a small number of all cases of type 2
Marshall 21.5 21.8 24.2 24.7
diabetes relate to genetic defects.33 As for environmental
section

Islands
factors, a considerable amount of compelling evidence
4

Kuwait 15.9 20.7 24.2 23.4

can be found that type 2 diabetes is strongly related to
Nauru 20.1 20.4 22.2 23.1
obesity. Ford et al.34 found that for each unit increase in
Qatar 14.1 19.8 21.4 22.5
body mass index (BMI) (kg/m2), the risk increased by 12%.
Saudi Arabia 16.2 19.6 20.8 22.3
The risk of diabetes is not limited to overall BMI, regional
Lebanon 18.9 19.6 20.9 22.3
fat distribution around the abdomen is also important.35
Bahrain 15.3 19.5 21.7 22.2 In countries with market economy, the prevalence of
Tuvalu 18.7 19.2 24.6 22 obesity ranges from 10% to 20%.36 Dietary factors and
United Arab 12.6 18.8 23.8 21.6 physical inactivity are seen as two modifiable factors.
Emirates Increasing physical activity has a protective effect on
reducing the risk of type 2 diabetes.37 By maintaining a
Third National Health and Nutrition Examination Survey somewhat active lifestyle, 43% of type 2 diabetes cases
(NHANES III),26 the prevalence for known diabetes during can be prevented.38 Consumption of trans-fat and simple
1988-1994 was estimated at 5.1% for US adults 20 years carbohydrates seems to increase the risk of diabetes,
and older. The prevalence increased to 6.3% in 2002.26 while the total intake of fat and carbohydrate was less
For race, non-Hispanic blacks had the highest prevalence relevant.39 A correlation between increased consumption
(6.9%) followed by Mexican-Americans (5.6%), and then of refined carbohydrates and prevalence of type 2 diabetes
non-Hispanic whites (5.0%). The prevalence of known was positively associated in the US.40 High caloric, sugar-
diabetes in Australia was 3.7%, when combined with sweetened soda is another dietary factor found responsible
newly diagnosed diabetes the total was 7.4%.27 In the for weight gain among American women, which in
Hoorn study of Dutch people the total diabetes prevalence turn increases the risk of type 2 diabetes.41 Conversely,
of known and newly diagnosed diabetes was 8.3%.28 The dietary fiber was found to hold a protective role in the
overall prevalence in Italians above 45 years of age from development of diabetes.42 Furthermore, a connection
the Health District of Cremona, Italy had a slightly lower between disparities in socio-economic status (SES) and
rate of 7.7% compared to the Dutch.29 Japan experienced the prevalence of diabetes is evident in industrialized
an astonishing prevalence rate of 10.1% among adults countries. Some studies observed a higher prevalence of
of 40–69 years. The rate was higher in women (10.8%) type 2 diabetes in low SES groups compared to high SES
than men (9.1%).30 In the United Kingdom, total prevalence groups; more strongly associated in women from low
was 5.4% in adults of 25–64 years.31 Canada appeared to SES.43,44 Similar trends are also observed in developing
have the lowest prevalence rate of 4.5% in 2000 to 2001. countries. The rate of the increase in numbers with
This rate was up from 3.4% in 1994–1995.32 diabetes is inversely related to current income status, with
The top 10 countries by diabetes prevalence shown the greatest increase expected in low-income countries
in Table 9.3 are dominated by pacific island states and (92%), followed by lower-middle income countries (57%),
countries in the Middle East. As might be expected, India, upper-middle income countries (46%) and finally higher
China and the US with the largest populations have the income countries (25%).
highest number of persons with diabetes. Only Pakistan
and Nigeria of the world’s 10 most populous countries GLOBAL DISABILITY-ADJUSTED LIFE YEARS
are not among the 10 countries with the highest diabetes
numbers (replaced by Mexico and Egypt) for 2011.5 The Global Burden of Disease Study proposed disability-
Contrary to the popular belief, countries with highest adjusted life years (DALYs) as the sum of years of life lost
numbers of persons with diabetes, do not demonstrate (YLLs) and years lived with disability (YLDs), to measure
high prevalence of diabetes. disease burden. Global DALYs calculated for 291 causes,
 Diabetes Mellitus in Developed Countries 137

Table 9.4: Global disability-adjusted life years in 1990 and 2010 for the indigenous group were much higher.54 Characteristics
all ages, both sexes combined and percentage change in a UK population of children 16 years and younger with
1990 2010 %Δ type 2 diabetes were similar to US findings. These children
All causes 2,502,601 2,490,385 – 0.5 were all obese, had a family history of type 2 diabetes, and
Diabetes mellitus 27,706 46,823 69.0 from a minority group.55 With the increase of childhood
Chronic kidney disease 2,642 4,675 76.9
obesity, type 2 diabetes56 is expected to become prevalent
due to diabetes mellitus
in obese white children.56 It is no coincidence that the

chapter
increase of type 2 diabetes is parallel to the increase of
20 age groups, both sexes, and for 187 countries, remained

9
childhood obesity. Increasingly, the trend of obesity in the
stable from 1990 (2.503 billion) to 2010 (2.490 billion).
young is being reported in developed nations, specifically
However, an important shift has occurred in DALYs due
the US.57,58 In the US, overweight and obese children were
to diabetes mellitus as shown in Table 9.4. Diabetes was
observed to show up to a 4% prevalence of type 2 diabetes
the 14th ranking leading cause of DALYs worldwide in
particularly in minority groups.49
2010 (up from 21st rank in 1990, increasing by 69%).
The epidemic of type 2 diabetes is rapidly growing
Alarmingly, the DALYs attributed to chronic kidney
among children and adolescents in the US and other
disease due to diabetes mellitus has increased by 77%,
developed countries. The ADA classifies children with
whereas the rise in DALYs due to ischemic heart disease
type 2 diabetes as generally overweight, with a family
was only 29%, between 1990 and 2010.45
history of diabetes, from non-European ancestry, and
most are over the age of 10 years.59 Since type 2 diabetes
Type 2 Diabetes in Children
is relatively a new health condition for children, misdia­
Type 1 diabetes is the commonly associated form of gnosis can occur and children may be treated as having
diabetes in children, but lately type 2 is also occurring type 1 diabetes. By 1997, type 2 diabetes accounted for
more commonly, including maturity-onset diabetes of 45% of the incident cases of diabetes in children in the
the young (MODY), maternally transmitted mitochondria US.51 White children in the UK are more likely to have the
mutations, and atypical diabetes.46 The incidence rate of condition MODY, a cell dysfunction caused by a single
type 1 diabetes in children 14 years and younger ranges gene disorder. Prevalence of MODY is 0.17/100,000, which
from 0.1/100,000 per year in China to 36.8/100,000 per is comparable to the rate of type 2 diabetes (0.21/100,000)
year in Italy.13 About 78,000 children under 15 years are in UK children.60
estimated to develop type 1 diabetes annually worldwide.
Of the estimated 490,000 children living with type 1 GESTATIONAL DIABETES
diabetes, 24% come from the European Region, and 23%
from the South-East Asia Region.5 Gestational diabetes mellitus is identified as glucose
The first sign of type 2 diabetes in children occurred in intolerance with onset or first recognition during
a population-based study in American Indians in 1979.47 pregnancy (ADA 2000).61 Detection of GDM occurs when
Evidence for increasing occurrence is found in various a blood glucose-screening test is performed in first
racial and ethnic groups: Pima Indians, Canadian First trimester during a prenatal visit, more often in 3rd month
Nations, African-Americans, Hispanics and Japanese.48 of pregnancy (well after the organogenesis is complete).
Pediatric centers in the US, Japan, Australia and the Glycosylated fibronectin is now introduced as a first-
United Kingdom provide most of the information on type trimester biomarker for predicting GDM as early as 5th
2 diabetes in children.49,50 The most affected population week gestation.62 Variations in diagnostic criteria for
in the US is American Indians.51 According to the Indian GDM are generally based on recommendations from
Health Services, the prevalence amongst American the World Health Organization (WHO) and the ADA.
Indian and Alaska Native aged 34 years and younger The diagnostic criteria from WHO is based on a 2-h 75g
increased by 46% between 1990 and 1998.52 American oral glucose tolerance test (OGTT).63 Recently, the ADA
Indian youth are more likely to be diagnosed with type 2 has listed the 2-h 75g OGTT for diagnosis. However, the
than type 1 diabetes.53 Diagnoses of type 2 diabetes has organization prefers the use of the validated criteria of a
increased annually by 27% for each year between 1990 3-h 100g OGTT (ADA 2004).64
and 2002. Although both indigenous and non-indigenous Women with certain risk factors are more likely to
Australian groups are significantly affected, the rates in develop GDM. The following risk factors are associated
138 Epidemiology

Table 9.5: Crude and age-adjusted prevalence of diabetes during status. Variation in estimating the prevalence of GDM
pregnancy, by race and ethnicity—United States, 1993–1995 is related to what criteria is used for screening. In a US
Prevalence (%) study using selective screening recommendations issued
Race/Ethnicity Number of Women Crude Age-adjusted by the ADA, only 4% of women with GDM who were at
Non-hispanic low-risk of developing GDM were missed.72 In Spain, the
White 6,996,046 25.3 24.3 prevalence of diabetes during pregnancy for low-risk
Black 1,770,102 22.6 27.5 patients varied from 0.5% and 0.6% and high-risk groups
section

Hispanic
resulted from 2.9% and 4.04%, using criteria from the ADA
4

and the American College of Obstetrics and Gynecologists

Mexican 1,331,361 22.8 27.5
(ACOG), respectively.73 Newly proposed diagnostic
Puerto Rican 161,065 31.6 38.7
strategies by the International Association of Diabetes
Cuban 35,148 24.9 22.7
and Pregnancy Study Groups (IADPSG) are based on
Central/South 271,639 25.4 24.3 demonstrated associations between glycemic levels and an
American
increased risk of obstetric and perinatal morbidities. They
American 108,982 43.9 52.4
rely on the administration of a 2-hour glucose tolerance
Indian/Alaskan
Native
test (a one-step approach) with a fasting component and
a 75 g glucose load. However, the one-step approach, as
Asian/Pacific
Islander proposed by the IADPSG, is anticipated to increase the
frequency of the diagnosis of GDM by twofold to threefold,
Chinese 77,329 39.1 27.3
to a prevalence of approximately 15–20%. There are
Japanese 25,885 26.8 21.6
several concerns regarding the diagnosis of GDM in these
Hawaiian 16,982 28.9 32.6
additional women, and NIH is currently debating the
Filipino 88,487 39.8 32.0
uncertainties and potential benefits associated with the
Asian Indian 31,574 56.1 48.3 use of these criteria.74
Korean 24,918 19.3 16.1 In the US, up to 14% of pregnant women are affected by
Samoan 4,855 25.7 28.7 GDM.63 A study by Ferrara et al.66 observed incidence trends
Vietnamese 34,140 24.3 19.5 between 1991 and 2000 among a multi-ethnic cohort, aged
Total 11,384,926 25.3 — 15–49 years. They found the cumulative incidence of GDM
increased in all age and race-ethnic groups, ranging from
CDC. Morbidity and Mortality Weekly Report. 1998:47;408-414
5.1% to 5.9%. Older women and Asians had the highest
with GDM: overweight or obese, minority ethnic groups, absolute cumulative incidence of GDM by the year 2000 of
older age, and family history of diabetes.65-67 In addition, 13.3% and 9.7%, respectively.75 These results corresponded
evidence has linked an increased risk of GDM in women with current estimates of increasing prevalence observed
known to be born with low birth weight who later delivered by Dabelea et al.76 in multi-ethnic groups. Furthermore,
macrosomic babies.68 Women previously diagnosed with GDM reported between 1993-1995 for US women aged
GDM were shown to have recurrence of GDM.69 Also, 20–49 years revealed variation of prevalence rates
these women are more likely to experience pregnancy within and between maternal race/ethnicity groups
complications compared to women without diabetes.70 (Table 9.5). Within the Hispanic population, the age-
Screening for GDM continues to rouse debate world­ adjusted prevalence of Puerto Ricans was found to
wide. To determine the prevalence of GDM, countries are have the highest prevalence rate (38.7%) and Cubans to
challenged between using selective or universal scree­ experience the lowest (22.7%). Overall, American Indian
ning. Studies have compared the performance of selective and Alaskan Native women had the highest prevalence
versus universal screening, generating wide-ranging (52.4%) of GDM.77 In Canada, ethnicity also plays a
differences in prevalence rates.71,72 According to the ADA, factor in the increased risk of GDM. Canadian aboriginal
women meeting all four clinical characteristics: obesity, women experienced higher prevalence rates compared
history of GDM, glycosuria, or family history of diabetes, to non-aboriginal Canadian women, of 6.4% and 3.7%,
are required to undergo testing.64 Women not possessing respectively, signifying that their aboriginal ethnicity is a
all four characteristics are considered to be of low-risk risk factor.78
 Diabetes Mellitus in Developed Countries 139

Further Reading 10. Tuomilehto J, Karvonen M, Pitkänieemi J, et al. record-high

incidence of type 1 (insulin-dependent) diabetes mellitus
1. Tuomilehto J, Karvonen M, Pitkänieemi J, et al. record-high in Finnish children. Diabetologia. 1999;42:655-60.
incidence of type 1 (insulin-dependent) diabetes mellitus 11. Kyvik KO, Nystrom L, Gorus F, et al. The epidemiology of
in Finnish children. Diabetologia. 1999;42:655-60. type 1 diabetes mellitus is not the same in young adults as
2. American Diabetes Association. Gestational diabetes mel- in children. Diatetologia. 2004;47:377-84.
litus. Diabetes Care. 2000;23:S77-9. 12. Feltbower RG, McKinney PA, Parslow RC, et al. Type 1 dia-
3. EURODIAB ACE Study Group. Variation and trends betes in Yorkshire, UK: time trends in 1-14 and 15-29-year-

chapter
in incidence of childhood diabetes in Europe. Lancet. olds, age at onset and age-period- cohort modeling. Diabet
2000;355:873-6. Med. 2003;20:437-41.

9
4. Gale EA, Gillespie KM. Diabetes and gender. Diabetologia. 13. Karvonen M, Viik-Kajanger M, Moltchanova E, et al. Incid­
2001;44:3-15. ence of childhood type 1 diabetes. Diabetes Care. 2000;
5. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk 23(10):1516-26.
for diabetes mellitus in the United States. JAMA. 2003;290: 14. Gale EA, Gillespie KM. Diabetes and gender. Diabetologia.
1884-90. 2001;44:3-15.
6. Bloomgarden ZT. Type 2 diabetes in the young: the evolving 15. Soltész G.. Diabetes in the young: a paediatric and epide-
epidemic. Diabetes Care. 2004;27:998-1010. miological perspective. Diabetologia. 2003;46:447-54.
7. Devendra D, Liu E, Eisenbarth GS. Type 1 diabetes: recent 16. Lora-Gómez RE, Morales-Pérez FM, Arroyo-Díez FJ, et al.
Incidence of type 1 diabetes in children in Caceres, Spain,
developments. BMJ. 2004;328:750-4.
during 1988-1999. Diabetes Res Clin Pract. 2005;69:169-74.
8. Qiao Q, Williams DE, Imperatore G, et al. Epidemiology and
17. EURODIAB ACE Study Group. Variation and trends
geography of type 2 diabetes mellitus. In International Text-
in incidence of childhood diabetes in Europe. Lancet.
book of Diabetes Mellitus, 3rd edition. R.A. Defronzo and
2000;355:873-6.
others, 33.56. Chichester, U.K: John Wiley & Sons; 2004.
18. Mauny F, Grandmottet M, Lestradet C, et al. Increasing
9. International Diabetes Federation. (2005). Facts and
trend of childhood type 1 diabetes in Franche-Comete
Figures. Diabetes Prevalence. [online] Available from www.
(France): analysis of age and period effects from 1980-1998.
idf.org. [Accessed October, 2013]. European Journal of Epidemiology. 2005;20:325-9.
19. Campbell-Stokes PL, Taylor BJ. Prospective incidence study
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57. Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and
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41. Schulze MB, Manson JE, Ludwig DS, et al. Sugar- sweetened
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59. American Diabetes Association. Type 2 diabetes in children
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Am J Clin Nutr. 2000;71:921-30. 60. Ehtisham S, Hattersley AT, Dunger DB, et al. First UK survey
43. Evan JM, Newton RW, Ruta DA, et al. Socio-economic of paediatric type 2 diabetes and MODY. Arch Dis Child.
status, obesity and prevalence of type 1 and 2 diabetes 2004;89:526-9.
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44. Robbins JM, Vaccarino V, Zhang H, et al. Socioeconomic litus. Diabetes Care. 2000;23:S77-9.
status and type 2 diabetes in African Americans and non- 62. Rasanen JP,  Snyder CK,  Rao PV,  et al. Glycosylated fibro­
Hispanics white women and men: evidence from the third nectin as a first-trimester biomarker for prediction of gesta-
National Health and Nutrition Examination Survey. Am J tional diabetes. Obstet Gynecol. 2013;122:586-94.
Public Health. 2001;91:76-83. 63. Jonanovic L, Pettitt DJ. Gestational diabetes mellitus. JAMA.
45. Murray CJ, Vos T, Lozano R,  et al. Disability-adjusted life 2001;28:2516-8.
years (DALYs) for 291 diseases and injuries in 21 regions, 64. American Diabetes Association. Gestational diabetes mel-
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46. Botero D, Wolfsdorf JI. Diabetes mellitus in children and Weight change and the risk of gestational diabetes in obese
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 Diabetes Mellitus in Developed Countries 141

66. Ferrara A, Kahn HS, Quesenberry CP, et al. An increase in 73. Jiménez-Moleón JJ, Bueno-Cavanillas A, Luna-Del-Castillo
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67. Davey RX, Hamblin PS. Selective versus universal screening 2002;146:831-7.
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69. MacNeill S, Dodds L, Hamilton DC, et al. Rates and risk fac- betes: a summary of the evidence for the U.S. Preventive

9
tors for recurrence of gestational diabetes. Diabetes Care. Services Task Force. Obstet Gynecol 2003;101:380-92.
2001;24:659-62. 76. Dabelea D, Snell-Bergeon JK, Hartsfield CL, et al. Increas-
70. Saydah SH, Chandra A, Eberhardt MS. Pregnancy experi- ing prevalence of gestational diabetes mellitus (GDM) over
ence among women with and without gestational diabetes time and by birth cohort: Kaiser Permanente of Colorado
in the U.S., 1995 National Survey of Family Growth. Diabe- GDM Screening Program. Diabetes Care. 2005;28:579-84.
tes Care. 2005;28:1035-40. 77. Centers for Disease Control and Prevention. Diabetes dur-
71. Di Cianni GD, Volpe L, Lencioni C, et al. Prevalence and ing pregnancy-United States, 1993-1995. MMWR Morb
risk factors for gestational diabetes assessed by universal Mortal Wkly Rep. 1998;47:408-14.
screening. Diabetes Res Clin Pract. 2003;62:131-7. 78. Dyck R, Klomp H, Tan LK, et al. A comparison of rates, risk
72. Williams CB, Iqbal S, Zawacki CM, et al. Effect for selec- factors, and outcomes of gestational diabetes between abo-
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1999;22:418-21. District. Diabetes Care. 2002;25:487-93.
 Chapter 10
Epidemiology of Diabetes in
Developing Countries:
The Scenario in Asia
Chamukuttan Snehalatha, Arun Nanditha, Samith A Shetty, Ambady Ramachandran

Epidemiology of Diabetes in Asia

Chapter Outline
♦♦ Scenario in South East Asia ♦♦ Diabetes in the Youth
♦♦ Rising Prevalence of Diabetes ♦♦ Scenario in the Middle East Countries
♦♦ Risk Factors ♦♦ Other Forms of Diabetes
♦♦ Chronic Complications of Diabetes ♦♦ Prevention of Diabetes

INTRODUCTION Democratic People’s Republic of Korea, India, Indonesia,

Maldives, Myanmar, Nepal, Sri Lanka, Thailand and
Prevalence of diabetes is increasing globally and it is one Timor-Leste. Most of these countries have witnessed
of the major health problems of the 21st century. In the considerable improvement in the socio-economic con­
year 2003, it was estimated that there were 194 million ditions in the last few years.3 They are also experiencing
adult subjects with diabetes (5.1%) and 314 million
rapid urbanization resulting in considerable changes
subjects with impaired glucose tolerance (IGT) (8.2%).1
in lifestyle with attendant health problems. Although
Today, as per the latest International Diabetes Federation
several infectious and parasitic diseases have been cont­
(IDF) World Atlas there are more than 371 million
rolled to a great extent, the non-communicable diseases
people with diabetes in the world.2 The rising trend has
(NCDs) are becoming increasingly common causing a
surpassed all the estimated projections. The latest figures
from the IDF Diabetes Atlas indicate that the highest double burden on many of the countries in this region.
burden of the epidemic is felt in the lower and middle Although significant economic improvement has occurred
income countries and also that the disease affects people in countries like India and China, the large population is a
in the working age, thereby affecting the economy of these hurdle in effectively reducing the problem of poverty and
countries. malnutrition.
Prevalence estimates of diabetes and IGT are high for According to the world population prospects, the
all Asian countries and are expected to increase further population size would reach 7.9 billion by 2025. Six
in the next two decades.2 The present trend indicates that countries of the world account for almost 50% of annual
more than 60% of the world’s diabetic population will be increase, of which three are from the South-East Asia
in Asia. region. India, China and Pakistan contribute 21, 12, and
5% respectively.3
SCENARIO IN SOUTH EAST ASIA In the year 2000, the population in the SEA region
The World Health Organization (WHO) Southeast Asia was 1.53 billion. It is expected to increase by 1.75 billion
(SEA) region covers 11 countries—Bangladesh, Bhutan, in the year 2010. It is also projected that by 2050 India’s
 Epidemiology of Diabetes in Developing Countries: The Scenario in Asia 143

Table 10.1: Prevalence (%) of type 2 diabetes in Southeast Asia-Indian subcontinent

Country Year National Urban Rural
India 19,10
1989 — 8.2 2.4
2006 18.6 9.2
Pakistan11 2006 — 10.6 7.7
Bangladesh 12,13
1997 — 4.5
2005 8.1 2.3

chapter
Sri Lanka 14,15
1994 10.3 5 —

10
2005 — —

population will exceed that of China. The density of in the prevalence of 64% and 62% among men and
population in SEA region is projected by the fact that women respectively. The age-standardized prevalence in
although only 5% of the global land mass is covered by 2009 was 22.3% among men and 20.2% among women.
the region, 25% of the world population lives here.3 The changes in traditional risk factors such as age, body
mass index (BMI), waist circumference, lifestyle factors,
RISING PREVALENCE OF DIABETES family history of diabetes and hypertension explained
the population-wide increase in the prevalence.8
Several reports from Fiji, Singapore, Mauritius, Tanzania,
In the last three decades, epidemiological studies
South Africa and the United Kingdom (UK) have shown
in several SEA countries including India have revealed
a high prevalence of type 2 diabetes (T2DM) among
a high and rising prevalence of T2DM among the urban
migrant Asian Indian population compared with the host
population in the homelands (Tables 10.1 and 10.2).
populations and other migrant ethnic groups.4
The reports published in 1980 by Zimmet et al.5
Change in Prevalence of Type 2 Diabetes
had shown interesting observations in the prevalence
of diabetes in the migrant Indians in Fiji. Indians, age Tables 10.1 and 10.2 show the major changes in the
more than 20 years, showed higher crude prevalence prevalence of diabetes in South Asians countries.9-28
of diabetes (13%) than the urban Melanesians (6.6%). Most phenomenal increase was noted in Nepal26-28 and
Surprisingly, there have been no later studies reported China.29-31 In most of these countries, the national preva­
in the Fiji-Indians. It seems probable that the prevalence lence increased by two-fold or more within a decade.
would have increased further, as studies conducted in Countries such as India, Nepal and China which had
Melanesians in Papua New Guinea show higher preva­ remained largely rural had seen a considerable increase
lence in the Melanesians. It is reported that foot sepsis in the prevalence of diabetes in rural populations which
is the most common single cause for the presentation of had contributed to the overall increase in the prevalence
diabetes in Fiji similar to the situations elsewhere in the of diabetes.
Pacific.6 Among the top 10 countries or territories with the
Mauritius, a southern Indian Ocean island has a mixed largest number of diabetic adults, five are in Asia.32 China
population consisting of Asian Indians, Creoles (Mixed tops the list with 90.0 million followed by India which has
Africans, Europeans and Indians) and Chinese ethnic 61.3 million persons affected by diabetes. The numbers
group. This island experienced a rising socio-economic are estimated to rise to 129.7 million and 101.2 million
standards due to industrialization. In 1990, it has been respectively by 2030. As the prevalence data are mostly
reported to have one of the highest mortality rates in the available for urban areas and reports from rural areas are
world. A national study conducted in 1990, showed that scanty, these estimates are likely to be underestimations.
the overall standardized prevalence of IGT was 16.6% India is largely a rural nation and the recent available
and diabetes was 11.9% in the age group of 25–74 years reports indicate the rising prevalence of the disease in
(12% in men and 11.7% in women). The prevalence of the rural areas also.10,33 With the rapid socio-economic
IGT was higher (19.7% in women and 11.7% in men). The changes occurring in the rural areas, the prevalence of
age and sex standardized prevalence of IGT and diabetes diabetes and other NCDs are bound to increase several-
was similar across all ethnic groups.7 After a gap of fold. These diseases contribute largely to early morbidity
22 years, a survey conducted in 2009 showed an increase and mortality among the population.
144 Epidemiology

Table 10.2: Prevalence (%) of type 2 diabetes in Southeast Asia-Other countries

Country Year National Urban Rural
Singapore16-18 1985 4.7 — —
1998 8.2 — —
2004 9.0 — —
Philippines19 1982 — 3.3 —
2002 — 4.9 —
section

Malaysia20,21 1982 — 2.1 —

2006 — 11
4

Thailand22,23 2000 6.7 — —

2004 9.6 — —
Vietnam24,25 1990 1.4 — —
2001 3.8 — —
Nepal26-28 1990 — 1.4 0.3
1999 — 14.6 2.5
2007 9.5 —

Rising Prevalence of Diabetes in India

In another 20 years, nearly one-fifth of the world’s
diabetic population will be in India. During the period
1971–2000, studies from different parts of India reported
a ten-fold increase in the incidence of diabetes in urban
India (from 1.2% in 1971 to 12.1% in 2000).34,35
In 2003–2005, a national survey was conducted in
persons of age more than or equal to 15 years, in which
self-reported prevalence of diabetes was 7.3% in the urban
areas, and 3.2% in peri-urban slum areas. The prevalence
in rural areas was significantly lower (3.1%).36 Urban
areas have witnessed a three-fold to four-fold increase in
diabetes prevalence in many regions of India.
Comparison of the prevalence rates in rural India
Fig. 10.1: Increasing prevalence of diabetes and impaired glucose
is beset with major difficulties due to methodological tolerance (IGT) in rural population
differences such as in the criteria for sample selection and
sample size, age, diagnosis, biochemical methods and
lack of age-standardization in many studies. Despite these Impaired Glucose Tolerance and
drawbacks, as reviewed by Misra et al.33 the prevalence Impaired Fasting Glucose
rates have increased since 1994 from a figure of 4.9% in Prevalence of impaired fasting glucose (IFG) is also
Tamil Nadu37 to a maximum of 13.2% in Andhra Pradesh.38 high in Indians and in many other Asian populations.10-13
The prevalence rates varied from 19 per thousand to IGT and IFG shows several metabolic aberrations which
132 per thousand in these studies.33 In the southern are risk factors for diabetes and cardiovascular diseases
states of Kerala, Tamil Nadu and Andhra Pradesh, and (CVD). They include insulin resistance, presence of
in Maharashtra the prevalence was reported to be higher hypertension and obesity. Clustering of the risk factors
than 9.0% since 2006. was also common in this conditions.39
A series of studies by the authors’ team in Chennai The National Urban Diabetes Survey (NUDS) study
have shown the rising trend in prevalence of diabetes in showed that IGT occurred at a very young age in the
rural Tamil Nadu (Fig. 10.1). Indians and its prevalence was significantly more than
 Epidemiology of Diabetes in Developing Countries: The Scenario in Asia 145

that of diabetes in the young population.40 The need for future increase in prevalence of diabetes with a risk
early screening for glucose intolerance in the population of approximately 50% conversion to diabetes in over
and also the need for an institution of preventive measures 10 years.46
at an early age are highlighted by these observations.
People with IGT have a high potential for conversion RISK FACTORS
to diabetes and they also have a high risk for CVD. The
prevalence of IGT is more than twice that of diabetes in The important risk factors for diabetes are: (1) urbanization,

chapter
the African and SEA regions.1,32 (2) a racial predisposition, (3) genetic risk, (4) aging,

10
A high prevalence of IGT has been reported in several (5) anthropometric characteristics such as obesity espe­
epidemiological studies in developing nations such as cially central obesity and (6) insulin resistance.
India,10 Pakistan,11 Bangladesh,12,13 South Korea41 and
Africa.1 The marked urban-rural difference seen in the Urbanization
prevalence of diabetes, was not seen in the prevalence
of IGT in many Asian populations.9,11,12 This probably The developing countries are undergoing rapid urbani­
indicates a genetic basis for T2DM as IGT is a prediabetic zation and migration of population to urban areas.
condition in most of the ethnic groups. In the next 30 years, a major redistribution of the population
A series of studies in Chennai, in southern India, will occur and by the year 2030, 60% of the world’s
made the interesting observation of a rapid increase in population would be living in urban areas.2 According
diabetes with a marked reduction in the prevalence of to the WHO estimates, in the last five decades two-fold
prediabetic conditions. In Chennai, the prevalence of to five-fold increase in urban population has occurred
diabetes was found to be 13.5% in 2000,40 which increased in most of the SEA countries. In India, the percentage of
to 14.3% in 2005,42 and increased further to 18.6% in urban population was 25.5% in 1990, 28.4%, in 2000 and it
2006.10 Increasingly, the prevalence of IGT had decreased is expected to increase to 45.8% in 2030.2
from 16.8% in 200040 to 10.2% in 200442 and further still to The rise in prevalence of diabetes has occurred as
7.4% in 2006.10 In 2006, the prevalence of diabetes and a result of environmental and behavioral changes and
IGT in the town of Kanchipuram were 16.7% and 4.3% cannot be attributed to altered gene frequencies since
respectively.10 The escalating prevalence of diabetes the increase has occurred within a few decades. The
from 2000 to 2006 is an indication of a rapid conversion increase in urban population and aging has been
of susceptible individuals, especially those with IGT attributed as main determinants of the global rise in
and/or IFG, to diabetes. This hypothesis is supported by prevalence of diabetes. Internal rural to urban migration
the rather unexpected decrease in the prevalence of IGT is yet another factor adversely impacting lifestyle factors
and IFG over the same period of time.10 Asian Indians such as a reduction in physical activity, unhealthy
with IGT have a high conversion rate of diabetes (55%
changes in dietary habits, and increasing adiposity
in 3 years).43 In the southern state of Kerala, where the
and obesity. As shown in the recent studies in India
crude prevalence of diabetes is 19.5%, IGT was detected in
and China, considerable changes have occurred in the
only 4.1% of the population,44 These figures are in agree­
lifestyle factors of rural populations resulting in marked
ment with recent reports from the neighboring state of
increase in overweight and diabetes in these countries.
Tamil Nadu.10,42
The situation is similar in most of the Asian countries. In
The prevalence of IGT was higher in almost all age
groups in Asian subjects. The prevalence of IGT increased 1980, less than 1% of the Chinese adults had diabetes and
with age whereas IFG did not. This finding was consistent in 2008 the prevalence had increased to nearly 10%.31 The
with the finding in the European populations. If only studies conducted in Chennai, Tamil Nadu have shown
fasting glucose determination were used for the diagnosis the impact of urbanization on the prevalence of diabetes
of diabetes there would be a significant underestimation in in rural areas (Fig. 10.1). Studies from different parts of
the Asians as postload hyperglycemia was more common India have shown that social and economic changes
in them.45 occurring in rural India have produced significant
An increase in prevalence of IFG was seen since changes in the occupational, dietary and activity levels.33
2000 onward, especially among the younger population Large number of villagers have sought jobs in urban
below 50 years of age.33 This is also an indicator of areas involving less of manual labor. Physical activity
146 Epidemiology

levels decreased significantly as better transport facilities fuel the epidemic in Asian countries undergoing rapid
were available. Increased calorie intake occurred as nutritional transitions.50
consumption of fat and carbohydrates became common. The genetic risk factors for T2DM are complex and
The changing demography of diabetes is evident from still largely elusive. However, the genetic predisposition
studies in Singapore47 and Malaysia.48 A phenomenal is obvious from the heritable nature of the disease. Strong
increase in diabetes had occurred in Singapore. It rose familial aggregation of the disease has been noted in
from 2% in 1975 to 4.7% in 1984, 8.6% in 1992 and 9% Indians51 and also in other Asian populations.11,12 In India,
section

in 1998, in the age group of 18–69. Malays (14.3%) and nearly 75% of type 2 diabetic patients have first degree
Indians (men 16.7%, women 16.7%) had the highest
4

family history of diabetes.51

prevalence.47 In addition, another 15% had IGT. Sedentary
lifestyle and increasing rate of obesity were strongly Aging
associated with the increasing prevalence of glucose
Continued increase in life expectancy and a decline in
intolerance. High prevalence of IGT and IFG were repor­
fertility are expected to result in faster aging of the global
ted by the diabetes epidemiology: collaborative analysis
population in the next 50 years. Diseases of the elderly,
of diagnostic criteria in Asia (DECODA) study group.45
such as diabetes, hypertension, CVD and cancer will
With the national initiatives taken to improve the
become more common due to aging of the population.
health status of the people, a decrease was seen for the
Prevalence of diabetes is known to increase linearly
first time in the prevalence of diabetes (from 9% in 1998
with increasing age. In the developed western countries,
to 8.2% in 2004).18 Remarkable reduction was seen in
diabetes generally occurs in individuals aged more than
other cardiovascular risk factors, such as hypertension,
65 years. In the developing countries onset of diabetes
dyslipidemia and smoking. Physical activity levels have
occurs at a younger age (45–65 years).52 Studies from
shown improvement, although much needs to be done
India have shown a much younger age at onset of diabetes
to tackle the problem of rising overweight and obesity.
compared to the western population.52 The DECODA
Racial Predisposition study has made a comparative analysis of age at diagnosis
of diabetes in different races.45 The overall effect of age
A racial predisposition to diabetes has been evident from on prevalence of diabetes differed considerably between
the migrant Indian studies which showed that the Asian ethnic groups even after correcting for other confounding
population living in different parts of the world had higher factors such as BMI. The association between age and
prevalence of diabetes compared with the coinhabitants diabetes was higher in the Indian and the Maltese
of other races.4 Recent studies have highlighted the fact population compared to all other populations studied
that even internal migration within a country, causing (Europeans, Chinese and Japanese). During an Oral
affluence and sedentary lifestyle, unmasks the tendency Glucose Tolerance Test (OGTT), in Indians, the plasma
for diabetes in the Asian races.49 glucose concentration rose with age and reached a peak
Asians have high racial predisposition to diabetes. at 60–69 years of age and then started to decline, but it
Wide variations have been noted in the prevalence rates continued to increase after 70 years of age in Europeans.
and age at development of diabetes in different Asian At each age group, the fasting and 2-hour plasma glucose
cohorts.79 were significantly higher for Indians than Chinese and
Japanese populations. The age and sex specific prevalence
Genetic Risk and the peak prevalence of diabetes were higher in the
Both the thrifty genotype and thrifty phenotype hypo­ Indian and in Singapore cohorts than in the Chinese and
theses appear to have etiological roles in the development Japanese cohorts. Reports from Pakistan also showed an
of diabetes in Asian populations. While the thrifty genotype age-related diabetes prevalence data similar to that in
hypothesis points to a mismatch between the ancestral India. The peak age was in the age group of 55–64 years.11
genes and modern environment, the thrifty phenotype An early occurrence of diabetes in the population
hypothesis postulates a mismatch between intrauterine has a severe economic impact as severe morbidity and
and adult life environments.50 The combination of gesta­ early mortality occurs in the most productive years of
tional diabetes, in uteronutritional imbalance, childhood life. The diabetic subjects live long enough to develop the
obesity, and overnutrition in adulthood will continue to debilitating vascular complications of diabetes.
 Epidemiology of Diabetes in Developing Countries: The Scenario in Asia 147

chapter
10
A B
Figs 10.2A and B: Risk for diabetes associated with increasing body mass index (BMI)

Anthropometric Characteristics above 22 kg/m2. The WHO Expert group has considered
a BMI of less than or equal to 23 kg/m2 as the cut-off
Although the prevalence of obesity and overweight
for normal in Asian population.60 A study by us had shown
are relatively lower in Asia compared with Western
that the risk of diabetes in Indian population increases
populations, the recent socio-economic transition in
significantly above a BMI of 23 kg/m2 indicating that
Asia is resulting in parallel increase in its prevalence of
a healthy BMI for Indians was definitely lower than this
obesity and diabetes. Among Asians, diabetes occurs
limit (Figs 10.2A and B).61
at lower levels of BMI than in Western populations and China has adopted its own standards for defining
small increments in weight trigger glucose intolerance overweight in the BMI of 24 kg/m2 or more and obesity at
in the susceptible subjects.53-55 Analysis of the National BMI of 28 kg/m2 or more. Abdominal obesity is defined
Health Interview Survey (NHIS) in the United States of by waist circumference of 85 cm in men and 80 cm in
America (USA) from 1997 to 2008 showed that Asian women.49 Similarly, the cut-off for waist circumference,
Americans had a significantly higher rate for diabetes which is an index of upper body adiposity, is also lower in
than the whites throughout the study period.54 There was the Asian population. The cut-off values for normal waist
significant upward trend in both groups for diabetes and circumference are 85 cm and 80 cm for men and women
BMI. However, Asian Americans, especially Asian Indians respectively in Indian population (Figs 10.3A and B).61
had higher odds of developing diabetes, despite having Asian Indians, in particular, have the above abnormalities
significantly lower BMI than the white populations.
which account for the high prevalences of insulin
An excess of body fat especially concentrated within
resistance and diabetes at low levels of BMI.
the abdomen has a range of potential harmful effects.
Several studies in Asian populations, particularly
It includes increased risk for diabetes, blood pressure,
in Asian Indians, have highlighted the “metabolically
dyslipidemia, insulin resistance, coronary artery disease
obese” phenotype among normal weight individuals.49
and some forms of cancer. It has also been observed that
This phenotype characterized by greater abdominal
Asian Indians have a higher percentage of body fat, for a
obesity despite a normal BMI, less muscle mass, higher
given BMI, when compared with the white population.56-59
percentage of body fat and increased propensity for insulin
For diabetes, obesity and specifically abdominal obesity
resistance compared with the Western pop­ulation, renders
are a major risk factor. In the white population, overweight
is defined as a BMI of more than or equal to 25 kg/m2 higher susceptibility for diabetes in Asian population.61-64
and obesity as a BMI of more than 30 kg/m2. However,
several studies have now shown that an average BMI Insulin Resistance
level in Asians ranges between 20 kg/m2 and 23 kg/m2 Despite their lean body mass, insulin resistance was
and the risk of metabolic disease increases progressively found to be a characteristic feature of Asian Indians and
148 Epidemiology
section
4

A B
Figs 10.3A and B: Risk for diabetes associated with increasing waist

it could be adversely affected by even small increments Long standing diabetes mellitus is associated with an
in body weight.49 In several ethnic populations, including increased prevalence of microvascular and macrovascular
the relatively non-obese Indian population, upper disease. Data from Chennai show that the prevalence
body adiposity [measured as waist-hip ratio (WHR)] was of complications of T2DM as follows: retinopathy
found to be a greater risk factor for T2DM than general 23.7%, nephropathy 5.5%, peripheral neuropathy 25.5%,
obesity.39,49 High WHR correlated with glucose intole­ CHD 11.4%, PVD 4.0% and stroke 0.9%. Prevalence of
rance, as well as with the presence of other components of hypertension is also high (38.2%).68 Similar results have
the syndrome “X”. The evidence favors a strong causative also been published by Mohan et al.69
role for insulin resistance and hyperinsulinemia for the
higher rates of coronary heart disease (CHD) and diabetes DIABETES IN THE YOUTH
in Asian Indians. As the prevalence of diabetes increases, the proportion
of young people with diabetes also increases. The
Chronic Complications of Diabetes rapidly increasing prevalence of T2DM in the youth is
The burden of diabetes involves the health care delivery highlighted by studies in the Asian populations in the
to the large number of diabetic subjects and also the native lands and in migrant countries. China showed an
treatment of vascular complications. There is a lack 88% increase in prevalence of diabetes in 35–44 years
of population-based data on the prevalence of micro­ age group within a period of 6 years.49 In southern India,
vascular complication and macrovascular complication the prevalence of diabetes in persons below 44 years
from different parts of the developing world. It is being has increased from 25% of the total prevalence in 2000 to
reported that retinopathy is prevalent in approximately 36% in 2006.10 Asian people with young-onset diabetes
30% of T2DM and its prevalence is significantly high in have substantial phenotypic heterogeneity, many with
the Asian and Pacific Island Nations.1 High rate of CVD is positive family history, impaired beta-cell function, no
reported from India65 and other Asian countries and also islet cell autoantibodies and with clustering of cardio
in the migrant Indian populations.66 No discernible metabolic disorders.70 The major cause for the increasing
patterns relating to geographical distribution were appa­ prevalence of T2DM in Asian children is the increasing
rent for nephropathy and amputations. Although it rate of obesity, and decreasing rate of physical activity
is reported that the prevalence of peripheral vascular leading to insulin resistance.49 Most of the Asian countries
disease (PVD) is lower in the Indian population, the are largely rural, hence a sudden change in the lifestyle
number of people suffering from foot complications is of the rural people would increase the number of people
quite high on account of its large populations.67 affected by metabolic disorders.
 Epidemiology of Diabetes in Developing Countries: The Scenario in Asia 149

The rising trend seen in the prevalence of gestational Table 10.3: National prevalence of type 2 diabetes and impaired
diabetes among Asian women and the increased risk glucose tolerance (IGT) in Arab countries in 201132
for future diabetes in them may also contribute to the National prevalence in 2011 values in %
escalating prevalence of diabetes in young people.71 Country Diabetes IGT
Recently, an increasing trend in total prevalence Iran 11.34 5.01
of diabetes of diagnosed and undiagnosed T2DM was Iraq 9.33 6.27
reported in Chinese adults.72 The rising trend was more Kuwait 15.94 15.71

chapter
rapid in the rural population when compared with the Bahrain 15.29 14.25

10
2002–2003 data and in the younger birth cohorts. In the Egypt 15.16 6.84

last 10 years, the prevalence of diabetes had increased Lebanon 18.93 7.39
Qatar 14.07 13.81
phenomenally in China, such that it has the highest
Saudi Arabia 16.21 1.04
number of diabetic people in the world today.
Sudan 7.58 9.48
In the developing countries such as India and China a
Syrian Arab Republic 8.22 6.64
continuous and rapid increase in the prevalence of T2DM
United Arab Emirates 12.57 13.39
had been occurring which mainly could be attributed
to rapid transition in lifestyle, accompanied by a rising
epidemic of obesity.49 Indian patients show the presence of pancreatic calculi
and/or signs of chronic pancreatitis.
SCENARIO IN THE MIDDLE EAST COUNTRIES
PREVENTION OF DIABETES
Diabetes is a growing public health problem in several
Arab countries also, which includes Kuwait, Saudi Arabia, Preventive measures, involving primary prevention and
Iraq and Egypt.32 Prevalence has been reported to be high, secondary prevention, are urgently needed in all the
despite the differences in the economic status among developing countries. Most of these countries pose a
these countries. Genetic susceptibility and cultural factors medical challenge, which is not matched by the budget
may be associated with the development of diabetes. The allocations for health care. In India, it is estimated that
Middle East countries went through significant economic the annual cost of diabetes care could be approximately
development over the last three decades, which has INR 902,001 million. The average expenditure per
resulted in financial, demographic and epidemiological patient per year would be a minimum of INR 8,930.76
changes. The expenses increase proportionally with the years of
As shown in the Table 10.3 prevalence of diabetes diabetes duration and also with the presence of diabetic
complications.
was more than 10.0% in 2011 in most of these countries.
The cost of diabetes care is high and increasing
Prevalence of IGT was also high, predicting a future rise in
worldwide. The economic burden is very high, especially
diabetes prevalence.
in developing countries, and more so in the lower
Prevalence of glucose intolerance was lower in the
economic groups, who spend 25–34% of their income on
most remote area (Musandam) of the country when
diabetes care.76 The cost of care increases substantially
compared with the capital city area (Muscat) (14% vs 23%
when complications occur or when admission to hospital,
respectively).73
surgery or insulin treatment is needed.
Increasing urbanization and increasing rates of
Steps toward primary prevention of diabetes are
obesity in the adults and children have been associated
urgently needed in developing countries to combat an
with the rising prevalence of diabetes in the Middle East
epidemic rise in the prevalence of the disorder. It is
countries also.
encouraging to note that primary prevention of T2DM
has been shown to be a reality in several long-term
OTHER FORMS OF DIABETES
prospective studies. Lifestyle modification and certain
Lean young patients with diabetes showing signs pharmacological agents.43,77,78 are shown to have a
of malnutrition with BMI less than 18 kg/m2, with significant role in the prevention of diabetes.
severe hyperglycemia and requiring insulin for metabolic The Chinese Da-Qing study79 and the Indian Diabetes
control are seen in India74 and Bangladesh.75 Some of the Prevention Program (IDPP-1)43 have shown that the
150 Epidemiology

lifestyle modification focused on improvement in physical Prediabetic conditions such as IGT and IFG are
activity and healthy dietary habits prevents or at least prevalent in the SEA countries, which indicate the possi­
delays the onset of diabetes in high-risk subjects. Lifestyle bility of a further increase in the number of diabetic
intervention can have sustained 43% reduction in the subjects.
incidence of diabetes over a 20-year period.80 Diabetes and prediabetic conditions are also asso­
Prevention of obesity and diabetes will be cost effective ciated with other cardiovascular risk factors, which tend to
as it will prevent not only the development of diabetes but cluster in metabolic syndrome.
section

can also prevent the occurrence of complications. Chronic complications such as retinopathy and neuro­
4

The serious epidemic nature of diabetes has been pathy are very common. Foot complications in diabetes
recognized by the United Nations and it recommends the are one of the major causes for high morbidity and poor
member countries to develop national policies to combat quality of life in India. Diabetes care causes a major socio-
the diseases. In several countries in Asia, the governments economic burden. Primary prevention of diabetes, early
have initiated national programs for prevention and diagnosis of diabetes and secondary prevention of
control of NCD.81 The health care programs implemented complications should be given priority in health care
by Singapore have been effective and fruitful.18 planning.

SUMMARY FURTHER READING

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230 million diabetic subjects in the developing countries. miology of diabetes in rural India. Diabetes Res Clin Pract.
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age and live long enough to develop the chronic compli­ 4. Unwin N, Whiting D, Guariguata L, et al. (Eds). IDF Dia-
betes Atlas, 5th Edition. Brussels, Belgium: International
cations. India has the second largest number of the dia­
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betic population. It is approximately 63 million in 2012 5. IDF Diabetes Atlas. (2012). 5th Edition. [online] Available
and may reach more than 101 million in 2030. from www.idf.org/diabetesatlas. [Accessed September,
The major causes for the high prevalence of diabetes 2013].
are: (1) Urbanization, (2) A racial predisposition, (3)
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545-8. men. J Clin Endocrinol Metab. 1999;84:137-44.
42. Mohan V, Deepa M, Deepa R, et al. Secular trends in the 58. Dudeja V, Misra A, Pandey RM, et al. BMI does not accur­
prevalence of diabetes and impaired glucose tolerance in ately predict overweight in Asian Indians in northern
urban South India—the Chennai Urban Rural Epidemiol- India. Br J Nutr. 2001;86:105-12.
ogy Study (CURES-17). Diabetologia. 2006;49:1175-8. 59. Gallagher D, Visser M, Sepúlveda D, et al. How useful is
43. Ramachandran A, Snehalatha C, Mary S, et al. The Indian body mass index for comparison of body fatness across age,
section

Diabetes Prevention Programme shows that lifestyle modi- sex, and ethnic groups? Am J Epidemiol. 1996;143:228-39.
fication and metformin prevent type 2 diabetes in Asian 60. Report of a WHO consultation. Obesity: Preventing and
4

Indian subjects with impaired glucose tolerance (IDPP-1). managing the global epidemic. WHO Tech Rep Ser. 2000;
894:1-253.
Diabetologia. 2006;49:289-97.
61. Snehalatha C, Vijay V, Ramachandran A. Cut off values for
44. Menon VU, Kumar KV, Gilchrist A, et al. Prevalence of
normal anthropometric variables in Asian Indian adults.
known and undetected diabetes and associated risk fac-
Diabetes Care. 2003;26:1380-4.
tors in central Kerala—ADEPS. Diabetes Res Clin Pract.
62. Raji A, Seely EW, Arky Ra, et al. Body fat distribution and
2006;74:289-94.
insulin resistance in healthy Asian Indians and Caucasians.
45. Qiao Q, Hu G, Tuomilehto J, et al. Age- and sex-specific J Clin Endocrinol Metab. 2001;86:5366-71.
prevalence of diabetes and impaired glucose regulation in 63. Chandalia M, Abate N, Garg A, et al. Relationship between
11 Asian cohorts. Diabetes Care. 2003;26:1770-80. generalized and upper body obesity to insulin resistance
46. Nichols GA, Hillier TA, Brown JB. Progression from newly in Asian Indian men. J Clin Endocrinol Metab. 1999;84:
acquired impaired fasting glucose to type 2 diabetes 2329-35.
mellitus. Diabetes Care. 2007;30:228-33. 64. Yoon KH, LEE JH, Kim JW, et al. Epidemic obesity and type
47. Lee WR. The changing demography of diabetes mellitus in 2 diabetes in Asia. Lancet. 2006;368:1681-8.
Singapore. Diab Res Clin Pract. 2000;50:S35-9. 65. Ramachandran A, Snehalatha C, Latha E, et al. Cluster-
48. Zaini A. Where is Malaysia in the midst of the Asian epi- ing of cardiovascular risk factors in urban Asian Indians.
demic of diabetes mellitus? Diabetes Res Clin Pract. 2000; Diabetes Care. 1998;21:967-71.
50:S23-8. 66. Enas EA, Yusuf S, Mehta JL. Pevalence of coronary artery
49. Ramachandran A, Ma RC, Snehalatha C. Diabetes in Asia. disease in Asian Indians. Am J Cardiol. 1992;70:945-9.
Lancet. 2010;375:408-18. 67. Vijay V. Prevention of diabetic foot complication (Review).
50. Yajnik CS. Nutrient-mediated teratogenesis and fuel-medi- Endocrine Update. 1999; p. 1.
ated teratogenesis: two pathways of intrauterine program- 68. Ramachandran A, Snehalatha C, Satyavani K. et al. Preva-
ming of diabetes. Int J Gynaecol Obstet. 2009;104:S27-31. lence of vascular complications and their risk factors in
51. Viswanathan M, McCarthy MI, Snehalatha C, et al. Famil- type 2 diabetes. J Assoc Physicians India. 1999;47:1152-6.
ial aggregation of type 2 (non-insulin-dependent) diabetes 69. Mohan V, Vijaya Prabha R, Rema M. Vascular complications
mellitus in south India; absence of excess maternal trans- in long term south Indian NIDDM of over 25 years’ dura-
mission. Diabet Med. 1996;13:232-7. tion. Diabetes Res Clin Pract. 1996;31:133-40.
52. Ramachandran A, Snehalatha C, Vijay V. Low risk threshold 70. Gill T. Young people with diabetes and obesity in Asia: a
for acquired diabetogenic factors in Asian Indians. Diabe- growing epidemic. Diabetes Voice 2007;52:20-2.
tes Res Clin Pract. 2004;65:189-95. 71. Chan JCN, Malik V, Jia W, et al. Diabetes in Asia: epidemi-
53. Nakagami T, Qiao Q, Carstensen B, et al. Age, body mass ology, risk factors, and pathophysiology. JAMA. 2009; 301:
index and type 2 diabetes association modified by ethnicity. 2129-40.
Diabetologia. 2003;46:1063-70. 72. Li R, Lu W, Jiang QW, et al. Increasing prevalence of type
54. Lee JW, Brancati FL, Yeh HC. Trends in the prevalence of 2 diabetes in Chinese adults in Shanghai. Diabetes Care.
type 2 diabetes in Asians versus whites: results from the 2012;35:1028-30.
United States National Health Interview Survey, 1997-2008. 73. Asfour MG, Lambourne A, Soliman A, et al. High preva-
Diabetes Care. 2011;34:353-7. lence of diabetes mellitus and impaired glucose toler-
55. Shelgikar KM, Jockaday TDR, Yajinik CS. Central rather ance in the Sultanate of Oman: results of the 1991 national
than generalized obesity is related to hyperglycaemia in survey. Diabet Med. 1995;12:1122-5.
Asian Indian Subjects. Diabet Med. 1991;8:712-7. 74. Mohan V, Ramachandran A, Viswanathan M. Tropical Dia-
56. Snehalatha C, Ramachandran A, Satyavani K, et al. Differ- betes. In: Alberti KGMM, Krall KP (Eds). Diabetes Annual.
ence in body fat percentage does not explain the gender Amsterdam: Elsevier; 1986. pp. 30-8.
dimorphism in leptin in Asian Indians. J Assoc Physicians 75. Khan AK, Mahtab H, Ahamed T, et al. Leanness in young
India. 1999;47:1164-7. diabetics of Bangladesh. Diab Res Clin Pract. 2000;50:125.
 Epidemiology of Diabetes in Developing Countries: The Scenario in Asia 153

76. Ramachandran A, Shobhana R, Snehalatha C, et al. 79. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in
Increasing expenditure on health care incurred by diabetic preventing NIDDM in people with impaired glucose toler-
subjects in a developing country: a study from India. Diabe- ance: the Da Qing IGT and diabetes study. Diabetes Care.
tes Care. 2007;30:252-6. 1997;20:537-44.
77. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction 80. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle
interventions to prevent diabetes in the China Da Qing Dia-
in the incidence of type 2 diabetes with lifestyle interven-
betes Prevention Study: a 20-year follow-up study. Lancet.
tion or metformin. N Engl J Med. 2002;346:393-403. 2008;371:1783-9.
78. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention

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81. Ramachandran A, Snehalatha C. Diabetes prevention and
of type 2 diabetes mellitus by changes in lifestyle among control programs in developing countries. In: Narayan

10
subjects with impaired glucose tolerance. N Engl J Med. KMV, Williams D, Gregg EW, Cowie CC (Eds). Diabetes
2001;344:1343-50. Public Health. Oxford university press; 2011. pp. 603-21.
 Chapter 11
Epidemiology of Diabetes
Mellitus in India
SV Madhu, Paturi V Rao

Epidemiology of Diabetes in India

Chapter Outline
♦♦ Type 1 Diabetes Mellitus ♦♦ Impaired Glucose Tolerance
♦♦ Type 2 Diabetes Mellitus ♦♦ Complications
♦♦ Factors Implicated in Causation of Dm in Asian Indians

INTRODUCTION are: diagnosis of diabetes, insulin treatment at the time

of registration and age below 15 years at the time of first
In order to understand the true extent and dimensions insulin administration.
of the problem and its impact on diabetes care, there is a According to a registry study,3 almost 95% of childhood
need to review the descriptive epidemiology of diabetes diabetes reportedly belongs to T1DM although with the
mellitus (DM). There is information that will help define increasing occurrence of type 2 diabetes in childhood, this
the burden of diabetes and also throw some light on its pattern may change in the future. Maturity onset diabetes
causes. of young (MODY), fibrocalculous pancreatic diabetes
(FCPD) and diabetes associated with genetic syndromes
TYPE 1 DIABETES MELLITUS are also seen at younger age groups in India. Studies on
Asian Indian children in UK have reported low prevalence
Clinical based data from the mid sixties to eighties
of T1DM; 4.8 per 10,000 in Leicester.4 Some studies on the
reported the prevalence of childhood diabetes with onset
incidence and prevalence of T1DM in India are shown
below 15 years of age as 1–4% of all the diabetic patients
in Table 11.1.5-10 Some of these studies show increasing
in different parts of the country.1 In a study between 1984
trends in T1DM even in India.
and 1988, it was reported that 5–6% of families with
diabetes in India had one or more type 1 diabetes patient.2 TYPE 2 DIABETES MELLITUS
Their age at diagnosis was 15 years or lower.
Setting up of registries in population groups have Type 2 diabetes mellitus (T2DM) accounts for more
been recommended as a useful way of ascertaining the than 90% of all patients with diabetes worldwide. The
incidence and prevalence of type 1 diabetes mellitus prevalence of diabetes in adults is showing an upward
(T1DM). New case identification is easily possible due to trend (6.4% in 2010 to an estimated 7.7% in 2030).11 The
its acute onset although it is an uncommon condition. majority of this increase will, however, occur in the
Therefore, registering and keeping a record of all identified developing world. Asians, particularly from the Indian
cases of T1DM would be an effective way of defining its subcontinent have received greater attention in diabetes
burden. Suggested criteria for inclusion for registries studies, because of their migration in large numbers.11
 Epidemiology of Diabetes Mellitus in India 155

Table 11.1: Incidence and prevalence rates of type 1 diabetes mellitus in India
Reference Center Methodology Age (Years) Incidence Prevalence
Rate per Rate per
10,000 10,000
Bai et al. 19915 Chennai (U) Glycosuria Students 3–20 — 1.9
Bai et al. 1995 6
Chennai (U) Glycosuria OGTT 5–19 — 0.1

chapter
Ramachandran Chennai (U) Hospital records, Children ≤ 15 — 2.6
19927 Questionnaire &

11
Chemists
Ramachandran Madras T1DM Registry group Newly diagnosed Children ≤ 15 10.5 —
19958 (U) (Period 1991–1994) T1DM registry
criteria
Dharamlingam 19979 Bangalore T1DM Registry — — 1.68 —
Group (U) (Period 1995–
1996)
Kalra et al. 201010 Karnal District — — — 1.020

(U: Urban; OGTT: Oral glucose tolerance test; T1DM: Type 1 diabetes mellitus).

screened by a post 50 g glucose capillary blood test.

Capillary blood glucose level of above 170 mg/dL was
defined as diabetes. The prevalence of diabetes was found
to be 2.1% in urban and 1.5% in rural areas.22 The Daryaganj
Diabetes Survey of known diabetes carried out in
1986 in an affluent urban Delhi population showed a
much higher prevalence (3.1%) giving an estimated total
prevalence of 6.2%, i.e. twice the known prevalence as
compared to the previous Indian surveys.23 This survey also
defined the age specific prevalence in men and women
unlike previous surveys. No cases of known diabetes
were found in people aged under the age of 30 years. The
age specific prevalence reported in the Daryaganj study
were strikingly similar to those found in South Asians in
Southall and at least five times higher than in Europeans
Fig. 11.1: Age specific prevalence of Asian Indians in New Delhi and
London24 in Southall aged 40–64 years.24 For the first time, it was
demonstrated that a high prevalence of diabetes may
Reports from different parts of India have also suggested occur within India as well, if the population was exposed
a rising trend in the prevalence of diabetes.12-20 In India, to appropriate environmental factors and similar levels
there were an estimated 50 million diabetes individuals of affluence.
in 2010; the number is projected to increase to nearly This study also suggested that Indians have a high
87 million in 2030.11 ethnic susceptibility to diabetes and that it occurred at a
Ancient Indian physicians called it Madhumeh (sweet younger age than in white Caucasians (Fig. 11.1).
urine) or Bahumoothra (excess urination), or sugar disease.21 In 1970s prevalence of diabetes in urban cities ran­
India was thought to be a low prevalence zone for ged between 0.5% and 2.3%.22,24,25 In 1988, a study from
diabetes till 1970 when little data on the prevalence of South India12 confirmed the high prevalence of diabetes
diabetes in India was available. The Indian Council for reported earlier.23 Indeed, a number of studies have
Medical Research (ICMR) study (1972–1975) was the shown an increasing prevalence of diabetes in India
first systematic nationwide collaborative study on the (Table 11.2).12-14,17,19,22-35 In the 1990s, the prevalence of dia­
prevalence of DM carried out in six representative betes ranged from 3.1% to 11.6%,13,14,17 which increased
centres.22 34,294 persons above the age of 14 years were further to 12.1–14.3% in 2001–2004.19,30,32 A prevalence
156 Epidemiology

Table 11.2: Prevalence studies of type 2 diabetes mellitus in India

Year Author Place Prevalence Refer-
(%) ence
1971 Tripathy et al. Cuttack 1.2 (Urban) 26
1979 Ahuja et al. New Delhi 2.3 (Urban) 23
1978 Gupta et al. Multicenter 0.5 (Urban) 27
1984 Murthy et al. Tenali 4.7 (Urban) 28
section

1986 Verma et al. New Delhi 3.1* (Urban) 24

4

1988 Ramachandran et al. Kudremukh 5.0 (Urban) 13

1996 Ahuja et al. New Delhi 3.1* (Urban) 18
1992 Ramachandran et al. Chennai 8.2 (Urban)
2.4 (Rural) 14
1997 Ramachandran et al. Chennai 11.6 (Urban) 15
2000 Zargar et al. Kashmir 6.1 (Urban) 29
2000 Raman Kutty et al. Kerala 12.4 (Urban) 30 Fig. 11.2: Prevalence of diabetes and IGT in Urban India13,14,19,30
2001 Ramachandran et al. Metros 12.1 (Urban) 31
2001 Misra et al. New Delhi 10.3 (Urban) 33
2001 Mohan et al. Chennai 12.1 (Urban) 17 the last 15 years, the diabetes prevalence has increased
2001 Iyer et al. Dombivili 7.5 (Urban) 35 by 72.3% (Fig. 11.2).19 However, the prevalence of IGT
2004 Sadikot et al. Mumbai 5.9 (Urban) decreased from 16.8% in 2000 to 10.2% in 2004 (Fig. 11.2).
2.7 (Rural) 36 This could be explained by two factors: firstly, it may
2006 Mohan et al. Chennai 14.3 (Urban) 20 be due to increased conversion rates of IGT to diabetes,
2006 Menon et al. Cochin 19.5 (Urban) 37 which could suggest a possible slowing of the epidemic
2009 Vijayakumar et al. Kerala 12.5 (Rural) 38 of diabetes in urban India, as the IGT (pre-diabetic)
*Known diabetes pool begins to shrink. Secondly, this could reflect rapid
progression from normal through IGT to diabetes, which
study of known diabetes in urban East Delhi (Swasthya could result in a drastic increase in prevalence of diabetes
Vihar) in 2000 found a high prevalence of known diabetes due to a worsening diabetogenic environment.
in an urban population (5.5%) especially in persons above The National Urban Diabetes Survey (NUDS),30 a
60 years (18.4%). landmark epidemiological study in which 11,216 subjects
Taking one unknown diabetes for every two known were studied using stratified random sampling method
diabetes individuals, the estimated prevalence of diabetes and the World Health Organization (WHO) criteria for
(known and unknown) for the population was estimated oral glucose tolerance test (OGTT), showed that 69.8% of
to be 8.2% and for those above 60 years of age, 27.6%. the diabetic patients were known cases, having records of
This study predicted that as longevity increases, so will treatment. The age standardized prevalence of diabetes
the prevalence of diabetes.18 and IGT were 12.1% and 14.0% respectively with no
A series of epidemiological studies showed that the gender differences. Subjects under the age of 40 years
prevalence of diabetes and impaired glucose tolerance had a higher prevalence of IGT (12.8%) than diabetes
(IGT) had steadily increased among urban Indian adults (4.6%) and this difference was statistically significant
studied at Chennai. The Chennai Urban Rural Epide­ (p < 0.0001). Diabetes showed a positive and independent
miology Study (CURES) conducted in 200419 reported association with age, body mass index (BMI), waist hip
the prevalence of diabetes to be 15.5% (age standardized: ratio (WHR), family history of diabetes, monthly income
14.3%), which includes 6.1% self reported diabetes and and sedentary physical activity whereas IGT showed an
9.4% previously undiagnosed diabetes. This study also association with age, BMI and family history of diabetes
examined the secular trend in prevalence of diabetes. The (Tables 11.3 to 11.6).
prevalence of diabetes increased by 39.8% in the period National urban diabetes survey30 showed that T2DM
1989 to 1995; there was a further increase by 16.3% in the begins at an earlier age in India and that the prevalence
next 5 years and 6% in the subsequent 4 years. Thus, in of diabetes is uniformly high in all urban cities of India
 Epidemiology of Diabetes Mellitus in India 157

Table 11.3: Prevalence (% with 95% confidence intervals in parentheses) of diabetes and IGT in the Urban Population in India30
Diabetes IGT
No. of cases Prevalence Age-standardized No. of cases Prevalence Age-stand standardized
Total 1684 13.9 12.1 1631 14.4 14.0
(n = 11216) (13.2–14.6) (11.5–12.7) (13.7–15.1) (13.3–14.8)
Men 813 13.8 12.5 776 14.6 14.0

chapter
(n = 5288) (12.8–14.8) (11.6–13.4) (13.5–15.6) (13.0–15.0)

11
Women 871 14.0 11.9 855 14.3 14.1
(n = 5928) (13.0–14.9) (11.1–12.7) (13.4–15.3) (13.1–15.3)

(IGT: Impaired glucose tolerance).

Table 11.4: Age and gender specific prevalence of type 2 diabetes and IGT30
Age group Total group Diabetes IGT
(Years) Diabetes IGT Men Women Men Women
n % n % n % n % n % n %

20–29 60 2.4 301 11.5 31 2.3 29 2.4 139 10.7 162 12.2
30–39 212 7.0 400 14.6 98 7.3 114 6.8 171 13.8 229 15.3
40–49 441 16.5 381 15.4 211 16.0 230 16.9 195 17.0 186 14.1
50–59 463 26.3 248 14.6 217 25.2 246 27.3 125 16.1 123 13.3
60–69 364 29.1 194 16.4 179 31.1 185 27.6 91 16.7 103 16.2
> 69 144 25.9 107 19.3 77 26.3 67 25.5 55 19.2 52 19.4
(IGT: Impaired glucose tolerance).

Table 11.5: Age at diagnosis of diabetes (new and known cases)30

Age group Total group Men Women
(Years) n % n % N %
20–29 91 5.4 44 5.4 47 5.4
30–39 332 19.7 166 20.4 166 19.1
40–49 488 29.0 230 28.3 258 29.6
50–59 452 26.8 208 25.6 244 28.0
60–69 233 13.8 120 14.8 113 13.0
> 69 85 5.0 42 5.2 43 4.9

but higher in southern cities—Hyderabad, Chennai and

Bangalore (Table 11.6). Also the prevalence of IGT was
high, indicating the potential of a future increase in the
number of diabetes subjects. All previous studies had Fig. 11.3: Age-specific prevalence of IGT and diabetes30
shown a lower prevalence of IGT as compared to diabetes,
but NUDS found it to be similar or higher. in subjects aged 25 years and above in India was carried
Higher prevalence of IGT than diabetes in the younger out in 77 centers (40 urban and 37 rural). Blood samples
age group (< 40 years of age) not only predicts a future were taken after a fast of 10–12 hours and 2 hours after
epidemic of DM but also a higher degree of glucose intole­ 75 g of oral glucose. The standardized prevalence rates
rance in the young (Fig. 11.3).30 for DM, in the total, urban and rural populations were
The Prevalence of Diabetes in India Study (PODIS),34 4.3%, 5.9% and 2.7%, respectively. The corresponding
a random multistage cross-sectional population survey IGT rates in the three populations were 5.2%, 6.3% and
158 Epidemiology

Table 11.6: Prevalence of diabetes and IGT in the various cities of India30
City n Males: Females Diabetes % (95% CI) IGT % (95% CI)
Chennai 1668 708:960 13.5 (11.8–15.2) 16.8 (14.6–19.0)
Bangalore 1359 638:721 12.4 (10.5–14.3) 14.9 (12.8–16.9)
Hyderabad 1427 685:742 16.6 (14.6–18.6) 29.8 (26.9–32.8)
Calcutta 2378 1163:1215 11.7 (10.4–13.0) 10.0 (8.7–11.4)
section

Mumbai 2084 987:1097 9.3 (7.7–10.1) 10.8 (9.3–12.2)

4

New Delhi 2300 11.7:1193 11.6 (10.3–12.9) 8.6 (7.4–9.7)

3.7%, respectively. This study found that the prevalence of

both DM and IGT was significantly greater in the urban
than the rural population. Another study evaluating the
prevalence of T2DM in urban and rural areas in southern
India, in a population with the same ethnic background,
found the prevalence of T2DM adjusted for age, to be
8.2% in urban and 2.4% in rural population. The preva­
lence was 8.4% and 7.9% in urban men and women and
2.6% and 1.6% in rural men and women, respectively.14
It has been observed that T2DM in India occurs a
decade earlier than in the developed world as shown by
the Daryaganj survey,23 NUDS30 and CURES19 although
the prevalence peaks at an older age. The peak age
prevalence was found to be in the age group 60–64 years
in the Daryaganj survey23 and 60–69 years in NUDS30 and Fig. 11.4: Prevalence of diabetes in different habitats37
CURES.19 In the Daryaganj23 survey there were almost twice
as many men as women with diabetes (crude prevalence Geographical Regions and Migration
3.8% and 2.3%, respectively) but NUDS30 found no such
difference. NUDS showed that the age standardized Prevalence of diabetes is higher in urban than rural areas.
prevalence of diabetes and IGT was 12.1% and 14.0%, In NUDS,30 the prevalence (age standardized) was 12.1%.
respectively with no gender differences in urban India.30 The prevalence of T2DM in urban areas of India is compa­

ICMR-INDIAB study, a national study to determine rable to Indians in western countries24 where similar age
the prevalence of diabetic and prediabetic in India, repor­ standardized prevalence rates were found. This indicates
ted a prevalence of 10.4 % of diabetes in Tamil Nadu, ethnic (possibly genetic) susceptibility to diabetes in
8.4% in Maharashtra, 5.3% in Jharkhand, 13.6% in Chandi­ Indians, which manifests with exposure to common
garh. This study estimated that in 2011 there would be environ­mental factors.36 The prevalence of diabetes in
around 6 million diabetics in Maharashtra, 4.8 million an urbanizing peripheral town in India (5.9%) was found
diabetics in Tamil Nadu, 0.9 million in Jharkhand, and to be more than two-fold higher than in a rural area
0.12 million in Chandigargh.31 (2.4%), but lower than in an urban metropolitan city
(11.6%)37 (Fig. 11.4).
FACTORS IMPLICATED IN Age
CAUSATION OF DM IN ASIAN INDIANS
A younger onset of diabetes has been noted in Asian
The factors implicated in causation of DM in Asian Indians Indians in several studies.38 In NUDS,30 onset of DM was
are geographic regions and migration, age, gender, obe­ before 50 years of age in 54.1% of cases. These are the most
sity, diet, physical inactivity, ethnic susceptibility, genetic productive years of the life of an individual. An earlier
factors, parity, stress and insulin resistance. onset increases chronic vascular complications thereby
 Epidemiology of Diabetes Mellitus in India 159

increasing the burden on the healthcare system. The made to assess this. It is evident that diets with excess
increase in prevalence of diabetes with age is seen both in calories and/or sugar and fat intake may contribute to the
the urban and rural areas with a peak prevalence in the development of diabetes. This was studied by our group in
60–69 years age group. hotel employees from four hotels of New Delhi who had
Until recently, most children and adolescents with access to rich diet; and prevalence of diabetes was found
diabetes had type 1 diabetes. However, T2DM is being to be 3.6%45 which was much higher than the ICMR report
increasingly reported in children from several parts of of 2.1% prevalence in the general population at that time.

chapter
the world including children of Indian origin living in NUDS30 and the Chennai Urban Population study (CUPS)16

11
other countries such as United Kingdom and Singapore. revealed a rising prevalence of diabetes with increasing
This may indicate an increasing prevalence of diabetes in family income which may be related to the richer diets
children in India who may then join the pool of diabetes associated with higher income. It is also recognized that
with complications.39 T2DM in children is probably under malnutrition may modulate and modify the expression of
diagnosed because it can exist without symptoms and different forms of diabetes but this is discussed in another
may be misclassified.40 chapter and hence is not considered here.

Sex Physical Activity

Earlier population based studies have shown that diabetes Exercise is a protective factor against the development
is more frequent in men than women in India26 and in of diabetes.46 Experimental evidence also supports the
migrant Indians. A female preponderance was reported value of physical exercise.42 When categorized according
in one study in South Indian diabetes subjects.12 Earlier to occupation in NUDS,30 the maximum prevalence of
reports from Chennai had shown a male preponderance diabetes was found among the unemployed and retired
which in subsequent years had shifted slightly towards a subjects. Prevalence of diabetes was significantly lower in
female excess.12-14 In the most recent NUDS30 and CURES,19 those in the highest quartiles of physical activity (11.0%)
similar prevalence of diabetes was found in both genders. compared to those in the lowest quartile (16.8%). Similar
data was observed in CUPS, which documented that the
Obesity prevalence of diabetes was higher among subjects with
light grade (17.0%) compared to moderate grade (9.7%)
In 1980, the second WHO expert committee on diabetes
and heavy grade physical activities (5.6%).32,47
concluded that the most powerful risk factor for T2DM
was obesity.41 The two most important aspects of obesity Ethnic Susceptibility and Genetic Factor
are its extent and duration.42 A study of prevalence of
Type 2 diabetes mellitus shows significant familial agg­
T2DM in elderly South Indian population showed an
regation. Vertical transmission through two or more
association with central obesity although the subjects had
generations is common in Asian Indians.48,49 The preva­
low BMI.43 Recent studies have focused on the importance
lence of diabetes increases with increasing family history
of central obesity and adiposity. In NUDS,30 an increasing
of diabetes. The prevalence among offspring with one
prevalence of obesity was found with increasing degrees
diabetic parent was 36%, which increased to 54% when
of glucose intolerance—46.8% subjects with diabetes
there was a positive family history of diabetes on the
were obese as compared to 36.4% and 26.2% in the IGT
non-diabetic parental side also. When both parents had
and normal glucose tolerance (NGT) groups, respectively.
diabetes, the prevalence rate increased further (62%).49
The differences between these groups were significant. A positive family history of diabetes was found in 16.9%
Increased WHR (0.9 in men and 0.85 in women) was seen of diabetes subjects in NUDS.30 Age and gender adjusted
in a total of 50.3% patients, with its prevalence in NGT, IGT prevalence of diabetes was significantly higher in those
and diabetes being 46.7%, 51.9% and 65.2%, respectively. with a family history (28.1%) than in those without a family
Higher WHR was found to be more common than general history (11.4%) and this difference was significant. In the
obesity (50.3% vs 30.8%). CUPS study, 55% of offspring of two diabetic patients had
either diabetes or IGT compared to 15.6% in those with
Diet no family history of diabetes.32 Thus it is clear that a large
Since the first WHO expert committee had proposed that proportion of diabetic subjects in India have a history of
under-nutrition protects against diabetes44 attempts were diabetes in first or second degree relatives.
160 Epidemiology

In the adult offspring of diabetic patients, hyperin­ been found to have an independent effect on glucose
sulinemia and decreased insulin sensitivity are observed intolerance but increasing parity may be associated with
before the development of glucose intolerance. Also, it has obesity, which in turn may predispose to diabetes.
been observed that haplotype combinations of calpain
10 gene polymorphisms are associated with an increased Insulin Resistance
risk of IGT and T2DM in South Indians.50 Polymorphic
Asian Indians have a low BMI but despite being thin,
variations in neurogenic differentiation-1, neurogenin-3
insulin resistance is a characteristic feature67 as shown by
section

and hepatocyte nuclear factor 1-α gene has been shown

higher levels of plasma insulin being required to maintain
4

to contribute to glucose intolerance.51 The incidence

normoglycemia.68 Glucose clamp studies proved that
of obesity, an important risk factor in the development
Indians are more insulin resistant than Europeans.69 They
of T2DM, is lower in Asian Indians as compared to
also have high central adiposity and high percentage
Caucasians. Insulin resistance results from environmental
body fat, features of insulin resistance, which worsens
or genetic factors or by a combination of both. Studies at
with even small increments in weight and with lack of
the Madras Diabetes Research Foundation, showed that
physical activity. Urban-rural differences observed in
the ENPP1 (K-Q polymorphism) gene confers suscepti­
plasma insulin responses could be explained at least
bility to Type 2 diabetes.52 It was also shown that the
by partly differences in BMI, diet and physical activity,
Thr-Thr Polymorphism of the PGC-1 gene confers
indicating the strong influence of environmental factors
susce­ptibility to diabetes,53 obesity54 and the metabolic
on insulin resistance patterns. Clustering of cardiovascular
syndrome.55 On the other hand, the Pro12Ala Polymor­
risk factors, of which insulin resistance is an important
phism of the PPAR gamma gene, which offers protection
against diabetes and insulin resistance in Europeans com­ponent, also occurs in a large proportion of the adult
does not appear to protect Indians.56 The Ala98Val poly­ urban Asian Indians.70
morphism of HNF1alpha gene is associated with MODY
and with earlier age at onset of type 2 diabetes in Indians.57 IMPAIRED GLUCOSE TOLERANCE
A study on the IRS2 gene revealed that the DD genotype
A study in urban and rural areas in South India found
of the G1057D polymorphism increases susceptibility to
that the prevalence of IGT was similar which implies that
type 2 diabetes by interacting with obesity.58 Finally, the
both these populations have a high genetic susceptibility
Thr54 allele in the FABP2 gene was found to be associated
to develop carbohydrate intolerance. It is thus probable
with metabolic syndrome and hypertriglyceridemia.59
that with increasing urbanization and life expectancy, the
These elegant studies have helped to explain, at least in
prevalence of T2DM would increase further. According
part, the increased genetic susceptibility of Indians to
to NUDS,30 the prevalence of IGT was equal to diabetes
diabetes.
in the urban areas. The CURES study indicated that the
Stress prevalence of IGT has now decreased to 10.2% compared
to NUDS (16.8%).19 Similar results were obtained in the
It is difficult to assess the contribution of stress in preci­ recent Amrita Diabetes and Endocrine Population Survey
pitating diabetes in people with genetic susceptibility to (ADEPS) which indicated that the prevalence of IGT had
diabetes, although there is evidence that it could play a further decreased to 4.2% while the prevalence of diabetes
part.42,60 Urban stress is more marked in ethnic minorities had further increased to 19.5%.35 This could indicate a
than the local population,61 which may contribute to the worsening diabetogenic environment with rapid progres­
higher rates of T2DM in these communities but obviously sion from normal through IGT to diabetes, resulting in a
this is an area for future work. drastic increase in pool of diabetes as described earlier.
ICMR-INDIAB study reported a prevalence of 8.3% of
Parity prediabetes in Tamil Nadu, 12.8 % in Maharashtra, 8.1% in
High parity may play a role as a causative62 or a promoting Jharkhand and 14.6% in Chandigarh. It also estimated that
factor63-65 in the development of diabetes. In South India, in 2011, there would be around 3.8 million, 9.2 million,
however, the impact of multiparity on the prevalence 1.5 million, and 0.13 million of prediabetics in Tamil Nadu,
of diabetes was found to be negligible.66 Parity has not Maharashtra, Jharkhand, and Chandigarh, respectively.31
 Epidemiology of Diabetes Mellitus in India 161

Primary prevention of diabetes, which aims to reduce in subjects with normal glucose tolerance.90 There is
the rate of conversion of susceptible individuals such evidence that Asian Indians have an increased risk of
as IGT to T2DM should be a public health priority. CAD94,95 The overall prevalence of CAD in CUPS study
was 11%90 which is 10 times higher than that reported
Impact of Revised Criteria in 1940s.96 The figures are also higher than that in other
ethnic groups and are approaching the numbers reported
A study carried out to compare the American Diabetes
in migrant Indians.94,97

chapter
Association (ADA) fasting criteria and WHO two-hour The prevalence of PVD was 6.3% among diabetic
criteria for diabetes in an urban South Indian population

11
subjects compared to 2.7% in non-diabetic subjects,91
found that the use of the ADA fasting criteria results in a however, the prevalence rate of PVD in Indians is lower
lower prevalence of diabetes and the overall agreement than that in other ethnic groups,98 related perhaps to their
between the two is poor.71 lower age.38 There is a striking difference in prevalence
rates of CAD and PVD in India, despite both being macro
Screening for High-Risk Groups vessel diseases. CAD occurs at a much younger age and at
Screening would be the ideal way to detect the early high rates while PVD appears to show the opposite trend,
stage of prediabetes and prevent diabetes. Some authors i.e. lower prevalence and occurrence at older age groups.
This could be related to differences in risk factors for those
feel that there is insufficient evidence for recommending
two complications.
routine screening of asymptomatic individuals for dia­
There is inadequate data on stroke and CVD in India.
betes.72 However, the ADA suggested that individuals aged
At the time of presentation to an endocrine center in South
45 and above must be regularly screened while those who
India, 1.12% had a diagnosis of CVD (186 among 16,570
are at high risk, e.g. those with IFG and IGT or belonging
subjects with T2DM).99 A review of CVD in T2DM from
to a high-risk ethnic group (e.g. Asian Indians) must be
India commented on the paucity of literature on the
screened with a shorter screening intervals.73 Recently, subject.100 CUPS has provided interesting data on carotid
risk scores based on simple anthropometric, demographic IMT which could be considered as a surrogate for CVD
and behavioral details have been computed to detect as well as of CAD. The mean IMT of diabetes subjects
high-risk individuals, as selective screening instead of was significantly higher than those of the non-diabetic
universal screening for diabetes, would be more cost- subjects.93 At any age point, the IMT values of diabetic
effective and less laborious.74,75 The Indian Diabetes subjects were significantly greater than among non-
Risk Score (IDRS) has been shown to be useful not only diabetic subjects. Prevalence of carotid atherosclerosis
to identify undiagnosed diabetes74 but also to predict defined as carotid IMT more than 1.1 mm in CUPS,
subjects with metabolic syndrome among those with was 1% among non-diabetic subjects and 20% among
normal glucose tolerance.76 diabetic subjects.93

COMPLICATIONS Microvascular Complications

Diabetic retinopathy, nephropathy and neuropathy
Table 11.7 presents studies on the prevalence of diabetic
constitute the microvascular complications in diabetic
complications in India based on clinic based and popu­
subjects.
lation based reports.77-93
In a clinic based study, the prevalence of retinopathy
was earlier reported to be 34.1%.77 In the CURES which
Macrovascular Complications
represents the population based data, the overall preva­
Macrovascular disease comprises coronary artery disease lence of retinopathy in diabetic subjects was 17.6%,
(CAD), peripheral vascular disease (PVD) and cerebro­ which included 20.8% in self reported and 5.1% in newly
vascular disease (CVD). Population based data has been diagnosed diabetic subjects.81 Prevalence of diabetic
generated from the CUPS90,91,93 on the prevalence of CAD, retinopathy in Indians thus seems to be lower than that
PVD and preclinical atherosclerotic markers like intimal reported in other ethnic groups.101-103 The prevalence of
medial thickness (IMT) of carotid artery. retinopathy at diagnosis in western population varies from
Coronary artery disease was present in 21.4% of 20% to 35%102,103 compared to 5.0–7.3% in Indians. Familial
diabetic subjects compared to 14.9% in IGT and 9.1% aggregation studies documented that familial clustering
162 Epidemiology

Table 11.7: Population and clinical based studies on prevalence of diabetes complications
Author Type of the study City Prevalence Reference
Retinopathy
Rema et al. 1996 Clinical based Chennai 34.1% 78
Dandona et al. 1999 Population based Hyderabad 22.6% 79
Ramachandran et al. 1999 Clinical based Chennai 23.7% 80
section

Narendran et al. 2002 Population based Palakkad 26.8 81

4

Rema et al. 2005 Population based Chennai 17.6% 82

Nephropathy
John et al. 1991 Clinic based Vellore Microalbuminuria: 19.7%
Diabetic nephropathy: 8.9% 83
Gupta et al. 1991 Clinical based New Delhi Microalbuminuria: 26.6% 84
Yajnik et al. 1992 Clinical based Pune Microalbuminuria: 23.0% 85
Vijay et al. 1994 Clinical based Chennai Proteinuria: 18.7% 86
Mohan et al. 2000 Clinical based Chennai Macroproteinuria with
retinopathy: 6.9% 87
Varghese et al. 2001 Clinical based Chennai Microalbuminuria: 36.3% 88
Unnikrishnan et al. 2007 Population based Chennai Microalbuminuria : 26.9%
Overt nephropathy with
diabetic retinopathy : 2.2% 89
Coronary Artery Disease
Mohan et al. 1995 Clinical based Chennai 17.8% 90
Ramachandran et al. 1999 Clinical based Chennai 11.4% 80
Mohan et al. 2001 Population based Chennai 21.4% 91
Peripheral Vascular
Disease
Premalatha et al. 2000 Population based Chennai 6.3% 92
Peripheral Neuropathy
Ramachandran et al. 1999 Clinical based Chennai 27.5% 80
Ashok et al. 2002 Clinical based Chennai 19.1% 93
Carotid Atherosclerosis
Mohan et al. 2000 Population based Chennai 20% 94

of diabetic retinopathy was three times higher in siblings population based study from India which showed that
of type 2 diabetic subjects with diabetic retinopathy the overall prevalence of overt nephropathy was 2.2%
compared to those without diabetic retinopathy.104 Simi­ and microalbuminuria was 26.9%.88 These figures are
larly, familial aggregation of nephropathy has also been comparable to that reported in the western population.108,109
reported from south India.105-107 Non-diabetic renal diseases should also be considered
Some studies in the UK have pointed out a higher in diabetic individuals.110,111
prevalence of diabetic nephropathy in Asian Indians The clinical diabetic neuropathies found at a teaching
compared to White Caucasians. However, studies from hospital in Cuttack were in the following order: Distal
India do not support these observations. Data from symmetrical sensorimotor neuropathy, cranial mononeu­
referral centers showed a prevalence of persistent protei­ ropathy, mononeuropathy multiplex, autonomic neuro­
nuria of 6.9% to 18.7%.82,85,86 Prevalence of microalbumi­ pathy.112 Peripheral neuropathy was found to be particu­
nuria ranges between 19.7% and 36.3%.82-84,87 CURES a larly common in the low body weight groups of DM.113
 Epidemiology of Diabetes Mellitus in India 163

Table 11.8: Mortality in type 2 diabetes mellitus

Authors Place Period No. of deaths DM Leading cause Reference
Patel et al. Mumbai KEM Hospital 1958–1964 86 CAD, CVA 117
Verma et al. Delhi Irwin Hospital 1970–1974 235 CAD, CRF, coma 118
Garg et al. Delhi AIIMS 1989–1993 12% of 3620 Vascular diseases,
DM admitted infections 119

chapter
Sriniwasan et al. Bangalore Ramaiah Medical College 1986–1994 205 CAD, infection, CVA 120

11
Sahay et al. Hyderabad NIMS University — 453 CAD, CRF, 121
infection, ketosis
Das et al. Cuttack SCB Medial College — 20% CAD, CVA, 122
infection
Bhansali et al. Chandigarh PGI 1991–1999 440 Infection, CAD
& CRF 123
Mohan et al. Chennai Population based 2003–2004 50 CAD, renal
(CUPS) disease 126
Zargar et al. Kashmir Institute of 1987–1996 269 Infections,
Medical Sciences renal failure 124
(CAD: Coronary artery disease; CVA: Cerebrovascular accident; CRF: Chronic renal failure; DM: Diabetes mellitus).

Table 11.9: Causes of Death among Hospitalized Adult Onset Mortality Trends
Diabetes Patient (n = 498 ) (Dead = 47)123
There are no large scale Indian studies on mortality in
N %
patients with T2DM (Table 11. 8).115-123
Renal failure 12 25.5
A retrospective study from Srinagar (Table 11.8)124
CAD 9 19.1
reviewed medical records of 133,374 patients admitted
Tuberculosis (including TBM) 5 10.6
from January 1987 to December 1996. Out of the 9,627
Septicemia 4 8.5 who died, 269 had diabetes. Infections contributed to over
DKA 3 6.4 30% of the death, which was followed by chronic renal
Hypoglycemia 3 6.4 failure (CRF) (30%) and CAD (16%). Another study of
CVA 1 2.1 440 patients with diabetes related mortality in a tertiary
care center in North India also revealed the common cause
(CAD: Coronary artery disease; DKA: Diabetic ketoacidosis; of death as infections (46.5%) followed by CAD (17.4%),
CVA: Cerebrovascular accident). CRF (9.7%), stroke (6.0%), DKA (3%), hyperosmolar coma
(2.2%) and hypoglycemia (2.1%).123 Analysis of the causes
Cranial mononeuropathies though uncommon were of death in DM versus non-diabetic hospital inpatients
found to be transient.114 From south India, one clinic based showed infection, CAD and CRF to be more frequent in
study reported the prevalence of diabetic neuropathy to be diabetics.123
19.1%.114 However, a 20-year follow-up of patients in Delhi by
The Chennai Urban Rural Epidemiology study our own group125 found that myocardial infarction was the
published in 2010 showed 17.5%, 25.7%, 5.1%, and 26.5% most frequent cause of death in diabetes (35.7%), followed
prevalence of retinopathy, neuropathy, overt nephropathy by CRF (21.4%), infections (7.1%) and diabetic coma
and microalbuminuria respectively.115 Age, glycated hemo­ (7.1%). Another study123 on the causes of death among
globin, duration of diabetes and serum triglycerides were hospitalized adult onset diabetes patients at our center
associated with the progression of all microvascular showed renal failure and CAD to be the leading causes of
complications of diabetes. Further, it concluded that death (Table 11.9).
association between retinopathy and nephropathy were Similar results were obtained in the CUPS study from
stronger that of neuropathy.115 south India.126 The all cause mortality among diabetic
164 Epidemiology

subjects in CUPS was found to be 18.9 per 1000 person Indian adults from 5.2% and 2.0% respectively in 1984 to
years (age standardized: 6.3 per 1000 person years) com­ 14.3% and 10.2%, respectively in 2004. The CURES showed
pared to 5.1 per 1000 person years (age standardized: that while the diabetes prevalence continue to rise in
4.4 per 1000 person years) among non-diabetic subjects. urban India that of IGT has begin to decrease. Similar
At any given age interval, diabetic subjects had increased trends were reported from Cochin in central Kerala
death rates compared to the non-diabetic subjects. also. The Prevalence of Diabetes in India Study (PODIS)
Mortality due to CVD (52.9% vs 24.2%) and renal causes carried out in 77 centers recently reported a standardized
section

(23.5% vs 6.1%) were higher among diabetic, compared prevalence rate for DM, in the total urban and rural
4

to non-diabetic subjects and were the main causes of population of 4.3%, 5.9% and 2.7%, respectively. The
death in diabetic patients. These results are similar to that factors implicated in causation of DM in Asian Indians are
reported in developed world. Thus it is clear that while geographic regions and migration, age, gender, obesity,
infections which were earlier the leading causes of deaths diet, physical inactivity, ethnic susceptibility and genetic
in patients with DM in developing regions like India, the factors, parity, stress and insulin resistance. T2DM affects
trend is progressively shifting towards the pattern seen in individuals in India at a younger age as compared to their
developed regions with cardiovascular disease and renal western counterparts. For the same BMI, Indian T2DM
diseases now becoming the leading causes of death. patients have more central obesity as compared to
Europeans. Studies on genetics of type 2 diabetes from
SUMMARY the Madras Diabetes Research Foundation have shown
India is in the midst of an ever-increasing epidemic of DM. unique susceptibility genes in Indians.
Data on T1DM from our country is scant. Clinic based data Earlier studies on diabetic complications have been
from the mid sixties to the eighties reported the prevalence clinic based which is subject to referral bias. More recently
of childhood diabetes with onset below 15 years of age as population based data on complications have begun
being 1–4% of all the diabetic patients attending clinics in to emerge. Overall CAD rates seem to be higher and
different parts of the country. According to a recent study that of PVD lower in Indians. The overall prevalence of
also, almost 95% of childhood diabetes reportedly belongs retinopathy and nephropathy appear to be lower than
to T1DM. Early onset type 2 diabetes, MODY, FCPD and reported in the west. However, given the large number of
diabetes associated with genetic syndromes accounted for people with type 2 DM in our country, the morbidity due
the remaining cases. Recent studies suggest that there is a to these complications would still be very high.
rise in the prevalence of Type 1 DM in India. Chennai Urban Population study is the only population
Type 2 DM accounts for more than 90% of all patients based study from India on mortality in diabetic subjects.
with diabetes in India. According to the WHO, there were This study showed that mortality rates in diabetic subjects
an estimated 50 million diabetes individuals in 2010, was at least twice as high as in non-diabetic subjects and
and this number is projected to increase to 87 million by cardiovascular and renal causes constituted the majority
2030. The ICMR study (1972–1975) was the first systematic of deaths. Earlier clinic based studies had concluded that
nationwide collaborative study on the prevalence of DM. infections were the leading causes of deaths in patients
It was carried out in 6 representative centers. The preva­ with DM in India. This trend is progressively shifting
lence of diabetes was found to be 2.8% in rural and 5% towards the pattern seen in developed regions where
in the urban population above the age of 40 years. The cardiovascular disease and renal deaths are becoming the
Daryaganj Diabetes Survey of known diabetes carried out common cause of death in individuals with type 2 diabetes
in 1986 by our group in an affluent urban Delhi population in India.
showed a much higher prevalence as compared to the
previous Indian surveys. Subsequent studies confirmed Further Reading
this high prevalence of diabetes in urban India. A series
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developing countries and effect of westernisation In: Hit- between PPARG, PPARGC1A, PPARG and UCP1 gene poly-
man GA (Ed) Type 2 diabetes: Prediction and Prevention. morphism and the metabolic syndrome in Asian Indians.
John Wiley and Sons; London: 1999. pp. 325-45. Metab Syndr Relat Disord. 2007;5:153-62.
40. Mohan V, Ramachandran A, Snehalatha C, et al. High prev- 57. Radha V, Vimaleswaran KS, Babu HN, et al. Role of genetic
alence of maturity onset diabetes of the young (MODY) polymorphism peroxisome proliferator—Activated Recep-
among Indians. Diabetes Care. 1985;8:371-4. tor – 2 Pro 12Ala on ethnic susceptibility to diabetes in
41. Fagot-Campagna A, Narayan KM, Imperatore G. Type 2 south Asian and caucasian subjects. Diabetes Care. 2006;29:
diabetes in children. Exemplifies the growing problem of 1046-51.
chronic diseases. BMJ. 2001;322:377-8. 58. Anuradha S, Radha V, Deepa R, et al. A prevalent amino
42. American Diabetes Association. Type 2 diabetes in children acid polymorphism at Codon 98 (Ala98Val) of the Hepat-
and adolescents. Diabetes Care. 2000;23:381-9. ocyte Nuclear Factor-1a is associated with maturity onset
43. WHO expert committee on diabetes mellitus. Second diabetes of the young and younger age at onset of Type 2
report. World Health Organ Tech Rep Ser. 1980;646:1-80. diabetes in Asian Indians. Diabetes Care. 2005;28:2430-5.
 Epidemiology of Diabetes Mellitus in India 167

59. Bodhini D, Radha V, Deepa R, et al. The G1057D polymor- 78. Rema M, Ponnaiya M, Mohan V. Prevalence of retinopathy
phism of IRS-2 gene and its relationship with obesity in in non insulin dependent diabetes mellitus in southern
conferring susceptibility to type 2 diabetes in Asian Indians. India. Diab Res Clin Practice. 1996;24:29-36.
Int J Obes (Lond). 2007;31:97-102. 79. Dandona L, Dandona R, Naduvilath TJ, et al. Population
60. Vimaleswaran KS, Radha V, Mohan V. Thr54 allele carriers based assessment of diabetic retinopathy in an urban pop-
of the Ala54Thr variant of FABP2 gene have associations ulation in southern India. Br J Ophthal. 1999;83:937-40.
with metabolic syndrome and hypertriglyceridemia in 80. Ramachandran A, Snehalatha C, Satyavani K, et al. Preva-
urban South Indians. Metabolism. 2006;55:1222-6. lence of vascular complications and their risk factors in

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63. Pyke DA, Peace NW. Parity and incidence of diabetes. Lan- betic Retinopathy in Urban India: The Chennai Urban Rural
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65. Fitzgerald MG, Malins JM, O’Sullivan DJ, et al. The effect nephropathy in non-insulin dependant diabetes mellitus.
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67. Rao KVR, Hariharan RS, Seshaiah V. Body mass, sex, 85. Yajnik CS, Naik SS, Raut KN, et al. Urinary albumin excre-
distribution and parity among south Indian non-insulin- tion rate (AER) in newly-diagnosed type 2 Indian diabetic
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68. Snehalatha C, Ramachandran A. Insulin resistance in Asian mia. Diabetes Res Clin Pract. 1992;17:55-60.
Indians. Pract Diabetes Int. 1999;16:19-22. 86. Vijay V, Snehalatha C, Ramachandran A, et al. Prevalence
69. Mohan V, Sharp PS, Cloke HR, et al. Serum immuno­reactive of proteinuria in non-insulin dependent diabetes. J Assoc
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European Type 2 (non-insulin dependent) diabetic 87. Mohan V, Meera R, Premalatha G, et al. Frequency of
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70. Sharp PS, Mohan V, Levy JC, et al. Insulin resistance in centre in Southern India. Postgrad Med J. 2000;76:569-73.
patients of Asian Indian and European origin with non 88. Varghese A, Deepa R, Rema M, et al. Prevalence of microal-
insulin dependent diabetes. Hormone and Metabolic buminuria in Type 2 diabetes mellitus at a diabetes centre
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71. Ramachandran A, Snehalatha C, Satyavani K, et al. Meta- 89. Unnikrishnan RI, Rema M, Pradeepa R, et al. Prevalence
bolic syndrome in urban Asian Indian adults—a popula- and Risk Factors of Nephropathy in an urband south Indian
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Pract. 2003;60:199-204. (CURES). Diabetes Care. 2007;30:2019-24.
72. Deepa R, Shanthirani CS, Premalatha G, et al. Comparison 90. Mohan V, Premalatha G, Sastry NG. Ischaemic heart dis-
of ADA 1997 and WHO 1985 criteria for diabetes in south ease in south Indian NIDDM patients—A clinic based study
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73. Hoerger TJ. Screening for type 2 diabetes mellitus: a cost- 91. Mohan V, Deepa R, Rani SS, et al. Prevalence of coronary
effectiveness analysis. Ann Intern Med. 2004;140:689-99. artery disease and its relationship to lipids in a selected
74. American Diabetes Association. Screening for type 2 diabe- population in south India. J Am Coll Cardiol. 2001;38:682-7.
tes. Diabetes Care. 2003; 26: S21–S24. 92. Premalatha G, Shanthirani CS, Deepa R, et al. Prevalence
75. Mohan V, Deepa R, Deepa M, et al. A simplified Indian and risk factors of peripheral vascular disease in a selected
Diabetes Risk Score for screening for undiagnosed diabetic south Indian population: The Chennai Urban Population
subjects. J Assoc Physicians India. 2005;53:759-63. Study (CUPS). Diabetes Care. 2000;23:1295-300.
76. Ramachandran A, Snehalatha C, Vijay V, et al. Derivation 93. Ashok S, Ramu M, Deepa R, et al. Prevalence of neuropa-
and validation of diabetes risk score for urban Asian Indi- thy in type 2 diabetic patients attending a diabetes centre in
ans. Diabetes Res Clin Pract. 2005;70:63-70. south India. J Assoc Physicians India. 2002;50:546-50.
77. Mohan V, Sandeep S, Deepa M, et al. A diabetes risk score 94. Mohan V, Ravikumar R, Shanthirani S, et al. Intimal medial
helps identify metabolic syndrome and cardiovascular risk thickness of the carotid artery in south Indian diabetic and
in Indians—The Chennai Urban Rural Epidemiology Study non diabetic subjects: the Chennai Urban Population Study
(CURES – 38). Diabetes Obes Metab. 2007;9:337-43. (CUPS). Diabetologia. 2000;43:494-9.
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95. Enas EA, Yusuf S, Mehta JL. Prevalence of coronary artery 111. Prakash J, Sen D, Usha, et al. Non-diabetic renal disease in
disease in Asian Indians. Am J Cardiol. 1992;70:945-9. patients with type 2 diabetes mellitus. J Assoc Physicians
96. Balarajan R. Ethnic differences in mortality from ischaemic India. 2001;49:415-20.
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lesterol levels and incidence of atherosclerosis in Delhi. 2002;50:1135-9.
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4

1989;42:597-609. 114. Das S. Introduction. In: Das S (Ed). Low body weight type
99. Feinglass J, Brown JL, LoSasso A, et al: Rates of lower extre­ 2 diabetes mellitus. Technical series, Academic wing of
mity amputation and arterial reconstruction in the United Association of Physicians of India, Mumbai 1999. pp. 1-4.
States, 1979 to 1996. Am J Public Health. 1999;8:1222-7. 115. Sridhar GR, Venkateswarulu K, Satyanarayana V. Acute

100. Sridhar GR. Diabetes in India: snapshot of a panorama. focal neurological events in diabetes mellitus. Int J Diab
Current Sci. 2002;83:791-2. Dev Countries. 1993;13:73-5.
101. Dalal PM, Parab PV. Cerebrovascular disease in type 2 dia- 116. Pradeepa R, Anjana RM, Unnikrishan R, et al. Risk factor
betes mellitus. Neurol India. 2002;50:380-5. for microvascular complications of diabetes among south
102. Klein R, Klein BE, Moss SE, et al. The Wisconsin Epidemio- Indian subjects with type 2 diabetes mellitus- CURES -5.
logic study of Diabetic Retinopathy III. Prevalence and risk Diabetic technology and therapeutics. 2010;12(10):755-61.
of diabetic retinopathy when age at diagnosis is 30 or more 117. Patel JC, Dhirawani M, Despande NM. Causes of deaths
years. Arch Ophthalmol. 1984;102:527-32.
in diabetes mellitus. Proc World Congress on Diabetes in
103. Wang WQ, Tai-Pang LP, Lam KSL. Changing prevalence
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118. Verma NPS, Gupta PS, Krishna PS, et al. Mortality in diabe-
diabetes mellitus patients in Hong Kong. Diabetes Res Clin
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in developing countries RSSDI, October 30. 1976.
104. Kohner EM, Aldington SJ, Stratton IM, et al. Diabetic

119. Garg MK, Shah P, Virmani A. Retrospective analysis of hos-
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pital deaths in diabetics in last five years. Clin Proc Nizam’s
tes mellitus and associated risk factors. United Kingdom
Inst Med Sci. 1994;9 (Suppl.1):38.
Prospective Diabetes Study, 30. Arch Ophthalmology.
120. Sriniwasan G, Vrunda JP, Swarna Das, et al. Clin Proc

1998:116:297-303.
Nizam‘s Inst Med Sci. 1994;9 (Suppl.1):39.
105. Rema M, Saravanan G, Deepa R, et al. Familial clustering
of diabetic retinopathy in south Indian Type 2 diabetic 121. Sahay R, Rao PV, Anita BT, et al. Gender differences in
patients. Diabet Med. 2002;219:910-6. reduction of life expectation as related to morbidity at
106. Vijay V, Snehalatha C, Shina K, et al. Familial aggregation of deaths in diabetes mellitus. Clin Proc Nizam‘s Inst Med Sci
diabetic kidney disease in Type 2 diabetes in south India. 1994;9(Suppl.1):48.
Diabetes Res Clin Pract. 1999;43:167-71. 122. Das S, Mishra RK, Jena BB, et al. Mortality events amongst
107. Samanta A, Burden AC, Feehally J, et al. Diabetic renal dis- non-insulin dependant diabetes mellitus patients in orissa.
ease: differences between Asian and white patients. BMJ J Assoc Physicians India. 1991;39:519-20.
(Clin Res Ed). 1986;293:366-7. 123. Bhansali A, Chattopadhyay A, Dash RJ. Mortality in diabe-
108. Mather HM, Chaturvedi N, Fuller JH. Mortality and mor- tes: a retrospective analysis from a tertiary care hospital in
bidity from diabetes in South Asians and Europeans: North India. Diabetes Res Clin Pract. 2003;60:119-24.
11-year follow-up of the Southall Diabetes Survey, London, 124. Zargar AH, Wani AI, Masoodi SR, et al. Mortality in diabetes
UK. Diabet Med. 1998;15:53-9. mellitus – data from a developing region of the world. Dia-
109. Olivarius Nde F, Andreasen AH, Keiding N, et al. Epidemiol- betes Res Clin Pract. 1999;43:67-74.
ogy of renal involvement in newly diagnosed middle aged 125. Verma NP, Madhu SV, Jain SK. A 20 years followup of dia-
and elderly diabetic patients. Cross-sectional data from the betic patients. J Diab Assos India 1987:15-9.
population based study “Diabetes Care in General Prac- 126. Mohan V, Shanthirani CS, Deepa M, et al. Mortality rates
tice”, Denmark. Diabetologia. 1993;36:1007-16. due to diabetes in a selected urban south Indian popula-
110. Klein R, Klein BE, Moss SE. Prevalence of microalbuminu- tion—the Chennai Urban Population Study (CUPS—16).
ria in older-onset diabetes. Diabetes Care. 1993;16:1325-30. J Assoc Physicians India. 2006;54:113-7.
 Chapter 12
Epidemiology of
Complications of Diabetes
Viswanathan Mohan

Epidemiology of Complications

Chapter Outline
♦♦ Microvascular Complications ♦♦ Hypertension and Diabetes
♦♦ Macrovascular Complications ♦♦ Mortality Associated with Diabetes

iNTRODUCTION MICROVASCULAR COMPLICATIONS

The diabetes pandemic is rapidly spreading, and mostly People with diabetes have an increased risk of developing
affects developing countries like India. Recent figures microvascular complications, which, if undetected, can
have shown that 62.4 million people currently have have a devastating impact on quality of life and place
diabetes in India,1 and this number is projected to rise to a substantial burden on health care costs.3
101.2 million by 2030.2 Although by definition, diabetes
is characterized by elevated glucose concentrations; Diabetic Retinopathy
the impact of diabetes on both the health of individuals
Diabetic retinopathy is considered the most specific
and on the health care systems is almost entirely due to
complication of diabetes, and indeed one of the hall­marks
the long term “complications” of diabetes which affect
of the disorder. DR is leading cause of new onset blindness,
almost every system in the body, but particularly the
eyes, kidneys, heart, feet and nerves. In this chapter, we among adults in developed countries and rapidly
will consider the prevalence of various diabetes related becoming so in developing countries also. DR affects
complications with special reference to India. the microvasculature in the retina, or the back portion
Diabetes related vascular complications can be broadly of the eye. The classification of DR has evolved as our
classified as: understanding of the disease has improved. DR is classified
• Microvascular complications: It affects the retina into two major types or stages: non-proliferative diabetic
[diabetic retinopathy (DR)], kidney (diabetic nephro­ retinopathy (NPDR) and proliferative diabetic retinopathy
pathy) and the peripheral nerves (diabetic neuropathy). (PDR). The sight-threatening forms are PDR and diabetic
• Macrovascular complications: It affects the heart macular edema (DME, retinal thickening and/or exudates
(cardiovascular disease), brain (cerebrovascular dis­ within 500 µ of the macula).4 In the early treatment diabetic
ease) and the peripheral arteries (peripheral vascular retinopathy study (ETDRS) classification of DME was (1)
disease). focal/multifocal leakage, well-defined focal or multifocal
170 Epidemiology

areas of leakage from microaneurysms; (2) diffuse leakage, between the years 1991 and 2010. The prevalence of
defined as the presence of widespread leakage from the DR among 117,359 type 2 diabetic subjects was noted to
retinal capillary bed or any intraretinal microvascular be 37.9%.33
abnormalities (IRMA); (3) diffuse cystoid leakage, where There are very few population based studies on
diffuse leakage and the pooling of dye in the cystic complications of diabetes in India but the available data
spaces of the macula in the late phase of angiogram is suggests that the prevalence of DR is lower in Indians.34-37
seen; and (4) ischemic maculopathy.5 All these previous To overcome possible referral bias in data collected at
section

forms can be associated with areas of macular ischemia, tertiary care centers, the CURES (Chennai Urban Rural
4

which can be seen as areas of capillary loss or an increase Epidemiology Study) eye study was conducted. In phase 1,
in the foveal avascular zone. The presence of macular in the urban component of CURES, 26,001 individuals
ischemia is an important finding in deciding the type were screened by a systematic sampling technique from
of treatment needed, and to help in those patients who 46 out of 155 corporation wards representative of the
suffer a loss of visual acuity of unknown origin. In 2003, city of Chennai. Individuals aged more than or equal to
Wilkinson et al.6 proposed a DR severity scale and a DME 20 years were screened for diabetes using capillary
severity scale, which can be used clinically to accurately fasting blood glucose.38 In phase 2, detailed retinal
grade DR by ophthalmoscopy after dilatation of pupil. evaluation was performed in 1,364 known diabetic (KD)
A four-stage disease severity classification for DR includes subjects in addition to 354 newly detected diabetic (NDD)
two stages of early to moderate NPDR, a third stage of subjects. All the subjects underwent four-field stereo
severe non-proliferative retinopathy, and a fourth stage color photography and retinopathy was assessed by
ETDRS grading of the color fundus photographs.
of PDR. DME has been classified by Wilkinson et al.6 as
The CURES eye study is the first population-based
apparently present or apparently absent. Identification
study, which used four-field stereo retinal photographs and
of specific severity levels of DME is done according to its
ETDRS grading to document DR in the Indian population.
relationship to the center of macula (fovea), and this is
The overall prevalence of DR in urban population in
critical in deciding on laser therapy in DME, since it may
this study was 17.6%.37 Among the KD subjects, 20.8%
or may not cause visual disability in the early stages of the
had DR while 5.1% of NDD subjects had DR. Prevalence
disease. This classification makes clinical documentation,
of DME in the total diabetic population was 5.0%
and also communication among physicians easier.
(KD subjects, 6.3%; NDD subject, 1.1%).37 In another
The prevalence of DR in type 2 diabetic individuals
population-based study conducted at Hyderabad, the
have been studied in many populations and racial groups.
overall prevalence of DR in self-reported diabetic subjects
Table 12.1 summarizes data from various epidemiological
was 22.4%.34 A marginally higher prevalence of DR (26.8%)
studies conducted from 1980 till date.7-30 The prevalence of was reported among self-reported diabetic subjects aged
DR was reported to be 50.3% in the Wisconsin epidemio­ 50 years and older from Palakkad.36 The Sankara Nethr­
logical study of diabetic retinopathy, United States,7 33.6% alaya diabetic retinopathy epidemiology and molecular
in the Liverpool diabetic eye study, United Kingdom15 genetic study (SN-DREAMS) conducted in Chennai
and 29% in the Blue Mountain Eye study, Australia.13 reported a DR prevalence of 18%.39
Most of the earlier studies on prevalence of DR from A cross-sectional study of 26,519 diabetic subjects
India have come from diabetic centers, and there are few who participated in DR screening camps conducted in
population-based studies. At Dr Mohan’s Diabetes Specia­ rural areas in three Southern districts of Tamil Nadu,
lities Centre, a tertiary diabetes care centre in South India, reported the prevalence of DR to be 17.6% among
India based on a paper published in 1996 in a study self-reported diabetic subjects.40 Another community-
of 6,792 type 2 diabetic patients, the prevalence of DR based study carried out in a rural setting in Goa reported
was reported to be 34.1%, which included 30.8% with a DR prevalence of 15.4%.41 A recent population based
NPDR, 3.4% with PDR and 6.4% had DME.31 Another study conducted in rural areas42 called as the Chunampet
study was done in 3,010 patients attending a diabetic rural diabetes prevention project (CRDPP) was conceived
clinic at Chennai, which reported prevalence of DR to with the aim of obtaining epidemiological data in rural
be 23.7%.32 A more recent and much larger study from Tamil Nadu, in addition to implementing comprehensive
the same centre looked at data of patients registered in diabetes screening, prevention and treatment using a
the Diabetes Electronic Medical Record (DEMR) system combination of telemedicine and personalized care as a
 Epidemiology of Complications of Diabetes 171

Table 12.1: Prevalence rates of diabetic retinopathy in type 2 diabetes in different populations
Populations studied Author/Year Participants with Age (years) Prevalence of
diabetes (n) retinopathy (%)
Wisconsin Epidemiologic Study of Diabetic Retin- Klein et al. 19847 1,313 ≥ 40 50.3
opathy (WESDR), Southern Wisconsin, USA
San Antonio Heart Study (SAHS), San Antonio, Haffner et al. 19888 351 ≥ 40–74 44.3
Texas

chapter
San Luis Valley Study (SLVDS), San Luis Valley, Hamman et al. 19899 360 ≥ 40–74 35.3

12
Colorado
Beaver Dam Eye Study (BDES), Wisconsin, USA Klein et al. 199210 410 43–86 35.1
Taiwan, Republic of China Chen et al. 199211 527 ≥ 40 35.0
Wakefield, UK Nagi et al. 1997 12
991 ≥ 15 37.8
Blue Mountains Eye Study (BMES), Blue Moun- Mitchell et al.199813 252 ≥ 50 29.0
tain, Australia
Barbados Eye Study, Barbados, West Indies Leske et al.199914 615 ≥ 40 28.8
The Liverpool Diabetic Eye Study, Liverpool, UK Broadbent et al.199915 395 13–92 33.6
Melbourne Visual Impairment Project (VIP), McKay et al. 200016 233 ≥ 40 27.5
Melbourne, Australia
Proyecto Vision Evaluation Research (VER), West et al. 200117 899 ≥ 40 44.3
Nogales and Tucson, Arizona
Australian Diabetes, Obesity and Lifestyle study Tapp et al. 200318 703 ≥ 25 13.7
(AusDiab), Australia
Los Angeles Latino Eye Study (LALES), Varma et al. 200419 1217 ≥ 40 46.9
Los Angeles, USA
Sandy Lake Diabetes Complications Study, Hanley et al. 200520 133 14–79 23.3
Ontario, Canada
Multi-Ethnic Study of Atherosclerosis (MESA), USA Wong et al. 200621 778 45–85 33.2
USA Candrilli et al. 200722 850 ≥ 40 27.4
Singapore Malay Eye Study (SiMES) Wong et al. 2008 23
757 ≥ 40 35.3
Beijing Eye Study, China Xie et al. 200924 232 ≥ 40 37.1
Fiji Brian et al. 2010 25
222 ≥ 40 27.2
Taiwan Huang et al. 201026 356 ≥ 65 21.6
USA Zhang et al. 2010 27
1006 ≥ 40 28.5
Handan Eye Study (HES), Yongnian County, China Wang et al. 201128 387 ≥ 30 43.1
Norway Kilstad et al. 2012 29
264 ≥ 30 24.0
Laxa, Sweden Olafsdottir et al. 201330 263 > 50 34.6

model for reaching underserved rural areas in India. This DR in urban India based on clinic-based and population-
project was undertaken in a cluster of 42 villages in and based reports.31-37,39-42 All these studies confirm the lower
around Chunampet village in Tamil Nadu in Southern prevalence of DR among Indians.
India. A telemedicine van was used to screen for diabetes Earlier studies have reported on prevalence of DR at
and its complications. This study reported the prevalence the time of diagnosis in clinic population. The prevalence
of DR among diabetic subjects to be 18.2%. The population of retinopathy at the time of diagnosis of diabetes in
based studies show that approximately 1 in every Western populations varies from 20% to 35%43,44 compared
5 diabetic individuals may have DR, which is much lower to 6.7–7.3% in Indians.45,46 A familial aggregation study47
than the figures reported from the west. The exact reasons conducted in 438 consecutive newly diagnosed type 2
for this are not clear, but point to the role of genetic diabetic patients reported that 7.3% already had DR,
factors. Table 12.2 presents studies on the prevalence of detected by four-field retinal color photography at the
172 Epidemiology

Table 12.2: Prevalence of diabetic retinopathy in urban south India (population and clinic based)
Author/year City No. of diabetic Prevalence of diabetic retinopathy
subjects Overall (%) Among KD Among NDD
subjects (%) subjects (%)
Clinic based studies
Rema et al. 199631 Chennai 6,792 34.1 — —
Ramachandran et al. 199932 Chennai 3,010 23.7 — —
section

Pradeepa et al. 2011 33

Nine clinics in South India 2,26,228 37.9 — —
4

Population based studies

Dandona et al. 199934 Hyderabad 124 — 22.4 —
Rema et al. 200035 Chennai 152 19.0 20.8 5.1
Narendran et al. 200236 Palakkad 260 — 26.2 -
Rema et al. 200537 Chennai 1,715 17.6 23.1 10.9
Raman et al. 200939 Chennai 1,414 18.0 20.6 6.0
Rani et al. 2009 40
Three Southern districts of Tamil 26,519 17.6 17.8 10.2
Nadu
Vaz et al. 201141 Goa (Rural) 130 15.4 — —
Mohan et al. 2012 42
Chunampet (Rural) 1,001 18.2 22.2 6.6

(KD: Known diabetic subjects; NDD: New detected diabetic subjects)

time of diagnosis of diabetes. It also documented that i.e. PDR and DME, all the risk factors need to be evaluated
familial clustering of DR was three-times higher in siblings and managed early and aggressively.
of type 2 diabetic subjects with DR compared to those As individuals even with sight-threatening retinopathy
without DR. In another study done on 249 Mexican- may not initially have any symptoms, lifelong evaluation
American type 2 diabetic siblings of probands with DR of retinopathy by retinal screening of all diabetic indivi­
showed that the severity of DR aggregates in families.48 duals is necessary.56 To prevent diabetes related visual
A study done in Australia in newly detected diabetes49 impairment, good control of diabetes is essential. Surgical
showed a prevalence rate of 9.9%. interventions include laser photocoagulation therapy and
The CRDPP study carried out in rural Tamil Nadu42 vitreoretinal surgery. Two large randomized, controlled
showed that the prevalence of DR increases significantly clinical trials demonstrated that laser photo­coagulation
with duration of diabetes. Even among diabetic subjects therapy decreases visual disability due to DR by 90% if
with less than 1 year duration, the prevalence of DR was instituted at the correct stages.57,58 In a clinic-based study
found to be 6.6%. The onset and progression of DR may be conducted in 261 eyes of 168 type 2 diabetic subjects
influenced by many systemic factors, including hormonal, who underwent Pan Retinal Photocoagulation (PRP) at
immunologic, genetic and ocular factors. There is growing Chennai, 73% eyes maintained more than or equal to 6/9
evidence that DR is not only related to hyperglycemia vision at 1-year follow-up. Visual acuity at baseline and
and disorder of diabetes50 but also to other risk factors duration of diabetes played a significant role in deter­
such as systolic blood pressure (SBP), urinary albumin, mining the post PRP visual acuity.59 Vitreous surgery
body mass index (BMI) and serum lipids, although these may allow visual rehabilitation in many eyes that are
have not been consistent in all studies.51-55 Increased otherwise untreatable.
prevalence of retinopathy with increased duration and
severity of hyperglycemia is well known. The CURES eye Diabetic Nephropathy
study clearly demonstrated that every 5-year increase in Diabetic nephropathy is the leading cause of end-stage
duration of diabetes, increases risk of diabetes retinopathy renal disease (ESRD) worldwide.60 This is due to the fact
by 1.89 times and for every 2% increase in HbA1c, risk of that (1) the prevalence of diabetes is increasing rapidly
DR increases by factor of 1.75 times.37 Hence, to decrease and (2) diabetic patients now live longer and are hence
the threat of developing sight-threatening forms of DR, more likely to develop diabetic kidney complications.61
 Epidemiology of Complications of Diabetes 173

Table 12.3: Prevalence of diabetic nephropathy in clinic and population based studies in India
Author Place Year Prevalence
Clinic based studies
Gupta et al.67 New Delhi 1991 Microalbuminuria: 26.6%
John et al.70 Vellore 1991 Microalbuminuria: 19.7%
Diabetic nephropathy: 8.9%
Yajnik et al.71 Pune 1992 Microalbuminuria: 23.0%

chapter
Vijay et al.72 Chennai 1994 Proteinuria: 18.7%

12
Mohan et al.73 Chennai 2000 Macroproteinuria with retinopathy: 6.9%
Varghese et al.74 Chennai 2001 Microalbuminuria: 36.3%
Pradeepa et al.33 Nine sites in India 2011 Microalbuminuria: 25.5%
Population based studies
Unnikrishnan et al.75 Chennai 2004 Microalbuminuria: 26.9%
Overt nephropathy with diabetic retinopathy:
20.2%
Mohan et al.42 Chunampet (Rural) 2012 Microalbuminuria: 24.3%

Nephropathy affects 20–30% of type 1 and type 2 diabetic 6.9% to 18.7%70,72,73 and microalbuminuria ranging bet­
patients.62 It has been estimated that 20% of type 2 diabetic ween 19.7% and 36.3%.33,42,67,70,71,74
patients reach ESRD during their lifetime.63 Compara­ The CURES is perhaps the first population based study
tively, ESRD develops in 50% of type 1 diabetic individuals from India to report on prevalence of diabetic nephro­
with overt nephropathy within 10 years and in more than pathy. This study showed that the overall prevalence of
75% by 20 years.62 Kidney disease in diabetic patients is overt nephropathy was 2.2% while that of microalbu­
clinically characterized by increasing rates of urinary albu­ minuria was 26.9%.75 The CRDPP study documented
min excretion, starting from normoalbuminuria, which a prevalence of microalbuminuria among rural popu­
progresses to microalbuminuria, macroalbuminuria and lation in Tamil Nadu to be 24.3%, which is similar to
eventually to ESRD. Microalbuminuria is the earliest that found among the urban population in CURES.42
clinically detectable stage of diabetic kidney disease Table 12.4 compares the prevalence of microalbumi­
at which appropriate interventions can retard, or reverse nuria and nephropathy in different populations.42,75-81 The
the progression of disease.64 In addition to its being the prevalence of overt nephropathy in Indians appears to be
earliest manifestation of nephropathy, album­inuria is a lower, while that of microalbuminuria is comparable to
marker of greatly increased cardiovascular morbidity and that reported in other populations.
mortality for patients with either type 1 or type 2 diabetes.62 Duration of diabetes and glycemic control along with
Earlier studies on migrant Asian Indians had sugges­ other risk factors have been reported to be associated with
ted a high prevalence of microalbuminuria and kidney microalbuminuria in clinic based studies.73,74 In the CURES
disease compared to native European population.65,66 population based study, glycated hemoglobin, duration
However, studies from India do not support these obser­ of diabetes and SBP were independently associated with
vations. Gupta et al. in 199167 reported the prevalence of diabetic nephropathy.75 Timely intervention at this stage
microalbuminuria in North India among type 1 diabetic can halt or reverse the progression of kidney damage.
subjects to be 7.6%. Prevalence of microalbuminuria in Development of persistent proteinuria is an ominous
type 1 diabetic subjects in South India was reported to be sign as glomerular filtration rate progressively declines
28.2%.68 In a study conducted in Mumbai, among type 1 after that.
diabetic patients the prevalence of microalbuminuria was There is substantial evidence that good diabetes control
12.5%.69 Data of patients registered in the DEMR system is important to prevent diabetic nephropathy; however,
between the years 1991 and 2010 showed that the preva­ some patients develop the disease despite good control
lence of microalbuminuria among 1,633 type 1 diabetic and others escape despite poor control. This suggests the
patients was 20%.33 Table 12.3 presents the prevalence role of genetic factors in susceptibility to nephropathy.82
rate of diabetic nephropathy from referral centres in Familial clustering of nephropathy has repeatedly
India33,42,67,70-75 with persistent proteinuria ranging from been observed in various populations studied and for
174 Epidemiology

Table 12.4: Prevalence of nephropathy and microalbuminuria in type 2 diabetes in different population based studies
Author Place/Year No. of diabetic Prevalence of Prevalence of
subjects microalbuminuria (%) macroalbuminuria (%)
Gatling et al.76 Poole, UK, 1988 450 — 7.0
Klein et al. 77
Wisconsin, USA, 1993 798 25.9 16.0
Neil et al.78 Oxford, UK, 1993 246 15 4
Collins et al.79 Western Samoa, 1995 162 22.0* 3.9*
section

17.2** 6.3**
Wirta et al.80 Finland, 1995 188 29* 4*
4

27** 7**
Bruno et al.81 Italy, 1996 1,574 32.1 17.6
Unnikrishnan et al.75 Chennai, India, 2007 1,716 26.9 2.2
Mohan et al.42 Chunampet, Rural 1,001 24.3 3.2
India, 2012

* NDD: New detected diabetes

** KD: Known diabetes

multiple etiologies of kidney disease.83-85 A threefold to People with diabetic neuropathy in developing countries
ninefold greater risk of ESRD is observed in individuals incur huge costs largely due to foot complications.
with a family history of ESRD.86 In South India, to study It is estimated that in India, diabetic subjects with foot
whether there was a familial clustering among subjects problems incur almost four-times higher costs as com­
with or without diabetic kidney disease and their siblings, pared to diabetic patients without foot problems.90
Vijay et al.87 compared sib-pairs, matched for age, Most studies of diabetic neuropathy have been done
duration of diabetes and the level of metabolic control in western populations91,92 and there is paucity of data in
and reported that there was strong familial clustering of developing countries, particularly from India, where a
diabetic kidney disease in patients with type 2 diabetes, large proportion of the population walks with bare feet.
which was independent of the familial clustering of Most studies published on prevalence of DN in India have
diabetes. This strongly suggests a genetic component, been clinic-based32,33,93-95 (Fig. 12.1). In a south Indian
although environmental exposures are still important. type 2 diabetic clinic population the prevalence of neuro­
It is imperative that nephrologists and primary care pathy was 27.5% in Chennai in the year 1999.32 In another
physicians recognize that individuals who have relatives study conducted in 2002 at Chennai a prevalence of
with advanced nephropathy are themselves at high 19.1% was reported.93 A surprisingly high prevalence
risk for subsequent kidney disease, proteinuria and of 64.1% was reported in a diabetic outpatient clinic at
atherosclerotic cardiovascular complications. Bangalore in the year 2006.95 In a multicentric study from
Chennai, Madurai, Vellore and Delhi, conducted in a
Diabetic Neuropathy total of 1,319 type 2 diabetic patients, the total prevalence
Diabetic neuropathy affects nearly 50% of all diabetic of neuropathy was reported to be 15%. The prevalence
subjects and is considered to be the main cause for rates in different centers vary from 9% to 17% as shown in
morbidity.88 The intensity and extent of the functional Figure 12.1.94 At Dr Mohan’s Diabetes Specialities Centre,
and anatomical abnormalities of diabetic neuropathy are a prevalence of 33.1% was reported among diabetic
parallel to the severity and duration of hyperglycemia. subjects.33 This variation could be attributed to the demo­
Among individuals with diabetes, neuropathy is a graphy of the study population and different diagnostic
common cause of morbidity (painful polyneuropathy, criteria employed (pinprick perception, clinical signs
neuropathic ulceration) and mortality (due to autonomic and symptoms, quantitative sensory tests or electrodiag­
neuropathy) presenting a huge economic burden to nostic tests).
society.89 Neuropathy occurs with the same frequency in The clinical diabetic neuropathies, found at a teac­
both type 1 and type 2 diabetes, suggesting a common hing hospital in Cuttack, were in the following order of
etiologic mechanism based on chronic hyperglycemia. frequency: distal symmetrical sensorimotor neuropathy,
 Epidemiology of Complications of Diabetes 175

chapter
12
Fig. 12.1: Prevalence of neuropathy in clinic based studies among Fig. 12.2: Prevalence of coronary artery disease. The Chennai urban
type 2 diabetes32,33,93-95 population study106

cranial mononeuropathy, mononeuropathy multiplex, MACROVASCULAR COMPLICATIONS

autonomic neuropathy.96 Among the young diabetic pati­
ents seen in North-Eastern India, peripheral neuropathy Macrovascular disease is considered to be a deadly trian­
was found to be common (43.5%) in patients with fibrocal­ gle, comprising coronary artery disease (CAD), periph­
culous pancreatic diabetes.97 eral vascular disease (PVD) and cerebrovascular disease
There are very few population based studies on dia­ (CVD) leading to high morbidity and mortality.
betic neuropathy in India. Pradeepa et al.98 from Chennai
in the CURES study reported the age-standardized preva­
Cardiovascular Disease
lence of neuropathy to be 13.1% (KD: 13.6% vs NDD Diabetes mellitus is an independent risk factor for cardio­
11.2%) whereas the crude prevalence rate was 26.1% (KD: vascular disease. Unlike type 1 diabetes, type 2 diabetes
27.8% vs NDD 19.5%). Vaz et al.41 reported a prevalence of has a higher risk for cardiovascular disease, the prevalence
60% among diabetic subjects in a rural Goa population. of which is estimated to be two-fold to four-fold higher
A prevalence of 30.9% was reported in the CRDPP study compared to non-diabetic subjects.104 This is because
in rural Tamil Nadu.42 type 2 diabetes is a component of the metabolic cluster,
It has been reported that along with the presence of which is associated with other risk factors like insulin
external risk factors, some associations have also been resistance, dyslipidemia, hypertension, abdominal obesity
noted between diabetic microvascular complications and proth­rombotic state.105
themselves.99,100 Thus the presence of DR itself may reveal In India, the cardiovascular disease epidemic appears
patients at risk of diabetic nephropathy,101 and neuro­ to overlap with the epidemic of diabetes. Indeed, of all
pathy.102 The CURES study identified some common risk diabetic complications, the most dangerous and life
factors for all the three microvascular complications of threatening is cardiovascular disease. Prevalence of CAD
diabetes. These were age, glycated hemoglobin, duration of is also increasing at an alarming proportion in India. The
diabetes and serum triglycerides. This study also reported present prevalence of this disease among Indians ranges
that the association between DR and nephropathy was from 9% to 14%.106,107 In a clinic based study, we showed
stronger than that with neuropathy.103 Approaches to that 17.8% of diabetic subjects had CAD and that the
prevention of neuropathy include tight control of hyper­ prevalence increased with age and duration of diabetes.
glycemia and regular foot examination. Most treatments Thus, nearly 40% of the subjects with diabetes duration
available for diabetic neuropathy focus on relieving pain. more than 20 years had CAD.108
176 Epidemiology

Coronary artery disease was documented in 21.4% of proximal usually the infra-renal aorta, iliac and superficial
diabetic subjects compared to 14.9% in IGT and 9.1% in femoral arteries with sparing of distal vessels whereas in
subjects with normal glucose tolerance in the Chennai diabetic patients, occlusive lesions occur in more distal
urban population study (CUPS) as shown in Figure 12.2.106 vessels such as the tibialis and peroneals.120,121 This may
There is a lot of evidence to suggest that Asian Indians partly explain the fact that PVD is frequently asymp­
have an increased risk for CAD compared to other ethnic tomatic in people with diabetes and may present with
groups.109,110 The overall prevalence of CAD in CUPS was ischemic foot ulceration or gangrene with no previous
section

11%,106 which is ten-times higher than that reported in claudication. Distal disease may allow a reasonable blood
4

1960s.111 These figures are also much higher than that supply to be maintained to the large muscles involved in
reported in other ethnic groups and are similar to figures walking while critically impairing the supply to the skin
reported in migrant Indians.109,112 of the feet. Coexistent neuropathy and exercise limitation
The CUPS has also provided interesting data on due to other diseases may also mask the symptoms
carotid intimal medial thickness (IMT), which could be of PVD. Thus, regular screening by `physical examination
considered as a surrogate for atherosclerosis. The mean and Doppler examination is necessary to identify people
IMT of diabetes subjects was significantly higher than with PVD.
those of the non-diabetic subjects.113 At any age point, the
The prevalence of PVD has been reported to be low
IMT values of diabetic subjects were significantly greater
among Asians ranging between 3% and 6%.32,122-125 Earlier
than among non-diabetic subjects. Prevalence of carotid
clinic-based reports have suggested that PVD is less
atherosclerosis, defined as carotid IMT more than or equal
common among Indian diabetic patients in the United
to 1.1 mm in CUPS, was 1% among non-diabetic subjects,
Kingdom126 and South Africa.127 In a clinic-based study,122
while it was 20% among diabetic subjects.113 In the same
we reported the prevalence of PVD in South Indian diabetic
population, arterial stiffness was also greater among
patients to be 3.9%. In another study in south Indian
diabetic subjects compared to their age and sex matched
type 2 diabetic subjects, PVD was present in 4%, which
non-diabetic counterparts, and endothelial function was
also severely impaired among diabetic subjects.114 These included 18 subjects with gangrene.124 In a large clinic
studies confirm that diabetic subjects are more prone based study, the prevalence of PVD was reported to be
to atherosclerotic changes compared to non-diabetic 3.9% among 123,563 type 2 diabetic subjects in a tertiary
subjects and that it tends to occur at a younger age. diabetic center southern India.33
The various risk factors identified for cardiovascular The Chennai urban population study (CUPS) was
disease include aging, smoking, strong family history the first population based study to report on prevalence
of CAD and diabetes, and lifestyle related factors like of PVD, and this study reported that the prevalence of
physical inactivity and stress. The INTERHEART study PVD was 6.3% among diabetic subjects compared to
conducted in 52 countries demonstrated that over 90% 2.7% among non-diabetic subjects123 confirming that the
of the population attributable risk of acute myocardial prevalence of PVD is low in our population. Comparative
infarction (AMI) was accounted for by nine modifiable risk figures in the Western population range from 17.2%
factors, which included smoking, diabetes, hypertension, to 45%.128,129 While the low prevalence of PVD may be
abdominal obesity, the ApoB/ApoA1 ratio, psychosocial attributed to the sample size, selection criteria and other
stress, decreased intake of fruits and vegetables, physical factors; this could also reflect true differences in ethnic
inactivity and regular alcohol consumption.115-118 CAD can susceptibility.130 Some of the factors to explain the low
often be asymptomatic and early screening is therefore prevalence of PVD in Indian diabetic patients could be:
beneficial in preventing major events. Since diabetes is (1) the age of onset of type 2 diabetes occurs 10–15 years
considered as a cardiovascular risk equivalent,119 routine earlier in Indians (2) the number of patients above the age
screening for CAD in diabetic patients is justified. of 70 years is low (3) duration of diabetes is shorter and
(4) the lower prevalence of smoking in Chennai (17.5% in
Peripheral Vascular Disease men and 0% in women in this study).131 The prevalence
Peripheral vascular disease (PVD) in diabetic patients of PVD rises sharply above 70 years of age,122,123 and hence
differs from that seen in non-diabetic individuals. In we may see a marked increase in PVD in the next decade
non-diabetic individuals, the sites of occlusion are more or so, with increased longevity of our diabetic patients.
 Epidemiology of Complications of Diabetes 177

Cerebrovascular Disease and major morbidity combined, including myocardial

infarction, angina, strokes and amputation.
Strokes are the third commonest cause of mortality in
Studies from India have shown that diabetes and
diabetic patients after heart disease and cancer, and
hypertension coexist in type 2 diabetes. About 50% of
represents a major health burden in our country.132
diabetic individuals in India have hypertension.141,142
Strokes are an important cause of morbidity and mortality,
The prevalence of hypertension was significantly higher
and important health and an economic burden. Patients
in subjects with diabetes (44.6%) in a study conducted
with diabetes have a higher frequency of stroke, and

chapter
in urban and rural Moradabad in the year 1998.143
also a poorer prognosis after a stroke.133 A recent study

12
A study conducted in Srinagar to assess the prevalence of
has reported that the prevalence of stroke is more than
double among type 2 diabetic subjects compared to the hypertension in newly diagnosed type 2 diabetic patients
general population.134 Prevalence rates of stroke vary from reported that overall 42% had hypertension.144 Recently,
one study to another. However, there has been a definite the screening India’s twin epidemic (SITE) cross-
increase in the prevalence and incidence of strokes in India sectional study conducted in 10 Indian states145 reported
over the last 30 years. Diabetes is one of the important that diabetes and hypertension were coexistent in 20.6%
risk factors for development of stroke.135 In a study patients, which demonstrates that the burden of diabetes
conducted in Asian Indians living in the United States, and hypertension is on the rise in India.
prevalence of stroke was significantly associated with It has been demonstrated that lowering blood pres­
systemic hypertension, diabetes CAD, ESRD and family sure in high-risk patients with diabetes can reduce
history of stroke, and myocardial infarction.136 complications and progression of disease.146 The United
Although medical and surgical therapies are available Kingdom prospective diabetes study (UKPDS) showed
for impending or recent onset stroke, prevention is that each 10 mm Hg decrease in mean SBP was asso­
the most effective strategy in reducing the ravages of ciated with 12% reduction in the risk for any complica­
cerebrovascular disease. To curb the rising trend of stroke tion related to diabetes, 15% reduction in deaths related
in India, the two principal risk factors, i.e. hypertension to diabetes, 11% reduction in myocardial infarction and
and diabetes mellitus need to be tightly controlled. 13% reduction in microvascular complications.147
Change in dietary habits to reduce intake of fat and
salt and a complete cessation of smoking and chewing MORTALITY ASSOCIATED WITH DIABETES
tobacco needs to be encouraged.
There are as yet no large scale Indian studies on mortality
in patients with type 2 diabetes and most available studies
HYPERTENSION AND DIABETES
are from clinical settings, and therefore have shown
Hypertension is a common comorbid condition in different results.
diabetes and vice-versa. Diabetes and hypertension A retrospective study from Srinagar148 reviewed medi­
coexist in approximately 40–60% of patients with type 2 cal records of 133,374 patients admitted from January
diabetes.137 Both type 1 and type 2 diabetic patients are 1987 to December 1996. Of the 9,627 individuals who
prone to develop hypertension which accelerates cardiac, died, 269 had diabetes. Infections contributed to over
renal, and cerebral dysfunctions, which are leading causes 30% of the deaths, which was followed by chronic renal
of death.138 Hypertension substantially increases the risk failure (30%) and CAD (16%). In another study done by
of both macrovascular and microvascular complications the same group,149 of the 234,776 admissions to the centre,
in diabetes. The hypertension in diabetes study-I (HDS-I) 16,690 (7.11%) died, of whom 741 had diabetes mellitus as
conducted to determine the prevalence of hypertension mentioned in the death certificate. The causes contributing
in newly diagnosed type 2 diabetic patients reported to death were infections (40.9%), chronic renal failure
that 39% of the patients were hypertensive at the time of (33.6%), CAD (16.9%), cerebrovascular disease (13.2%),
diagnosis of diabetes.139 The HDS-II,140 which looked at chronic obstructive pulmonary disease (6.9%), acute
the role of hypertension as a risk factor for macrovascular renal failure (6.2%), malignancy (4.2%), hypoglycemia
and microvascular complications in type 2 diabetes, (3.5%) and diabetic ketoacidosis (3.4%). Another study
reported that hypertensive patients had a greater incidence of 440 patients with diabetes related mortality seen at a
of death from diabetes-related, mainly cardiovascular tertiary care centre in North India also revealed the most
events and a greater incidence of diabetes-related death common cause of death to be infections (46.5%) followed
178 Epidemiology

complications include dietary modification, which inclu­

des substituting: (1) saturated fat, dietary cholesterol
and transfatty acids with non-hydrogenated mono and
polyunsaturated fats (2) high glycemic foods with low
glycemic foods, increasing fiber intake and reducing salt
intake. In addition to tight diabetes control, good control
of blood pressure and dyslipidemia and other measures
section

such as tobacco cessation and increasing physical activity

4

would also help to prevent macrovascular complications.

ACKNOWLEDGMENT
I would like to thank Dr R Pradeepa for her contribution
to the studies presented in this chapter and for her help in
preparation of this chapter.

Fig. 12.3: Causes of mortality rates in diabetic and non-diabetic FURTHER READING
individuals. The Chennai urban population study151
1. Ramachandran A, Snehalatha C, Viswanathan V. Burden of
type 2 diabetes and its complications: The Indian scenario.
by CAD (17.4%), chronic renal failure (9.7%), stroke Current Science. 2002;83:1471-6.
2. Madhu SV. Diabetes complications: overview In: Chanda­
(6.0%), diabetic ketoacidosis (3%), hyperosmolar coma
lia HB, Sridhar GR, Das AK, Rao PV, Madhu SV, Mohan V,
(2.2%) and hypoglycemia (2.1%). Analysis of the causes of (Eds). RSSDI Textbook of Diabetes Mellitus, 3rd Edition.
death in diabetic versus non-diabetic hospital inpatients New Delhi: Jaypee Brothers Medical Publishers; 2014 pp.
showed infection, CAD and chronic renal failure to be 771-785.
more frequent in diabetic subjects.150 3. Rema M, Pradeepa R. Eye disease in Diabetes. In: Chan­
dalia HB, Sridhar GR, Das AK, Rao PV, Madhu SV, Mohan
A follow-up of the original CUPS cohort in Chennai
V. (Eds). RSSDI Textbook of Diabetes Mellitus, 3rd Edition.
showed that the overall mortality rates were nearly New Delhi: Jaypee Brothers Medical Publishers; 2014. pp.
threefold higher (18.9 per 1,000 person-years) in people 935-955.
with diabetes compared to non-diabetic subjects (5.3 per 4. Mohan V, Venkatraman JV, Pradeepa R. Epidemiology
1,000 person-years, p = 0.004).151 The hazard ratio (HR) of cardiovascular disease in type 2 diabetes: the Indian
scenario. J Diabetes Sci Technol. 2010;4:158-70.
for all cause mortality for diabetes was found to be 3.6
compared to non-diabetic subjects. This study also showed
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 Chapter 13
Epidemiology of
Diabetes in Migrant Groups
Venkata Ranga Rao Kodali

Migration and Diabetes

Chapter Outline
♦♦ Overseas and Transcontinental Studies ♦♦ Risk Factors for Diabetes in Migrants
♦♦ Migration within India ♦♦ Other Migrants and Special Populations
♦♦ Type 1 Diabetes and Other Forms

BACKGROUND this was under stressful conditions unlike the economic

migration of peaceful times. The communication to their
Migration is not a new phenomenon as trade on the land native population has become easy with advent of commu­
and overseas dislocated populations from centuries. nication networks as is the transglobal food transportation
Continental drift separated genetically similar popul­ to satisfy the migrant palate.
ations. These lead to people’s separation and sometimes
People arrived from India and Africa into France;
isolation from native people. Migrants settle in the new
Chinese, Japanese, Hispanics and Indians to the United
environment with entirely different geographic charac­
States; Greeks to Australia and Sri Lankans, Indians and
teristics, flora and fauna. The weather especially sunlight
the French people to Canada. In colonial times, people
is a primary factor that has profound effects on the sleep
were transported mostly for manual work in agriculture
patterns and in the current context physical activity. The
and industry. This was restricted to professions in need.
global epidemic of diabetes with a significant increase
in Asian Indians irrespective of their location suggests The most amazing character of the Asian Indians is their
ethnicity is a non-modifiable risk factor for disease. strong adherence to their culture and culinary.
The incidence of diabetes is increasing in migrant Asian Diabetes in Asians was investigated in Fiji,1 British
Indians across the globe. Guyana,2 Malaysia,3 Mauritius,4 Netherlands,5 Singapore,6
The word migration immediately makes one think of South Africa,7 Tanzania,8,9 UK,10-12 and West Indies.13
moving to the western world. This is true in the jet age. Diabetes in Indian immigrants is gaining public health
However, there is also a rural to urban migration, urban importance in the USA as the number of Asian Indians
to rural, transurban and transrural migration within India. has swollen in the last 2 decades.14-18 There is one study
In the recent times, there has been generational migra­ in migrants within India.19 Almost all studies addressed
tion such as two or three generations living in one country type 2 diabetes while few looked at other forms. Table 13.1
and subsequent generation moving to entirely different summarizes the recent studies on prevalence of diabetes
country such as Indians from South Africa, Kenya and in migrants. The previous studies have been reviewed in
Uganda moving to the UK and elsewhere. Sometimes the last edition and also elsewhere.20
 Epidemiology of Diabetes in Migrant Groups 185

Table 13.1: Studies on the prevalence of diabetes in migrant Indians*

Country and Year (Ref) Age (years) Prevalence % Population screened
Transcontinental migrants
UK8 > 15 7.4 Bhatia community in UK
Tanzania > 15 15.6 Bhatia community in Dar es Salaam
Tanzania9 > 15 9.1 Hindu community
Mauritius4 > 25 12.4 Hindu Indians

chapter
10.4 Creoles

13
11.9 Chinese
USA17 > 18 30.3 Indo-Guyanese
South Africa7 > 25 9.8 Indians with type 2 diabetes
USA13 > 20 7.6 Indians with type 2 diabetes
UK10 > 20 11.2/8.9 Asians (mostly Punjabi)
2.8/4.3 Europeans
Migrants within India
Karnataka19 > 30 9.1 Rural migrants from Coastal Andhra
2.2 Native Kannada population
Ascertained IDDM**
Leicester, 198611 0–15 0.054 Asians
0.099 Caucasians
Coventry, 199012 > 20 0.12 Asians
0.16 Europids
*Results for men/women; ** Expressed for 1000. For other previously published reports see reference 20.
(IDDM: Insulin-dependent diabetes mellitus)

OVERSEAS AND chewing tobacco and access to health care, which are all
TRANSCONTINENTAL STUDIES environmental influences. The author had concluded
that diabetes was largely a genetic condition in the Asian
United Kingdom migrants. Indicators of obesity are absent more often in
Indians than in White Europeans.22
A large number of publications on heart disease and
In an elegant study, Bhatnagar et al.23 compared
diabetes appeared in the UK literature but there are no
the body mass and other risk factors for diabetes and
recent epidemiological screening data. In Coventry, Asian cardiovascular disease in Punjabi’s in Southall, UK with
Indian (70% Punjabi’s) men had four times higher preva­ their siblings living in Punjab, India. They found low
lence of diabetes than white men, and women had two insulin sensitivity and high fasting glucose concent­
times higher prevalence than white women. At younger rations in migrants. It is possible that over nutrition after
age the prevalence in migrant men was higher than migration could lead to low insulin sensitivity in Asian
women, however, the prevalence was similar in both Indians. The Fiji Indian data do not show that migrants
sexes above the age of 60 years, possibly due to death at are over obese.
younger age of Asian men. Interestingly, there was no Health survey of ethnic minorities24 reports a
significant difference in the body mass indices between 2.5–5 times risk of diabetes in Asian Indians. Diabetes UK
the migrants and the whites.10 in association with South Asian Health Foundation have
A recent review21 proposed etiopathogenetic mecha­ recognized the alarming trends in diabetes as shown in
nisms in the development of diabetes and its complica­ the self-reported surveys and made recommendations
tions in British South Asians, analyzed the problems for further research.25 At least three studies are relevant
of mig­rants in relation to access to resources and the in the context of surveys for known diabetics. Mather and
effects of psychosocial stress and economic deprivation. Keen used house-to-house survey methodology and filled
Most hypotheses were discussed with focus on acquired in a questionnaire about known diabetics in Southall,
obesity, physical inactivity, vitamin D deficiency, smoking, West London.26 The communities were European and
186 Epidemiology

Indian, the latter largely Punjabi Sikhs. A small portion of MIGRATION WITHIN INDIA
the Indians were from secondary migration. Even there,
known diabetes was 3.8 times higher in Asians than Euro­ Like in any other developing country the migration in
peans. Questionnaire surveys in Eluru-urban and rural27 India is largely from rural to urban. An unusually large
and hotel employees in New Delhi, India28 confirmed rural migration started about 5 decades ago from the
similar prevalence rates of known diabetes in adults above South Indian State of Andhra Pradesh, India to the rural
the age of 40 years. villages in the neighboring state of Karnataka. This is for
section

cultivating the virgin lands when an opportunity had

come for farming as a new water dam was constructed
4

Other Countries across the river “Tungabhadra”, India. The staple diet of
A new study supported by Centers for Disease Control the migrants was refined rice while the natives were sub­
and Prevention (CDC) reports a very high prevalence of sisting on “jowar” and “millets”. Preliminary dietary and
self-reported diabetes in migrated Guyanese of Indian nutritional assessments showed that migrants consume
descent in Schenectady, New York.17 This data in this less fiber and high fat diets while the natives consume
unique population generation has an estimated preva­ high fiber and low fat diets. Higher prevalence of
lence of 30.3% compared to 16% in non-Hispanic diabetes is seen in the adult rural to rural migrants from
whites. Currently, 25% of the foreign born non-Hispanic Coastal Andhra Pradesh (9.6%) than the native Kannada
Americans are Indians with 50% living in the Western population (2.2%). Body mass indices were higher in
states and almost all in urban areas. A larger number are the migrants as is the prevalence of hypertension.19
graduates and had higher incomes compared with non- The prevalence of diabetes is high in urban southern
Hispanic whites but were also living in poverty, however Karnataka.33 The prevalence rate of known diabetes in
these census data combine Asians and Pacific Islanders.29 the rural villages in the coastal belts of Andhra Pradesh is
Such geographic migration into urban environs is a also high.27 Genetic differences between the populations
risk factor for non-communicable diseases (NCD). Indian living in the adjacent states within India cannot be ruled
migrants constitute more than 50% of the 6 million popu­ out. This migration was under normal circumstances.
lations of the Fiji Islanders. In the 1980 survey by Zimmet’s High prevalence of impaired glucose tolerance in Indians
has been reported from several countries.4,9,34
group, prevalence rates of diabetes did not differ between
rural and urban groups of Indians while an urban or
Type 1 Diabetes and Other Forms
rural gradient existed in Melanesian men and women.1
One of the early reports of high prevalence of diabetes There is little published information on Type 1 Diabetes.
in migrants in South Africa comes from Durban and Cape Properly ascertaining registers and records of 20,267
Town.30 The crude rates from Cape Town were higher in Asian and 44,268 white Caucasian children (0–15 years)
Indians > colored > Malay > Bantu > White. In Singapore, living in Leicester city and surroundings, Samanta et al.
the equation is Indians > Malays > Chinese.6 Similar noted a low prevalence of diabetes (0.54 vs 0.99 per 1,000)
pattern is seen in Malaysia.31 Diabetes is common in Indian in migrant children.11 Similar low rates are reported from
communities in Tanzania9 but these are considerably West Yorkshire (0.36/1,000)35 and Coventry.12 Type 1
long-settled and well-established migrants and some diabetes in migrant Asians is considered to have increased
are secondary migrants from Muscat. Data on the length to the frequency as in the native British populations
of stay or comparisons with the native populations are after migration.36 In the NCD study in Mauritius, the
missing to provide more useful information. A further study incidence is 1.9/100,000 for people below the age of
in Bhatia community, which migrated from Tanzania, 19 years and is similar in Asians, Chinese and Creole.37
shows lesser prevalence of diabetes upon migration to
the UK.8 Data on diabetes in second generation mig­ Complications of Diabetes
rants and secondary migrants are not available except Achieving glycemic control in migrant Asians is as diffi­
from Singapore where the rise in diabetes in Indians is cult as in India. Many migrants lack understanding of
relatively less than in the Chinese.32 the health services, which is completely different from
 Epidemiology of Diabetes in Migrant Groups 187

their native countries. Therefore, it is not surprising to diets and were leaner and had lower body mass.1 Leptin
observe higher glycated hemoglobin (HbA1c%), hyper­ estimations in ethnic groups in Mauritius point to its
tension, dyslipidemias, coronary artery disease, neuro­ role in insulin resistance syndrome.42 Central obesity is
pathy and reno-retinal disease early in the course. often seen in migrant Asians in the UK.43 Body composi­
Type 2 diabetics from India living in Malaysia had tion and body mass indices are not identical in terms of
high concentration of acute inflammatory markers even their risk for cardiovascular disease and diabetes. This
with normoalbuminuria while the Chinese had higher is apparent at low body mass indices.

chapter
concentrations only in presence of microalbuminuria.38

13
Indians in South Africa had diabetic retinopathy detected Genetics and Family Histories
at longer duration of diabetes than the native Africans.39
In the clinical experience of the author, the ethnic mino­ The migrants have varied genetic background; work
rities underutilize resources, do not have an in-depth in a highly competitive environment and in the midst
of plenty in terms of nutrition. The proposed theory
understanding of the resources for diabetes and the
of thrifty genotype continues to be relevant.44 Positive
minorities have a callous approach and non-compliance.
family history for diabetes was more frequently noticed in
However, foot disease is not seen frequently. The early
Indians than Chinese and Malays in Singapore.6 Indians
mortality of diabetics from cardiac and cerebrovascular
had the tradition of marriages within the caste and comm­
events might account for such an apparently low
unities. Among the inbred Tamilians living in South
prevalence.
Africa, the rates were alarmingly high; 37% of 365 adults
were diabetic.30 Studies in India show a positive family
RISK FACTORS FOR DIABETES IN MIGRANTS
history in one-third of the diabetic propositi, high paternal
Gender influence and higher conjugal diabetes.45 Its contribution
to “western diseases” both within India and upon migra­
The preponderance of men over women in the diabetes
tion has not been explored. Multi-generation family
prevalence surveys is noted in most studies within and
studies in migrants are likely to yield useful information.
outside India, though this is not a universal finding.
The Schenectady study, though had a small sample
The differences can be accounted for by the location of
confirms the unforeseen health risks in the migrant
the center, i.e. rural or urban and economic background of
Indian diaspora.17 A clear evaluation of the differences in
the patients attending the institutions in both the private
the sociocultural background of the migrants, education
and government sector.
of the community and integrating the ethnic minorities
into the mainstream are essential steps that will reduce
Stress and Lifestyle the risk factors and diabetes and its complications.
The stress at work is high in migrants in almost all
professions; the first generation migrants consider higher Acculturation and Duration of Stay
achievements and success in careers as a priority in life, in the Foreign Environment
simultaneously maintaining high cultural and ethnic
Studies showed that acculturation to the new locality
values, bondage and lifestyle. Such results are seen in
is associated with increase in risk factors46 for diabetes.
Asian immigrants to USA.29 Migrants are subjected to
A study in Arabs in America found lack of acculturation
environmental, climatic and linguistic challenges upon
increasing the risk.47 The study of diabetic women atten­
arrival. In the host societies, migrants have reduced
ding the Indian American Medical Association Health
entitlements.40
Clinic in Chicago provide insight into the incre­ased risk
for diabetes and poor glycemic control with increased
Physique and Physical Activity
duration of stay in the USA.16 The Multi-Ethnic Study of
Physical inactivity measured, as a score is associated with Atherosclerosis (MESA) and the recently started Mediators
high 2-hour post-glucose concentrations in Indians in of Atherosclerosis in South Asians Living in America
Mauritius.41 The rural urban differences are not significant (MASALA) are addressing the risk factors with special
in Fiji Indians; the rural people were consuming low fat focus on atherosclerosis.48,49
188 Epidemiology

Dietary and Metabolic Factors and Others diabetes. In an experimental study, aborigines living
in the urban environment in Australia spent 3 months
Hyperlipidemias, obesity, lack of physical activity, low
in a hunter-gatherer lifestyle. After 3 month follow-up,
fiber intake are noted in Asian immigrants.50 Low intake insulin response to glucose improved on reverting to their
of antioxidants, lack of vitamin D, chemical toxins such lifestyle.58 Migration and trade to Australia has started
as nitrosamines in the chewing nut are some of the risk much earlier than the British invention. The tamarind
factors associated with diabetes. trees, Indian Dingo, some linguistic similarities such as
section

native names ending with vowels have a lot more commo­

OTHER MIGRANTS AND nality to South Indian tradition. Macassan traders are
4

SPECIAL POPULATIONS believed to have arrived to the northern part of Australia

where they are established. A recently published genome-
In the context of diabetes epidemiology, special popula­
analysis confirms the possibility of Indian arrival and
tions refer to those with unusual prevalence rates. Isola­
gene flow about 4,000 years ago.59
tion from the mainstream of development and accul­
turation leaves some communities to follow their own
Do Migrants Influence Diabetes Rates
traditional lifestyles. Studies in Pima Indians in Arizona
and the Nauru Islanders in the Pacific reveal interesting
in the Local Population?
data. Genetic admixture is anticipated over generations as
Obesity and diabetes are common in Nauruans51 and inter-racial breeding occurs and hence the changes in
in Pima Indians.52 There is a high probability of inbreeding diabetes. More interesting is the data from Leeds, UK.60
because of their geographic and cultural isolation. Similar It is believed that exposure to infections early in
admixture due to inbreeding is likely in Asian Indians childhood is different from that of late exposure. Migrant
settled abroad. Nearly half the Pima Indians above the population in the area is considered a marker of diversity.
age of 35 years have diabetes. The evolution of diabetes Their presence increases the chance of exposure of the
in them shows the impact of Western acculturation. indigenes to infections. Bodansky’s group showed that
The Pimas in the Sierra Madre Mountains in Mexico and the incidence of type 1 diabetes is less in those indigenes
those in Arizona are genetically similar with dissimilar where there is a diversity of population. In simple terms,
rates for diabetes. They have moved apart a few centuries this hygiene hypothesis reveals that migrants have
ago. The Pima Indians in the Arizona-Mountain Region influenced the disease in the indigenes. Thinking along
of the US switched to the Western dietary and sedentary similar lines—the Indian diets are much popular and
lifestyle from the beginning of the century when they gave becoming the favorite dishes for the Caucasians in the
up farming. Now, they have the highest prevalence rates UK. The long-term impact of this on obesity and other
of diabetes. Renal failure is six times more common in diseases will be an area of study. During a survey19 in
them than in the non-Hispanic white Americans. Nauru Karnataka state, India, the author noticed that the native
is a small island in the Pacific about 8 square miles in populations as well as the migrants are shifting from
size with a population of 12,000. The energy intake is their high fiber staple diets to polished and milled rice.
more than 3,000 kcals/day. The people have high body Diabetes in reverse migrants, genome analysis of
mass indices and the prevalence of diabetes is more than Australian aborigines and diabetes in the later generation
30%. In the Polynesian Island populations—Western migrants are potential areas for future exploration.
Samoa and Tuvalu,53 where the people’s levels of physical
activity is high the prevalence rates are low, as expected. Further Reading
Impaired glucose tolerance and diabetes are reaching 1. Ramaiya KL, Kodali VRR, Alberti KGMM. Epidemiology of
alarming proportions in both urban and rural settings.54,55 diabetes in Asians of the Indian subcontinent. Diabetes/
In the surveillance period of 1994–2002, the age-adjusted Metabolism Rev. 1990;6:125-46.
prevalence was double for the American Indians (native) 2. Parslow RC, McKinney PA, Law GR, et al. Population
and Alaska natives than among the US whites.56 mixing and childhood diabetes. Intl J Epidemiol 2001;
30:533-8.
Aboriginal populations in Australia have three times
3. Kandula NR, Diez-Roux AV, Chan C, et al. Association of
higher prevalence of diabetes. The prevalence of diabetes acculturation levels and prevalence of diabetes in the
is not higher in people born overseas compared with multi-ethnic study of atherosclerosis (MESA). Diabetes
Australians.57 Urbanization leads to high prevalence of Care. 2008;31:1621-8.
 Epidemiology of Diabetes in Migrant Groups 189

4. Pugach I, Delfin F, Gunnarsdóttir E, et al. Genome-wide data atherosclerosis in South Asians living in America study and
substantiate Holocene gene flow from India to Australia. the multi-ethnic study of atherosclerosis. Metabolic Syndr
Proc New York Acad Sci. 2012; Published online before Relat Disord. 2010;8:157-64.
print January 14, 2013, doi: 10.1073/pnas.1211927110. 16. Rahman A, Kuzawa C, Leonard W. The effect of time lived
in the US on risk factors for type II diabetes among Indian
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Section 5

ETIOPATHOGENESIS OF
DIABETES MELLITUS
Section Editor: Hemraj B Chandalia
 Chapter 14
Etiology of Diabetes:
An Overview
Ashok Kumar Das, BB Tripathy

Etiology of Diabetes

Chapter Outline
♦♦ Type 1 (A) Diabetes Mellitus ♦♦ Gestational Diabetes Mellitus
♦♦ Type 2 Diabetes Mellitus ♦♦ Other Types

Introduction Table 14.1: Etiological classification of diabetes mellitus

I. Type 1 diabetes (β-cell destruction, usually leading to absolute
Diabetes mellitus (DM) comprises of a group of metabolic
insulin deficiency)
disorders that share the phenotypic expression of hyper­
A. Immune-mediated
glycemia. Several causative factors are known to induce
B. Idiopathic
hyperglycemia and diabetes, yet in the vast majority of
patients the etiology of the disorder is nebulous, highly II. Type 2 diabetes (may range from predominantly insulin resist-
ance with relative insulin deficiency to a predominantly insulin
complex, confusing by and large unclear. These cases
secretory defect with insulin resistance)
fall into two major classes previously known as Juvenile
III. Other specific types of diabetes
onset and Maturity onset types of diabetes. In yester years,
A. Genetic defects of β-cell function characterized by mutations in:
these were termed insulin-dependent diabetes mellitus
1. Hepatocyte nuclear transcription factor (HNF) 4α (MODY 1)
(IDDM) and non-insulin dependent diabetes mellitus
(NIDDM). More recently based on etiopathogenesis, the 2. Glucokinase (MODY 2)
terms “type 1” and “type 2” are applied to classes of 3. HNF-1α (MODY 3)
diabetes with clinical pictures similar to the above. Etiolo­ 4. Insulin promoter factor (IPF) 1 (MODY 4)
gically based new classifications tables were introduced 5. HNF-1β (MODY 5)
by American Diabetes Association (ADA) in 1997 which 6. Mitochondrial DNA
has been almost totally endorsed by World Health 7. Proinsulin or insulin conversion
Organization (WHO) consultation (Table 14.1). B. Genetic defects in insulin action:
Patients of type 1 diabetes mellitus (T1DM) category
1. Type A insulin resistance
are characterized by presence in the serum of auto­
2. Leprechaunism
antibodies for some constituents of pancreatic beta cells
3. Rabson-Mendenhall syndrome
as well as some genetic markers such as human leukocyte
antigen (HLA) class II genes mainly DR, DQ isoforms. 4. Lipoatrophic diabetes
Contd...
194 Etiopathogenesis of Diabetes Mellitus

Contd... In a proportion of patients with similar phenotypic

C. Diseases of the exocrine pancreas: expression (Type 1B) neither the serological markers of
1. Pancreatitis autoimmunity nor the genetic markers can be identified
2. Pancreatectomy (Chapter 15). The proportion of such cases is higher
3. Neoplasia (up to 30%) in non-Caucasian populations such as in
4. Cystic fibrosis India and Japan. The etiology (except age and ethnicity)
5. Hemochromatosis and pathogenesis of this subtype of type 1 diabetes are yet
section

6. Fibrocalculous pancreatopathy to be worked out.

5

D. Endocrinopathies: Along with type 1B, no specific etiology has so far

1. Acromegaly been determined in the type 2 class of diabetes mellitus
2. Cushing’s syndrome (T2DM). The etiology of T2DM discussed here are more or
3. Glucagonoma less speculative.
4. Pheochromocytoma Yet a plethora of predisposing factors has been eluci­
5. Hyperthyroidism dated that facilitate the genesis and progress of diabetes
6. Somatostatinoma in the modern society. These belong to two major catego­
7. Aldosteronoma ries: (1) Genetic and; (2) Environmental.
E. Drug- or chemical-induced; pentamidine, nicotinic acid,
glucocorticoids, thyroid hormone, diazoxide, β-adrenergic
agonists, thiazides, phenytoin, α-interferon, protease inhibi- Type 1 (A) Diabetes Mellitus
tors, clozapine, beta-blockers
F. Infections:
Genetic Factors
1. Congenital rubella Familial aggregation of type 1 diabetes has been recog­
2. Cytomegalovirus nized for many years, and 10–13% of newly diagnosed
3. Coxackie
children have a first-degree relative affected with type 1
G. Uncommon forms of immune-mediated diabetes:
diabetes. The major type 1 diabetes susceptibility genes
1. “Stiff-man” syndrome
are found within the HLA class II region on chromosome
2. Anti-insulin receptor antibodies
6 (IDDM1). HLA genes are thought to contribute as much
H. Other genetic syndromes sometimes associated with
as 50% of the genetic risk for type 1 diabetes. Remarkably,
diabetes:
whereas several HLA genotypes confer increased risk,
1. Down’s syndrome
2. Klinefelter’s syndrome
other HLA genotypes confer protection. In Caucasians,
3. Turner’s syndrome
islet autoimmunity and type 1 diabetes are strongly asso­
4. Wolfram’s syndrome ciated with HLA DR3-DQ2 and DR4-DQ8 haplotypes,
5. Friedreich’s ataxia and recent studies from different European countries
6. Huntington’s chorea have confirmed that the HLA DR3-DQ2 or DR4-DQ8
7. Laurence-Moon-Biedl syndrome genotype is associated with the highest diabetes risk and
8. Myotonic dystrophy DR2-DQ6, DR5 confer a protective effect.
9. Porphyria
10. Prader-Willi syndrome Environmental Factors
IV. Gestational diabetes mellitus (GDM)
A series of evidences support a critical role of exogenous
(MODY: Maturity onset diabetes of the young; DNA: Deoxyribonucleic
acid) factors in the initiation of autoimmunity in susceptible
subjects. These are:
Some sets of DR-DQ genes set the stage for auto­ • The fact that less than 10% of individuals with HLA-
immune destruction of β-cells of the pancreatic islets conferred diabetes susceptibility do progress to clinical
at different paces in otherwise susceptible individuals disease
resulting ultimately in absolute insulin deficiency and • A less than 40% concordance of type 1 diabetes among
insulin dependence (Type 1A). monozygotic twins
 Etiology of Diabetes: An Overview 195

Table 14.2: Viruses implicated in the etiology of type 1 diabetes

Virus Involvement of genetic factors Remarks
• RNA Viruses:
Picornaviridae Not determined Evidence from epidemiological studies, anecdotal reports and isolated
Coxsackie B virus viruses causing diabetes in infected animals
Retroviridae Not determined Association of beta cell-specific expression of retroviral gene with
Retrovirus development of human autoimmune IDDM

chapter
Togaviridae Not determined Possible association with autoimmune IDDM, especially congenital

14
Rubella virus rubella syndrome
Paramyxoviridae Yes Possible induction of islet-cell autoantibodies
Mumps virus
Reoviridae Not determined Association with islet autoimmunity
Rotavirus
• DNA Viruses:
Herpesviridae Not determined Association with autoimmune IDDM
Cytomegalovirus
Epstein-Bar virus Not determined Possible induction of autoimmune IDDM
(RNA: Ribonucleic acid; DNA: Deoxyribonucleic acid; IDDM: Insulin-dependent diabetes mellitus)

• A more than ten-fold difference in the disease inci­ of type 1 diabetes in certain geographical areas with
dence among Caucasians living in different parts of high incidence of the disorder. Early exposure of infants
Europe to cow’s milk protein may be an important factor in
• A several-fold increase in the incidence over the last the initiation of the β-cell destructive process in some
50 years, and individuals.2 Firm evidence for involvement of any of the
• Migration studies indicating that the disease increased above are yet to be at hand (Chapter 15).
incidence in population groups who have moved from Age, sex, geographical distribution and seasonal peaks
a low-incidence to a high-incidence region. in the incidence of T1DM are of considerable interest.
Unfortunately, the exact nature of the putative trigge­ Known for long as Juvenile diabetes due to occurrence
ring environmental factor as yet remains elusive. especially in young children it is now known to involve as
Viruses are considered to be the most likely candi­ many below 20 years of age as above. Some 30% cases may
dates in this regard; Rubella, Coxsackie B, Mumps and present at age 30 years and above.
cytomegalovirus are uppermost in the counting along There may be a minor male predilection in some
with some others (Table 14.2). areas with high incidence at younger age, but by and
The possible mechanism for triggering of β-cell large the sex distribution is equal. Finland and Sweden
autoimmunity by viruses is discussed in Chapter 15. in North Europe, Great Britain in the West and Sardinia
Ingested materials such as toxic chemicals and some in the South, USA and some other countries with Europid
dietary factors have been incriminated. Chemical toxins Caucasian population are in the high incidence bracket
can precipitate T1DM through a variety of mechanisms. (Chapter 9), while in Japan and most Asian and African
They can poison β-cells directly and cause the destruction countries including India, T1DM is far less common.
of a critical mass of β-cells; alternatively, they can trigger Seasonal peaks in incidence of T1DM have been
autoimmune processes directed against β-cells; or observed in some cold countries at times of high viral
finally, they can augment the diabetogenic properties populations. This has been considered to be indicative of
of another agent, such as a virus, to hasten the onset of the role of virus in triggering of the immune mechanism.
clinical manifestations.1 Nitroso compounds, early infant Increase in the prevalence of type 1 diabetes in many
feeding with cow milk, certain cereals and trace elements countries is said to be due to rise in incidence of the
have been observed to be associated with development disorder in children around 5 years of age.
196 Etiopathogenesis of Diabetes Mellitus

Type 2 Diabetes Mellitus Both these basic factors are modulated by both genetic
and environmental factors. Possibly insulin secretory
Genetic Factors defect is relatively more dependent on genetic influence
Unflinching data on hereditary background and familial whereas insulin resistance may be more so on environ­
aggregation (Chapter 16) are highly indicative of the great mental promoters.
importance of genetic factors in the etiology of T2DM. “Insulin resistance” (Chapter 17) is a key component
Several lines of evidence suggest that genetic susceptibility of the metabolic syndrome (syndrome X of Reaven). This
section

plays a major role in the pathogenesis of T2DM. Hence, condition is extremely common in contemporary society,
risk varies widely across populations, from 5% or less in
5

more so in urban Indian population than in the West.

white Caucasian populations to 40% among Pima Indians Insulin Resistance, hyperinsulenimia, hypertension and
and some South Pacific Islanders. Further lifetime concor­ “obesity”, particularly truncal (abdominal) adiposity are
dance rates among identical twins may approach 100%. salient features of the syndrome.
Concordance increases with the duration of follow up, The explosive increase in the prevalence of diabetes
while more conservative estimates place random concor­ in India may be due to high prevalence of the metabolic
dance at nearly 60%. This concordance rate is at least syndrome in ethnic Indians. As established by Yajnik
double that of dizogotic twins or siblings, whose lifetime (Pune), Anoop Mishra (Delhi) and V Mohan (Chennai)
risk has been estimated at approximately 25–38%. Such adiposity is greater in ethnic Indians compared to Western
figures are consistent with major gene effect. population with equivalent body mass index (BMI).
Unfortunately, so far no major gene or genes with direct These findings can possibly be explained by Neel’s
association with the disorder have been discovered in hypothesis of thrifty genotype rendered detrimental by
spite of extensive gene testing and genome wide scanning progress as well as Barker’s hypothesis of thrifty phenotype.
for mutation or polymorphism. The most important promoters of metabolic syndrome
On the basis of available data, it has to be presumed and diabetes among environmental factors are identified
that the disorder is polygenic and multifactorial in origin. as the present “lifestyle” particularly in case of urbanite
Various genetic loci may be contributing for the suscepti­ and migrated Indians. Dietary practices and physical
bility of the subjects to T2DM and environmental factors activity are the two major wings of “lifestyle”. These topics
contribute to the rest (Chapter 21). are discussed in Chapters 30 and 33 respectively.
Most recently (2006) a fairly strong association of Principal changes in diet consist of greater consump­
T2DM with a gene identified as a variant of transcription tion of calorie dense food particularly fast foods with
factor line 2 (TCF7L2) has been discovered in the greater fat and refined carbohydrate contents and decrea­
laboratory of Kari Stephenson. More data and a practicable sed preference for natural fiber containing whole grain
laboratory test to detect the genotype are needed so that products, fruits and vegetables with low glycemic index.
strict measures can be adopted to prevent or delay the Increase in intake of higher total calories with higher
onset of diabetes in the subjects’ positive for the gene. proportion of fat particularly of those composed of
saturated and transfatty acids (hydrogenated vegetable
Environmental Factors oils) lead to obesity, carbohydrate intolerance and dyslipi­
While multiple genetic loci may operate in combination demia characteristic of type 2 diabetes. Changing to
and lend susceptibility to a large number of subjects, traditional diet has been shown to improve glucose
over and above environmental factors also operate to tolerance in Australian aboriginals and in Diabetes
determine the age of onset, severity and rate of progress Prevention Studies.
to a considerable extent. Developments in diabetogenesis
occur slowly to manifest characteristic lipid abnormality, Malnutrition in Utero
impaired fasting glucose (IFG), impaired glucose tole­ Studies in infants and children have shown that malnu­
rance (IGT) and finally diabetes may be diagnosed by trition “in utero” and retarded intrauterine growth was
plasma glucose tests in course of some 7–8 years. associated with impaired glucose homeostasis when a
As discussed in Chapter 16 basically decline in β-cell glucose challenge is given. Probably, fetal malnutrition
function frequently associated with insulin resistance alters the pancreatic β-cell function and decreases pan­
operate together leading to β-cell decompensation and creatic cell mass. Decompensation in the β-cell functions
dysglycemia in stages: IFG or IGT and diabetes mellitus. occur in subjects who enjoy prosperity in later life.
 Etiology of Diabetes: An Overview 197

Physical Inactivity observed that some 10–30% of subjects with clinical features
of type 2 diabetes were positive for particularly glutamic
The importance of adequate physical activity including
acid decarboxylase (GAD) 65ab and/or islet antigen
exercises in prevention and amelioration of diabetes
2 (IA-2) or islet cell antigen (ICA) 512 autoantibodies.
cannot be overestimated. Sedentary life style with constant
Taking lack of association of autoantibodies against
use of automobiles even for short distances, sitting long
insulin (IAA), ICA antibodies as well as differences in the
hours at office or study table and more so in watching
genetic make up, many such cases cannot be considered

chapter
television and using computers have transformed the lives
to be genuine T1DM although a variable proportion of this
of most urbanites starting from childhood throughout the

14
may be so. These, popularly known as latent autoimmune
rest of life. These practices have increased the incidence
diabetes in adult (LADA), have been suggested to be
of diabetes and ischemic heart disease with progress of
considered to have type 1½ diabetes (Chapter 7).
civilization.
Increase in physical activity by regular walking,
gardening and both endurance and resistance types of Newer Hormones
exercises have been found to prevent onset of diabetes Apart from insulin, incretins and certain counterregulatory
in several well planned prevention studies (Chapter 92). hormones that have been long known to play important
The glaring urban-rural differences in prevalence of roles in development and progression of diabetes,
DM are based more or less on these dietary and physical (Chapters 2 and 26) several newly discovered hor­mones
activity factors. such as Leptin, Resistin, Ghrelin and Adiponectin as
well as the cytokine tumor necrosis factor alpha (TNFα)
Obesity and BMI are now known to regulate certain metabolic pathways
The risk of diabetes is estimated to increase by 9% for and may facilitate or retard (adiponectin) the process
every increase in 1 kg weight. Obesity alone accounts for of diabetogenesis. These are specifically discussed in
nearly 64% of diabetes in men and about 74% in women. Chapter 18.
Also, independent of BMI, android distribution of fat and
waist circumference predicts diabetes risk. Weight gain Gestational Diabetes Mellitus
beyond 5 kg after the age of 18 years also predisposes to
Gestational diabetes mellitus is a common and special type
diabetes by a factor of 2–3. But weight is not an absolute
of diabetes that constitutes a class on its own. Diabetes
or essential factor for the development of type 2 diabetes.
diagnosed for the first time during pregnancy may exist
Obesity predisposes to both insulin resistance and β-cell
from before pregnancy in an asymptomatic state or may
failure; it inhibits insulin effect of suppression of endo­
have developed in course of pregnancy. Pregnancy can
genous glucose production and insulin-induced reduction
promote diabetogenesis in a number of ways (Chapter 79).
in large artery stiffness. The effect of exercise, regular and
In any case diabetes in pregnant subjects poses a
sustained physical activity was most protective in people
number of special problems that entitles it to be counted
with risk of type 2 diabetes such as positive family history
as a special class of the disorder. Etiology can be stated
of diabetes, history of hypertension and those with a
to be pregnancy over and above the predisposing factors
high BMI. Diabetes risk increases with physical inactivity
discussed mostly in case of type 2 diabetes. Pregnancy
regardless of BMI. Physical inactivity is an independent
occurring in already known patients with type 1 diabetes
risk factor for both diabetes and diabetes-related cardio­
is an entirely different matter.
vascular disorders. Inactivity increases insulin resistance
and poor glycemic control. Increased physical activity
and diet modifications when coupled with weight loss Other Types
(3–5 kg) leads to reduction in risk of diabetes in high risk
In covering etiology of type 1, type 2, LADA and GDM
individuals (both males and females) by almost 40–60%
this overview has dealt with some 98% of patients with
over 3–4 years (Chapter 91).
diabetes. Yet there are seven more types of monogenic
[maturity onset diabetes of the young (MODY)] dia­
Autoimmunity in Type 2 Diabetes
betes and scores of other conditions associated with
As laboratory tests for major islet cell autoantibodies in diabetes that are listed in Table 14.1. Other specific types
serum were standardized and widely available, it was of diabetes comprising of subdivisions “b” to “h” are in
198 Etiopathogenesis of Diabetes Mellitus

fact forms of secondary diabetes, the etiology of which is overlap between type 1 diabetes and MMDM as in case
evident from the captions. of LADA. But in case of MMDM, there are several positive
On the other hand disorders listed as class III A in and negative differences. The gross differences in clinical
the table are monogenic forms of primary diabetes that features are certainly attributable to gross malnutrition
are characterized by age of onset by 25 years and three in fetal life and throughout childhood. MMDM patients
generation vertical inheritance. Popularly known as are typically young at onset with low BMI, require insulin
MODY, this class of diabetes is specially discussed in treatment for glycemic control, have insulin resistance,
section

Chapter 6. and do not develop ketosis on withdrawal of insulin.4

5

Rest of the conditions in class III (B to H) in the list This presentation is an overview of several components
are discussed in Chapter 26 in Secondary Diabetes. Class of the diabetes syndrome while details on each can be
III B should preferably be not considered as secon­dary found in special chapters devoted to each of the important
diabetes while diabetes in the rest (III C to H) is obviously types of diabetes.
secondary.3 It has been suggested that in many of the
conditions the primary disorders may manifest glucose References
intolerance and diabetes of variable severity only in those
1. Wilson GL, LeDoux SP. The role of chemicals in the etiology
who are otherwise prone to develop diabetes, the etiology of diabetes mellitus. Toxicol Pathol. 1989;17:357-63.
of which has already been discussed. 2. Infant feeding practices and their possible relationship to
Lastly, we in this part of the world cannot ignore the the etiology of diabetes mellitus. American Academy of
factors related to genesis of malnutrition modulated dia­ Pediatrics work group on cow’s milk protein and diabetes
betes mellitus (MMDM). Although it has not found a place mellitus. Pediatrics. 1994;94:752-4.
3. Joslin EP, Kahn RC et al. Joslin’s Diabetes Mellitus, 14th
in the classification table, both ADA and WHO experts
edition. Lippincott Williams & Wilkins: USA;2005.
have dealt with it adequately over the background of the 4. Kanungo A, Samal KC, Sanjeevi CB. Molecular mechanisms
International Workshop held at Cuttack in 1995. Recent involved in the etiopathogenesis of malnutrition-modu­
research reveals that there is immunogenetically some lated diabetes mellitus. Ann N Y Acad Sci. 2002;958:138-43.
 Chapter 15
Pathogenesis and Metabolic
Alterations in Type 1
Diabetes Mellitus
Alok Kanungo, Priyanka Modi, Carani B Sanjeevi

Pathogenesis of Type 1 DM

Chapter Outline
♦♦ Epidemiology ♦♦ Autoimmunity
♦♦ Pathogenesis ♦♦ Immune Intervention Trials
♦♦ Genetics ♦♦ Metabolic Alterations in Type 1 Diabetes
♦♦ Environment and Type 1 Diabetes

INTRODUCTION of occurrence in childhood (between 5 years and 7 years

of age) and adolescent (occurring at or near puberty).6
Diabetes mellitus represents a heterogeneous group of Studies have shown that although women are at a
disorders, which is characterized by insulin insensitivity higher risk of autoimmune disorders, type 1 diabetes is
and/or hyposecretion. Type 1 diabetes is generally slightly more common in boys and men.7 In addition,
characterized by immune associated destruction of the incidence of type 1 diabetes varies as a function of
insulin producing pancreatic islet β-cells.1,2 CD4+ and seasonal changes, higher in winter months and lower in
CD8+ T-cells and macrophages infiltrate the pancreas summer months.8 The pathogenic mechanisms under­
and play a role in destroying the insulin producing islet lying these observations are not clear but recent studies
β-cells.3 Type 1 diabetes has largely been considered on development of type 1 diabetes associated autoim­
a disorder mainly in children and adolescents, but munity (formation of auto antibodies characteristic of
studies done over the past decade show that age is not a the disease) in the months to years before the onset of
restricting factor for symptomatic onset of the disease.4 symptomatic type 1 diabetes follows the seasonal synchro­
The symptoms associated with the disease are classically
nization theory to a certain degree.9 This concept supports
polyuria, polydipsia and polyphagia along with overt
the theoretical role of environmental agents initiating
hyperglycemia, which remains as diagnostic hallmark in
or driving the pathogenic processes in type 1 diabetes.
children and adolescent, albeit to a lesser extent in adults.
The global incidence and prevalence of type 1 diabetes
Another hallmark for type 1 diabetes is the immediate
dramatically varies with more than a 350 fold variation in
requirement of exogenous insulin replacement which is a
incidence among reporting countries.10,11 The incidence
lifelong treatment.
of type 1 diabetes globally follows a north-south gradient
but has exceptions to the rule. Countries like China, India,
EPIDEMIOLOGY
and Venezuela have an incidence of 0.1 cases/100,000
Type 1 diabetes is the most common chronic disease of per year;12 in contrast Finland averages a high incidence
childhood.5 One of the established fact about epidemio­ of 60 cases/100,000 per year with Sardinia coming second
logy of type 1 diabetes is that the disease shows two peaks at 40 cases/100,000 year. The worldwide incidence of
200 Etiopathogenesis of Diabetes Mellitus
section
5

A Figs 15.1A and B: Incidence of type 1 diabetes in children aged

0–14 years, by geographical region and over time. (A) Estimated glob-
al incidence of type 1 diabetes, by region, in 2011.11; (B) Time-based
trends for the incidence of type 1 diabetes in children ages 0–14 years
in areas with high or high-intermediate rates of disease
Source: (For Figure 15.1A) Whiting DR, Guariguata L, Weil C, et al. IDF
diabetes atlas: global estimates of the prevalence of diabetes for 2011
and 2030. Diabetes Res Clin Pract. 2011;94:311-21.
Source: (For Figure 15.1B) Berhan Y, Waernbaum I, Lind T, et al. Thirty
years of prospective nationwide incidence of childhood type 1 diabetes:
the accelerating increase by time tends to level off in Sweden. Diabetes.
2011;60:577-81.
Ehehalt S, Dietz K, Willasch AM, et al. Epidemiological perspec-
tives on type 1 diabetes in childhood and adolescence in Germany:
20 years of the Baden-Wurttemberg Diabetes Incidence Registry
(DIARY). Diabetes Care. 2010;33:338-40.
Knip M. Pathogenesis of type 1 diabetes: implications for incidence
trends. Horm Res Paediatr. 2011;76 (suppl 1):57-64.
TEDDY Study Group. The Environmental Determinants of Diabetes in
B the Young (TEDDY) Study. Ann NY Acad Sci. 2008;1150:1-13.

diabetes represents an epidemiological conundrum. increase.13,14 Moreover, genetic predisposition contributes

Wide variations are present between neighboring areas less now than in the past as a factor prerequisite for
in Europe and North America. Studies show that the developing type 1 diabetes.15,16 It should be noted that the
incidence of type 1 diabetes is on a steady rise in several rise in incidence has not been equal across all age groups.
countries and the number is going to double over in Significant increase in incidence is observed in individuals
the next decade. There is no underlying mechanism to of age group below 5 years17,18 as well as in young children
explain the geographical incidence and increased rates (age group 5–7 years) from high incidence countries
of type 1 diabetes but can be considered as attributes of (Figs 15.1A and B). A wide range of environmental influ­
environmental influences because genetic alterations ences have been shown to affect the epidemiology of type
or improvement in delivery rate of offsprings of type 1 1 diabetes. Developing models to study the influence
diabetes mothers could not alone explain the rates of of environment on type 1 diabetes including hygiene
 Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 201

chapter
15
A B C

Figs 15.2A to C: Physiological contributions to the pathogenic processes underlying type 1 diabetes
Source: Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464:1293-300.
Roep BO, Peakman M. Diabetogenic T lymphocytes in human type 1 diabetes. Curr Opin Immunol. 2011;23:746-53.
Atkinson MA, Bluestone JA, Eisenbarth GS, et al. How does type 1 diabetes develop? the notion of homicide or beta-cell suicide revisited.
Diabetes. 2011;60:1370-9.
Lehuen A, Diana J, Zaccone P, et al. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10:501-13.
(MHC: Major histocompatibility complex; APC: Activated protein C; VNTM: Variable number tandem repeat).

hypothesis19 and gut microbiome20 is gaining much very young children. However, the regeneration potential
importance. However, no specific agents with unequivocal is not seen in adolescent and adults.25 Most findings
influence on the pathogenesis have been identified.21 on the pathogenesis of type 1 diabetes are derived from
analysis of pancreatic samples, serum and peripheral
PATHOGENESIS blood lymphocytes obtained from the patients. The
study shows that functional defects in the bone marrow,
The pathogenesis of type 1 diabetes is a result of the thymus, immune system and β-cells collectively contri­
autoimmune destruction of insulin secreting pancreatic bute towards type 1 diabetes (Figs 15.2A to C).2,26-28
islet β-cells. The basis of this observation is the presence In mid 1980’s a model was developed combining the
of chronic inflammatory infiltrates, which affect the pan­ genetic, autoantibody and metabolic markers of type 1
creatic cells at the symptomatic onset of the disorder.21,22 diabetes to better understand the disease.29,30 According
The pancreas in patients with longstanding type 1 to the model, individuals with high genetic predisposi­
diabetes is devoid of insulin producing cells and remaining tion having a fixed number of β-cells when exposed to
β-cells are incapable of regeneration.23,24 However, recent environmental trigger induce β-cell autoimmunity. This
studies show that despite type 1 diabetes patient having develops islet reactive autoantibodies, which signals the
a small number of residual β-cells, the evidence of development of activated auto reactive T-cell capable
regeneration potential of β-cells is present in infants and of destroying β-cells resulting in the progressive loss of
202 Etiopathogenesis of Diabetes Mellitus
section
5

Fig. 15.3: History of type 1 diabetes: a 25-year-old concept

Source: Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986;314:1360-8.
Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358:221-9.

insulin secretory function. Thus, the symptomatic onset of at the onset of hyperglycemia,32 which may be related to
type 1 diabetes does not present until more than 80–90% subject age and other factors (e.g. body mass index or
of β-cells are destroyed and there is a marked gap physical activity). This could explain the insulin secretion
between the onset of autoimmunity and onset of diabetes. function being stable for long periods in patients with type
The model has thus been modified to update recent data 1 diabetes despite persistent autoimmunity.33 Decreased
(Fig. 15.3). Environmental factors may influence as early C-peptide response at least 2 years before onset,34 glucose
as in utero and continue during the first month to years fluctuations when approaching onset,35 and a linear rise
of life thus affecting the onset and continuity of β-cell and last minute surge in plasma glucose before onset
autoimmunity. Immune system development and natural are some of the metabolic changes of type 1 diabetes.36
turnover of β-cell may also contribute to pathogenic The loss of first phase insulin response is followed by
processes.27 Immune dysregulation facilitated by genetic glucose intolerance and a period of clinically silent
susceptibility results in early β-cell destruction, i.e. altered diabetes.37 Loss of β-cell mass may affect remaining β-cells
amino acids and auto antibodies associated with type 1 and other islet cells. This feature could have implications
diabetes. Studies show pancreatic β-cell may persist in in detecting and defining the decline and therapeutic
some individuals with type 1 diabetes for extended period interventions.38
of time unlike in established type 1 diabetes patients Improved understanding of prediabetes is critical for
with few to none β-cells.31 Another aspect is the degree further studies aimed at the prevention of type 1 diabetes.
of β-cell destruction for the symptomatic onset as recent Identification of gene controlling disease susceptibility,
studies suggest that 40–50% viable β-cells may be present understanding autoimmunity and the mechanisms
 Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 203

Table 15.1: Type 1 diabetes susceptible loci

Locus Chromosome Candidate genes
IDDM1(HLA) 6p21.3 HLADR/DQ
IDDM2(INS) 11p15.5 INSULIN VNTR
IDDM3 15q26 IL2
IDDM4 11q13 LRP5, FADD
IDDM5 6q25 mnSOD, SUMO4

chapter
IDDM6 18p12-q21 JK(kidd), ZNF236,

15
BCL2
IDDM7 2q31-33 NEUROD
IDDM8 6q25-27 –
IDDM9 3q22-q25 –
IDDM10 10p11-q11 GAD2
IDDM11 14q24.3-q31 ENSA, SEL-IL
IDDM12(CTLA-4) 2q31-q33 CTLA-4, CD28
IDDM13 2q34-q35 –
IDDM15 6q21 –
IDDM16(IGH) 14q32 –
IDDM17 10q25 –
IDDM18 1q42 –
5q31.1-33.1 IL12B
7q25 –
8q22-q24 –
16q22-q24 –
PTPN22 1p13 PTPN22(LYP)
SUMO4 6q25 SUMO4 Fig. 15.4: Position of the HLA subtypes on the MHC complex
Source: Wu YL, Ding YP, Gao J, et al. Risk factor and primary preven- (HLA: Human leukocyte antigen; MHC: Major histocompatibility
tion trials for type 1 diabetes. Int J BiolSci. 2013;9:666-79. complex).
(IDDM: Insulin-dependent diabetes mellitus; HLA: Human leukocyte
antigen).

underlying the loss of immune regulation, identifying developing type 1 diabetes. Monozygotic twins have a
environmental agents influencing the disease, are disease concordance rate of 30–50% and dizygotic twins
examples that would have an impact on the efforts toward have 6–10% risk. A recent study on twins shows that the
the prevention of the disease. It is also important to under­ percentage reaching concordance for type 1 diabetes
stand events following the symptomatic onset (e.g. rate would come close to being uniform.44 However, about 85%
of C-peptide loss, presence of residual β-cells) for they of new type 1 diabetes cases are found in individuals with
can help in the research to reverse the disease in patients no known family history for the disease.45 There is also a
already affected. difference in risk which is dependent on the parent with
the disease; mothers with type 1 diabetes have children
GENETICS with a risk of 2% for developing the disease whereas
children of type 1 diabetes father have a 7% risk for develo­
Type 1 diabetes is considered a mutlifactorial polygenic ping the disease.44
disorder with nearly 50 loci so far known to affect the The first type 1 diabetes susceptibility locus identified
disease susceptibility.39-42 Table 15.1 lists a few of the sus­ in human is the human leukocyte antigen (HLA) complex,
ceptibility loci. Familial aggregation and twins studies located on chromosome 6p21 also known as insulin
support the importance of both genetic and environ­ dependent diabetes mellitus (IDDM)1 locus (Fig. 15.4)
mental risk factors43 as individuals with a first degree is responsible for nearly half of the genetic susceptibility
relative with type 1 diabetes have 1 in 20 risk factor for risk that lead to type 1 diabetes.46 There are three classes
204 Etiopathogenesis of Diabetes Mellitus

of HLA genes and the class II HLA gene shows the either haplotype DQ6.4, DQ5.1, DQ4 or DQ6.3 contributes
strongest association with type 1 diabetes.44 The class for about 69% of all children and adolescents with type 1
II HLA gene loci namely DP, DQ and DR encode for the diabetes before the age of 18 years.50 In the general
heterodimer protein and each heterodimer consists of α population the same genotype has a 14% contribution
and β chains. The class I molecule has a transmembrane for type 1 diabetes. It should be noted that the haplotypes
protein coded by the HLA class I gene, which is bound DQ6.4, DQ5.1, DQ4 or DQ6.3 on their own are not
to β2 microglobulin. These are present on the surface considered as risk factors for type 1 diabetes but only when
section

of nucleated cells and help in presenting the antigen to together with DQ8 or DQ2.
The HLA class II allele, DQB1-0602 (haplotype
5

CD8+ T cells.
Human leukocyte antigen class II specific alleles at DRB1*1501 and DQA1*0102-DQB1*0602) provide disease
DRB1, DQA1 and DQB1 loci are strongly associated with resistance and has been studied in 20% of the population
type 1 diabetes. The mechanism of action of DR and DQ but is found in only 1% of patients with type 1 diabetes.44
in the etiology of type 1 diabetes is the peptide binding The HLA class I allele contribute towards the etiology
activity of HLA class II molecules in antigen presenting of type 1 diabetes in a much lesser capacity than HLA
cells (APCs) for the T lymphocyte peptide recognition class II. The class I contain HLA-A, HLA-B and HLA-C.
(CD4+ T-cells).48 Thus, the effect of MHC allelic variability HLA-B*39 is associated with lower age at the diagnosis
on type 1 diabetes risk can be explained by the differences of type 1 diabetes,51 HLA-A*02 increases the risk of type 1
in presentation of β-cell antigens either by promoting diabetes in individuals with the class II DQ2/8 genotype
anti-self-reactivity or by the failure to impart regulated and HLA-A*02:01 is found in about 60% of type 1 diabetic
immune response.47 The difference in ability of the DQ patients.
allele to predispose to diabetes may reside in particular Genes outside of the HLA region have been found to be
amino acids. Haplotypes carrying DQB1 allele, which associated with the risk for type 1 diabetes.39 The individual
encodes uncharged amino acid (alanine, serine or valine) effect of these genes is smaller compared to HLA-DQ
but they would contribute towards the risk of either islet
at position 57, increases the risk of type 1 diabetes while
autoimmunity or progression to clinical symptomatic
non-diabetogenic allele encode a negatively charged
onset in patients that have developed islet autoimmunity.
amino acid (aspartic acid).52 The amino acid residues at
Insulin is a major β-cell auto-antigen in type 1 diabetes.
position 57 and 70 of the DQB1 chain and at position 52 of
The insulin gene INS is mapped at chromosome 11 and
DQA1 chain may play a critical role in peptide binding and
contains a polymorphic region (VNTR) located near 5’
recognition by T-cells. X-ray crystallography studies show
promoter region of insulin gene (chromosome 11p15.5).
that residue at position 57 lie in a crucial position in the
This region was first reported in 1984 to be associated
groove of HLA molecule where the antigen to be presented
with type 1 diabetes in Caucasians.53 Mutation in the
is bound and thus modulates the antigen presentation. VNTR region is associated with susceptibility to type 1
Majority of type 1 diabetes patients carry the HLA- diabetes. The magnitude of risk and disease association is
DR3 or -DR4 class II antigen with 30% being DR3/DR4 related to the number of tandem repeats. Shorter repeats
heterozygous. In Caucasians the DR3/DR4 genotype (VNTR type I homozygous individuals) confers high risk
(haplotype DRB1*0401-DQB1*0302 and DRB1*0301- to type 1 diabetes whereas longer repeats (VNTR type III
DQB1*0201 confer greatest susceptibility) has the highest individuals) confers low risk and protects against type 1
risk for type 1 diabetes followed by DR4/DR4 and DR3/DR3 diabetes.54 VNTR regulates insulin expression levels in
homozygous genotype, respectively.44,46 The haplotypes the thymus by affecting the AIRE binding to its promoter
conferring susceptibility are usually found common region.54-56 Recent studies show that the medullary thymic
among different racial groups however few differences epithelial cell (mTEC) specific insulin depletion leads to
have been noted. The haplotype DR7-DQA1*0301- diabetes in animal model.57 Thus, VNTR type I promote
DQB1*0201 found in African blacks is susceptible to type 1 lower transcription of insulin and its precursors in the
diabetes whereas in white Caucasians the haplotype DR7- thymus, which reduces tolerance and develops type 1
DQA1*0201-DQB1*0201 is neutral and DR7-DQA1*0201- diabetes. Individuals with VNTR type III allelic variant
DQB1*0303 is protective in function. The DR3/DR4 show efficient destruction of insulin reactive T cells by
heterozygous genotype is also referred as DQ2/8.49 Studies negative selection in the thymus.
on patients with type 1 diabetes in Swedish population Protein tyrosine phosphate non-receptor type 22
show that the haplotype DQ8 or DQ2 in combination with (PTPN22) mapped at chromosome 1, is another non-HLA
 Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 205

gene influencing the risk for type 1 diabetes. The gene Programmed cell death 1 (PD-1) is an immuno­
codes for lymphoid protein tyrosine phosphate (LYP).58-60 inhibitory receptor of the CD28/CTLA-4 family and is
The protein functions as a negative regulator in the T-cell expressed on activated T-cells.96-98 PD-1 dysfunction in
receptor signaling by dephosphorylating Src kinases Lck peripheral immune tolerance may lead to autoimmune
and Fyn, ITAMs of the TCRζ/CD3 complex, ZAP-70, Vav, diseases. Studies from Non-obese diabetic (NOD) mice
valosin containing proteins and other important signaling show that type 1 diabetes onset accelerates in absence of
molecules.61 One hypothesis explains the mechanism PD-1. In humans, a single nucleotide polymorphism of

chapter
of action as a gain-of-function mutation, increasing PD-1(PD-1 7146G/A) is seen to be associated with type 1

15
PTPN22 activity which suppresses T-cell antigen receptor diabetes. Further research highlights the role of PC-1 in
signaling in developing thymocytes and results in lack of immune tolerance in pancreas.
negative selection of autoreactive T-cell. In contrast the c-kit is a tyrosine kinase receptor. It is an important
loss-of-function mutation results in lower threshold for hematopoietic stem cell marker involved in the develop­
autoreactive T-cell activation.62,63 This particular genetic ment and function of β-cell proliferation, maturation
factor may be of importance in promoting progression
and survival.99 Over expression of c-kit in mouse model
to diabetes in the islet autoantibody positive cases rather
improves β-cell proliferation and function and protects
than initiating islet autoantibody in them.
from developing diabetes. c-kit can be considered as a
Variations in the interleukin (IL) 2 receptor α-gene
biomarker for β-cell destruction and may factor in for
(IL2RA) region is another genetic risk factor in type 1
improved islet cell based therapies in insulin dependent
diabetes.64-66 The gene is mapped at chromosome 10 in
diabetes.
humans. The alpha chain of the IL2 receptor complex
(IL2Rα, CD25) is expressed on T-cell upon activation and
T regulatory cells. T regulatory cells depend on IL-2 for
ENVIRONMENT AND TYPE 1 DIABETES
their survival and growth. IL2Rα also enhances the affinity Much insight and knowledge has been gained on type 1
of IL-2 receptors.39,67 Recent studies show that IL2RA diabetes based on the studies on genetic susceptibility
susceptible genotypes in type 1 diabetes are associated and immune response. Due to the gap seen between
with lower levels of soluble IL2Rα.64-69 In vitro stimulated onset and detection of type 1 diabetes, the causative
peripheral blood mononuclear cells (PBMCs) from type 1 environmental factors affecting the disease are not well
diabetes individuals show lower levels of sIL2Rα.70 identified. The environmental factors play an important
Thus, even in the presence of normal T regulatory
role in the pathogenesis of diabetes as seen from studies
frequencies in type 1 diabetes,70 the IL2RA polymorphisms
on twins, increase in global incidence of the disease,
account for the functional defects in T regulatory cell
geographic variation of the disease. Various models have
compartment. It seems that genetic variability in IL2RA
been proposed to explain the environmental effect on the
gene results in severe autoimmune disease such as type 1
pathogenesis of the disease. The hypothesis accelerator-
diabetes but the mechanism and extent that sIL2Rα levels
overload points to environmental stress increasing insulin
mediate the condition differs significantly.
demand which overwhelms the islet cells and drives the
Another type 1 diabetes risk allele is the gene encoding
for the protein cytotoxic T lymphocyte associated β-cell destruction.75-77 According to the hygiene hypothesis,
protein 4 (CTLA-4) present in the IDDM12 region.71,72 environmental factors reduce the stimulation of immune
CTLA-4 plays an important role in the negative regulation system thus increasing the incidence of autoimmune
of immune response as loss of function of the gene results disease.78-80 Another hypothesis fertile field states that
in severe lymphoproliferative disorders.73 As seen with microbial infections can induce other antigens to act easily
other regions, the allelic variants of CTLA-4 are associated which results in autoreactive T-cells.81 Wasserfall et al.
with high risk to autoimmune disorders. put forth a threshold hypothesis which is a mathematical
Genome wide analysis studies on type 1 diabetes have model calculating the type 1 diabetes risk.82 However,
found over 40 loci affecting the risk of the disease, including there are numerous environmental factors that are
newly identified coding regions for immunoregulatory thought to influence the disease than explained by various
molecules such as IL-10.74 Such studies prove that autoi­ hypotheses. The setbacks faced to prove a hypothesis or
mmune diseases share many of the genetic factors and identify the agent associated with the disease can be due to
underlying pathways. low disease risk conferred by genetic and environmental
206 Etiopathogenesis of Diabetes Mellitus

factors identified till date. In a population with high known effects of coxsackie virus infection. In Japanese
risk HLA genotypes, most do not develop type 1 diabetes. population, hyper expression and viral presence leads to
Also taking into account are factors like age of disease an extremely aggressive form of type 1 diabetes.
onset, natural history of the disease and disease develo­
ping in families with no history of type 1 diabetes. Other Viruses
Environmental factor such as infectious agents are
known to influence type 1 diabetes despite there being Population studies on role of viruses such as rotavirus,
section

no direct evidence. Studies to relate viruses (several cytomegalovirus, parvovirus, retrovirus, Lungan virus,
types) with type 1 diabetes have resulted in weak non- encephalomyocarditis virus infection in type 1 diabetes
5

reproducible data83 and the effect of viral infection can onset has been inconclusive. Cases involving congenital
be considered either a trigger of islet autoimmunity or rubella virus infection have been shown to progress to
act as an accelerator for the present islet autoimmunity. type 1 diabetes. Vaccine against the rubella virus has
A study done on islet autoantibody by Diabetes and been efficient thus reducing the increase in incidence of
Autoimmunity Study in the Young (DAISY) showed diabetes occurring from infection.
enterovirus infection in children with persistent islet
autoantibodies, accelerated the progression of the disease Bacteria
and clinical onset of type 1 diabetes.84 Detailed study on
The relationship between diabetes and bacterial infection
the precise viral serotypes related to type 1 diabetes would
has not been extensively studied although the microbial
help in developing vaccines and other therapeutic agents.
flora in the intestine has been an important factor
affecting type 1 diabetes. Clinical trial studies show that
Enteroviruses development of type 1 diabetes may be influenced by
Enteroviruses belong to the picornavirus family. The administration of antibiotics and probiotics. Studies on
genetic component is non-enveloped RNA and these are NOD mice lacking MyD88 protein develop diabetes in
the common disease causing viruses. Gamble et al. in the absence of germs in the gut. Mycobacterium avium
196985 were the first to suggest the role of Coxsackie viruses paratuberculosis (MAP), is recently discovered as risk
in type 1 diabetes. Studies done by Yoon et al.86 in mouse factor for diabetes. Presence of the bacteria has been
models proved the role of CVB4 in infecting β-cells thus found in blood cultures from type 1 diabetes patient.
causing insulitis and diabetes susceptibility. They also Polymorphism in SLC11A1 gene has been associated with
were successful in isolating a strain of CVB4 virus from the presence of MAP genome in type 1 diabetes patients.
a child with recent onset of type 1 diabetes.87 At the time The mutation may affect the presentation of MAP antigens
of diagnosis, CBV4 reactive T-cells (memory cells) are thus leading to diabetogenic response.
seen to be majorly found in children with type 1 diabetes.
Population studies done in Finland show a significant Dietary Factors
association of enterovirus with the development of The α casein component in cow’s milk may be a trigger
diabetes. Viral infection of islet cells is known to increase for type 1 diabetes because cross reactivity is with human
the levels of HLA class I and interferon (IFN)-α in type 1 β-cell specific protein (insulin).88 Major studies in Finnish
diabetic children. Apart from viral infection of pancreatic population such as the Trial to Reduce IDDM in Geneti­
cells, sequence homology between the 2C protein of cally at Risk (TRIGR) compares whether infant formula
Coxsackie virus and glutamic acid decarboxylase (GAD) com­pared to cow’s milk decreases the risk of developing
autoantigen proves the role of viruses in type 1 diabetes. type 1 diabetes in children with high genetic suscepti­
Suspected individuals of type 1 diabetes may suffer from bility. The various components of either cow’s milk or
subclinical insulitis for years and upon viral infection may breast milk have been studied by various research groups
trigger the destruction of β-cells and hyperglycemia. It is in relation to development of type 1 diabetes but none of
interesting to find that in 75% of type 1 diabetes patients, the results are reproducible or hold any supporting data.
the intestinal biopsy showed the presence of enteroviruses Another study shows that polymorphism in PTPN22
as compared to that of 10% in control patients. CXCL10 gene is associated with type 1 diabetes in infants fed
upregulation in pancreatic cells is one of the earliest with cow’s milk before 6 months. Thus both genetic
 Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 207

and environmental factors may contribute to the protein (HSP), islet specific glucose-6-phosphate catalytic
contradictory findings of cow’s milk in type 1 diabetes. subunit related protein (IGRP) and imogen-38. Apart
Few studies have shown the effect of wheat protein in from the above well characterized autoantibodies, there
diabetes. DAISY and BABY-DIAB both give evidence is potential for other different autoantibody/autoantigen
of susceptibility to type 1 diabetes with exposure to combinations in type 1 diabetes. The concept on role of
cereal and gluten.89,90 Type 1 diabetes patients show autoantibodies in type 1 diabetes is changing. Studies
T-cell reactivity to wheat gluten more than the healthy support the role of autoantibodies in presentation of

chapter
controls. Vitamin A and D are known to influence the self-antigen to the cytotoxic T-cells responsible for

15
immune system. Large population studies show that destruction of β-cells. Administration of B lymphocyte
increased vitamin D supplements in infants reduced the depleting agent anti-CD20 (rituximab) in recent onset of
risk for type 1 diabetes. It can be considered an important type 1 diabetes patient shows therapeutic promise. It is
environmental factor and responsible for self-tolerance important to identify the role of B lymphocyte immune
and protection against autoimmunity. Treatment of lineage in pathogenesis of diabetes apart from providing
type 1 diabetes with vitamin D analogs may be considered a potential diagnostic and predictive value. In newly
as a promising future venture. detected type 1 diabetes patients around 70–80% have type
1 associated autoantibodies. The number of autoantibodies
AUTOIMMUNITY present and autoantibody titer can be considered as
independent predictors for type 1 diabetes. Presence of
Type 1 diabetes is an autoimmune disease where the
high titer values in young patients or association with
auto antibodies destroy the insulin producing β-cells in
high risk HLA genes makes autoantibodies an accurate
the pancreas. The first symptomatic onset of the disease
predictor for type 1 diabetes. The first reported data
is apparent when majority of the cells are destroyed
showed that high titer values of ICA autoantibodies carries
or dysfunctional making the individual dependent on
a risk of 60–70% for developing type 1 diabetes. Since then
external supply of insulin. It is unclear as to why
type 1 diabetes autoantibodies have been extensively used
specifically insulin producing β-cells are targeted by
as diagnostic markers and prediction for the disease. The
autoantibodies in type 1 diabetes. Over the years different
autoantibodies when present in combination increase
studies have proposed the causes to autoimmunity
the risk for type 1 diabetes. In Diabetes Prevention
resulting in type 1 diabetes but the most direct evidence
Trial-1 (DPT-1) studies the risk factor for developing
comes for the histological finding of the pancreas. Few diabetes with one autoantibody was 20–25%, with two
cases of insulitis are available for study and data from this autoantibodies the risk factor increases to 50–60%, for
show that insulitis occurs in β-cell containing islet and the patients with three autoantibodies the risk is 70% and the
population left behind are islet cells devoid of β-cells. The risk factor is nearly 80% for those with four autoantibodies.
pancreatic biopsies are not ethically feasible and autopsy Diagnosis for diabetes has been greatly simplified by using
samples from recently diagnosed type 1 diabetes patients autoantibodies as biomarkers. The diagnostic criteria vary
are very rare, thus to remove this roadblock and improve for the week to distinguish the patients natural IAAs from
the research opportunities programs like Belgium type 1 antibodies against therapeutic insulin. Even though IAA
diabetes registry, PEVNET (Finland), Network for panc­ tests are considered to be highly specific and sensitive
reatic organ donor with diabetes have been initiated to for type 1 diabetes, it has a few practical problems
collect samples for research studies.91 This would help in such as requiring high serum volumes and the various
understanding the pathogenesis and natural history of subtypes of the autoantibody have different capacities for
type 1 diabetes. predicting the disease. GADAs are seen in 60–70% of newly
Presence of autoantibodies to islet or β-cell antigen is onset type 1 diabetes patients and are considered to be
identified with autoimmunity in type 1 diabetes. These are primary biomarker for detecting LADA. Autoantibodies
detected at the time of diagnosis and also can be found to several forms of IA-2 have been observed in type 1
much earlier before symptomatic onset of the disease. diabetes patients but opinions differ on the significance of
Well established type 1 diabetes associated autoantibodies such forms of autoantibodies.
are islet cell autoantibodies (ICAs), glutamic acid decar­ The most significant research to understand the
boxylase (GADAs), insulinoma antigen 2-autoantibodies autoimmune nature of type 1 diabetes has been the
(IA-2As), insulin autoantibodies (IAAs), heat shock identification and characterization of autoantibodies.
208 Etiopathogenesis of Diabetes Mellitus

When combined with genetic susceptibility, it has become were detected with 2 major B-cell epitopes. Studies done
easier to predict the patients who might develop type 1 in NOD mice show that PDX1 is a target for CD4+ T-cell
diabetes from an early age. whereas in human type 1 diabetes patients this needs
further investigation.
Newly Discovered Autoantibodies in Chromogranin A belongs to the granin family of
Type 1 Diabetes neuroendocrine secretory proteins. It acts as precursor
to several peptides such as vasostatin-1, pancreastatin,
B-cell specific autoantibodies newly discovered include
section

catestatin, chromostatin and WE-14.94 CHGA is found in

zinc transporter-8 (ZnT8), pancreatic duodenal homeobox
5

secretory vesicles of neurons and endocrine cells. Human

factor 1 (PDX1), chromogranin A (CHGA) and islet amyloid
CHGA is a 439 amino acid protein with highly conserved
polypeptide (IAPP).
Pancreatic β-cells have the highest levels of zinc amino and carboxyl terminal ends. CHGA is considered
compared to other cells in the body. The SLC30A ZnT8 as a non-specific neuroendocrine tumor marker. T-cells
protein helps in carrying the zinc ions from cytoplasm response to CHGA is well documented in mice whereas in
into insulin secretory vesicles in the pancreatic β-cells. human type 1 diabetes its occurrence is doubtful. Recent
ZnT8 is evolutionary highly conserved and has six study failed to detect the autoantibodies in recent onset
transmembrane domains as well as cytoplasmic NH2- and and long standing diabetes patients. Autoantibodies to
COOH- terminals. ZnT8 plays a major role in providing CHGA may be of transient nature during type 1 diabetes
zinc for the maturation and storage of insulin in β-cells development, though studies can focus on detecting the
secreting insulin. It also protects pancreatic cells from autoantibodies in prediabetes stage.
cytokine induced destruction which is found in type 1 Islet amyloid polypeptide or amylin is 37 amino acid
diabetes patients.92 ZnT8 was identified as an autoantibody peptide hormone and is co-secreted along with insulin by
from a multi-dimensional microarray analysis of mRNA the β-cells.95 IAPP show glycemic regulation by inhibiting
expression profiling experiments and screening with RIA. insulin and glucagon secretion in islet cells and reduces
ZnT8 has become a good diagnostic biomarker for type the postprandial increase in blood glucose levels. IAPP
1 diabetes as 60–70% of recent onset type 1 patients are autoantibodies previously have been shown to occur in
shown to be ZnT8 positive. Genetic studies show ZnT8 type 1 diabetes patients but with no relation to the disease.
has 3 variants at the amino acid position 325, ZnT8-R IAPP is co-secreted with insulin into the blood stream.
(Arginine), ZnT8-W (tryptophan), and ZnT8-Q (Gluta­ Hyposecretion of IAPP has been seen in type 1 diabetes.
mine). ZnT8 is also associated with autoreactive CD4+ and Injection of insulin along with synthetic IAPP improves
CD8+ T-cells in human type 1 diabetes. This association glycemic controls by suppressing glucagon secretion. Like
can help in designing therapeutic or preventive agents insulin, ZnT8, IAPP is a target for CD4+ and CD8+ T-cells.
that target ZnT8 specific T-cells and stop the disease
IMMUNE INTERVENTION TRIALS
progression.
Pancreatic and Duodenal Homeobox 1 (PDX1) is Advances in the treatment modalities for type 1 diabetes
also known as insulin promoter factor 1(IPF-1). This have made it possible for the individual to have a normal
transcription factor plays important role in development life. Exogenous insulin injections, islet transplantation,
of pancreas, β-cell maturation and maintenance of continual pump therapy have greatly helped in reducing
function. The PDX-1 gene consists of 2 exons coding a the glycemic levels and also decreasing the risk for
283 amino acid protein. The NH2 terminal contains a complications associated with type 1 diabetes.
transactivation domain and the COOH- terminal contains
autoepitopes for T- and B-cell recognition.93 The insulin Primary Intervention Trials
gene promoter regulated by glucose is by activation These trials are mainly for children with high risk for
and nuclear transportation of PDX1. Genetic defects type 1 diabetes and include several dietary manipulations.
in PDX1 causes maturity onset diabetes of the young These prevention trials are required to be robust and
type 4 (MODY4). PDX1 also shows immunomodulatory free of side effects as the individuals do not show clinical
functions. PDX1 autoantibodies were first detected in NOD symptoms of type 1 diabetes. As of now, all primary
mice. In humans with type 1 diabetes, the autoantibodies interventions have been of dietary nature and so far
 Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 209

no specific factor has been proved to be a risk factor for Studies on nasal insulin have shown signs of immune
β-cell destruction or type 1 diabetes, which makes the tolerance after administration of insulin and trials such
efficacy of the treatment difficult to study. as INIT and DIPP show that nasal insulin is safe and can
be used as a treatment modality. Future challenges would
Secondary Intervention Trials be to study the dosage response and to understand the
Individuals with islet autoantibodies are ideal candidates association between immune response and HLA genotype
for secondary intervention trials. The various trials con­ in individuals.

chapter
ducted are as follows:

15
Proinsulin Peptides
Nicotinamide A cocktail of proinsulin peptides can be considered in
It has been shown that nicotinamide when administered preventing type 1 diabetes. Pilot study using a single
prior to the onset of diabetes increases insulin synthesis proinsulin peptide with epitopes recognized by HLA-DR4
and inhibits the development of diabetes. The European as a treatment option was administered to type 1 diabetes
Nicotinamide Diabetes Intervention Trial (ENDIT) patients. Since then several trial using different type of
showed nicotinamide to have no effect on the prevention proinsulin peptides are being used as a form of antigen
or delaying the onset of diabetes in at risk relatives of type specific therapy against type 1 diabetes.102
1 diabetes patients.100 Although clinical trials using insulin as the immune
modulatory agent have been underway, none have passed
Antigen specific therapy: This therapy makes use of
beyond phase II- phase III stages to be prescribed as active
autoantigens, which can elicit a response towards impro­
agents against type 1 diabetes.
ving the immune system rather than destroying it and
also help in restoring immune tolerance. The antigens
Immunomodulation
are specific for type 1 diabetes101 and have no impact on
the general immune response. One of the best examples A pilot trial was carried out in first degree relatives of
has been the use of insulin as intervention therapy. Pilot type 1 diabetes patients with islet autoantibodies using
studies of parenteral insulin used as prophylactic agent low dose cyclosporine along with immunosuppression.
along with anti-ICAs in first degree relative of type 1 The result indicated that the administration of immuno­
diabetes showed delayed disease progression. modulant may improve the glucose tolerance and delay
the development of type 1 diabetes.103
Oral Insulin
METABOLIC ALTERATIONs IN
Trial studies from DPT-1 shows that oral administration
TYPE 1 DIABETES
of insulin does not delay the clinical symptomatic onset of
type 1 diabetes. However, a small population of patients Insulin plays an important role in many cellular processes
with high anti-insulin autoantibodies demonstrated delay and has been extensively studied in regards to glucose
in type 1 diabetes onset. β-cell function and viability homeostasis. In type 1 diabetes individual insulin defici­
improves when the patient is on oral insulin medication. ency leads to alterations in carbohydrate, lipid and protein
TrialNET is an international network working to test metabolism, defects in immune response, prostaglandin,
the effects of oral insulin on relatives of type 1 diabetes arachidoic acid, leukotrienes, neurotransmitters, nucle­
patients. otide and anti-inflammatory responses. Insulin has
Nasal insulin: Another form of insulin tested for regulatory effect on the transcription, translation and
immune tolerance is nasal insulin. INIT-1 trial on indivi­ post-translational modifications of protein. As many as
duals with anti-insulin autoantibodies and first degree 24 metabolic pathways can be distinguished between type
relatives with type 1 diabetes showed that the immune 1 diabetes and non-diabetes. Hormones such as insulin-
tolerance improves with nasal insulin administration like growth factor-1(IGF-1) are found to be dysregulated
whereas no effect is seen on the functional aspect of in children and adolescent with type 1 diabetes. IGF-1 is a
β-cells. An ongoing INIT-2 trial is underway to evaluate the major regulator for bone growth and metabolism.104 Low
effectiveness of nasal insulin against islet autoantibodies. IGF-1 levels in type 1 patients may lead to complications
210 Etiopathogenesis of Diabetes Mellitus

such as a poor linear growth and decreased bone mineral gluconeogenesis. In muscle and adipose tissue, glucose
content. During the growth spurt in adolescents the levels transporter (GLUT)-4; helps in uptake of glucose when
of IGF-1 greatly increase and low blood glucose could stimulated by insulin with increase transcription and
significantly hamper bone development and growth. translocation of the glucose transporter to the plasma
Also post-menopausal type 1 diabetic patients are membrane. In fasting state, low insulin level decreases
10 times more prone to hip injuries than women without glucose uptake and fatty acids and ketones become major
type 1 diabetes.105 This observation favors the role of oxidative fuels for the tissues. In newly diagnosed type 1
section

low metabolic controls in type 1 diabetes in decreasing diabetes individuals, the plasma insulin levels are greatly
5

the bone density. Few reports state that interaction reduced and show increased glucagon and catecholamine
between inflammatory mediators and IGF system may levels. In the fasting state, there is increased hepatic
help in understanding the dysregulation of IG-1 in glucose output and further increases in post-prandial state
type 1 diabetes.106 However, the precise mechanism that due to reduced suppression of hepatic glucose production
may link poor glycemic control with reduced IGF-1 factor and reduced uptake of glucose by peripheral tissues.
is not clear.
Emerging techniques like ultra performance liquid Protein Metabolism
chromatography quadruple time of flight mass spectro­
In non-diabetic individuals fasting insulin levels promotes
metry (UPLC-ToF-MS) based metabolomic profiling
protein synthesis in liver and inhibits protein breakdown
studies help in distinguishing impaired glucose and normal
in liver and peripheral tissues. In type 1 diabetes patients,
glucose levels in diabetic patients. Such approaches
insulin deficiency causes increased in protein breakdown
are useful in designing strategies to prevent the disease
which results in increased levels of branched chain amino
and resultant complications. In type 1 diabetes patients,
acids (valine, leucine, isoleucine). Increased uptake
administration of insulin normalizes the glucose level
of glutamine and alanine by liver for gluconeogenesis
but its effect on other metabolic pathways is not clearly
reduces their levels as seen in fasting state in severe type
understood. Insulin treatment causes hyperinsulinemia
1 diabetes. Proteolysis occurs in both fasting and after
and alters the hepatic: peripheral insulin ratio of 2:1
protein ingestion in poorly controlled type 1 diabetes.
found in non-diabetic individuals. Future research on
This brings about negative nitrogen balance, muscle
discovering new metabolic pathways affected by insulin
wasting and overall growth retardation.
deficiency would pave way for treatment based on whether
these pathways contribute to the mortality and morbidity
Fatty Acid Metabolism
in type 1 diabetes despite insulin treatment.
Lipolysis and ketogenesis are a result of insulin deficiency.
Carbohydrate Metabolism The levels of catecholamines and other stress hormones
increase in the absence of insulin. Lipolysis increases
In normal human body the plasma glucose level is
the levels of non-esterified fatty acid in plasma and
balanced by hepatic glucose production versus uptake
decreased insulin with elevated glycogen drives the rate
of glucose by important tissues like brain, muscle and
of ketogenesis in type 1 diabetes individual. The increased
fat. The liver produces glucose by glycogenolysis and
non-esterified fatty acids act as substrate for ketogenesis
gluconeogenesis. One of the important enzymes involved
and glucagon elevation increases hepatic ketone formation
in glucagon breakdown is glycogen phosphorylase,
by stimulating the carnitine pathway.
which is stimulated by glycogen and is inhibited by
insulin. Low levels of insulin and increased glucagon
CONCLUSION
and epinephrine levels stimulate gluconeogenesis.
Glucagon and epinephrine both inhibit fructose-2, Type 1 diabetes mellitus represents a heterogeneous group
6-biphosphate. The enzyme fructose-1, 6 biphophatase of disorders which is characterized by insulin insensitivity
increases the conversion of fructose-1, 6 biphophatase and/or hyposecretion. The symptoms associated with the
to fructose 6 phosphate and diminishes the function of disease are classically polyuria, polydipsia and polyphagia
phosphokinase enzyme thus inhibiting glycolysis. Low along with overt hyperglycemia. It is the most common
insulin levels through inhibition and/or stimulation chronic disease of childhood. Genetic susceptibility,
of other enzymes increases pyruvate thus promoting geographical distribution, environmental factors are
 Pathogenesis and Metabolic Alterations in Type 1 Diabetes Mellitus 211

important criteria affecting the risk and prevalence of the 7. Ostman J, Lonnberg G, Arnqvist HJ, et al. Gender differ-
disease. Till date 50 known loci have been implicated as ences and temporal variation in the incidence of type 1
high risk for the development of type 1 diabetes of which diabetes: results of 8012 cases in the nationwide Diabetes
Incidence Study in Sweden 1983–2002. J Intern Med 2008;
HLA genotype carries the maximum genetic susceptibility.
263: 386-94.
Present research also throws light on important non-HLA 8. Moltchanova EV, Schreier N, Lammi N, et al. Seasonal vari-
genes that are involved in the genetics of type 1 diabetes. ation of diagnosis of type 1 diabetes mellitus in children
Another important research area is to understand the worldwide. Diabet Med. 2009;26:673-8.

chapter
effects of environmental factors in developing type 1 9. Kukko M, Kimpimäki T,, Korhonen S, et al. Dynamics of

15
diabetes and would help in creating better and improved diabetes-associated autoantibodies in young children with
treatment options. Type 1 diabetes is an autoimmune human leukocyte antigen-conferred risk of type 1 diabetes
recruited from the general population. J Clin Endocrinol
disorder. In the past decade much work has been done
Metab. 2005;90:2712-7.
to study the immune response in the disease resulting in 10. Vandewalle CL, Coeckelberghs MI, De Leeuw IH, et al. Epi-
identification of autoantibodies that help in the diagnosis demiology, clinical aspects, and biology of IDDM patients
and treatment of type 1 diabetes. This has made possible under age 40 years. Comparison of data from Antwerp with
for new and improved treatment options to be available complete ascertainment with data from Belgium with 40%
for type 1 diabetes patients. Worldwide clinical trials for ascertainment. The Belgian Diabetes Registry. Diabetes
type 1 diabetes are trying to identify the most promising Care. 1997;20:1556-61.
11. Patterson CC, Dahlquist GG, EURODIAB Study Group,
treatment option which would reduce the mortality and
et al. Incidence trends for childhood type 1 diabetes
morbidity associated with the disease and also to identify in Europe during 1989–2003 and predicted new cases
factors that can help to diagnose the disease before 2005–20: A multicentre prospective registration study. Lan-
symptomatic onset in high risk individuals. cet. 2009;373:2027-33.
12. Maahs DM, West NA, Lawrence JM, et al. Epidemiol-
Further Reading ogy of type 1 diabetes. Endocrinol Metab Clin North Am.
2003;39:481-97.
1. Fernandez-Valverde SL, Taft RJ, Mattick JS. MicroRNAs in
13. Hermann R, Knip M, Veijola R, et al. 2003. Temporal
Beta cell biology, insulin resistance, diabetes and its com-
changes in the frequencies of HLA genotypes in patients
plications. Diabetes. 2011;1825-31.
with type 1 diabetes—Indication of an increased environ-
2. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes.
Lancet. 2013;6059:1-7. mental pressure? Diabetologia. 2003;46:420-5.
3. Lee HS, Briese T, Winkler C, et al. Next generation sequenc- 14. Soltesz G, Patterson CC, Dahlquist G, EURODIAB Study
ing for viruses in children with rapid onset of type 1 diabe- Group. Worldwide childhood type 1 diabetes incidence—
tes. Diabetologia. 2013;56:1705-11. What can we learn from epidemiology? Pediatr Diabetes.
4. Nokoff N, Rewers M. Pathogenesis of type 1 diabetes: Les- 2007;8:6-14.
son from natural studies of high risk individuals. Ann. N. Y. 15. Gillespie KM, Bain SC, Barnett AH, et al. The rising
Acad. Sci 2013;1-15. incidence of childhood type 1 diabetes and reduced con-
5. Padgett LE, Broniowska KA, Hansen PA, et al. The role of tribution of high-risk HLA haplotypes. Lancet. 2004;364:
reactive oxygen species and proinflammatory cytokines in 1699-700.
type 1 diabetes pathogenesis. Ann. N. Y. Acad. Sci 2013;16-35. 16. Steck AK, Armstrong TK, Babu SR, et al. Stepwise or
linear decrease in penetrance of type 1 diabetes with
lower-risk HLA genotypes over the past 40 years. Diabetes.
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94. Stadinski BD, Delong T, Reisdorph N, et al. Chromogra- a randomized controlled trial of intervention before the
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recruiting src homology 2-domain-containing tyrosine 103. Carel JC, Boitard C, Eisenbarth G, et al. Cyclosporine delays
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5

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97. Carreno BM, Collins M. The B7 family of ligands and its 104. Strasser-Vogel B, Blum WF, Past R, et al. Insulin-like growth
receptors: new pathways for costimulation and inhibition factor (IGF)-I and –II and IGF-binding proteins-1, -2, and -3
of immune responses. Annu Rev Immunol. 2002;20:29-53. in children and adolescents with diabetes mellitus: correla-
98. Okazaki T, Iwai Y, Honjo T. New regulatory co-receptors: tion with metabolic control and height attainment. J Clin
inducible co-stimulator and PD-1. Curr Opin Immunol. Endocrinol Metab. 1995;80:1207-13.
2002;14:779-82. 105. Nicodemus KK, Folsom AR, Iowa Women’s Health Study.
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and postnatal rat pancreas. Dev Dyn. 2004;229:813-25. 106. Van Sicklea BJ, Simmonsa J, Halla H, et al. Increased circu-
100. Gale EA, Bingley PJ, Emmett CL, et al. European Nicotina- lating IL-8 is associated with reduced IGF-1 and related to
mide Diabetes Intervention Trial (ENDIT) Group. Euro- poor metabolic control in adolescents with type 1 diabetes
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 Chapter 16
Pathogenesis of
Type 2 Diabetes
Devjit Tripathy, BB Tripathy, Hemraj B Chandalia

Pathogenesis of Type 2 DM

Chapter Outline
♦♦ Glucose Homeostasis ♦♦ Impaired b-Cell Function
♦♦ Insulin Resistance ♦♦ The Natural History of Type 2 Diabetes

INTRODUCTION progressive autoimmune destruction of β-cells, MODY is

attributed to a single gene mutation (monogenic).
Diabetes mellitus, a pan-metabolic disorder is charac­ Besides these two forms with more or less known
terized by chronic hyperglycemia. A syndrome, rather pathogenesis the rest of 80–88% patients presenting as
than a disease entity, diabetes is classified according to NIDDM have type 2 diabetes, a heterogeneous disorder
whether hyperglycemia is the primary feature or is a part with highly complex pathogenicity. After extensive
of some other disorder, such as those of the pancreas, research, it is presently considered that basically the
endocrine system or some well-defined genetic syndromes following two factors operate in collusion for evolution
(secondary). The primary category of diabetes is presently of the metabolic disarray that constitutes type 2 diabetes:
differentiated into type 1 and type 2 depending on whether 1. Impaired insulin action/sensitivity, i.e. insulin resis­
it emerges from subtotal destruction of β-cells of the tance (IR)
pancreas with predominant absolute insulin deficiency 2. β-cell defect: Insulin secretory dysfunction
(Type 1) or evolves out of a complex interaction between Both genetic and environmental factors contribute to
impairment of insulin action and relative inadequacy of their interaction.
insulin secretion (Type 2). Discussion of pathogenesis of type 2 diabetes has to
Type 2 diabetes, previously known as non-insulin- revolve around these basic problems, their interactive
dependent diabetes mellitus (NIDDM) accounts for contribution to the evolution and progress of the disorder
85–95% of patients with diabetes in various populations and available information on the nature and genesis of
of the world. The genesis of this widely prevalent primary IR and β-cell defects. Both insulin sensitivity and β-cell
function are modulated by hereditary (genetic) and
metabolic disorder is highly complex and varied with
environmental factors.
marked heterogeneity. The disorder evolves slowly and
remains subclinical for variable periods of time estimated
GLUCOSE HOMEOSTASIS
as several years. Among patients clinically diagnosed as
Type 2 diabetes around 10% may have latent autoimmune In healthy individuals, plasma glucose is maintained
diabetes in adults (LADA) or maturity-onset diabetes within a narrow range. It is essential to maintain the
in the young (MODY). While LADA evolves from slowly glucose levels in plasma and tissue fluids at a certain
216 Etiopathogenesis of Diabetes Mellitus

minimum level to meet the energy requirements forvital Table 16.1: Pathogenesis of type 2 diabetes
functions of the brain and other vital organs. On the • β-cell defect:
other hand, glucose levels above certain limits are – Inappropriate and deficient secretion of insulin in the basal
state and in response to meals
deleterious or toxic for vascular endothelium and several
– Morphologic alteration in beta-cells and depletion of beta-cell
other tissues. Under basal conditions, bulk of glucose mass
utilization occurs in insulin-independent tissues such • Impaired insulin action/insulin resistance:
as the brain (50%) and splanchnic areas (25%) while the – Skeletal muscle insulin resistance, diminished glucose
section

rest (25%) is consumed principally by muscles. Basal disposal

– Hepatic/insulin resistance—inadequate suppression of gluco-
5

glucose utilization of around 2 mg/kg/minute is precisely

neogenesis and hepatic glucose production
matched by glucose production by liver. Following a
– Diminished endothelial lipoprotein lysis and decreased
meal or glucose ingestion, the hyperglycemia and raised removal of lipids from circulation as well as increased
insulin secretion stimulate peripheral glucose uptake, adipose tissue lipolysis with excess release of FFA and
particularly by the skeletal muscles that account for glycerol to circulation
the bulk (80%) of the disposal of the extra glucose. The (FFA: Free fatty acid).
magnitude of rise in level of plasma glucose during the
next 2 hours depends on the rate of glucose disposal and time with appearance of impaired glucose tolerance and
on the degree of suppression of hepatic glucose produc­ type 2 diabetes.6 This phenomenon has been called the
tion (HGP) modulated by the insulin secreted in response “genetically pro­grammed failure of β-cell to compensate
to the meal. for IR”.7
Insulin stimulation of lipoprotein lipase (LPL) in the More recently investigations using more refined pro-
endothelium of vessels leads to lipolysis of lipoproteins ce­dures to assess β-cell function have shown abnorma­
with increased removal of chylomicrons and very low lities in insulin secretion to be the basic defect in the
density lipoproteins (VLDL) from the circulation. Further­ development of prediabetes and overt diabetes mellitus.
more, inhibition of hormone-dependent tissue LPL Instead of coming to the fore on account of failure to
results in suppression of release of free fatty acids (FFA) adequately compensate for primary IR in maintaining
from the adipose tissue. Therefore, any deficiency in secre­ homeostasis β-cell secretory defects may antedate or
coexist along with decline in tissue sensitivity to insulin
tion of insulin from β-cells or in its action at the level of
sensitivity.8-10
muscles, liver and adipose tissue may lead to glucose
The following sections discuss some of the available
intolerance along with and abnormalities in the levels of
information on the nature and relative roles of “insulin
plasma lipids.
resistance” and “impaired β-cell function” in the patho­
Dysfunction at any of the above facets would disturb
genesis of type 2 diabetes (Table 16.1).
metabolic regulation and promote development of
prediabetic and lead toward diabetic state. By general
consensus, it is accepted that these factors must operate
INSULIN RESISTANCE
in collusion for development of type 2 diabetes;1 however, Insulin resistance has been defined as “diminished” ability
controversy exists, as to which of the two, “insulin secretion of insulin to exert its biological action across a broad range
defect” or “insulin resistance”, is primary.2 of concentration, thereby showing a shift of the dose
Based on a large number of observations, it is belie­ response curve to the right.11 It is clinically apparent when
ved that in a majority of cases mostly, IR operates as a certain dose of insulin fails to lower plasma glucose to
the primary pathogenic factor.3-5 It may exist for some the extent expected and insulin requirement for control
years before onset of diabetes. Early on in course of the rises above the normal endogenous production.
process, increase in activity of β-cells compensates for The concept of variable insulin sensitivity was first
the diminished sensitivity of the target cells to insulin. described by Himsworth in 1936, when he observed
When healthy, even in cases with severe IR as in Leprecha­ wide differences in hypoglycemic effect of similar doses
unism, beta cells may continue secretion of excess insulin of insulin on different sets of patients with diabetes.12
so as to maintain normal glucose tolerance (NGT) for He was the first to suggest that some patients are hyper­
long periods of time. On the other hand, however, when glycemic because of resistance to the action of insulin
β-cells are defective, as in those genetically predis­ rather than from lack of insulin. This proposition became
posed to diabetes, decompensation occurs in course of generally acceptable when Yalow and Berson (1960)
 Pathogenesis of Type 2 Diabetes 217

most; β-cell remain competent to secrete enough insulin

to compensate for the impaired insulin action. Further, not
all obese people have IR. In a study of 50 obese subjects,
24 had IR. They also had higher 2 hour post meal glucose
plasma glucose, high triglycerides (TG) and lower high
density lipoprotein (HDL) cholesterol suggesting the link
of IR to cardiovascular disease. Obesity is stated to contri­

chapter
bute to about 25–30% of IR overall.18

16
Insulin resistance is a consistent finding in patients
with type 2 diabetes and the IR maybe traced to a number
of years before onset of diabetes.19

The relationship of IR with type 2 diabetes is evident
from both cross-sectional and prospective studies. While
findings in the former may be vitiated by the glucotoxicity
Fig. 16.1: Estimates of whole body glucose disposal (M) in controls factor, prospective studies carried on subjects with NGT
and in patients with type 2 diabetes by hyperinsulinemic euglycemic
followed up until some of them develop diabetes provide
clamp technique17
more definitive evidences. Cross-sectional studies in three
ethnic populations, non-Hispanic whites, Hispanics and
reported that a set of patients with diabetes (Type 2) African Americans, revealed that only 4–17% of subjects
were hyperinsulinemic rather than insulin deficient.13 with type 2 diabetes were insulin sensitive.20 Prevalence of
In Obesity14 as well as in borderline diabetes with or insulin sensitive type 2 diabetes after exclusion of LADA
without obesity, hyperinsulinemia was described.15 Hims­ and MODY is very low.21,22 Several prospective studies
worth devised glucose-insulin sensitivity test which was have shown IR to be an early feature that is predictive of
utilized for over 3 decades to assess effect of a particular Type 2 diabetes.3-5
dose of insulin on restriction of glucose-induced hyper­
glycemia. Reavan and coworkers (1970)16 are credited Sites of Insulin Resistance
for adopting a new approach for grading insulin sensitivity
Skeletal Muscle
by measuring glucose disposal in response to varying
doses of exogenous insulin. The currently used clamp Skeletal muscle is the major site for disposal of excess
technique was devised by DeFronzo et al.17 toward the end plasma glucose following a meal or a glucose load. It is also
of the next decade. the prime site for glucose storage by converting glucose
Relatively high levels of insulin at fasting and in resp­ to glycogen. In the insulin stimulated post-prandial state
onse to secretagogues are indicative of IR. Euglycemia, skeletal muscle accounts for over25 75% of the excess
hyperinsulinemia, clamp studies, estimating rate of peri­ glucose uptake and in the diabetic patients it accounts
pheral glucose disposal, are currently used to measure for the largest part of impairment of glucose disposal
degree of impairment of insulin action. In controls, typi­ as assessed by euglycemic clamp technique (Fig. 16.2).
cally glucose disposal measures up to 7 mg/kg/minute Adipose tissue mass being smaller in size, accounts for the
while in overweight persons with type 2 diabetes it has rest while there may not be any change in case of the brain
been estimated to be 2.5 mg/kg/minute. Even in normal and splanchnic tissues. There is considerable controversy
weight subjects with type 2 diabetes there is substantial on the major site of IR in the myocyte, whether peripheral
reduction in whole body glucose uptake on estimation by (glucose transport) or central (glucose utilization).23
clamp technique (Fig. 16.1). Minimal model, Homeostatic Studies where glucose/insulin clamp techniques were
Model Assessment (HOMA) and Continuous Infusion of combined with indirect calorimetry reveal that defective
Glucose with Model Assessment (CIGMA) models have insulin stimulated glycogen synthesis in skeletal muscle
also been used to assess grades of IR. is the hallmark of IR in type 2 diabetes.24 In a study
Insulin resistance is a well-known associate of obesity. from Malmo, Sweden, 203 men of same age but varying
Most patients of type 2 diabetes are overweight or obese. grades of glucose tolerance participated in a study with
However, not all obese patients develop diabetes as in euglycemic clamp technique combined with indirect
218 Etiopathogenesis of Diabetes Mellitus
section
5

Fig. 16.2: Glucose uptake: Total and major components in controls Fig. 16.3: Contribution of oxidative (black bars) and non-oxidative
and in patients with type 2 diabetes estimated by euglycemic clamp glucose metabolism (gray bars) to total body insulin stimulated
technique17 glucose metabolism in relation to sixtiles of fasting plasma glucose
(3.8–5.3, 5.7–6.1, 7.0–9.7 and 9.9–20.8 mmol/L)25

It has been amply demonstrated that insulin resistance

in skeletal muscle cells correlates well with triglyceride
content of the muscle. Several studies have shown that
insulin stimulated glucose uptake is inversely related to
the amount of intramyocellular triglycerides.28 By use of
proton nuclear magnetic resonance imaging, it has been
determined that intramyocellular fat and not the interfiber
deposit happens to be the regulatory factor.29

Liver
A major action of insulin is to suppress endogenous HGP.
While postprandial hyperglycemia in the early stages
of type 2 diabetes is attributed to diminished uptake of
Fig. 16.4: Common sites for defects in glucose uptake in skeletal mus-
cle: (1) Glucose transport; (2) Glycogen synthesis; and (3) Carbohy-
glucose by muscles, during the postabsorptive period the
drate oxidation fasting level is maintained by hepatic glucose output. Both
sources of HGP, glycogenolysis and gluconeogenesis are
regulated by insulin control. Yet in the event of IR the latter
calorimetry. Subjects were divided into groups based on contributes to nearly the entire increase in hepatic glucose
the fasting plasma glucose levels. Figure 16.3 shows that output.
with worsening glucose tolerance, the reduction in glucose Approximately 25% of the glucose derived from a meal
uptake was accounted for by a decrease in non-oxidative is extracted by the liver during recycling of portal and
glucose metabolism.25 systemic blood. Insulin is not required for this uptake,

Furthermore, evidence for impaired effect of insulin but there are evidences to suggest that insulin facilitates
on glucose transport, insulin receptor tyrosine kinase (TK) storage of glucose as glycogen. Even greater amount of
activity and other insulin sensitive metabolic pathways glycogen is derived from gluconeogenesis. Glycogenolysis
has been demonstrated in skeletal muscle cells and is inhibited during the process of active gluconeogenesis
adipocytes in patients with type 2 diabetes.23,26,27 The major and this accounts for the excess hepatic glycogen in
sites of IR are illustrated in Figure 16.4. uncontrolled diabetes.30
 Pathogenesis of Type 2 Diabetes 219

tissue. Simultaneous increase in FFA and concomitant

hyperglucagonemia facilitate gluconeogenesis.
Further, IR promotes synthesis of VLDL and apo-B
in the liver while HDL is reduced because of increased
exchange of cholesterol ester transport protein. Small
dense low density lipoprotein particles are also increased
in the process.

chapter
16
Adipose Tissue
The contribution of adipose tissue to IR was under rated
as it accounts for only a small fraction of glucose uptake
estimated by clamp techniques. With renewed interest in
Randle’s hypothesis on glucose-fatty acid cycle, adipose
tissue has been counted as the “fourth musketeer”30
Fig. 16.5: Dose response curve for glucose uptake (cyan line) and along with the triumvirate of β-cell, muscle and liver.
suppression of endogenous glucose production (black line) in controls
Lipogenesis and lipolysis in the adipose tissue are most
(broken line) and patients with type 2 diabetes (cyan line) in response
to insulin32 sensitive to regulation by insulin. IR results in acceleration
of lipolysis with flooding of the circulation with FFA. As
described later, raised levels of FFA in circulation exerts
Recent observations have shown that restraining effect profound influence on glucose and lipid homeostasis.
of insulin on HGP is impaired in type 2 diabetes.31 Hepatic Further, adipose tissue is by now known to be a large
output of glucose has been estimated to be raised to 17 g endocrine organ that secretes a number of hormones
compared to 10 g in controls during a period of 3–5 hours. called adipokines, which have influence on energy meta­
While 25 μU of insulin may be needed to suppress HGP in bolism and glucose homeostasis (Chapter 18).
cases with type 2 diabetes only 12 μU is required in con- Irisin, a recently characterized peptide is encoded
trols. Using the euglycemic clamp technique combined by FNDC 5 gene and expressed in adipose tissue and
with titrated glucose infusion Groop et al.32 have shown
skeletal muscle. Its concentration in muscle is almost
that the dose response curve relating to inhibition of HGP
200-fold than that in the adipose tissue. Irisin significantly
to plasma insulin concentrations are shifted to the right
expresses the uncoupling protein (UCP-1) in the muscle
in patients with type 2 diabetes (Fig. 16.5).
and induces conversion of white adipose tissue into brown
Since HGP is highly sensitive to insulin raised fasting
adipose tissue. The presence of Brown adipose tissue,
glucose in spite of elevated fasting insulin is indicative
has been questioned in adult humans in the past, but
of hepatic IR. Direct measurement of HGP may show
is now recognized that it is present in neck and thorax.
substantial elevation only in cases with severe fasting
Brown adipose tissue contributes to non-shivering ther­
hyperglycemia (12.5 mmol/L). Although this would indi­
mic energy expenditure due to the increased expression
cate HGP abnormality to be a late phenomenon in type 2
diabetes, it is unlikely to be so as altered fasting glucose of UCP-1 and increased mitochondrial mass. Exercise
and insulin relationship is observed early at onset of releases irisin from the cell membrane of the skeletal
type 2 diabetes. The only prospective study on the role of muscle and reaches adipose tissue to exert its effect.34,35
endogenous glucose production (EGP) in the progression Obesity with excess of adipose tissue is intimately
toward manifest type 2 diabetes was reported in Pima associated with IR. Influence of distribution of body fat on
Indians.5 While the absolute rate of EGP was not predictive IR has been debated for last few decades. Intra-abdominal
of type 2 diabetes, diminished suppression of EGP by visceral fat, accounting for 5–10% of total has been shown
insulin was in the longitudinal study on Pima Indians. to be more labile with greater tendency to release excess
Excessive EGP was observed early during transition from of FFA into the portal circulation. Although widely acce­
impaired glucose tolerance (IGT) to diabetes. pted as pivotal, there are findings to suggest that visceral
Accelerated gluconeogenesis in type 2 diabetes may be adiposity is a consequence, rather than the basic cause
attributed to raised circulating levels of precursors: Lactate of IR. Excess free fatty acids in the circulation is more
and alanine from muscles and glycerol from adipose avidly taken up and deposited in the abdominal area
220 Etiopathogenesis of Diabetes Mellitus

as neutral fat suggesting relatively preserved insulin

sensi­tivity at the location.36 On the other hand, large size
adi-p­ocytes in truncal subcutaneous fat has been sugges-
ted to be more predictive of type 2 diabetes.37
Patients with type 2 diabetes not only have excess
body fat but also an abnormal distribution of fat with
disproportionate deposition in the visceral adipocytes,
section

skeletal muscles and liver. Visceral fat being more liable

5

tends to release FFA more readily. Excess fat in muscles

and the liver induces organ-specific IR. Treatment with
thiazolidinediones leads to decreased intra-abdominal
and intrahepatic fat content and thereby improves both
peripheral as well as hepatic insulin sensitivity. Conse­
quently it increases subcutaneous fat.
While excess of fat in obesity leads to IR, complete Fig. 16.6: Effect of increased free fatty acid oxidation on muscle
glucose utilization and hepatic glucose production
lack of it as seen in patients with lipodystrophy and in
corresponding rodent models is also associated with
serious significant IR. This could be due to increase in oxidation as well as glycogen synthase activity.40-42 Glucose
fatty acids in cells other than adipocytes and/or due to oxidation is reduced due to increase in intracellular
lack of some adipokines. Implanting adipose tissue on acyl-CoA and citrate content. Acyl-CoA inhibits pyru­
lipodystropic mice leads to the reversal of many of the vate dehydrogenase while citrate inhibits glycolysis by
metabolic abnormalities. Overall in type 2 diabetes, the inhibiting phosphofructokinase.
synthesis and secretion of “adiponectin” is reduced while Acute elevation of FFA has been shown to decreases PI
other adipokines such as leptin, resistin, tumor necrosis 3-kinase and increase protein kinase C (PKC) activity, thus
factor-alpha (TNF-α) and angiotensinogen are increased. leading to impairment of insulin action. The mechanism
Although adipokines are dealt with more elaborately in of FFA-induced IR could additionally be due to increased
a separate chapter (Chapter 18), the effects of some of oxidative stress and proinflammatory effect by inducing
them on IR will be mentioned later in this section. the transcription factor NF-Kβ B.42,43
Elevated FFA levels in the circulation are instrumental
Free Fatty Acid and Insulin Resistance in accumulation of excess triacylglycerol in skeletal mus­
Majority of patients with type 2 diabetes are obese. Obesity cle (myocytes) as well as in the hepatocytes, which is
is associated with persistently elevated FFA in circulation. known to lower insulin sensitivity. Excess of lipid within
Even lean patients with type 2 diabetes manifest raised the b-cell impairs its secretory function. It is postulated
FFA levels, in either situation FFA are refractory to sup­ that presence of excess triglycerides in the muscles is
pression in response to a mixed meal as well as to hyper­ not directly responsible for insensitivity to insulin action.
insulinemic states. FFA are released from fat cells through Some derivative, possibly long chain fatty acyl-CoA
lipolysis. In insulin-resistant states, accelerated lipolysis when present in greater amounts retards tyrosine phos­
results in flooding of plasma with FFA. Acute elevation phorylation. Moreover, increased supply of FFA induces
of FFA leads to further rise in IR in a dose-dependent increased production of triglycerides in the liver that is
manner.38 Elevated FFA predicts progression from IGT released into the circulation mostly in the form of VLDL.
to diabetes.39 The adverse metabolic effects of excess of The resultant hypertriglyceridemia is regarded as an inte­
plasma FFA has been termed lipotoxicity. gral component of the dysmetabolic syndrome.
Free fatty acid flux from increased visceral fat lipolysis
has been implicated in deranged hepatic handling of
Adipokines
glucose and gluconeogenesis as well as glucose uptake by Adiponectin possibly, is the most important factor in
muscles (Fig. 16.6). Raised FFA levels decrease insulin- promoting insulin sensitivity. Decreased adiponectin
induced glucose transport, phosphorylation, intracellular levels have been reported in obese and obese type 2
 Pathogenesis of Type 2 Diabetes 221

diabetic subjects.44 Levels increase with weight loss and

on thiazolidinedione therapy.
Tumor necrosis factor-α is one of the proinflammatory
cytokine derived from adipocytes. Its expression is incre­
ased in obese humans and rodents. Prospective studies
have shown higher levels of TNF-α to be associated with
a greater risk of development of type 2 diabetes. TNF-α

chapter
impairs insulin sensitivity by inducing serine phos­

16
phorylation of insulin receptor substrate (IRS)-1 resulting
in depressed insulin receptor kinase activity.45,46
Leptin was first described to be absent in mutated
monogenic obesity in ob/ob mice. Leptin deficiency leads
to hyperphagia and obesity. But in common forms of
obesity in humans and mice leptin levels are found to be
higher suggesting resistance to leptin action at the level of Fig. 16.7: Sketch indicating insulin binding to its receptor and the cas-
hypothalamus. It has been found that leptin can promote cade of intracellular signaling molecules implicated in insulin-mediated
IR in the obese through the process of inflammation.47 metabolic function
(SHC: Src homology 2 domain containing; MAP: Mitogen-activated
Resistin is a novel protein discovered in preadipocytes protein; PKC: Protein kinase C; MEK: Mitogen-activated protein
undergoing differentiation to mature adipocytes. It has kinase; SOS: Son of sevenless; PIP3: Phosphoinositol 3 phosphate;
been shown to induce IR in animal studies. However, the PI3K: Phosphoinositol 3-kinase).
relative contribution of resistin in skeletal muscle IR in
humans is not clear. Only a very small number of such patients have been
documented so far. Further, screening of samples of type 2
Cellular Mechanism of Insulin Resistance diabetes patients from different populations have failed to
Impairment of insulin action can occur at the receptor or reveal any genetic defect in insulin receptors.
the postreceptor level. Downregulation of insulin receptor In the insulin-resistant state, raised concentrations
numbers on the plasma membrane of target cells to the of insulin ensures maximal binding with receptors, but it
extent of 20–30% has been observed in the majority of fails to achieve normal disposal by uptake of glucose either
persons with type 2 diabetes. Reduced binding of insulin in vivo or in vitro. Hence, the focus has to be on events
to monocytes and adipocytes observed in-vitro, occurs beyond the step of binding to receptors (post-receptor
due to reduction in number of receptors on the cells rather defects).
than affinity. Intracellular signaling follows binding of insulin to
Hyperinsulinemia as well as defects in internalization its specific receptors (Fig. 16.7). The insulin receptor con­
and recycling have been considered as causes for decrease sists of two subunits—α and β. Signal generated on bind­
in number of receptors. However, this defect at the ing of insulin molecule to the extracellular α− receptor
receptor level does not appear to play a substantial role in transmitted across the cell membrane into the internal
the degree of IR. β-receptor leads to activation of TK. The activated enzyme
Around one-third of the patients may not manifest induces autophosphorylations involving more and more
loss in the number of insulin receptors. Authentic data of IRS that is recruited into the β-receptor. IRS consists
on receptor status in myocytes and hepatocytes are of four-cloned proteins (IRS 1–4) and two more recently
still not available. Results of dose res­ponse studies on described proteins: IRS 5/DOC4, IRS 6/DOK 551 which on
insulin-mediated glucose disposal suggest a block at phosphorylation function as adaptors between IRS and
the postreceptor level.48 Further it has not been possi­ble phosphoinositol 3-kinase (PI 3-K) so as to enable activation
to make out any correlation between receptor binding of PI 3-K and lead to formation of PI 3, 4, 5-phosphate
and IR.49 Mutations identified in the insulin receptor (PIP3). PIP3 inturn binds to several oncogenes and
gene (chromosome 19) have been found to account for induces translocation of glucose trans­porter-4 (Glut-4),
severe IR (Type A)50 at times leading to IGT and diabetes. leading to increase in transport of glucose into the cell.
222 Etiopathogenesis of Diabetes Mellitus

Table 16.2: Major post-receptor extracellular sites known to be Table 16.3: Candidate genes for insulin resistance
invol­ved in insulin resistance
• Insulin receptor
• Tyrosine kinase generation
• Insulin receptor substrate (IRS 1 and IRS 2)
• PI 3-K postbinding signal transduction
• PI 3-kinase Rad
• Glut-4-translocation
• Glut-4
• Glucose phosphorylation
• Glycogen synthase
section

• Glycogen synthesis
• Liver glucokinase promoter
5

• b3 adrenergic receptor

Furthermore PIP3 activates Akt and PKC isoforms which The above aberrations in the cascade of postre­
mediate insulin effect on various metabolic functions ceptor events (Table 16.2) are considered responsible for
including protein synthesis (Fig. 16.7). Diminished auto­ interference in gene expression of enzymes for glycogen
activation of insulin receptors obtained from skeletal synthesis,11,53 glycolysis, glucose oxidation, lipogenesis,
myocytes and adipocytes of patients with type 2 diabetes protein synthesis and cell growth.
has been reported. A decline in TK has been observed in
most but not all cases.52 Phosphorylation of serine kinases Genetic Associated Factors in
in the receptor and in IRS protein by serine threonine Pathogenesis of Insulin Resistance
kinase is known to suppress TK release in patients with
type 2 diabetes. Overproduction of TNF-α from large Candidate genes for IR are shown in Table 16.3.
adipocytes in the obese promotes phospho­ rylation of Insulin receptor gene mutation as already mentioned
serine at both these sites thereby retarding formation is very rare. Although disruption of IRS-1 and IRS-2 results
of TK. in IR and hyperglycemia in mice, mutation in IRS genes
Approximately 80% decrease in insulin stimulated are inconsequential in humans. Mutations in PI 3-K gene
phosphorylation of IRS and 90% decline in PI 3-K release have been seen in some Scandinavians with IR, but the
have been observed in animals with IR. Pari passu there same mutation in Pima Indians increase insulin response
is an increase in the glucose transporter binding protein. to glucose thereby preventing diabetes. There is no evid­
As a result, there is reduction in the insulin-stimulated ence so far of genetic linkage for the rest of the factors
glucose transport across the cell membrane. except that polymorphism in b3 adrenergic receptors
It has been ascertained that the defect is due to non­ have been linked to early onset of obesity and type 2 dia­
migration of Glut-4 units rather than decrease in number. betes.54 In addition, two families have been described with
The contribution of IRS-1 and IRS-2 to IR has recently mutation in peroxisome proliferator activated recep­tor
been studied by targeted disruption of respective genes (PPAR) leading to severe IR and diabetes.55
in mice. IRS-1 knock out mice were insulin resistant but The thrifty genotype hypothesis was proposed by
not hyperglycemic while IRS-2 knock out mice have severe Neel (1962)56 to explain the rise in incidence of type 2
hyperglycemia. diabetes with progress of time. Beginning from the hunter
In addition to the limitation on facilitated entry of gatherer stage until recent past, several groups of people
glucose into the cells even the amount that enters through have passed through long or short-spells of deficient food
mass action may not be adequately phosphorylated by supply and food deprivation. Genetically programmed
hexokinase in subjects with IR, thereby reducing the entry metabolic adaptation has been required for conservation
of glucose into the metabolic cycle. of glucose from utilization by insulin-dependent tissues
Limitation in insulin-mediated increase in glycogen such as the muscles in order to maintain supply to vital
storage has been noticed as a characteristic early defect areas such as the brain and the viscera for survival during
in type 2 diabetes with IR. Glycogen storage accounts for such periods. This could be achieved mostly by induction
90–95% non-oxidative glucose disposal. The rest 5–10% of IR at the levels of the skeletal muscles.
may be utilized for lipogenesis. A 50% decrease in glycogen Although genetic factors predispose to IR, acquired
synthesis is the major defect in the utilization of glucose elements operate its expression. Reduced physical activity
by the myocytes. and obesity are crucial factors in the development of IR.
 Pathogenesis of Type 2 Diabetes 223

Consumption of energy dense food in excess fosters IR by Homeostatic model assessment: Fasting values of plasma
inducing obesity. glucose and insulin are used to estimate insulin sensitivity
Gerald M Reavan who first described IR syndrome and β-cell function.64 The formulae for assess­ment of the
(Syndrome X) suggests that physical inactivity and obesity, above are:
each accounts for approximately 25% of the variability of • HOMA IR = Ins.μu/mL × (gluc. mmol/L)/22.5
insulin sensitivity with genetic factors responsible for an • HOMA β-cell = 20 × (Ins.mic U/mL)/(gluc.mmol/L) – 3.5.
additional 50% of this variation.57 Ethnic differences in the This model assumes that normal weight subjects

chapter
incidence of IR among people of European, South Asian or aged less than 35 years have an IR of 1% and 100% β-cell

16
Mexican ancestry suggest the strong genetic factor in the function. Graph drawn from glucose and insulin values
pathogenesis of IR. provided by Mathews, the deviser of HOMA64 appears very
Intrauterine growth retardation from inadequate explicit in determination of both IR and β-cell function.
protein diet during pregnancy has been shown to lead to Presently, HOMA is considered suitable for clinical
metabolic programming in the areas leading to IR. and epidemiological work, but does not have the accuracy
The related topic of thrifty phenotype58 is dealt within for purposes of research. It has been suggested that log
Chapter 19. HOMA-IR is a better measure of insulin sensitivity.65
Exogenous insulin or OHA therapy may interfere with
Glucose Toxicity results derived from HOMA.

Persistent hyperglycemia induces IR by impeding insulin Quantitative Insulin Sensitivity Check Index:
signaling cascade at several steps. Downregulation of
Glut-4 translocation has been implicated as an important (QUICKI)
step.59 The involvement of hexosamine pathway in which QUICKI = 1/[log(fasting insulin µU/mL) + log (fasting
the enzyme glutamine glucose-6 phosphate aminotrans­ glucose mg/dL)]
ferase diverts glucose from the glycolytic pathway at the Derived from fasting insulin and glucose values the
results are stated to be close to those from log HOMA-IR.66
level of fructose-6-phosphate resulting in glucosamine-6-
phosphate.60 In the myocyte, it reduces insulin stimulated Continuous infusion of glucose with model assessment:
Glut-4 translocation.61 Tight glycemic control by whatever Following a constant infusion of glucose for 1-hour
measures improves insulin sensitivity by ameliorating based on the steady state of plasma glucose and insulin
glucotoxicity.62 Although not operative at the basic pre- levels, insulin sensitivity is derived from the model.
IGT stage this factor may be playing some role in the The weakness of this model is that insulin concentrations
progress from IGT to frank diabetes and more importantly achieved remain at a modest level between 10 μU/mL
thereafter. and 20 μU/mL.
Minimal model analysis: Insulin resistance and β-cell
Methods of Estimation of Insulin Sensitivity function are indicated by insulin sensitivity index (Si)
and glucose effectiveness index (Sg) calculated from
These are discussed at length in chapter 19, however, some measurement of glucose and insulin in multiple samples
common tests are briefly described in this subsection. collected for 3 hours following IV glucose bolus of
Euglycemic hyperinsulinemic clamp: This technique first 0.3 g/kg.67,68 This method has been validated and corre-
described by DeFronzo and coworkers17 is considered lates well with results obtained from euglycemic clamp.
as the gold standard for assessment of insulin action in There is some likelihood of underestimation of Si and
inducing glucose disposal. Maintaining a high insu­ lin over­estimation of Sg by this method. An estimation by
level in plasma the amount of intravenous (IV) glucose this method depends on secretion of endogenous insulin.
needed to maintain euglycemia is calculated to quantify It has to be modified when applied to patients with frank
glucose disposal (M). The technique has been utilized diabetes.
to assess ability of insulin to suppress lipolysis and Botnia clamp: A modification of the clamp technique invo­
FFA release.63 Hyperglycemic clamp method has been gue for years, this test aims at independent estimations
used more for estimation of β-cell function and insulin of insulin secretion and insulin sensitivity.69 The first
response. These tests are expensive, time-consuming and phase of insulin response to 0.3 g/kg of IV glucose is
labor intensive. measured following which insulin sensitivity is estimated
224 Etiopathogenesis of Diabetes Mellitus

from a 2 hour euglycemic clamp started 60 minutes after

the glucose bolus. The procedure has been seen to provide
highly reproducible measures of both insulin secretion
and insulin sensitivity. The subject of insulin resistance, in
all its aspects, is further dealt with in Chapter 20.

The Insulin Resistance (Metabolic) Syndrome

section

Modan et al. (1985) were the first to link certain common

5

chronic disorders with IR and hyperinsulinemia.70 The

concept sprang to limelight when Reaven in his Banting
Memorial Lecture (1988)71 collated IR, glucose intolerance,
hyperinsulinemia, hypertension, high triglycerides and
low HDLC to constitute a syndrome and termed it as
“Syndrome X”. While his observation on concurrence was
based upon findings in a group of non-obese subjects, it Fig. 16.8: Biphasic insulin response to intravenous glucose
was soon appreciated that syndrome X was much more
common among the obese, particularly those with android
insulin release is best elicited by an IV bolus of glucose as
type of truncal adiposity. Proneness to atherothrombotic
illustrated in Figure 16.8.
disorders, chiefly coronary artery disease, was soon added
Around 50% (20–80%) of insulin released into the
to the list. In course of time, raised apo-B, excess of small
portal circulation by β-cells are extracted by the liver from
dense LDL particles, microalbuminuria, raised plasmi­
the blood, whereas C-peptide fraction of proinsulin is not.
nogen activator inhibitor-1 (PAI-1), polycystic ovarian
Further the half-life of insulin in the peripheral blood is
syndrome have been considered for inclusion. Presently
very short while that of C-peptide is much longer. Hence,
known as metabolic or dysmetabolic syndrome, the core
C-peptide estimation is of value in assessment of β-cell
components as defined by WHO are: (1) abdominal
function. Further usual procedures for immunoassay of
obesity, (2) dyslipidemia, (3) micro-albuminuria, and
insulin incorporate proinsulin and some intermediate
(4) Hypertension. The syndrome and its impact in patho­
split products which are biologically less active. Excess
genesis of type 2 diabetes are discussed in Chapter 19.
of these elements gives a false impression of degree of
IMPAIRED β-CELL FUNCTION hyperinsulinemia particularly in obese patients with type
2 diabetes.
Insulin Secretion Certain special characteristics of insulin secretion
The physiology of insulin secretion and insulin action can be elicited, by assay of insulin in portal blood and
has been dealt with in previous chapters (Section 2). minute-to-minute testing of peripheral blood. Instead
Very briefly, it may be recalled that secretion of insulin is of smooth flow from the islet cells insulin release occurs
basically modulated by the ambient levels of glucose in in waves with rapid spurts occurring at intervals of
plasma and interstitial fluid. During the postabsorption 5–15 minutes, as well as broad ultradian oscillations
period (fasting state), the basal rate of secretion is such waxing and waning every 90–120 minutes. Experimentally,
as to maintain a plasma level of 4–14 μU/mL. With inges­ it has been observed that infusion of similar amounts of
tion of food a prompt increase in the rate of secretion insulin in a pulsating manner achieves better metabolic
occurs, initially in response to neural (cephalic) stimuli outcome than at a constant rate.27
and release of incretin from the gut, followed by the rise in Ambient level of plasma glucose is the principal factor
the level of plasma glucose. The rise in insulin secretion as regulating insulin secretion. The first phase of insulin
reflected in plasma insulin occurs in two phases—a sharp secretion following a rise in plasma glucose is by prompt
first phase in course of 5–10 minutes followed by a gradual release of insulin from the insulin secretory granules
rise to reach the highest level in course of 30–90 minutes located close to β-cell plasma membrane. In response
depending on the nature of the feed: glucose or mixed to an increase in the level of glucose, there is an increase
meal. Plasma levels fall gradually thereafter to touch basal in the intracellular adenosine triphosphate (ATP) and
levels by two and half to four hours. The early spurt of adenosine monophosphate (AMP) causing closure of the
 Pathogenesis of Type 2 Diabetes 225

Table 16.4: Assessment of β-cell function In addition to glucose, raised levels of amino acids,
Basal state-fasting (8–12 hour) free fatty acids (acute) and GI hormones (incretins) such
Early, mid and remote postprandial periods as glucagons-like peptide (GLP-1) and gastric inhibitory
Standard OGTT, areas under the curves (AUC) peptide (GIP) augment insulin secretion. On the other
Insulinogenic index (I: G ratio) in response to glucose load hand, catecholamines, cortisol, growth hormone, leptin
Intravenous glucose bolus with rapid sampling and TNF-α depress α-cell response to secretagogues.
Insulin levels during continuous glucose infusion with variations and The appropriateness or adequacy of insulin values in

chapter
hyperglycemic clamp technique different situations must be assessed based on the preva­

16
In response to other secretagogues arginine, glucagon lent glucose levels as well as degree of IR. Kreisberg et al.
Monitoring of insulin levels in portal and hepatic venous blood described hyperinsulinemia in obesity.14 Hyperinsuline­
HOMA β-cell: Index of β-cell function at fasting state = 20 x insulin mia was later described in a large series of borderline
(mU/L)/ glucose (mmol/L)-3.5 diabetics (so termed impaired glucose tolerance curren­
Oral minimal model: measure of insulin secretion by mathematical
tly) in the absence of obesity, thus establishing the concept
modeling from glucose, insulin and C-peptide concentrations during
OGTT
of IR in diabetes15 (Figs 16.9A and B). Karam et al. first
Calculation of disposition index (interaction between insulin sensi-
demonstrated increased β-cell glucose sensitivity and
tivity and insulin secretion) secretory activity in obese subjects with IR. Subsequently,
(OGTT: Oral glucose tolerance test; HOMA: Homeostatic model
Bergman et al. demonstrated that as tissue sensitivity to
assessment). insulin decreases, β-cell function is augmented in order
to maintain appropriate homeostasis in persons not
ATP-sensitive potassium channels. With the resulting without proneness to diabetes.76,77 Furthermore, they devi­
depolarization of the cell membrane, there is an influx of sed a quantitative measure of the relationship between
calcium through voltage sensitive Ca2+ channels. Increase insulin sensitivity and insulin secretion. It was postulated
in the resultant intracellular calcium levels lead to that in case of normal β-cell function the product of
movement of insulin granules further toward the plasma insulin secretion and insulin sensitivity values (AIR × Si)
membrane and release of insulin from the granules into would equal a constant termed “Disposition Index”.
the circulation. Reduction in target tissue insulin sensitivity should upre­
The second phase of insulin release invokes synthesis gulate β-cell sensitivity to secretagogues and vice versa.
of new insulin and ATP-dependent mobilization of insulin β-cell defect can be envisaged if in case insulin secretion
granules from the storage pool to the site of release. This is not properly augmented in the presence of IR. This was
requires energy from metabolism of glucose following its shown in among a group of Pima Indians who initially
entry into the β-cells and its phosphorylation by gluco­ had NGT; those while manifesting IR did not show raised
kinase. insulin response to 1VGTT developed dia­betes during
The first phase of insulin release is important in that 7 years follow-up.5,76
it helps to suppress gluconeogenesis as well as facilitate The procedures for assessment of β-cell function are
glucose uptake by insulin sensitive tissues. The importance listed in Table 16.4.
of these metabolic phenomena was first elicited by Seltzer
et al. in 196773 who described depressed early insulin Defects in β-cell Function
response indicated by lower insulin levels at 30 minutes Cross-sectional studies reveal the following insulin sec­
after a carbohydrate test meal. The higher insulin levels at retory abnormalities indicative of β-cell dysfunction
2 hours, often attributed to IR, is in fact due to relatively (Table 16.5): Some of the defects may be secondary to
higher levels of glucose in the early post-meal period.74,75 glucotoxicity and lipotoxicity.
The reduction in early response to IV glucose estimated Hence, the possible primacy of the role of β-cell abnor­
at 3–5 minutes or a CHO test meal observed at 30 minutes malities and/or IR in pathogenesis of type 2 diabetes has
is evident even in individuals with impaired fasting glyce­ to be further examined by:
mia (IFG) and/or mild IGT. • Cross-sectional studies on normoglycemic subjects
Suppression of this early phase of secretion experi­ with genetic predisposition to type 2 diabetes
mentally by administration of somatostatin in normal • Studies on subjects with IFG and/or IGT
controls also elicits hyperinsulinemia at 2 hour, post­ - • Longitudinal follow-up studies on the evolution of type
cha­llenge. 2 diabetes
226 Etiopathogenesis of Diabetes Mellitus
section
5

A B
Figs 16.9A and B: Mean glucose and insulin levels during a 5-hour oral glucose tolerance test in normal weight patients15

Table 16.5: Beta-cell secretory characteristics in type 2 diabetes most up-to-date clamp technique. The results showed
• Inadequate first phase insulin secretion followed by relative
significant decrease in both first and/or second phases
hyperinsulinemia around 2 hours following carbohydrate load of insulin secretion (p < 0.001 and 0.01) in 50 normo­
• Decreased or loss of pulsatility in insulin secretion glycemic first degree relatives of T2DM compared to
controls; whereas difference in their insulin sensitivity
• Impaired sensitivity of b-cells to glucose as secretagogue as
well as impaired response to non-glucose stimuli such as was not significant.8 They concluded that defects in insulin
arginine, glucagon, SU compounds, and GLP-1 secretion rather than insulin sensitivity is likely to be the
• Higher proportion of proinsulin and split products in b-cell major factor predisposing to diabetes.
secretion (Plasma non-specific immunoreacting insulin) Gerich79 and Van Haeften et al.80 examined the relative
• Altered gene expression and transcription factor (C-MyC) importance of impaired β-cell function and insulin insen­
• Excessive secretion of amyloid polypeptides sitivity as the more important genetically determined
• Increased b-cell apoptosis
factor in the pathogenesis of T2DM and elicited evidences
to suggest the former to be the primary defect.
(GLP: Glucagon-like peptide).
Further Kahn81 and Pratley et al.82 have described
β-cell failure with impaired early phase insulin secretion
A number of studies on genetically predisposed nor- to be the key factors for the development of T2DM.
moglycemic subjects from highly susceptible groups Altered homeostatic adaptation of first and second phase
such as Pima Indians, Pacific islanders, Mexican β-cell secretion was shown in the offsprings of patients
Americans have revealed IR as a precursor and predictor with T2DM, which are considered to be important in the
of IGT and type 2 diabetes during the 80s and early development of diabetes. In Pima Indians early phase
90s. With the use of more sensitive methods for asses­ of insulin secretion (AIR glucose) in normoglycemic
sment of insulin secretion, more recently, an equally offsprings of diabetic mothers was found to be lower,
or even more important role of β-cell secretory defects particularly in those with onset of diabetes by 35 years of
were brought to the fore. age.83
O’Rahilly et al. were one of the earliest to assert β-cell Heritability for IGT and T2DM in twins (monozygotic
dysfunction rather than insulin insensitivity to be the and dizygotic) has been estimated as 50% for insulin
primary defect in familial type 2 diabetes.78 In order to secretion versus 26% for IR.84
test whether IR precedes impaired insulin secretion in A combination of IR and impaired insulin secretion
individuals genetically predisposed to T2DM, Pimenta has been documented in normoglycemic kindreds of
et al. examined 100 volunteers of European ancestry by patients with T2DM. Heritability is more remarkable
 Pathogenesis of Type 2 Diabetes 227

when disposition index calculated from Si × AIR is taken study, Van Haeften et al, assessed b-cell function and
into account than when either is considered alone.85 Both insulin sensitivity index with hyperglycemic clamps (10
IR and impaired β-cell function were found to be asso­ mmol/L). This study included 24 patients with impaired
ciated with impaired glucose metabolism in four ethnic fasting plasma glucose (FPG between 6.1 and 7 mmol/L),
groups in the US while β-cell dysfunction was found to 15 patients with type 2 diabetes (FPG > 7 mmol/L) and 280
be more important in determining glucose disposal.86 In subjects with normal fasting glucose (FPG < 6.1 mmol/L).
lean non-diabetic offsprings of T2DM patients, defective Mean first phase insulin release (0–10 minutes) was lower

chapter
insulin secretion was characteristic of patients with high in IFG (541 pmol/L) compared to 814 pmol/L in controls.

16
IR.87 Thus impaired β-cell function appears to precede The second phase insulin secretion was also lower in
appearance of abnormality in dysglycemia levels in subjects of IFG (251 pmol/L) relative to 295 pmol/L
genetically susceptible subjects. IR and insulin secretory in those with normal fasting glucose (NFG). They also
dysfunction are documented to be independent predic­ found a stepwise decline in first phase and second phase
tors of worsening of glucose tolerance during each stage secretion in NFG subjects with progressive decline in oral
of development of T2DM.9 A study on IR and impaired glucose tolerance. They concluded that the early stages
β-cell function in 2100 first degree relatives of T2DM of dysglycemia are associated with disturbances in β-cell
(FH+) and 388 controls (FH-) showed that both were function, while IR occurs more markedly in later stages.94
co-inherited in the pathogenesis of T2DM.88 Of the two, A large population-based study (n = 5396) from Fin­
impaired insulin secretion was considered to be deter­ land indicated that IFG and IGT represent two different
mined more by genetic factors than IR, consistent with populations with abnormal glucose metabolism. IGT
the findings from a study of monozygotic and dizygotic differed from IFG subjects with respect to impaired insulin
twin study by Lehtovirta et al.89 Thus the hitherto general secretion relative to level of glycemia measured as early
belief that insulin resistance does not happen to be the insulin response from OGTT and corresponding to the
primary factor while β-cell dysfunction occurs as a late degree of insulin sensitivity.95 Further, observations on
phenomenon due to exhaustion in course of compensatory subjects with isolated IGT in a population at high-risk for
hypersecretion85 appears to be untenable. It is more likely type 2 diabetes by Hanefeld et al. revealed a more severe
that predominantly acquired IR accelerates β-cell failure deficit in early and late phases of insulin secretion in
leading to development of T2DM. While accepting such comparison to subjects with IFG.96
an assumption, it has to be borne in mind that both factors Early insulin response as measured by plasma insulin/
are shown to be partly inherited and partly induced by plasma glucose (I: G) at 30 minutes revealed a significant
environmental factors although possibilities are that deficit in those with IFG, IGT and combined glucose
β-cell defects are mainly inherited,8,86,90 while IR depends intolerance (CGI) which was highest in the CGI group.
relatively more on acquired factors. In this study, IR was of minor importance in IGT while it
Longitudinal follow-up studies in Swedish women91 was more evident in subjects with IFG.
and men92 revealed fasting serum insulin concentration It has been observed that in genetically susceptible
and early insulin response as risk determinants for devel­ subjects lower acute insulin secretory response (AIR)
oping T2DM. In a 5-year follow-up study of initially non- to IV glucose and low rate of insulin stimulated glucose
diabetic Japanese Americans, a lower 30 minute insulin disposal (M) predicted conversion of NGT to IGT and
response to oral glucose used as an indicator of β-cell type 2 diabetes.9,97 Weyer et al. (1999) in either obser­
defect, appeared earlier than visceral adiposity in the vations on natural history of the process observed that
course of development of the disease.93 The predictive both abnormalities deteriorated progressively as indivi­
potential of IR and insulin secretory dysfunction asse­ duals traverse from NGT to IGT and then to diabetes.5
ssed by Weyer et al. revealed that during each stage of With use of less sensitive methods some observation
development of T2DM, IR with low insulin-stimulated suggest insulin secretory defect causes the transition from
glucose disposal (M) and low acute insulin response NGT to IGT while IR carries it from IGT to diabetes.96
(AIR) to glucose were independent predictors of worse­ On the other hand, Saad et al.(1991)98 found roles to be
ning of glucose tolerance.9 reverse in Pima Indians. Adopting the best available
Investigations in subjects with IFG and IGT or both methods in 2001, Weyer et al. observed that while subjects
have revealed similar results. In a recent cross-sectional of NGT with evidence of both lower AIR and M values were
228 Etiopathogenesis of Diabetes Mellitus

most prone to develop IGT over the course of 4 years, amyloid polypeptide (lAPP, amylin) which is copackaged
those with either AIR or M have comparable predictability in β-cell granules and is cosecreted with insulin in much
for the effect. A similar phenomenon was documented smaller amounts (–1.0%). Insoluble fibrils formed from
for the evidence of progression from IGT to diabetes.9 amylin may be deposited between the β-cells and the
In a large study with a long follow-up period, pro­ adjacent blood vessels. Deposits are observed in some
portional hazard analysis revealed that defects in both, subjects at advanced age (20%) and those with diabetes
insulin secretion and insulin action are independent and even by middle age (70–90%). Spontaneous islet amyloid
section

additive predictors of transition from NGT to IGT and deposits may occur in some other mammals as primates
IGT to diabetes.9 While disturbances in β-cell function and cats but not in rodents. With discovery of amylin gene’
5

underlies early stages of disturbed glucose homeostasis,94 (1988), it has been possible to induce similar amyloid
isolated IFG is more often associated with features of IR.95 deposits in mice for experimental observations.
Both IFG and IGT are reckoned as prediabetic stages. Not much significance was attached to these changes
Meta-analysis of several follow-up studies conclude that until Haward demonstrated correlation of extent of
the presence of both offers the highest risk of progression deposits to onset and progress of diabetes in Macacanigra
to diabetes while in spite of interstudy differences the risk species of monkeys.103 This led to intensive investigations
is almost similar in case of isolated IFG and IGT. on the role of amyloid deposits in the islets on structure
and function of β-cell.
Mechanism of β-Cell Dysfunction Amylin in large doses inhibits insulin secretion,
Primary Factors insulin-mediated glycogen formation in skeletal muscles
and delays gastric emptying but these actions are unlikely
Failure of β-cells to maintain appropriate level of insulin to have physiological significance in man. No defect
secretion is the final common path in the pathogenesis in amylin gene has been observed in cases with type 2
of diabetes mellitus. Subtle defects in β-cell secretory diabetes. Oversecretion of amylin in obese subjects with
function have been elicited to occur in normoglycemic long standing hyperinsulinemia does not necessarily lead
subjects genetically predisposed to T2DM. A further to amyloid deposits in the majority of cases who do not
decline occurs with the onset of prediabetes either isolated develop diabetes.
IFG, IGT or both. So far, there is hardly any clue for A reduction of number of β-cells by 40–50% occurs in
identifying the genetic determinants of β-cell dysfunction. pancreas affected by amyloid deposits, suggesting it has a
Unlike the monogenic (MODY) forms of diabetes T2DM is cytotoxic effect on β-cells, which have been demonstrated
known to be polygenic in origin. Collective contributions in some in vitro studies.104 Yet the relevance of the process
from a number of genes are thought to be operational in in vivo is open to question.
the pathogenetic process. Genetic defects may possibly In transgenic mice in spite of high amount of serum
involve glucose sensing, glucose phosphorylation and amylin (5 times) and greater extent of amyloid deposits
metabolism, ion channel, microfilament and microtubular some promoting agents are required to manifest cytotoxic
activity, islet proteins necessary for synthesis, packaging, effect on β-cells. There is no clue to say that amylin
movement and release of secretory granules.99 So far Pro- promotes apoptosis of β-cell. It is more probable that
12Ala in the PPAR and calpain-10 that modulates insulin amyloid deposits follow degeneration of β-cells in the
release have been identified to be involved.100 Further islets.
β-cell regeneration and apoptosis are most likely to be A pathogenic role for amyloid deposits in islet is
under genetic control. as yet totally unsettled.104 On the other hand, there are
However, the genesis of primary β-cell failure is still obser­vations to suggest a beneficial effect of amylin on
elusive, while secondary failure has been attributed to β-cell development and function.105,106 Pramlintide, a
“convergence of glucotoxicity and lipotoxicity”.101 synthetic analog of amylin with much longer half-life, has
been found to improve control of postprandial plasma
Amylin
glucose when given along with insulin, by delaying gastric
The possible role of islet amyloid deposits in the emptying time and suppressing glucagon. Pramlintide
progressive decline of β-cell function has been discussed (Symlin) has recently received approval of FDA (USA) for
extensively.102 The deposits are derived from a 37 AA islet clinical use.
 Pathogenesis of Type 2 Diabetes 229

Incretins, Glucagon-Like Polypeptide-1 has been observed to have a very short plasma half-life
(1–2 minutes), which makes it unsuitable for therapeutic
Incretins are physiologically operative regulators of insulin
use. A natural congener of the incretin “extendin 4” has
secretion. Both GLP-1 and glucose-mediated insulino­
been located in the salivary gland of Gila monster, a large
tropic polypeptide (Gastric Inhibitory polypeptide, GIP)
lizard living in the South Western desert of USA. This has
are derived from specific cells (L and K) located in the
led to synthesis of “exenatide”, a molecule with a long half-
intestinal mucosa, the former in the distal ileum and
life that can be used parenterally in 5–10 μg doses twice

chapter
colon and the latter in the duodenojejunal locations.
daily to achieve salutary therapeutic results.
Release of incretins occurs in response to reflex neural

16
Exenatide (Byetta) and Liraglutide have already
stimuli from ingestion of food and directly by products
been tested in large clinical trials and are in clinical use.
from carbohydrate, fat as well as (to a lesser extent)
These compounds have been found to achieve control of
protein components of the meal. Both GLP-1 and GIP
hyperglycemia and lower HbA1c when optimal doses of
powerfully potentiate glucose-mediated insulin secretion
metformin along with a sulfonyluria fail to achieve control.
very early in the postprandial period. This accounts for
Contrary to most other glucose lowering drugs, exenatide
the higher levels of plasma insulin in response to oral
helps to reduce body weight because of its effects on gastric
glucose in comparison to IV glucose at similar levels of
emptying and satiety. Hence supplement of exenatide
glycemia. Between the two incretin hormones, GLP-1 is
may be more desirable than insulin in obese patients in
of greater interest as it continues to be relevant inspite
such situation.108
of hyperglycemia in patients with diabetes, whereas GIP
Thus, as with amylin, although the role of GLP-1 defi­
does not. GLP-1 activity as a glucose-dependent insulin
ciency in the pathogenesis of type 2 diabetes is uncertain,
secretagogue is to an advantage as it stops operating when
it has provided clue for a group of very promising products
glucose levels fall below 60 mg/dL and thus appears safer
for therapeutic use for control of diabesity, i.e. diabetes
compared to sulfonylurea compounds. Further GLP-1
along with obesity.
exerts negative effect on appetite and reduces food intake
by promoting satiety.
Secondary Causes
In addition to functioning as a stimulator of β-cell
activity GLP-1 acts on other islet cells (α and δ) with an Several acquired factors may accentuate defects in β-cell
overall inhibiting effect on glucagon secretion and mod­ function leading to dysglycemia and diabetes mellitus.
ulatory effect on insulin hypersecretion. It has inhibitory One of the earliest to operate may be “malnutrition in utero
action on gastric mobility, thereby delaying gastric and early childhood”. Hoet and coworkers demonstrated
emptying as well as acid secretion. In addition, GLP-1 impairment of β-cell function in litters of rats fed on low
promotes glycogenesis in the liver and muscles and protein diet.109 Persistent impairment of insulin secretory
lipogenesis in adipose tissue thus helping in the reduction response has been observed in 3–week-old rats after
of hepatic glucose output and lowering of glucose in limited periods and intermittent feeding of low protein
circulation. On the β-cells, GLP-1 acts as an antagonist diet.110 The same phenomenon has been documented in
to leptin and counteracts its suppressing effect on insulin young rhesus monkeys.111 Such β-cell dysfunction, in case
secretion. In addition GLP-1 has the property of promoting of malnutrition in utero as well as in infancy and early
proinsulin synthesis and β-cell replication to compensate childhood, has been projected as the basic mechanism
for cell loss from natural apoptosis. in the pathogenesis of malnutrition-modulated diabetes
Any possible role of altered GLP-1 status in the mellitus seen among the poor in some tropical areas.112,113
pathogenesis of type 2 diabetes is yet to be defined. No Barker and coworkers59 during the last decade of the 20th
abnormality has been detected in genes for GLP-1 or its century, have clearly established the role of maternal
specific receptors. Lower postprandial plasma levels of malnutrition and low-birth weight on the development of
GLP-1 in type 2 diabetes reported by some but contradicted T2DM later in life. It has been proposed that malnutrition
by others has to be, if at all, an acquired phenomenon. in utero and during first few months after birth may
Glucoincretin effect of GLP-1 has been reported to be damage β-cell development as well as may program the
diminished in type 2 diabetes.107 Its significance can be β-cells so as to limit its ability to cope with overnutrition
assessed only from the effect of the peptide or its ana­ and obesity in later life. This acquired weakness of β-cells
log on glycemic control. On IV administration, GLP-1 may lead to failure of β-cells to compensate for raised IR.
230 Etiopathogenesis of Diabetes Mellitus

Details of this novel concept and related observations are others that do not depend on insulin for glucose transport.
discussed in Chapter 19. Hence, broadly glucose toxicity covers damage to the
The possibilities of iatrogenic adverse affect on β-cells tissues that manifest chronic diabetic complications in
are far from meagre. β-cell dysfunction may be induced addition to its crucial effect on function and structure of the
by thiazide diuretics, diphenylhydantoin, pentamidine β-cells. The phenomenon that exposure to high circulating
and cyclosporin among drugs in common use. Chemical glucose of 350 mg/dL for short periods (48 hour), renders
agents such as alloxan and streptozotocin used for experi­ the β-cells refractory to further glucose stimulation has
section

mental induction of diabetes, rat poison pyriminil (vacor) been noticed in case of cultured β-cells in vitro.119 In
subjects with uncontrolled type 2 diabetes reduction
5

and other nitroso compounds are well known as β-cell

of blood glucose by any means, even by metabolically
toxic agents.
inactive phlorizin, improves β-cell secretory response to
Discussed below are two far more important metabolic
glucose stimulus.58 For a period, β-cells remain responsive
phenomena—glucotoxicity and lipotoxicity, that univer­
to non-glucose secretagogues such as arginine, glucagon,
sally interfere with insulin action as well as β-cell function tolbutamide, although in course of time effectiveness of
in patients with type 2 diabetes. these agents is blunted or lost. Experimentally prolonged
raising of mean blood glucose by 15 mg over the accepted
Glucotoxicity norm in partially pancreatectomized animals induce
During the last several years, it has been established irrevocable failure of β-cells to respond to glycemic
that hyperglycemia has a deleterious effect on secretory stimuli.120 During periods of hyperglycemia with desensi­
tization of β-cells, there may be an increase in proportion
function of the β-cells. First suggested by Haist et al. in
of proinsulin as observed clinically in patients with
1940,114 the phenomenon was later studied in detail by
T2DM.121
distinctively elucidated half a century later by Rossetti and
Biochemically, β-cell desensitization and secondary
DeFronzo and named under the caption of glucotoxicity.115
defects are believed to be brought about by excessive
It has been observed that acute spurts of hyperglycemia
oxidative stress. Glucose metabolism is normally asso­
adversely affects secretory response to glucose by “desen­
ciated with generation of oxygen free radicals. Physio­
sitizing” the β-cells.116
logically the radicals so generated are mopped up by usual
Chronic hyperglycemia adversely affects insulin secr­
defense mechanism. In the event of hyperglycemia, there
etion in three stages: glucose desensitization, β-cells
is excessive generation of reactive oxygen species (ROS)
exhaustion and glucotoxicity. Glucose desensitization
in the insulin secreting cell, thereby interfering with its
occurs after short exposure to elevated glucose and during function.122
the early phases of chronic hyperglycemia. It connotes Such adverse effect may be experimentally pre­vented
refractoriness of the secretory mechanism to glucose by appropriate antioxidant therapy, such as aminogu­
stimulus which is reversible following alleviation of the anidine.123 Chronic oxidative stress due to ROS is known to
hyperglycemia state.117 operate through the induction of excess of glucose auto-
β-cells exhaustion implies depletion of the readily oxidation, PKC activation, methyl glycosal formation of
releasable pool of intracellular insulin. It follows pro­ proteins and glycosylation.124
longed stimulus from high level glucose in perfusion This biochemically-induced desensitization stage of
fluid. Although the whole spectrum of changes is reco­ glucotoxicity is largely reversible by induction of normo­
gnized as glucotoxicity the term more strictly refers to glycemia. Improvement occurs in glucose tolerance
irreversible β-cell changes following long periods of (Fig. 16.10), insulin secretion126 (Figs 16.11A and B) as well
exposure to unrelenting hyperglycemia.117 In the long as insulin sensitivity.126
run, chronic hyperglycemia may reduce β-cell mass by In the long-run persistent hyperglycemia for prolonged
promoting apoptosis.118 Thus hyperglycemia is not only periods may induce non-reversible changes in the β-cell
a signal marker of diabetes mellitus, it also operates as function because of involvement of gene transcription
a pathogenic factor for aggravating and perpetuating it leading to a decrease in insulin synthesis and secretion.
by continued impairment of insulin production. Further­ Robertson et al. assert that the term “glucotoxicity” should
more hyperglycemia initiates tissue damage to cells in a be reserved for such a stage, while the reversible phase
variety of tissues such as the vascular endothelium and should be described as “desensitization”.117
 Pathogenesis of Type 2 Diabetes 231

chapter
16
Fig. 16.10: Mean plasma glucose (solid line) and insulin values (dotted lines) in response to oral glucose before therapy and on control of
hyperglycemia by any form of therapy126

A B
Figs 16.11A and B: Plasma insulin level expressed for gram of residual pancreatic tissue during hyperglycemic clamp studies performed on
sham-operated (cyan bars) and 90% pancreatectomized diabetic rats (gray bars) before and after control of hyperglycemia with phlorizin (black
bars). Left panel-first phase insulin secretion (0–10 minutes); Right panel-second phase, insulin secretion (10–60 minutes)126

Lipotoxicity acyl-CoA which is transported into the mitochondria

by carnitine palmitoyltransferase to be metabolized by
The effects of chronically raised FFA on the diabetic state β-cells . In the event of postmeal, rise in glucose concen­
has been termed “lipotoxicity”.127 The role of persistently tration impedes this process, leading to rise in intracyto-
elevated FFA in circulation and in tissue cells on IR128 solic content of FA acyl-CoA which enhances synthe-
has already been discussed. Recent investigations have sis and release of insulin. On the other hand, chronic
established its adverse action on secretory function of the exposure to elevated levels of FFA and consequent rise
β-cells. in intracellular FA acyl-CoA leads to inhibition of insulin
Physiologically lipids play an auxiliary role in glu- secretion. Randle129 attributed this effect to increase in
cose-induced insulin secretion. FFA molecules are inter­ β-oxidation with rise of acetyl CoA. This leads to inhibition
nalized into β-cells with help of fatty acid binding protein of pyruvate dehydrogenase and elevation of citrate levels
2 (FABP 2). These are conjugated to form long-chain FA which inhibit phosphofructokinase and glycolysis. There
232 Etiopathogenesis of Diabetes Mellitus

is an increase in diacyl glycerol with activation of PKC. Lorenzo et al, have shown that human amylin is toxin to
The resultant downregulation of insulin secretion and bio- insulin producing b-cells of the adult pancreas of rats and
synthesis was shown from observations on experimental humans.135 The role of amylin, its effect on islet structure
animal models.130,131 Impaired insulin secretion persists for and b-cell function has already been discussed above.
long periods after exposure of islets (in vitro) to high levels
of lipids.132 β-Cell Mass
Thus, fatty acids which are essential β-cell fuels in In the face of difficulties in accurately estimating β-cell
section

normal state become toxic when chronically in excess. mass in autopsy material morphometric analysis sug­
5

There is inhibition particularly of glucose-induced insulin gests a modest loss of 30% in subjects of type 2 diabetes
secretion.133 In addition, inhibits insulin gene expression
compa red to controls.136 More recently a study at Mayo
in the presence of elevated glucose. Moreover, excess of
Clinic (2003) showed β-cell mass to be reduced by appro­
FA may also induce β-cell death by apoptosis.134
ximately 40%, both in case of the obese and the lean
Thus both chronic hyperglycemia and hyperlipidemia
subjects.137 Yet this loss can only partly account for over
exert deleterious effects on β-cell function and accelerate
80% decrease in insulin secretory capacity of the patients
the progression of type 2 diabetes. It has been observed
as estimated by hyperglycemic clamp technique.138 There
that hyperglycemia is a prerequisite of lipotoxicity. Pro­
is usually a small increase in number of β-cells in the islets
longed exposure of isolated islets to fatty acids decrease
examined at autopsy.
insulin gene expression only in the presence of high
glucose concentration. Results from in-vivo experiments The loss of β-cell mass has been attributed to on
on JDF and Goto-Kakizaki (GK) rats also support the accelerated β-cell apoptosis.134 Chronic hyperglycemia
hypothesis that hyperglycemia is a prerequisite for and hyperlipidemia are considered as important patho­
lipotoxicity.101 β-cell secretory defect is not apparent in genetic factors for this process.139
familial hyperlipidemias.
Hyperproinsulinemia
β-cell failure in type 2 diabetes is an evolving process.
Chronically elevated blood glucose and FFA levels by One other secretory defect that may account for failure of
adverse effects on β-cell function (glucolipo-toxicity) glycemic control is disproportionate increase of proinsulin
operate to enhance the severity of the diabetic state in the in the β-cell secretory product.140 Hyperproinsulinemia is
usual course of the disease. a marker of β-cell dysfunction in type 2 diabetes mellitus.
The increase in proinsulin levels correlate directly with the
Islet: β-Cell Changes in T2DM grade of hyperglycemia.141
Islet Amyloid Both the basic factors in the pathogenesis of T2DM,
IR and β-cell dysfunction depend on genetic and environ-
Characteristically amyloid deposits are observed in a
mental factors for their origin, development and operation.
high proportion of pancreatic islets in patients with type
2 diabetes. Amylin, major constituent of the amyloid Islet : α-Cells Changes in T2DM
deposits, is cosecreted with insulin. Amylin (Islet amyloid
polypeptide) has been observed to restrict insulin release Extensive work by Unger and coworkers has led to the
from perfused rat pancreas only in hyper physiological concept of diabetes mellitus as a bihormonal disorder
doses. It is unlikely to be a factor in the pathogenesis of characterized by insulin deficiency along with a relative
T2DM as higher amounts secreted in hyperinsulinemic excess of glucagon.142 The subtle role played by glucagon in
obese subjects does not lead to diabetes in majority of the pathogenesis of type 2 diabetes has been clearly elici­
them. ted by Lasson and Ahren of Malrno, Sweden. AIR to oral
Experimentally, islet amylin polypeptide (IAPP) defi­ glucose and glucagon response to 5 g arginine revealed low
cient mice develop more severe form of alloxan-induced insulin (disposition index) and high glucagon in subjects
diabetes. Gebre-Medhin et al, suggest a beneficial effect with IGT. Further, those with IGT had lower glucose-
of amylin on b-cell function by postulating that up-regula­ induced inhibitory effect on glucagon secretion.143 It may
tion of IAPP expression compared with that of insulin be construed that inappropriately high levels of glucagon
in experimental rodent diabetes could protect islets in in prediabetes promotes hyperglycemia by raising hepatic
a metabolically challenging environment.105 Alternately, glucose output and mobilization of free fatty acids.
 Pathogenesis of Type 2 Diabetes 233

The clinical usefulness of suppression of glucagon secr­ Despite the plethora of data on familial aggregation
etion by use of GLP1, its long acting analog exenatide of diabetes the mode of inheritance has defied definition
and a DPP-4 inhibitor (LAF-237) that protect endogenous and it has been even more difficult to identify the involved
GLP1 indicates the persistent role of glucagon for main­ genes.
taining hyperglycemia in type 2 diabetes mellitus. Using the candidate gene approach, genes for several
crucial key factors such as gene for insulin, intestinal
Genetic Factors FABP 2, glycogen synthase, glucose transporters, b-adre­

chapter
The prime importance of genetic factors in the patho­ nergic receptor (b3 AR), hexokinase II, PI3-kinase, islet

16
genesis of diabetes was realized by ancient Indian physi­ amyloid polypeptide, Vitamin D receptor, etc. have been
cians Charak and Sushruta (~600 BC) who first described studied thoroughly and scanned without much success in
Madhumeha (diabetes) as a genetically determined establishing specific linkage.
disease and hence incurable. During the last several The more recent emphasis on “adiponectin” gene may
decades, large data has been generated to establish that yield some useful results.
type 2 diabetes is basically a heritable disorder. Results The other possibly superior method termed “positi­
from cross-sectional and longitudinal studies of families, onal cloning”, makes a priori no assumptions about the
offspring of diabetic parents, (both or either) siblings, underlying biochemical abnormality. Instead it aims at
other first degree relatives and above all mono and identification of chromosomal regions where affected
dizygotic twins of diabetic probands clearly establish the sib pairs share alleles more than expected by Mendelian
hereditary character of the disorder. inheritance. Genome wide scans for type 2 diabetes in
The risk of parents of diabetic probands to manifest different populations have pointed at regions on chrom­
the disease is nearly twice of that in general population. osome 2 and 15 in Mexican Americans,151 chromosome lq
The lifetime risk of offsprings of a diabetic parent is (NIDDM 2) and chromosome 20 in Finnish population,152
2–3 times higher, more when the probands developed chromosomes 1, 7 and 11 in Pima Indians as constituents
diabetes below age of 50 than above 50 years of age.144 of the polygenic substrate of type 2 diabetes.153
Sibs of younger diabetic probands are at higher risk Intronic variation in Calpain 10 gene, which encodes
(45 times) than the older patients (2–3 times). All these the protein calpain 10, has been associated with type 2
indicate the importance of genetic inheritance in the diabetes in Mexican Americans and Europeans.154, 155
young, while environment plays a relatively greater role Genome wide scans have revealed chromosomes 17, 6,
in the older group. Observation on offsprings of conjugal 11 and 14 to have loci for susceptibility to diabetes among
(both parents) diabetes and twin studies provide further Europeans while in the Chinese linkage to chromosome
evidence on the role of genetic inheritance. Up to 60% of 6 and chromosome 1 has been implicated in genesis of
offsprings of conjugal diabetes develop the disorder by 60 type 2 diabetes.
years of age in Caucasians145 while the proportion has been Currently, out of a variety of candidate genes, a few are
found to be higher among South Indians.146 Monozygotic considered important in the pathogenesis of type 2 dia­
twins of diabetic patients have a 50% to over 90%147 risk of betes. These are: Calpain-10, Kir 6.2, hepatocyte nuclear
manifesting diabetes within 5–15 years. Twins with strong factor 4 α gene, transcription factor 7 like gene and peroxi­
family history are much more likely to develop diabetes. some proliferator-activated receptor-α gene. Many of
Investigations such as glucose tolerance test, insulin these genes, specifically the PPAR-α gene operate through
secretion and clamp studies detect prediabetes (IFG, IGT), the production of obesity. In the non-obese Asians Indians,
early insulin secretory abnormalities and/or IR in a larger ENPP-1K121Q gene causes IR.156
proportion of subjects with familial predisposition. Nearly The topic of Genetics of Diabetes is separately dealt
half of those detected with prediabetes may progress to with in Chapter 21.
manifest frank diabetes.
The prevalence of diabetes varies considerably in Environmental (Acquired) Factors
different ethnic groups living in the same social and geo­
graphic environment. Genetic admixture between high Over a background of complex polygenic patterns of
and low prevalence populations such as native Americans inheritance the development of diabetes is largely deter­
or Pacific islanders with Caucasians as in Mexican Ame­ mined by several environmental factors. While both imp­
ricans148 and some Nauruan subjects149 predicts prevalence aired β-cell function and IR are basically inherited, the
almost with mathematical accuracy.150 latter, in particular, is greatly modified by the environment.
234 Etiopathogenesis of Diabetes Mellitus

excess TG in hepatocytes, myocytes and β-cells as well

as raised circulating free fatty acids and humoral
factors such as TNF-α associated with obesity have already
been discussed.
Appropriate control of body weight has been utilized
both for prevention and amelioration of type 2 diabetes.
Control of adiposity by exercise, diet or drugs has been
section

seen to improve glycemic control, lipid profile and quality

5

of life.

Physical Activity
Studies on several ethnic groups have revealed the preva­
lence of diabetes in the sedentary physically inactive
subjects is 2–3 times higher than the people of the same
Fig. 16.12: Correlations of prevalence of diabetes and mean body community who are physically active.159 Prospective
weight in adult populations of 10 countries studied by KM West
studies have shown that even modest levels of physical
activity are associated with lower risk of type 2 diabetes.160
This is most apparent by comparing frequency of the
Based on a feasibility study162 at Malmo, Sweden, several
disease among migrants with persons in the native comm­
randomized studies have shown that lifestyle modification
unity. While having the same genetic make up migrant
mainly characterized by appropriate physical activity
Asian Indians in South Africa, Fiji, Caribbeans and many
in subjects with impaired glucose tolerance lowers the
other places used to have greater prevalence of diabetes in
progression to overt diabetes by more than 50%.162-164
a much larger proportion of subjects than among natives
in India until the 80s of the last century. Similar is the case The wide difference in the prevalence of diabetes
with the Chinese and the Japanese.157 The prevalence of between rural and urban populations is substantially
type 2 diabetes in Pima Indians increased by more than attributed to the corresponding levels of physical activity.
40% between 1967 and 1977 when they were housed in Urbanization is recognized as a potent environmental
comfortable reservations.158 The recent explosive rise in predisposing factor for development of T2DM. Urban and
prevalence of diabetes in several developing countries is rural differences in prevalence of diabetes in the same
fully attributed to acquired factors, viz. changes in lifestyle community were highlighted in most epidemiological
involving increase in calorie intake and reduced physical studies in India165 (Fig. 16.13) and by global estimates by
activity. The environmental factor may operate through King et al.166 The difference is estimated to be on the rise
epigenesis. (Fig. 16.14). Apart from the hypothetical effect of stress,
reduction in physical activity and alteration in dietary
Obesity pattern are the factors that fosters pathogenesis of type 2
diabetes and raise the prevalence of the disease among the
Aging and obesity are estimated to account for 35%
urban population.
variation in insulin action. While aging has a relatively
minor effect, obesity contributes substantially to IR and
progression to diabetes in those genetically susceptible.
Diet and Nutritional Factors
There is a close relationship between obesity and the Alterations in the dietary pattern in migrant and urbanized
risk of development of type 2 diabetes in any community populations are important factors that predispose to the
(Fig. 16.12). The risk rises steadily along the median range increased prevalence of diabetes, along with adoption
of BMI (19–25) but exponentially above that range such as of western lifestyle among them. The recent explosive
30–40. Even more than gross-generalized adiposity, the increase in incidence of diabetes in populations of
risk for diabetes may be determined by the distribution developing coun­tries has been largely attributed to dietary
of fat in the body. Central (visceral) adiposity assessed by changes based on western acculturation.
waist-hip ratio or waist circumference is a more powerful The food practices adopted by migrants and urbanites
predictor of the risk of diabetes than BMI alone. Adverse in developing countries in recent decades are shown in
effects of large adipocytes in truncal subcutaneous tissue, Table 16.6.
 Pathogenesis of Type 2 Diabetes 235

chapter
16
Fig. 16.13: Prevalence of diabetes in rural and urban habitats (Indian Fig. 16.14: Rural prevalence ratio for diabetes in 1995 and as projec­
data)165 ted up to 2025 in developing countries166

Table 16.6: Food practices adopted by migrants and urbanites in important role in the mechanism of insulin release.
developing countries in recent decades Deficiency of Vitamin D has been linked to lower insulin
Diet and related factors that promote diabetogenesis: secretion and glucose intolerance among South Asian
• Calorie (energy) intake in excess of physical needs leading to residents of East London167 (see chapter 70).
obesity
• Preferential and excess consumption of high glycemic index THE NATURAL HISTORY OF
carbohydrate rich-food items bereft of plant fibers, viz. TYPE 2 DIABETES
– Refined flour, pasta, raw rice
– Overcooked products of the above by baking or roasting
Progressive β-Cell Decompensation
– Aerated soft drinks Inappropriate and inadequate secretion of insulin is basic
– Sweets and free sugar to pathophysiology of diabetes mellitus. Reduced insulin
•  Consumption of High fructose corn syrup secretion can be attributed to: (1) Loss of β-cell mass or
• High fat diet with greater content of saturated fat such as dairy (2) Defects in β-cell function. While β-cell loss is crucial
and/or meat fat for development of type 1 diabetes, functional defect is of
– Coconut or palm kernel oil greater importance in the pathogenesis of type 2 diabetes.
– Hydrogenated oils with excess transfatty acids (vanaspathi) Although a proportion of cases with T2DM may mani­
– Disproportionately high Omega 6 fatty acid intake particularly fest at younger age, most of them are diagnosed later in
as corn, sunflower, safola oils in proportion to Omega 3 life. As such common evidence for altered β-cell function
• Excess consumption of energy dense (fat and sugar rich) snacks may be traceable only around the thirties or later years.
and meals at fast food outlets in urban and semiurban areas
Up to then β-cells, although genetically programmed
• Reduced consumption of legumes, fresh fruits and vegetables for gradual failure in the event of stress,7 function adeq­
uately so as to maintain fasting plasma glucose between
While obesity from excess calorie intake and excessive 70 mg/dL and 90 mg/dL and postprandial values within
fat consumption leads to IR, consumption of high glyce­ 130 mg/dL. Beyond this period of apparent normalcy,
mic index fiber free diet causes stress on genetically predi­ the story of β-cell decompensation may be considered
sposed β-cells leading to its failure. to develop in four hypothetical phases.139 Complex inter­
Deficiencies of certain trace elements such as chro­ action with IR that is substantially inherited and largely
mium, zinc, selenium and antioxidants have been acquired is intimately involved in the process.
discussed as factors involved in the pathogenesis of These phases have been defined based on experi­
diabetes. More recently Vitamin D deficiency has been mental evidence in rodent models for 1type 2 diabetes as
added to the list. Vitamin D has been found to play an well as on clinical observations. Phase 1 is characterized
236 Etiopathogenesis of Diabetes Mellitus

Phase 4—Decompensation with structural damage:

Along with the gross-functional decompensation of β-cells
structural changes have been demonstrated in rodent
models (Sand rats, JDF and GK rats) as well as in humans
at autopsy. These comprise of: (1) Amyloid deposits;
(2) hydropic degeneration; (3) Lipid droplets; (4) Glycogen
deposit; (5) apoptosis of cells and (6) fibrosis. The absence
section

of neogenesis and cell replication results in around

40% loss in the β-cell mass. Figure 16.15 provides a sche­
5

matic diagram indicating events during the four phases of

β-cell failure.
These observations corroborate the dictum of Polonsky
and co-workers suggesting that type 2 diabetes is a
genetically programmed failure of the b-cell to compensate
for IR.7 Further, Groop et al and, Defronzo and co-workers
Fig. 16.15: Schematic presentation of developments in course of share a similar view where it has been proposed that
evolution of type 2 diabetes in four hypothetical phases abdominal obesity with fat deposits in muscle, liver and
pancreatic b-cells can provide a common explanation
by successful adaptation to increased demand for insu­ for defects in insulin sensitivity, insulin secretion and
lin to overcome IR in the vast majority of cases with in HGP.32,168 The genes predisposing to the metabolic
predisposition to T2DM mostly in obese but also in syndrome and type 2 diabetes are energy-saving thrifty
the non-obese. There is an increase in the β-cell mass genes56 that increased the survival of our ancestors by
with apparent preservation of glucose-induced insulin storing energy as visceral fat. This may be working as
secretion of individual cells. Serum insulin levels remain background for high prevalence of type 2 diabetes among
normal or higher (hyperin­sulinemia). Pima Indians, Pacific islanders, Australian aboriginals
Phase 2 is indicated by earliest signs of decompen­ and recent explosive epidemics in several developing
sation. As the intrinsic weakness of β-cells is manifested countries.
by rise of basal plasma glucose up to 100 mg/dL (5.6
The vexing question of relative priorities in the
mmol/L), there is impairment of acute glucose-induced
defective insulin secretion and insulin action remains still
insulin response. By the time FPG rises up to 115 mg/dL
a matter of debate. The overemphasis on primacy of IR
(6.4 mmol/L), there is complete loss of first phase of
up to early 1990s was mainly possibly due to the finding
insulin response while insulin stores remain normal and
of hyperinsulinemia in the early stages of T2DM. Higher
response to non-glucose secretagogues is preserved (stage
insulin response to glucose may be noted in course of
of prediabetes). Second phase of insulin response may be
progression from NGT to IGT. The second phase of insulin
higher and persists longer.
Phase 3: Overt decompensation sets in with pro­ secretion may rise higher than in controls for some years
gressive β-cell dysfunction and is manifested by rise of after onset of diabetes mellitus. Yet when insulin values are
glucose levels to diabetic range. Glucose-induced insulin compared to corresponding glucose levels the hypothesis
secretion is grossly impaired and responses to non-glucose loses strength.169
secretagogues are compromised. The second phase of Hence, it is possible that both factors are equally
insulin response may remain high, normal or higher but responsible for the pathogenesis of type 2 diabetes. So far
grossly inappropriate for the levels of plasma glucose, it is conceded that whichever comes first the other follows.
β-cells are degranulated with a fall in insulin mRNA. The biological and cytological changes detected in the islet
Cell differentiation is grossly deranged with alteration in cells during the phases of development of type 2 diabetes
metabolic genes and key transcription factors. are listed in Table 16.7.
As observed in the UKPDS study following onset Skyler in a leading article170 reported that greater
of overt diabetes, β-cell dysfunction continues to progress emphasis was laid by US investigators on IR while in
at variable pace while IR maintains its level (except may be Europe due attention has been paid to defects in insulin
in special situations). secretion. This is reflected in the recent report of WHO171
 Pathogenesis of Type 2 Diabetes 237

Table 16.7: Major biochemical and cytological changes in beta-cell

during evolution of type 2 diabetes
Prediabetes
• Normal enzymatic and genetic profile
• Slow rise in plasma glucose within normal range
• Reduced acute glucose induced insulin secretion at basal
plasma glucose level of 100 mg/dL

chapter
• Preservation of responses to non-glucose secretagogues

16
• Normal insulin stores
• Early b-cell dedifferentiation
Frank Diabetes
• Decompensation, plasma glucose in the diabetes range
• Decreased gene expression of Glut 2, glucokinase, pyruvate
decarboxylase
• Increased gene expression of LDH, hexokinase, glucose- Fig. 16.16: Stages of glucose tolerance and corresponding levels of
6-phosphatase and the transcription factor C-Myc beta-cell function and insulin sensitivity from stage of prediabetes to
type 2 diabetes174
• Second phase insulin secretion near normal or high, but tardy
and inappropriate (low corresponding to levels of plasma glu-
cose)
• Grossly diminished or loss of glucose induced insulin secretion been estimated to be heritable up to 60% and as conceded
as well as to non-glucose secretagogues by Gerich is an equally important risk factor in the
• Increased ratio of proinsulin to insulin pathogenesis of type 2 diabetes. Based on reports from
• b-cell degranulation, reduced insulin stores Kahn,83 Partley and Weyer84 and Gerich174 the natural
Structural Damages course of insulin sensitivity and β-cell function during the
• Apoptosis evolution of type 2 diabetes is shown in Figure 16.16.
• Amyloid deposits
The concept of possible simultaneous operation of the
two basic pathogenetic factors suggested by DeFronzo169
• Glycogen deposits
has been corroborated by recent work of Tripathy et al.25
• Fibrosis
who observed that defects in muscle, liver and islets
• Perceptible (40%) loss of b-cell mass
occur in parallel and correlate with increase in abdominal
obesity and circulatory FFA concentration (Fig. 16.17).
and American Diabetes Association (ADA).172 WHO report Thus, there are observations to suggest that both IR and
expresses that there may be predominant IR with relative impaired β-cell function are usually present early in
insulin deficiency or predominantly insulin secretory the natural history of the disease and that both operate
defect with or without IR. On the other hand, from ADA's in parallel often in an interdependent manner to account
perspective, IR has to be the key factor either way. The for the pathogenesis and progression of type 2 diabetes
observations of Arner et al,173 using euglycemic clamp mellitus.
technique suggested different etiologies of type 2 diabetes Classically, the pathophysiological perturbations in
mellitus in obese and non-obese subjects. This small type 2 diabetes have been described in the beta cell,
study revealed a combination of insulin resistance and liver and muscle, as the so-called triumvirate. DeFronzo
defective insulin secretion in 16 obese diabetic subjects has synthesized the ideas regarding the contribution of
compared to only a secretory defect noted in 12 lean other organ systems: adipose tissue, intestine (incretins),
diabetic subjects. These results support the view expressed pancreatic α-cell, kidneys and brain.175 The role of
in the WHO group report. adiposity, increased free fatty acids and lipotoxicity has
As summarized by Gerich174 present evidences suggest been described above. The intestinal mechanisms operate
impaired β-cell function originates from to be the genetic via deranged incretin axis as described above.176-181
component while IR evolves from the environmental The non-suppressibility of glucagon has been descri­
factors, although there could be an overlap. Yet IR has bed in type 2 diabetes.182-187 It may be responsible for
238 Etiopathogenesis of Diabetes Mellitus

Basically the pathogenesis of type 2, the most prevalent

class of diabetes, centers around “insulin resistance” and
idiopathic “α-cell dysfunction”.
Although it is clear that diabetes cannot appear until
β-cells fail to secrete the amount of insulin required to
maintain metabolic homeostasis, up to 1990s IR was for
long considered to be of prime importance in the patho­
section

genesis of type 2 diabetes in contrast to type 1 occur­

5

ring from absolute insulin deficiency. Observations of

adequate or high insulin levels at stages prior to and
during prediabetes, particularly in populations with high
prevalence of diabetes corroborated such views. Reduced
insulin sensitivity (IR) in skeletal muscle, liver and adipose
tissue is the major factor in the vast majority of subjects,
Fig. 16.17: Total body insulin sensitivity (closed circles), b-cell function typically overweight or obese, for increasing the demand
(opened circles) expressed as disposition index and hepatic insulin
sensitivity (closed triangels) in relation to sixtiles of fasting plasma
on secretion of insulin and expression of diabetes in those
glucose genetically prone, as β-cells fail to meet the excessive
Source: UK Prospective Diabetes Study Group. UK Prospective Dia- demand.
betes Study 16: overview of 6 years’ therapy of type II diabetes: a
progressive disease. Diabetes 1995;44:1249-58.
On the other hand in course of the last 10–12 years,
however, recently with the application of more sensitive
methods for assessment of β-cell function, evidence of
increased HGP.188 More recently, the kidneys have been
defective insulin secretion was shown across the entire
added to this list. Normally, the kidneys filter about
spectrum suggesting that both are responsible for T2DM.
160 g of glucose daily; 90% of this is reabsorbed by a
These observations have been elicited right from the period
transporter called SGLT-2 at the proximal convoluted
of genetic predisposition and during subsequent phase of
tubule. The remaining 10% is absorbed from the desce­
prediabetes. Hence more recently, it has been proposed
nding proximal tubule with the help of another glucose
that a more or less parallel decline in β-cell function along
transporter called SGLT-1. In type 1 diabetes the maximal
with coexistence of IR operates in course of development
tubular reabsorptive capacity for glucose (Tm-glucose)
of type 2 diabetes.
is increased.189 This may also be true of type 2 diabetes.
Furthermore, in addition to the role of hyperglycemia
Inhibition of SGLT2 can cause increased glucose excretion
(glucose toxicity) in aggravating the diabetic state and
in the urine, thus providing a newer avenue for diabetes
its consequences, the role of raised plasma FFA and its
management. Lastly, in obese as well as type 2 diabetics,
consequent effects on IR, b-cell function and certain
the ventromedial and paraventricular nuclei in the hypo­
metabolic aberrations leading to short and long-term
thalamus region are resistant to insulin action. Hence,
complications of type 2 diabetes has been recognized.
inspite of higher insulin levels, the suppression of appetite
Both IR and β-cell dysfunction are genetically deter­
normally produced by insulin is not seen.190-195 This leads
mined. Of these, the former is more liable to be modified
to disruption of satiety mechanism.
by environmental factors.
In conclusion, it may be stated that while the dictum of
SUMMARY
Polonski et al. (1995) that Type 2 diabetes is a genetically
Type 2 diabetes was in the past referred to as maturity programmed failure of β-cell to compensate for IR still
onset type and NIDDM. Both these clinical types were holds good, the DeFronzo (1998) hypothesis of “combined
widely heterogeneous. With stress on etiology in classi­ defects in insulin sensitivity and insulin secretion” appear
fication both ADA and WHO (1997, 1998) opted for the to hold more ground in the light of recent research in
term “type 2”. This serves to exclude minor forms such the field. More recently, the roles of incretin hormones,
as MODY and LADA having similar clinical spectrum hypothalamic nuclei and renal tubular glucose resorption
but distinctive pathogenic origin (Chapter 20). have been highlighted.
 Pathogenesis of Type 2 Diabetes 239

Further Reading 8. Pimenta W, KorytKowski A, Mitrakou A, et al. Pancreatic

b-cell dysfunction as the primary genetic lesion in NID-
1. Kreisberg RA, Boshell BR, DiPlacido J, et al. Insulin secre- DM. Evidence from studies in normal glucose-tolerant
tion in obesity. N Engl J Med. 1967;276:314-9. individuals with a first-degree NIDDM relative. JAMA.
2. Unger RH, Aguilar-Parada E, Muller WA, et al. Studies of 1995;273:1855-61.
pancreatic b-cell function in normal and diabetic subjects. 9. Weyer C, Antonio Tetaranni P, Gourgardus C, et al. Insulin
J Clin Invest. 1970;49:837-48. resistance and insulin secretory dysfunction are independ-
3. Nauck M, Stockmann F, Ebert R, et al. Reduced incretin ent predictors of worsening of glucose tolerance during

chapter
effect in type 2 (non-insulin-dependent) diabetes. Diabe­ each stage of type 2 diabetes development. Diabetes Care.
tologia. 1986;29:46-52. 2001;24:89-94.

16
4. Reaven GM. Banting lecture 1988: Role of insulin resistance 10. Leahy JL. Natural history of β-cell dysfunction in NIDDM.
in human disease. Diabetes. 1988;37:1595-607. Diabetes Care. 1990;13:992-1010.
5. Reaven GM. The fourth musketeer, from Alexander Dumas 11. Matthaei S, Stumvoll M, Kellerer M, et al. Pathophysiol-
to Claude Bernard. Diabetologia. 1995;53:3-13. ogy and pharmacological treatment of insulin resistance.
6. Le Roith D, Zick Y. Recent advances in our understand- Endocr Rev. 2000;21:585-618.
ing of insulin action and insulin resistance. Diabetes Care. 12. Himsworth HP. Diabetes Mellitus: its differentiation to
2001;24:588-97. insulin sensitive and insulin insensitive types. Lancet.
7. Obici S, Feng Z, Karkanias G, et al. Decreasing hypotha­ 1936;1:127-30.
lamic insulin receptors causes hyperphagia and insulin 13. Yalow RS, Berson SA. Immunoassay of endogenous plasma
resistance in rats. Nat Neurosci. 2002;5:566-72. insulin in man. J Clin Invest. 1960;39:1157-75.
8. Tripathy D, Wessman Y, Gullstrom M, et al. Importance of 14. Kreisberg RA, Boshell BR, DiPlacido J, et al. Insulin secre-
obtaining independent measures of insulin secretion and tion in obesity. N Engl J Med. 1967;276:314-9.
insulin sensitivity during the same test: results with Botnia 15. Boshell BR, Chandalia HB, Kreisberg RA, et al. Serum
clamp. Diabetes Care. 2003;26:1395-401. insulin in obesity and diabetes mellitus. Am J Clin Nutr.
9. Tripathy D, Ariksson KF, Orho-Melander M, et al. Parallel 1968;21:1419-28.
manifestation of insulin resistance beta cell decompensa- 16. Shen SW, Reaven GM, Farguhar JW. Comparisons of
tion is compatible with a common defect in Type 2 diabe- impedance on insulin-mediated glucose uptake in normal
tes. Diabetologia. 2004;47:782-93. subjects and in subjects with latent diabetes. J Clin Invest.
10. DeFronzo RA. Banting Lecture. From the triumvirate to the 1970;49:2151-60.
ominous octet: a new paradigm for the treatment of type 2 17. DeFronzo RA, Tobin JD, Andres R. Glucose clamp tech-
diabetes mellitus. Diabetes. 2009;58:773-95. nique: a method for quantifying insulin secretion and
resistance. Am J Physiol. 1979;237:E214-23.
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 Chapter 17
Insulin Resistance
Ramachandra Dattatray Lele, A Rosalind Marita

Insulin Resistance

Chapter Outline
♦♦ Concept of Hormone Resistance ♦♦ Clues from Animal Models of Insulin Resistance
♦♦ Evolution of the Concept of Insulin Resistance ♦♦ Insulin Resistance and Endothelial Dysfunction
♦♦ Molecular Mechanisms of Insulin Resistance ♦♦ Insulin Resistance and Atherosclerosis
♦♦ Role of Proinsulin in Insulin Resistance ♦♦ Insulin Resistance and Obesity
♦♦ In-Vivo Measurement of Insulin Resistance ♦♦ Insulin Resistance and Hypertension
♦♦ In-Vitro/Ex-Vivo Studies on the Nature of ♦♦ Essential Fatty Acids
Insulin Resistance ♦♦ Diet and Inflammation

CONCEPT OF HORMONE RESISTANCE • Antibodies to hormone receptor

• Defect in number and/or affinity of hormone receptors
The concept that disease can result from the failure of on target tissue
target tissues to respond to normal or even increased • Defect in postreceptor signal transduction in the target
levels of a hormone emerged from the deduction that tissue.
pseudohypoparathyroidism is due to peripheral tissue Insulin resistance is now known to occur in humans
resistance (renal tubules) to the action of parathyroid through each of the above mentioned defects with the
hormone.1 This hypothesis was made before the identi­ last being the most common defect. The ideal means of
fication of cell surface receptors and effector systems for assessing endocrine function is to measure the result
any hormone. of hormone action in the target tissue for the hormone.
A common feature of hormone resistant states is the Such an assay must provide insights into the hormone
presence of normal or elevated levels of the hormone in levels, hormone receptors, second messengers and tissue
circulation despite deficient hormone action. This feature responses.
is a consequence of the fact that hormones are normally
under a regulatory feedback control; failure of hormone
Insulin: A Unique Hormone
action leads to compensatory increase in hormone
production. Insulin is unique as a hormone compared to other
Diseases are now known to result from hormone hormones. While more than 80 known hormones result
resistance to most hormones including insulin. Concept­ in activation of cyclic adenosine monophosphate (cAMP),
ually, this can arise due to: insulin [along with three others, atrial natriuretic peptide
• Alteration in hormone structure (mutants) (ANP), brain natriuretic peptide (BNP) and nitric oxide
• Antibodies to hormone—exogenous or endogenous (NO)] activates cyclic guanosine monophosphate (cGMP).
246 Etiopathogenesis of Diabetes Mellitus

Insulin has rapid, intermediate and delayed actions, each Insulin signals primarily through insulin receptors
with various concentrations of insulin. (IR-A and IR-B) with lower affinity for insulin-like growth
• Rapid action (within seconds): Increased glucose and factor (IGF)-1 receptor (IGF-1R). Activation of IR-B and
amino acid uptake into cells. IGF-1R initiates metabolic signaling. Activation of IR-B
• Intermediate action (within minutes): Stimulation of and IGF-IR initiates mitogenic signaling. IGF receptors are
protein synthesis; inhibition of protein degradation; expressed on a wide variety of cancer cells.
activation and inactivation of various enzymes. Hybrid receptors [(IR-A and IGF-1R) and (IR-B and
section

• Delayed action (within hours): Increased transcription IGF-1R)] are commonly seen in many type 2 diabetes
5

of over 100 genes; ribonucleic acid (RNA) translation; mellitus (T2DM) patients in their muscle and adipose
regulation of growth and development of vital organs tissues. Hyperglycemia, via the glucosamine pathway
such as the brain and ovaries; food intake and energy may facilitate hybrid receptor formation. Since hybrid
expenditure control; sympathetic and central neuronal receptors bind IGF-1 but not insulin with high affinity,
modulation and regulation of endothelial function. IGF-1 is as potent as insulin in stimulating glucose uptake.
These are mediated by insulin receptors (Fig. 17.1). Activation of IR-A and IGF-1R hybrid gives mitogenic
Using I-125 and I-124 labeled human insulin, in-vivo signals while activation of IR-B and IGF-1R hybrid results
imaging of its biodistribution in various organs including in metabolic signals.3 Figure 17.2 illustrates insulin
the brain has been shown in rats.2 signaling through hybrid receptors. Insulin-signaling and

Fig. 17.1: Insulin signaling events leading to stimulation of metabolism

(MAPK: Mitogen-activated protein kinase; PKC: Protein kinase C; IRS: Insulin receptor substrate).
 Insulin Resistance 247

chapter
17
Fig. 17.2: Signaling through insulin and insulin-like growth factor (IGF) receptors
The insulin receptors (IR-A and IR-B), the insulin-like growth factors 1 receptor (IGF-1R) and the hybrid receptors (IGF-1R/IR-A and IGF-1R
and IGF-1R/IR-B). Insulin signals primarily through IR-A and IR-B with lower affinity for IGF-1R. IGF-1 binds to the IGF-1R and IGF-1R/IR-A
and IGF-1R/IR-B hybrids. IGF-2 binds to the IR-A, IGF-1, and IGF-1R/IR-A hybrid receptor. Binding of insulin and IGF-2 to the IR-A by insulin
predominantly results in mitogenic signaling. Activation of the IR-B receptor initiates metabolic signaling. IGF-1 and IGF-2 signaling through the
IGF-1R mostly activates mitogenic signaling pathway, as does binding to the IGF-1R/IR-A hybrid. Activation of the IGF-1R/IR-B hybrid leads to
more metabolic effects

the regulation of glucose and lipid metabolism have been Table 17.1: Clinical syndromes associated with insulin resistance
reviewed previously.4 Insulin receptor structure, function I. Due to overactivity of anti-insulin hormones
and evolution have also been discussed.5 A Growth hormone Acromegaly
Studies in insulin and IGF-1R knockout mice as well as B Glucocorticoids Cushing’s syndrome
mutation studies in small organisms such as Drosophila C Glucagon Glucagonoma
and Caenorhabditis elegans indicate the role of these II. Primary impairment in insulin action
receptors in intermediate metabolism, growth, energy A Pre-receptor Mutated insulins, antibodies to
homeostasis, reproductive function and longevity. insulin (exogenous or endogenous).
Thus, normal insulin action influences diverse tissues, B Receptor and Obesity:
and consequences of insulin resistance can affect diverse post-receptor Type A syndrome (absent or
dysfunctional receptors)
tissue functions, although not all to the same extent.
Type B syndrome (antibodies to insulin
Reaven6 in his Banting lecture discussed the role of receptor)
insulin resistance in human diseases. Insulin resistance Lipodystrophy: Partial or genera­lized
syndrome (IReS) is currently implicated in a variety of Leprechaunism
clinically important conditions like obesity, hypertension, Ataxia-Telangiectasia
Rabson-Mendenhall syndrome,
diabetes and atherosclerosis.7 Whether IReS is the primary
Werner syndrome
event or it is secondary to endothelial dysfunction is Alström syndrome
currently being debated. This chapter attempts to review Pineal hyperplasia syndrome
the existing knowledge on the subject (integrating the Acanthosis nigricans
available information on insulin resistance and endo­
thelial dysfunction) and the therapeutic implications of EVOLUTION OF THE CONCEPT OF
that knowledge. INSULIN RESISTANCE
Table 17.1 summarizes the clinical syndromes asso­ After the discovery of insulin by Banting and Best in
ciated with insulin resistance 1921, the first patient to be successfully treated by insulin
248 Etiopathogenesis of Diabetes Mellitus

injections was a 14-year-old boy with diabetic ketosis.8 In Radioreceptor assay (RRA) of insulin has provided
the next decade, insulin routinely became available for additional information (not available by RIA alone) such
large diabetic populations. The paradigm in the 1930s was as distinguishing insulin (of molecular weight 6KD) from
that diabetes mellitus is due to insulin deficiency, made other immunoreactive species like proinsulin (9KD). The
good by insulin injections. Sir Harold Himsworth was key element in RRA is biological activity, particularly the
the first one to observe that a large number of diabetic ability to bind to insulin receptors. Proinsulin has only
patients were “insulin insensitive”. He differentiated 20% of the biological activity of insulin although both are
section

diabetic patients into two types: (1) insulin sensitive and measured as insulin by RIA. For RRA of insulin, human
5

(2) insulin insensitive.9 At that time, there was no reliable peripheral blood lymphocytes provide a suitable source of
method available to measure endogenous insulin in insulin receptors.18 Abnormal insulins have less than 15%
diabetic patients. The development of the technique of of the biological activity of insulin in RRA. Diabetes due to
radioimmunoassay (RIA) by Solomon Berson and Rosalyn secretion of an abnormal insulin has been reported.19 Point
Yalow in the late 1950s opened the door to measure peptide mutation in human insulin gene giving rise to structurally
hormones with high degree of sensitivity, specificity and abnormal insulin was described in 1983.20 Thus far three
reliability and to study in vivo hormone regulation.10 mutant insulins have been identified in man.21 Abnormal
In the first major description of RIA of insulin and its insulin molecule is not able to bind normally to the insulin
application to diabetic patients,11 it was discovered that receptor.
levels of immunoreactive insulin (contrary to expectation) The role of insulin receptors as sites of insulin resis­
were higher than normal in many patients with maturity- tance came to be recognized in the 80s.22 While insulin
onset diabetes, in the presence of hyperglycemia. Further, resistance was appreciated in NIDDM patients, its pro­
patients with mild diabetes showed some capability of minent role was pointed out in patients with insulin-
increasing their insulin secretion in response to increased dependent diabetes mellitus as well.23
caloric intake. Thus, the paradigm shifted from insulin Application of RRA led to the discovery of many
deficiency to insulin resistance and insufficient insulin syndromes of severe insulin resistance (SSIR) due to
action. Further, the significance of basal insulin levels in antibodies to insulin receptors.24 The elucidation of the
the evaluation of insulin response to glucose in diabetic three-dimensional structure of insulin receptor and clon­
and non-diabetic subjects was increasingly recognized.12 ing of the complementary deoxyribonucleic acid (cDNA)
Resistance to insulin-stimulated glucose uptake was has made it possible to define the molecular defects
demonstrated as a characteristic feature in patients with in the insulin receptor causing hormone resistance.25
non-insulin dependent diabetes mellitus (NIDDM) and Naturally occurring mutations have resulted in several
forms of inherited insulin resistance. Insulin receptors
impaired glucose tolerance (IGT).13 Furthermore, it was
have intrinsic tyrosine kinase activity, which is important
observed that resistance to insulin-stimulated glucose
for hormone action. Human diabetes associated with a
uptake of a similar degree of severity as in NIDDM and
deletion mutation in tyrosine kinase domain of insulin
IGT occurred in at least 25% of the normal population
receptor has been identified.26 The molecular defects
representing the prevalence of the thrifty genotype.
in insulin action have also been discussed.27 Now that
The concept of insulin resistance and acanthosis
subtle defects in receptor function can be identified, it is
nigricans, as a marker of insulin receptor disorders in
becoming clear that hormone resistance is more common
humans was described in 1976.14 Clinically, insulin resis­
than previously recognized. Mutation of insulin receptor
tance is defined as a state in which normal serum insulin
at Tyr 1146 alters the growth-stimulating potential but not
levels produce subnormal biological responses. Thus,
its metabolic activity, whereas mutation of Tyr 1150 and
the entity of insulin resistance independent of diabetes
Tyr 1151 produce the opposite effect.28-30
mellitus was recognized.15
Although antibodies to exogenous insulin in the blood
Evolution of the Concept of Insulin Resistance
of diabetic patients receiving insulin injection were detec­
ted,16 clinically significant insulin resistance due to insulin
Syndrome and Metabolic Syndrome
antibodies occurred only in about 1 in 10,000 diabetic In 1973, patients with angina pectoris with angiographi­
patients. Presence of autoimmune antibodies to insulin cally normal coronary arteries were recognized, receiving
was also recognized as a cause of insulin resistance.17 the label of “Syndrome X”. Vascular hyperactivity was a
 Insulin Resistance 249

chapter
17
Fig. 17.3: Endothelial dysfunction and insulin resistance
(LDL: Low-density lipoprotein; HDL: High-density lipoprotein; TG: Triglyceride; PAI-1: Plasminogen activator inhibitor-1; IRS: Insulin receptor
substrate).37

plausible explanation of the ischemic pain. Patients with consequence of endothelial dysfunction in different
this syndrome were also reported to have hyperinsu­ vascular beds.37 A cardiovascular dysmetabolic syndrome
linemia. In 1985, hyperinsulinemia was shown as a link (CDS) was proposed as a culmination of insulin resistance
between hypertension, obesity and glucose into­lerance.31 and endothelial dysfunction.38 The current perspective of
In 1988, Reaven postulated the link between insulin insulin resistance syndrome and its relevance to Indians
resistance, obesity, hypertension and dyslipidemia [high was also reviewed.39 In this review, we have attempted an
triglyceride (TG) and low high-density lipoprotein (HDL)], integration of all published literature to date on insulin
and cardiovascular disease (CVD). Again in 1993, Reaven resistance. We propose a scheme in which endothelial
gave an expanded definition of syndrome X. dysfunction is the initial event but insulin resistance,
In 1989, the term “deadly quartet” comprising central although a consequence further aggravates the situation
obesity, hypertension, IGT and hypertriglyceridemia, (Fig. 17.3).
came to be associated with insulin resistance.32 In
1991, the multifaceted nature of the insulin resistance A New Elaboration of Thrifty Gene Hypothesis
syndrome (IReS) was established.33 Subsequent additions
to the syndrome were small dense low-density lipoprotein Ability to store energy in excess of what is required for
(LDL), increased proinsulin, increased plasminogen immediate use is essential for survival. In 1962, Neel
activator inhibitor (PAI)-1 and microalbuminuria. suggested that evolutionary selection for traits that confer
In 1995, Godsland and Stevenson raised the question: the ability to survive when food supplies are unreliable,
Is insulin resistance a syndrome or a tendency?34 In 1996, might select also for genes that increase the risk of diabetes
the association between insulin resistance and endothelial when food is abundantly available.40 Neel originally
dysfunction was established.35 suggested that hyperinsulinemia might be a primary
A comparative study of 40 women with polycystic trait leading to increased fat storage. However, it is now
ovarian disorder (PCOD) with metabolic syndrome (MBS) realized that hyperinsulinemia is a consequence of insulin
and 60 women with PCOD but without MBS showed that resistance which is the primary trait.
the increase in body mass index (BMI) in PCOD with MBS In 1992, the thrifty phenotype was hypothesized.41
was not due to adipose tissue but due to muscle mass Fetal malnutrition results in an alteration in fetal growth
(a result of high free testosterone) and higher prevalence which is adaptive to scarcity in adult life. Selective insulin
of acanthosis nigricans, suggestive of insulin resistance resistance in the liver [whereby insulin fails to suppress
and greater risk for CVD.36 gluconeogenesis by phosphoenolpyruvate carboxykinase
Pinkney from Yudkin’s group proposed a hypothesis (PEPCK) enzyme] has survival advantage during condi­
that the insulin resistance syndrome, together with many tions of prolonged starvation when the brain must have an
aspects of atherogenesis can be viewed as the diverse assured supply of glucose via gluconeogenesis.
250 Etiopathogenesis of Diabetes Mellitus

Selective insulin resistance in the skeletal muscle MOLECULAR MECHANISMS OF

also has survival advantage, under conditions of food INSULIN RESISTANCE
restriction. By this strategy, the possible competition for
Over the past two decades, Shulman’s group from Yale
glucose from the large muscle mass is curbed in favor
University School of Medicine have extensively used
of the priority requirement for the brain. On the other
in- vivo nuclear magnetic resonance (NMR) spectroscopy
hand, adipose tissue is initially highly sensitive to insulin
to non-invasively probe the cellular and molecular mech­
action; hence the ability to store fat rapidly and efficiently
section

whenever food is available in abundance also has survival anism of insulin resistance in humans. This technique
is ideal for human studies since it is capable of monitor­
5

advantage.
The single gene model of Zucker rat (fa/fa) chara­ ing particular intracellular metabolic concentrations and
cterized by selective insulin resistance in the liver and kinetics non-invasively and in real time.46-47 Applying C-13
skeletal muscle along with an insulin-sensitive adipose NMR spectroscopy (NMRS) to examine rate of insulin-
tissue (which makes the animal fat) is an example of thrifty stimulated muscle glycogen synthesis in humans, they
gene adaptation due to a mutation. were able to demonstrate that skeletal muscle accounts for
Insulin receptor signaling pathways control cellular the majority of insulin-stimulated glucose uptake in both
metabolism in insects, nematodes vertebrates. The path­ patients with T2DM as well as age and weight matched
way involves IRS-1 to 4, phosphatidylinositol 3-kinase non-diabetic volunteers. In patients with T2DM, the rate
(PI3K) and protein kinase B (PKB). These pathways of insulin-stimulated muscle glycogen synthesis was
regulate growth in response to nutritional availability, by decreased by over 50% and this was the major factor
the co-ordinated regulation of cell growth, cell prolifer­ resposible for their insulin resistance under hyperinsu­
ation and metabolism. This function is conserved during linemic (~ 80 U/mL) hyperglycemic (10 mmol/L) clamp
evolution and is operative in all species including humans. conditions.
Growth is dependent on the availability of nutrition. To determine the rate-controlling step responsible for
Under inadequate maternal nutrition condition, fetuses this reduced rate of glycogen synthesis they applied C-13
show small size (less than 2.5 kg at birth), with small head and P-31 NMR to monitor intracellular glucose, glucose-
circumference, but still have the ability to conserve fat. The 6-phosphate (G6P) concentration and intramuscular
mutant CHICO (small size) drosophila, are only half of glycogen synthesis under similar conditions. With this
the size of normal flies but have almost two-fold increase multinuclear NMRS approach, glucose transport, rather
in lipid storage compared to their heterozygous siblings. than hexokinase activity was determined to be the rate
The dramatic increase in lipid in CHICO mutant males controlling step.
is similar to the hypertriglyceridemia in IRS-1 deficient Therefore, glucose transport represents the best target
mice. Hence, IRS-1 inhibition is also a component of the to correct insulin resistance in skeletal muscle in T2DM.
thrifty gene.42 Fortunately, regular physical exercise achieves this effect.
Thermogenesis is maintained by mitochondrial Insulin-stimulated glucose uptake in muscles from
uncoupling proteins (UCPs) [UCP-1 in the brown fat, young, lean, non-smoking insulin resistant offspring of
UCP-2 in white fat and UCP-3 in muscle]. Mutation in parents with T2DM was also studied. They had none of
UCPs with diminished ability for thermogenesis, while other confounding factors that may contribute to insu­
harmful in cold climates, are not a handicap in warm lin resistance such as obesity and hyperglycemia. Using
climates; actually they may have a survival advantage similar C-13/P-31 NMR methods, it was again found
under conditions of food restriction because of greater that they too had defects in insulin-stimulated muscle
ability to store fat at any level of calorie intake. Hence, UCP glycogen synthesis due to defect in glucose transport or
mutants can also be considered components of the thrifty phosphorylation.
gene.43-45 Fasting plasma free fatty acid (FFA) concentration
Leptin regulates food intake according to the status was found to be the best predictor for insulin resistance
of adipose storage, by regulating the appetite. Ability to in this otherwise young healthy cohort. Subsequently, it
consume large amounts of food when available and store was found that intramyocellular lipid (IMCL) content,
excess fat has survival advantage in conditions of frequent assessed by H-1 NMR is an even better predictor for insulin
famines. Hence, leptin resistance is also a component of resistance in skeletal muscle in both adults and children.
the thrifty gene. A muscle punch biopsy study in Pima Indians had found
 Insulin Resistance 251

chapter
17
A B
Figs 17.4A and B: Fat-induced insulin resistance
The molecular mechanism of fat-induced insulin resistance in skeletal muscle (A) and Liver (B). (A) Increases in intramyocellular fatty acyl-CoAs
and diacylglycerol due to increased delivery of plasma and/or reduced β-oxidation due to mitochondrial dysfunction activate serine/threonine
kinases such as protein kinase C (PKC)-t rodents, PKC-b and d humans in skeletal muscle. The activated kinases phosphorylate serine residues
on insulin receptor substrate (IRS)-1 and inhibit insulin-induced phosphoinositide (PI) 3-kinase activity, resulting in reduced insulin-stimulated
AKT2 activity. Lowered AKT2 activity fails to activate glucose transporter (GLUT) type 4 translocation, and other downstream AKT2-dependent
events. And consequently, insulin-induced glucose intake is reduced. (B) Increases in hepatic diacylglycerol (DAG), content due to increase
delivery of fatty acids from the plasma and/or increased de novo lipid synthesis and/or reduced β-oxidation activate PKC-e (and potentially other
serine kinases), leading to reduced insulin receptor kinase activity and reduced IRS-2 tyrosine phosphorylation, resulting in reduced insulin
stimulation of glycogen synthase activation and decreased phosphorylation of forkhead box protein O (FOXO), leading to increased hepatic
gluconeogenesis.
(DAG: Diacylglycerol; PTB: Phosphorylation binding domain; PH: Pleckstrin homology domain; SH2: SRC homology 2 domain; GSK3: glycogen
synthase kinase 3).

a strong relationship between insulin resistance and parents. Serine phosphorylation prevents PI3K activation.
intramyocellular TG content. Intracellular increase in long-chain fatty acyl-CoAs and
The mechanism of fat-induced insulin resistance is diacylglycerol (DAG) activates protein kinase C (PKC)
beginning to be understood (Figs 17.4A and B). Insulin which inactivates the IRS-1 PI3K-AKT pathway. PKC
binds to the α-subunit of the insulin receptor and knock-out mice are protected from fat-induced insulin
activates the tyrosine kinase activity of the β-subunit. resistance in skeletal muscle.
The tyrosine kinase phosphorylates the IRS (insulin In the liver, accumulation of intracellular lipid
receptor substrate) proteins. The phosphotyrosine resi­ metabolites activates a serine kinase cascade involving
dues on the IRS protein become good targets for the PKC-e, leading to lower IRS-2 and PI3K-AKT signaling
p85 regulatory subunit of PI3K, which in turn catalyzes activity. These defects in insulin signaling result in reduced
the conversion of phosphatidylinositol 4, 5 disphosphate insulin-stimulated glycogen synthase activity resulting
to phosphatidylinositol 3, 4, 5 triphosphate. This lipid decreased glycogen production. Further, reduced activity
further activates downstream effectors such as phos­- of AKT2 results in decreased phosphorylation of forkhead
phati­dylinositol-dependent kinase (PDK) and PKB (or box protein O (FOXO), allowing it to enter the nucleus and
AKT). In skeletal muscle, this PI3K-AKT activation is an activate the transcription of the rate-controlling enzymes
essential step for insulin-stimulated glucose transporter of gluconeogenesis (PEPCK and G6Pase). Mitochondrial
(GLUT)-4 translocation to the plasma membrane, leading glycerol-3 phosphate acyl transferase (mtGPAT) is a key
to glucose uptake. enzyme in de novo fat synthesis in the liver, leading to
Raising plasma FFAs abolish insulin activation of fatty liver.
IRS-1 mediated PI3K activity in skeletal muscle via serine The rate of mitochondrial oxidative phosphorylation
phosphorylation on IRS-1 (Fig. 17.5). In general, serine activity in skeletal muscle has been measured by NMR
phosphorylation negatively regulates IRS signaling. using C-13/P-31, in healthy lean elderly volunteers with
This is seen in lean insulin-resistant offspring of T2DM severe muscle insulin resistance. A 40% reduction in
252 Etiopathogenesis of Diabetes Mellitus
section
5

Fig. 17.5: Serine phosphorylation on insulin receptor substrate (IRS)

Serine/threonine phosphorylation on IRS-1, IRS-1 contains ~70 potential serine/threonine sites. Shown here are the individual residues on
mouse IRS-1 and human IRS-1. In addition, the serine/threonine kinases, hormones and circulating factors that lead to the phosphorylation
on IRS-1 at specific sites are shown. The top row illustrates reported human or animal model sited in which phosphorylation sited have been
confirmed in vivo. Each residue is drawn corresponding to the position based upon the homology between human and mice
(PCOS: Polycystic ovarian syndrome, T2DM: Type 2 diabetes mellitus; PKC: Protein kinase C; AMPK: Adenosine monophosphate-activated
protein kinase; TPA: Tissue plasminogen activator; ET-1: Endothelin-1; GRK: G-protein receptor kinase; mTOR: Mammalian target of rapamycin;
TNF: Tumor necrosis factor; RA: Retinoic acid; IGF: Insulin-like growth factor).

the ratio of oxidative phosphorylation was found to be sensitive control subjects. Electron microscopic study
associated with intramyocellular and intrahepatic lipid of mitochondrial density showed a 38% reduction in
content compared with BMI-matched young control insulin resistant offspring, similar to lower mitochondrial
subjects. This study from Shulman’s group48 showed that density in patients with T2DM. Mitochondrial cytochrome
an acquired loss of mitochondrial function asso­ ciated C-oxidase I was reduced by ~ 50% in insulin-resistant
with aging predisposes elderly subjects to intra­ myo- children, and a tendency for succinate dehydrogenase
cellular fat accumulation which results in insulin
and pyruvate dehydrogenase to be reduced by a similar
resistance through the mechanisms described earlier.
amount was also observed. Insulin resistant children of
Young, lean, insulin-resistant offspring of patients
with T2DM were studied with P-31 NMR to examine patients with T2DM may have an inherited reduction in
mitochondrial function and H-1 NMR for IMCL. There was mitochondrial content in skeletal muscle which in turn
a 30% reduction in the rate of mitochondrial adenosine may be responsible for the reduced rates of mitochondrial
triphosphate (ATP) production and 80% increase in IMCL, oxidative phosphorylation predisposing them to IMCL
compared with age, weight and activity matched insulin accumulation.
 Insulin Resistance 253

caused by selective impairment of insulin and IGF

signaling.49 This idea was fuelled by evidence that gene
expression and phosphorylation of Tau protein are
regulated through insulin and IGF signaling cascades.
Many key aspects of the central nervous system (CNS)
degeneration that occurs in AD can be effectuated by
impaired insulin signaling. Insulin and IGF-1 mediate

chapter
their effects by activating complex intracellular signaling

17
pathways starting with ligand binding to cell surface rece­
Fig. 17.6: Mitochondrial biogenesis ptors followed by autophosphorylation and activation of
The molecular mechanism of mitochondrial biogenesis. The mitochon- the intrinsic receptor tyrosine kinases which eventually
dria have their own genome which encoded 13 proteins, 2 ribosomal activate extracellular signal-regulated kinases/mitogen-
ribonucleic acids (rRNAs) and 22 transfer RNAs (tRNAs). It is also
activated protein kinases (ERK/MAPK) and IRS/PI3K/AKT
known that most of the mitochondrial proteins are encoded by nuclear
genome and translated proteins are transported in to mitochondria. pathways. Major biological responses to insulin signaling
The Extracellular stimuli induce mitochondrial biogenesis by peroxi- include increased cell growth, survival, energy metabolism
some proliferator-activated receptor-gamma coactivator (PGC)-1 in and cholinergic gene expression, inhibition of oxidative
brown fat and skeletal muscles. Increased PGC-1 production leads
to increased expression of its target gene including nuclear respira-
stress and apoptosis. These very same signaling pathways
tory factor (NRF)-1. NRF-1 is a transcription factor stimulating many are activated in various cell types, tissue and target organs
nuclear-encoded mitochondrial gene such as oxidative phosphoryla- including the brain. Oligodendroglia requires intact
tion (OXPHOS) gene and mitochondrial transcription factor A (MtTFA).
insulin/IGF signaling mechanism for myelin synthesis.
A key transcriptional factor for mitochondrial genome, myocardin-relat-
ed transcription factor A (MrTFA) can bind to D loop of the mitochon- Reduced insulin and IGF-1 receptor expression in
drial genome and increase transcription of the mitochondrial gene and neurons begins early and progresses as disease becomes
replication of mitochondrial deoxyribonucleic acid (DNA). severe and global.50 Growth factor withdrawal is a well-
(ATPsyn: Adenosine triphosphate synthase; CytC: Cytochrome C;
MTCO I: Mitochondrial cytochrome C oxidase subunit I).
established mechanism of neuronal death. Post mortem
studies of advanced AD patients have shown significant
abnormality in the expression of genes coding insulin,
Mitochondrial biogenesis is regulated by peroxisome IGF-1 and IGF-2 peptides and their receptors and down-
proliferators-activated receptor gamma coactivators stream signaling molecules. These abnormalities can occur
(PGC) (PGC-1a and PGC-1b) which are transcriptional with or without T2DM. Epidemiological data indicate
factor activators that regulate mitochondrial biogenesis, increased risk of developing mild cognitive impairment,
and potential candidates for therapeutics intervention dementia or AD in individuals with T2DM and metabolic
(Fig. 17.6). In addition, AMP kinase which is activated syndrome.
(during exercise and ischemia) by a reduction in the ATP/ Peroxisome proliferator-activated receptors (PPARs)
AMP ratio is an important regulator of mitochondrial (PPARα, PPARδ and PPARγ) are expressed in adult human
biogenesis, mediating its effects through myocyte- brain and function at the level of the nucleus to activate
enhancing factor 2 (MEF-2) and cAMP response element insulin-response genes and signaling pathways. PPARδ
binding protein (CREB)-mediating increased PGC-1a agonists preserve insulin and IGF receptor bearing
expression. Extracellular stimuli such as cold, thyroid cells including neurons and oligodendroglia. Deficient
hormone and exercise stimulate mitochondrial biogenesis insulin/IGF signaling decreases expression of choline
through PGC-1 in brown fat and skeletal muscle. acetyl transferase leading to reduced acetyl choline
P-31 NMR studies have demonstrated that insulin is production. Insulin resistance in AD patients is associated
an important regulator of mitochondrial ATP synthesis with IGF-1 resistance, IRS-1 dysregulation and cognitive
in skeletal muscle of healthy subjects and that insulin- decline.51
stimulated ATP synthesis is markedly decreased in the Referring to AD as type 3 diabetes mellitus (T3DM)
muscle of insulin resistant offspring of parents with T2DM. is justified because the fundamental molecular and bio­
chemical abnormalities overlap with insulin-resistance
New Concept: Alzheimer’s and T2DM. This is confirmed by demonstration of cogni­
Disease is Type 3 Diabetes tive improvement and/or stabilization of cognitive impair­
Since 2005 a new concept has arisen that Alzheimer’s ment in subjects with early AD following treatment with
disease (AD) is intrinsically a neuroendocrine disorder intranasal insulin or a PPAR agonist.
254 Etiopathogenesis of Diabetes Mellitus

ROLE OF PROINSULIN IN high-performance liquid chromatography (HPLC) and

INSULIN RESISTANCE confirmed the presence of 31-32 split proinsulins as the
major component. However, there was no significant
Proinsulin (9KD) is a biosynthetic precursor of insulin. difference between normal and diabetic patients, in both
During the processing of proinsulin to insulin (6KD) and South Asians and Caucasians, in this major component
C-peptide (3KD) by proteolytic cleavage, the peptide can using this method. It remains to be seen what causes this
break at position 64-65 resulting in Des 64-65 proinsulin 31-32 split proinsulins to be present in hyperinsulinemia.
section

or it can break at position 31-32 resulting in Des 31-32 Two mutations in the insulin gene (on short arm of human
proinsulin. Therefore, at least three forms of proinsulin chromosome number 11) have been identified which
5

(intact proinsulin, 31-32 split proinsulin and 64-65 impair proteolytic processing of proinsulin to insulin.
split proinsulin) exist in plasma.52 In normal subjects, Elevated proinsulin level (a possible marker for islet beta
insulin to proinsulin ratio in the blood is 6:1; it is 1:1 in cell dysfunction) and PAI-1 are already known to occur in
insulinomas. RIA of insulin measures both insulin and adults with low birth weight.60 Since proinsulin RIA kits are
proinsulin. Fasting plasma concentration of both 31-32 not commonly used, the only indirect clue for the presence
split proinsulin (40%) and intact proinsulin (15%) were of high proinsulin (in the conventional RIA of insulin) is to
observed to be higher in patients with insulin resistant see the ratio of C-peptide to insulin. Correlation of systolic
diabetes. Proinsulin stimulates PAI-1 synthesis in aortic blood pressure (BP) to insulin (fasting and postglucose
endothelium. This may contribute to impaired fibrinolysis load) but not to C-peptide has been reported.61 In an
which has emerged as an important risk factor for coronary analysis of insulin and C-peptide levels in patients of
heart disease. Proinsulin as well as PAI-1 are suppressed by hyperinsulinemia studied at Jaslok Hospital (Lele and
treating T2DM patients with sulfonylureas (SU) or insulin. Karnik, personal communication), there was relatively
Although proinsulin has only 2% of the metabolic less rise of C-peptide compared to immunoassayable
potency of insulin, it is half as potent as insulin as a insulin, implying a major presence of proinsulin.
stimulator of mitogenesis.53 One can speculate about the Significant association between plasma concentrations
pathogenetic role of proinsulin in the insulin resistance of proinsulin and 32-33 split proinsulins with BP and
syndrome. Non-parallel evolution of metabolic and cardiovascular risk factors has been reported.62 The
growth promoting functions of insulin has been noted. half-life of proinsulin is longer than insulin. Decreased
Kahn’s group has shown the growth promoting effects of hepatic extraction of proinsulin will permit higher levels
insulin and insulin-like factors on cells from bovine retinal in peripheral circulation. Asian Indians showed higher
capillaries and aorta. circulating concentrations of proinsulin and its split
Insulin is a member of a family of related peptides product than white Caucasian subjects.63,64
termed IGFs. In contrast to insulin, IGF-1 and IGF-2 are
produced in many tissues and contribute to the regulation Proinsulin to Insulin Ratio
of growth rather than metabolism. Serum proinsulin is disproportionately elevated both in
The receptors for insulin and IGFs are closely related; the basal state and after an oral glucose load in T2DM
hence insulin can bind to IGF receptors with low affinity with an increase in the proinsulin to insulin ratio (normal
and vice versa. The growth promoting actions of insulin 15%).65-66 The hypothesis that a greater demand for
appear to be mediated partly through IGF receptors. insulin secretion in response to insulin resistance, when
The mitogenic activity of insulin and proinsulin in accompanied by beta cell secretory dysfunction leads to
hyperinsulinemic states may contribute to increased hypersecretion of proinsulin by beta cells, was experi­
risk of atherosclerosis. Chronic infusion of insulin in one mentally confirmed.67 Dexamethasone (6 mg/day for
femoral artery in dogs caused vascular smooth muscle 3 days) raised the proinsulin to insulin ratio from normal
cell hypertrophy on the ipsilateral side.54 Elevations in 13% to 21% in control and from 29% to 57% in T2DM
plasma proinsulin and 31-32 split proinsulins have been patients. Further evidence of “increased demand theory”
described in patients with T2DM.55-57 Fasting proinsulin of proinsulin secretion was provided in 1996.68 Healthy
and 32-33 split proinsulins independently predict the donors for pancreatic transplantation had a prehemipan­
development of T2DM.58 These methods had used special createctomy fasting proinsulin level of 6.24 + 1.14 pmol/
immunoassays using different antibodies which identify mL. At 1 year postdonation, the basal proinsulin was 34.63
immunologically similar components in the plasma. + 17.47 pmol/mL. A healthy control group showed normal
Recently, scientists59 have validated immunoassays with level (5.78 + 1.12 pmol/mL) initially and one year later.
 Insulin Resistance 255

Apart from T2DM, subjects with IGT also show taken together with normal blood sugar is considered
increased levels of proinsulin.55 These authors have to be an indicator of insulin resistance. Normal fasting
suggested that beta cells release immature granules richer insulin level is 3–10 µU/mL, never exceeding 14 µU/mL,
in proinsulin content as well as mature granules in the and its ratio to fasting glucose is less than 0.4. Estimation
overstimulated state. of plasma insulin levels in the fasting state and post-oral
Effect of dietary treatment on insulin and proinsulin glucose load indicate the magnitude of insulin resis­
response in newly diagnosed T2DM has also been tance.34 The rationale for using insulin concentration as a

chapter
evaluated.69 On a diet of 25–30 kcal/kg ideal body weight, surrogate for insulin resistance is that (assuming that the

17
plasma glucose decreased from 197 + 35 to 113 + 10 and pancreatic insulin response to glucose is undiminished)
proinsulin to insulin ratio decreased from 32% to 24%. insulin concentration will rise (to maintain normogly­
cemia) to a degree which is related to insulin resistance.
Predictive Value of Proinsulin Strictly speaking it is the insulin sensitivity, the inverse of
Increased proinsulin level was suggested as a cardiovascu­ insulin resistance that is being measured.76
lar risk factor in non-diabetic subjects.70 Further, a proin­ The ratio of plasma insulin levels during oral glucose
sulin to insulin ratio more than 20% is a predictor of future tolerance test (OGTT) to plasma glucose levels [area under
T2DM.60,71,72 A large epidemiological study (IRIS-1, 4,265 the curve (AUC) in the same individual] is also a measure
patients) confirmed that fasting hyperproinsulinemia is a of insulin sensitivity.
highly specific marker of insulin resistance73 hence thera­ Homeostatic model assessment (HOMA) is a simple
py should focus on reducing proinsulin levels. Proinsulin measure of in-vivo insulin action, available to all clini­
stimulates PAI-1 secretion and blocks fibrinolysis, there­ cians.77 It is applicable in epidemiological studies and has
by increasing risk of cardiovascular microvascular and been used extensively.78 The fasting plasma glucose and
macrovascular disease. We have urged the Indian diabe­ insulin ratio of an individual is compared with a nomo­
tologists to routinely measure proinsulin to insulin ratio gram constructed by Matthews, in 1985, to indicate the
in epidemiological studies. Predicting future T2DM pro­ individual’s insulin sensitivity. Normal fasting plasma
vides a 10 years window of opportunity for preventive insulin ranges between 3–10 µU/mL. It is assumed that
measures [regular physical exercise, weight reduction, elevated insulin levels above a fasting plasma glucose level
dietary modification with eicosapentaenoic acid/doco­ of 3.5 mM, is a sign of insulin resistance in the basal state.
sahexenoic acid (EPA/DHA) and antioxidants]. De Fronzo and coworkers79 described the glucose
Relative persistence of hyperproinsulinemia of T2DM clamp technique as a method of quantifying insulin secre­
despite the reduction of hyperglycemia has been demon­ tion and insulin resistance. Even today it is considered as
strated in patients on insulin and SU therapy.74 This may the gold standard for measuring insulin resistance. Insu­
reflect an additional defect in the converting prohormone lin is infused intravenously (IV) at a predefined rate and
convertase enzyme (PC)-3 and PC-2 as in familial hyper­ euglycemia is maintained by infusing glucose IV. The
proinsulinemia. In a study of 35 T2DM and 50 healthy steady state for glucose disposal is reached after 2–3 hours.
controls, three examples of defective PC enzyme were At this time, the glucose disposal rate (GDR) is equal to
detected with low insulin and high proinsulin. the amount of glucose infused. More the glucose infused,
Hansen and coworkers75 have suggested another the greater is the insulin sensitivity of the individual.
mechanism viz. effect of interleukin (IL)-1 on biosynthesis Tracer-determined GDR by infusion of H3-labeled glu­
of proinsulin and insulin in isolated rat pancreatic islets. cose, expressed as mg/kg/minute was 20% lower in T2DM
The high levels of tumor necrosis factor-alpha (TNFα) compared to controls, despite up to 30 times higher blood
found in T2DM and their correlation with proinsulin insulin levels. Obese subjects also showed 10% lower
suggest a testable hypothesis that TNFα acts similar to GDR despite two-fold higher insulin levels compared to
IL-1, in the islet cells, inhibiting insulin biosynthesis and controls.
attenuating the rate of conversion of proinsulin to insulin. Although ideal for experimental purposes, the eugly­
cemic clamp technique is expensive, time-consuming,
IN-VIVO MEASUREMENT OF
requires multiple blood samples and is poorly accepted by
INSULIN RESISTANCE the patients. One criticism of the clamp technique is that
Plasma insulin level is properly interpretable only in in normal physiological conditions, there is never such
conjunction with simultaneous measurement of plasma a sustained hyperinsulinemia; rather there are transient
glucose. Hyperinsulinemia, especially in a fasting sample, excursions in insulin level. Thus, whilst clamp-derived
256 Etiopathogenesis of Diabetes Mellitus

measurements provide an adequate reference, the results been reported to undergo changes parallel to those in
should be viewed with some caution. target tissues.87
The clamp technique revealed the important fact that To study whether insulin binding to intact human
subjects with normal OGTT can be insulin resistant.80 MNCs results in the physiological endpoints of insulin
On the basis of clamp studies, healthy subjects can be action, we used freshly isolated intact human MNCs and
categorized into four quartiles: insulin resistance in studied the effect of insulin on glucose metabolism.88
quartile four (most insulin resistant) was comparable Insulin (1µM) caused a 60% stimulation of glucose
section

to that in patients with T2DM or IGT. Persistent and metabolism to lactate in MNCs of normal (non-obese, non-
unrelenting hyperinsulinemia in persons with a normal diabetic) subjects. However, it caused only 8% increase in
5

OGTT is considered ominous, over a period of time, to obese and 6% increase in diabetic patients. In the same
developing insulin resistance syndrome. study, we also investigated insulin receptors using I-125
An alternative method is an IV GTT and minimal labeled insulin. Non-obese non-diabetic subjects had
model analysis of the non-steady state glucose and insulin maximal specific insulin binding of 2.60 ± 0.39%/107cells.
concentrations to provide a measure of the constant that T2DM subjects had showed 60–65% decrease in insulin
best relates changes in GDR to changes in plasma insulin binding; Downregulation of the cell surface receptors is
concentrations. The technique assumes that there is some suggested as a cause of reduced insulin binding and action
islet beta cell response to glucose. on glucose metabolism in NIDDM patients.
The technique of continuous infusion of glucose with Circulating MNCs and cultured lymphocytes have
model assessment (CIGMA) allows estimation of the been used to study the tyrosine kinase activity of the
relative contribution of impaired islet beta cell function insulin receptors of patients with Type A extreme insulin
and insulin sensitivity.81 In this technique glucose is resistance.89
infused at 5 ng/kg/minute. Prior to the infusion of glucose, The development of RRA for insulin using human
three basal blood samples are obtained at 5 minutes erythrocytes by Gambhir and coworkers90 has made in
interval (to allow for the 15 minutes periodicity of plasma vitro studies easy and practicable. In our previous study,
insulin levels). Further samples are taken every 2 minutes we showed insulin receptor defects in erythrocytes of
for the first 10 minutes after starting infusion, and then obese Indian women with acanthosis nigricans, using
every 5 minutes up to 60 minutes. Mean plasma glucose at the above method.91 Although erythrocytes possess
50, 55, 60 minutes is defined as achieved plasma glucose insulin receptors they do not have postreceptor mecha­
(APG). Mean plasma insulin at 50, 55, 60 minutes is nism of signal transduction nor are they classical target
defined as achieved plasma insulin (API). APG and API tissues.
are used for the minimal model assessment for evaluating
insulin sensitivity. Studies of Insulin Resistance in
3T3-L1 Adipocytes
IN-VITRO/EX-VIVO STUDIES ON
THE NATURE OF INSULIN RESISTANCE 3T3-L1 cells are fibroblasts capable of undergoing differ­
entiation into adipocytes. Mature 3T3-L1 adipocytes are
Study of Insulin Action on Human highly responsive to insulin when compared to fibroblasts
Mononuclear Cells and Erythrocytes and have been used extensively as an in-vitro model to
Investigations into the nature of insulin resistance in study insulin action in the laboratory.92-94 Using 3T3-L1
humans have been hampered by the difficulty in obtaining adipocytes we had previously showed six-fold to seven-
adipose tissue and skeletal muscle, the two classical fold increase in insulin-stimulated glycogen synthesis
target tissues. A defect in insulin receptor number and/or and three-fold to four-fold increase in insulin-stimu­
affinity can be assessed by radiolabeled insulin binding lated lipogenesis. We also demonstrated the profound
to mononuclear cells (MNCs), ex vivo.82 Insulin-stimulated effect of the synthetic glucocorticoid dexamethasone at
glucose transport and glucose metabolism can be studied 100 nM on insulin response. At maximum concentration
by measuring glycogen synthesis,83 lipogenesis84 and of insulin, 50% decrease in glycogenesis was observed.
lactate production.85 RU486, a glucocorticoid receptor antagonist relieved the
Klein and colleagues86 showed the usefulness of readily dexamethasone induced insulin resistance at 0.1 and
accessible peripheral blood MNCs for studying insulin 1.0 µM concentrations and was able to completely reverse
receptors. Enzymes of glucose metabolism in MNCs have dexamethasone effect.95 Further sodium orthovanadate
 Insulin Resistance 257

acted as an insulin sensitizer in the dexamethasone indu­ resistance as a secondary event, by reducing tyrosine
ced insulin resistant adipocytes.96 kinase activity of the insulin receptor. Leptin is the only
identified suppressor of the insulin signal in hepatocytes
Insulin and Cell Cholesterol Homeostasis for PEPCK. TNFα suppresses insulin signal in adipose
tissue and muscle but not in the liver.
Brazg and Bieuman studied the role of insulin on cell A role for TNFα in insulin resistance has been
cholesterol homeostasis by incubating cultured human recognized, both in skeletal muscle and adipose tissue.102

chapter
skin fibroblasts with varying concentrations of insulin. The enzyme lipoprotein lipase (LPL) is synthesized in

17
Insulin excess (1–100 nM/L) resulted in a significant the adipocytes, secreted into the extra­ cellular space
dose-dependent reduction in HDL-mediated cholesterol and attached to the luminal surface of nearby vascular
efflux from the intracellular unesterified cholesterol pool endothelium. At this location, LPL hydrolyzes TGs of
of cultured human fibroblasts.97 Similar insulin concen­ the circulating TG rich lipoproteins in the plasma. The
trations resulted in impaired HDL-mediated cholesterol released fatty acids (FAs) are taken up by adipocytes,
efflux from the cell membrane but had no effect on the converted into TGs and stored with the help of insulin.
non-HDL mediated efflux. Excessive LPL is seen in obese rodents and humans.
The effect of insulin on cholesterol esterification More importantly, levels of LPL do not return to normal
and biosynthesis was assessed by 14C oleate labeling. following weight reduction, which explains the propensity
The addition of HDL3 (50 μg) resulted in a significant of obese people to quickly regain weight following weight
decrease in 14C labeled cholesterol ester, reflecting a reduction. The only known inhibitor of LPL is cachetin or
decrease in intracellular unesterified cholesterol, which TNF. It is conceivable that increased TNFα is an effort to
was partially reversed on addition of insulin. Insulin counteract the hyperinsulinism, hence the effect rather
had no effect on the incorporation of C14-oleate into than the cause of hyperinsulinism.
unesterified cholesterol. During simultaneous incubation
Glucagon: If glucagon had been discovered earlier
of fibroblasts with LDL and HDL, insulin caused an
than insulin, T2DM would well be defined as a state
increase in cholesterol esterification and inhibited ability
of hyperglucagonemia resulting in hyperglycemia due
of HDL to promote the decrease in esterification. Thus,
to glucagon-induced hepatic gluconeogenesis. Hyper­
insulin excess counteracts the beneficial effects of HDL
glucagonemia is a characteristic of both T1DM and T2DM.
that involve removal of cellular cholesterol and may in
Unger103-105 has discussed the role of pancreatic islet alpha
part promote atherogenesis by this mechanism.
and beta cell interrelationship in health and disease and
the role of glucagon in diabetes. The normal reciprocal
Role of Other Agents in Insulin Resistance
response of insulin and glucagon regulates postprandial
Amylin or islet amyloid polypeptide (IAPP) is a polypep­ glucose levels. Impaired alpha cell regulation leads to
tide consisting of 37 amino acids and is expressed exclu­ excessive glucagon release in the fasting and postprandial
sively in the pancreatic beta cells. The IAPP content of state, with increased hepatic glucose production (HGP)
beta cells is only 1% that of insulin. The possible role of and hyperglycemia. The incretin concept was put forward
amylin in insulin resistance may be through regulation by Creutzfeldt and colleagues106 indicating the role of
of glycogen metabolism in skeletal muscle.98,99 However, two incretins—glucagon-like peptide-1(GLP-1) secreted
the concentration of amylin is so low that a definite role by intestinal L cells and glucose-induced insulinogenic
in pathogenesis has not been established. polypeptide (GIP) secreted by intestinal—K cells in
Newly formed adipocytes secrete adiponectin, an insu­ regulation of islet alpha and beta cell function. Thus, a
lin sensitizer while distended adipocytes secrete leptin, new approach to achieve normalization of hyperglycemia
TNFα and resistin which cause insulin resistance. with exogenous GLP-1 and the ability of GLP-1 to increase
Leptin is a peptide of 167 amino acids expressed postprandial insulin secretion and suppress postprandial
exclusively in the adipose tissue.100 Leptin acts through glucagon secretion was established.107
the hypothalamus of the brain and controls appetite in Because of the rapid inactivation of GLP-1 by the
animals. Mutation in leptin gene, “ob” gene results in enzyme dipeptidyl peptidase 4 (DPP4), several incretin
massive obesity in ob/ob mice101 while db/db mice has a analogs were developed: GLP-1 receptor agonist, exenatide
defective “ob” gene receptor. Leptin and TNFα, secreted (synthetic exendin 4) and liraglutide (conjugation of
by adipocytes as they become enlarged, cause insulin GLP-1 with circulating albumin). The acute effect of GLP-1
258 Etiopathogenesis of Diabetes Mellitus

and GLP-1 receptor agonists on beta cells is stimulation of is 1–20 ng/mL; 19 patients had levels of 40–100 ng/mL,
glucose dependent insulin release, followed by enhance-­ 8 had more than 100 ng/mL and another 8 more than
ment of insulin biosynthesis through stimulation of 200 ng/mL. Equally significant was the low adiponectin
insulin gene transcription. The chronic action is stimu­ (< 6 mg/L) and high proinsulin in all of them.74
lation of beta cell proliferation, induction of islet beta cell A positive correlation has been found between
neogenesis and inhibition of beta cell apoptosis, thereby abdominal obesity and circulating levels of TNFα. Adipose
promoting expansion of beta cell mass as observed in tissue macrophage number increases in obesity. Compared
section

rodent diabetes and cultured beta cells. Exenatide and to lean individuals obese adipose tissue produced more
5

liraglutide enhance postprandial beta cell function. Orally proinflammatory cytokines by the macrophages as well
active DPP4 inhibitors, like sitagliptin and vildagliptin as stromal vascular cells (SVCs) in adipose tissue. Kupffer
also promote beta cell proliferation and neogenesis and cells of the liver are also a major source of TNFα.
inhibit beta cell apoptosis in rodents.108,109 The molecular mechanism of TNFα induced insulin
The recent availability of incretin enhancers (inhibitors resistance has been explained.117,118 TNFα causes serine
of DPP4 which normally inactivates incretins) and incre­ phosphorylation of IRS-1 in muscle and IRS-2 in liver
tin mimetics have brought a new approach viz. glucagon thereby abrogating the IRS-PI3K-AKT signaling pathway of
suppression to control hyperglycemia in T2DM.110-112 insulin action which is necessary for GLUT4 translocation,
Intravenous infusion of exenatide not only promotes glucose transport and glycogen synthesis. In the liver,
glucose-induced insulin secretion, it counter-regulates reduced AKT activity decreases phosphorylation of FOXO
insulin secretion during hypoglycemia.113
which leads to activation of PEPCK and G6Pase and
Incretin mimetics (Exenatide—Byetta, and Liraglu­
increased gluconeogenesis. mtGPAT is a key enzyme in de
tide) have to be injected, while DPP4 inhibitors (sitaglip­
novo fat synthesis in the liver, leading to fatty liver. Obese
tin, vildagliptin) can be given orally. These agents are anti­
mice lacking TNFα function have shown protection from
hyperglycemic, not hypoglycemic (unlike insulin and SU)
developing insulin resistance.
and do not cause weight gain [unlike insulin and thiazo­
lidinediones (TZDs)]. Postprandial glucagon suppression Adiponectin: Adiponectin, a 244 amino acid protein
can also be achieved by pramlintide (amylin analog) when produced exclusively by adipocytes, has an important
injected 15 minutes before meals. A novel approach is role in health and disease. Normal levels of adiponectin
therapeutic antisense oligonucleotide drug (ISIS 325568) are 7.9 + 0.5 mg/mL in males and 16.6 + 5 mg/mL in
directed to the glucagon receptor (GCGR) to reduce HGP. females. Adiponectin circulates in multimeric forms.
Data from animal studies regarding protective effects Recent reports have focused on high molecular weight
of incretin mimetics and enhancers has to be reproduced (HMW) adiponectin, which is found to be lower in Asian
in human clinical studies. This evidence can be created Indian pregnant women compared to Caucasians.119 Asian
only by measuring C-peptide, proinsulin and amylin Indians with T2DM have low adiponectin levels with
before and after therapy. Therapy for beta cell preservation higher risk for coronary artery disease (CAD).120
will assume great importance in future.114 Adiponectin receptors (Adip-R1 and Adip-R2) expres­
Tumor necrosis factor-alpha: Increased expression of sed on vascular endothelial cell, interact with APPL-1 an
TNFα in adipose tissue in human obesity and insulin intracellular protein to mediate endothelial NO synthase
resistance102 was first reported in 1993. Subsequently, it (eNOS) activation leading to NO production and vasodi­
was shown that IL-1 and TNFα inhibit the expression and lation.121 Hypoadiponectinemia is linked to endothelial
activity of PPARγ which is highly expressed in adipose dysfunction in hypertension, CAD and T2DM. Adiponectin
tissue and is the trigger for adipocyte differentiation inhibits endothelial nuclear factor kappa B (NF-kB) signa­
and proliferation.115 Newly formed adipocytes produce ling through a cAMP dependent pathway.122 The role
adiponectin while distended hypertrophied adipocytes of adiponectin in insulin resistance, MBS and athero­
produce leptin, resistin, TNFα and IL-6. It is known that sclrosis has been confirmed by other workers.123 Reduced
increased TNFα and IL-1 inhibit adipose tissue expression adiponectin levels (< 6 mg/mL in males; < 10 mg/mL in
of adiponectin messenger RNA (mRNA) by 80% thereby females) can be caused by genetic defects [such as single
lowering plasma adiponectin levels.116 nucleotide polymorphisms (SNPs) 276 in the adipo-
In a study of 35 Asian Indians with T2DM, high levels nectin gene on chromosome 3Q27] or caused by lifestyle
of TNFα were a striking feature. Normal range of TNFα changes causing obesity such as high fat diet. Reduced
 Insulin Resistance 259

adiponectin plays a causal role in the development of Table 17.2: Animal models of insulin resistance127
insulin resistance, T2DM and atherosclerosis. Adiponectin Insulin resistant mice with stable non-ketotic diabetes
knock-out mice shows the characteristics of the metabolic 1 db/db mutant mouse
syndrome—insulin resistance, hyperlipidemia, glucose 2 ob/ob “diabese” mouse (diabetic obese)
intolerance, hypertension and atherosclerosis.
3 Yellow and KK “diabese” mice
In a study of 500 subjects with T2DM, the specificity
4 Polybrominated biphenyls (PBB)/Ld mouse
and sensitivity of fasting intact proinsulin, adiponectin

chapter
5 New Zealand obese (NZO) “diabese” mouse
and the proinsulin or adiponectin ratio as markers for

17
6 Wellesley hybrid mouse
insulin resistance was assessed by homeostatic model
Insulin resistant rats with non-ketotic diabetes and obesity
assessment (HOMA) score. More than two-fold elevation
1 Zucker fa/fa rat
of proinsulin seemed more specific (96%) and sensitive
2 WKY fatty rat
(70%) as a marker for insulin resistance and increased
cardiovascular risk than suppression of adiponectin.124 3 Hypertensive corpulent SHR/N rat

Adiponectin is also a regulator of energy homeostasis.125 4 BHE rat

Increasing plasma adiponectin levels or the development Nutrition-evoked diabetes and insulin resistance
of Adipo-R agonists are appropriate therapeutic strategies. 1 Sand rat (Psammoys obesus)
PPARγ agonists such as TZDs stimulate adipocytes to 2 Spiny mouse (Acomys cahirinus)
secrete adiponectin. TZDs suppress macrophage-media­ 3 Mongolian gerbil (Meriones unguiculatus)
ted production of proinflammatory cytokines [TNFα, IL-6 4 Tuco-tuco (Ctenomys talarum)
IL1b, PAI-1, inducible NOS (iNOS)].
Osmotin, a member of a large pathogenesis-related
db/db Mouse
(PR)-5 protein family is ubiquitous in fruits and vegetables
and is a homologue of mammalian adiponectin.126 The The db/db mutation occurred in the C57/BL/KS inbred
beneficial effects of a diet containing 400 g of fruits and strains of mice and was extensively investigated128 in the
vegetables may partly be due to the osmotin content Jackson Laboratory, USA. Placing the db gene in the C57
apart from the antioxidants and high fiber, low fat mice on the BL/6 background produced long-lasting
content. Osmotin activates adenosine monophosphate- mild hyperglycemia, hyperinsulinism and obesity. On the
activated protein kinase (AMPK) via. adipo-R. Further KS background, the same gene produces highly insulin
research examining the similarities between osmotin resistant, severely hyperglycemic phenotype with the
and adiponectin may facilitate development of potential pancreas succumbing to the glycemic onslaught. This is
adiponectin agonists. a cogent illustration of the impact of the genomic back­
ground on the time course, severity, clinical characteristics
CLUES FROM ANIMAL MODELS OF and final outcome of the diabetic syndrome caused by a
INSULIN RESISTANCE single gene.
The db/db mutant mice, within 10–14 days after birth,
Most common human disorders like diabetes mellitus show hyperphagia and hyperinsulinism. Upto 1 month
are multigenic. More than 250 candidate genes have been these mice are obese and normoglycemic. Then hypergly­
explored in relation to NIDDM. Mutations have been cemia develops, peaking between 9 weeks and 12 weeks.
detected in the genes coding for insulin, insulin receptor, Blood sugar ranges between 400 mg/dL and 500 mg/dL
mitochondrial components, glucokinase and glycogen in the face of hyperinsulinemia (6–10 times higher than
synthetase. normal levels). Between 3 months and 6 months the
Animal models of diabetes with insulin resistance insulin levels drop to normal and subnormal, the mice
also involve multiple genes, but a few models have been lose weight, become severely diabetic and ketotic. At this
developed with a single gene mutation (Table 17.2). time, they exhibit various complications and die in less
Animal models are not to be used as replicas of human than 10 months.
diabetes but they are useful to elucidate the various The single gene mutation in db/db mouse is inherited
mechanisms involved in human diabetes with insulin as an autosomal allele on chormosome number 4 link-
resistance.127 age group VIII with complete penetrance. The basic
260 Etiopathogenesis of Diabetes Mellitus

defect is that the liver cell does not recognize the insulin Table 17.3: Classification of sand rats according to plasma glucose
signal as a suppressant of the rate limiting enzyme and Insulin levels on a “free choice” abundant diet127
for gluconeogenesis, PEPCK. Normally synthesis of Class Class B Class C Class D
PEPCK is effectively reduced by a small physiological control compen- decompen- failing B
rise in circulating insulin. In these mice, in spite of sated sated cells
hyperinsulinemia there is a marked elevation of PEPCK. Distribution (%) 32 125 735 86.4
C-14 lactate and alanine are converted to glucose at a Insulin 53 ± 7 266 ± 21 685 ± 93 61 ± 15
section

higher rate than normal resulting in over production (uU/mL)

of glucose by the liver. There is also increased level of Glucose (mg/dL) 85 ± 4 81 ± 5 249 ± 18 255 ± 16
5

glucagon indicating insensitivity of the alpha cells of islet Body weight (g) 157 ± 7 196 ± 10 224 ± 9 198 ± 23
to glucose suppression. Administration of antiglucagon
antibodies reduces hepatic glucose output.127
sugar level; similarly in-vitro glucose uptake by muscle
The hepatic insulin resistance is selective. It does not
and adipose tissue is low.
extend to enzymes of lipogenesis which remain responsive
to insulin, hence the obesity. Defective satiety center in Spontaneously Hypertensive/NIH (National
db/db mice has been shown by parabiosis experiment
Institutes of Health)-Corpulent (SHR/N-Cp) Rat
with non-diabetic mice. The latter stop eating and starve
to death within 2–4 weeks of the operation indicating an The usefulness of this model is underscored by the
exaggerated response to satiety factor (probably mediated occurrence of diabetic changes both in the obese and
through leptin derived from the donor diabetic obese lean siblings and the concomitant hyperinsulinemia,
mice which are themselves insensitive to the satiety signal hypertension, hyperlipidemia and susceptibility to athero­
because of a defect in the receptor for leptin). When sclerosis, which renders these animals suitable for dietary,
db/db mice are parabiosed with wild type partners, pharmacologic and other interventions.
the db/db mice lose weight showing that they have no
defect in the satiety center. Insulin Resistance in Animals with
Normal mice respond to bilateral ventromedical Nutritionally Induced Diabetes
hypothalamic (VMH) lesion with hyperphagia, obesity, The sand rat is of great interest for diabetologists since
hyperinsulinism and IGT. In contrast, the same lesion in there appears to be no genetic defect causing diabetes,
db/db mice leads to amelioration of the diabetes including only a genetic predisposition of a desert-adopted species
a reduction in the hepatic glucose output. to the effects of nutritional abundance, to which some fail
The ob/ob mouse has a single gene defect in leptin gene to adjust. Classification of sand rats according to plasma
in contrast to the db/db mouse. The islet beta cells have a glucose and insulin levels, on exposure to abundant “free
long standing non-exhaustive compensatory capacity for choice” diet is given in following Table 17.3.
insulin production resulting in hyperinsulinism without These animals show marked peripheral insulin resi­
IGT or diabetes. In contrast to db/db, the ob/ob mice do stance (decreased glucose uptake by muscle) and hepatic
not develop any vascular complications. insulin resistance (excessive gluconeogenesis due to
A gene that codes for the enzyme protein tyrosine non-suppressed PEPCK activity), yet hepatic lipogenesis
phosphatase 1B (PTP-1B) is active in fat mice. Genetically remains susceptible to insulin (rise in activity of lipo­
engineered mice that lacks the PTP-1B gene, gain only genic enzymes and increased FA synthesis). All these
half much as weight when fed the same high fat chow.
abnormalities can be altered by food restriction. Hence, the
In muscle and liver cells, the PTP-1B enzyme acts as an
sand rat may serve as a model for the study of mechanisms
on/off switch for insulin action.
evoking hyperinsulinism and IR in populations subjected
The interest in the PBB/Ld mice with insulin resistance
to nutritional abundance.
is the presence of diabetes-related hyperlipidemia,
not seen in the other single gene defective models. INSULIN RESISTANCE AND
New Zealand obese (NZO) mice show the same defect
ENDOTHELIAL DYSFUNCTION
viz. increased PEPCK enzyme activity in the liver despite
hyperinsulinemia. Insulin is incapable of suppressing Insulin promotes vasodilation by stimulating NO prod­
gluconeogenesis from alanine in isolated perfused liver. uction from endothelial cells. Inhibition of NO-synthase
Large amounts of exogenous insulin hardly affect blood with L-NG-monomethylarginine, acetate salt (L-NMMA)
 Insulin Resistance 261

inhibited both insulin-induced blood flow (completely) foam cell formation, white cell adhesion molecule expres­
and muscle glucose uptake (by 30%). L-NMMA infusion sion, monocyte chemoattractant protein, macrophage
significantly increased BP. Scherrer and colleagues colony stimulating factor production and inflammatory
suggested that impaired vasodilatory responses to insulin cytokine release. These changes not only enhance athero­
could contribute to the hypertension associated with sclerotic lesion formation, but also promote rupture of the
insulin resistance.129 atheromatous plaque, the major event leading to myo­
The cause for the common defect in insulin-mediated cardial infarction.

chapter
glucose uptake and insulin-mediated NO production Nitric oxide inhibits many of the processes that fol­

17
may be the same signaling pathway, the phosphatidyl low endothelial damage (such as growth and migration
inositol-3 kinase (PI3K).Chronic exercise and estrogen of VSMCs, intimal hyperplasia, expression of adhesion
therapy improve endothelial production of NO and also mole­­
cules such as vascular cell adhesion molecule 1
improve insulin resistance. In IR, the vascular protective (VCAM-1), ICAM and E-selectin, proinflammatory cyto­
effects of insulin, specifically NO production, are blunted kines such as TNFα and chemokines). NO induces and
while the proatherosclerotic effects proceed normally via stabilizes the NF-kB inhibitor IKBα. As a result NO atte­
stimulation of vascular smooth muscles cells (VSMCs) nuates the binding of inflammatory cells to the vascular
mediated by the MAPK pathway. wall. NO also inhibits the thrombotic process (platelet-
adhesion and aggregation) via prostacyclin.
Endothelial Dysfunction as
Cause of Insulin Resistance Endothelial Dysfunction as Initial Event
The endothelium is a dynamic tissue that maintains
In two epidemiological studies, Von Willebrand factor
the integrity of the vasculature. Endothelium produces
(VWF) concentrations (as markers of endothelial dys­
vasodilators such as NO, BNP, prostacyclins and endo­
function) were correlated with those of insulin, a surrogate
thelium-derived hyperpolarization factor. These sub­
marker for IR in non-diabetic subjects. However, no
stances balance the production of vasoconstrictors such
as angiotensin II [formed from the enzymatic action direct association between IR and circulating markers of
of angiotensin-converting enzyme (ACE) located on endothelial dysfunction has been demonstrated.
endothelial cells], endothelin and vasoconstrictive cyclo- In a study of 33 subjects (25 men and 8 women) with
oxygenases (such as thromboxane and prostaglandin T2DM, with BMI 29 kg/m2, glycated hemoglobin (HbA1c)
H2). These autocrine and paracrine mediators not only of 10.1% and diabetic duration 5 years, circulating levels
direct the behavior of the underlying VSMCs but also of VWF antigen correlated with the metabolic clearance
mediate interaction of circulating cells such as platelets, rate of glucose, HDL cholesterol, mean systolic BP
neutrophils, monocytes and macrophages with the (r = –0.35) and marginally with total TGs.37 These data
vascular wall. Damage to endothelium shifts the balance suggest a relationship between endothelial dysfunction
from a vasodilator state to a vasoconstrictor state. Reduced at capillary level and insulin action, as well as providing
NO activity results in loss of vascular protection (inhibition further evidence for a relationship with other features of
of platelet and leucocyte aggregation and migration, the insulin resistance syndrome.
inhibition of VSMC migration and growth). Thus, an The hypothesis is that peripheral endothelial dys­
important measure of endothelial health is the ability
function at the arteriolar and capillary level arises through
to produce NO. Defect in NO production or excessive
a complex interplay of genetic and environmental factors
inactivation of NO are seen in subjects with risk factors for
and leads to a multifaceted metabolic disturbance
atherosclerosis. Endothelial responses are abnormal in
the presence of these risk factors even in the absence of comprising of insulin resistance and other features of the
angiographically defined disease. insulin resistance syndrome. Thus, IReS is a marker for
Endothelial injury initiates the process of platelet peripheral endothelial dysfunction. In contrast, central
aggregation releasing platelet-derived growth factors, large vessel endothelial dysfunction plays a major role
cyto­kines, vasoconstrictors and other substances includ­ in atherogenesis but has little direct metabolic impact.
ing those that enhance activation of the transcription The coexistence of peripheral and central endothelial
factor, NFKB an important mediator of inflammation. dysfunction explains the observed association between
Enhanced NF-kB activity increases monocyte chemotaxis, atherosclerotic vascular disease and IReS.
262 Etiopathogenesis of Diabetes Mellitus

Not all patients with CAD have IReS prototype. IReS is The Childhood Origin of Atherosclerosis
not an obligatory precursor of large vessel atherogenesis
In a multicenter collaborative research program titled,
but rather a marker of peripheral endothelial dysfunction.
“Pathobiological Determinants of Atherosclerosis in Youth
Those with IReS phenotype (e.g. diabetic patients) will
(PDAY)”, 14 United States (US) Medical Research Centers
accelerate endothelial dysfunction among other things
co-operated to study 1,532 sudden death victims aged
by increased advanced glycation end-products (AGEs)
15–34 years.135 Even in the teenage group of 15–19, all the
and accelerate atherogenesis in large vessels. The most
aortae and nearly one-half of the right coronary arteries
section

rigorous criteria for causality are temporal precedence and

had lesions. Raised lesions (fibrous plaques) increased
5

experimental reversibility. The chronological relationship

with age in prevalence and extent. The percentage of
of arteriolar and capillary endothelial dysfunction to
intimal surface involved in the lesions was positively asso­
insulin resistance has not been addressed directly by
ciated with serum very low-density lipoprotein (VLDL)
prospective studies. Interventions such as NO donors
and LDL cholesterol concentrations, elevated HbA1c, and
and antioxidants may be useful tools with which to test
higher BMI, and negatively associated with HDL. Thus,
reversibility.
the study provides evidence for the childhood origin
of atherosclerotic lesions associated with multiple risk
INSULIN RESISTANCE AND factors implicated in CAD.
ATHEROSCLEROSIS The endothelium has an important role both in the
The process of atherosclerosis of arteries is multifactorial transendothelial insulin transport to the tissues and as
and hyperinsulinemia has emerged as an important a target for insulin action. Physical integrity and normal
contributing factor. function of the arteriolar and capillary endothelium are
Data from the Paris Prospective Study was among the prerequisites for normal insulin action. Hence, endo­
earliest to show increasing cardiovascular mortality with thelial dysfunction is proposed as an important factor in
progression from normal glucose tolerance (NGT) to IGT the pathogenesis of insulin resistance. There are cogent
to diabetes.130 Subsequent data from this study show a reasons to suppose that endothelial function and insulin
progressive increase in CAD frequency across quartiles action are linked.
of fasting insulin levels suggesting the importance of
insulin resistance.131 Individuals with atherosclerosis Insulin Resistance in Diabetes
exhibit both endothelial dysfunction and impaired Insulin resistance is seen in both obese and non-obese
insulin action. Several prevalence and prospective studies individuals with T2DM.136 The defect viz. decreased
on patients have shown consistently good correlation receptor tyrosine kinase activity has been demonstrated
of hyperinsulinemia and CAD. The most recent study in liver biopsy specimens, from humans with obesity and
included 91 males and 105 matched controls.132 T2DM137 and also in human skeletal muscle in obesity and
Ethnic differences with regard to insulin and athero­ T2DM.138,139
sclerosis have been noted. In the insulin resistance Reaven postulated that resistance to insulin-stimu­
and atherosclerosis study (IRAS), less atherosclerosis lated glucose uptake is necessary but not sufficient for
(measured by carotid intima-media thickness) and higher the development of T2DM. The fact that insulin resistant
insulin sensitivity was seen in Hispanic and non-Hispanic subjects may not become diabetic does not mean that
whites but not in blacks.133 Indians in India as well as Indian they suffer no untoward consequences. Attempts to
immigrants in various parts of the world have significantly compensate for hyperinsulinemia by counter-regulatory
higher prevalence of CAD.134 Hyperinsulinemia, central mechanisms set into motion a series of events that play
obesity and increased Lp(a) are significantly more an important role in development of hypertension and
common in Indians living in South Africa, East London coronary atherosclerosis.
and in Singapore. Using the glucose clamp technique, Reaven demon­
Hyperinsulinemia and hypertriglyceridemia are strated that insulin stimulated glucose uptake is lower
closely related, and inversely related to HDL cholesterol. than normal in patients with both T2DM and IGT. Glucose
Indians have lower HDL and higher Lp(a), increased uptake is reduced to almost the same degree in IGT and
apolipoprotein B-100 and decreased apolipoprotein A, as T2DM. They are all insulin resistant, whether their fasting
compared to Americans. plasma glucose is 100 or 250 mg/dL. Thus, some factor
 Insulin Resistance 263

other than insulin resistance, presumably glucagon ex­ These associations of birth weight with cardiovascular risk
cess, must be invoked to explain why fasting plasma were independent of adult obesity and lifestyle factors.
glucose is 100 mg/dL in one patient and 250 mg/dL in Further studies showed that low birth weight (probably
another. The main locus of insulin resistance is the liver the result of maternal malnutrition) is associated with
cell which fails to recognize insulin signal as a suppressor insulin resistance in adult life.
of PEPCK. There is also resistance to insulin suppression of Yajnik collaborated with Barker’s group to study the
plasma FFAs in T2DM; hence sustained hyperinsulinemia relationship between low birth weight and glucose and

chapter
is required to prevent elevation of circulating FFAs. insulin metabolism in 4-year-old urban Indian children.

17
The ability of the islet beta cells to compensate (for the Plasma glucose and insulin were inversely related to birth
insulin resistance) by secreting more insulin is a crucial weight and head circumference in 201 children studied.
determinant of the glucose tolerance. This compensatory With birth weight less than 2 kg, higher glucose and insulin
increase in insulin secretion maintains normoglycemia in levels during OGTT (glucose 8.1 mmol/L and insulin 321
the insulin resistant individual. However when islet beta pmol/L at 30 minutes) were indicative of insulin resistance.
cells are unable to sustain the hypersecretion of insulin, In a study of 321 rural adults, head circumference and
blood glucose starts rising. Levels of circulating FFAs height were used as surrogates for growth and nutrition in
become elevated in the face of inadequate insulin response early life (since birth weights were not available). Even in
(though insulin levels are apparently in the normal range). the thin rural subjects OGTT revealed hyperinsulinemia
Decreased insulin sensitivity in offspring both of whose and insulin resistance.
parents had T1DM has been reported. Higher than normal Yajnik suggested that unlike Barker’s hypothesis which
plasma FFAs in the face of hyperinsulinemia is an indicator is confined to prenatal influences, importance should be
of insulin resistance. given to events in later life too for the genesis of insulin
A role for amylin has been suggested in the development resistance syndrome. The development of cardiovascular
of insulin resistance in diabetes. Amylin deposits in the risk is an ongoing process and prevention is possible
islet beta cells may be the consequence of overproduction, through lifestyle modification.
and may contribute to the late failure of insulin production
in long-standing T1DM. Endothelial Function in Diabetes
The characteristics of newly diagnosed T2DM and IGT
have been studied in an urban diabetic clinic in Western Endothelium dependent vasodilation is impaired in
India.62 T2DM is diagnosed in Indian population at a angio­graphically normal coronary arteries in patients
younger age (one-fifth before age 35, one-half below age of both T1DM and T2DM140 There is increased oxidative
40); obesity on the criterion of BMI is uncommon (22% stress and raised levels of reactive oxygen species (ROS) in
of men and 47% of women compared to 80% in Western diabetes. Oxygen-derived free radicals impair NO-induced
clinics), but increased waist/hip ratio (> 0.9 in men and vasodilation in both T1DM and T2DM. There is excessive
> 0.8 in women), was characteristic of T2DM and IGT inactivation of NO by superoxide ions (O2–) to form stable
compared to non-diabetic patients (0.88 men and 0.77 peroxynitrite anion (ONOO–).
women). Plasma TGs and FFAs were significantly elevated Sustained hyperglycemia causes non-enzymatic glyca­
in both T2DM and IGT (1.02 mmol/L) compared to non- tion of proteins. There are many adverse effects of AGEs—
diabetic patients (0.81 mmol/L). BP was significantly promotion of auto-oxidation and increased inacti­vation
higher in both T2DM and IGT compared to non-diabetic by quenching of NO. Binding of AGEs to their endothelial
subjects; half the patients in the hyperglycemic groups receptors causes activation of NF-kB which causes changes
were hypertensive. Hyperinsulinemia and insulin resis­ in endothelial phenotype expression-promoting platelet—
tance preceded the diabetes. aggregation, macrophage migration and cyclooxygenase
Comparative studies in migrant Indians in United catalysis.
Kingdom (UK) and elsewhere suggest that Indians have The oxidative hypothesis of atherosclerosis was pro­
more central obesity for a given BMI compared to white posed by Witztum in 1994.141 Ting and colleagues found
Caucasians and that Indians are more insulin resistant. that acute intra-arterial administration of antioxidant
A series of studies by Barker’s group showed an vitamin C improved endothelium-dependent vasodilation
association of adult diabetes, hypertension, dyslipidemia in both type 1 and type 2 diabetes. Similar benefits have
and abnormal coagulation profile with low birth weight. been shown with vitamin E.142
264 Etiopathogenesis of Diabetes Mellitus

The NO systems of the endothelium of the corpus The coexisting postbinding defect in insulin action can be
cavernosum are crucial for erectile function, mediated demonstrated in euglycemic clamp studies. Possibly the
by NANC (non-adrenergic non-cholinergic) nitrinergic postbinding alteration in insulin action in obesity initiates
autonomic nerves. Impaired NO-mediated vasodilation the IR; the compensatory response by insulin secretion
is commonly found in animal models of diabetes as well is triggered and insulin levels rise. This in turn leads to
as in several studies on diabetic patients.143 The beneficial downregulation of insulin receptor numbers and this
effects of an antioxidant, α-lipoic acid have been shown; further aggravates the insulin resistance.
section

it scavenges ROS, prevents lipid peroxidation, improves We have shown insulin receptor defect in the erythro­
5

tissue glutathione (GSH) content and attenuates the cytes of obese Asian Indian women with acanthosis
activation of NF-kB. Long-term treatment with amino­ nigricans and exhibiting IGT.91 In both insulin-deficient
guanidine, an inhibitor of AGEs, prevents and reverses and insulin-resistant states, adipocytes release FFAs,
the endothelial NO defect. increasing hepatic VLDL production and leading to
The oxidative stress and antioxidant status of 80 dia­ hypertriglyceridemia. The enzyme LPL is regulated by
betic patients with microvascular complications (retin­ insulin. In insulin deficient as well as insulin resistant
opathy, neuropathy, nephropathy) were assessed and states there is decreased LPL activity, which further
compared with 30 normal controls.144 Plasma malon­ increases TG levels; 3–5% of the population have genetic
dialdehyde (MDA) and nitrite (NO2) were measured LPL abnormality. These individuals are most prone to
as markers of free radical-mediated endothelial injury, develop hypertriglyceridemia if they develop insulin
and plasma superoxide dismutase (SOD) as a measure resistance.
of anti­oxidant capacity. Patients with both T1DM and
T2DM were included. Patients with ketoacidosis, chronic Insulin Resistance and Endothelial
tobacco use, hypertension and CAD were excluded. Most Dysfunction in Obesity
of the patients had poor glycemic control. MDA was a
poor discriminant between diabetic patients and controls, Insulin has a specific physiologic action to vasodilate
although the mean MDA and nitrite levels were signifi­ skeletal muscle vasculature in humans. NO release
cantly elevated compared to controls. The elevated SOD accounts for insulin’s vascular effect in humans.146 This
in diabetic patients compared to controls probably repre­ hemodynamic action appears to be important both for the
sents compensatory effort to control increased oxidative maintenance of vascular tone and modulation of substrate
stress, albeit insufficient to protect the patient. uptake. Steinberg and coworkers35 proposed the novel
Elevated plasma lipid hydroperoxide levels were seen concept that the endothelium is not merely a passive site
in patients of CAD (4.31 ± 0.23 nmol/mL) compared for insulin transit to the tissues, but rather a target tissue
for insulin action, at least with respect to the NO system
to normal controls (2.34 ± 0.13 nmol/mL).145 Plasma
(and perhaps others).
lipid peroxide levels were less than 6 nmol/mL in all
To test the hypothesis that insulin resistance in obesity
controls; 20% of CAD patients had more than 6 nmol/mL.
is associated with defective endothelium-dependent
Measured plasma total lipid peroxide levels are a refle­
vasodilation, healthy subjects with a large range of obesity
ction of circulating oxidized LDL, and as such, should be
were studied. Further, to better distinguish the effects of
considered to be pathologically significant.
adiposity versus those of diabetes, a group of patients with
T2DM were also studied. Normotensive, non-diabetic,
INSULIN RESISTANCE AND OBESITY
non-obese (BMI 23.2 ± 0.7) subjects were used as controls
Insulin resistance in obesity is due to alterations in both (C). Leg blood flow (LBF) responses to graded intrafe­
receptor number and postreceptor binding signal trans­ moral artery infusion of methacholine chloride (MCH),
duction function. Characteristically, circulating insulin a congener of acetyl choline and sodium nitro­prusside
levels are elevated and correlate inversely with insulin (SNP) were studied during saline infusion and during
receptor number. This is probably due to down regulation euglycemic hyperinsulinemia.
in response to high insulin levels. If insulin levels are Methacholine induced increments in LBF were 40%
lowered by diet or drugs that lower insulin secretion, the lower in obesity and 55% lower in T2DM compared to
insulin receptor number returns to normal even though normal controls. Euglycemic hyperinsulinemia augmented
the degree of obesity may not be significantly changed. LBF response to MCH by 50% in controls but not in obesity
 Insulin Resistance 265

and T2DM. SNP caused comparable increment in LBF diabetes. Indians in Singapore have higher WHR, fasting
in all groups. There was a significant inverse correlation hyperinsulinemia and IGT compared to Malays and
between maximal LBF changes in response to MCH and Chinese; they also have higher PAI-1 and tissue plasmi­
body fat. Thus in obesity, insulin resistance is associated nogen activator (tPA) levels.148
with: (1) blunted endothelium-dependent but normal Polymorphism of the beta 3 adrenergic receptor
endothelium-independent vasodilation, and (2) failure of gene (Try 64 Arg) has been shown to be associated with
euglycemic hyperinsulinemia to augment endothelium- abdominal obesity and insulin resistance thus contributing

chapter
dependent vasodilation due to impaired production or to early onset of T2DM.149

17
release of NO. This suggests the novel idea that obesity
is associated with endothelial dysfunction which may INSULIN RESISTANCE AND HYPERTENSION
be related to insulin resistance, since the impaired
The first observation of the presence of hyperinsulinemia
vasodilation was proportional to the insulin resistance.
in hypertension150 led to a study of the effects of insulin on
Glucose disposal rates in the obese group were 35%
renal handling of sodium, potassium, calcium and phos­
lower than in controls. Thus, insulin appears to act at the
phorus. Under the influence of insulin, sodium is retained
level of the endothelial cell to modulate NO production or
by both proximal and distal tubules. Hyperinsulinemia
release, and this insulin effect is blunted in obese subjects
augments intracellular Na+ and Ca2+. Much later, a pos­
with or without T2DM. It is possible that small dense LDL
sible role for magnesium was suggested in hypertension
which is more prevalent in insulin resistant subjects and
and peripheral vascular resistance.151 Reduced activity of
more susceptible to oxidation may contribute to impaired
Na/K ATPase and decreased intracellular magnesium,
endothelial function.
and increased sodium-lithium counter transport are pro­
Induction of acute euglycemia by the insulin clamp
posed as possible links.
technique did not improve endothelium-dependent-
A high prevalence of insulin resistance was discovered
vasodilation in T2DM, suggesting that decreased NO
in an epidemiological study of GTT and BP in two
production or release was not due to hyperglycemia.
population samples.152 By using the euglycemic insulin
Differences in FFA concentrations did not account for the
clamp technique it was seen that in normal humans, insulin
marked differences in vasodilation between the groups.
causes a dose-related increase in plasma norepinephrine
The FFA levels were the same in control and obesity and
level which was closely correlated with an increase in
the nearly 50% higher levels in T2DM did not cause further
pulse rate and BP.153
impairment in the LBF response to intrafemoral infusion
The effect of age on insulin-induced stimulation of
of MCH.
sympathetic nervous system activity was studied in human
Steinberg raises the question whether differences
subjects.154 A central action of insulin was postulated,
in endothelium dependent vasodilation among various
perhaps in insulin sensitive areas in the hypothalamus.
reports examining hypertensive subjects may actually
Insulin and IGF-1 stimulate vascular smooth muscle cell
reflect differences in body fat content rather than BP
proliferation.
alone as many hypertensive subjects also have increased
Association of hypertension and hyperinsulinism
adiposity. It is important to note that levels of the potent
was found in obese subjects155,156 as well as in non-obese
vasoconstrictor endothelin 1 (ET-1) increases in T2DM
subjects.157 Insulin resistance is observed in as many as
subjects in response to euglycemic hyperinsulinemic
50% of subjects with essential hypertension. Resistance
clamp.147
to insulin-stimulated glucose uptake was shown in
hypertensive subjects.158 The defect persisted in spite of
Central Obesity and Waist-Hip Ratio lowering the BP with drugs. Chronic hyperinsulinemia
Although the general discussion on obesity (BMI > 27 kg/m2) (rather than acute or intermittent rise of insulin) is
does not give further characterization about the distribu­ required to raise the BP.
tion of body fat, recent interest has focused on central or Insulin resistance and hyperinsulinemic dyslipidemia
visceral obesity as indicated by a waist/hip ratio (WHR) was shown in individuals with a hypertensive parent.159
more than 0.9 in men and more than 0.85 in women. Indian immigrants in UK have a high prevalence of insulin
As noted earlier Asian Indians, at any value of BMI, resistance and also higher prevalence of hypertension,
tend to have a WHR in the abnormal range and which diabetes and coronary heart disease.160 In comparison to
is now considered to be an independent risk factor for other ethnic populations in UK, USA, the Caribbean, Africa,
266 Etiopathogenesis of Diabetes Mellitus

Malaysia and China, Indians have a significant association insulin resistance and hypertension with endothelial dys­
of central obesity (WHR > 0.9), hyperinsulinism, dys­ function viz. inability to produce sufficient endothelium
lipidemia and CAD. derived NO.
In subjects who develop T2DM, BP may be elevated It is pertinent to recall here that salt-sensitive hyper­
years before IGT develops. In a large study of T2DM as tension in susceptible Sprague Dawley rats can be
many as 40% of men and 53% of women were hypertensive prevented by providing exogenous L-arginine, a substrate
at the time of diagnosis of diabetes. for NO. This suggests that either L-arginine availability or
section

Association does not necessarily prove cause and NOS (nitric oxide synthase) activity is abnormal in salt-
5

effect relationship. Alberti161 raised doubt about the direct sensitive rats. Salt-resistant rats are capable of producing
cause-and-effect relationship between hyperinsulinism sufficient NO to prevent hypertension. There may well be
and hypertension, based on a study of 5,036 subjects a human counterpart of this model, which is a fertile field
belonging to different ethnic groups in Mauritius namely of research.
Hindu and Muslim Indians, Chinese and Creoles. The
link may be indirect through mechanisms of an inherited ESSENTIAL FATTY ACIDS
or acquired nature, including sympathetic nervous Polyunsaturated FAs (PUFAs) of omega 6 class (w6)
system over-reactivity, and inability to synthesize NO in [linoleic acid (LA)] and omega 3 class [alpha linolenic acid
endothelium adequately (vide infra). (ALA)] are essential dietary sources since they cannot be
Racial differences in the relation between high BP synthesized by the organism. Omega 6 FAs are present in
and insulin resistance have also been reported.162 For maize, sunflower and sesame oil; omega-3 are present in
instance, Pima Indians had higher plasma insulin levels linseed oil, nuts, soyabeans, wheat and cold water fish.
than the whites or blacks (176 pmol/L, 138 pmol/L, 122 All cell membranes contain ω6, arachidonic acid and ω3,
pmol/L, respectively). They also had lower rates of whole EPA and DHA. The ideal ratio of ω6:ω3 is 2:1, maximum
body glucose disposal both during low dose insulin 6:1. Higher ratio is detrimental since it leads to increase in
infusion (12.7 mmol/minute, 17.1 and 19.5, respectively) the arachidonic acid-induced proinflammatory cytokines
and high dose insulin infusion (38 mmol/minute, 43.1, (PGE1, IL-1, IL-6 and TNFα). EPA/DHA lead to decreased
45.7) compared to whites and blacks. Yet, they had lower production of proinflammatory cytokines and increased
prevalence of hypertension than whites and blacks in USA production of anti-inflammatory lipoxins, resolvins
population. and protectins and IL-10, which play active role in the
Many Indian studies have documented hyperin­ resolution of inflammation.174,175
sulinism in hypertension163–165 including ours.166,167 Higher Eicosapentaenoic acid is a source of resolvins (rvE1,
than normal plasma FFAs in the face of hyperinsulinemia E2), DHA (RvD1D2D3D4) and protectins (PD1 and NPD1).
seen in our study in non-diabetic, non-obese hypertensive DHA derived neuroprotectins (NPD1) protect against
elderly subjects is an indicator of insulin resistance. neuronal decline through excessive oxidative stress and
A population based study involving 3,518 individuals apoptosis, while promoting cell survival and maximizing
in the age range of 5–26 years showed consistent relation­ cognitive function throughout the human life span.176
ship between insulin levels and BP.168 Normo­tensive Omega-3 FAs maintain membrane fluidity and
offspring of hypertensive parents showed evidence of longer residence of transporters such as GLUT. Brain cell
insulin resistance.169 Insulin resistance is present in the membranes have a high content of EPA/DHA, essential
offspring of Indian hypertensive parents as well, when for neurotransmission, brain development and function
they are young and have normal BP.170 including learning tasks.
Abnormal endothelium dependent vascular relaxation Epidemiological data indicate the association of low
has been demonstrated in patients with essential hyper­ EPA/DHA with depression [(with higher levels of inflam­
tension.171 The beneficial effect of increased availability matory markers including high-sensitivity C-reactive pro­
of NO precursor on endothelium—dependent vascular tein (hsCRP), intercellular adhesion molecule-1 (ICAM-1),
relaxation in normal subjects and in patients with essential IL-6)] and coronary heart disease.177 Epidemiological
hypertension was shown.172 data support a relationship between higher fish intake
Defective L-arginine-nitric oxide pathway has been and depression or suicide.178 Dietary supplement of DHA
reported in offspring of patients with essential hyperten­ for 3 months prevented young students from developing
sion.173 All these studies suggest a genetic factor linking aggressive behavior during time of stress.179
 Insulin Resistance 267

DIET AND INFLAMMATION

Prof PC Calder has given an excellent review of inflam­
mation in health and disease.190 He has emphasized the
important role of dietary essential FA, omega 3 PUFA,
EPA and DHA, in the suppression of proinflammatory
cytokines and production of anti-inflammatory lipoxins,

chapter
resolvins and protectins. This is crucial in many disease

17
states including inflammatory disorders (such as arthritis),
atherosclerosis, asthma and cancer.
Zinc, selenium, vitamin A, vitamin C, vitamin E, folic
acid, vitamin B6 and vitamin B12 are important nutrients
whose deficiency affects susceptibility to infection and
Fig. 17.7: Beneficial effect of eicosapentaenoic acid/docosahexaenoic
acid (EPA/DHA) in cells membrane phospholipids host immune response. The role of vitamin D in relation to
immune competence has only recently been discovered.
Dendritic cells and macrophages have receptors for
EPA/DHA ratio plays essential role in maintaining
vitamin D. Deficiency of vitamin D and vitamin D receptor
normal endothelial function by inhibiting endothelial
inflammation, the starting point of atherosclerosis. polymorphism increase susceptibility to tuberculosis.191
Figure 17.7 describes the beneficial effects of essential There is a two-way interaction between nutrients
FAs. The Early Adult Reduction of weight through LifestYle and human genes.192 How genetic variation influences
intervention (EARLY) study evaluated the role of DHA respo­nse to nutrients and how nutrients influence gene
in restoring endothelial function in children with hyper­ expression, transcription and metabolism are the sub­
lipidemia as measured by increased flow-mediated ject of nutrigenomics. The effect of maternal malnutrition
vasodilation.180 Higher concentrations of EPA/DHA on suppression of fetal insulin IRS-PI3K, AKT pathway
improve brachial artery dilatation in patients with CAD.181 is well-known as the basis of MBS and insulin resistance
Red cell membrane EPA/DHA level of 5% of total FAs with consequent hyperinsulinemia.
is associated with a 70% reduction in the risk of primary Raheja pointed out the adverse impact of replacement
cardiac arrest.182 Higher concentrations of EPA/DHA of the traditional fat sources in Indian diets such as
decrease the risk of sudden cardiac death,183 ensure plaque ghee, mustard oil and coconut oil which have very
stability via reducing abundance of macrophages.184 Low low concentrations but normal proportions of n–6, n–3
EPA/DHA is associated with acute coronary syndrome.185 viz. 2:1 with refined vegetable oils with a very high n–6:
Dietary PUFAs function as fuel partitions, inducing FA n–3 ratio.193 This has contributed to the sharp rise in the
oxidation and reducing FA synthesis and reduce fat incidence of diabetes, hypertension and CAD in South
deposition. High intake of trans-FAs (TFAs) in cafeteria Asian populations.194 Correction of the adverse n–6:n–3
foods, bakery and meat products, margarine, frying oils
ratio by suitable dietary modification in recent onset
and desserts reduce the conversion of ALA to DHA, and
diabetic patients has shown improvement in blood sugar
promote abdominal obesity. Hence, reducing the dietary
control, correction of dyslipidemia and lowering of BP.
intake of TFAs is an important goal186 in healthcare.
Gamma-linolenic acid (GLA)-enriched diet has been
Skeletal muscle membrane lipid composition is related
claimed to suppress acute and chronic inflammation as
to insulin action.187 Skeletal muscle membrane fatty acid
composition is altered by omega-3 PUFA increasing the well as joint tissue injury in several animal studies.
fluidity, thereby permitting prolonged residence of GLUT- Regulating energy levels is a fundamental process
4 in the plasma membrane. Breast milk contains ideal in every living organism. At a cellular level, ATP must
proportion of n–6:n–3 (2:1) and breast fed infants have be maintained at relatively high levels [normally about
a muscle membrane fatty acid composition similar to 10-fold above the concentration of adenosine diphos­
insulin sensitive adults. Formula fed infants have a muscle phate (ADP)] in order to drive essential metabolic pro­
membrane composition similar to insulin resistant cesses. AMPK is activated in response to ATP depletion,
adults.188 The relation of n–3 FAs and MBS has been which causes a concomitant increase in the AMP:ATP
emphasized by Carpentier.189 ratio (Fig. 17.8). Activated AMPK causes switching off of
268 Etiopathogenesis of Diabetes Mellitus

When nutrients are available, the insulin/IGF-1 sig­

naling pathway is activated. When cells are starved of
carbon source, the AMPK pathway is activated: glucose
deprivation, ischemia and exercise activate AMPK which
inhibits acetyl-CoA carboxylase (ACC) and malonyl CoA
via malonyl CoA decarboxylase thereby inhibiting TG
synthesis and simultaneously increasing FA oxidation
section

in the mitochondria. AMPK is an important regulator of

5

mitochondrial biogenesis, mediating its effects through

myocyte enhancer factor 2 (MEF2) and CRFB-mediated
PGC-1a and PGC-1b.
AMPK also increases expression of UCP-2 in adipose
tissue and UCP-3 in skeletal muscle. AMPK activation
of GLUT-4 in muscle is not suppressed by wortmannin
Fig. 17.8: Adenosine monophosphate-activated protein kinase (inhibitor of P13K) but by compound C, a selective
(AMPK): cellular energy sensor and regulator
(AICAR: Aminoimidazole carboxamide ribonucleotide; PPARα: Peroxi- inhibitor of AMPK.
some proliferator-activated receptor-alpha; UCP3: Uncoupling protein AMPK activation underlies many of the health benefits
type 3; ACC: Acetyl-CoA carboxylase; TG: Triglyceridemia; IMCL: of regular physical exercise, as well as beneficial effects of
Intramyocellular lipid; TNFα: Tumor necrosis factor alpha; IL-6:
Interleukin-6; PEPCK: Phosphoenolpyruvate carboxykinase; FOXO1: caloric restriction.
Forkhead box protein O1; PGC: Peroxisome proliferator-activated In at least three animal models of resistance to in­
receptor gamma coactivator). duced obesity (UCP-1, UCP-3 overexpression or mice with
a knock-out of enzyme, Stearoyl-CoA desa­tu­ra­ se-1) there
ATP-utilizing pathways (e.g. FA synthesis) and switching- is persistent activation of AMPK. Leptin, adiponectin and
on of ATP generating pathways (e.g. FA oxidation). AMPK osmotin (plant homolog of adiponectin), 5-aminoimi-
is a sensor as well as regulator of cell energy status and dazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR),
plays a key role in maintenance of energy balance at the metfor­min and exercise all activate AMPK. AMPK is a key
cellular as well as whole body level.195 player in the development of new treatments of obesity
Sirtuin-1 (SIRT-1), activated by AMPK, plays an and metabolic syndrome.64
important role in metabolic function and longevity in
mammals. Both act in concert with PGC-1a which inter­ Importance of Physical Exercise
acts with multiple transcription factors to stimulate
mitochondrial metabolic capacity. Fibroblast Growth When the body is at rest, the muscles take up no more
factor-21 (FGF-21) regulates energy metabolism by than about 20% of the total body oxygen consumption
activating AMPK-SIRT1-PGC-1a pathways. In animal (60–70 mL of O2 per minute out of 300 mL/minute).
models of obesity, FGF-21 reduced abdominal fat by 50%.196 During exercise, as in running or swimming, the active
Further research is needed to expand our understanding muscle needs about 3,000 mL/minute or about 50 times
of the diagnostic and therapeutic relevance of FGF-21- their resting requirement. Thanks to the presence of
dependent pathways in humans and the potential to myoglobin (the special oxygen store), the muscle cell is
ameliorate both obesity and diabetes. extraordinarily tolerant to a temporary shortage of oxygen
AMPK activity in the hypothalamus regulates feeding supply. The amount of myoglobin in muscle tissue can be
behavior. Ghrelin activates AMPK and neuropeptide Y increased by physical training.
(NPY) leading to increased food intake and decreased The increased fuel requirements of exercising muscles
energy expenditure. Leptin by suppressing AMPK and NPY (FFAs and glucose) are ensured by the production of three
decreases food intake and increases energy expenditure hormones—noradrenaline, adrenaline and glucagon
in periphery. Alpha-lipoic acid, a naturally occurring co­ abetted by growth hormone and cortisol. Physical training
factor of mitochondrial dehydrogenases, inhibits AMPK results in improved myocardial performance, improved
in hypothalamus while activating AMPK in skeletal oxygen transport as well as increased oxygen extraction by
muscle.197,198 muscle, the myoglobin levels are elevated, mitochondrial
 Insulin Resistance 269

size and numbers increase so also their enzyme content How to Improve Endothelial Function?
and activity. Exercise increases fibrinolytic activity in
Dean Ornish set-up a study in 1977 to explore the effect of
plasma which is important in diabetic patients.
diet and lifestyle modification on the reversal of coronary
Skeletal muscle contains two types of fibers: type 1 (slow
atherosclerosis, using the techniques of quantitative
twitch) fibers are red because they contain myoglobin
coronary arteriography and quantitative myocardial blood
(a reservoir of oxygen) and high number of mitochondria.
flow using N13 ammonia positron emission tomography
They maintain relatively sustained contraction (such
(PET) imaging.204-207 It became obvious that modification

chapter
as maintaining of posture) and their metabolism is of cardiovascular risk factors that contribute to endothelial

17
aerobic. dysfunction improves patient outcome disproportionate
Type 2 (fast twitch) muscles have very few mitochon­ to the regression in the anatomic atherosclerotic lesions.
dria, exhibit short duration of contraction and derive their Patients with “mild” coronary artery lesions can have
energy from phosphocreatine and anaerobic glycolysis of severe endothelial dysfunction. Long-term follow-up
glycogen. Athletes training for marathons have increase in showed more cardiac events in such patients. Myocardial
the number of type 1 fibers in certain leg muscles, whereas ischemia can occur during exercise in patients without
100 meter sprinters have an increased number of type significant epicardial vessel stenosis, due to endothelial
2 fibers. dysfunction. Recent insights into vascular biology help
Exercise increases GLUT-4 and hexokinase II and us to understand how the benefit occurs in relation to
glycogenin expression in human skeletal muscle.199 In endothelial dysfunction.
human skeletal muscle exercise results in increased MAPK High glucose inhibits insulin-stimulated NO produ­
activity and activation of downstream targets of MAPK. ction without reducing endothelial NOS Ser 1177 phos­
Impact of exercise training (ET) on insulin sensitivity phorylation in human aortic endothelial cells. A single high
and physical fitness and muscle oxidative capacity has sugar intake may induce heart rate acceleration and BP
been shown in healthy first degree relatives of T2DM elevation as a result of sympathetic activation secondary to
patients.200 Physical exercise is the most physiological way insulin response and alteration in endothelial function due
to overcome insulin resistance in muscle. to activation of oxidative stress. Hyperglycemia activates
Regular physical exercise improves glucose utilization PKC-b which depresses eNOS expression and increases
and enhances insulin sensitivity in normal and diabetic ET-1 activity. Treatment with vitamin E inhibits PKC, by
subjects. Beneficial effects of long-term physical training increasing enzymatic degradation of DAG, the source
on body fat, metabolism and BP in obesity have been of PKC, or by activating protein phosphatase-2 which
shown.201 Benefits of exercise have not only been shown in dephosphorylates PKC. This action may be independent
MBS but also in cancer. Female breast cancer patients who of the antioxidant effect of vitamin E.
did regular physical exercise lived longer on chemotherapy Endothelial dysfunction caused by vascular PKC-b
compared to sedentary patients.202 activation due to hyperglycemia is critical for diabetic
Immunomodulatory effects of aerobic training in obe­ microvascular complications. This can be prevented by
sity have also been demonstrated. The effect of 10 weeks- selective PKC-b inhibitors such as ruboxistaurin. A single
intensified ET in obese subjects has been analyzed.203 high fat meal transiently reduced endothelial function for
There was significant reduction in waist circumference up to 4 hours in healthy, normocholesterolemic subjects,
and oxidized LDL levels and increase in serum adipo­ probably through accumulation of triglyceride-rich pro­
nectin levels, and upregulation of biotinyl-dodecanoyl- teins. This decrease was blocked by pretreatment with
cysteaminyl-alprenolol (BDCA)-1 and dendritic cells antioxidants, vitamins C and E suggesting an oxidative
(DCs), Toll-like receptor (TLR)-4 and TLR-7, indicating an mechanism which increases superoxide production and
enhanced immune competence with higher antibacterial, deactivates NO.208
antiviral and antitumor activity. Lipid lowering agents and antioxidants provide more
The traditional Indian practice of “Surya Namaskar” NO and reduce superoxide, thereby enhance endo­
is an excellent combination of 12 Yoga Asanas (which thelial function, reduce thrombotic potential, reduce
maintain flexibility of all tendons and joints in the inflammatory response thereby preventing rupture of
body) with dynamic aerobic exercise and deserves to be the vulnerable plaque. Clearly mechanisms other than
promoted universally. regression of the atherosclerotic stenosis are operating.
270 Etiopathogenesis of Diabetes Mellitus

Statins, apart from lowering cholesterol also improve reserve. In healthy adults, oral-glucose induced hypergl­
nitric oxide production. Patients with low hsCRP do not ycemia and endothelial dysfunction are reversed acutely
get significant benefit with statin therapy compared to with BH4 infusion; the same benefit is seen in T2DM.210
those with high hsCRP. Normal diet contains 8 g of L-arginine. An additional
Advanced glycosylation end products through their 8 g/day nutritional supplement on a long-term basis
receptors on the endothelium contribute to endothelial improves endothelial function.211,212 Endothelial proge­
dysfunction. Impairment of endothelium-dependent nitor cell (EPC) dysfunction is a normal concept in the
section

vasodilation in T2DM occurs independent of epicardial pathogenesis of vascular complications in diabetes.213

5

coronary atherosclerosis and causes major cardiac events. Endothelial NOS uncoupling impairs EPC mobilization
Strict glycemic control reduces production of AGEs. and function in diabetes.214
Nitrates (glyceryl trinitrate, isosorbide dinitrate) act Erythropoietin (EPO) promotes endothelial progenitor
as NO donors and thereby improve endothelial function cell proliferation and adhesive properties in a PI3 kinase-
apart from decreasing the preload and after load of the dependent manner. Recombinant human EPO protects
ventricles. Long-term use of nitrates can produce drug the myocardium from ischemia reperfusion injury and
tolerance which can be overcome by a combination of promotes beneficial remodeling, a novel protective effect
nitrate and hydralazine. in the infarcted heart.
Newer selective α1 adrenoreceptor antagonists such The vascular action of insulin to stimulate endothelial
as nebivolol inhibit ET-1 liberation and increase the production of NO leading to vasodilation and increased
availability of NO. blood flow is an important component of insulin-
Pioglitazone increases insulin sensitivity by activating stimulated whole body glucose utilization.
insulin receptor kinase and the insulin signaling pathway Exercise training improves coronary flow reserve as
which are mediated through its binding to the PPARγ a result of improved vasodilation. By increasing shear
receptors.209 stress, it induces increase in NO. Regular physical exercise
ACE inhibitors (ACEIs) and angiotensin receptor improves insulin resistance in muscles and improves
blockers prevent angiotensin-induced endothelin and glucose uptake and glycogen synthesis.
superoxide production. ACEIs improve endothelial func­ The FA composition of skeletal muscle membrane
tion in subcutaneous, epicardial, brachial and renal phospholipid is altered by n–3 PUFA, increasing its flui­
circlation, whereas they are ineffective in potentiat­ dity, thereby permitting prolonged residence of GLUT-4
ing the blunted response to acetylcholine in the forearm in the plasma membrane.
of patients with essential hypertension. They can also A daily dietary supplement of essential FAs, EPA and
selectively improve endothelium-dependent vasodilata­ DHA is recommended.
tion to bradykinin, probably related to hyperpolarization. Role of DHA in stress management by modulation
Treatment with an angiotensin I-receptor antagonist can of sympathetic activity in the CNS has already been
improve basal NO release and decrease the vasoconstric­ discussed.
tor effect of endogenous ET-1. Calcium channel blockers Yoga and lifestyle have shown reversal of athero­
can reverse impaired endothelium dependent vasodila­ sclerosis. A prospective study done by the Caring Heart
tation in subcutaneous, epicardial, renal and forearm Project of International Board Yoga has shown the
circulation. beneficial effects of Yoga on reversibility of ischemic heart
Nifedipine and lacidipine can improve endothelial disease.215
dysfunction in the forearm circulation by restoring NO Lifestyle modification is the cornerstone of manage­
availability probably through an antioxidant mechanism. ment of insulin resistance syndrome. Cessation of tobacco
Tetrahydrobiopterin (BH4) oral tablets are available but smoking decreases oxidative stress and improves endo­
are prohibitively expensive; hence no clinical trials thelial function. Dietary modification, with emphasis
have been undertaken. BH4 supplementation prevents on a lactovegetarian diet with at least 400 g green
endothelial dysfunction and restores adiponectin levels, leafy vegetables and fruits will give adequate natural
as described in an earlier section. Administration of antioxidants (vitamins C, E, carotenoids and flavonoids).
sepiapterin (precursor of BH4) restores coronary flow Such a diet is low in sodium, high in potassium and fiber.
 Insulin Resistance 271

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 Chapter 18
Endocrine and Metabolic
Role of Adipose Tissue in the
Pathogenesis of Diabetes
A Rosalind Marita

Adipose Tissue and Diabetes

Chapter Outline
♦♦ Adipokines and their General Functions ♦♦ Adipokines and Inflammation
♦♦ Adipokines and Insulin Resistance ♦♦ Adipokines and Cardiovascular Disease
♦♦ Adipokines and b-cell Function

INTRODUCTION extensively reviewed by several scientists.3-6 Adipokines

act as messengers in regulating various physiological
Our image about the adipose tissue or fat depots in our functions including food intake, energy expenditure, sys­
body has changed dramatically in the last 2 decades. temic energy balance, body weight, glucose homeostasis
Adipose tissue is no longer considered to be a passive and immune functions. These adipokines include leptin,
blob, hanging in our bellies and hips that does nothing tumor necrosis factor alpha (TNF-α), resistin, adiponectin
more than store energy. Today adipose tissue is recognized and visfatin. In addition to the secretion of adipokines,
as an endocrine organ (in fact the largest endocrine fat cells also express cell surface receptors for various
organ), with multiple functions controlling whole body growth factors and enzymes that participate in energy
energy homeostasis, satiety and inflammation. This image homeostasis. In this chapter, I shall attempt to highlight
make-over stems from the discovery of leptin in 1994 as the recent developments briefly since excellent reviews
a communication signal between adipose tissue and the are already available for the reader for further reference.
brain. According to Professor Hotamisligil of the Harvard
School of Public Health, it is the fat tissue that controls the ADIPOKINES AND THEIR
brain rather than the reverse.1 This new understanding GENERAL FUNCTIONS
has led scientists to explore numerous functions of adipo­
kines or chemical messengers secreted from the fat cells. Adipokines are involved in a range of physiological proce­
The endocrine function of the adipose tissue is sses. Some of the well characterized adipokines include
emphasized by the adverse consequences of having too leptin, adiponectin, TNF-α, interleukin (IL)-6 while other
many or too few fat cells in the body. We know that newer adipokines are being evaluated for their physio­
having excess fat leads to obesity which gives rise to logical functions as detailed below.
type 2 diabetes mellitus (T2DM), cardiovascular disease
(CVD) and some type of cancers. On the other hand having Leptin
too little fat (a condition known as lipodystrophy), also Leptin was the first fat cell-derived hormone to be
results in the metabolic syndrome.2 The role of adipose discovered. In 1994, Friedman reported the discovery of
tissue-derived adipokines in health and disease has been the “obese (ob)” gene and named the new hormone
 Endocrine and Metabolic Role of Adipose Tissue in the Pathogenesis of Diabetes 279

encoded by the “ob” gene as leptin.7 Leptin is a 167 the messenger ribonucleic acid (mRNA) transcript most
amino acid protein that controls food intake and energy highly expressed in adipocytes of mice.19 Adiponectin
expenditure.8 It is synthesized primarily in the adipocytes circulates in three isoforms: (1) a trimer of low-molecular
and the level of circulating leptin is proportional to the weight; (2) a hexamer (trimer-dimer) of medium mole­
total amount of fat in the body. Circulating levels of cular weight; and (3) a multimeric high molecular weight
leptin reflect energy stores in the body, increasing with isoform.20 Adiponectin exerts its metabolic action through
overfeeding and decreasing with starvation. Leptin specific receptors. So far, two receptors, (1) adiponectin

chapter
controls fatty acid oxidation, lipolysis and peripheral receptor 1 (ADIPOR1); and (2) adiponectin receptor 2

18
insulin sensitivity. The absence of leptin or a mutation in (ADIPOR2) have been identified.21
leptin gene or the leptin receptor gene induces massive
hyperphagia and obesity in animals.9,10 Resistin
After release from adipocytes, leptin is transported
through the blood and acts through the central nervous Resistin was discovered in 2001 by Lazar’s group.22 It is
system (CNS). Leptin binds to the leptin receptor situated a 12 KDa cysteine-rich polypeptide with a molecular
in the hypothalamus and acts to inhibit food intake and structure similar to adiponectin23 and is encoded by the
induces satiety. This action is mediated through inhibition RETN gene.24 Resistin is involved in the pathogenesis
of the secretion of neurotransmitters including agouti- of insulin resistance. Human resistin is expressed in
related peptide and neuropeptide Y (NPY), the strongest monocytes and macrophages and its expression in human
hunger stimulator. Leptin stimulates anorexigenic (appe- adipose tissue in predominantly mediated by stromal
tite suppressing) pathways through cocamine ampheta- cells.25,26 Secretion of resistin is remarkably increased by
mine regulated transcript (CART), a neuropeptide found proinflammatory stimuli.27,28
in the hypothalamus.11 In animal studies leptin has a
strong inhibitory effect on feeding behavior, which encou­ Interleukin-6
raged scientists to explore the role of leptin as a magic
In humans, approximately 30% of circulating IL-6
bullet to induce weight loss in morbidly obese subjects.
origi­
nates from adipose tissue. Within adipose tissue,
However, this hope faded with the observation of leptin
IL-6 and IL-6R are expressed by adipocytes and adipose
resistance12 in obese subjects. Leptin resistance is descri­
bed as a reduced sensitivity to the anorectic response to tissue matrix. IL-6 concentrations are higher in visceral
exogenous leptin.13 Three possibilities have been postu­ fat compared to subcutaneous fat.15 IL-6 is associated
lated as mechanisms of resistance: (1) a failure of circulat- with obesity and insulin resistance.29
ing leptin to reach the target site in the brain; (2) decreased
expression of leptin receptors; and (3) inhibition of signal- Apelin
ing pathway.14 Apelin was identified in 1998 by Fujino’s team. Apelin
is synthesized as a 77 amino-acid prepropeptide which
Tumor Necrosis Factor-α is cleaved into four active isoforms, (1) apelin-12; (2)
Adipocytes synthesize TNF-α, as a 20 KDa transmembrane apelin-13; (3) apelin-17; and (4) apelin-36. Of these four,
protein precursor which undergoes cleavage to release (Pyr1)-apelin-13 is the most abundant and active form.30
17 KDa soluble TNF-α molecule. TNF-α is also secreted Apelin was detected in both the stromal-vascular cells and
by the macrophages in the stromal vascular fraction.15 differentiated adipocytes and appears to be responsive
TNF-α from adipose tissue can influence whole body to metabolic changes in insulin.31 Apelin production in
energy homeostasis and can act in a paracrine manner adipose tissue is regulated by several factors including
to regu­late adipose tissue function and expansion.16 insulin, hypoxia, growth hormone and TNF-α. Apelin
These effects are thought to be regulated, in part, by the has reciprocal interaction with insulin since insulin
transmembrane receptors, TNF-α receptor 1 and TNF-α stimulates apelin expression32 while apelin inhibits insulin
receptor 2 and their soluble forms (soluble TNF receptor). secretion.33

Adiponectin Retinol Binding Protein 4

Adiponectin was one of the earliest adipokines iden­ The role of retinol binding protein 4 (RBP4) in obesity and
tified.17,18 Adiponectin was first characterized in 1996 as insulin resistance was first discovered by Barbara Kahn’s
280 Etiopathogenesis of Diabetes Mellitus

group. RBP4 belongs to the lipocalin family of proteins expressed both in liver and white adipose tissue.43,44
that transport retinol (vitamin A) in the circulation.34 RBP4 In addition, there is omentin, discovered in 2005.45 A novel
acts on muscle and/or liver, in either retinol-dependent or adipokine, nesfatin was discovered in 2006 and is secreted
retinol-independent way, affecting insulin sensitivity.35 from brain tissue and β-cells, in addition to adipose
tissue. Excess nesfatin leads to loss of appetite and a drop
Visfatin in body fat and body weight.46 Nesfatin stimulates insulin
Visfatin has been described to be a highly expressed pro­ secretion from the pancreatic β-cells of both rats and
section

tein with insulin mimetic effect predominantly found in mice.47 Table 18.1 presents a list of all the adipokines and
5

visceral adipose tissue.36 their functions.

Proteins of the Renin Angiotensin System ADIPOKINES AND INSULIN RESISTANCE

Several proteins of the classic renin angiotensin system Adipokines have been identified as potential contributors
(RAS) are also produced in adipose tissue. These include to insulin resistance. Recent studies have shown that adipo­
renin, angiotensinogen (AGT), angiotensin I, angiotensin
kines might provide a molecular link between increased
II, angiotensin receptors type I (AT1) and type 2 (AT2),
adiposity seen in obesity and impaired insulin sensitivity.
angiotensin-converting enzyme (ACE), and other pro­
Leptin improves insulin sensitivity by limiting the
teases capable of producing angiotensin II such as
accumulation of triglycerides in liver and skeletal muscle
chymase, cathepsins D and G and tonin.37
through activation of adenosine monophosphate-acti­
Plasminogen Activator Inhibitor-1 vated protein kinase (AMPK). Insulin secretion in lean
animals has been shown to be inhibited by leptin.48 It has
Plasminogen activator inhibitor (PAI-1) is a member of been shown that intracerebral administration of leptin
the serine protease inhibitor family and is the primary
significantly increases insulin sensitivity and glucose
inhibitor of fibrinolysis.15 PAI-1 expression and secretion
uptake in peripheral tissue in rats.49 The role of leptin in
are greater in visceral relative to subcutaneous (SC)
clinical studies has given conflicting data. Leptin levels
adipose tissue.38 PAI-1 is implicated in the pathogenesis
of T2DM patients were comparable to non-diabetic
of CVD as its levels are increased in myocardial infarction
subjects50 in one study. We have previously found reduced
and venous thrombosis.39
serum leptin levels in non-obese T2DM subjects from
Adipsin and Acylation Stimulating Protein Mumbai.51 Serum leptin levels have been reported to be
increased by insulin treatment both in type 1 and type 2
Adipsin (complement factor D) is one of several comple­ diabetic subjects.52,53
ment components that are required for the enzymatic Adiponectin is a marker and perhaps a mediator of
production of acylation stimulating protein (ASP), a metabolic risk. In many studies, adiponectin levels have
complement protein that affects both lipid and glucose been found to be inversely associated with insulin sensi­
metabolism.40 tivity.54 Many clinical studies in different populations have
supported these outcomes suggesting that adiponectin
Macrophages and Monocyte contributes to the development of insulin resistance and
Chemoattractant Protein-1 independently predicts the progression to diabetes.55-58
Monocyte chemoattractant protein-1 (MCP-1) or chemo­ Furthermore, in animal models, exogenous adiponectin
kine (C-C motif) ligand 2 (CCL2) secreted from white reversed insulin resistance21 and protected against diet-
adipose tissue has been reported to contribute to accumu­ induced obesity.59 Adiponectin transgenic mice showed
lation of macrophages in adipose tissue.41 Obesity is suppression of endogenous glucose production.60 Other
associated with increased plasma levels of MCP-1 and studies have demonstrated that adiponectin modulates
overexpression in adipose tissue.42 insulin sensitivity by stimulating glucose utilization and
fatty acid oxidation via activation of AMPK in muscle
Other Adipokines and liver.61
There are some more adipokines whose biochemical The effects of adiponectin on glucose metabolism
actions have not been well defined. These include visceral are mediated through two distinct receptors termed as
adipose tissue-derived vaspin and chemerin which is (1) ADIPOR1 and (2) ADIPOR2. Both receptors activate
 Endocrine and Metabolic Role of Adipose Tissue in the Pathogenesis of Diabetes 281

Table 18.1: Adipokines and their functions in the body

Adipokine Function or Effect References
Leptin • Appetite control through the central nervous system 9, 48
• Stimulates lipolysis
• Inhibits lipogenesis
• Improves insulin sensitivity
• Increases glucose metabolism

chapter
• Stimulates fatty acid oxidation

18
Adiponectin • Increases insulin sensitivity 146, 147
• Overexpression protects against atherosclerosis
• Anti-inflammatory and antiadhesive
• Inhibits transformation of monocytes into macrophage foam cells
TNF-α • Reduces insulin secretion and insulin sensitivity. 69, 70
• Stimulates lipolysis
• Decreases adipocyte differentiation
• Increase in obesity
Resistin • Interferes with the insulin-mediated cellular glucose uptake 22
• Involved in the development of insulin resistance in obesity
• Inhibits adipocyte differentiation
IL6 • Affects glucose and lipid metabolism 29, 74
• Increase in morbidly obese patients
• Proinflammatory
• Decreases insulin and leptin signaling
Apelin • Inhibits glucose-induced insulin secretion
• Reduces food intake
Visfatin or NAMPT • Regulates cellular levels of NAD 80, 81
• Proinflammatory
• Insulin mimicking
• Hypoglycemic effects by stimulating glucose uptake
• Promotes insulin sensitivity
• Proadipogenic and lipogenic action
RBP4 • Implicated in systemic insulin resistance 35, 82
• Increased hepatic glucose output
• Increased in obesity and insulin resistance
Vaspin • Improve glucose tolerance and insulin sensitivity 83
Chemerin • Enhance the insulin stimulated glucose uptake 85
• Affects adipogenesis and inflammation
Omentin • Insulin-mediated glucose transport 86, 87
• Triggers AKT signaling
• Decreases insulin sensitivity
Adipsin or ASP • Affects lipid and glucose metabolism 40
• Stimulates triglyceride storage, inhibits lipolysis
MCP-1 • Increases lipolysis and leptin secretion 42
• Decreases insulin-stimulated glucose uptake
• Increased plasma concentrations in obesity
• Disturbs insulin sensitivity
PAI-1 • Inhibits plasminogen activation 15
• Contributes to atherothrombosis and insulin resistance 
RAS • Linked to vascular inflammation 37
• Increased plasma levels in obesity
• Increased blood pressure

Contd...
282 Etiopathogenesis of Diabetes Mellitus

Contd...
Adipokine Function or Effect References
Nesfatin • Loss of appetite 46, 47
• Stimulates insulin secretion
TGFα • Regulate proliferation, differentiation and apoptosis 15
RANTES or CCL5 • Proinflammatory
IL-8 • Proinflammatory chemokine
section

• High levels in obesity

Lipocalin • Promotes insulin resistance and inflammation through TNFα secretion in adipocytes
5

FGF • Increase α-cell proliferation 107

IGF1 • Increase α-cell mass 108
GLP1 • Positively regulate a-cell mass 104
DPP-IV • Cleave GLP1 104
• Decrease α-cell mass

(TNF: Tumor necrosis factor; IL: Interleukin; NAMPT: Nicotinamide phosphoribosyltransferase; NAD: Nicotinamide adenine dinucleotide; RBP:
Retinol binding protein; AKT: Protein kinase B; ASP: Acylation stimulating protein; MCP: Monocyte chemoattractant protein; PAI: Plasminogen
activator inhibitor; RAS: Renin-angiotensin system; TGF: Transforming growth factor; RANTES: Regulated on activation, normal T-cell
expressed and secreted; CCL5: Chemokine (C-C motif) ligand 5; FGF: Fibroblast growth factors; IGF: Insulin-like growth factor; GLP1:
Glucagon-like peptide 1; DPP: Dipeptidyl peptidase)

signaling molecules such as AMPK, peroxisome proli­ inhibitors of NF-κB kinase (IKK) and through increased
ferator-activated receptor alpha (PPAR-α) and mitogen- expression of suppressor of cytokine signalling-3 (SOCS-3).72
activated protein kinase (p38 MAPK) in-vitro.21 Many The inflammatory regulator, IL-6 has emerged as
human studies have shown the association of adiponectin one of the potential mediators that link obesity-derived
receptor expression in adipose tissue or muscle, with chronic inflammation with insulin resistance.29 Overall
insulin resistance.62-65 Highly divergent data on polymor­ circulating IL-6 levels are increased in obese subjects.73,74
phisms in both adiponectin receptor genes and their IL-6 modulates insulin resistance through JNK1-mediated
interaction with insulin resistance are known.66,67 Thera­ serine phosphorylation of Insulin receptor substrate 1
peutic approaches that aim to increase adiponectin (IRS-1) or IκB kinase (IKK)-mediated nuclear factor-κB
levels deserve evaluation for the prevention of T2DM. (NF-κB) activation, and induction of SOCS-3.75 Further­
Further, clinical and experimental investigation should more, peripheral administration of IL-6 induces hyper­
illuminate the pathophysiological mechanism of action of
lipidemia, hyperglycemia and insulin resistance both in
adiponectin.
rodents and humans.
Studies show that mRNA expression of TNF-α in
In rodents, resistin levels are elevated in both diet-
adipose tissue is strongly implicated in the pathogenesis
induced obesity and genetic models of obesity (ob/ob)
of insulin resistance. It has been demonstrated that TNF-α
and diabetes (db/db). Administration of exogenous
can impair insulin signaling in hepatocytes and adipose
resistin or transgenic overexpression of resistin decreases
tissue.68 The deletion of genes expressing TNF-α and
TNF-α receptors resulted in significantly improved insulin insulin sensitivity. This effect was blocked by antibodies
sensitivity in both diet-induced obese mice and leptin against resistin or in the resistin knockout mice.76,77 Results
deficient ob/ob mice.69 Neutralization of TNF-α improved from clinical studies have been conflicting, with only
insulin resistance in obese rats.70 These evidences support some studies identifying a significant correlation between
the pathogenic role of TNF-α in obesity related insulin resistin level and obesity or insulin resistance.78,79
resistance. Neutralization of TNF-α in obese T2DM human Visfatin lowered plasma glucose levels in mice by bind­
does not appear to improve glucose tolerance or insulin ing to and activating the insulin receptor.80 Visfatin acts as
sensitivity. However, prolonged treatment does improve nicotinamidephosphoribosyl-transferase (NAMPT). Thus
insulin sensitivity in individuals without established it is able to regulate cellular levels of nicotinamide adenine
T2DM.71 TNF-α is thought to inhibit the insulin receptor dinucleotide (NAD), exerting an influence on cellular
substrate signaling through the activation of serine energy metabolism.81 Other studies, however, have not
kinase such as the C-Jun-N terminal kinase (JNK) or confirmed association of visfatin to insulin sensitivity.
 Endocrine and Metabolic Role of Adipose Tissue in the Pathogenesis of Diabetes 283

Retinol binding protein 4, is suggested to be associated Deletion of PTEN in mouse models has demonstrated
with obesity and T2DM.82 However, clinical data are con­ protection against defects in β-cell function and mass.94
flicting. Serum RBP4 level has been considered as an Increased adiponectin levels have been associated with
important predictive marker of T2DM.35 Furthermore decreased islet β-cell apoptosis.95 Further, adiponectin
transgenic overexpression of human RBP4 or injection has been reported to increase glucose stimulated insulin
of recombinant RBP4 in normal mice caused insulin secretion (GSIS)96 and β-cell proliferation.97 Similarly,
resistance.35 Decrease in weight or intensive exercise visfatin has also been reported to stimulate β-cell proli­

chapter
results in decreased RBP4 levels and thus correlate with feration. Visfatin is reported to inhibit β-cell apoptosis

18
the improvement in insulin sensitivity. induced by palmitate. These actions of visfatin are
Administration of vaspin has been shown to improve mediated via extracellular-signal-regulated kinases (ERK)
glucose tolerance and insulin sensitivity in diet induced 1 or 2 and phosphatidylinositol 3-kinase (PI3K) or AKT
obese mouse.83 In humans, serum vaspin concentrations signaling pathways.98 It is yet to be determined whether
were elevated in obesity and insulin resistance.84 Chemerin the overall effect of visfatin is beneficial or deleterious to
has been reported to enhance insulin stimulated glucose β-cells.
uptake and IRS-1 tyrosine phosphorylation in 3T3-L1 TNF-α has been implicated in the immune system
adipocytes.85 This finding suggests that chemerin may mediated induction of β-cell death in type 1 diabetes.
increase insulin sensitivity. TNF-α has been demonstrated to induce β-cell apoptosis
Finally, omentin stimulates insulin mediated glucose via the NF-κB pathway.99,100 Studies have shown that TNF-α
transport in human adipocytes and triggers protein decreases insulin gene transcription.101 In-vitro studies
kinase B (AKT) signaling.86 Plasma levels and adipose have shown that resistin downregulates insulin receptor
tissue gene expression of omentin-I, the predominant expression thus causing insulin resistance in pancreatic
circulating iso­form, are decreased in obesity. Omentin islets.102 This leads to decrease in the β-cell mass. The
levels are nega­tively correlated with body mass index (BMI) =role of resistin in regulating human pancreatic β-cell
and insulin resistance and positively with high-density mass or function has not been demonstrated.
lipoprotein (HDL) and plasma adiponectin levels.87 Recently, primary mature adipocytes have been shown
to release the enzyme, dipeptidyl peptidase- IV (DPP-
ADIPOKINES AND β-CELL FUNCTION IV)103 which is known to cleave the incretin, glucagon-like
peptide 1 (GLP-1) at the NH2 terminus.104 Studies suggest
A decrease in pancreatic β-cell mass or impaired β-cell that GLP-1 stimulates proliferation of pancreatic β-cells
function can lead to glucose intolerance and diabetes. thus positively regulating β-cell mass.105 Apelin described
Insulin resistance in adipose tissue leads to β-cell failure.88 before inhibits insulin secretion by acting through
Adipokines constitute an important part of the “adipo- Apelin recptors.106 Apart from these, other adipokines
insular axis”. Any shift in the regulation of this inter­ like fibroblast growth factors (FGF), insulin-like growth
relationship between adipose tissue and pancreatic β-cell factor 1 (IGF-1), IL-6 have also shown to increase β-cell
will contribute to β-cell failure. proliferation, β-cell mass and glucose induced insulin
Leptin has been considered as an important regulator secretion, respectively.107-109 Non-esterified fatty acids
of pancreatic β-cell function at various levels including also are considered as adipokines and they have been
insulin gene expression, secretion, β-cell apoptosis and reported to decrease insulin gene transcription110 and
cell growth.89 Experiments in knockout mice with specific induce apoptosis of β-cells.111 Table 18.2 describes the list
deletion of the leptin receptor in the pancreas or in the of adipokines involved in pancreatic function.
β-cell have shown alterations in glucose homeostasis
and reduced β-cell mass.48,90 In-vitro, leptin has been ADIPOKINES AND INFLAMMATION
shown to have an inhibitory effect on insulin secretion
from pancreatic β-cells.91 It has been demonstrated that Many recent studies indicate that obesity is associated
leptin decreases uncoupling protein-2 (UCP2) expression with a chronic low-grade inflammation which contributes
in the islets which reduces β-cell apoptosis possibly via to the development of obesity-related disorders.112 Adipo­
its ability to upregulate β-cell lymphoma 2 (BCL-2) and kines have been shown to have proinflammatory or anti-
Bax expression.92 Leptin inhibits phosphatase and tensin inflammatory activities. Adipose tissue of lean subjects
homolog (PTEN) in the insulin signaling pathway.93 and animals is composed of adipocytes, preadipocytes,
284 Etiopathogenesis of Diabetes Mellitus

Table 18.2: Summary of adipokines with demonstrated effects on pancreatic β-cells

Adipokine Effect References
Adiponectin Increases GSIS 96
Increases proliferation 97
Apelin Inhibits insulin secretion 106
DPP-IV Inhibits GLP1 103
section

FGF Increases α-cell proliferation, increases insulin transcription 107

IGF1 Increases α-cell mass 108
5

Interleukin-1α Increases nitric oxide

Cytotoxic
Interleukin-6 Increases GSIS 9
Leptin Decreases pre- or proinsulin levels, Inhibits GSIS
Protects from apoptosis 92
MCP1 Increased amylin expression
Non-esterified fatty acids Increases GSIS (acute)
Inhibits GSIS (chronic)
Decreases insulin transcription 110
Induces apoptosis 111
Resistin Decreases insulin receptor and increases cell viability 92
TGFα Regulates insulin transcription
TNFα Decreases insulin transcription, Inhibits GSIS 101
Induces apoptosis 99
Increases amylin but not proinsulin gene expression 6
Visfatin Increases insulin secretion 97

Source: Dunmore SJ, Brown JE. The role of adipokines in β-cell failure of type 2 diabetes. J Endo. 2013;216:T37-45.
(GSIS: Glucose-stimulated insulin secretion; DPP: Dipeptidyl peptidase; FGF: Fibroblast growth factors, IGF: Insulin-like growth factor;
TNF: Tumor necrosis factor; TGF: Transforming growth factor; MCP: Monocyte chemoattractant protein)

lymphocytes, macrophages, fibroblasts and vascular Proinflammatory Adipokines

cells. However, in obesity there is a change in the cellular
composition of the adipose tissue. In obesity, there is The production of most proinflammatory adipokines
increased infiltration of macrophages in the adipose is upregulated in obesity. The key players that promote
tissues. These macrophages exhibit a proinflammatory inflammation are TNF-α, leptin and IL-6. In addition to
(M1) phenotype contrary to an anti-inflammatory pheno­ these, resistin, RBP4, IL-18, CCL2 and CXC-chemokine
type (M2) observed in the tissues of lean individuals. ligand 5 (CXCL5) also contribute to the development of a
The M1 phenotype represents the classically activated chronic inflammatory state. Some of these cytokines are
macrophages and is characterized by increased expression released by the adipocytes whereas others are secreted by
of adipokines such as TNF-α, IL-1β and IL-6. These the recruited inflammatory cells.
cytokines lead to the generation of reactive oxygen species Tumor necrosis factor alpha (TNF-α) is a major proin­
and nitrogen intermediates.113 They also adversely affect flammatory cytokine that is primarily produced by the
glucose uptake thus contributing to peripheral insulin macrophages infiltrating the adipose tissue. TNF-α is
resistance. The M2 phenotype represents alternative also the major proinflammatory cytokine of the innate
activation associated with anti-inflammatory cytokines immune system. Overproduction of TNF-α in obesity,
such as IL-10, IL-4 and TGF- β. These macrophages help results in a chronic inflammatory state. It activates the
in maintaining an immune environment and assist in proinflammatory pathways within the cells resulting in
adipose tissue remodeling.113 the generation of reactive oxygen species. This oxidative
 Endocrine and Metabolic Role of Adipose Tissue in the Pathogenesis of Diabetes 285

stress activates the stress responsive pathways involving

enzymes, JNK and inhibitor of NF-κB , IκB.114-117
Leptin is structurally similar to helical cytokines and
is thought to have proinflammatory activities. It increases
the production of TNF-α and IL-6 by monocytes118,119 and
also stimulates the production of CC-chemokine ligands
(namely, CCL3, CCL4 and CCL5) by macrophages by

chapter
activating the Janus kinase 2 (JAK2)–signal transducer

18
and activator of transcription 3 (STAT3) pathway. Further­
more, leptin increases the production of the M1 cytokines
such as IL-2 and interferon gamma (IFNγ) and suppresses
the production of the M2 type cytokine, IL-4 by T-cells
or mononuclear cells, thus polarizing T-cells towards the
M1 phenotype.120
Interleukin-6 is a proinflammatory cytokine that may
also be involved in obesity-related insulin resistance.
Increased levels of IL-6 cause the release of acute phase
response proteins that induce an inflammatory response
Fig. 18.1: Adipokines in inflammation and cardiovascular disease (CVD)
within the cells. The adipokine, resistin is also a pro-
inflammatory cytokine as it promotes the expression
of TNF-α and IL-6 by the monocytes.121 It plays a crucial Adiponectin suppresses the production of proinflam­
role in leukocyte adhesion by increasing the expression of matory cytokines. It inhibits lipopolysaccharide (LPS)-
vascular cell adhesion molecule 1 (VCAM1), intercellular stimulated TNF-α production by macrophages131 as well
adhesion molecule 1 (ICAM1) and pentraxin 3.122 It as Toll-like receptor-mediated NF-κB activation in mouse
contributes to endothelial inflammation by directly macrophages.132 Also, overexpression of adiponectin in
inhibiting the action of adiponectin on vascular cells. ob/ob mice leads to a reduction in the number of infiltra­
IL-18 is another proinflammatory cytokine that it is ting macrophages in the adipose tissue and decreased
produced by the adipose tissues.123 Studies indicate expression of TNF-α in fat pads.133 Furthermore, adipo­
increased serum IL-18 levels in obese individuals.124 IL-18 nectin stimulates the production of the anti-inflammatory
increases the recruitment of infiltrating macrophages in cytokine, IL-10 by human macrophages.134 Peritoneal
the blood vessels causing vascular abnormalities. It also macrophages isolated from adiponectin-deficient mice
increases the expression of endothelial cell adhesion show increased expression of proinflammatory, M1-type
molecules in rats.125 High levels of IL-18 have been detec­ markers and decreased expression of anti-inflammatory
ted in atherosclerotic lesions in humans,126 whereas IL-18 M2-type markers. Stimulation of cultured macrophages
deficiency led to smaller lesions in a mouse model of with adiponectin results in an increase in the levels of
atherosclerosis.127 Thus, IL-18 plays a key role in modula­ M2-type markers and a reduction in generation of reac­
ting inflammation and vascular function. tive oxygen species.135 Overall, adiponectin can modulate
macrophage phenotype through multiple mechanisms
Anti-inflammatory Adipokines and thus play a significant role in the inflammatory
Adiponectin is the only adipokine that has been demons­ and metabolic diseases. Figure 18.1 describes the patho­
trated to have anti-inflammatory action. Various reports genesis of obesity induced inflammation.
indicate that adiponectin also exhibits cardioprotective ADIPOKINES AND
and anti-atherogenic properties.128 The association bet­
CARDIOVASCULAR DISEASE
ween adiponectin levels and proinflammatory markers
has been studied in obesity and diabetes. Circulating Adipokines are involved in mediating the vascular compli­
adiponectin levels are reduced in obesity and T2DM.129 cations of obesity, especially atherosclerosis. Here the
Plasma adiponectin levels negatively correlate with role of adipokines viz. leptin, resistin, adiponectin and
C-reactive protein (CRP) levels, a liver derived inflam­ the novel adipokine apelin in the progression of CVD is
matory marker in obese or diabetic patients.130 briefly discussed.
286 Etiopathogenesis of Diabetes Mellitus

Leptin modulates cardiac metabolism and cardio­ should pave the way for newer therapeutic avenues that
vascular physiology. It impairs vasodilation and thus offer promising medicines for lifestyle diseases that
acts as an important link between obesity and hyper­ currently affect our society.
tension.136 In recent studies, leptin has been associ-
ated with increased risk of CVD.137 Furthermore, it has ACKNOWLEDGMENTs
been shown to increase oxidative stress and throm­
bosis inanimal studies.138,139 Resistin also plays a role in I would like to acknowledge the help rendered by
section

the development and progression of atherosclerosis. Ms Suparna Dipak and Ms Gauri Patade of Haffkine Insti­
tute, Mumbai for their contribution in literature review.
5

It induces oxidative stress in human coronary arteries by

decreasing endo­ thelial nitric oxide synthase enzyme I am grateful to Dr Sunil Gupta and Dr Mittal, contributors
(eNOS) expression. Resistin increases the expression of to this chapter in the previous edition of this textbook.
adhesion molecules in human saphenous vein76 thus
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5

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18
 Chapter 19
Fetal Programming of
Type 2 Diabetes Mellitus
Kalyanaraman Kumaran, Chittaranjan S Yajnik

Fetal Origin of Type 2 DM

Chapter Outline
♦♦ Current Strategies for Prevention of Type 2 ♦♦ Mechanisms of Nutritional Fetal Programming
Diabetes Mellitus ♦♦ Implications for Prevention and Policy
♦♦ Programming Hypothesis and the Developmental
Origins of Health and Disease

CURRENT STRATEGIES FOR PREVENTION OF

TYPE 2 DIABETES MELLITUS

It is generally believed that individual susceptibility to

type 2 diabetes mellitus (T2DM) has its roots in genes.
The genetic susceptibility is thought to be exacerbated by
lifestyle behaviors such as high energy and fat intake and
reduced physical activity, leading to the development of
the disease (Fig. 19.1). Of the known risk factors, obesity
or excessive body mass index (BMI) is one of the most
common features associated with T2DM.1 The prevalence Fig. 19.1: Type 2 diabetes mellitus: the conventional dogma (genetic +
of obesity has been increasing in many populations.2 Even lifestyle) and the alternative explanation (fetal programming) for its
in individuals who are not apparently obese, or meet etiology

definitions of obesity by western standards, there may

be a high proportion of body fat relative to muscle mass individuals with pre-existing disease or risk factors.
(adiposity). The accumulation of body fat in the abdominal However, these measures can at best be termed secondary
areas leads to higher diabetes risks.3 This strong inter- prevention and do not address the impact of the disease
relation between obesity or adiposity and T2DM is now on future generations. Genetic research has so far also
well recognized and together called “diabesity”.1 failed to provide any major breakthrough towards primary
Most of the current preventive strategies and recomm­ prevention. In order to stem the epidemic of T2DM, it is
endations to reduce the burden of T2DM focus mainly imperative to find etiologic clues that will help develop
on reducing adult lifestyle risk factors in middle-aged strategies to prevent the condition in unborn generations.
 Fetal Programming of Type 2 Diabetes Mellitus 293

chapter
19
Fig. 19.2: Programming hypothesis: different pathways by which fetal undernutrition influences risk of adult chronic non-communicable
diseases; inadequate maternal nutrition or disturbances in maternal ability to transport nutrients to the growing fetus leads to fetal undernutrition.
The fetus adapts by altering the structure and metabolism of its organs and tissues; these adaptations result in permanent changes which
“program” the development of risk factors for non-communicable diseases in later life
(IGF-1: Insulin-like growth factor).

PROGRAMMING HYPOTHESIS AND suggested that these organs “fail” to function optimally
THE DEVELOPMENTAL ORIGINS OF in later life leading to disease. These individuals have
HEALTH AND DISEASE higher adiposity, insulin resistance and increased risk of
T2DM, similar to obese individuals, but at lower levels of
The most promising possibility for primary prevention BMI (Fig. 19.2).
comes from David Barker’s programming hypothesis. Early work in this field of research dates to the 1970s
He suggested that alterations in the nutritional supply when Forsdahl demonstrated a significant positive
during critical stages of intrauterine development perma­ correlation between arteriosclerotic heart disease in
nently alter the structure and metabolism of the fetal middle-aged adults and the prevailing infant mortality
organs (fetal programming).4 The growing fetus depends rates during their childhood in twenty counties in Norway.5
on the mother for its nutritional needs, and therefore He attributed this finding to poor living conditions in
any disturbance in the maternal nutritional status or its childhood followed by affluence in later life. Subsequently,
supply to the fetus will adversely impact fetal growth. Barker and colleagues in Southampton showed a positive
When there is a poor nutritional supply, the available significant correlation between coronary heart disease
nutrition is utilized for the growth of the fetal brain, (CHD) mortality rates in local authorities in England and
which is vital for survival. This compromises the growth Wales in the 1970s and corresponding infant mortality
and functions of “less important” insulin sensitive rates in the earlier part of the century.6 There was a
organs like the pancreas, liver and skeletal muscles. It is strong relationship with neonatal mortality also, and
294 Etiopathogenesis of Diabetes Mellitus
section
5

Fig. 19.3: Birth weight and type 2 diabetes mellitus and impaired glucose tolerance in Hertfordshire men aged 60–70 years; as birth weight
increases, the prevalence of type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) decreases.
Courtesy: MRC Lifecourse Epidemiology Unit Southampton.

as low birth weight was the most common cause of Obesity, hypertension and diabetes can be programmed
neonatal mortality in the early 1900s, Barker suggested by under or overnourishing the fetus, by changing the
low birth weight as the link between neonatal and infant pregnant mother’s diet.15-17
mortality and adult CHD. The group then moved on The fetal insulin hypothesis offers an alternative
from ecological studies to studies on individuals and explanation to the association between birth weight
demonstrated that the prevalence of CHD in Hert­ and diabetes and suggests that low birth weight,
fordshire in the UK was highest in adults who had the insulin resistance and ultimately T2DM are all linked
lowest birth weights.7 Further work showed similar through genetic factors.18 However, a study examining
findings for T2DM and impaired glucose tolerance the associations between birth weight differences and
(Fig. 19.3).8 The relationship with birth weight was glucose tolerance in monozygous and dizygous twins
continuous and graded, without any threshold. These suggested that shared genetic determinants for birth
findings have subsequently been replicated in several weight and glucose tolerance were neither very prevalent
parts of the world including developing countries.9-12 It nor powerful.19 Birth weight is only partly determined
was however soon apparent that birth weight was not by genetic factors and the relative importance of genes
the major issue, and in fact, both low and high birth and environment has been an active area of research
weights were associated with later T2DM indicating over the past 2 decades. It is therefore likely that an
a U-shaped relationship.13 It was suggested that birth interaction between genetic and environmental factors
weight was a marker of a multitude of exposures during influences not only fetal growth but also the development
fetal life, and not one single exposure. of T2DM.
Subsequently, postnatal growth has also been shown
to be associated with risk of T2DM; individuals with the
DOHaD Work in India
highest risk of T2DM are those who had low birth weight The DOHaD hypothesis may be particularly applicable
but high current BMI.11,14 Thus, the fetal programming to the Indian situation with a high burden of maternal
hypothesis was expanded to include postnatal factors malnutrition and low birth weight.20 India is also consi­
and is now referred to as the “Developmental (or early) dered one of the diabetes capitals of the world and is
Origins of Health and Disease” hypothesis (DOHaD). estimated to have the highest number of people with
The DOHaD hypothesis is strongly supported by T2DM by 2030 (10.1 crores).21 More importantly, it will
animal studies showing that maternal nutritional disproportionately affect the young and economically
status can influence disease outcomes in the offspring. productive age groups resulting in significant social and
 Fetal Programming of Type 2 Diabetes Mellitus 295

economic consequences. Indian diabetic patients are in BMI in childhood.24 Conditional growth analysis was
known to be younger, shorter and thinner compared performed to separate out associations of linear growth
to western patients but tend to be centrally more obese and weight-for-height gain (relative weight gain) with
(as measured by waist-hip ratio), with greater subcut­ adult body composition and risk of CHD and T2DM.
aneous fat and insulin resistance. Metabolic syndrome is Faster linear growth throughout childhood and faster
common in Indians, and occurs at a young age and low relative weight gain in the first 6 post-natal months were
BMI compared to white Caucasians, attributed to Indians’ associated more strongly with adult lean mass than fat

chapter
typically low lean mass and high percentage body fat mass.28,29 In contrast, faster relative weight gain after

19
(thin-fat Indian phenotype).22 11 years was associated more strongly with adult fat
The DOHaD work in India was sparked off by the visit mass, and with a higher risk of impaired glucose tolerance
of David Barker and Caroline Fall in the early 1990s. They and T2DM. The studies in India therefore confirmed
established collaborations with a group of interested western findings that lower birth and infant weight,
researchers after contacting approximately 300 hospitals followed by rapid childhood or adolescent weight gain
across India and initial studies in India were set up in are associated with adiposity, insulin resistance and
Pune and Mysore. This collaboration led to the formation
glucose intolerance in later life (Figs 19.4A to C).
of the Society for the Natal Effects of Health in Adults
All these initial studies were retrospective, based on
(SNEHA) which has grown in strength and is currently
obstetric birth records. These were followed by setting
the longest established “fetal origins” society. This group
up of new prospective cohorts in Pune and Mysore,
organized the first world congress on fetal origins of
collecting detailed maternal data and following up the
disease at Mumbai in 2001. The growing work in this field
across the world led to the formation of the International children at birth and into childhood and adolescence.
DOHaD Society with a world congress organized every The Pune Maternal Nutrition Study was the first ever
2 years. study in the developing world to prospectively study the
DOHaD research in India date back to 1991 when effects of maternal nutrition (even before conception)
a study in Pune showed that children with lower birth on the cardiovascular risk of the offspring. The study
weights had higher insulin and glucose levels.23 At 8 years recruited married non-pregnant women in six villages
of age, the children of lower birth weight who had the near Pune consisting mostly of subsistence farming
highest current weight had higher insulin resistance.24 communities in a drought-prone area. Anthropometry
In 40–60 year old adults in Mysore, the risk of CHD was (height, weight, circumferences and skinfolds) was
higher in those who had been small at birth as measured recorded every 3 months. Women missing two successive
by birth weight, birth length and head circumference periods underwent an ultrasound examination to confirm
at birth.25 In Mysore however, the prevalence of T2DM pregnancy and assess gestational age. During pregnancy,
was higher in those with a greater ponderal index information was collected on socioeconomic status,
(a ratio of birth weight to birth length; heavier weight dietary intake and physical activity. Anthropometry,
and shorter length leads to greater ponderal index).10 glucose and insulin, and lipids were also measured.
This led to the suggestion that these heavier babies At birth, newborn measurements included birth weight,
may have been offspring of diabetic mothers and that length, head circumference and skinfolds. These
further work was necessary to look beyond birth size children have subsequently been followed up every
measurements. Younger adult cohorts with detailed 6 months for anthropometry and detailed cardiometa­
childhood growth data were retraced in Delhi and Vellore; bolic measurements at 6 and 12 years. This study for
these studies demonstrated that lower birth weight the first time demonstrated a link between maternal
followed by higher childhood weight gain were associated micronutrient intake and offspring size; mothers who
with adult insulin resistance and glucose intolerance.26,27 had the most frequent intake of green leafy vegetables
In Delhi, those with impaired glucose tolerance or and who had the highest red cell folate levels gave birth
T2DM had a low BMI up to the age of two years, followed to the heaviest babies.30 Interestingly, there were no
by early adiposity rebound (the age after infancy when relationships with total energy or protein intake. The study
body mass starts to rise) and an accelerated increase in also demonstrated that the “thin-fat” Indian phenotype
BMI until adulthood. However, none of these subjects was present at birth and not a consequence of post-
were obese at the age of 12 years despite this increase natal life as previously presumed (Figs 19.5A and B).31
296 Etiopathogenesis of Diabetes Mellitus
section
5

A B

Figs 19.4A to C: Insulin resistance-homeostatic model assessment

(IR-HOMA) and 120-minute glucose according to birth weight and
current body mass index (BMI) in three Indian cohorts; lower birth
weight and higher current BMI predict higher insulin resistance
C (IR-HOMA) and 2-hour glucose levels

A B

Figs 19.5A and B: (A) The “thin-fat” Indian baby; (B) Figure showing the Indian babies at birth had considerably lower birth weight, were shorter
and had smaller head circumferences but were relatively adipose compared to UK babies30,31
 Fetal Programming of Type 2 Diabetes Mellitus 297

chapter
19
Fig. 19.6: Maternal vitamin B12, folate and insulin resistance in the Fig. 19.7: A diagrammatic representation of the Pedersen and Freinkel
offspring; children whose mothers had low vitamin B12 and high folate hypotheses;37,38 Transfer of maternal fuels during pregnancy influence
levels during pregnancy had the highest insulin resistance at 6 years32 newborn size as well as the future development of risk factors for type
2 diabetes mellitus

When the Pune babies were compared to babies born Fetal overnutrition (due to maternal obesity and
in UK, the Indian babies were 700 gm lighter but had hyperglycemia) may also program the offspring for
comparable subscapular skinfold compared to the English T2DM. These babies are born “larger”, and develop early
babies. Further studies using whole body magnetic obesity, central obesity, higher insulin resistance and
resonance imaging (MRI) in the newborn confirmed that impaired glucose tolerance and T2DM similar to the
Indian babies have higher intra-abdominal fat at birth offspring of undernourished mothers. The Pima Indian
compared to the English babies,32 and also that they have studies provide support that the association between high
higher insulin levels in the cord blood. birth weight and T2DM may be linked through maternal
Follow-up work demonstrated a direct association diabetes.36 Maternal diabetes mellitus [gestational
between maternal micronutrient levels and risk factors diabetes mellitus (GDM)] provides classical example of
for diabetes in the children. Higher folate concentrations fetal programming by intrauterine oversupply of fuels
in the mothers during pregnancy predicted higher adipo­ including glucose, lipids and amino acids. Pedersen
sity in the offspring at 6 years.33 Vitamin B12 deficiency in proposed that the transfer of excess maternal glucose in a
the pregnant mothers was associated with increased diabetic pregnancy stimulates fetal islets to produce fetal
insulin resistance in their children at 6 years of age; hyperinsulinemia which leads to macrosomia.37 Freinkel
the highest insulin resistance was in children born to suggested that a “mixture” of maternal nutrients (glucose,
mothers with low vitamin B12 and high folate during lipids and amino acids) affects not only fetal growth and
pregnancy (Fig. 19.6). The 1-carbon metabolism cycle, a development but also influences risk of future obesity,
network of inter-related biochemical reactions that involve diabetes and neurocognitive development (fuel-mediated
the transfer of 1-carbon groups from one compound to teratogenesis) (Fig. 19.7).38 Though the mechanisms are
another, is crucial for cell growth and differentiation. poorly understood, the inheritance of genes responsible
Both vitamin B12 and folate (along with other B group for both obesity and GDM has been suggested as a
vitamins) are coenzymes for several of these reactions. cause.39 However, it has been shown that offspring born
Insufficiency or imbalance of these micronutrients can to diabetic mothers had higher rates of obesity and
cause an increase in homocysteine levels, which has T2DM compared to the offspring born before the diagnosis
been linked to higher CHD risk.34 In the Pune study, lower of the mother’s diabetes.40 These findings suggested
vitamin B12 was also associated with higher homocysteine, that it is the intrauterine diabetic environment, rather
which predicted lower birth weight.35 These findings than genes that predicted offspring diabetes in this
were particularly significant in a context where the popu­ population. The Mysore Parthenon Study was specifically
lation was folate sufficient (0.2% deficiency) but vitamin set up to study the long-term effects of GDM on the
B12 deficient (~70% deficiency). offspring. The study recruited women during pregnancy in
298 Etiopathogenesis of Diabetes Mellitus
section
5

A B
Figs 19.8A and B: Median subscapular skinfold thickness (mm) for offspring of diabetic mothers (ODM), offspring of diabetic fathers (ODF) and
controls 0–9.5 years; Offspring of diabetic mothers had greater skinfold thicknesses suggestive of subcutaneous fat through early childhood
(Continuous lines with black squares: offspring of diabetic mothers (ODM); long-dashed lines with cyan triangles: offspring of diabetic fathers
(ODF); short-dashed lines with black circles: Control offspring. P for difference between ODM and controls was significant (<0.05) at birth for
boys, and all time points, except 1-year for girls).41

a charitable hospital which attracts patients from all strata However, more recent research suggests these effects
of society. Measurements during pregnancy included may act through “epigenetic” mechanisms that alter
anthropometry, glucose and insulin, and lipids. This study expression of genes without altering the base sequence
showed that the children born to GDM mothers were (i.e. change in phenotype independent of change in
larger at birth and had higher subcutaneous adiposity genotype). The most likely mechanisms may be through
compared to the newborns of non-GDM mothers.41 The methylation of deoxyribonucleic acid (DNA) and modifi­
difference in adiposity continued to increase throughout cation (acetylation) of histones; both processes modify
childhood, and at 9 years, the children of GDM mothers gene expression and could result in different phenotypes
had higher glucose and insulin concentrations and higher for the same genotype.45 Vitamin B12 and folate are both
insulin resistance (Figs 19.8A and B).42 Maternal vitamin methyl donors and therefore may influence epigenetic
B12 deficiency was also associated with an increased risk methylation reactions, which is well shown in many
of GDM and subsequent T2DM in the mother.43 animal models. Animal studies have shown that epige­
Thus, the prospective cohorts in India have enabled netic changes during early development may be an
the identification of nutritional and metabolic factors in important mechanism linking early nutrition to later
the mothers that predict fetal growth and later outcomes health. The normal process of demethylation and reme­
in their offspring. thylation of fetal DNA in early gestation is nutritionally
sensitive. Nutritional interventions in preg­nant mothers
MECHANISMS OF NUTRITIONAL (mostly using methyl donors in 1-carbon metabolism
FETAL PROGRAMMING such as vitamin B12, folic acid, betaine and choline)
induce permanent changes in DNA methylation, gene
Findings from across the world have now demonstrated
expression, and later phenotype in the offspring.46-48
that an individual’s fetal, infant and childhood nutritional
history influences their adult risk of T2DM. In women,
their nutritional and metabolic status influences fetal
Dual Burden in India
nutrition and the birth size, body composition, and risk In populations undergoing rapid economical and demo­
of T2DM in the next generation. The possible mecha­ graphic changes, both maternal undernutrition and
nisms are still poorly understood. It has been suggested overnutrition coexist creating a double burden of dis­
that permanent structural changes in an organ due ease. India is still burdened with widespread maternal
to suboptimal conditions during a critical period of undernutrition and low birth weight. At the same time,
development44 may result in T2DM (e.g. the permanent more and more women exposed to urban lifestyle are
reduction in beta cell mass in the pancreas). becoming obese and glucose intolerant during pregnancy.
 Fetal Programming of Type 2 Diabetes Mellitus 299

chapter
19
Fig. 19.9: Nutritional transitions causing disease: double burden of under and overnutrition. Both undernutrition and rapid transition to an
overnourished state influence the future risk of developing type 2 diabetes mellitus (T2DM); preventive measures should address breaking the
cycle at an earlier stage48

The combination of poor fetal growth followed by pregnant so that the incidence of diabetes in future gene­
rapid weight gain in later life is most evident in India’s rations will be minimized. The only sustainable way of
urban populations as they are increasingly exposed to a tackling the epidemic is to protect the young and stop
calorie rich diet with high saturated fats, sugar and salt the intergenerational transmission of susceptibility to
as well as reduced levels of physical activity. However, diabetes. The DOHaD hypothesis suggest several potential
rural areas are also rapidly urbanizing. Given their greater ways to break this intergenerational transmission:
early life undernutrition, we would expect the conseq­ improving the nutrition of pregnant women, intervening in
uences to be worse in these communities as urbanization adolescence or the periconceptional period, or optimising
increases. nutrition to achieve good linear growth in infancy and/or
The DOHaD studies in India suggest problems with prevent excessive childhood adiposity.
both undernutrition and overnutrition. Maternal under­ However, evidence in humans is largely limited to
nutrition is associated with low birth weight and stunting observational studies, using birth weight or extreme
in the children, who develop metabolic incompetence in nutritional situations (e.g. famine) as exposures, with little
the form of lower lean mass, poorer cognitive function information on maternal nutrition. Some recent studies
and insulin resistance (nutrient-mediated teratogenesis). have followed up children whose mothers took part in
If fetal undernutrition is followed by rapid childhood nutritional supplementation trials. Indian adolescents
weight gain, the result is excess adiposity, a further increase whose pregnant mothers were supplemented with
energy and protein had lower insulin resistance and
in insulin resistance and adult cardiometabolic disease. In
arterial stiffness,50 and Nepali children whose mothers
women, this leads to gestational diabetes, which exposes
were supplemented with multiple micronutrients had
the fetus to “fuel-mediated teratogenesis” and exacerbates
lower blood pressure.51 In contrast, supplementation of
diabesity in the next generation (Fig. 19.9).49
Gambian women with energy and protein had no effect
IMPLICATIONS FOR on the children’s body composition or blood pressure.52
However, these trials all started in mid-pregnancy, after
PREVENTION AND POLICY
important early-gestation processes such as epigenetic
Current recommendations to reduce the burden of T2DM programming, placentation, and fetal organogenesis.
do not address the impact on the next generation. It is Epigenetic studies applied to DOHaD in humans are
vital that measures to combat T2DM focus on the health limited but maternal nutrition has been shown to
and nutrition of young women before they become influence gene-specific differences in DNA methylation
300 Etiopathogenesis of Diabetes Mellitus

at birth and in later life and DNA methylation at birth 7. Barker DJP, Osmond C, Winter PD, et al. Weight in
has been related to later adiposity.53-55 infancy and death from ischaemic heart disease. Lancet.
1989;2:577-80.
Based on Indian research findings, the field of DOHaD
8. Hales CN, Barker DJ, Clark PM, et al. Fetal and infant
in India has now moved on to intervention studies with growth and impaired glucose tolerance at age 64 years.
two randomized controlled studies in Mumbai and Pune. BMJ. 1991;303:1019-22.
The trial in Mumbai involved food based micronutrient 9. Mi J, Law C, Zhang KL, et al. Effects of infant birthweight
supplementation of women before and during pregnancy; and maternal body mass index in pregnancy on compo-
section

nents of the insulin resistance syndrome in China. Ann

the study is now complete and results are being analyzed. Intern Med. 2000 132:253-60.
5

The Pune trial which has just commenced involves offe­ 10. Fall CH, Stein CE, Kumaran K, et al. Size at birth, maternal
ring preconceptional vitamin B12 supplements in capsule weight and type 2 diabetes in South India. Diabet Med.
form to adolescents. The trial offers a unique opportunity 1998;15:220-7.
11. Eriksson JG, Forsen T, Tuomilehto HJ, et al. Early growth
to investigate not only the effects of maternal supplemen­
and coronary heart disease in later life: longitudinal study.
tation on offspring health, but also examine epigenetic BMJ. 2001;322:949-53.
changes in the offspring. The results of these trials will 12. Victora CG, Adair L, Fall C, et al. Maternal and child
have significant implications for public health policy in undernutrition: consequences for adult health and human
India. If successful, they offer, for the first time, a primor­ capital. Lancet. 2008;371:340-57.
13. Whincup PH, Kaye SJ, Owen CG, et al. Birthweight and
dial prevention approach to reduce and halt the epidemic risk of type 2 diabetes: a quantitative systematic review of
of T2DM in India. published evidence. JAMA. 2008;300:2885-97.
14. Eriksson JG, Forsen T, Tuomilehto J, et al. Early adiposity
Further reading rebound in childhood and risk of type 2 diabetes in adult
life. Diabetologia. 2003;46:190-4.
1. Hales CN, Barker DJP. Type 2 (non-insulin-dependant) 15. Gardner DS, Jackson AA, Langley-Evans SC. The effect of
diabetes mellitus: the thrifty phenotype hypothesis. Diabe- prenatal diet and glucocorticoids on growth and systolic
tologia 1992; 35:595-601. blood pressure in the rat. Proc Nutr Soc. 1998;57:235-40.
2. Barker DJP. Mothers, babies and health in later life. 2nd 16. Vickers MH, Krechowec SO, Breier BH. Is later obesity
Edition. Edinburgh, UK, Churchill Livingstone, 1998. programmed in utero? Curr Drug Targets. 2007;8:923-34.
3. Yajnik CS, Fall CHD, Coyaji KJ, et al. Neonatal anthropom- 17. Warner MJ, Ozanne SE. Mechanisms involved in the
etry: the thin-fat Indian baby; the Pune Maternal Nutrition developmental programming of adult disease. Biochem
J. 2010;427:333-47.
Study. Int J Obesity 2002; 27:173-80.
18. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an
4. Yajnik CS. Nutrient-mediated teratogenesis and fuel-medi-
alternative explanation of the association of low birthweight
ated teratogenesis: two pathways of intrauterine program-
with diabetes and vascular disease. Lancet. 1999;353:
ming of diabetes. Int J Gynaecol Obstet. 2009; 104:S27-31.
1789-92.
19. Baird J, Osmond C, MacGregor A, et al. Testing the fetal
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1. Astrup A, Finer N. Redefining type 2 diabetes: ‘diabesity’ 20. Ramachandran P. Maternal nutrition–effect on fetal growth
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1:57-9. 21. International Diabetes Federation. IDF Diabetes Atlas, 5th
2. Seidell JC. Obesity, insulin resistance and diabetes—a edn. Brussels, Belgium: International Diabetes Federation,
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3. Yajnik CS. Early life origins of insulin resistance and type 2 22. Shelgikar KM, Hockaday TD, Yajnik CS. Central rather than
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2004;134:205-10. Indian subjects. Diabet Med. 1991;8:712-7.
4. Hales CN, Barker DJP. Type 2 (non-insulin-dependant) 23. Yajnik CS, Fall CH, Vaidya U, et al. Fetal growth and glucose
diabetes mellitus: the thrifty phenotype hypothesis. Diabe- and insulin metabolism in four year old Indian children.
tologia. 1992;35:595-601. Diabet Med. 1995;12:330-6.
5. Forsdahl A. Are poor living conditions in childhood and 24. Bavdekar A, Yajnik CS, Fall CH, et al. Insulin resistance
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heart disease? Br J Prev Soc Med. 1977;31:91-5. at 8 years, or both? Diabetes. 1999;48:2422-9.
6. Barker DJP, Osmond C. Infant mortality, childhood 25. Stein C, Fall CH, Kumaran K, et al. Fetal growth and
nutrition and ischaemic heart disease in England and coronary heart disease in South India. Lancet. 1996;
Wales. Lancet. 1986;1:1077-81. 348:1269-73.
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26. Bhargava SK, Sachdev HP, Fall CH, et al. Relation of neonatal anthropometry. Acta Obstet Gynecol Scand.
serial changes in childhood body mass index to impaired 2005;84:159-65.
glucose tolerance in young adulthood. N Engl J Med. 2004; 42. Krishnaveni GV, Veena SR, Hill JC, t al. Intra-uterine
350:865-75. exposure to maternal diabetes is associated with
27. Raghupathy P, Antonisamy B, Geethanjali FS, et al. Glucose higher adiposity and insulin resistance and clustering of
tolerance, insulin resistance and insulin secretion in young cardiovascular risk markers in Indian children. Diabetes
south Indian adults; relationships to parental size, neonatal Care. 2010;33:402-4.
size and childhood body mass index. Diabetes Research 43. Krishnaveni GV, Hill JC, Veena SR, et al. Low plasma

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Clin Pract. 2010;87:283-92. vitamin B12 in pregnancy is associated with gestational
‘diabesity’ and later diabetes. Diabetologia. 2009;52:2350-8.

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28. Sachdev HP, Fall CH, Osmond C, et al. Anthropometric
indicators of body composition in young adults: relation to 44. Barker DJP. The fetal origins of coronary heart disease. BMJ.
size at birth and serial measurements of body mass index 1995;311:171-4.
in childhood; the New Delhi birth cohort. Am J Clin Nutr. 45. Tarry-Adkins JL, Ozanne S. Mechanisms of early life
2005;82:456-66. programming: current knowledge and future directions.
29. Adair L, Fall C, Osmond C, et al. Associations of linear Am J Clin Nutr. 2011;94:1765S-71S.
growth and relative weight gain during early life with adult 46. Burdge GC, Lillycrop KA. Nutrition, epigenetics, and
health and human capital in countries of low and middle develop­mental plasticity: implications for understanding
income: findings from five birth cohort studies. Lancet. human disease. Ann Rev Nutr. 2010;30:315-39.
2013; 382:525-34. 47. Waterland RA, Jirtle RL. Transposable elements: Targets for
30. Rao S, Yajnik CS, Kanade A, et al. Intake of micronutrient- early nutritional effects on epigenetic gene regulation. Mol
rich foods in rural Indian mothers is associated with the Cell Biol. 2003;23:5293-300.
size of their babies at birth. J Nutr. 2001;131:1217-24. 48. Sinclair K, Allegrucci C, Singh R, et al. DNA methyla-
31. Yajnik CS, Fall CH, Coyaji KJ, et al. Neonatal anthropom- tion, insulin resistance, and blood pressure in offspring
etry: the thin-fat Indian baby; the Pune Maternal Nutrition determined by maternal periconceptional B vitamin and
Study. Int J Obesity. 2002;27:173-80. methionine status. Proc Nat Acad Sci USA. 2007;104:
32. Modi N, Thomas EL, Uthaya SN, et al. Whole body magnetic 19351-6.
resonance imaging of healthy newborn infants demon- 49. Yajnik CS. Nutrient-mediated teratogenesis and fuel-
strates increased central adiposity in Asian Indians. Pediatr media­ted teratogenesis: two pathways of intrauterine pro-
Res. 2009;65:584-7. gramming of diabetes. Int J Gynaecol Obstet. 2009;104:
33. Yajnik CS, Deshpande SS, Jackson AA, et al. Vitamin B12 S27-31.
and folate concentrations during pregnancy and insulin 50. Kinra S, Sarma KVR, Ghafoorunissa, et al. Effect of
resistance in the offspring: The Pune Maternal Nutrition integration of supplemental nutrition with public health
Study. Diabetologia. 2008;51:29-38. programmes in pregnancy and early childhood on cardio­
34. Refsum H, Ueland PM, Nygård O, et al. Homocysteine and vascular risk in rural Indian adolescents: long term
cardiovascular disease. Annu Rev Med. 1998;49:31-62. follow-up of Hyderabad nutrition trial. BMJ. 2008;337:a605.
35. Yajnik CS, Deshpande SS, Panchanadikar AV, et al. Maternal 51. Vaidya A, Saville N, Shrestha BP, et al. Effects of a maternal
total homocysteine concentration and neonatal size in multiple micronutrient supplement on children’s weight
India. Asia Pac J Clin Nutr. 2005;14:179-81. and size at 2 years of age in Nepal; follow-up of a double
36. Dabelea D, Pettitt DJ. Intrauterine diabetic environment blind randomised controlled trial. Lancet. 2008;371:492-9.
confers risks for type 2 diabetes mellitus and obesity in the 52. Hawkesworth S, Prentice A, Fulford A, et al. Maternal
offspring, in addition to genetic susceptibility. J Pediatr protein-energy supplementation does not affect adolescent
Endocrinol. 2001;14:1085-91. blood pressure in the Gambia. Int J Epidemiol. 2008;38:
37. Pedersen J. Weight and length at birth of infants of diabetes 119-27.
mothers. Acta Endocrinol. 1954;16:330-42. 53. Godfrey KM, Sheppard A, Gluckman PD, et al. Epigenetic
38. Freinkel N. Banting Lecture 1980. Of pregnancy and gene promoter methylation at birth is associated with
progeny. Diabetes. 1980;29:1023-35. child’s later adiposity. Diabetes. 2011;60:1528-34.
39. Whitaker RC, Dietz WH. Role of the prenatal environment 54. Khulan B, Cooper WN, Skinner BM, et al. Periconceptional
in the development of obesity. J Pediatr. 1998;132:768-76. maternal micronutrient supplementation is associated
40. Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine with widespread gender related changes in the epigenome;
exposure to diabetes conveys risks for type 2 diabetes a study of a unique resource in the Gambia. Hum Mol
and obesity: a study of discordant sibships. Diabetes. Genet. 2012;21:2086-101.
2000;49:2208-11. 55. Relton CL, Groom A, St Pourcain B, et al. DNA methylation
41. Hill JC, Krishnaveni GV, Annamma I, et al. Glucose patterns in cord blood DNA and body size in childhood.
tolerance in pregnancy in South India: Relationships to PLoS One. 2012;7:e31821.
 Chapter 20
Sleep and Type 2
Diabetes Mellitus
Ashok Kumar Das

Sleep and Type 2 DM

Chapter Outline

♦♦ Effect of Sleep on Metabolism and Hormones ♦♦ Pathophysiology of Obesity and Insulin Resistance
♦♦ Influence of Sleep Disturbances on the ♦♦ Obstructive Sleep Apnea and Insulin Resistance:
Onset of Diabetes A Pathophysiological Mechanism
♦♦ Studies Linking Sleep Disturbances to Diabetes ♦♦ Other Factors
♦♦ Sleep Disturbances and Obesity ♦♦ Obstructive Sleep Apnea and Endocrine Dysfunction
♦♦ Lose Sleep, Gain Weight: Pathophysiology ♦♦ Links Between Obstructive Sleep Apnea
♦♦ Role of Hunger Hormones and Cardiovascular Disorders
♦♦ Obesity, Obstructive Sleep Apnea ♦♦ Pathophysiology: Obstructive Sleep Apnea
and Diabetes: A Correlation and Cardiovascular Disease

INTRODUCTION The concomitant decrease in sleep duration and

the increased incidence of DM has led to the belief
Diabetes mellitus (DM) is associated with an increased
that reduced duration of sleep might be a risk factor
frequency of sleep disturbances, which may be due to
for development of DM. Obesity and aging are both
the disease itself or due to the physical complications
associated with sleep disturbances.5,6 As the prevalence
of the disease.1 During the past few decades, sleep
curtailment has become a very common problem. The of obesity and DM increase, and also as the number of
trend for shorter sleep duration has been accompanied elderly people increases, it is imperative to focus on sleep
by a dramatic increase in the prevalence of obesity and disturbances in the overall management of patients with
diabetes. When compared with non-diabetics, patients DM. Well-defined cohort studies such as the American
with diabetes report higher rates of insomnia, excessive Cancer Prevention Survey, the Nurses’ Health Study, the
daytime sleepiness (EDS) and unpleasant sensations in Sleep Heart Health Study and the National Health and
the legs that disturb sleep.2,3 Up to 71% of this population Nutrition Examination Survey (NHANES) have shown that
complain of poor sleep quality4 and high rates of hypnotic altered sleep duration, both of short and long duration, are
use.2 Present evidence indicates that chronic partial associated with adverse health outcomes7 including the
sleep loss may increase the risk of obesity and DM. In causation and morbidity of type 2 DM.
type 2 DM, sleep disturbances are believed to be com­ Sleep curtailment is a part and parcel of modern
mon and have been attributed to both impaired glucose society. Evidence from the aforementioned cohort stu­
metabolism and general physical distress associated with dies has shown that short sleep, as in sleep fragmentation
painful diabetic neuropathy and polyuria. caused by obstructive sleep apnea (OSA) or behavioral
 Sleep and Type 2 Diabetes Mellitus 303

sleep curtailment as a result of lifestyle choices, is asso­ These important changes in glucose metabolism
ciated with an increased incidence of DM. during sleep would imply that poor sleep on a regular
Several studies suggest an independent association basis would affect overall glucose homeostasis.
of OSA with several components of metabolic syndrome,
particularly insulin resistance and abnormalities in lipid INFLUENCE OF SLEEP DISTURBANCES
metabolism.8-11 There has been data that long-term ON THE ONSET OF DIABETES
intermittent hypoxia and sleep fragmentation increase

chapter
sympathetic activity, which in turn lead to disorders of Interactions between sleep and the endocrine system

20
glucose metabolism.12 Alternatively, some studies have are bi-directional. Several hormones have the capacity
suggested that insulin resistance and chronic hypoxemia to affect sleep and recent research has described sleep as
may in turn lead to development of sleep apnea syndrome.13 the key factor in physiological restitution, which has far-
Factors influencing and increasing the risk of sleep apnea reaching medical implications.25
include male sex,2,14,15 obesity,16,17 age8,18 and race.18,19

The sleep cycle is closely related to endocrine and
Somers et al. found that sleep disturbance negatively affects metabolic function and to sympathovagal balance, with
glucose metabolism and endocrine function. They demon­ sleep deprivation being detrimental to these systems.
strated a significant increase in sympathetic activity after Therefore, although the primary function of sleep may be
6 nights of 4 hours sleep (P < .02).20 Taken together with cerebral restoration, sleep debt would affect the peripheral
the epidemiologic evidence for an association between function, and would, if maintained chronically, have
short sleep and the prevalence or incidence of DM an impact on carbohydrate metabolism and endocrine
and/or obesity, various studies support a role for reduced function, including decreased glucose tolerance and
sleep duration in the current epidemic of these metabolic insulin sensitivity.26 These effects are similar to those seen
disorders. Screening for sleep hygiene in patients with in normal ageing and, therefore, sleep debt may increase
“diabesity” is therefore of great importance.21 the severity of age-related chronic disorders such as type 2
This review summarizes the current evidence indicating DM27 (Fig. 20.1).
that sleep loss may contribute to the pathophysiology of The effects of sleep loss on glucose metabolism
DM and obesity. are likely multi-factorial, involving several interacting
pathways.
EFFECT OF SLEEP ON METABOLISM
AND HORMONES Hormonal Dysregulation
Sleep deprivation causes disturbances in the secretion of
Sleep is a “restorative” process of both the mind and the counter regulatory hormones, growth hormone and
the body. It plays a major role in normal functioning of cortisol.28 A study revealed that young, healthy volunteers
an individual by directly affecting many metabolic and who slept only for 4 hours/night for 6 nights showed a
hormonal processes.22
Normal sleep evolves through five stages: rapid eye
movement (REM) sleep and stages 1, 2, 3 and 4 of non-REM
sleep. The later stages of non-REM sleep, namely stages
3 and 4, also known as slow-wave sleep are thought to be
the most refreshing and restorative. The onset of slow-wave
sleep is associated with transient metabolic, hormonal and
neurophysiologic changes, all of which adversely affect
glucose homeostasis. The brain utilizes less glucose, the
pituitary gland releases more amounts of growth hormone
and less corticotropin, the sympathetic nervous system
becomes less active, and conversely, vagal tone is increased.
As a result, in the early part of the night, when slow-wave
sleep predominates, glucose metabolism is slow. These Fig. 20.1: Potential interrelationship between sleep disturbances,
effects are reversed in the later part of the night, when REM glucose metabolism, obesity and diabetes
(T2DM: Type 2 diabetes mellitus)
sleep, stage 1 and awakening are more likely.23,24
304 Etiopathogenesis of Diabetes Mellitus

change in their patterns of growth hormone release from Flow chart 20.1: Obstructive sleep apnea: diabetes interaction model
with the central concept of insulin resistance
a normal single pulse to a biphasic pattern. They were
exposed to a higher overall amount of growth hormone
in the sleep-deprived period, which could contribute to
higher glucose levels.29 Also, evening cortisol levels were
significantly higher in young, healthy men who were
allowed to sleep only 4 hours/night for 6 nights, as well as
section

in young, healthy women who were allowed to sleep only

5

3 hours for 1 night. A cross-sectional analysis that included

2,751 men and women also demonstrated that short
sleep duration and sleep disturbances are independently
associated with more cortisol secretion in the evening. This
elevation in the evening cortisol levels could contribute to
morning insulin resistance.30

Insulin Resistance
The combination of factors such as visceral obesity, insulin
resistance and environmental factors are hypothesized
as principal culprits that contribute to worsening of factor-alpha (TNF-α) contribute to the pathogenesis of
metabolic syndrome and sleep disturbances. Progressive type 2 DM regardless of obesity or insulin resistance.34
deterioration of the sleep cycle would accelerate the These inflammatory cytokines play an important role
worsening of visceral obesity and metabolic syndrome in mediating peripheral insulin resistance by inhibiting
by providing a stress stimulus and causing nocturnal glucose uptake by fat and muscle tissue, increasing the
elevations of hormones, such as cortisol and insulin that concentrations of counter-regulatory hormones, and
promote visceral adiposity, metabolic abnormalities and inducing the release of free fatty acids via stimulation of
cardiovascular complications.31 lipolysis. A recent study has demonstrated that a restriction
Insulin sensitivity is known to decrease with advancing of sleep to 2 hours/night for 1 week in young healthy men
age and is closely correlated with increased body fat. and women is associated with a significant increase in
After years of obesity, persistent resistance to glucose sleepiness, decrements in psychomotor performance and
uptake (despite the compensatory mechanism of elevated increased secretion of the pro-inflammatory cytokines
glycemia and insulinemia) gradually leads to type 2 DM IL-6 and TNF-α.
and the pathogenesis of metabolic syndrome.
Punjabi and co-workers reported insulin resistance
Sympathetic Nervous System Activity
even in mild forms of sleep apnea.32 To determine whether
pathogenic mechanisms of sleep apnea were observed A higher sympathetic nervous system activity, lower
in disorders in which insulin resistance is a primary parasympathetic activity, or both has been observed in
abnormality, Vgontzas and co-workers investigated if this patients who have been sleep-deprived.35 The sympa­
sleep disorder was present in women with polycystic ovary thetic nervous system inhibits insulin release while the
syndrome. They found that women with polycystic ovary parasympathetic system stimulates it, so both these
syndrome were 30 times more likely to suffer from sleep- changes both increase glucose levels. Moreover, overac­
disordered breathing than controls. The data suggested tivity of the sympathetic nervous system results in insulin
that insulin resistance was probably a primary factor resistance.36
involved in the pathogenesis of OSA33 (Flow chart 20.1). Sleep-deprived subjects have been found to have a
decreased brain glucose utilization on positron emission
Inflammation tomography imaging.
The levels of inflammatory cytokines, inflammation or Excess weight is a well-established risk factor for type 2
both increases as sleep duration decreases, which in turn DM. Studies have suggested that sleep loss may increase
cause an increase in insulin resistance. Higher plasma the risk of becoming overweight or obese, which would
concentrations of interleukin (IL)-6 and tumor necrosis ultimately increase the risk of type 2 DM.37
 Sleep and Type 2 Diabetes Mellitus 305

in a vicious cycle. The various factors responsible for sleep

disturbances in individuals with diabetes are:
1. Obstructive sleep apnea:10 Obstructive sleep apnea is
defi- ned as a condition involving intermittent obstruc­
tion of the upper airway that produces apnea (a cessa­
tion of respiratory airflow for at least 10 seconds) and
hypopnea (decreased airflow by 50% that is associated

chapter
with oxygen desaturation). It is a serious disorder that is

20
independently associated with hypertension, ischemic
heart disease, stroke, driving-related accidents and
Fig. 20.2: Sleep disorders in individuals with diabetes premature death. The condition occurs due to the
(CHD: Coronary heart disease; CVD: Cardiovascular disease) collapse of airway between the tongue and the soft
palate during sleep. This leads to a reduction in the
A primary mechanism linking sleep deprivation level of oxygen in the blood and the person then wakes
and weight gain is likely to be hyperactivity of the up to reopen the airway. Patients with OSA have been
orexin system. Orexigenic neurons play a central role in found to have a smaller airway that pre-disposes it to
wakefulness and also promote feeding. Studies in animals collapse. In patients with OSA, the sleep is extremely
have indicated that the orexin system is overactive during fragmented and of poor quality. The risks for OSA
sleep deprivation, which could be in part-mediated by the include excess weight, being male, being over the
increase in activity of the sympathetic nervous system.38 age of 40, a family history of OSA, having a large neck
An increase in the sympathetic activity also affects levels (17 inches) and a recessed chin, abnormalities in the
of peripheral appetite hormones; it inhibits leptin release structure of the upper airway, smoking, alcohol use
and stimulates ghrelin release. These hormonal changes, and ethnicity (African-American, Pacific Islander and
i.e. lower levels of leptin and higher ghrelin levels act Mexican). Obesity has been considered the most
in concert to activate orexin neurons, resulting in an important risk factor as 60–90% of adults with OSA are
increased food intake.39 Moreover, less time spent sleeping overweight. Reduced pharyngeal lumen size due to the
also allows more opportunity to eat. fatty tissue within the airway is thought to compromise
the opening of the airway.
Reduced Energy Expenditure 2. Depression: 41 Depression has a bi-directional rela-
tionship with insomnia: sleep disturbance leads to
There may be a reduction in energy expenditure due to depression and depression can lead to sleep difficulties.
less exercise, but this is more importantly due to less Major depressive disorder is found to be present in
non-exercise activity thermogenesis in sleep-deprived approximately 15% of patients with DM. Sleep problems
individuals in addition to the sense of sleepiness and of are very common in patients with diabetes and have
fatigue. This pathway linking reduced energy expenditure been estimated to be as high as 80%. This can include
with short sleep, the risk of obesity and ultimately DM is needing more time to fall asleep, little or no deep sleep
unexplored as yet. In many overweight and obese people, and more frequent awakenings. Alcoholism is also
this cascade of negative events is likely to be accelerated associated with depression further accentuating sleep
by sleep-disordered breathing, which is by itself an difficulties.
independent risk factor for insulin resistance.40 3. Peripheral neuropathy: Pain, poor quality sleep and
Hence, disturbed sleep alters the inflammatory and functional disturbances are common in patients who
hormonal profile and metabolism, which increase the develop diabetes-related distal sensory peripheral
risk of DM, hypertension and obesity which in turn neuropathy. Peripheral neuropathy-associated tingling,
increase all-cause mortality as shown in Figure 20.2. burning and pain in the feet are major contributors
There are multiple factors contributing to sleep to sleep disruption. Chronic hypoxia is an independ-
disturbances in individuals with diabetes. They occur ent risk factor for the development of neuropathy.
as a result of interaction between the various factors As sleep disturbances worsen hypoxia, the severity of
listed below. Moreover as these factors worsen sleep neuropathy increases which affects sleep, thereby caus-
disturbance, the glycemic control also worsens resulting ing a vicious circle.
306 Etiopathogenesis of Diabetes Mellitus

4. Restless legs syndrome:42 Restless legs syndrome (RLS) is The first NHANES43 examined the effect of sleep dura­
a neurological condition characterized by unpleasant tion on the risk of incident DM in roughly 9,000 men
sensations deep inside the legs that occur at rest, espe- and women over a period of 8–10 years. Those who slept
cially at bedtime. These paresthesias are accompanied 5 hours or less per night were significantly more likely
by an irresistible urge to move the limbs, with move- to develop type 2 DM than those who slept 7 hours/
ment causing temporary relief of symptoms. Because night [odds ratio (OR) 1.57, 95% confidence interval (CI)
DM is a common cause of polyneuropathy, a higher 1.11–2.22] and so were those who slept 9 or more hours
section

prevalence of RLS is expected in patients who have per night (OR 1.57, 95% CI 1.10–2.24).
diabetes. The intensity of sensory and motor symptoms
5

Kawakami et al.44 followed 2,649 Japanese men for

usually varies through a patient’s lifetime, but generally 8 years. Those who had difficulty going to sleep and staying
tends to increase with age. RLS patients experience asleep, which are both likely to result in shorter sleep
discomfort and complain of disturbances in initiating duration, had higher age-adjusted risks of developing type
and maintaining sleep, sleepiness, and report less- 2 DM, with hazard ratios of 2.98 and 2.23, respectively.
refreshing sleep.
5. Hypoglycemia and hyperglycemia: Fear of hypoglycemia
SLEEP DISTURBANCES AND OBESITY45,46
and hyperglycemia by itself can disrupt normal sleep.
Hypoglycemia will awaken a patient with symptoms Sleep curtailment is associated with a dysregulation of the
of weakness, tremors, palpitations and hunger. On the neuroendocrine control of appetite causing a reduction
other hand, hyperglycemia can awaken a person with in the satiety factor, leptin and an increase in the hunger-
poorly controlled diabetes by causing polyuria, poly- promoting hormone, ghrelin. A reduction in sleep may
dipsia and a sense of uneasiness. Thus, poor glycemic alter the ability of leptin and ghrelin to accurately signal
control contributes to sleep disruption. caloric need, which in concert produces an internal
misperception of insufficient energy availability. The
STUDIES LINKING SLEEP adverse impact of sleep deprivation on appetite regulation
DISTURBANCES TO DIABETES is likely to be driven by increased activity in neuronal
Laboratory and epidemiologic evidence support an asso­ populations expressing the excitatory peptides orexins
ciation between short sleep duration (< 7 hours/night) that promote both waking and feeding. Both laboratory
and poor sleep quality with the risk of DM. evidence and epidemiologic studies have shown an
Multiple cross-sectional epidemiologic studies have asso­ciation between short sleep and higher BMI after
suggested an association between short sleep duration and controlling for a variety of possible confounders.47,48
DM, and have suggested that short sleep has a causative
role in DM. The landmark observations of Spiegel et al. LOSE SLEEP, GAIN WEIGHT:
led to a number of epidemiologic studies examining the PATHOPHYSIOLOGY
relationships between sleep duration, sleep disturbances
and diabetes risk.27 There is mounting evidence that lack of sleep is related to
The Sleep Heart Study5 was a large, cross-sectional, obesity and the development of impaired blood glucose
community-based study of the cardiovascular conse­ metabolism and type 2 DM. Insulin resistance and
quences of sleep-disordered breathing. After adjustment blood glucose disturbances are linked to weight gain,
for age, sex, race, body habitus and apnea-hypopnea index creating what some researchers have called “diabesity”.
(AHI), the prevalence of impaired glucose tolerance and A recent sample of United States (US) adults found that
type 2 DM were higher in those who reported sleeping self-reported insufficient rest or sleep is associated with
6 hours or less per night, or 9 hours or more per night. DM, obesity as well as cardiovascular disease (CVD),
The Nurses Health Study31 followed 70,000 non-diabetic coronary heart disease and stroke. Furthermore, carefully
women for 10 years. Compared to nurses who slept for controlled studies have shown that 2 nights of insufficient
7–8 hours per 24 hours, those who slept for 5 hours or sleep are linked to a decrease in disposition index, the
less had a relative risk of DM of 1.34, even after controlling most commonly used predictor of an individual’s diabetes
for many covariables such as body mass index (BMI), risk, as well as impairments in glucose tolerance and
shift work, hypertension, exercise and depression. insulin sensitivity.
 Sleep and Type 2 Diabetes Mellitus 307

Experimental evidence has shown that induced sleep appetite and increased serum concentrations of ghrelin,
loss in healthy volunteers decreases insulin sensitivity which might add to the risk of developing obesity. The
without an adequate compensation in beta-cell function. hypoxic (low oxygen) stress that occurs in sleep apnea
This reduction in insulin sensitivity is rapid and marked causes nocturnal falls in circulating concentrations of a
without adequate compensation in beta-cell function, hormone involved in fat regulation namely adiponectin.
resulting in an elevated risk of diabetes. This led one group Studies have been conducted linking levels of adipo­
of researchers to conclude that “taken together with the cytokines to normal insulin sensitivity and weight control.

chapter
epidemiologic evidence for an association between short Lower levels of adiponectin, on the other hand, are

20
sleep and the prevalence or incidence of DM and/or obesity, found to be associated with metabolic, cholesterol, blood
these results support a role for reduced sleep duration in the pressure and blood sugar imbalances. Studies have found
current epidemic of these metabolic disorders”. that Caucasian women are probably the most susceptible
Reductions in sleep quantity or quality are known to to falls in adiponectin levels after sleep deprivation.
lead to increased hunger and appetite, and in sleep apnea Another hormone which is impacted by sleep loss is
patients insulin resistance is made worse by nocturnal melatonin. A number of animal studies have shown that
hypoxemia due to apnea severity. Melatonin (highest melatonin plays a role in maintaining healthy weight.
in the night), cortisol (highest in the a.m.), testosterone
In one study, researchers investigated the effects of mela­
(highest in the a.m., especially in men) are all time-based
tonin on obesity and obesity-associated systolic hyper­
hormones. The prevalence of sleep apnea and other
tension and lipid problems in diabetic fatty rats, an experi­
sleep disorders is particularly alarming due to the link
mental model of the metabolic syndrome. The results
between sleep loss and obesity and obesity’s known role
indicate that melatonin reduced mean weight gain without
in predisposing an individual to a number of diseases.
food intake differences. Because these benefits occurred
in young age before advanced metabolic and vascular
ROLE OF HUNGER HORMONES
complications set in, it has been postulated that melatonin
One of the ways by which sleep loss is linked to obesity might help in prevention of CVD-associated with obesity
is through appetite regulating hormones. Lack of sleep and dyslipidemia. Melatonin also plays an important
down-regulates the satiety hormone leptin and upregu­ role in the regulation of glucose metabolism as evidenced
lates the appetite-stimulating hormone ghrelin, thereby by the fact that when the melatonin receptor type 1 is
increasing hunger and food intake. removed in mice, it significantly impairs the ability of
The metabolic regulatory system would be expected the animals to metabolize glucose. This inability is likely
to initiate caloric intake to counter-balance additional due to increased insulin resistance in the rodents and
energy expenditures from increased wake time, but, in this indicates that these melatonin receptors are implicated in
case, the increased energy expenditures were presumed the pathogenesis of type 2 DM.49
to be negligible, since the experimental protocol called It has also been found that fragmented sleep disrupts
for the extra hours of wakefulness to be spent lying in bed testosterone rhythm in men and prevents the normal rise
or sitting in a comfortable chair. In light of evolutionary in testosterone that normally occurs during sleep.
pressures such as the thrifty genotype that favors weight
gain and maintenance, it is not surprising that the OBESITY, OBSTRUCTIVE SLEEP APNEA
metabolic regulatory system could overcompensate for AND DIABETES: A CORRELATION
additional energy expenditures and lead to obesity over
time. The analysis of data from the Wisconsin Sleep Cohort Obesity is generally regarded as a risk factor for both
Study, a population-based longitudinal study of sleep OSA and insulin resistance.50 Obesity, in particular cen­
disorders, demonstrated that short sleep duration was tral obesity, is the strongest risk factor for sleep apnea
found to be associated with reduced leptin levels, elevated and diabetes.51-60 The recent pandemic of DM is largely
ghrelin levels and increased BMI in subjects between the attributed to the epidemic of obesity.61 The effect of obesity
ages of 30 years and 60 years.48 as a predictor of OSA is almost four times greater than
Two nights of sleep, restricted to 4 hours, compared the influence of age and twice as great as the influence
to 2 nights of 10 hours in bed, results in a reduction of the of male gender.60 However, factors other than obesity
satiety hormone leptin, accompanied by an increased appear to play a significant role in the development of
308 Etiopathogenesis of Diabetes Mellitus

insulin resistance and metabolic disturbances in patients glucose tolerance tests (OGTTs) results and higher levels
with OSA6,62-65 including sleep fragmentation, increased of glycated hemoglobin (HbA1c).89 Finally, concrete evi­
sympathetic activity and intermittent hypoxia.27,66-68 dence came from the Sleep Heart Health Study. In a
In patients with Type 2 diabetes, increasing severity of community sample of 2,656 subjects, the Apnea Hypo­
OSA is associated with poor glycemic control.69 pnea Index (AHI) and average oxygen saturation during
sleep were associated with elevated fasting and 2-hour
PATHOPHYSIOLOGY OF OBESITY glucose levels during an oral glucose tolerance test
section

AND INSULIN RESISTANCE (OGTT). Sleep apnea severity was also associated with
the degree of insulin resistance independent of BMI and
5

Over the last 40 years, the average BMI in men and women waist circumference, amongst other confounders. Thus,
aged 20–74 years has increased from just over 25 kg/m2 there is strong evidence to suggest that OSA and the risk
to almost 28 kg/m2.70-72 Also, many subjects with OSA of type 2 diabetes are associated, but the evidence
have central obesity and other features of metabolic synd­ supporting a role for OSA in the development of type
rome, which is most widely accepted as being comprised 2 diabetes is still fairly limited. The reverse direction of
of hyperinsulinemia, glucose intolerance, dyslipidemia, causality (i.e. that diabetes may be a cause for breathing
central obesity and hypertension.73 Insulin resistance, abnormalities during sleep) is also possible, as autonomic
hypertension, DM, sleep-disordered breathing and OSA neuropathy could indeed disturb the control of respira­
syndrome increases with increasing levels of obesity.74 It tion.63 Meslier et al.65 showed that DM was present in
has been observed that patients with OSA and nocturnal 30.1% of OSA patients and 13.9% of non-apneic snorers.
hypoxia have increased leptin75 and C-reactive protein EDS is a common symptom in patients with OSA91 and
(CRP),76 indicating a possible role in the pathogenesis recent evidence suggests that EDS may be an independent
of cardiovascular morbidity. Thus, obesity is strongly risk factor for diabetes.32 Vgontzas et al. suggested that
associated with OSA,77 insulin resistance,73 leptin78 and insulin resistance was a risk factor stronger than BMI and
CRP79 levels and may be the major confounding factor in testosterone plasma levels for OSA and daytime sleepiness
the relationship of OSA to insulin resistance and cardio­ in premenopausal women suffering from polycystic
vascular morbidity. ovarian syndrome.90
More recently, Punjabi et al.32 found in 150 healthy
mildly obese men that the severity of OSA-correlated
OBSTRUCTIVE SLEEP APNEA AND INSULIN
with levels of insulin 2 hours after an oral glucose load
RESISTANCE: A PATHOPHYSIOLOGICAL and reported a two-fold increase in insulin resistance
MECHANISM in subjects with an AHI, after controlling for BMI and
Several studies have tried to establish the association percent body fat. Ficker et al.87 assessed the presence of
OSA (AHI 610) in a group of diabetic patients with and
between OSA and diabetes.80-83 Insulin resistance has been
without diabetic autonomic neuropathy (DAN). They
induced among healthy volunteers by sleep restriction.
found a prevalence of OSA or OSA-hypopnea syndrome
Sleep restriction on the other hand has also resulted in
(OSAHS) amounting to 26% in diabetics with DAN;
an increase in evening cortisol level and sympathetic
whereas none of the diabetics without DAN met the
activation.27 A number of studies have also examined the
criteria for OSAHS. Neumann et al. demonstrated a close
cross-sectional relationship between OSA, as assessed correlation between nocturnal oxygen desaturation and
by overnight polysomnography and metabolic abnor­ the presence of DAN in a popula­tion of diabetic patients.88
malities.80-82,84-86 Most of the studies suggest that OSA is In humans, as mentioned, several studies have shown
related to impaired glucose tolerance and insulin resis­ increased sympathetic nervous system activity and
tance. Recent studies also confirm the high prevalence increased catecholamine levels, which in turn results in
of habitual snoring in DM84 or higher prevalence of meta­ hyper-insulinemia.93,94
bolic syndrome in habitual snorers.85 Over the past decade,
there has been increasing clinical and experimental OTHER FACTORS
evidence of the association between insulin resistance
and OSA in non-obese diabetic patients with autonomic Hypothalamic-pituitary-adrenal dysfunction: Hypoxia and
neuropathy.86-88 Frequent snoring was associated with sleep fragmentation may lead to activation of the hypo­
reduced glucose tolerance, as assessed by abnormal oral thalamic-pituitary-adrenal (HPA) axis and excessive
 Sleep and Type 2 Diabetes Mellitus 309
Flow chart 20.2: Relationship between sleep apnea and type 2 diabetes96

chapter
20
and/or abnormal pattern of elevation of cortisol levels partial or total sleep deprivation has been shown to
with negative consequences on insulin sensitivity and insu­ increase plasma cortisol level by 37% and 45%, respec­
lin secretion. OSA patients have been shown to have hig­ tively. The link of OSA to insulin resistance in humans
her levels of inflammatory markers94,95 as well as increased has not been fully elucidated (Flow chart 20.2). Several
monocyte and lymphocyte activation with evidence that plausible explanations can be proposed.27 Leproult et al.
these changes are independent of adiposity.91 hypothesized that the pathway between OSA and glucose
Adipokines: Leptin levels are higher32 and adiponectin intolerance was stimulation of the HPA axis due to
levels lower in patients with OSA. However, the data are hypoxias and fragmented sleep and leading to an increase
inconsistent as to whether this is independent of obesity87 in cortisol with corresponding hyperglycemia. OSA is also
and it is not known whether the levels improve with characterized by a proinflammatory state and elevated
treatment of OSA. cytokine levels (e.g. TNF-α) which may lead to insulin
resistance.79-81 TNF-α is usually elevated in individuals with
Sleep architecture: A recent study92 examined selective
obesity-induced insulin resistance. Studies have suggested
suppression of slow-wave sleep (a phase of sleep thought
to be the most “restorative” stage) in healthy young adults, that subjects with OSA had higher concentrations of
without affecting sleep duration or causing hypoxia. The IL-6 and TNF-α than obese subjects without OSA. Insulin
intervention markedly reduced insulin sensitivity and led resistance is also caused by increased lipolysis and fatty
to an impairment of glucose tolerance. The fatigue and acid availa­bility. OSA may act through this mechanism
somnolence resulting from OSA may reduce physical by virtue of its association with central obesity and sympa­
activity, and thus leading to increased risk of diabetes. thetic activation.57 Sympathetic activation raises circula­
The following Flow chart 20.2 illustrates the relationship ting free fatty acids via stimulation of lipolysis and pro­
between OSA, insulin resistance and DM. motes insulin resistance. Leptin, IL-6 and inflammatory
mediators have also been implicated in the pathogenesis
OBSTRUCTIVE SLEEP APNEA AND of insulin resis­ tance and other features of metabolic
ENDOCRINE DYSFUNCTION syndrome.

Hypoxia can cause enhanced activation of the sympathoa­ LINKS BETWEEN OBSTRUCTIVE SLEEP
drenergic system increasing plasma insulin irrespective APNEA AND CARDIOVASCULAR DISORDERS
of the glycemic level.76 Sympathetic hyperactivity can also
lead to increased glycogen breakdown and gluconeo­ Obstructive sleep apnea is associated with a variety
genesis. Further, OSA may cause metabolic dysfunc­ of cardiovascular conditions ranging from hypertension
tion through its effects on the HPA axis. Experimental to heart failure95 and OSA has become increasingly
310 Etiopathogenesis of Diabetes Mellitus

considered as a potential therapeutic target for either 4. Effects on lipids: Several animal studies have shown
primary or secondary prevention of CVD. that intermittent hypoxia upregulates genes of lipid
bio-synthesis and that dyslipidemia and lipid peroxida-
Hypertension tion are dependent on the severity of the hypoxia. Both
Obstructive sleep apnea has been shown to be an inde­ increased levels of oxidized low-density lipoprotein
pendent risk factor for the development of hypertension. (LDL) and dysfunction of high-density lipoprotein
In this study, patients with mild to moderate OSA (AHI (HDL) have been described in OSA. Physical inacti­
section

5–14.9) were twice as likely to develop hypertension as vity and both OSA and diabetes can also increase the
5

were those without OSA (OR = 2.89). Recent guidelines risk of CVD.
recommend screening for the presence of OSA in patients
with refractory hypertension.94 Further reading
1. Parish JM, Somers VK. Obstructive sleep apnea and cardio­
Cardiovascular Disease vascular disease. Mayo Clin Proc. 2004;79:1036-46.
Obstructive sleep apnea is associated with an increased 2. Joo S, Lee S, Choi HA, et al. Habitual snoring is associated
with elevated hemoglobin A1c levels in non-obese middle-
prevalence of CVD (Ischemic Heart Disease, Heart Failure,
aged adults. J Sleep Res. 2006;15:437-44.
Stroke). In the Sleep Heart Health Study,95 Shaher et al, 3. Mehra R, Benjamin EJ, Shaher E, et al. Association of
found that the prevalence of CVD increased progressively nocturnal arrhythmias with sleep disordered breathing:
with AHI based on multi-variable adjusted relative odds The Sleep Heart Health Study. Am J Respir Crit Care Med.
(95% CI) of prevalent CVD for the second, third and fourth 2006;173:910-16.
quartiles of the AHI (versus the first) of 0.98 (0.77–1.24), 4. Peker Y, Carlson J, Hedner J. Increased incidence of coro-
nary artery disease in sleep apnoea: a long-term follow-up.
1.28 (1.02–1.61) and 1.42 (1.13–1.78), respectively. Other
Eu Respir J. 2006; 28:596-602.
studies have reported that cardiac arrhythmias are 5. Lindberg E, Berne C, Franklin KA, et al. Snoring and
commonly seen in patients with OSA.97,98 Also, there is daytime sleepiness as risk factors for hypertension and
evidence to support a link between OSA and myocardial diabetes in women: a population-based study. Respir Med.
infarction and death.99,100 2007;101:1283-90.
6. Tasali E, Mokhlesi B, Van Cauter E. Obstructive sleep
PATHOPHYSIOLOGY: OBSTRUCTIVE SLEEP apnea and type 2 diabetes: interacting epidemics. Chest.
2008;133:496-506.
APNEA AND CARDIOVASCULAR DISEASE 7. Zizi F, Jean-Louis G, Brown CD, et al. Sleep disturbance
and risk of diabetes mellitus: epidemiological evidence
A variety of mechanisms and pathways may promote the
and pathophysiological insights. Curr Diab Rep. 2010;
development of CVD in those with OSA. 10:43-7.
1. Hypoxia and oxidative stress: In chronic hypoxia and
hyper-carbia, chemoreceptors may undergo long-term
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Section 6

Genetics and immunology

Section Editor: Viswanathan Mohan
 Chapter 21
Genetics of
Type 2 Diabetes
Venkatesan Radha, Viswanathan Mohan

Genes and Type 2 Diabetes

Chapter Outline
♦♦ Genetics of Monogenic Diabetes ♦♦ Candidate Gene Approach
♦♦ Implications of Monogenic Diabetes Genes in Adult ♦♦ Genome-Wide Association Studies
♦♦ Linkage Analysis

INTRODUCTION The genetics of type 2 diabetes can be considered

under two broad groups: genetics of monogenic forms of
Type 2 diabetes mellitus is a heterogeneous disease diabetes, where a single gene is causal in the development
resulting from defects of both insulin secretion and insulin of the disease, and genetics of polygenic forms of
action.1 The etiopathogenesis of type 2 diabetes involves diabetes, where a number of genes are responsible for the
interplay of both genetic and environmental factors. susceptibility of the disease.
Although the recent increase in diabetes prevalence
Patterns of inheritance suggest that type 2 diabetes
reflects the effects of changing environmental factors,
is both polygenic and heterogeneous, that is, multiple
multiple lines of evidence support the view that genetic
genes are involved and different combinations of genes
factors are equally important:
play a role in different subsets of individuals. Exactly how
• The observation that the disease prevalence varies
many genes and what their relative contributions are still
substantially among ethnic groups that share a similar
remains ambiguous. It is generally accepted that type
environment, supports the idea that genetic factors
contribute to predisposition to the disease.2 2 diabetes results from a complex interplay of genetic
• Familial aggregation suggests a genetic contribution to and environmental factors influencing a number of inter­
the disease, although shared common environmental mediate traits of relevance to diabetic phenotypes (b-cell
traits play a role. The odds ratio for offspring of a mass, insulin secretion, insulin action, fat distri­bution and
single affected parent is 3.5 compared to those with no obesity) (Fig. 21.1).
parental diabetes history, and this increases to 6.1, if To unravel the genetics of type 2 diabetes, four
both parents are affected.3,4 approaches have been used over the past two decades,
• The high concordance in monozygotic twins each with some success. The first approach was to focus
(over 80%) compared to 50% concordance in dizygotic on forms of type 2 diabetes transmitted with a Mendelian
twins provides evidence for a genetic component in dominant pattern of inheritance and/or other specific
etiology of type 2 diabetes.5,6 clinical features, which resulted in the discovery of
• Data from various studies are in support of a genetic genes involved in Maturity-Onset Diabetes of the Young
basis for measures of both insulin sensitivity and (MODY), several syndromes of severe insulin resistance,
insulin secretion.7,8 neonatal diabetes, mitochondrial diabetes, and other rare
318 Genetics and Immunology

genetically heterogenous. NDM can be either permanent

[permanent neonatal diabetes mellitus (PNDM)] requiring
lifelong treatment or transient [transient neonatal dia­
betes mellitus (TNDM)] with insulin dependence in the
first months only, and a spontaneous remission usually by
18 months of age.13-15
The severe hyperglycemia and minimal ketosis appea­
section

ring in the first days of life may have dramatic complica­

6

tions in the neonate, such as failure to thrive, acidosis,

dehydration, and neurological alterations.14,16 Neonatal
diabetes is a monogenic disorder, mostly unrelated to
autoimmunity, and is conferred by mutations in genes that
play a key role in β-cell function or development including
glucokinase, the KATP channel and insulin gene.13,17
Fig. 21.1: Gene-environment interaction in type 2 diabetes Activating mutations in the gene encoding the Kir6.2
and SUR1 (ABCC8) subunits of the KATP channel are the
genetic syndromes. Together, these monogenic forms most common cause of PNDM, accounting for about
of type 2 diabetes account for less than 5% of all forms of half of the cases.18 These mutations prevent the channel
type 2 diabetes.9 The second was to search for genetic vari­ closure, and thereby of insulin secretion. The specific
ants in candidate genes that might be associated with the mutations determine the phenotype,19,20 and for KIR
common type 2 diabetes.10 In general, these studies have mutations, there is a correlation with functional severity
focused on functional candidate genes, i.e. genes whose of the mutation.21 TNDM can also result from mutations
products are known to play a role in glucose homeostasis, in KCNJ11 or ABCC8.22 Besides diabetes, around 20% of
or positional candidate genes, i.e. genes located in the patients with KATP channel mutations have neuro­
chromosomal regions that had been identified in linkage logical symptoms, which may constitute severe syndrome
studies. The third approach was to perform microarray of developmental delay, epilepsy, and neonatal diabetes
gene expression analysis in an attempt to define genetic (DEND); sometimes an intermediate form may result,
alterations in type 2 diabetes. The fourth and more DEND, characterized by diabetes and less severe develop­
recent approach has been to perform high throughput mental delay without epilepsy.21 The identification of
Genome-Wide Association Studies (GWAS), which is KATP channel mutations can profoundly impact the type
expected to accelerate the speed of gene identification in of diabetic therapy; many of these neonates and infants
type 2 diabetes. can be managed by oral sulfonylurea drug.23

GENETICS OF MONOGENIC DIABETES Studies on Neonatal Diabetes in India

Monogenic diabetes consists of different subtypes of The molecular basis of neonatal diabetes has been repor­
single gene disorders comprising a large spectrum of ted in India in four isolated case reports.24-26 The genes
phenotypes, namely neonatal diabetes mellitus (NDM) or implicated were KCNJ11, ABCC8 and INS. In a recent
monogenic diabetes of infancy, dominantly inherited report,27 we identified mutations of KCNJ11, ABCC8,
familial forms of early-onset diabetes called MODY and INS, AGPAT2, SLC2A2 and EIF2AK3 in 10 children
rarer diabetes-associated syndrome diseases. All these (Table 21.1), when children with the first two mutations
forms are diagnosed at a very-young age and are unrelated could be shifted to oral agents.
to autoimmunity.
Maturity-Onset Diabetes of the Young
Neonatal Diabetes
A less severe form of diabetes with a dominant mode
Neonatal diabetes mellitus is defined by diabetes of inheritance was first reported in three families by
diag­nosed within the first 6 months of life.11 It is rare Tattersall in 1974;28 the term “MODY” for Maturity-Onset
(1:100,000–260,000 live births)12,13 and is clinically and Diabetes of the Young was first used in 1975 following
 Genetics of Type 2 Diabetes 319

Table 21.1: Mutations causing neonatal diabetes in south Indian pedigrees

S. No Diabetes subtypes Mutation identified in gene Nature of mutation Age at onset Developmental
delay
1. PNDM KCNJ11 Known 82 days No
2. PNDM KCNJ11 Known 5 months No
3. PNDM KCNJ11 Known 48 days Yes

chapter
4. PNDM ABCC8 Known 6 months No

21
5. PNDM ABCC8 Novel 2 months No
6. PNDM INS Known 4 months No
7. Infantile onset INS Known 10 months No
8. Syndromic form of diabetes AGPAT2 Novel 1 month Yes
9. Syndromic form of diabetes SLC2A2 Novel 1 month Yes
10. Syndromic form of diabetes EIF2AK3 Known 3 months Yes
(PNDM: Permanent neonatal diabetes mellitus)

further clinical description.29,30 MODY is defined as a whereas heterozygous loss-of function GCK mutations
dominantly inherited young-onset non-autoimmune result in alterations of both glucose-stimulated insulin
diabetes that occurs in adolescence or young adulthood secretion and hepatic glycogen synthesis, leading to mild
(usually less than 25 years of age) due to a primary fasting hyperglycemia (5.5–8.0 mmol/L).44-46 Homozygous
defect in pancreatic β-cell function.30-32 Type 1 diabetes GCK mutations causing PNDM have also been reported.43
requires insulin even from the time of diagnosis due to Mutations in HNFIα gene results in MODY 3 subtype.
lack of insulin secretion. MODY, which is a subtype of More than 200 HNF1α gene mutations were reported in
type 2 diabetes, accounting or 1–3% of all type 2 diabetes ~370 families of various ethnic origins.44 MODY 3 is the
cases33 and does not generally require insulin initially commonest form of MODY worldwide.45 Clinically, the
because residual insulin secretion is still maintained for patients are non-obese; they often present with severe
some years. hyperglycemia and may develop microvascular complica­
Heterozygous mutations or partial/whole gene dele­ tions. The prevalence of MODY 3 in early-onset type 2
tions in eleven susceptibility genes, explain the clinical diabetes mellitus varies from 2.5% to 36%.47-50 The pene­
heterogeneity of the MODY subtypes (Table 21.2). The trance of MODY 3 is high, and it often evolves insulino­
MODY genes encode the enzyme glucokinase (GCK),34 penia and microvascular complications.51
transcription factors HNF1α, HNF4α, HNF1β, PDX1 and HNF1α and HNF4α mutations are associated with
NEUROD1,31,32 preproinsulin INS,35 KLF11,36 CEL,37 PAX438 early-onset, and progressive diabetes often requiring oral
and BLK.39 Each has a crucial role in the development hypoglycemic agents or even insulin. This shared pheno­
and/or function of the pancreatic β-cells (Table 21.2). type is consistent with the interdependence between
Mutations in GCK, HNF1α and HNF4α are the most HNF1α and HNF4α forming part of a regulatory network in
common causes of MODY. the pancreatic β-cell.52
Maturity-onset diabetes of the young 1 subtype is Two other transcription factor genes, PDX1 and
caused by mutations in HNF4α gene with 31 mutations NEUROD1, have an important role in the development
reported in 40 MODY families.40 This gene plays a role in of the endocrine pancreas, although representing a rare
development of the liver, kidney, and intestines. Hetero­ cause of MODY.
zygous mutation leads to progressive decrease in insulin PDX1 or IPF (MODY 4) is co-expressed with insulin in
production.41 HNF4α also determines fetal birth weight the developing β-cell and is required for maintaining the
and hyperinsulinemia in utero and at birth.42 β-cell phenotype. A frame-shift mutation in the coding
Currently more than 600 GCK mutations were repor­ sequence of the PDX1 gene was found to co-segregate
ted in more than 1,400 families worldwide.43 Heterozygous with MODY in a five-generation family presenting a
gain-of-function GCK mutations cause hypoglycemia consanguineous link.53 In heterozygous mutation carriers,
320 Genetics and Immunology

Table 21.2: Novel Mutations/ Polymorphisms identified in HNF1A, HNF4A genes in Indian MODY pedigrees
S. no Diabetes subtypes Mutation identified in gene Region Variant
–1009 G/C
1. MODY 1 HNF4A Promoter 2 –129 T/C
–79 C/T
Promoter –538G>C
section

Arg114Cys
Val134Val
6

Exon 2
Arg171Gly
2. MODY 3 HNF1A Glu235Gln
Gly245Arg
Exon 4
Arg263His
Exon 7 Pro488Pro
Intron 6 IVS6-12C>T
(MODY: Maturity-Onset Diabetes of the Young)

the phenotypes range from impaired glucose tolerance caused by mutation in CEL gene on chromosome 9. It is
to overt non-insulin-dependent diabetes. caused by frame shift deletions in the variable number of
Mutations in HNF1β/TCF2 were at first associated tandem repeats (VNTR) of the carboxyl-ester lipase gene.37
with MODY 5 in a few families.31 In addition to having an Paired box gene 4 encodes for PAX4 protein, and
important role in early pancreas development, HNF1β mutations in this gene results in MODY 9.60 The paired box
function is also crucial in kidney development and neph­ gene 4 is involved in pancreatic islet development.
ron differentiation, and HNF1β mutations were shown The proinsulin, precursor of insulin, is encoded by the
to be a more common cause of renal cystic diseases and INS gene.61 MODY type 10 is caused by mutation in INS
multiple renal malformations.54,55 This has been called (PROINSULIN) gene. MODY type 11 is caused by muta­
renal cysts and diabetes syndrome (RCAD). More than tion in B lymphocyte kinase (BLK) gene.62 This gene
65 mutations were reported in 143 families.56,57 Although preferentially expresses in B-lymphoid cells, and probably,
HNF1β was initially described as a MODY gene, patients it functions in a signal transduction pathway specific to
usually present with renal disease or RCAD rather than this lineage.
with MODY.56
The basic helix-loop-helix (bHLH) transcription factor Studies on MODY in India
NEUROD1 (or BETA2) with other factors (like NEUROG3)
specifies the pancreatic endocrine lineage. This is also Earlier studies using the clinical criteria used at that
known as MODY 6. Heterozygous loss-of-function muta­ time reported on the high prevalence of MODY in South
tions in NEUROD1 were reported in a few MODY fami­ Indians (4.8%).63 Recently, we identified nine novel vari­
lies,31 and very rare homozygous mutations associate with ants comprising seven mutations and two polymorphisms
PNDM, cerebellar hypoplasia, learning difficulties, visual in the HNF1A gene.64 Functional studies revealed reduced
and hearing impairment.58 This syndrome highlights the transcriptional activity of the HNF1A promoter for two
critical role of NEUROD1 in the development of both of the promoter variants. One of the novel mutations,
endocrine pancreas and central nervous system. Arg263His, was identified in a family of 30 individuals.
Kruppel-like factor 11 is a protein that in humans is The mutation co-segregated with diabetes in this family
encoded by the KLF11 gene.36 MODY 7 is caused by muta­ and was not seen in non-diabetic members in the family,
tions in the KLF11 gene. KLF11 regulates exocrine cells showing that it was involved in causing MODY.64 There
growth and behaves like a tumor suppressor for pancreatic further three novel MODY 1 mutations have also been
malignancy.59 identified in HNF4 A gene.65 Thus, about 9% of the clinically
Carboxyl-ester lipase gene (CEL) controls both exoc­ diagnosed MODY subjects are MODY 3, and 3% are MODY
rine and endocrine function of the pancreas. MODY 8 is 1 in south India (Table 21.2).
 Genetics of Type 2 Diabetes 321

A molecular genetic diagnosis in patients suspected are pre­sent in both healthy individuals, and type 2 diabetes
of MODY aids in confirming the diagnosis, classifies the patients, although with different frequencies. The variants
subtype, predicts the likely clinical course, defines risk for associated with an increase in the risk of disease are sus­
relatives and may change the patient’s treatment. ceptibility variants but not unequivocal causative factors.
Type 2 diabetes has been at the forefront of human
IMPLICATIONS OF MONOGENIC diseases and traits studied by new genetic analyses. The
DIABETES GENES IN ADULT primary methods used to establish a link between genotype

chapter
and phenotype were linkage analysis and candidate gene
Polygenic Type 2 Diabetes

21
approaches.
Common polymorphisms in genes implicated in mono­
genic diabetes can increase the risk of common adult LINKAGE ANALYSIS
type 2 diabetes; common variation in HNF1A gene are
Linkage analysis is a method of mapping disease genes
associated with impaired insulin secretion and I27L
in affected families by genotyping about 400–500 genetic
and A98V polymorphisms in the MODY 3 gene (TCF1)
markers. Finding that affected family members share a
with increased risk of type 2 diabetes in overweight
individuals.66 An association of Val 98 allele with MODY certain marker that is identical by descent, i.e. identical
phenotype was reported in South Indian patients.67 because it was inherited from the same parent, is evidence
This allele was also associated with an earlier age at that a disease causing variant is in linkage analysis with
onset of type 2 diabetes mellitus.67,68 Single-nucleotide the genotyped marker. This method has been useful in
polymorphisms (SNPs) rs4810424 and rs3212198 in the identifying familial genetic variants with large effects
HNF4A gene showed a modest association with type 2 such as those giving rise to MODY.51 However, it has been
diabetes, in line with previous studies.69,70 The –30G/A less successful in identifying genes that cause complex
polymorphism in the GCK gene β-cell promoter has diseases such as type 2 diabetes. Despite efforts, only
been associated with increased fasting plasma glucose two genes have been identified by linkage: calpain 10
and reduced β-cell function71 and to affect birth weight.72 (CAPN10) and transcription factor 7-like 2 (TCF7L2). In
In a recent meta-analysis, this SNP was shown to have a the case of TCF7L2, a type 2 diabetes locus was mapped
modest, but significant effect on type 2 diabetes risk.73 to chromosome 10q in both an Icelandic and a Mexican-
A common polymorphism in KCNJ11 (encoding American population.78 This region was later fine-mapped
Kir6.2), E23K, was shown to be associated with an incre­ in the Icelandic population by use of 228 microsatellite
ased risk of developing type 2 diabetes in European markers covering a 10.5 Mbp region, pinpointing the locus
populations.74,75 This finding has been replicated in large- to intron 3 of the TCF7L2 gene.79 The association between
scale association studies and meta-analyses.75,76 The long- type 2 diabetes and a number of SNPs in the TCF7L2 gene
standing exploration of various subtypes of monogenic have since been confirmed in different ethnic groups.80-84
diabetes and their genetic dissection have improved our All of these demonstrate evidence of association with
understanding of the β-cell physiology and regulation of diabetic risk and consistent effect sizes. The risk allele
insulin secretion in humans. confers a relative risk of approximately 1.4 compared to
homozygous carriers of the non-risk allele, making this the
Genetics of Polygenic Type 2 Diabetes strongest association with type 2 diabetes by far.
Unlike monogenic forms of diabetes as described above, In a South Indian population, we genotyped two
the more common type 2 diabetes is a polygenic disorder. important SNPs in the TCF7L2 genes (rs12255372 and
The individual susceptible and protective genes are more rs7903146). The ‘T’ allele of both rs12255372 and rs7903146
difficult to identify, and interact with environmental polymorphisms was associated with type 2 diabetes and
factors. The genetic susceptibility to type 2 diabetes is with non-obese type 2. This adds to the evidence that
associated with polymorphisms that create amino acid TCF7L2 is an important risk factor for type 2 diabetes in
variants in exons, influence the expression of genes Asian Indians as well.85 Similar association have been
in the regulatory pathways,77 or serve as sign posts in demonstrated in Khatri Sikhs from North India.86 These
linkage disequilibrium. Alleles of these polymorphisms were confirmed in meta-analyses and large GWAS.87
322 Genetics and Immunology

The mechanisms by which TCF7L2 affects diabetes ratio (OR) of ~1.2.95 The risk of type 2 diabetes by this SNP
susceptibility are still not completely understood. T-allele has been studied prospectively in the Finnish Diabetes
of SNP rs7903146 was associated with risk of type 2 Prevention Study and the larger Botnia Prevention Study.
diabetes, impaired insulin secretion, incretin effects, and In the Finnish study, 500 subjects with impaired glucose
an enhanced hepatic glucose production.88 tolerance, the relative risk of developing diabetes was
The other gene mapped by linkage analysis is a locus doubled in alanine carriers, contradicting the prior
on chromosome 2.89 This locus was fine mapped and the evidence that the alanine allele was protective. In the
section

causative gene shown to be CAPN10, the gene for calpain larger Botnia study, comprising more than 2,000 subjects,
6

10, a cysteine protease with largely unknown functions proline homozygotes were 1.7 times more likely to develop
diabetes than alanine carriers.96 In contrast, we found
in glucose metabolism.90 Despite a number of negative
that the Pro12Ala polymorphism of the PPAR–γ gene
replication studies, several meta-analyses have shown
which is protective against diabetes of Caucasians do not
consistent association of CAPN10 with type 2 diabetes.91,92
offer protection in two cohorts of South Asians studied at
Nevertheless, none of the large GWAS has identified
Chennai, India and Dallas in US.97
CAPN10 as being associated with type 2 diabetes.
The SNP E23K of KCNJ11 has now been associated with
type 2 diabetes. Although initial smaller studies failed to
CANDIDATE GENE APPROACH replicate the association of the E23K polymorphism with
Identification of disease genes can also be made on the type 2 diabetes, large-scale studies and meta-analyses
basis of association testing in populations rather than in have consistently associated the lysine variant with type 2
families. Based on this hypothesis, the candidate gene diabetes, with an OR of 1.15.98
approach focuses on the search for an association The plasma cell glycoprotein-1 (PC-1) gene impairs
between type 2 diabetes and sequence variants in or near insulin signaling at the insulin receptor level. The K121Q
polymorphism of the ENPP1/PC-1 gene is associated with
biologically defined candidate genes, chosen based on
insulin resistance/atherogenic phenotypes, including
their known physiological function. The starting point for
earlier onset of type 2 diabetes, and myocardial infarction.99
the candidate gene approach is that either altered expres­
The Q121 variant binds and inhibits insulin receptor more
sion and/or function of a particular gene product may
strongly than the K121 variant and is associated with
affect a biological function or a disease. The importance of
insulin resistance and related metabolic abnormalities in
these or other nearby variants is tested by comparing the
the majority of populations. Prudente et al.100 suggested
frequency in type 2 diabetes patients and normal glucose-
that the Q121 allele is a gene variant with pleiotropic
tolerant subjects.
deleterious effects on insulin resistance, obesity and type
Extending the analysis of genes implicated in mono­
2 diabetes. Our study supports that ENPP1 121Q predicts
genic forms of diabetes has proved successful also for type genetic susceptibility to type 2 diabetes in both South
2 diabetes, as exemplified by HNF4A, HNF1A and KCNJ11 Asians and Caucasians.101
genes. Common variants of HNF4A (MODY1) have been Peroxisome proliferator-activated receptor-γ coacti­
associated with type 2 diabetes.65-70 vator-1α (PGC-1A) is a cofactor involved in adaptive
One of the main candidate genes implicated in adipo­ thermogenesis, fatty acid oxidation and gluconeogenesis.
genesis, insulin resistance and type 2 diabetes is the Dysfunction of this protein is likely to contribute to the
peroxisome proliferator activated receptor-γ (PPAR-γ) development of obesity and the metabolic syndrome.
gene. This is a transcription factor that is involved in Expression of PGC-1A is downregulated in muscles of
adipogenesis via regulation of adipocyte gene expression type 2 diabetic subjects. In addition, a common polymor­
and in glucose metabolism. Within a domain of PPAR-γ2 phism of the PGC-1α gene (Gly482Ser), expressing redu­
gene that enhances ligand independent activation, a ced PGC-1A activity, has been linked to an increased risk
common Pro12Ala polymorphism has been identified.93 of type 2 diabetes. These observations suggest that either
Deeb et al. (1998) reported94 that the Ala allele of this reduced levels or compromised activity of PGC-1A can
polymorphism was associated with increased insulin be associated with the development of insulin resis­tance
sensitivity and decreased risk of type 2 diabetes. Since this and type 2 diabetes.102 In a study on seven PGC1A variants
initial work, the preponderance of evidence has supported only Gly482Ser polymorphism was associated with a 1.34
PPARG’s association with type 2 diabetes, with an odds relative risk of type 2 diabetes.103 Studies on Thr394Thr,
 Genetics of Type 2 Diabetes 323

Gly482Ser and +A2962G, of the peroxisome proliferator GENOME-WIDE ASSOCIATION STUDIES

activated receptor-co-activator-1 alpha (PGC-1A) gene
with type 2 diabetes in Asian Indians showed that The ability to interrogate the entire genome was made
Thr394Thr (G-A) polymorphism is associa­ted with type possible by two the Human Genome Project and the
2 diabetes104 and with body fat.105 Another study showed International HapMap project. GWAS allowed the
that the Thr394Thr and Gly482Ser variant genotypes pro­ discovery of multiple gene variants with individually small
vide protection against type 2 diabetes mellitus in North effects. Once a specific polymorphism is associated with

chapter
Indian populations.106 a disease, it is usually annotated by naming the gene in

21
Adiponectin, encoded by the ADIPOQ gene, is one of closest proximity to it. However, this does not necessarily
mean that the variant in question is the molecular defect
the adipocyte-expressed proteins that enhance insulin
responsible for the phenotype, nor does it implicate the
sensitivity. It regulates the homeostatis of glucose, lipid
nearest gene; it simply flags a genomic region that harbors
and energy metabolism.107,108 Genome-wide scans have
the causal variant, which may itself be acting at a certain
mapped a susceptibility locus for type 2 diabetes and
distance, for instance, by modulating expression of a far-
obesity/metabolic syndrome to chromosome 3q27, where
away gene. Therefore, while association signals are often
the ADIPOQ gene is located.109-112 SNPs of ADIPOQ gene
identified by gene names, deep sequencing effort, fine-
have been genotyped and several SNPs associated with
mapping and functional approaches are required to
hypoadiponectinemia, obesity and type 2 diabetes were
demonstrate a causal relationship between gene locus
identified.113-117 Two SNPs in the adiponectin gene, a
and the phenotype. Progress in high-throughput and
silent T to G substitution in exon 2 (+45T/G) and a G to T
affordable genotyping technology; analytical tools to
substitution in intron 2 (+276G/T), were associated
assist in the data mining, cleaning and interpretation
with type 2 diabetes and adiponectin level in Japanese
of large databases; and the assembly of international
population and with insulin resistance in some Caucasian
collaborations combining well-phenotyped cohorts made
populations.113,118,119 SNP 45 was associated with obesity
using these advances possible. Type 2 diabetes has been
in a German population.120 In the proximal promoter a beneficiary in this as substantial progress in our know­
region of the APM1 gene: SNP-11426A/G and -11391A/- ledge has been elucidated by GWA studies.
11377G haplotype predicted the associations with The first GWAS for type 2 diabetes was conducted
fasting plasma glucose, type 2 diabetes and adiponectin in a French discovery cohort composed of 661 cases of
levels.113,121 Adiponectin has been associated with low type 2 diabetes and 614 non-diabetic controls: 392, 935
diabetes risk. The metabolic effects of adiponectin are SNPs were analyzed for association with type 2 diabetes.
mediated by adiponectin receptors 1 (ADIPOR1) and This study identified novel and reproducible association
2 (ADIPOR2). Among six polymorphisms in ADIPOR1 and signals at SLC30A8 and HHEX and validated the well-
16 polymorphisms in ADIPOR2 a significant association known association at TCF7L2.124 Investigators from the
was seen between ADIPOR1 haplotypes and diabetes Icelandic company deCODE and their collaborators
risk.122 Adiponectin is an adipose tissue specific protein con­firmed the association of loci SLC30A8 and HHEX
that is decreased in subjects with obesity and type 2 with type 2 diabetes and identified an additional signal
diabetes. We showed for the first time that the +10211T→G in CDKAL1.125-130 Three other collaborating groups, the
polymorphism in the first intron of the adiponectin gene Wellcome Trust Case Control Consortium (WTCCC), the
is associated with type 2 diabetes, obesity and hypo­ Finland-United States Investigation of NIDDM Genetics
adiponectinemia in Asian Indian population;123 thereby, (FUSION) group, and the Diabetes Genetics Initiative
suggesting adiponectin to be important for obesity and (DGI) published their findings replicating SLC30A8 and
type 2 diabetes (Table 21.3). HHEX, and independently discovering novel associations
Both the linkage analysis and candidate gene at CDKAL1, IGF2BP2, and CDKN2A/B.131 These discoveries
approaches faced limited success and were not able to led to a plethora of studies which replicated the top
satisfactorily explain the genetics of complex diseases. signals in various ethnic populations.131-139 A number
Therefore, efforts were made to study genome completely of loci were replicated and more number of them were
for multiple gene variants which led to GWAS. unable to replicate.
324 Genetics and Immunology

Table 21.3: Summary of genetic studies in type 2 diabetes in different populations using candidate gene approach
1 PPAR g gene (Pro12Ala) Deeb et al.199894; Lyssenko et al. 200596 Pro12Ala polymorphism protective in Caucasians
2 PPAR g gene (Pro12Ala) Radha et al. 200697 Pro12Ala polymorphism not protective in South Asians
3 PGC-1α gene (Gly482Ser) Ek et al. 2001103
Associated with relative risk of type 2 diabetes in a European
population
4 PGC-1α gene (Thr394Thr) Vimaleswaran et al. 2005104; 2006105 Associated with type 2 diabetes and with body fat
5 PGC-1α gene (Gly482Ser) Liang et al. 2006102 Associated with the development of insulin resistance and
section

type 2 diabetes
6

6 PGC-1α gene (Thr394Thr, Bhat et al. 2007106 Associated with type 2 diabetes
Gly482Ser)
7 PC-1 gene (K121Q) Bacci et al. 200599 Associated with insulin resistance/atherogenic phenotypes
8 PC-1 gene (K121Q) Abate et al. 2005101 Associated with type 2 diabetes
9. TCF7L2 gene Grant et al. 2006 ; Scott et al. ;
79 80
T allele of rs7903146 associated with an increased risk of
(rs7903146) Cauchi et al.81 type 2 diabetes
10 TCF7L2 gene Chandak et al. 200784 Associated with type 2 diabetes
(rs7903146)
11 TCF7L2 gene Bodhini et al. 200785 Associated with type 2 diabetes in Asian Indians
(rs12255372; rs7903146)
12 TCF7L2 gene Sanghera et al. 200886 Associated with type 2 diabetes in Asian Indians
(rs7903146)
13 Adiponectin gene Hara et al. 2001118; Menzaghi et al. Significantly associated with type 2 diabetes and adiponectin
(+45T/G; +276G/T) 2002113; Vasseur et al. 2002119 level in Japanese population and with insulin resistance in
some Caucasian populations
14 Adiponectin gene Stumvoll et al. 2002120 SNP 45 is associated with obesity in a German population
15 Adiponectin gene Vimaleswaran et al. 2008123 +10211T→G Associated with type 2 diabetes
16 FTO gene Frayling et al. 2007 133
Associated with body mass index
17 FTO gene Dina et al. 2007136; Chang et al. 2008137 Associated with obesity-related traits
18 FTO gene Yajnik et al. 2009 138
Associated with type 2 diabetes in south Asian Indians
19 FTO gene Ramya et al. 2011139 Associated with type 2 diabetes and obesity in South Asian
Indians

A genome-wide association study for type 2 diabetes with generalized obesity, and that there was no indepen­
in a UK population revealed a novel locus associated dent association of rs8050136 C→A with type 2 diabetes
with body mass index (BMI)—the Fat Mass and Obesity mellitus as its association with type 2 diabetes mellitus
Associated (FTO) gene on chromosome 16.133 The repre­ appears to be linked through obesity.139
sentative SNP rs9939609 was associated with elevated The identification of novel genes by GWAS is the
BMI after replication in over 38,000 study participants discovery phase of work while the replication of these
of European ancestry. In addition, adiposity appeared loci formed the validation phase of the work. Both these
to mediate the association between FTO variant and the phases are essential for the discovery of novel genes/gene
risk of type 2 diabetes.131,135 Several other studies have locus. Our own replication study in CURES resulted in the
also observed associations between FTO variants and identification of genes/gene variants such as rs7756992,
obesity related traits.136,137 Earlier studies on rs9939609 rs7754840, and rs6931514 of the CDKAL1, rs7020996 of
T→A and rs7193144 C→T variants of the intron 1 of the the CDKN2A/B gene, rs7923837 of the HHEX gene, and
FTO gene showed an association with type 2 diabetes, rs12056034 of the BAZ1B genes were associated with
which was independent of BMI in Asian Indians.138 We type 2 diabetes in our population.140
recently showed that rs8050136 C→A variant is associated The coming together of large groups of investigators
with both generalized and central obesity among south in collaboration resulted in meta-analysis of the GWAS
Indians. The rs8050136 C/A polymorphism was associated identified genes,87,126 increasing the power of the study
 Genetics of Type 2 Diabetes 325

Table 21.4: Summary of genetic studies in type 2 diabetes in Asian Indian populations by replication and genome-wide association studies
(GWAS) approach
1 CDKAL1 gene Chidambaram et al. 2010140 Associated with type 2 diabetes in south Indians
CDKN2A/B gene
HHEX gene
BAZ1B gene
2 GRB14 gene Kooner et al. 2011141 Associated with type 2 diabetes in south Asian ancestry

chapter
ST6GAL1 gene including South Indians
VPS26A gene

21
AP3S2 gene
HMG20A gene
HNF4A gene
3 TCF7L2 gene Tabassum et al. 2012142 Associated with type 2 diabetes in Indians
TMEM163 gene
TMEM163 gene
MAP3K1 gene
TGFBR3 gene
FLJ35379 gene

to discover common variants with frequency more than Firstly, deep sequencing and fine mapping needs to
5%. In a collaborative effort to study the population of be done around these loci to pinpoint the gene region,
South Asian ancestry, we performed a GWAS followed and then functional studies need to be performed to
by replication of top SNPs and identified novel common understand the mechanisms of action by which these
genetic variants at six loci (GRB14, ST6GAL1, VPS26A, associated loci influence disease, and finally to predict
HMG20A, AP3S2 and HNF4A) newly associated with potential implications of these findings in clinical
type 2 diabetes (P = 4.1 × 10−8 to P = 1.9 × 10−11).141 SNPs settings. In the meantime new loci are being identified
at GRB14 were also associated with insulin sensitivity and validated, and these findings reveal new mole­cular
(P = 5.0 × 10–4), and SNPs at ST6GAL1 and HNF4A were pathways underlying diabetes etiology, gene-environment
also associated with pancreatic β-cell function (P = 0.02 interactions, epigenetic modifications and gene functions.
and P = 0.001, respectively). These provide insight into
mechanisms underlying type 2 diabetes and show the FURTHER READING
potential for new discovery from genetic association
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in nerve terminals.142 TMEM163 variants also showed tus in India. In: Kumar D, (Ed). Genomics and Health in
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section

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6

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multiple susceptibility variants. Science. 2007;316:1341-5. 140. Chidambaram M, Radha V, Mohan V. Replication of

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association analysis. Nat Genet. 2010;42:579-89. 141. Kooner JS, Saleheen D, Sim X, et al. Genome-wide asso­
133. Frayling TM, Timpson NJ, Weedon MN, et al. A common ciation study in people of South Asian ancestry identifies
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2007;316:889-94. 142. Tabassum R, Chauhan G, Dwivedi P, et al. Genome wide
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 Chapter 22
Immunologic Features of
Type 1 Diabetes
Carani B Sanjeevi, Chengjun Sun, Alok Kanungo

Immunologic Features of Type 1 DM

Chapter Outline
♦♦ Immunological Aspects of Type 1 Diabetes ♦♦ Possible Environmental Mechanisms
♦♦ Autoimmune Antibodies in Autoimmune Diabetes ♦♦ Clinical Implications and Future Direction
♦♦ Cellular Immune Response and Cytokines ♦♦ Immunological and Genetic Studies on Different Clinical
♦♦ Genetic Aspects of Type 1 Diabetes Types of Diabetes Patients from India
♦♦ Natural History of Type 1 Diabetes ♦♦ Autoimmunity and Genetics in Indian Diabetic Patients
♦♦ Environmental Factors in Type 1 Diabetes (Type 1 and Type 2)

INTRODUCTION the most prevalent form of diabetes, which results mostly

from insulin resistance along with an insulin secretory
The current etiologic classification of diabetes as proposed defect. Although the exact causes of the insulin resistance
by the American Diabetes Association (ADA) and the and the insulin secretory defect are not fully known,
World Health Organization (WHO) recognizes two major both are strongly genetically determined while the b-cell
forms of diabetes: defect does not have an autoimmune etiology.2
1. Type 1 diabetes (T1D) mellitus [formerly known as Epidemiological studies have suggested that the
insulin-dependent diabetes mellitus (IDDM)] and incidence rate of T1D peaks twice, once close to puberty
2. Type 2 diabetes (T2D) (formerly known as non-insulin- and again around 40 years of age. It has also been suggested
dependent diabetes mellitus, NIDDM).1 that the overall incidence rate of T1D is approximately
Type 1 diabetes (T1D) encompasses the vast majority equivalent above and below the age of 20.2 Many of the
of patients with pancreatic islet b-cell destruction and older patients, especially early in the course of their
proneness to ketoacidosis. This form includes those diabetes, are clinically similar to classical T2D patients.
patients where b-cell destruction is currently ascribable to This relatively high incidence rate of T1D in adults is often
an autoimmune process and those for which the etiology not appreciated, probably because of the over ten-fold
is as yet unknown. While T1D is mostly characterized greater frequency of T2D in this age group. Furthermore,
by the presence of autoantibodies (an indication of the the finding of antibodies characteristic of T1D such as islet
autoimmune process that leads to b-cell destruction), in cell antibodies (ICA) and glutamic acid decarboxylase
some subjects no evidence of autoimmunity can be found; antibodies (GADab) in 10–30% of T2D patients suggests
these cases are classified as “Type 1 idiopathic”. T2D is that in older individuals the T1D process may result in a
332 Genetics and Immunology

similar clinical phenotype as the T2D process. This subset different from those seen in other GAD65ab positive
has been variously described as latent autoimmune dia­ individuals.14 Studies in LADA subjects demonstrate that
betes in adults (LADA), slowly progressive IDDM, late- antibodies to the carboxy terminal of GAD (GADab-C)
onset T1D and type 1½ diabetes.3-7 have a diagnostic specificity for predicting insulin depen­
dency as high as 99.4% (compared with 96.6% for GADab
IMMUNOLOGICAL ASPECTS OF measured in the traditional radiobinding assay), sugges­
TYPE 1 DIABETES ting that epitope-specific assays can improve the diag­
section

nostic specificity of GAD as regards insulin requirement.15

Autoantibodies
6

Through very elegant experiments, Christie et al.

demonstrated antibodies in T1D to a 64K islet protein
Autoantibodies reactive with antigens contained in panc­
distinct from known isoforms of heat shock protein (HSP)
reatic islet cells are characteristic of T1D.8 Most of these
or GAD. Antibodies recognizing a 37 kd cryptic fragment
antibodies occur with high prevalence in newly diagnosed
of this non-GAD 64K antigen were more predictive of T1D
T1D subjects. Their presence prior to clinical appearance
than GAD autoantibodies.16 These autoantibodies are now
of T1D is useful for indicating b-cell autoimmunity and
known as ICA512 or IA-2 (directed to the neuroendocrine
in assessing risk of subsequent clinical T1D in genetically
protein insulinoma-associated protein 2, a member of
susceptible individuals. Of all the autoantibodies descri­
the protein tyrosine phosphatase (PTP) family).17 IA-2
bed in T1D, four are clinically most useful: ICA, insulin
antibodies were detected in 65–70% of patients with
autoantibodies (IAA), GADab and islet antigen-2 antibody
new-onset T1D and 60–65% of prediabetic relatives of
(IA-2 Ab).
patients with T1D.18 With sophisticated studies, it has now
When ICAs were first discovered in 1974, it was felt that
been demonstrated that a major unique epitope for IA-2
all individuals with ICAs would eventually develop clinical
autoantibodies is localized to amino acids 762–887.
T1D. However, subsequent investigations have revealed
Further studies have demonstrated that a combination
that this is not necessarily so. When ICAs are detected in
of the genetic markers and autoantibodies increase the
non-diabetic individuals with some other autoimmune
positive predictive values of all autoantibodies substan­
diseases, the risk of subsequent clinical T1D is less than
tially, which may have clinical implications when evalua­
when ICAs occur in relatives of T1D patients.9 Similarly,
ting the risk of developing T1D at the individual level or
ICA positive individuals from the general population
when recruiting high-risk individuals for intervention
without a family history of T1D have a much lower risk of
trials.19 Increased prevalence of all the antibodies was
T1D than ICA-positive relatives of T1D patients.10 Insulin
closely associated with human leukocyte antigen (HLA)
autoantibodies have an equally complex relationship to identity to the index case, the DR4 and DQB1*0302
the risk of subsequent T1D. In relatives of T1D patients, alleles, the DR3/4 phenotype and the DQB1*02/0302
the presence of IAAs in addition to ICAs greatly increases genotype (see subsequent section in this chapter for more
the risk of subsequent clinical T1D compared to ICAs detailed discussion on genetic aspects of T1D). GADab
alone, but relatives with IAAs without ICAs have only a were also associated with the DR3 and DQB1*02 alleles,
minimally increased risk of clinical T1D.11 and siblings carrying the protective DR2 and DQB1*0602-
In 1990, Baekkeskov and colleagues reported that 3 alleles were characterized by lower frequencies of ICAs,
the 64K autoantigen recognized by antibodies from T1D IA-2Ab and GADab. However, because such combinations
patients was glutamic acid decarboxylase (GAD).12 GAD also resulted in reduced sensitivity, autoantibodies alone
exists in at least two major isoforms: rather than in combination with genetic markers are
1. GAD65 and recommended as the first-line screening in siblings.
2. GAD67.
Their respective distribution in b-cells and neural AUTOIMMUNE ANTIBODIES IN
tissue varies between species. Antibodies to GAD65 are
AUTOIMMUNE DIABETES
predominantly associated with T1D in humans.13 GAD
autoantibodies are very common in the rare neurologic The immune markers in autoimmune diabetes are
disorder, Stiff-man syndrome, and only a small percentage autoantibodies directed to several autoantigens. The
of these patients develop T1D. It is now known that major autoantigens are (Table 22.1) GAD, Isoform 65
recognition of GAD epitopes by GAD65ab in T1D are (GAD65), Tyrosine pyrophosphatase (ICA512 or IA-2)
 Immunologic Features of Type 1 Diabetes 333

Table 22.1: Major and minor autoantigens in autoimmune diabetes

Major autoantigens Minor autoantigens
Insulin ICA69
Glutamic Acid Decarboxylase (GAD65) Carboxypeptidase
Protein-Tyrosine Phosphatase (Ica512) Gangliosides (GM2-1)
Zinc Transporter-8 (ZnT8) Sulphatides
60K Heat Shock Proteins

chapter
22
Table 22.2: Salient points about GAD65 antibodies of 312 recent-onset Belgian T1D patients, the prevalence
• GAD65 enzyme present mainly in beta-cells, cerebellum and of GAD65 antibody among children less than 9 years
testis old (64%) was found to be lower than that of ICA (86%)
• Increased in patients with type 1 diabetes or IAA (78%). GAD 65 antibodies are associated with
• GAD65 antibodies higher in females than male type 1 diabetes slower rate of disease progression.27,28 However, while
patients the prevalence of ICA and IAA decreased with incre­
• GAD65 antibodies are associated with slower rate of disease asing age at onset of the disease, the prevalence of
progression GAD65 antibody remained unchanged (80% and 78% in
• GAD65 antibody prevalence remains same with increasing age 10–19 years and 20–39 years age groups, respectively).
at onset of the disease These data indicate that GAD65 antibody may have the
• GAD65 antibody positivity in pre-diabetes marks impending highest diagnostic sensitivity for T1D among 20–39 years
autoimmune diabetes old patients (Table 22.2).
• Associates more in type 1 diabetes patients positive for DR3
DQ2
ICA512/IA-2 Antibodies
and Insulin autoantibodies (IAA). Recently another T1D Immunoprecipitates of 64K antigens when treated with
autoantibody, antibody against the zinc transporter proteases result in three distinct fragments called 50K,
(ZnT8) was discovered and is now used for the prediction 37K and 40K.29 Fragments 37K and 40K immunopre­
and diagnosis of T1D.20 There are also several minor auto­ cipitated distinct class of antibodies and was shown to
be derived from islet membrane associated protein.
antigens which are not discussed here.
Screening of human islet complimentary deoxyribonucleic
acid (cDNA) expression library using pooled sera from
GAD65 Autoantibodies
new onset T1D patients resulted in precipitation of an
GAD65 is an enzyme that catalyzes the conversion of important protein, ICA512. ICA512 is a 60 kDa protein
glutamate to inhibitory neurotransmitter g-amino butyric containing a putative tyrosine phosphatase domain
acid (GABA). Studies on prediabetic individuals showed homologous to the T-cell surface molecule CD45. Some of
occurrence of GAD65 antibodies in large numbers. In the properties identified for ICA512 were identified to be
first degree relatives of patients with T1D, the presence similar to 37K/40K antigen. A longer clone was reported
of GAD65 antibodies appeared as a better marker for independently, called IA-2 and the nucleotide sequence
subsequent onset of clinical disease. The cloning of suggested that ICA512 was a partial sequence of IA-2.
human islet GAD65 allowed the development of highly The protein it encoded had a predicted molecular weight
sensitive and specific radioimmunoassay to detect GAD65 of 105 kDa. Later studies showed IA-2 to be precursor for
autoantibodies in T1D.21,22 GAD65 antibody positivity 40K antigen.30
was observed in 70–80% of new onset T1D in several However, 37K protein was identified to be a protein
populations compared to 1–2% of healthy controls.23-26 It related to, but distinct from IA-2.31 Studies on the mouse
was found that the prevalence of GAD65Ab was signifi­ pancreatic endocrine cell line led to the discovery of a
cantly higher among T1D females than among T1D males. protein with high degree of homology to IA-2. It was called
This gender-dependent difference in occurrence of GAD65 “IA-2b”. A similar protein in the rat model was designated
antibody seems to be more pronounced in patients less “phogrin”.32 It was later shown that IA-2b/phogrin was
than 12 years old, and, in that group, GAD65 antibodies recognized by antibodies in T1D sera and IA-2b/phogrin
were found in 80% females and 61% males.21 In a study inhibited the binding of 37K antibodies suggesting that
334 Genetics and Immunology

Table 22.3: Salient points about ICA512 antibodies Table 22.4: Salient points about insulin autoantibodies (IAA)
• ICA512 and IA-2 are refer to the same autoantigen: protein- • Approximately 40–45% of new onset untreated patients are posi-
tyrosine phosphatase tive for IAA
• ICA512 is increased in new-onset type 1 diabetes patients • The IAA recognizes a conformational epitope of the insulin
• ICA 512 is expressed in pancreas and brain molecule (Leu A13)
• ICA512 antibodies are associated with younger age at onset • IAA in the presence of ICA in pre-diabetics enhances the risk to
develop type 1 diabetes
section

• ICA512 antibodies in pre-diabetics are associated with rapid

progression to type 1 diabetes • IAA in younger patients is associated more with DR4
6

• ICA512 antibodies are associated more in type 1 diabetes

patients positive for DR4-DQ8

Table 22.5: Salient points about zinc transporter 8 autoantibodies enhances the risk to the development of T1D.34 There are
• Approximately 60% of new onset type 1 diabetes patients are no studies available on the prevalence of IAA in Indian
positive for ZnT8A T1D patients (Table 22.4).
• There are two major polymorphic variants of ZnT8, one with a
tryptophan and the other with an arginine at position 325 of the Antibody against the Zinc Transporter
molecule. Most patients have autoantibodies recognizing both
variants Autoantibodies against islet b-cell zinc cation efflux
transporter ZnT8 (Slc30A8) represent a newly identified
T1D autoantibody.20 ZnT8 was found to be specifically
IA-2b/phogrin was precursor for 37K antigen. Antibodies
and highly expressed in islet b-cells, making it a possible
to IA-2 are more prevalent than IA-2b/phogrin. T1D sera
recognizing IA-2b/phogrin and not IA-2 have not been antigen target for autoantibodies. ZnT8 is associated
demonstrated. There is 80% identity in the amino acid with the regulation of insulin secretion. It facilitates
sequence of IA-2 and IA-2b PTP like domains and the the transportation of Zn2+ from the cytoplasm into the
antibodies in the T1D sera are directed to epitopes in insulin secretory granule, where zinc is complexed with
this region. ICA512 is expressed in pancreas and brain. insulin, forming insulin crystals. Autoantibodies against
IA-2 and IA-2β antibodies are shown to be associated ZnT8 are present in most patients with T1D and assay
with rapid progression to T1D and are associated in specificity and sensitivity are similar to those for GAD65
patients with younger age at onset (Table 22.3). autoantibodies.20 For populations which are at risk for
Both GAD65 antibodies and ICA512 antibodies T1D, such as relatives of patients with T1D and individuals
account for patients positive for ICA. Hence, it may no with high-risk HLA alleles, it has been found that indivi­
longer be necessary to screen diabetes patients for ICA to duals who were positive for ZnT8 autoantibodies would
identify autoimmune diabetes. have two or more T1D autoantibodies and thus have a
much higher risk of progressing to T1D (Table 22.5).35-37
Insulin Autoantibodies
Immune Markers in Autoimmune Diabetes
Insulin is a 51 amino acid molecule made of A chain and
B chain connected by a disulphide bond. Antibodies To summarize, subjects develop autoantibodies to increa­
to insulin were initially described in untreated T1D sing number of islet antigens during the preclinical per­
and T2D patients in 196333and subsequently in newly iod,38 and multiple islet autoantibodies are much more
diagnosed T1D patients before treatment with insulin.33 predictive of future T1D than a single antibody.11,28
IAA as measured in a radioassay format react with Although autoantibodies could damage b-cells by anti­
high affinity to a conformational epitope of the insulin body-dependent complement cytotoxicity or by targeting
molecule critically dependent upon the leucine amino acid natural killer cells to b-cell antigens, transfer of T1D
residue at position A13. Approximately, 40–45% of new in the animal models requires T-cells, and consequently
onset T1D patients show positivity for IAA. In prediabetic a major direct role for antibodies in causing the b-cell
individuals, IAA when detected with ICA significantly damage of T1D is unlikely.
 Immunologic Features of Type 1 Diabetes 335

CELLULAR IMMUNE appears to confer protection against T1D.46,47 The Th1/Th2

RESPONSE AND CYTOKINES paradigm may not be as distinct in humans as in the
mouse.
Type 1 diabetes is thought to result from a T-cell-mediated Parenteral insulin therapy has been shown to protect
destruction of the pancreatic b-cells. Antigen-specific against T1D in the animal models, and in pilot studies in
T-cell activation requires two signals: humans.48-50 Several observations support an immunologic
1. One is imparted by interaction of the T-cell receptor effect of insulin as mediating, at least in part, the protec­

chapter
(TCR)/CD3 complex with the antigen: major histocom­ tion in the non-obese diabetic (NOD) mouse. If parenteral

22
patibility complex (MHC) class II protein complex insulin prevents clinical T1D and if this were mediated
expressed by antigen-presenting cells (APC). by an immunologic response to insulin, the mechanism
2. The second signal is provided by cell-bound and would likely be a shift in the immune response towards
secreted co-stimulatory molecules which, while not a Th2 type pattern.51 Th2 type immune responses are
imparting any antigenic specificity, synergize with preferentially generated by antigen presentation via the
TCR/CD3 signals in augmenting T-cell activation. 39 gut and consequently “oral tolerance” and the resultant
Several signal transduction pathways operate as a result protection against autoimmune disease is in some ways
of T-cell activation.40 analogous to the Th1/Th2 paradigm. Oral tolerance is a
As part of the insulitis process, a number of cytokines
term used to describe the tolerance that can be induced by
(soluble polypeptide mediators) are released from the
the exogenous administration of antigen to the peripheral
immune cells infiltrating the islet. In addition to their
immune system via the gut. It is a form of antigen-driven
immunologic function to modulate, amplify and direct
peripheral immune tolerance, and appears to involve
the immune response, several of the cytokines have been
two main mechanisms that are in part dependent upon
found to have direct effects on the pancreatic b-cells.
the antigen dose. The tolerance induced by lower doses
The cytokines interleukin-1 (IL-1), tumor necrosis factor
of orally administered antigen appears to be mediated
(TNF) and interferon (IFN) have been the most intensively
predominantly by active suppression, whereas, higher
studied. In general the above mentioned cytokines, espe­
doses tend to induce clonal anergy and/ or deletion.52 The
cially when administered in combination, are cytotoxic
active suppression by low doses of oral antigen appears
to pancreatic b-cells.41,42 Cytokines also cause alterations
in the b-cell expression of many other proteins besides to be mediated by the oral antigen generating regulatory
insulin. Some proteins are stimulated whereas others are T-cells that migrate to lymphoid organs and to target
inhibited. IL-1 inhibits the expression of GAD and stimu­ organs expressing the antigen, and confer suppression via
lates the expression of other islet proteins.43,44 Cytokines the secretion of down-regulatory cytokines including IL-4,
are recognized to be an important component of the IL-10 and TGF-b.53 Unfortunately, the diabetes prevention
immune mechanism determining whether the immune trial type 1 (DPT-1) did not confirm the beneficial effect of
response of CD4+ T-cells to an antigen is primarily cellular either parenteral or oral insulin on the T1D disease process
(Th1) or humoral (Th2). T helper cells differentiate into at in humans.54Another approach in the DPT-1 involved
least two major subtypes: administration of insulin orally in first-degree relatives
1. Th1 and of T1D patients; however, the treatment failed to delay or
2. Th2 prevent T1D.55 Administration of nasal insulin in children
which are functionally distinct and distinguished by carrying high-risk HLA (for T1D) soon after detection of
different cytokine secretion patterns. Th1 and Th2 respo­ autoantibodies failed to prevent or delay the disease.56
nses are largely mutually inhibitory; Th2 cytokines sup­ The PrePOINT (Primary Oral/intranasal Insulin Trial)
press Th1 responses and vice versa. A large number of is a dose-finding safety and immune efficacy pilot study
factors, including antigen dose, antigen affinity, route of aiming at primary prevention in children genetically at
administration, genetics including HLA type, and type of risk to T1D, using oral or intranasal insulin.57 The divergent
antigen-presenting cell control differentiation into Th1 findings could be explained by any of several variables,
versus Th2 responses. Several data have suggested that including disease severity at the time of recruitment to
Th1 type immune responses against islet antigens are the study (established diabetes versus high-risk subjects),
associated with progression to clinical T1D in animals.45,46 age, disease subtype (LADA or classical T1D), and ethnic
In contrast, a predominantly Th2 type immune response background (Japanese or North American). It is important
336 Genetics and Immunology

not to over interpret these negative findings, since they for disease development while other MHC alleles (such as
only apply to high-risk subjects, as defined by the DPT-1, MHC I-Ek) act to protect NOD mice from developing the
and to insulin at the doses and by the routes tested. disease.60,61
Type 1 diabetes is positively associated with HLA-DR3
GENETIC ASPECTS OF TYPE 1 DIABETES and DR4 in Caucasians; the frequency of these alleles is
increased in subjects with T1D when compared to normal
Human Leukocyte Antigen Associations controls, while the frequency of DR2 is decreased. Studies
section

The association between HLA and T1D was first demon­ of MHC class II genes have shown that DQ8, when in
6

strated for HLA-B8 and/or B15.58 Recent technologies have linkage with DR4 is more strongly associated with TID
allowed a rapid detection of new alleles now explained than the DR genes. On the other hand, other mechanisms
by gene sequencing.59 may be important since DR3 is more strongly associated
Several genes have been studied in exploring the with T1D than DQB1*0201. T1D is positively associated
pathogenesis of T1D, but the most important of them all with HLA-DQ2, DQ8 in Caucasians. Taken together, DQ8
is the HLA complex also called as major histocompatibility (DQB1*0302-DQA1*0301), DQ2 (DQB1*0501-DQA1*0201)
complex (MHC). HLA class II genes were identified as or both account for as many as 89% of Caucasian T1D
IDDM1 locus. It is located on the short arm of chromo­ patients with clinical onset before 15 years of age. These
some 6. two haplotypes showed the strongest association as con­
The class II genes are located at the centromeric end firmed in numerous studies but it is important to notice
of the MHC and they span a region of 1 million base that DQ8, DQ2 or both do not account for all (100%)
pairs. The class II molecules are hetero-dimeric proteins patients developing the disease.
Several DQ haplotypes are negatively associated with
consisting of an a-chain and b-chain expressed on the
T1D of which the most negative is DQB1*0602-DQA1”
cells of the immune system, i.e. monocytes, macrophages,
0102(DQ6). A single copy of this haplotype or of
B-lymphocytes, dendritic cells and activated T-cells.
DQB1*0602 is adequate to confer significant negative
Products of the HLA class I and class II loci show high
association interpreted to represent protection from TID.
degree of polymorphism. For the class II region, DRA
DQ6 molecules (B1*0603 and B1*0601) share the same
is non-polymorphic, but DRB, DQA1 and DQB1 show
DQa chain (A1*0103) and hence both are negatively
high degree of allelic variability. Many of these alleles
associated. In the Indian population, DQ6 (B1*0602)
differ from each other by several amino acids and these
is infrequent but DQ6 (B1*0601) is the most frequent
polymorphic loci are located in the peptide binding and
(Table 22.6).
T-cell recognition area of the molecule. As more and more
In Caucasians, DQ6 (B1*0602) is negatively associated
populations are studied newer polymorphisms and addi­ with T1D, but DQ6 (B1*0604) shows positive association.
tional combinations of allelic sequences are identified. Both molecules share the same DQa chain but differ
HLA-DQ molecules when identified by serological techni­ in the b chain by 6 residues at position 9b, 30b, 57b,
ques were previously called as DQ1, DQ2, DQ3 and DQ4. 70b, 86b and 87b. The protective effect of DQ6 (B*0602)
Subsequently, with improved techniques, DQ1 could be is identified to be due to changes at Asp (D) at b57 and
subdivided into DQ5 and DQ6; DQ3 was divided into Gly (G) at b70. When Swedish patients (n = 425) with
DQ7, DQ8 and DQ9. Since the DQ molecule is made T1D were compared to controls (n = 367), D57/G70 was
of DQA chain and DQB chain each one of them being present in 24/425 (6%) patients compared to 160/367
polymorphic, identification of the DQA and DQB subtypes (44%) controls (OR 0.08; Pc < 0.01). When the genotypic
was possible by DNA typing techniques. Many of these combination of D57/ G70-D57/G70 was analyzed 0/425
alleles differ from each other by several amino acids patients had this combination when compared to 31/367
and these polymorphic loci are located in the peptide (8%) controls (OR 0.01; Pc < 0.01) suggesting the important
binding and T-cell recognition area of the molecule. The role these two residues play in protection from T1D.
MHC molecules have been suggested to account for both The mechanisms by which HLA-DQ molecules control
positive and negative selection of auto reactive T-cells the development of diabetes and allow autoimmune reac­
by binding antigen peptides in the groove created in the tions to specific beta-cell antigens are not fully under­
molecules. In NOD mice, the MHC I-Ag7 allele is essential stood. Molecular modeling studies showed positively
 Immunologic Features of Type 1 Diabetes 337

Table 22.6: Type 1 Diabetes: Genotype and Haplotype Association In children or young adults, the overall findings are
Type 1 DM Association that more than 90% of T1D patients were positive for DR3,
Types Positive Negative DR4, or both compared with 60% of the controls. It was
Genotypes also found that among Caucasians as many as 35–40% of
DR DR4, DR3 DR2 T1D patients were DR 3/4 (heterozygotes).66 Monozygotic
DQA1 0301 0102 twins concordant for T1D showed an increased frequency
DQB2 0302 0602 of DR 3/4 hetero-zygosity.

chapter
Haplotypes Studies in identical twins67 and in families68 suggest

22
Positive association DQB1*0302- that the genetic factors may only account for 30–40% of
DQA1*0301(DQ8)-DR4
disease susceptibility, the rest being accounted for by
Negative association DQB1*0602-
environmental factors. Among the genetic factors, link­
DQA1*0501(DQ6)-DR2
age analysis suggests that HLA only contributes 60%.68
Individual alleles may be considered, such as DQB1 *0302,
associated DQ molecules to have distinctly different which is positively associated with T1D, or DQB1*0602,
physicochemical properties than negatively associated which is negatively associated with T1D. The association
molecules. Electrostatic potentials (ESP) displayed over between HLA and T1D with the DQB1 alleles therefore
the solvent accessible surface of the peptide binding and would take into account one-half of the HLA-DQ class II
T-cell recognition areas showed that polymorphic amino molecule, and a functional consequence that controls
acid residue side chains contribute to a surface chemistry T1D development needs to be identified. Therefore, T1D
which confer susceptibility from resistance molecules. susceptibility and protection is most likely controlled by
In NOD mice, it has been found that the amino acid resi­ the expression and function of HLA-DQ class II molecules.
due in risk MHC molecule I-Ag7 has a wider peptide-
binding groove around b57 which favors the binding of Association with Other Genes
peptide derived from GAD antigen. This finding indicated
that there might be a subsequent diffe­ rence between The genes for TNF-a and TNF-b are also located in the
susceptible HLA molecule and other HLA molecules in MHC region. Both genes have polymorphisms associated
their interaction with TCR which might result in the with T1D.69 Although TNF-b alleles differ between
generation of auto-reactive T-cells.60 HLA-DR matched Caucasian T1D patients and controls,
Lifetime risks for T1D in first-degree relatives of an this was not found in North Indian Asians, suggesting that
individual with T1D have been calculated to be about TNF-b does not directly predispose to T1D.69 The genes
3% for parents, 7% for siblings and 5% for children.62 for HSP are also located in the MHC region. The increased
A recent study including patients at an older age at onset frequency of an HSP70-2 9.5-kb Pst fragment among
and a longer follow-up than in previous studies indicated T1D patients compared with controls was explained by
that 25% of T1D patients had at least one affected sibling. linkage disequilibrium with DR3. Consistent with this
The lifetime recurrence risk for siblings from time of birth conclusion is the observation that Japanese T1D patients
up to 30 years of age was 6%, which increased to 10% at do not show an association with HSP70.70
60 years of age. Studies of families with multiple affected Other genetic markers for T1D have been obtained
members have shown that the occurrence of T1D is by recent human genome scanning studies to support
16% if the parent sibling shares both HLA markers with the previous observation that other genetic factors may
the pro band (HLA identical), 5% for one HLA marker contribute to the risk for T1D. DNA collections available
(HLA haplo-identical) and 1% or less for HLA non- to investigators throughout the world through the
identical.63 Certain HLA-DR specificities, such as DR2 or Human Biological Data Interchange (HBDI)71,72 made it
HLA haplotypes such as DQB1*0602- DQA1*0102 (DQ6.2), possible to identify several T1D risk loci.73 There may be
are rarely found among young T1D patients,64 although as many as 40 such risk loci although it is a controversy as
the frequency of the haplotype among patients increases to how many of them are reproducible in all populations74
with age of diagnosis of diabetes.65 The association with (Table 22.2).
the disease is negative, which is interpreted as protection Previous candidate gene studies have revealed loci
from T1D. that are associated with risk of T1D, include variable
338 Genetics and Immunology

number tandem repeat (VNTR) in the gene encoding around forty new T1D risk loci have been identified.79,80
insulin (INS).75 gene encoding PTP, non-receptor type 22 However, the function of these genetic loci in T1D is
(PTPN22),76 gene encoding cytotoxic T-lymphocyte not fully understood. Further studies would reveal a
associated protein 4 (CTLA4)77 and gene encoding inter­ clearer pathogenetic pathway of T1D that might lead to
leukin 2 receptor alpha (IL2RA).78 The functional impor­ better management of the disease (Table 22.7).
tance of these genes has been partly uncovered, for inst­ To conclude, while HLA seems necessary, it is clearly
ance, the susceptible VNTR in INS gene leads to less not sufficient for appearance of T1D. However, HLA in
section

insulin expression in the thymus, thereby inhibiting the combination with one or several contributing genes may
6

development of immune tolerance to insulin and predis­ affect the pathogenetic process thereby affecting age at
posing to islet autoimmunity and T1D. The susceptible onset. It can, however, not be excluded that other genetic
PTPN22 gene alters the responsiveness of TCR and B cell factors important to b-cell function may contribute to
receptor, and IL2RA risk allele offers a more aggressive T1D risk.
immune response by up-regulating IL-2 receptor expres­
sion in immune cells. NATURAL HISTORY OF TYPE 1 DIABETES
Recent advances in molecular biology and bioinfor­
matics has made possible the genome wide association The natural history of T1D invokes the following concepts,
studies (GWAS), in which millions of single nucleotide firstly there is a long preclinical period. During this
polymorphisms (SNPs) across the human genome can time antibodies and T-cells reactive with b-cell antigens
be genotyped and analyzed in association with disease can be detected, possibly indicative of an immunologic
in a case-control design. In GWAS on T1D, not only have attack on the b-cells. Decline in b-cell function has been
the previously identified loci been confirmed but also observed years prior to the onset of clinical T1D. At least

Table 22.7: Different genetic loci associated with type 1 diabetes development identified by genome wide association studies.
No. Region SNP Marker Causal gene candidate No. Region SNP Causal gene candidate
rs10877012,
rs10877015,
1. 1p13.2 rs2476601 PTPN22 29. 12q13.3 rs703842 CYP27B1
rs2760524,
2. 1q31.2 rs2816316 RGS1 30. 12q24.12 rs3184504, SH2B3
rs653178
3. 1q32.1 rs3024505 CD55, IL10 31. 13q22.2 rs539514
4. 2p23.3 rs478222 unknown 32. 13q32.3 rs9585056 GPR183
rs10865035,
rs1160542,
5. 2q11.2 rs9653442 AFF3 33. 14q24.1 rs1465788 unknown
6. 2q24.2 rs1990760 IFIH1 34. 14q32.2 rs4900384 unknown
rs3821236,
rs6752770,
rs7574865,
7. 2q32.2 rs7582694 STAT4 35. 14q32.2 rs941576 DLK1
rs17574546,
8. 2q33.2 rs3087243 CTLA4 36. 15q14 rs7171171 RASGRP1
9. 3p21.31 rs11711054, rs333 CCR5 37. 15q25.1 rs3825932
rs12599402,

Contd...
 Immunologic Features of Type 1 Diabetes 339

Contd...
No. Region SNP marker Causal cene candidate No. Region SNP Causal gene candidate
10. 4p15.2 rs10517086 unknown 38. 16p13.13 rs12708716 unknown
rs17388568,
rs2069762,
rs2069763, rs12927773,
11. 4q27 rs4505848 IL2, IL21 39. 16p13.13 rs12928822 unknown

chapter
HLA-DQB1,

22
HLA-DRB1, rs151181,
HLA-B, rs4788084,
12. MHC HLA-A 40. 16p11.2 rs8049439 IL27
rs10806425,
13. 6q15 rs11755527 BACH2 41. 16q23.1 rs7202877 unknown
rs2290400, GSDMB,
14. 6q22.32 rs9388489 unknown 42. 17q12 rs2872507 ORMDL3
rs10499194,
rs2327832,
15. 6q23.3 rs6920220 TNFAIP3 43. 17q21.2 rs7221109 unknown
rs1893217,
rs45450798,
16. 6q25.3 rs1738074 TAGAP 44. 18p11.21 rs478582 PTPN2
17. 6q27 rs924043 45. 18q22.2 rs763361 CD226
18. 7p15.2 rs7804356 SKAP2 46. 19p13.2 rs2304256 TYK2
19. 7p12.2 rs10272724 IKZF1 47. 19q13.32 rs425105 unknown
20. 7p12.1 rs4948088 unknown 48. 19q13.4 rs602662 FUT2
21. 9p24.2 rs7020673 GLIS3 49. 20p13 rs2281808 unknown
rs11594656,
rs12251307,
rs12722495, rs11203203,
22. 10p15.1 rs2104286 IL2RA 50. 21q22.3 rs3788013 UBASH3A
rs11258747,
23. 10p15.1 rs947474 PRKCQ 51. 21q22.3 rs760426 AIRE
rs1250550,
rs1250552, rs2412973,
24. 10q22.3 rs1250558 ZMIZ1 52. 22q12.2 rs5753037, unknown
rs713875
25. 10q23.31 rs10509540 RNLS 53. 22q12.3 rs3218253 IL2RB
INS-IGF2,
26. 11p15.5 rs689 INS 54. 22q13.1 rs229527, IL2RB
rs229541
TLR7,
27. 12p13.31 rs4763879 unknown 55. Xp22.2 rs5979785 TLR8
28. 12q13.2 rs2292239 unknown 56. Xq28 rs2664170 unknown

80–90% of the functional capacity of the b-cells must by the insulitis in the presence of antibodies and T-cells
be lost before hyperglycemia occurs. Third, as implied directed against islet antigens, the B-cell pathology has to
340 Genetics and Immunology

be autoimmune in nature. This autoimmune destructive for diabetes associated autoantibodies at diagnosis see­
process specifically occurs in genetically susceptible med to have a milder degree of b-cell destruction, but their
individuals. It seems reasonable that on one hand in those metabolic decompensation is similar to that seen in other
who carry the high genetic susceptibility (e.g. risk HLA affected children, and they also do represent classical T1D.
haplotype), the requirement for multiple environmental
triggers is low and patients will lose beta-cell mass Latent Autoimmune Diabetes in Adults
linearly. On the other end, subtle predisposing mutations
In the LADA group mentioned earlier, it is believed that
section

or their combinations may by themselves never lead

the autoimmune b-cell destructive process proceeds
6

to T1D. more slowly, or the destruction stops at a moderate

The autoimmune attack on pancreatic b-cells has two stage. A prospective observation on the natural history
distinct stages: of the ICA-positive T2D patients in Japan4 disclosed the
1. Insulitis and characteristic findings, which included a late-onset, a
2. Diabetes family history of T2D, a slow progression of b-cell failure
Progression of the former to the latter appears to be over several years with persistently positive low-titer ICA,
regulated. A major question pertaining to the natural and incomplete b-cell loss. Similar presentations have
history of T1D centers around whether the diabetogenic been described in various other countries. The typical
process, once initiated, is relentlessly progressive and patient, however, is generally more than 35 years (age at
always culminates in clinical T1D. The alternative is that onset 30–50 years), non-obese (lower body mass index),
the process is more variable, waxing and waning, and the diabetes is often controlled with diet, but within a
sometimes remitting without eventual progression to short period (months to years), metabolic control by oral
overt T1D.81 It is now recognized that insulitis can occur in agents fails, and progression to insulin dependency is
animals that will not develop clinical T1D and changes in more rapid than in antibody-negative, obese T2D. The
immune markers may not always be reflective of changes eventual clinical features of these patients include weight-
in the immune attack on the b-cells. ICA and even other loss, ketosis-proneness, unstable blood glucose levels,
antibodies such as IAA, GADab, and IA-2 antibodies show and an extremely diminished C-peptide reserve;4 in
fluctuations in their levels over time.82-85 In non-diabetic retrospect these subjects possess additional classical
individuals with autoantibodies directed against islet features of T1D including increased frequency of HLA-DR3
antigens, impaired b-cell function is not uncommon. A and DR4, and islet cell antibody positivity. Various studies
combination of immune markers with impaired b-cell have shown that patients positive for GADab and/or ICA
function is associated with a greater risk of subsequent have a more rapid decline in C-peptide, fail oral agents,
clinical T1D than immune markers in combination with and require insulin treatment earlier.66 Another study86
normal b-cell function. But impaired b-cell function is showed that the positivity rate for GADab was as high as
also common in ICA-negative relatives of T1D patients. 23.8% in the non-obese and insulin-deficient patients
Because less than 20% of these individuals would be with sulfonylurea failure, suggesting that autoimmune
expected to progress to clinical T1D, these observations mechanisms may play an important role in the patho­
suggest that in many of these individuals the b-cell genesis of secondary failure of sulfonylurea therapy. Thus,
destructive process may remit. The German BABY DIAB loss of b-cell function in approximately two-thirds of
study85 demonstrated that autoimmunity associated phenotypic T2D subjects can be predicted by GADab and
with childhood diabetes is an early event and a dynamic ICA. However, as a result of lower cost and relative ease
process, presence of IAAs is a consistent feature of this of performance, and the availability of several simple and
autoimmunity, and IAA detection can identify children robust assays for GADab,87 GADab may provide a practical
at risk. The Childhood Diabetes in Finland Study Group84 alternative to ICA assay, particularly in population
showed that positivity for multiple diabetes-related screening. Early detection of these immune markers of
autoantibodies is associated with accelerated b-cell b-cell damage creates the future potential for immune
destruction and an increased requirement for exogenous modulation to limit such damage. The associations
insulin over the 2nd year of clinical disease, indicating between clinical T1D and HLA genotype appear in part
that multiple autoantibodies reflect a more aggressive to be determined by age of diagnosis. It appears that
progression of b-cell destruction. Patients testing negative the T1D disease process is more aggressive resulting in
 Immunologic Features of Type 1 Diabetes 341

clinical presentation at a younger age in individuals with Table 22.8: Type 1 diabetes: role of environmental factors-mechanisms
more susceptibility genes and fewer protective genes; and • Direct β-cell toxicity
vice versa, the disease process is less aggressive resulting • Trigger an autoimmune reaction targeted against the β-cells
in clinical presentation at older ages in individuals with • “Molecular mimicry”
fewer susceptibility genes and/or more protective genes. • Induction of increased insulin need that cannot be met by dam-
aged β-cells
• Increased β-cell susceptibility to damage
ENVIRONMENTAL FACTORS IN

chapter
TYPE 1 DIABETES

22
children, and reported standardized average annual inci­
Various environmental triggers, e.g. certain viruses and dence rates ranging from 3.2 cases/100,000/year in the
dietary factors, may initiate the autoimmune process, Former Yugoslav Republic of Macedonia to 40.2 cases/
leading to the destruction of the pancreatic b-cells and 100,000/year in two regions of Finland.94
consequent T1D.88 Several epidemiological observations Analytical epidemiological studies have further indi­
such as the age of onset, seasonality, marked geographic cated exposures that are associated with an increased risk
differences in incidence and prevalence provide circum­ for the disease. In early perinatal life the immune system is
stantial evidence in support of environmental factors inducible and exposures in this period may initiate auto­
being involved in T1D. Initial studies in monozygotic immunity.95 Findings from Sweden and Finland suggest
twins had shown that fewer than 50% of such twins are that entero-virus exposure during fetal life may initiate
concordant for T1D.89 Concordance can be the result of autoimmunity leading to diabetes.95 In addition, food
genetic and/or environmental similarity, but discordance, components such as nitrosamine components, cow’s
espe­cially of this degree, suggests that T1D, at least in part, milk protein, gliadin and vitamin D intake have been pro­
is due to non-genetic factors. More recent longitudinal posed to initiate the autoimmunity of T1D.95,96 Recently,
twin studies, with up to 39 years of follow-up from the the gut immune system and gut microbiota have been
onset of diabetes in index twins have shown that identical proposed and studied in the etiology of T1D97. The
twins may develop diabetes after a prolonged period of diversity of determinants that are associated with T1D risk
discordance and approximately two-thirds of long-term points to a complex interaction between the genome and
discordant twins have evidence of persistent autoimmunity environment and multivariate analyses have disclosed
and/or b-cell damage.90 This presence of discordance of different risk profiles in different age groups. Evidence has
age at disease presentation also supports the role of been accumulating indicating that perinatal exposures
environmental factors. The diagnosis of T1D follows a may be important for the initiation of b-cell destruction.
seasonal pattern with incidence peaks in autumn and Such risk factors may be the targets for primary prevention
winter and another in late spring/early summer.91,92 This strategies of T1D.
seasonality has suggested a viral connection, but a single
virus is unlikely to be responsible, because in children POSSIBLE ENVIRONMENTAL MECHANISMS
the autumn peak is primarily entero-viral infections and The precise mechanisms whereby environmental factors
the winter peak, respiratory viruses (Table 22.8). contribute to the pathogenesis of human T1D are not
Another epidemiological observation supporting a known. Some of the major possibilities include:
pathogenetic role for environmental factors is the marked • The agents may be directly toxic to the b-cells;
geographic variation in incidence of T1D. Earlier studies • The agents, by an effect on the b-cells may trigger an
had reported the age-adjusted incidence rates for T1D autoimmune response directed against the b-cells;
to have a 30-fold difference between the population • The agents, by providing specific peptides that share
extremes; the highest incidence rate, 29.5/100,000 person/ antigenic epitopes with host-cell protein (molecular
year, was noted from Finland and the lowest, 1.6/100.000 mimicry) may trigger an immune response against
person/years, from Hokkaido, Japan.93 The EURODIAB b-cells;
collaborative group prospectively analyzed geographically • The agents may cause insulin resistance; and
defined registers of new cases diagnosed under the age of • The agents may alter the b-cells in a way that increases
15 years in several centers representing most European their susceptibility to damage by other mechanisms
countries with population coverage of about 28 million (Table 22.8).
342 Genetics and Immunology

These mechanisms are not mutually exclusive. Poten­ 1. Mumps,

tial environmental factors fall into three main groups: 2. Coxsackie, and
1. Specific drugs or chemicals, 3. Rubella.
2. Viruses, and Numerous investigators have noted temporal asso­
3. Nutritional constituents consumed in the diet. ciations between T1D and mumps infections, although
the proposed time interval between the reported viral
Drugs and Chemicals infection and T1D has ranged from several years to weeks
section

or months.92 However, available data about mumps and

Specific drugs or chemicals include alloxan, streptozocin,
6

T1D is incomplete and difficult to interpret.102

pentamidine and vacor. The major mechanism underlying
Several studies have indicated that enterovirus infec­
the diabetes in these patients appears to be direct b-cell
tions, particularly Coxsackie virus B (CVB) infections, are
toxi­
city, but these patients also provide evidence that
frequent at the diagnosis of clinical T1D or may play a
primary b-cell damage can result in secondary autoim­
role in the initiation of the b-cell damaging process.103,104
munity, as ICA have been found in some of these patients.98
Prospective studies have suggested that enterovirus
Recently, attention has been paid to the long-term
infections can also initiate the process several years
adverse effects of highly active antiretroviral therapy
before clinical T1D.105 A temporal relationship between
(HAART).99 Nucleoside and nucleotide reverse trans­
enterovirus infections and the induction of autoimmunity
criptase inhibitors induce mitochondrial toxicity (inhibi­
was demonstrated in the Finnish Diabetes Prediction and
tion of mitochondrial DNA polymerase-g) and this is the
Prevention Study.103
most likely cause of the adverse effects associated with
“Molecular mimicry” is one mechanism by which
these drugs.99 Patients treated with human immunodefi­
infectious agents (or other exogenous substances) may
ciency virus-1 protease inhibitors often develop impaired
trigger an immune response against auto antigens. Struc­
glucose tolerance or diabetes, most likely due to an
tural similarity (mimicry) between viral epitopes and self-
induction of insulin resistance; the protease inhibitor,
peptides can lead to the induction of auto aggressive T-cell
indinavir has been shown to alter insulin signaling.
responses.106 It has been proposed that a self-peptide
It is unlikely, except in rare cases, that drugs or chemi­
could replace a viral epitope for T-cell recognition and
cals in the external environment are common and/or
therefore participate in pathophysiological processes in
major etiologic factors in human T1D. The observations
which T-cells are involved. The tolerance to auto antigens
cited are important primarily because they document
breaks down and the pathogen-specific immune response
that b-cells are uniquely sensitive and can be selectively
that is generated cross-reacts with host structures to cause
destroyed by certain chemicals, and that primary b-cell
tissue damage and disease.107 Mimicry related to viral
damage can elicit an immune response directed against
infection has been proposed on the basis of sequence
the b-cells. The latter view is also supported by studies in
homology between GAD65 and Coxsackie virus P2-C, an
transgenic mice expressing lymphocytic choriomeningitis
enzyme involved in the replication of Coxsackie virus B.
virus (LCMV) in their b-cells.100,101 Animals are tolerant
To conclude, the currently available information supports
to the transgene and remain non-diabetic until infected
the assumption that the role of entero-virus infections
with the virus exogenously. They then develop an immune
may be more important than previously estimated.
response to LCMV, severe insulitis and T1D.
The incidence of diabetes in the congenital rubella
syndrome is approximately 10–20%.108 Most importantly,
Viruses the diabetes induced by rubella is similar genetically and
In a variety of animal species, viral infections can cause immunologically to the T1D occurring spontaneously in
diabetes, frequently with important similarities to human the absence of rubella. These similarities suggest that the
T1D. Although it is clear that, in certain animal species, diabetes associated with congenital rubella is not etiolo­
viruses can cause diabetes and that sometimes the gically distinct, but that rubella virus triggers at least
diabetogenic process is in part immune-mediated, the some of the same mechanisms that are operative in most
situation in humans is far more controversial. spontaneous cases of T1D. Rubella virus has also been
Among the many viruses potentially involved in the demonstrated to infect human b-cells and to result in
etiology of human T1D, three have received the greatest impaired insulin production, and there is antigen homo­
attention, namely: logy between a rubella virus capsid protein and an epitope
 Immunologic Features of Type 1 Diabetes 343

in an unidentified 52 kd islet protein.109 The similarity first 6 months of life in genetically at-risk infants prevents
between these findings and those previously summarized the subsequent development of T1D during the first 10
for Coxsackie virus make it tempting to speculate that years of life.113 This “Trial to Reduce IDDM in Genetically
molecular mimicry may be applicable to both viruses.110 at Risk” (TRIGR) project is a randomized, prospective
Recently data has also been reported regarding an trial and involves newborn infants with first-degree
association of rotavirus infection and T1D.111 Rotavirus, relatives with T1D. Those genetically determined to be at
the most common cause of childhood gastroenteritis, con­ high risk are randomized to receive a baby formula free

chapter
tains peptide sequences highly similar to T-cell epitopes of cow’s milk (the formula containing a non-antigenic

22
in the islet autoantigens GAD and tyrosine phosphatase protein hydrolysate) or a conventional cow’s milk-based
(IA-2), suggesting that rotavirus could also trigger islet formula. The intervention period is for a 6-month period,
autoimmunity by molecular mimicry. It appears that with a follow-up of 10 years. This would be a “true” primary
rotavirus infection may trigger or exacerbate islet auto­ prevention strategy.
immunity in genetically susceptible children.
Gut Microbiota and Gut Environment
Dietary Factors: Exposure to In NOD mouse model, the pathogen-free mice lacking
Cow’s Milk in Neonatal Life MyD88 gene, a major downstream signaling molecule in
Amongst the environmental triggers, exposure to cow’s toll-like receptors (TLRs) pathway, prevented the
milk in early neonatal life and development of T1D has development of autoimmune diabetes, which demon­
received considerable attention.112 The hypothesis was strates the importance of microbial stimulus in the disease
developed more than a decade ago, and the issue is process.119 More importantly, the transfer of microbiota
still not settled.88,113,114 The major reasons for this discre­ from mice MyD88 knockout mothers to their wild-type
pancy could be problems with case-control studies (mater­ off-spring attenuated diabetes development. It indicated
nal recall bias of early infant feeding history), problems that knocking out MyD88 caused profound changes in
with population controls, and use of smaller odds ratios the interactions between the immune system and the
(OR)/relative risk (RR < 2). microbiota thus modified the predisposition towards T1D.
Epidemiological and experimental evidence suggested At the same time, it has been found that high-risk or
that denial of dietary cow milk protein early in life pro­ diagnosed T1D individuals have an abnormal intestinal
tects genetically susceptible children and animals from barrier (leaky gut) which enhances exposure of the inte­
T1D.115,116 Elimination of intact cow milk proteins from stinal immune system to antigens. The increased gut
the diet significantly reduced the incidence of T1D in the permeability has been shown to be associated with both
spontaneously diabetic biobreeding (BB) rat, the elimina­ autoimmunity and T1D.120,121 Current studies are focused
tion being most effective when it occurs during the on the alteration of the intestinal tight junctions and their
preweaning period.117 Bovine serum albumin (BSA) was role in the decrease of gut permeability and increasing
proposed as a candidate milk-borne mimicry antigen antigen exposure.122
responsible for the diabetogenic effect of cow milk.118 It has also been shown that bacteria in the gut are able
Elevated anti-BSA antibodies have been observed in to alter the host immune system. It has been reported
diabetic rodents. The anti-BSA antibodies cross-react with that Lactobacillus Johnsonii mediated enhanced Th17
a b-cell membrane protein of Mr 69,000 (known as p69 or differentiation of T-cells upon TCR stimulation. The up-
ICA 69), and precipitate p69 from islet-cell lysates. BSA- regulation of IL-17 immunity in mucosal surface has been
specific T-cells have recently been detected in culture shown to activate antimicrobial response together with
system, and this response is mapped to a 17 amino acid mucosal repair mechanisms.123 Meanwhile, IL-17 was
sequence of BSA, known as ABBOS peptide (preBSA shown to potentiate inflammatory response and apoptosis
position 152-169) previously identified as a possible mimi­ of human islet cells and mouse insulinoma cells in-vitro
cry epitope.112,118 indicating that Th17 immunity has a destructive effect
A multicenter trial is being conducted in the United on beta-cells and contributes to diabetes development
States, Canada, Europe and Australia to test whether as demonstrated in both126,127 mice models and human
avoidance of dietary cow’s milk protein for at least the T1D.124,125
344 Genetics and Immunology

CLINICAL IMPLICATIONS AND Table 22.9: Classification of diabetes mellitus then and now
FUTURE DIRECTION WHO-1985 ADA-1997 WHO-1998
IDDM Type 1 diabetes Type 1 diabetes
Dramatic advances have been made in recent years in
NIDDM Type 2 diabetes Type 2 diabetes
our understanding of the pathogenesis of T1D. Using this
NRDM PDDM Not included Not included
information plus genetic and immunologic measure­
FCPD Secondary form of Secondary form of
ments, non-diabetic individuals can now be identified at diabetes diabetes
section

high risk of subsequent clinical T1D. In turn, this ability (IDDM: Insulin dependent diabetes mellitus; NIDDM: Non-insulin
to identify high-risk subjects and to predict subsequent
6

dependent diabetes mellitus; NRDM,; PDDM: Protein-deficient pan-

clinical T1D plus knowledge of pathogenic mechanisms creatic diabetes mellitus; FCPD: Fibrocalculous pancreatic diabetes).
set the stage for large scale intervention trials to test
whether T1D can be prevented [recently completed, According to the published literature, T1D prevalence
Diabetes Prevention Trial-Type 1 (DPT-1) and ENDIT, in India has been reported to be low.133,134 In a large scree­
European Nicotinamide Diabetes Intervention Trial; ning for diabetes in school children, no case of diabetes
and ongoing trials which include DIPP, Finnish Diabetes was detected.135 T1D prevalence was estimated to be 0.26/
type 1 Prediction and Prevention Project; and TRIGR, Trial 1,000 in children less than 15 years of an urban population
to Reduce T1D in Genetically at Risk]. The T1D disease from South India.136 In a retrospective study, the incidence
process may be susceptible to interruption and some of T1D from Madras was identified to be 10.5/100,000/
people may be prevented from developing clinical T1D.2 year, which was higher in boys when compared to girls.137
This aspect is specifically discussed in Chapter 91. A nationwide multicenter study conducted in 1970s,
showed an overall prevalence of 1.8% for T2D in popula­
IMMUNOLOGICAL AND GENETIC STUDIES tion over 15 years and a higher rate was reported in urban
ON DIFFERENT CLINICAL TYPES OF as compared to rural areas (2.1% and 1.5%).138 However,
DIABETES PATIENTS FROM INDIA from later studies the prevalence of T2D has been repor­
ted to be 10–12% of the population (age over 20 years) in
The WHO classified diabetes mellitus into IDDM, NIDDM urban Indians.139 (Chapter 92).
and malnutrition-related diabetes mellitus (MRDM) in
1985.128 MRDM was further classified into protein-defici­ Autoimmunity in Diabetes
ent pancreatic diabetes mellitus (PDPD) later known as
Autoimmunity in phenotypically T2D characterized by
PDDM and fibrocalculous pancreatic diabetes (FCPD).129
absence of proneness to ketonuria and ketoacidosis along
In a meeting held in Cuttack, India, FCPD was pointed
with glycemic control by diet, exercise and oral drugs may
out to be a secondary form of diabetes and PDDM was be heterogeneous (etiologically variable).
renamed as malnutrition-modulated diabetes mellitus With the advent of assays to detect autoantibodies
(MMDM).130 This classification of diabetes is based on the becoming simpler, more and more patients were identi­
clinical criteria and not based on the pathophysiology of fied as autoantibody positive in the T2D category. This led
the disease process. However, the ADA in their classifica­ to the identification of a group called “Late-onset Auto­
tion, proposed in 1997, have recommended the terms immune Diabetes in the Adults or LADA”.3,140 LADA is
“Type 1” diabetes and “Type 2” diabetes for exclusive described in detail in Chapter 7. This group of LADA first
use and have dropped MRDM from the classification.131 described by Paul Zimmet, subsequently turned out to be
After this classification it has become clear that the terms observed in the younger individuals with diabetes of the
“Type 1” diabetes and “Type 2” diabetes are used to T2D category.
indicate two different disease processes, while the IDDM Several studies have shown that either GAD65 and
and NIDDM are terms that describe clinical categories or ICA512 antibody positive patients have more rapid
of diabetes. According to the current ADA classification, decline in C-peptide levels and do not respond adequa­
clinically described IDDM patients and the autoantibody tely to oral drugs and require early insulin treatment.
positive NIDDM patients are to be referred to as “Type 1” In a study from Japan, in non-obese and insulin-deficient
diabetes. As there are no markers available for the etiologic patients with sulfonylurea failures, 11% were posi­
diagnosis of “Type 2” diabetes, the diagnosis of the T2D is tive for GAD65 antibodies suggesting that autoimmune
determined by exclusion of T1D131,132 (Table 22.9). mechanism may play a role in the secondary failure to
 Immunologic Features of Type 1 Diabetes 345

Table 22.10: Clinical clues for autoimmunity in T2DM the GAD65 antibodies in South Indian T1D patients was
• Patients with sulfonylurea failure 59% in recent onset-T1D patients (duration less than 2
• Patients who do not have family history of diabetes years), but the frequency increased to 69% in patients with
• Body mass index-obese individuals are less likely to be autoim- duration between 6 years and 10 years. All patients below
mune T2D the age of 5 years were GAD65 antibody positive.143 A recent
• Presence of other autoimmune diseases like autoimmune
multicenter study showed that 64–72% were GAD positive
thyroid, Celiac and Addison disease.
among T1D at different disease duration.144 This suggests
• Age at onset – from our data autoimmunity in T2D patients can

chapter
occur at all age groups not necessarily young patients that the T1D seen in India is not different from that seen

22
in Caucasians. Obese T1D patients had significantly less
GAD65 antibodies when compared to undernourished
sulfonylurea therapy.86 When ICA and GAD65 antibodies
and normally nourished patients. However, in T1D
were compared in relation to beta-cell function, the
patients from Cuttack, GAD65 antibodies were lower in
positive predictive values for insulin deficiency in GAD65
frequency than in South Indian patients. In this group of
antibody positive and ICA positive patients were 39% and
patients, the predominant autoantibody was to ICA512
78% respectively. The sensitivity of both antibodies for
and not GAD65, while in European Caucasians, the
detecting insulin deficiency was 50%. The specificity for
predominant autoantibody is for GAD65 and not ICA512.
detecting insulin deficiency was 85% for GAD65 antibodies
On analysis of the T2D patients from Cuttack, GAD65
and 97% for ICA. Positivity for both GAD65 antibodies
antibodies were present in 7% of patients as well as a
and ICA gave a specificity and positive predictive value
similar proportion of controls. However, the predomi­
for insulin deficiency of 99% and a sensitivity of 50%.
nant autoantibody in T2D patients was ICA512. In T2D
GAD65 antibody index has also been shown to correlate
patients from Madras, GAD65 antibodies decreased with
well with HbAlc in T1D patients. Patients with low
increasing age.145
GAD65 antibodies have better glycemic controls and
require less insulin. However, the ICA512 index did not
correlate with HbA1c.141 Thus, loss of beta cell function
ICA512/IA-2 Autoantibodies in
in majority (two-thirds) of individuals with clinical Type 1 and Type 2 Diabetes
T2DM can be predicted by GAD65 antibody and ICA. In Indian T1D patients from Cuttack, ICA512 was the
Early detection of immune markers of beta-cell damage predominant autoantibody and was present in 43% of
creates the potential for immuno-modulation to limit patients (n = 74) and it was lower in patients with short
such damage.142 duration of disease, less than 4 years (32%) than in
those with longer duration of disease, more than 4 years
Clinical Clues for Autoimmunity in (60%). This finding is opposite to that found in GAD65
T2DM Patients autoantibodies, which is higher in Indian patients with
Antibodies to GAD65 and ICA512 are relatively easy to shorter rather than longer duration of the disease.144,145
perform, costs less and several hundred samples could In the T2D patients from Cuttack (n = 218), ICA512 auto
be tested in a single day by one individual. These assays antibodies were present in 39% of all patients and were
provide easy way to identify the slowly progressive T1D seen in 40% of early onset (onset less than 35 years)
patients (who fare better with insulin) from the classical T2D patients (n = 128) and 38% of late onset (onset
T2D patients who can be effectively controlled by oral more than 35 years) T2D patients (n = 90). When all the
agents. However, in situations where these assays cannot T2D patients were divided into different age groups,
be performed, there are clues to suspect patients to belong the maximal ICA512 antibody positivity was present in
to autoimmune category of clinical T2D (Table 22.10). 20–30 age group (30/41, 73%) and in 50–60 age group
(14/23, 60%). This finding suggests that slow-onset T1D is
AUTOIMMUNITY AND GENETICS IN INDIAN more frequent in Indian patients and WHO clinical
classification of diabetes does not allow this group of T1D
DIABETIC PATIENTS (TYPE 1 AND TYPE 2)
patients to be properly classified as it relies on clinical
GAD65 Autoantibodies in criteria. This finding may suggest that autoimmune
Indian Type 1 and Type 2 Diabetes diabetes is probably as high as observed in European or
There are very few studies on the prevalence of GAD65 American Caucasians and proper follow-up studies are
antibodies in Indian T1D patients. The prevalence of necessary to confirm this finding. The reason why the
346 Genetics and Immunology

Table 22.11: Number (%) of subjects positive for GAD65 autoanti- and were described as PDPD and FCPD under the class
body and ICA512 autoantibody in Indian MMDM patients MRDM by WHO Expert Committee in 1985.153 In 1987, it
Controls IDDM MMDM was pointed out that the term PDPD was inappropriate
GADab 8 (7%) 12 (16%) 11 (15%) and this entity was thereafter known as PDDM. Currently
ICA512 3 (2%) 25 (34%) 15 (21%) termed MMDM this clinical type is characterized by
Either GADab or ICA512 11 (9%) 34 (46%) 22 (31%) onset at young age, extreme leanness (BMI 12–16), severe
hyperglycemia but absence of ketonemia or ketonuria.
section

(IDDM: Insulin dependent diabetes mellitus; MMDM: Malnutrition-

modulated diabetes mellitus).155 Totally unresponsive to sulfonylurea class of drugs,
6

they require high doses of insulin for glycemic control.

FCPD, characteristically presents with presence of calculi
slow-onset diabetes is more common in Indian patients is
in the pancreatic ducts and paraductal fibrosis. As it
not clear. Studies on Swedish patients with T1D showed
is found to occur in better nourished persons as well,
that those who were DR3 positive, had a mild disease with
FCPD is now classified as a form of diabetes secondary
less ketonuria at diagnosis, were less often ketoacidotic
to pancreatic disease130,131,154 (Chapters 25 and 26).
and more often had partial remission than patients
who were DR4 positive or heterozygous for DR3/DR4.
Malnutrition-Modulated Diabetes Mellitus
The predominant HLA observed in the autoantibody
positive Indian T2D patients is DR3 and genetic factors Tests for evidence of autoimmunity in both these forms of
could be one of the reasons for the slow-onset autoimmune diabetes have been carried out during 1990s on patients
form of diabetes in Indian diabetics. mostly from Cuttack (Orissa) and some from South India
(Chennai). Although protein (calorie) malnutrition has
HLA in Indian Patients with Type 1 Diabetes been both experimentally and clinically established to
lead to hypoinsulinemia and glucose intolerance it is
The first study demonstrating HLA association with T1D
very unlikely to induce severe diabetes as in MMDM. In
in Indian patients was done in 1973,146 in which it was
view of anthropometric similarities between patients
shown that HLA-B15 and B-8 were positively associated
with T1D and those with MMDM autoimmunity has been
and B-7, negatively associated with T1D starting a new
considered as a likely factor in the pathogenesis of the
area of research which continues to be intensive even
latter. Seventy one patients with diagnosis with MMDM
after 25 years. However, in North Indian T1D patients,
were tested for GADab and 1A-2-ICA512 antibodies along
B-21 was significantly positively and HLA B-7 negatively
with 123 normal controls and 74 patients with T1D. The
associated.147 In a study on South Indian patients using
findings are presented in Table 22.11.
DNA typing techniques, DR3 association was predominant
While 46% of T1D patients were positive for one or
when compared to association of DR4 with T1D.146,147
the other major autoimmune antibody, 31% of MMDM
This was also confirmed in patients from Madras and
were found to be so. Additionally 14% were positive for a
North Indians of Punjabi origin from Britain. Recent
minor antigen, ICA 12. When positivity for tissue transglu­
studies on HLA haplotypes has also confirmed that HLA
taminase (TTG) autoantibodies is taken into account,
B8 and DR3 is the dominant T1D risk allele/haplotype
53% of MMDM patients were positive for either one or the
in Indian population.148,149 This topic is discussed more
other among the above.155
specifically in Chapter 15.
Thus, it may be construed that autoimmunity very
likely plays some role in pathogenesis of MMDM. Yet it is
Autoimmunity and Genetics of unclear how it is clinically so different from T1D particu­
Other Clinical Types larly in features such as ketosis resistance, low insulin
In addition to the major classes of diabetes mellitus, sensitivity and life long preservation of residual b-cell
termed T1D and T2D, two other clinical types are seen function. Analysis of genetic markers provide some
frequently in some tropical areas principality among older evidence that MMDM is genetically a distinct type of dia­
children, adolescents and young adults. These have been betes with clinical manifestations modulated by a different
characterized by Hugh-Jones (1955),150 Tripathy and Kar environmental factor, i.e. maternal and early childhood
(1965)145 and Gee Varghese (1962151 and 1968152). Both the gross nutritional deficiency. It is observed that although
types were considered as connected to deficient nutrition HLA, DR3 and DQ2 are associated with MMDM, the
 Immunologic Features of Type 1 Diabetes 347

Table 22.12: Association of MICA Alleles with T1D and MMDM as Table 22.13: Prevalence of islet cell autoantibodies in patient
compared to controls156 groups: Number (%)157
MICA Alleles (n=23) Controls (n=52) T1D (n=41) MMDM GADab IA-2Ab GADab or IA-2Ab
4 a 19 (26%) 14 (27%) a 4 (10%) T1D (N=73) 29 (40%) 16 (22%) 36 (73%)
5 b 18 (25%) b 20 (38%) 19 (46%) MMDM (N=30) 7 (23%) 1 (3%) 8 (27%)
5.1 24 (33%) 28 (48%) 12 (29%)
PDDM (N=27) 2 (70%) 0 (0%) 2 (7%)
6 25 (34%) 18 (25%) 9 (32%)
(MMDM: Malnutrition-modulated diabetes mellitus; PDDM: Protein

chapter
c9 c 22 (30%) 19 (37%) c 25 (6%) deficient diabetes mellitus)

22
a: Odds ratio (OR) = 0.31 (P < 0.05)
b: OR 2.64: P < 0.05
c: OR 3.62: P < 0.001

strong connection of DR4-DQ3 with T1D is not observed with TCP have a common genetic abnormality, i.e. N34S
in MMDM. Further the negative association of HLA DR7- mutation of SPLNC 1 gene159 irrespective of endocrine
DQ2 with T1D is not seen in case of MMDM. On the other status. This does not explain why only a proportion of
hand there was positive association of this allele with cases with TCP develop diabetes while others do not.
antibody negative cases of MMDM. A more convincing Of the 31 patients with FCPD examined at Lucknow
finding distinguishing MMDM from T1D is the difference (North India) only two patients were positive for GADab
in association with MICA alleles (Table 22.12).156 while IA-2A was not found at all.157 MMDM and FCPD
While allele 9 of MICA was positively associated with are discussed in detail in Chapters 25 and 26 respectively.
MMDM, allele 4 had negative effect (OR 0.31, P < 0.05).
On the other hand, T1D is associated only with MICA 5 Implication in the Treatment of Autoimmune
(OR 2.69, 0.05) compared to controls. MICA is a HLA class 1 versus Non-autoimmune Variety of T2D
antigen gene located in short arm of chromosome 6. Insulin treatment has been shown to be the best for
Thus, MMDM is a different type of diabetes with some autoimmune variety of diabetes both in animal models
genetic and autoimmune overlap with T1D. In addition, and in humans. Insulin reduces hyperglycemia, thereby
the differences in clinical expression can be attributed to giving the beta-cell rest and also has a potential immu­
modulation by fetal and early childhood malnutrition. nologic effect. In the animal model of insulin, parenteral
A recent study157 for presence of autoimmunity markers insulin had been shown to protect both NOD mouse
in 31 patients of MMDM and 83 T1D of Lucknow, North model and BB rat model of the disease. In humans with
India, positivity for GADab was detected in 23% cases T1D, the Diabetes Control and Complications Trial
of the former. On the other hand, 1A-2Ab was positive only (DCCT) provides evidence that parenteral insulin may
in one case of MMDM (3.3%) compared to 22% in T1D slow or inhibit T1D disease process by a metabolic
(Table 22.13). effect. Patients treated by intensive therapy with insulin
and by conventional insulin received similar doses and
Fibrocalculous Pancreatic Diabetes types of insulin. Intensive insulin treatment resulted
Forty seven cases of FCPD have been investigated in the in less beta-cell stimulation, meaning more beta-cell
same way as the other types of patients from Cuttack rest, which resulted in beta-cell protection compared to
(Orissa). None of these patients were positive for GADab patients in the conventional therapy group. A pilot study
while 17 showed ICA512 antibodies in their sera. Mohan on antibody positive T2D done in Japanese patients
et al. from Chennai have reported autoimmune markers showed the preventive effect of small doses of insulin
to be present in 7% of 57 patients of FCPD. No HLA given subcutaneously compared to sulfonylurea treated
genetic predilections for FCPD were observed for FCPD patients. Four of the five patients in the antibody positive
as compared to controls. FCPD occurs in a proportion of T2D group became antibody negative after follow up
patients with so called tropical calcific pancreatitis (TCP) for 30 months while all five in the sulfonylurea group
but not in all. It may be that diabetes manifests in those remained antibody positive at the end of 30 months.160
subjects who have some other proclivity for the disease.158 Currently, the national health institute (NIH) sponsored
Autoimmunity, observed in 17% of our cases of FCPD, (DPT-1) trial in USA addresses the question of paren­
may be one such factor. Genetically 42.5% of patients teral insulin to block or slow the T1D disease process in
348 Genetics and Immunology

humans. The disease process in the antibody positive 3. Tuomi T, Groop LC, Zimmet PZ, et al. Antibodies to
T2D patients are recognized as T1D and insulin may be glutamic acid decarboxylase reveal latent autoimmune
diabetes mellitus in adults with a non-insulin-dependent
preferred treatment in this group.
onset of disease. Diabetes. 1993;42:359-62.
Recognizing these findings, the ADA has recommended 4. Kobayashi T. Subtype of insulin-dependent diabetes melli-
in their recent classification that autoantibody positive tus (IDDM) in Japan: slowly progressive IDDM--the clinical
patients are to be grouped under the category of T1D and characteristics and pathogenesis of the syndrome. Diabetes
autoantibody negative diabetes patients to be grouped Res Clin Pract. 1994;24:S95-9.
section

5. Juneja R. Hirsch IB, Naik RG, et al. Islet cell antibodies

under the category of T2D. WHO in their preliminary and glutamic acid decarboxylase antibodies, but not the
6

report of their revised classification have more or less clinical phenotype, help to identify type 1(1/2) diabetes
adopted the ADA classification. in patients presenting with type 2 diabetes. Metabolism.
In the Indian diabetes scenario, combining T1D and 2001;50:1008-13.
6. Palmer JP, Hirsch IB. What’s in a name: latent autoimmune
antibody positive T2D as T1D, alters the picture of the
diabetes of adults, type 1.5, adult-onset, and type 1 diabe-
incidence and prevalence of T1D and it can no longer be tes. Diabetes Care. 2003;26:536-8.
considered as rare or less frequent. Approximately 40% of 7. Naik RG, Palmer JP. Latent autoimmune diabetes in adults
the diabetes in India will be of autoimmune variety that (LADA). Rev Endocr Metab Disord. 2003;4:233-41.
would benefit from insulin therapy. 8. Atkinson MA, Holmes LA, Scharp DW, et al. No evidence for
serological autoimmunity to islet cell heat shock proteins in
insulin dependent diabetes. J Clin Invest. 1991;87:721-4.
ACKNOWLEDGMENTS 9. Bosi E, Becker F, Bonifacio E, et al. Progression to type I
diabetes in autoimmune endocrine patients with islet cell
We are thankful to funding agencies that supported us and antibodies. Diabetes. 1991;40:977-84.
10. Knip M, Karjalainen J, Akerblom HK. Islet cell antibodies
our research, which include: Swedish Medical Research
are less predictive of IDDM among unaffected children in
Council, European Foundation for the Study of Diabetes the general population than in sibs of children with diabe-
(EFSD), Karolinska Institute, Svenska Diabetes Stiftelsen. tes. The Childhood Diabetes in Finland Study Group. Dia-
betes Care. 1998;21:1670-3.
11. Krischer JP, Schatz D, Riley WJ, et al. Insulin and islet cell
Further Reading autoantibodies as time-dependent covariates in the devel-
opment of insulin-dependent diabetes: a prospective study
1. Incidence trends for childhood type 1 diabetes in Europe
in relatives. J Clin Endocrinol Metab. 1993;77:743-9.
during 1989-2003 and predicted new cases 2005-20: a mul-
12. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification
ticentre prospective registration study. Patterson CC, Dahl- of the 64K autoantigen in insulin-dependent diabetes as
quist GG, Gyürüs E, Green A, Soltész G; EURODIAB Study the GABA-synthesizing enzyme glutamic acid decarboxy-
Gruop. Lancet. 2009;373:2027-33. lase. Nature. 1990;347:151-6.
2. Intensive Diabetes Therapy and Glomerular Filtration Rate 13. Hagopian WA, Michelsen B, Karlsen AE, et al. Autoantibod-
in Type 1 Diabetes The DCCT.EDIC Research Group N Engl ies in IDDM primarily recognize the 65,000-M(r) rather
J Med 2011;365:2366-76. than the 67,000-M(r) isoform of glutamic acid decarboxy-
3. Insulin-Pump Therapy for Type 1 Diabetes Mellitus John. C lase. Diabetes. 1993;42:631-6.
Pickup, B.M., D.Phill. N Engl J Med 2012;366:1616-24. 14. Hampe CS, Ortqvist E, Rolandsson O, et al. Species-specific
4. Diagnosis and Classification of Diabetes Mellitus. Ameri- autoantibodies in type 1 diabetes. J Clin Endocrinol Metab.
can Diabetes Association, Diabetes Care. 2012; 35:S64-71; 1999;84:643-8.
doi:10.2337/dc12-s064. 15. Falorni A, Gambelunghe G, Forini F, et al. Autoantibody
5. Type 1 diabetes. Atkinson MA, Eisenbarth GS, Michels AW. recognition of COOH-terminal epitopes of GAD65 marks
Lancet. 2013; doi:pii: S0140-6736:60591-7. the risk for insulin requirement in adult-onset diabetes
mellitus. J Clin Endocrinol Metab. 2000;85:309-16.
16. Christie MR, Hollands JA, Brown TJ, et al. Detection of pan-
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2005;102:2916-21. 140. Zimmet PZ, Tuomi T, Mackay IR, et al. Latent autoimmune
123. Onishi RM, Gaffen SL. Interleukin-17 and its target genes: diabetes mellitus in adults (LADA): the role of antibodies to
mechanisms of interleukin-17 function in disease. Immu- glutamic acid decarboxylase in diagnosis and prediction of
nology. 2010;129:311-21. insulin dependency. Diabet Med. 1994;11:299-303.
124. Marwaha AK, Crome SQ, Panagiotopoulos C, et al. Cut- 141. Hoeldtke RD, Bryner KD, Horvath GG, et al. Antibodies to
ting edge: Increased IL-17-secreting T cells in children with GAD and glycemic control in recent-onset IDDM. Diabetes
new-onset type 1 diabetes. J Immunol. 2010;185:3814-8. Care. 1997;20:1900-3.
125. Honkanen J, inen JK, Gao R, et al. IL-17 immunity in human
142. Naik RPJ. Late-onset Type 1 diabetes. Curr Opin Endocrinol
type 1 diabetes. J Immunol. 2010;185:1959-67.
Diabet.1997:308-15.
126. Emamaullee JA, Davis J, Merani S, et al. Inhibition of Th17
143. Sanjeevi CB, Shtauvere A, Ramachandran A. Prevalence of
cells regulates autoimmune diabetes in NOD mice. Diabe-
GAD65 autoantibodies in South Indian patients with IDDM
tes. 2009;58:1302-11.
and their parents. Diab Nutr Metab. 1997;2:60-4.
127. Bending D, e la Peña H, Veldhoen M, et al. Highly

144. Unnikrishnan AG, Bhatia E, Bhatia V, et al. Type 1 diabetes
purified Th17 cells from BDC2.5NOD mice convert into
versus type 2 diabetes with onset in persons younger than
Th1-like cells in NOD/SCID recipient mice. J Clin Invest.
20 years of age. Ann N Y Acad Sci. 2008;1150:239-44.
2009;119:565-72.
145. Sanjeevi CB, Kanungo A, Shtauvere A, et al. Association
128. Group WS. Diabetes mellitus. WHO Technical Report
of HLA class II alleles with different subgroups of diabetes
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mellitus in Eastern India identify different associations with
129. Tripathy BB, Kar BC. Observations on Clinical Patterns of
IDDM and malnutrition-related diabetes. Tissue Antigens.
Diabetes Mellitus in India. Diabetes. 1965;14:404-12.
1999;54:83-7.
130. Tripathy BB, Samal KC. Overview and consensus state-
146. Singal DP, Blajchman MA. Histocompatibility (HL-A)

ment on diabetes in tropical areas. Diabetes Metab Rev. antigens, lymphocytotoxic antibodies and tissue antibod-
1997;13:63-76. ies in patients with diabetes mellitus. Diabetes. 1973;22:
131. Report of the expert committee on the diagnosis and
429-32.
classi­fication of diabetes mellitus. Diabetes Care. 1997;20: 147. Sanjeevi CB, Seshiah V, Moller E, et al. Different genetic
1183-97. backgrounds for malnutrition-related diabetes and type
132. Alberti KG, Zimmet PZ. Definition, diagnosis and classi- 1 (insulin-dependent) diabetes mellitus in south Indians.
fication of diabetes mellitus and its complications. Part 1: Diabetologia. 1992;35:283-6.
diagnosis and classification of diabetes mellitus provisional 148. Kumar N, Kaur G, Mehra N. Genetic determinants of type
report of a WHO consultation. Diabet Med. 1998;15:539-53. 1 diabetes: immune response genes. Biomark Med. 2009;
133. Amutha A, Datta M, Unnikrishnan R, et al. Clinical profile 3:153-73.
and complications of childhood- and adolescent-onset 149. Kanga U, Vaidyanathan B, Jaini R, et al. HLA haplotypes
type 2 diabetes seen at a diabetes center in south India. associated with type 1 diabetes mellitus in North Indian
Diabetes Technol Ther. 2012;14:497-504. children. Hum Immunol. 2004;65:47-53.
 Immunologic Features of Type 1 Diabetes 353

150. Hugh-Jones P. Diabetes in Jamaica. Lancet. 1955;269:

157. Singh AK, Bhatia E, Dabadghao P, et al. Role of islet auto-
891-7. immunity in the aetiology of different clinical subtypes
151. Gee Varghese PJ, Joseph PV, Pichumani CS. The diagnosis of of diabetes mellitus in young north Indians. Diabet Med.
pancreatogenic diabetes mellitus. Assoc. Phys India. 1962; 2000;17:275-80.
173-80. 158. Hassan Z, Ali L, Azad Khan AK. Tropical Calcific Pancreatitis
152. Gee Varghese PJ. Pancreatic Diabetes. Bombay: Popular and Fibrocalculous Pancreatic Diabetes. In: Balakrishnan
Prakasan. 1968. V, et al. (Eds). Chronic Pancreatitis and Pancreatic Diabetes
153. WHO Study Group on Diabetes Mellitus WHO Technical in India.Kochi: The Indian Pancreatitis Study Group; 2006.

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Report Series, 727, Geneva. 1985. pp. 193-6.

22
154. WHO Consultation Report on Definition, Diagnosis and 159. Chandak GR, Idris MM, RN, et al. Genetic Studies in Chron-
Classification of Diabetes Mellitus, WHO Department of ic Pancreatitis in India. Balakrishnan V, et al. (Eds). Chronic
Non-communicable Disease Surveilliance, Geneva. 1999. Pancreatitis and Pancreatic Diabetes in India. Kochi: The
155. Kanungo A, Samal KC, Sanjeevi CB. Molecular mechanisms Indian Pancreatitis Study Group 2006, 2006. pp. 243-59.
involved in the etiopathogenesis of malnutrition-modulat- 160. Kobayashi T, Nakanishi K, Murase T, et al. Small doses of
ed diabetes mellitus. Ann N Y Acad Sci. 2002;958:138-43. subcutaneous insulin as a strategy for preventing slowly
156. Sanjeevi CB, Kanungo A, Samal KC. Immunogenetic stud- progressive beta-cell failure in islet cell antibody-posi-
ies on malnutrition-modulated diabetes mellitus. Ann N Y tive patients with clinical features of NIDDM. Diabetes
Acad Sci. 2002;958144-7. 1996;45:622-6.
Section 7

CLINICAL PROFILE
Section Editor: Viswanathan Mohan
 Chapter 23
Clinical Features of
Type 1 Diabetes Mellitus
Ashok Kumar Das, P Raghupathy, BB Tripathy

Clinical Features of Type 1 DM

Chapter Outline
♦♦ Classes of Type 1 Diabetes ♦♦ Type 1 Diabetes in Adults
♦♦ Distribution ♦♦ Chronic Complications of Type 1 Diabetes
♦♦ Etiology ♦♦ Other Manifestations with Type 1 Diabetes
♦♦ Natural History ♦♦ Atypical Forms of Type 1 Diabetes
♦♦ Clinical Features

Introduction 90% of patients with DM around the world. On the other

hand, T1DM happens to be the most common form of
The first reference of childhood diabetes is attributed to chronic disorder in children for which it used to be known
Richard Morton who coined the term “Diabetes infantalis” as “Juvenile Diabetes”. Insulin dependence connotes
in 1689 to denote this special subgroup. This class of need of insulin for survival. Typically patients of T1DM
diabetes, occurring more often in children, was known are insulin dependent so as to justify the acronym IDDM.
as juvenile diabetes until 1980s and insulin-dependent Yet the terms are not synonymous as IDDM can accrue
diabetes mellitus (IDDM) thereafter, has been termed from surgical removal of the pancreas, vacor poisoning
as “type 1 DM” (T1DM) in the new classification by the (in rodents), occasionally from congenital rubella or
American Diabetes Association (ADA) in 1997 and the mumps and as a part of an autoimmune polyendocrine
World Health Organization (WHO) in 1998 and 1999 syndrome due to a single defect in chromosome 211 as
(see Chapter 6). Although announced as “Etiological well as in maturity-onset diabetes of the young type 3
Classification” the claims cannot be fully justified as (MODY 3), a monogenetic disorder. Further patients with
etiology of type 2 and type 1 diabetes mellitus thus far T1DM may not manifest insulin dependence for variable
remains unknown. In a way, the new classification may be periods of time as is the case with latent autoimmune
considered as based on pathogenesis, so that while T1DM diabetes of adults (LADA) (see Chapter 7).
accrues from gross destruction of β-cell and absolute
lack of insulin, type 2 diabetes mellitus (T2DM) develops Classes of Type 1 Diabetes
predominantly on account of insulin resistance and/or Although discovery of immune mechanism of β-cell
inadequate secretion of insulin resulting in relative insulin destruction of the pancreatic islets of patients with IDDM
insufficiency. in 1970s was the major factor in prompting the current
Thus, T1DM can be considered as a replica of typical etiological classification of diabetes, it was very soon
endocrinopathy and a pure form of diabetes entirely found that all cases of IDDM were not autoimmune
based on deficiency of insulin. Yet T1DM is not the more mediated. A small proportion (~10%) of IDDM patients
common form of the disease as T2DM constitutes over among Europid Caucasians may not have any evidence of
358 Clinical Profile

autoimmunity for pancreatic β-cells. But the proportion of Diabetes mellitus type 1 may occur almost at any age,
such patients is larger (2–40%) among Hispanics, African- although it is very rare below 9 months of age. Incidence
Americans and Japanese as well as in India.2 starts to rise by age 5 with a peak between 10 years and
Diabetes mellitus type 1 may therefore be divided into: 14 years around puberty and earlier in girls than in boys.
• Type 1A—Immune mediated Thereafter, the incidence declines, remaining relatively
• Type 1B—Idiopathic high up to 19 years but continues to appear at all subse­
quent ages, relatively less commonly beyond 35 years
Both are primary types of diabetes (see Chapter 6)
section

up to the ripe age of 69 years. Yet in a recent estimation

and by and large present similar clinical picture and
7

in USA, while incidence of T1DM was estimated to be

course. But the stages through which autoimmune type
13 per 100000/year in those less than 20 years of age,
1A progresses cannot be discerned in type 1B.
it was 16 per 100000/year in older adults.6 This ratio
There may be subtypes of type 1B diabetes as well. A
may be reversed in near future as the annual rate of
recent report from Japan describes patients with explosive
increase in incidence of T1DM in Europid population
onset of IDDM without any evidence of autoimmunity.3
estimated at 3.4% occurs only among those with onset
Furthermore, glycosylated hemoglobin (HbA1c) values
below 15 years of age.7
were normal at onset suggesting the absence of a preceding
Gender distribution is practically even except that it
prediabetic phase [impaired fasting glucose (IFG) or
may be slightly higher among males in high prevalence
impaired glucose tolerance (IGT)].
areas.
Flatbush diabetes, first described by Lebovitz and
coworkers4 mostly in African-Americans, presents with
Etiology
features of IDDM at onset. Following an acute phase
comprising of diabetes with ketoacidosis, the disease Diabetes mellitus type 1 develops under influence of
gradually progresses to evince features of T2DM. The both inheritance and environmental factors. Influences
acute phase cannot be attributed to autoimmune of hereditary and familial factors are not as strong as in
destruction of pancreatic β-cells. case of T2DM. Generally inheritance is known to be from
In addition to the above, a sizeable proportion of 6% to 8% from fathers, 2–4% from mothers and up to 12%
patients with evidence of autoimmune disorder of the in case of both parents. Even among identical twins, the
β-cell present clinically with features of T2DM. Positive concordance rates for autoimmune T1DM are only 30–
for glutamic acid decarboxylase autoantibodies (GADA) 40% at the most.
and/or islet antigen-2 (IA-2) autoantibodies, these Linkage and association analyses have demonstrated
patients do not develop insulin dependence for variable that T1DM has a very strong genetic component, with
periods of time (usually measured in years). More comm­ specific alleles and haplotypes at major histocompatibility
only, they require insulin for control much earlier in the complex (MHC) class II genes, as well as human
course of follow-up compared to other patients with leukocyte antigen (HLA)–A and B alleles, conferring either
genuine T2DM.5 At present popularly known as LADA, susceptibility to or protection from T1DM.
this group may be considered as a subclass of T1DM. The Laboratory data for diagnosis, monitoring and
phenomenon of LADA has been extensively discussed in follow-up are discussed in detail in Chapter 77.
Chapter 7.
Natural history
Distribution The model of the natural history of T1DM suggests stages
that commence with a genetic susceptibility, autoim­
Diabetes mellitus type 1 is unevenly distributed among munity without clinical disease, and finally clinical
races and geo­graphic areas. It is common among Nordics diabetes.8 The appearance of islet autoantibodies early in
of Finland and other northern European states, Sardinia, life is influenced by genetic and environmental factors.
UK and Europid Caucasians of North America and Oce­ Once islet autoantibodies have developed, the progression
ania while it is uncommon in Afro-Asian countries, parti­ to diabetes in antibody-positive individuals is determined
cularly Japan and China as well as India. Prevalence and by the age of antibody appearance and by the magnitude
incidence data are described in greater detail in other of the autoimmunity, in turn related to the age of the
chapters in this text. subject (Table 23.1).
 Clinical Features of Type 1 Diabetes Mellitus 359

Table 23.1: Lifetime risk of type 1 diabetes mellitus in relatives glucose. This is considered as a marker for progression to
Relatives Risk (%) the next stage.
Monozygotic twins 36%
Siblings 7% Stage 5: Overt Diabetes
Offspring of diabetic father 6%
Offspring of diabetic mother 1% This stage is characterized by clinical diabetes where
HLA identical siblings 10–16% elevated blood glucose (BG) levels coexist with decreased

chapter
(HLA: Human leukocyte antigen) insulin and C-peptide levels below specified limits less
than 0.3 mmol/L (see Chapters 15 and 21).

23
Stage 1: Genetic Susceptibility Stage 6
The natural history of T1DM begins with genetic sus­ Progressive destruction of the residual b-cell mass leads
ceptibility. Everyone who develops T1DM has inherited to reduction of serum C-peptide to undetectable levels
susceptibility genes, a major portion of which relates to in course of a few years after onset of diabetes. This stage
the HLA region of chromosome 6. The class II alleles are of total diabetes may be characterized by brittleness of
most commonly associated with diabetes. glycemic control.
HLA-A*24 has been proved as an independent
predictor of 5-year progression to diabetes in antibody Clinical Features
positive first degree relatives of patients with T1DM. This
can help select a subgroup at extremely high risk.9 T1DM accounts for 5–10% of all diagnosed cases of
diabetes, but is the leading cause of diabetes in children.
Stage 2: Induction of Autoimmunity It is relatively insidious onset or may present, as a medical
emergency in the form of diabetic ketoacidosis (DKA) or
Multiple environmental factors have been implicated in
even hyperosmolar coma. Generally younger children
the pathogenesis of T1DM. Rapid increase in the incid­
have a more abrupt onset. Typically T1DM presents
ence of T1DM can be due to a growing environmental
more or less rapidly with loss of weight (1–2 kg/week)
influence acting on a rather common genetic suscepti­
along with polyuria, increased thirst (polydipsia) and to
bility. The details of the pathogenesis have been discussed
start with, hunger (polyphagia) with need for more food.
elsewhere in the textbook (see Chapter 15).
Weakness, overwhelming fatigue with cramps and pains
in legs may supervene. When unnoticed and uncared for,
Stage 3: Expression of Autoantibodies symptoms of anorexia, nausea, abdominal pain and signs
Autoantibodies associated with T1DM: of dehydration appear which may progress to ketoacidosis
• Insulin autoantibodies (IAA) with drowsiness, heavy breathing, dry skin and fruity
• Glutamic acid decarboxylase (GAD65) or GADA odour in the breath.
• Islet cell antibody (ICA) 512 or IA-2 Simple testing of urine and a sample of blood for glucose
• ICA 69 analysis reveals the diagnosis. High plasma glucose above
• Carboxypeptidase H 250–300 mg/dL along with heavy glycosuria (++++) and
• Zinc transporter 8 (ZnT8). ketonuria establish the diagnosis beyond doubt.
This stage is characterized by normal insulin and Further tests for detection of autoimmunity and genetic
glucose levels. data can be conveniently deferred for the time being until
achieving fair degree of glycemic control and abolition of
ketoacidosis.
Stage 4: Progressive Loss of Insulin Secretion
Further discourse on clinical features is described
During this stage the insulin levels progressively decrease, separately for different age groups such as infants,
however, the glucose levels still remain normal and (see Chapter 76), children (see Chapter 77), adolescents
the patient remains asymptomatic. This stage precedes and young adults (see Chapter 78). Presenting features
clinical diabetes. Loss of first (quick) phase of insulin of diabetes in children, infants and toddlers along with
secretion may be evident in response to intravenous (IV) behavior of disease in adults, its course and development
360 Clinical Profile

Table 23.2: Differential diagnosis of secondary enuresis and poly­ Table 23.3: Subtle clues to diagnosis of diabetes
uria in children10
Unexplained weight loss
Urinary tract infections
Loss of appetite (resulting from ketosis)
Renal disease
Headache, constipation, abdominal pain (secondary to dehydra­
Constipation
tion)
Urge syndrome or dysfunctional voiding
Psychological stress Visual disturbance (due to hyperglycemia)
Diabetes Replaced and persistent monilial diaper rash in infants and
section

Diuretic abuse toddlers

7

Obstructive sleep apnea Vulvovaginal candidiasis in teenage girls

of common complications are described briefly in the required to recognize the condition as the history of
following paragraph. polyuria and polydipsia is difficult to elicit in this age
The cardinal clinical features of T1DM in children are: group. Cerebral edema may be present before treatment
• Polyuria or may occur after treatment is begun. Symptoms and
• Polydipsia signs of cere­bral edema are variable and include gradual
• Nocturnal enuresis decrease or deterioration in level of consciousness,
• Weight loss and failure to thrive inappropriate slow­ing of the pulse rate and an increase in
• Lethargy blood pressure.
• Dehydration
These features occur secondary to hyperglycemia. Toddlers
The classic symptom of polyphagia is often absent in
children. Polyuria and nocturnal enuresis are classical Toddlers as compared to older children are more likely to
manifestations of diabetes in children. Diabetes is a very present at diagnosis with a shorter duration of symptoms
common cause of secondary enuresis in children. History and very often manifest with moderate to severe ketoa­
of bed wetting at night, in a previously continent child cidosis, lethargy, vomiting and altered sensorium. The
should arouse suspicion of diabetes.10 A high urine output higher frequency of ketoacidosis in younger children
in the presence of dehydration should alert the clinician to at diagnosis may partly reflect age-related delay in
consider DM (Table 23.2). verbalization and toilet training, which can mask diabetes
Other non-specific symptoms which may indicate the symptoms. Older children have free access to fluids, a
presence of childhood diabetes include.11 form of self-medication, as opposed to younger children
Diabetes can also present as poor weight gain and who are totally dependent on their caregivers for food and
“failure to thrive” in children, in fact, every astute drink. Children in this group have a higher incidence of
physician should consider diabetes in a child or adole­ concomitant systemic illness like viral fever, moreover,
scent for failure to thrive without any obvious reason around 80% of them present with DKA at diagnosis.12
(Table 23.3). Additional manifestations of T1DM may
include loss of energy, irritability, deteriorating school Clinical Features of Diabetic Ketoacidosis
perfor­mance, impaired growth and increased suscep­
tibility to infections. Thus, a proper history will facilitate Nearly two-thirds of children with T1DM present with
appro­priate diagnosis. variable grades of DKA at initial diagnosis, often due to
The highest increase of incidence in T1DM over the delayed recognition of early symptoms by the parent. If
past decade occurred in children under 5 years of age. the initial clinical manifestations of polyuria, polydipsia,
Diabetes in this group often presents acutely and poses a lethargy and weight loss are not promptly diagnosed
major diagnostic challenge. as DM, DKA develops following accelerated catabolic
processes (Table 23.4) (see Chapter 53).13
Neonates and Infants The biochemical findings suggesting the diagnosis of
Neonates and infants may often present at diagnosis DKA include:
with “hyperosmolar diabetic coma” (severe hyperglycemia • Hyperglycemia (blood glucose > 200 mg/dL)
with no ketosis). A high clinical index of suspicion is • Serum bicarbonate less than 15 mEq/L
 Clinical Features of Type 1 Diabetes Mellitus 361

Table 23.4: Signs and symptoms in diabetic ketoacidosis CHRONIC COMPLICATIONS OF

Symptoms Signs TYPE 1 DIABETES
Vomiting Dehydration Development of chronic complications14 is largely related
Abdominal pain Deep and rapid respiration to duration of diabetes, particularly so for microvascular
Poor appetite Fruity odor of breath disease.
Drowsiness

Microvascular Complications

chapter
23
• Venous pH less than 7.3 along with ketonuria, Background lesions of retinopathy rarely appear before
glucosuria, acidosis and electrolyte disturbances. 5 years from onset. Incidence of retinopathy increases
The severity of DKA is graded as follows:13 from 10 years to 15 years. By 20 years of disease some
• Mild (venous pH < 7.30, bicarbonate level < 15 mEq/L) 90% of patients may manifest retinopathy. Proliferative
• Moderate (venous pH < 7.20, bicarbonate level < 10 retinopathy manifests several years following onset
mEq/L) with higher prevalence after 15 years in patients more
• Severe (venous pH < 7.1, bicarbonate level < 5 mEq/L) susceptible to the condition (see Chapter 65).
Nephropathy in T1DM develops in course of 10–
Type 1 Diabetes in Adults 15 years following onset in around 20% of patients.
In the pre-insulin era, T1DM with onset in childhood Inci­dence of nephropathy is slower by 20 years of the
was fatal before adult stage of life. With advent of insulin disease up to a maximum of 45% among the survivors.
therapy, availability of a variety of preparations of the Genetic predisposition appears to be more important
hormone and a number of modalities for administration, in case of renal involvement than other microvascular
survival up to 50 years after onset is no longer a rarity. disorders. Mogensen’s staging of diabetic nephropathy
In addition to the surviving childhood onset T1DM, (see Chapter 66) was based on observations in patients of
patients with onset of T1DM in adults (over 30%) are T1DM, where date of onset could be clearly determined.
under care particularly in the Europid Caucasian T1DM patients with microalbuminuria have been
communities. Some 20% of patients with T1DM are estimated to have a 20-fold greater risk for development
diagnosed at or beyond 35 years of age. A proportion of of clinical nephropathy. Furthermore, microalbuminuria
these patients present initially with features of T2DM is counted as a strong risk factor for development of
(LADA) (see Chapter 7). Early requirement of insulin cardiovascular disease (CVD).
for control, low insulin and C-peptide levels (< 0.6 Diabetic neuropathy is in all respects similar in T1DM
mmol/L) and positivity for autoi­mmune markers are and T2DM (see Chapter 67). It has been estimated that
characteristics of such patients. prevalence of neuropathy is lower (1.4%) in T1DM than in
Apart from LADA, T1DM may express itself in older T2DM (14.1%) at the time of onset.
adults and the aged. Diabetes manifests less abruptly In addition to acute reversible hyperglycemic peri­
in adults than in children. Primary failure of oral insulin pheral neuropathy in neglected patients, chronic progr­
secretagogues (sulfonylurea, meglitinide or D-pheny­ essive sensory motor and autonomic neuropathy is equally
lanine derivatives), ketonuria and leanness and near common in adults with T1DM as in T2DM. Neuropathy
absence of positive family history is highly suggestive of is known to be uncommon in young children. Incidence
diagnosis of T1DM. Positive tests for immuno-markers, starts increasing from 9–10 years following diagnosis. Apart
low C-peptide, low insulin levels and appropriate genetic from duration, incidence and symptoms of neuropathy
make up are diagnostic. can be predicted on the basis of grade of glycemic control
Not withstanding the slower onset, the rest of the in T1DM as in T2DM.
course is as in the case of older children. Progress to total
diabetes is slower than in young children. Elderly patients Cardiovascular Complications
are more susceptible to both DKA and hyperosmolar coma In young patients with T1DM those diagnosed before
than the middle aged. 20 years of age there is preponderance of renal death
362 Clinical Profile

Table 23.5: Clinical features of type 1A and type 1B diabetes Table 23.6: Clinical features of type 1A, 1B and 1C diabetes mellitus
Type 1A diabetes Type 1B diabetes Type 1A Type 1B Type 1C
Genetics and Autoimmune in origin Non-autoimmune Signs of anti-islet Present Absent Absent
pathogenesis HLA association No HLA association autoimmunity
present Symptom duration before 8 months 7 months < 1 week
Family history of Absent Family history of type diagnosis
diabetes 2 diabetes may be Ketoacidosis at diagnosis Frequent Frequent Constant
present
section

Blood glucose at diagnosis High High Very high

Clinical Lean May be overweight HbA1c at diagnosis High High Normal
7

characteristics or slightly
Treatment Insulin mandatory Require insulin for high
continued control
(HbA1c: Glycosylated hemoglobin)
(HLA: Human leukocyte antigen)

during 3rd decade after onset of diabetes while beyond growing infants for childhood-onset T1DM, these
30 years of diagnosis, cardiovascular death predominates. observations may represent some degree of differential
In those diagnosed at later age (35 years and above), renal pathogenesis between diabetes developing in infancy and
death accounts for around 2% while CVD accounts for diabetes developing later in childhood. Infants who are
over 50% of mortality. small at birth or during the first year of life may experience
Pathogenesis, clinical features and natural history of intrauterine or early infantile stress, predisposing them to
cardiovascular complications are similar in T1DM and a variety of diseases in childhood and adulthood, including
T2DM (see Chapters 57 to 61) T2DM (Tables 23.5 and 23.6).
Complications such as hypoglycemia (see Chapter 54),
infections (see Chapters 55 and 56) and ketoacidosis Celiac Disease and Type 1 Diabetes
(see Chapter 53) are described elsewhere.
Celiac disease (CD) occurs more commonly in children
(1.5–4.6%) and adults (2–4%) with T1DM than in the
Other manifestations with general population (0.5–1%). The likely explanation for the
type 1 diabetes frequent simultaneous occurrence is the shared genetic
susceptibility provided by the alleles DQA1*501 and
Stature and Type 1 Diabetes
DQB1*201 in the two diseases. The clinical presentation of
Recent studies have shown that the heights of children CD in T1DM is classified as symptomless in approximately
with newly diagnosed diabetes beyond infancy exceed half of cases, but a more accurate analysis often discloses
those of age-matched control subjects (except pre- and a wide array of symptoms suggestive of CD. More than
early adolescent ages 8–10 years).15 Increased stature 10% of children with new-onset T1DM will develop
may represent an epiphenomenon of the islet-cell hyper­ serologic markers for CD within 6 years of the diagnosis
plasia and hyperinsulinemia, which characterize the of T1DM. It is therefore recommended that children with
preclinical stages of diabetes children between 8 years diabetes have screening serologic tests for CD at the time
and 10 years, perhaps failed to demonstrate discrepant of onset of T1DM and annually for at least several years
heights because growth variability introduced by the after the diagnosis of diabetes.16
timing of puberty overwhelmed any underlying relation­
ship between diabetes and height in this age group. Association with other Autoimmune
The impact of parental height adjustment, however, Disorders including Polyendocrine Syndrome
favors the hypothesis that increased stature enhances the Association with other autoimmune disorders including
risk of childhood diabetes, at least among the children autoimmune polyendocrine syndrome (APS) with type
older than 3 years. 1A diabetes is well known. Among these, CD is possibly
Small infants have also been found to have increased most important (vide supra).
risk for early-onset diabetes. Although recent evidence Thyroid related autoimmune antibodies can be
supports increased risk among larger or more rapidly detected in 25% of cases of type 1A diabetes patients,
 Clinical Features of Type 1 Diabetes Mellitus 363

although only a few of them develop hypothyroidism or However, patients with Flatbush diabetes do not have
hyperthyroidism. Addison’s disease, myasthenia gravis, antibodies against β cells; unlike “regular” T1DM. This is
juvenile rheumatoid arthritis, pernicious anemia and why it was sometimes called idiopathic T1DM.
multiple sclerosis may be other autoimmune disorders Patients with Flatbush diabetes are also often over­
that may be associated with type 1A diabetes. weight, as in T2DM, and have relatives with T2DM, and
Type 1A diabetes may be manifested as a component they may have some insulin resistance, which is one
of polyendocrine syndrome: APS1 and APS2.17 reason some people use the term type 1.5 diabetes. A major

chapter
distinguishing feature of Flatbush diabetes is that when

23
Atypical forms OF TYPE 1 diabetes the very high BG levels on diagnosis are brought down
with insulin, the patients can often do quite well with
Type 1B Diabetes or Idiopathic Diabetes oral drugs, or even just diet and exercise, for months or
A minority of people with T1DM (10%) show absence even years. Patients with “regular” T1DM often have a
of β-cell autoimmunity markers and lack of association “honeymoon period” in which their insulin requirements
with HLA haplotypes predisposing to diabetes. This are fairly low, but they always progress toward insulin
sub­group of T1DM has been called type 1B diabetes.4 dependence, and if they stop taking insulin, they go
Some individuals with this form of diabetes episodes into DKA.
develop ketosis or ketoacidosis and exhibit various
degrees of insulin deficiency between episodes. Most Type 1C Diabetes
patients in this category are of African-American origin.
This form of diabetes has an explosive onset, with
The initial manifestation of the diabetes in these cases
symptom duration as low as 4–5 days. So rapid is the onset
may be ketoacidosis similar to type 1A diabetes, although
that majority of the people have near normal HbA1c levels
the course of the disease is unusual in that while insulin
at diagnosis, despite profound loss of insulin, very high
therapy is initially needed to maintain metabolic control,
BG and ketoacidosis. This form of diabetes is common
after a variable period of time (usually within months),
in Japan and is thought to result from an inflammatory
good control can be achieved with either diet or oral
reaction against the pancreas. Antibodies are usually
agents. On the other hand, these patients differ from those
absent in this form of diabetes (Table 23.6).3
with type 1A diabetes because their physical charac­
teristics are more typical of patients with T2DM; they
Latent Autoimmune Diabetes of Adults
are often obese or overweight at the time of diagnosis
and, in most of the cases, there is a family history of Latent autoimmune diabetes of adults, a slowly progr­
T2DM. Described initially by Lebovitz and coworkers,3 essive form of autoimmune diabetes associated with auto­
this condition is popularly known as Flatbush diabetes.4,18 antibodies that develops in adults and does not require
Apart from the atypical form of diabetes known as insulin therapy for some time after diagnosis, was first
Flatbush diabetes, most patients with type 1B (around described over 25 years ago. It is called “latent” because
20–40%) in Asian countries are not known to differ from without testing for diabetes-associated autoantibodies it
type 1A patients in clinical features, course and complica­ would not be possible to identify these patients as having
tions, except for absence of autoimmune markers in them. autoimmune diabetes and “adult” because at that time it
Flatbush diabetes is found primarily in non-white was suggested that this form of diabetes was not present
populations, especially those of sub-Saharan African in juveniles. This form of diabetes has also been called
descent and non-white Hispanics. The hallmark of “slowly progressing insulin dependent diabetes” or “type
Flatbush diabetes is presentation with sudden onset of 1.5 diabetes”.
extremely high blood sugar levels (blood glucose levels LADA is defined by three features including:19
of 700 mg/dL and HbA1c’s of 12–14 are not uncommon), 1. Adult age at diagnosis more than 30 years.
or in DKA. Because DKA used to be considered a 2. The expression of single autoantibody particularly
hallmark of T1DM, patients with Flatbush diabetes were GAD65.
originally considered to be type 1, and hence the name 3. Delay from diagnosis in the need for insulin therapy to
“atypical type 1” or “type 1B”. manage hyperglycemia.
364 Clinical Profile

Some of the salient clinical characteristics of LADA 4. Eisenbarth GS. Clinical ramification of an autoimmune
include:20 diathesis. Kahn CR, Weir G, King G, et al. (Eds). Joslin’s
• Absence of family history of diabetes Diabetes Mellitus, 14th edition: Indian edition. Noida:
Lippincott Williams & Wilkins; 2005. pp. 400-62.
• Body mass index (BMI) less than 19
• High opening sugars
• Response to oral hypoglycemic agents (OHAs) for
REFERENCES
limited period of time 1. Cetani F, Barlesino G, Bosori S, et al. A novel mutation of the
section

• More likely to retain greater β-cell function. autoimmune regulator gene in Italian kindred with autoim-
7

Latent autoimmune diabetes in adults (LADA) is a mune polyendocrinopathy acting in a dominant fashion.
disorder in which, despite the presence of islet antibodies J Endocrinol Metab. 2001;86:4747-52.
2. Balasubramian K, Debadghas P, Bhatia V, et al. High
at diagnosis of diabetes, the progression of autoimmune frequency of type 1 B (idiopathic) diabetes in North
β-cell failure is slow. LADA patients are therefore not Indian children with recent onset diabetes. Diabetes Care.
insulin requiring, at least during the first 6 months after 2003;26:2697.
diagnosis of diabetes. Among patients with phenotypic 3. Imagawa A, Hanafusa T, Miyagawa J, et al. A novel subtype
type 2 diabetes, LADA occurs in 10% of individuals older of type 1 diabetes mellitus characterised by a rapid onset
and an absence of diabetes related antibodies. Osaka IDDM
than 30 years and in 25% below that age. Prospective Study Group. N Engl J Med. 2000;342:301-7.
studies of β-cell function show that LADA patients with 4. Banerji MA, Chaiken RL, Huey H, et al. GAD antibody
multiple islet antibodies develop β-cell failure within negative NIDDM in adult black subjects with diabetic
5 years, whereas those with only GAD antibodies or only ketoacidosis and increased frequency of human leukocyte
islet cell antibodies (ICAs) mostly develop β-cell failure antigen DR3 and DR4. Flatbush diabetes. Diabetes. 1994;
43: 741-5.
after 5 years. Even though it may take up to 12 years until 5. Turner R, Stratton I, Horton V, et al. UKPDS 25: auto-
β-cell failure occurs in some patients, impairment in the antibodies to islet-cell cytoplasm and glutamic acid
β-cell response to intravenous glucose and glucagon can decarboxylase for prediction of insulin requirement in type
be detected at diagnosis of diabetes. Consequently, LADA 2 diabetes. UK Prospective Diabetes Study Group. Lancet.
is not a latent disease; therefore, autoimmune diabetes 1997;350:1288-93.
6. American Diabetes Association. Diabetes 2001 Vital statis-
in adults with slowly progressive β-cell failure might be a tics. Alexandria, VA: American Diabetes Association; 2001.
more adequate concept. Insulin is the treatment of choice 7. Eurodiab Ace Study Group. Variation and trends
in patients with LADA.21 in incidence of childhood diabetes in Europe. Lancet.
Definition of LADA is unsatisfactory in many respects. 2000;355:873-6.
The present diagnostic criteria do identify some patients 8. Verge CS, Eisenbarth G. Natural history of autoimmun-
ity in type 1 diabetes mellitus. In: Diabetes mellitus: A
with slowly progressive β-cell destruction but leave out Fundamental and Clinical Text. Lippincott-Raven Publi­
many more, including young adults and adolescents, and shers; 1996. pp. 287-97.
current description fails to capture insulin resistance, a 9. Mbunwe E, Van der Auwera BJ, Vermeulen I, et al. Belgian
unique pathogenic mechanism and a therapeutic target in Diabetes Registry. HLA-A*24 is an independent predictor
this form of autoimmune diabetes.22 of 5-year progression to diabetes in autoantibody-positive
first-degree relatives of type 1 diabetic patients. Diabetes.
Management of T1DM is dealt in other chapters. 2013;62:1345-50.
10. Robson LW, Leung AK, Howe RV. Primary and Secondary
further reading Nocturnal Enuresis: Similarities in Presentation. Pediatrics.
2005;115:956-9.
1. Imagawa A, Hanafusa T, Miyagawa J, et al. A novel subtype 11. Sperling MA. Diabetes mellitus. In: Sperling MA (Ed).
of type 1 diabetes mellitus characterised by a rapid onset Pediatric Endocrinology. Philadelphia: Saunders; 2002. pp.
and an absence of diabetes related antibodies. Osaka IDDM 323-66.
Study Group. N Engl J Med. 2000;342:301-7. 12. Hathout EH, Hartwick N, Fagoaga OR, et al. Clinical, auto-
2. American Diabetes Association. Diabetes 2001 Vital statis- immune, and HLA characteristics of children diagnosed
tics. Alexandria, VA: American Diabetes Association; 2001. with type 1 diabetes before 5 years of age. Pediatrics.
3. Balasubramian K, Debadghas P, Bhatia V, et al. High freq­ 2003;111:860-3.
uency of type 1 B (idiopathic) diabetes in North Indian 13. Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES
children with recent onset diabetes. Diabetes Care. 2003; consensus statement on diabetic ketoacidosis in children
26:2697. and adolescents. Arch Dis Child. 2004;89: 189-94.
 Clinical Features of Type 1 Diabetes Mellitus 365

14. Pickup JC, William G. Chronic Complications of diabetes. 18. Pinero-Pilona A, Litonjua P, Aviles–Santa L, et al. Idiopathic
London: Blackwell Scientific Publications; 1994. type 1 diabetes mellitus in Dallas, Texas. Diabetes Care.
15. DiLiberti JH, Carver K, Parton E, et al. Stature at time of 2001;24:1014-8.
diagnosis of type 1 diabetes mellitus. Pediatrics. 2002;109: 19. Leslie DG, Williams R, Pozzilli P. Clinical review: type 1
479-83. diabetes and latent autoimmune diabetes in adults: one
end of the rainbow. J Clin Endocrinol Metab. 2006;91:1654-9.
16. Barera G, Bonfanti R, Viscardi M, et al. Occurrence of celiac
20. Ashida T, Das AK, Sridhar M. Heterogeneity of type 2
disease after onset of type 1 diabetes: a 6-year prospective diabetes mellitus. J Assoc Physicians India. 2007;55:245-6.

chapter
longitudinal study. Pediatrics. 2002;109:833-8. 21. Stenstrom G, Gottsater A, Bakhtadze E, et al. Latent auto­
17. Eisenbarth GS. Clinical ramification of an autoimmune

23
immune diabetes in adults: definition, prevalence, beta-cell
diathesis. Kahn CR, Weir G, King G, et al. (Eds). Joslin’s Dia- function, and treatment. Diabetes. 2005;54:S68-72.
betes Mellitus, 14th edition: Indian edition. Nodia: Lippin- 22. Redondo MJ. LADA: time for a new definition. Diabetes.
cott Williams & Wilkins; 2005. pp. 400-62. 2013;62:339-40.
 Chapter 24
Clinical Features of
Type 2 Diabetes Mellitus
SV Madhu

Clinical Features of Type 2 dm

Chapter Outline
♦♦ Types of Diabetes ♦♦ Complications of Type 2 DM at Diagnosis
♦♦ Epidemiology ♦♦ Low Body Weight Type 2 DM
♦♦ Natural History of Type 2 DM ♦♦ Differential Diagnosis
♦♦ Clinical Features

INTRODUCTION genitourinary, cardiovascular and sexual dysfunction

and foot ulceration secondary to peripheral neuropathy
Diabetes is a group of common metabolic disorders and peripheral arterial disease.
characterized by hyperglycemia and altered carbohydrate, Subjects with diabetes have 2–3 times higher risk of
protein and fat metabolism associated with absolute or developing atherosclerotic cardiovascular, peripheral
relative deficiency in insulin secretion and/or insulin arterial and cerebrovascular disease. Hypertension and
action on target tissues. The full expression of the disease dyslipidemia are also more frequent in patients with
is associated with fasting and postprandial hyperglycemia diabetes mellitus (DM).
but the disease can also be detected in earlier stages as
it marches from normoglycemia to a stage of impaired TYPES OF DIABETES
glucose tolerance (IGT) and impaired fasting glucose
(IFG). The chronic hyperglycemia of diabetes is associated The classification and diagnosis of diabetes was developed
with long-term damage, dysfunction and failure of various by National Diabetes Data Group (NDDG) and published
organs especially eyes, kidneys, nerves, heart and blood in 1979,1 which was later revised by expert committee
vessels. of American Diabetes Association (ADA)2 in view of
Symptoms of hyperglycemia include polyuria, poly­ recent advances in the understanding of the etiology and
dipsia, weight loss, polyphagia and visual impairment. pathogenesis of diabetes. Currently, diabetes has been
Impairment of growth and susceptibility to certain infec­ classified as type 1 diabetes, type 2 diabetes, gestational
tions also accompanies chronic hyperglycemia. Acute life diabetes mellitus (GDM) and secondary diabetes due to
threatening consequences of diabetes are hyperglycemia other causes.3 The accepted broad classification based on
with ketoacidosis or hyperosmolar hyperglycemic state. etiology as type 1 DM and type 2 DM is relevant.4 Adoption
Long-term complications include retinopathy with visual of new terminology has helped to avoid confusion
impairment, nephropathy resulting in renal failure, generated by the fact that patient labeled as non-insulin
peripheral neuropathy leading to gastrointestinal (GI), dependent previously may develop insulin dependence
 Clinical Features of Type 2 Diabetes Mellitus 367

Table 24.1: Differences between type 1 and type 2 diabetes mellitus

Type 1 Type 2
Race Frequency low in Asians and native Americans, high in High in Native Americans, African- Americans,
Caucasians (Nordics) Hispanics, South Asians
Age Mostly < 40 years Mostly > 40 years
(Peak = 12 years) (Peak 60–70 years)
Mode of onset Acute or severe Insidious, slow or moderate

chapter
Genetics Polygenic Polygenic

24
Insulin secretion Very low to nil Variable, high to low normal
Insulin sensitivity Normal Decreased
Insulin dependence Permanent None, may be insulin requiring
Obesity Uncommon, thin, loss of weight Common
Acanthosis Nil Present
Autoimmunity Yes No
Family history Less common More common
Metabolic syndrome Nil Usually present
C-peptide status* Negative Positive

* C-peptide positive: plasma C-peptide levels >0.6 mmol/L 6 min after 1 mg glucagon injected intravenously

with gradual b-cell exhaustion. The differences between China in the number of persons affected with diabetes. It
type 1 and type 2 diabetes are shown in Table 24.1. is estimated that 61 million individuals have diabetes in
Age is no longer a criterion for classifying DM.5 India as of 2011, and the number is projected to increase
Although type 1 diabetes generally occurs at an early age to 101 million by 2030.8
and accounts for 5–10% of all the cases, it is also seen in the
age group of 40–50 years. Conversely, type 2 DM, though NATURAL HISTORY OF TYPE 2 DM
more frequently found in the older age groups, can also
The clinical presentation of type 2 DM can be quite varied
occur in children particularly in obese adolescents. Type
and covers a wide spectrum of features. A patient with type
2 DM accounts for 90–95% of all cases of diabetes. It may
2 diabetes passes through phases of insulin resistance,
be due to insulin resistance with relative insulin deficiency
hyperinsulinemia, b-cell secretory decompensation and
or predominantly secretory defect with added insulin
finally hyperglycemia. The clinical presentation would
resistance.
depend on the stage at which the patient presents to the
physician.
EPIDEMIOLOGY
The stages of insulin resistance, hyperinsulinemia and
The prevalence of type 2 DM is steadily increasing world­ early b-cell secretory decompensation constitute predia­
wide and has now assumed epidemic proportions. Increa­ betes and are clinically silent. However, certain features
sing prevalence is related to changing lifestyle like high predict the development of diabetes in these stages.
calorie intake, weight gain, lack of adequate exercise, Obesity is strongly associated with insulin resistance and
physical and mental stress, and sedentary habits in the promotes hyperglycemia. Hypertension and dyslipidemia
background of genetic susceptibility. People who initially particularly hypertriglyceridemia and low high-density
had normal body mass index (BMI) on crossing over lipoprotein (HDL) cholesterol are also important predic­
to higher BMI later in life also had a high rate of type 2 tors. Family history of diabetes is strongly associated
diabetes.6 The International Diabetes Federation (IDF) with future development of diabetes. Therefore, when a
estimates that more than 371 million people worldwide patient is seen in these stages the physician should always
have diabetes as of 20127 and this number is projected to make an effort to identify these risk factors and correct
increase to 552 million by 2030.8 India is second only to those that can be modified (Table 24.2).
368 Clinical Profile

Table 24.2: Major risk factors for type 2 diabetes Table 24.3: Common presenting complaints of patients with type 2
diabetes mellitus* (n = 800)
• Family history of diabetes
• Osmotic symptoms (polyuria, polydipsia) 60%
• Overweight (BMI > 23 kg/m2)
• Nocturia 59.4%
• Habitual physical inactivity
• Lassitude 57.3%
• Race or ethnicity (South Asians)
• Weight loss 54.7%
• Previously identified IFG or IGT
• Headache 44.1%
• Hypertension (> 140/90 mm Hg in adults)
section

• Progressive loss of vision 46.9%

• HDL cholesterol < 35 mg/dL and/or triglyceride
• Giddiness 35%
7

levels > 250 mg/dL

• Paresthesias 40.9%
• History of GDM or delivery of baby weighing > 9 lbs
• Respiratory complaints 33%
• Polycystic ovary syndrome
• Cardiovascular complaints 33%
(BMI: Body mass index; IFG, Impaired fasting glucose; IGT: Impaired
• Muscle ache 24.4%
glucose tolerance; HDL: High-density lipoprotein; GDM: Gestational
diabetes mellitus). * Source: Unpublished data from UCMS-GTB Hospital, Delhi, SV
Madhu et al.

In fact in type 2 DM, the onset and progress of hyper­ period. Other presentations could include a non-healing
glycemia are so slow as to remain imperceptible. These wound or ulcer, recurrent boils, unexplained vaginal
asymptomatic patients come to attention by accident, as itching, fungal infections and recurrent bacterial infec­
a part of preoperative evaluation, screening camps and tions. Male patients may complain of impotence as first
in individuals having regular annual checkup. Apart from symptom.9,10,12,13 Collection of ants at places of urination
this, some patients are detected when they are under stress is a common indicator in the rural setting. Whitish spots
such as acute myocardial infarction (AMI) or stroke. GDM from dried up urine on hard surfaces or under garments
also comes in this group where pregnancy imposes the may offer another indication for glycosuria.
stress. These patients could become normoglycemic once In a retrospective analysis of 800 type 2 diabetic
the stressful condition is over but remain quite prone to patients attending our diabetic clinic at GTB hospital in
develop diabetes in future and should be closely watched. East Delhi about 41% patients presented with gradual
Clinically, patients with type 2 DM present with overt onset, 7.9% with rapidly progressive disease while 51.1%
disease usually around 50 years or above but in Indian had indefinite onset. Average age of the patients was 49.13
population it often occurs some 2 decades earlier.9,10 ± 12.4 years. 42.1% were males and 57.9% were females.
Indians have high susceptibility of developing vascular This male female ratio of 3:4 is interesting and may repre­
complications earlier and more frequently.11 Recently, sent a rise in prevalence of obesity and type 2 diabetes
type 2 diabetes is becoming increasingly common in among urban Indian women. Mean duration of diabetes
children and young adults all over the world including was 5 ± 5.47 years. Of the total patients, 56.2% were obese
India. Pointers to the diagnosis of type 2 diabetes include (BMI > 23 kg/m2), 10.6% were lean (BMI < 18.5 kg/m2)
positive family history, obesity especially central obesity, and 33.83% were normal weight (BMI 18.5–23 kg/m2).
acanthosis, polycystic ovarian syndrome, insidious onset The differentiation of type 2 diabetes patients into obese,
of symptoms and absence of ketosis. normal weight or lean was based on the revised World
Health Organization (WHO) definition of obesity for
CLINICAL FEATURES Asian Indians. In many other areas, particularly in eastern
and southern India, several reports indicate diagnosis of
The classical osmotic symptoms of polyuria, polydipsia diabetes at relatively earlier age with a lower proportion
as well as polyphagia, when present are very suggestive of of overweight patients.
diabetes. However, these symptoms are more applicable Presenting complaints in these patients (Table 24.3)
to type 1 diabetes. On the other hand, fatigue, tingling of were osmotic symptoms (polyuria, polydipsia) in 60%,
hands and feet, generalized muscle ache and pains are nocturia in 59.4%, lassitude in 57.3%, weight loss in
more often seen in type 2 diabetes. Even these symptoms 54.7%, headache in 44%, giddiness in 35%, progressive
usually occur after a long and variable asymptomatic loss of vision in 46.8%, paresthesias in 40.9%, respiratory
 Clinical Features of Type 2 Diabetes Mellitus 369

Table 24.4: Symptoms at onset in patients with type 2 diabetes commonly seen in patients of type 2 diabetes is evident
mellitus* (n = 800) in Figure 24.1, while the replica of a lean patient with
• Osmotic symptoms 43.5% type 2 diabetes is presented in Figure 24.2.
• Weakness 12.7% In this group of patients, 28% were asymptomatic. DM
• Leg pains 10% was detected on routine investigation because of family
• Giddiness 8.3% history, during annual or pre-employment check up,
• Weight loss 4.8% for life insurance proposal, in diabetes screening camp,

chapter
• Paresthesias 4% prior to dental extraction or surgical procedure and in the

24
• Fever 3.7%
presence of illness unrelated to DM, viz. hypothyroidism,
• Headache 2.8%
epilepsy, jaundice, menorrhagia, skin disorders and sleep
disturbance. Tiredness, thirst and mild urinary frequency
• Others 10.2%
were the most common symptoms. Hypertension, IHD
* Source: Unpublished data from UCMS-GTB Hospital, Delhi,
SV Madhu et al.
(two were postcoronary bypass) and dyslipidemia led
to detection of DM in 14%, 5% and 7% respectively.
complaints in 33%, cardiovascular complaints in 33%
and muscle ache in 24.4%. A significant proportion of COMPLICATIONS OF
patients were asymptomatic. Symptoms at onset, which TYPE 2 DM AT DIAGNOSIS
included those that were obtained on questioning, had a The clinical spectrum, particularly distribution of body
wider spectrum as shown in Table 24.4. These were poly­ weight, has been found to be different in patients observed
uria, polydipsia, weakness, leg pains, giddiness, weight
in charitable hospitals and diabetes clinics (vide-infra).
loss, parasthesias, burning and numbness of feet, fever,
In a subset of patients, the presentation of diabetes is
headache, infections, skin lesions, weight loss, generalized
with target organ damage. A nationwide study involving
itching, symptoms indicative of ischemic heart disease
2,343 newly diagnosed subjects has revealed sensory
(IHD), boils, non-healing foot ulcer, pulmonary tuber­
peripheral neuropathy in 11.5%, retinopathy in 5.5%,
culosis, pruritus vulvae, balanitis, posthitis (men), erectile
nephropathy (microalbuminuria) in 1.02%, hypertension
dysfunction, lethargy, blurring of vision, shoulder periar­
in 20.6%, IHD in 5.5% and dyslipidemia in 5.5%.14 Patients
thritis, cranial nerve palsy, depression, increased swea­
may have features of:
ting, weight gain in some, increased hunger, itching
• Retinopathy with decreased visual acuity, blurring
groin due to fungal infection and dysuria from urinary
of vision and occasionally blindness. Examination
tract infection. In addition a significant proportion of
reveals microaneurysms, hemorrhages and cotton
patients were asymptomatic with chance detection on
wool spots in non-proliferative diabetic retinopathy
routine checkup or investigation for surgery, systemic
and neovascularization in proliferative diabetic retino­
illness or pregnancy.
pathy.
A prospective analysis of 300 consecutive type 2
• Atherosclerotic heart disease in form of stable angina,
diabetic patients (urban and rural) seen over a period
in a private Bangalore hospital also provides useful data unstable angina, myocardial infarction and occasi­
regarding clinical presentation where age of onset was onally congestive heart failure.
found to be 16% between ages of 30 years and 39 years, • Neuropathy (polyneuropathy) with distal sensory loss,
41% between 40 years and 49 years, 25% between 50 years paresthesia and pain. Examination reveals sensory
and 59 years and 3% above the age of 70 years. There were loss, loss of ankle reflexes and abnormal position sense.
more males than females in this series. On the basis of Polyradiculopathy—severe pain in distribution of one
BMI, 14% were severely obese, 42% obese, 20% overweight, nerve root viz. truncal radiculopathy, mononeuro­
20% had ideal weight and 4% were of low body weight. pathy—single cranial or peripheral nerve, e.g. 3rd, 4th,
The BMI of over 30 kg/m2 was more in females than in 6th, 7th.
males. Waist-hip ratio (WHR) exceeded the upper limits • Nephropathy with facial puffiness, presence of micro
of normal in all groups for a given BMI including those or overt proteinuria and hypertension.
below 19 kg/m2. Thus these subjects had central obesity Rarely patient may report to the emergency room with
which is a risk factor for type 2 DM. Abdominal obesity, drowsiness, heavy glycosuria and sometimes in coma.
370 Clinical Profile
section
7

Fig. 24.1: A patient with type 2 diabetes and waist-hip (WH) ratio 1.15 Fig. 24.2: A patient with lean type 2 diabetes

Table 24.5: Clinical suspicion of type 2 diabetes These would include increased WHR, elevated triglyce­
• Easy fatigability or weakness rides, low HDL, elevated blood pressure and a raised fast-
• Polyuria, polydipsia and polyphagia
ing plasma glucose.15
• Pruritis vulvae or balanitis
LOW BODY WEIGHT TYPE 2 DM
• Weight loss
• Visual refractory changes In the West, the majority, perhaps 80–85% of patients
• Periarthritis shoulder with type 2 diabetes are overweight but some may have
• Paresthesias in the legs, fingers and toes normal weight and may occasionally be lean. Obesity
• Muscle cramps is less frequent in Indian patients (14%) and there is
• Erectile dysfunction usually a male preponderance. Some Indian patients are
• Delayed wound healing
lean (low BMI) but may be centrally obese with raised
WHR.16-19 These patients termed as low body weight
• Giddiness
type 2 diabetics were reported way back in 1965 by
• Ants crawling at the site of urine voiding
Tripathy and Kar with a hospital incidence of 28%. These
• Itching and skin infections
patients had significant differences in clinical, bioche­
• Sleep disturbances
mical, hormonal and mortality profiles.20 Homocysteine,
• One or the other micro- or macrovascular complications a non-lipid risk factor of atherosclerosis, is markedly
low in these patients as were plasma insulin levels. These
Coma in type 2 diabetes is generally due to hyperosmolar patients had lower BMI, absence of protein deficiency,
hyperglycemic state but can also be due to ketoacidosis higher prevalence of peripheral neuropathy and infec­
which generally occurs secondary to a major stressful tion, and lower prevalence of hypertension and coronary
event. artery disease.
In view of the wide and varied clinical spectrum
of clinical features, the physician should always have DIFFERENTIAL DIAGNOSIS
a high index of suspicion of DM in all these situations
(Table 24.5) and undertake a careful evaluation for Type 2 DM is to be differentiated from other causes of
diabetes. hyperglycemia. Common conditions to be differentiated
Type 2 DM can occur as a part of metabolic syndrome are maturity onset diabetes of young (MODY) and latent
where insulin resistance clusters with other cardiovas- autoimmune diabetes of adults (LADA). MODY consti­
cular risk factors, endocrine and metabolic disturbances. tutes of a group of disorders characterized by autosomal
 Clinical Features of Type 2 Diabetes Mellitus 371

Table 24.6: Differences between type 2 diabetes mellitus, MODY and LADA
Type 2 DM MODY LADA
Race Native Americans, African-Americans, Caucasian North European
Hispanics, Asians, Pacific Islanders
Age Mostly > 40 years < 25 years 35–50 years
(Peak 60–70 years)
Mode of onset Insidious Insidious Insidious

chapter
Genetics Polygenic Monogenic Polygenic

24
Autosomal
Dominant
Insulin secretion Variable Variable Decreased
Insulin sensitivity Grossly decreased Normal or decreased Normal
Insulin dependence Nil Nil Later in life
Obesity Common Variable Uncommon
Acanthosis Present Nil Nil
Autoimmunity No No Yes
Family history Present Invariable Of Type 1 DM in a relative
Metabolic syndrome Usually present Rare Nil

(DM: Diabetes mellitus; MODY: Maturity onset diabetes of the young; LADA: Latent autoimmune diabetes in adults).

Table 24.7: Differential diagnosis of type 2 diabetes of type 2 DM from secondary diabetes will be on the basis
• Latent autoimmune diabetes of adults of features of the primary disease that would be evident
• Maturity onset diabetes of young in the latter (Table 24.7).
• Endocrine diseases It is clear from the above discussion that type 2 DM
– Cushing’s syndrome presents in various forms and the spectrum extends from
– Acromegaly an asymptomatic individual on the one hand to the patient
• Diabetogenic drugs who presents with features of multiple complications.
– Glucocorticoids The outcome and prognosis in a given patient will depend
– Thiazide diuretics
upon how early the diagnosis is made. For this, a high
– Pentamidine
index of suspicion is required not only by diabetologists
• Pancreatic diseases
– Chronic pancreatitis but also by professional colleagues of other disciplines as
• Rare syndromes
diabetes may be seen by any of the medical disciplines:
– Lipodystrophies non-healing ulcer by surgeon, blurred vision by an oph­
– Mitochondrial deoxyribonucleic acid (DNA) mutations thalmologist, impotence by an urologist and neuropathy
– Insulin or insulin receptor mutations by a neurologist. Routine screening for diabetes of all
patients presenting to hospitals can also be a useful stra­
dominant inheritance. Onset is usually before 25 years tegy to increase the yield of diabetes early in its course.
of age and patients present generally with mild hyper­
glycemia and a strong family history spanning three SUMMARY
generations. LADA is a form of autoimmune diabetes not
requiring insulin at diagnosis. It is also described as a Diabetes mellitus represents a heterogeneous group of
slowly progressive type 1 DM as they are as a rule posi­ disorders, of which hyperglycemia is the key feature.
tive for antibodies to glutamic acid decarboxylase. Many Various types of diabetes occur as a result of complex
of the patients are lean and require insulin within 5 years interaction of genetic, environmental and lifestyle factors.
of onset. The differentiating features of MODY, LADA and Hyperglycemia is caused by decreased insulin production,
type 2 DM are mentioned in Table 24.6. Differentiation sub-optimal action on target organ and enhanced hepatic
372 Clinical Profile

glucose production. Type 1 and type 2 DM are the main 4. Alberti KG, Zimmet PZ. Definition diagnosis and classi­
types of DM prevalent all over the world. fication of diabetes mellitus and its complications. Part 1:
diag­nosis and classification of diabetes mellitus: provisional
Gradual decline in b-cell function precedes the diag-
report of a WHO consultation. Diabet Med. 1998;15:539-53.
nosis in type 2 DM. This stage lasts for many years and 5. Katsilambros N, Tentolouris N. Type 2 Diabetes: an over-
a significant proportion of patients may present while view. In: Pickup JC, Williams G (Eds). Textbook of Diabetes,
asymptomatic. Clinical features in type 2 DM are varied 3rd edition. Oxford, Blackwell Publishing; 2003.
and cover a wide spectrum of symptoms—osmotic symp- 6. Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial
section

toms, weight loss, aches, pains and giddiness. The patient changes in childhood body-mass index to impaired glucose
tolerance in young adulthood. N Eng J Med. 2004;350:865-75.
7

may also present for the first time with features of com- 7. International Diabetes Federation. (2012). IDF Diabe-
plications. Sometimes, presentation is in the form of life tes Atlas, 5th edition, Update 2012. Brussels, Belgium:
threatening complication such as hyperosmolar hypergly- International Diabetes Federation, 2012. IDF website.
cemic state or occasionally ketoacidosis. Available from http://www.idf.org/diabetesatlas/5e/Up-
While obesity is an important association of type 2 DM, date2012 [Accessed September 2013].
8. International Diabetes Federation. (2011). IDF Diabetes At-
a significant number of Indian type 2 DM patients have
las, 5th edition. Brussels, Belgium: International Diabetes
normal or low BMI and are termed as low body weight Federation, 2011. IDF website. Available from http://www.
type 2 DM. As the vast majority of patients are asympto­ idf.org/diabetesatlas [Accessed September 2013].
matic, opportunistic screening is required for timely 9. Salans LB. Non-insulin dependent diabetes mellitus.
diagnosis and early intervention for the detection of the In: Lavin N (Ed). Manual of Endocrinology and Metabo-
lism, 2nd edition. New York, Little, Brown and Co; 1994.
disease, as and when patient presents to the hospital to
10. Viswanathan M. Diabetes in the tropics. Diamet. 1994;5.
avoid the complications. 11. Ramachandran A, Viswanathan M, Mohan V. Epidemiology
of NIDDM in Indians. J Assoc Physicians India. 1993;41:1-3.
Further Reading 12. Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD,
Foster DW (Eds). William’s Textbook of Endocrinology, 7th
1. De Joysa VP. Clinical variations of the diabetes syndrome
edition. Philadelphia, W.B. Saunders; 1985.
in a tropical country (Ceylon). AMA Arch Intern Med.
13. Bennett PH. Definition, diagnosis and classification of dia-
1951;88:812-8. betes mellitus. In: Kahn CR, Weil GC (Eds). Joslin’s Diabetes
2. Tripathy BB, Kar BC. Observations and clinical patterns of Mellitus 13th edition. Philadelphia, Lea and Febiger; 1994.
diabetes mellitus in India. Diabetes. 1965;14:404-12. 14. Aravind SR, Bajaj S, Prasanna Kumar KM, et al. Complica-
3. World Health Organization. Diabetes Mellitus: report of tions in newly diagnosed diabetes in India (CINDI). A mul-
a WHO study group. Geneva, World Health Organisation; ticentric study presented at the Diabetes India Conference,
1985. Mumbai; 2012.
4. Expert Committee on the Diagnosis and Classification of 15. Expert Panel on Detection, Evaluation and Treatment of
Diabetes Mellitus. Report of the expert committee on the High Blood Cholesterol in Adults. Executive summary
diagnosis and classification of diabetes mellitus. Diabetes of the third report of the National Cholesterol Educa-
Care. 2002;25: s5-s20. tion Program(NCEP)(Adult Treatment Panel III). JAMA.
2001;285:2486-509.
REFERENCES 16. De Joysa VP. Clinical variations of the diabetes syndrome
in a tropical country (Ceylon). AMA Arch Intern Med.
1. National Diabetes Data Group. Classification and diagnosis 1951;88:812-8.
of diabetes mellitus and other categories of glucose intoler- 17. Cosnett JE. Diabetes among Natal Indians. Br Med
ance. Diabetes. 1979;28:1039-57. J. 1959;1:187-92.
2. World Health Organization. Diabetes Mellitus: report of 18. Tulloch JA. Diabetes Mellitus in the Tropics. Edinburgh,
a WHO study group. Geneva, World Health Organisation; E & S Livingstone; 1962.
1985. 19. Tripathy BB, Samal KC. Overview and consensus state-
3. Expert Committee on the Diagnosis and Classification of ment of diabetes in tropical areas. Diabetes Metab Rev.
Diabetes Mellitus. Report of the expert committee on the 1997;13:63-76.
diagnosis and classification of diabetes mellitus. Diabetes 20. Tripathy BB, Kar BC. Observations and clinical patterns of
Care. 2002;25: s5-s20. diabetes mellitus in India. Diabetes. 1965;14:404-12.
 Chapter 25
Fibrocalculous
Pancreatic Diabetes
Dukhabandhu Naik, Nihal Thomas

Pancreatic Diabetes

Chapter Outline
♦♦ Definition and Terminology ♦♦ Investigations
♦♦ Historical Background and Prevalence ♦♦ Complications
♦♦ Clinical Presentation ♦♦ Criteria for Diagnosis of FCPD
♦♦ Pathology ♦♦ Life Expectancy, Survival and Causes of Mortality
♦♦ Etiopathogenesis ♦♦ Management

INTRODUCTION considerable overlap in the characterization of these two

types. In PDDM, there is lack of evidence of generalized
Type 2 and type 1 are the most common forms of diabetes pancreatic pathology. The clinical presentation of PDDM
worldwide. However, about 1–5% of patients who present resembles that of type 1 diabetes; however insulin with­
with diabetes are secondary to other disorders. Of these, drawal does not lead to ketoacidosis. FCPD is characterized
the disorders of the pancreas are the most common.1 by abdominal pain, pancreatic calculi on imaging and
Various pancreatic disorders can cause diabetes inclu­ loss of some exocrine pancreatic function. FCPD is more
ding pancreatic infections, inflammation, neoplasms, prevalent in developing countries and is precipitated by
post pancreatic surgery, cystic fibrosis and hemochro­ non-alcohol related chronic pancreatitis.
matosis, however chronic pancreatitis is the commonest In a recent classification of diabetes by the American
pancreatic disorder associated with diabetes.2 Chronic Diabetes Association, FCPD has been included as a disease
pancreatitis is a heterogeneous disease. From a worldwide of the exocrine pancreas under other specific forms of
perspective, alcoholism is the most common cause of diabetes, as suggested by a workshop held at Cuttack
chronic pancreatitis.3 However, in many tropical count­ (Orissa), India in 1995.7 However, MRDM and its subclass
ries including India, the etiology frequently includes PDDM has been deleted from the current classification.
so-called “tropical chronic pancreatitis”.4,5
Malnutrition and its association with various types DEFINITION AND TERMINOLOGY
of diabetes have been reported from several tropical
countries since the beginning of this century. The WHO Fibrocalculous pancreatic diabetes has been defined as a
classification of 1985 gave a prominent categorization to type of diabetes that is secondary to chronic non-alcoholic
malnutrition related diabetes mellitus (MRDM).6 The calcific pancreatitis that is seen almost exclusively in
MRDM was further classified into two main subgroups developing countries of the tropical world. A variety of
namely fibrocalculous pancreatic diabetes (FCPD) and names have been used to identify this entity like tropical
protein deficient diabetes mellitus (PDDM). There is a calcific pancreatitis, tropical chronic pancreatitis, tropical
374 Clinical Profile

Table 25.1: Differences between tropical chronic pancreatitis and 45 patients of pancreatic calcification with diabetes melli­
alcoholic chronic pancreatitis tus from Indonesia.14 The patients in his study were poor
Tropical calcific Alcoholic and consumed a very low protein and calorie diet. Clinical
pancreatitis pancreatitis features were striking in that they had gross emaciation,
Demographic features parotidomegaly and hair and skin changes resembling
Peak age of onset 20–30 30–50
that of Kwashiorkor. Following this report there were a
(years)
series of publications of similar type of patients from vari­
Male: Female 70:30 90:10
section

ous parts of Asia (India, Bangladesh and Sri Lanka),15,16

Socioeconomic status Poor > affluent All groups
7

Alcohol abuse Absent Present

Africa (Uganda, Nigeria, Zambia, Madagascar)17-19 and
Pancreatic morphology
even in Brazil.20 The majority of publications are from
Prevalence of calculi 90% 50–60% southern India.21-28
Features of calculi Large, in large duct Small specked, The first case of pancreatic calculi from India was
in small ducts reported by Kini in 1937.29 In 1954, Elizabeth and Stephen
Duct dilation Usually marked Usually moderate reported cases of pancreatic calculi that were observed
Fibrosis Heavy Variable during postmortem studies at the Christian Medical
Risk of pancreatic Markedly increased Increased College, Vellore (Tamil Nadu) in Southern India.30 The
cancer largest series of cases of FCPD initially reported were from
Diabetes South Western parts of Kerala.4,31 Geevarghese who was
Prevalence > 90% 50% one of the pioneers in the field has reported more than
Time course Rapid evolution Slower evolution 1,700 cases in his monographs, and indeed it is one of the
Source: Adapted from Ranjit Unnikrishnan and V Mohan. Pancreatic largest series reported.4,32 He is therefore often referred to
Disease and Diabetes. In: Richard IG. Holt, Clive Cockram, Allan as “The Father of Pancreatic Diabetes”. In Kerala, FCPD
Flyvbjerg, Barry J. Goldstein (Eds). Text book of diabetes: A Clinical constituted about 29.3% of the total diabetes registered
Approach, 4th edition. Wiley-Blackwell; UK: 2010. pp. 298-312.
and 1.35 % of the total inpatients in Kottayam Medical
College in the 1960’s. However, this figure later dramati­
pancreatic diabetes, nutritional pancreatitis and endemic
cally reduced to 0.03% in 1971 and 0.09% in 1980.4
pancreatic syndrome, all of which essentially refers to the
A population based study by Balaji et al. (1994) in
same condition. The term “tropical calcific pancreatitis” 28,567 inhabitants from Quilon district of Kerala detected
is based on its geographic distribution but the disorder a prevalence of 0.09%.33 A study from Chennai showed a
has been recently reported in developed countries in similar trend and a reduction in the prevalence of FCPD.
immigrants from tropical regions.8 FCPD is the preferred Initial studies during 1991–1995 showed a prevalence
term used by diabetologists and endocrinologists while the of 1.6%. However, subsequent studies have shown a
term tropical calcific pancreatitis (TCP) has been used by prevalence of 0.36% during 2001–2003 and 0.2% during
gastroenterologists. FCPD and TCP are considered as two 2006–2010, respectively.34,35 Balakrishnan et al. (2008)
different stages of the same disease, i.e. TCP is considered conducted a nationwide study on chronic pancreatitis
as the prediabetic stage of FCPD.9,10 Chronic pancreatitis based on clinical and radiological criteria and reported a
has a number of etiologies of which alcohol consumption prevalence of tropical chronic pancreatitis of 3.2% while
accounts for the majority of the cases in Western countries idiopathic pancreatitis (60.2%) and ACP comprised 38.7%,
and alcoholic pancreatitis (ACP) is also seen in India.3,11 which suggests a low prevalence of FCPD. However,
The differences between the clinical profiles of tropical it is possible that the idiopathic pancreatitis’ included
and alcoholic chronic pancreatitis are summarized in FCPD. These studies have demonstrated the presence
Table 25.1.12,13 of a changing profile of chronic pancreatitis in India.36
Studies from different parts of India showed variable
HISTORICAL BACKGROUND prevalence and changing trends of FCPD patients with
AND PREVALENCE changing times.37,38

Over the past six decades there have been several

CLINICAL PRESENTATION
publications of pancreatic calcification in non-alcoholic
young individuals from various tropical countries. The typical clinical presentation and natural history of
It was Zuidema (1959) who originally reported a series of FCPD have been elegantly described by Geevarghese in
 Fibrocalculous Pancreatic Diabetes 375

However, all symptoms need not be present in every

patient at the time of diagnosis.

Abdominal Pain
Most patients give history of childhood or adolescent-
onset abdominal pain. Abdominal pain is the major and
most common presenting complaint, seen in 30–90%

chapter
of patients in a number of series.43-45 Abdominal pain in

25
FCPD has no definite diagnostic pattern. However, it is
typically located in the epigastric region and radiates to
the back and gets relieved by stooping forward or lying in
a prone position. Pain is episodic in nature with periods
of remission and exacerbation. Continuous pain is seen
in 20% of patients. The onset of pain usually occurs prior
to the detection of diabetes although occasionally the
diabetes may be seen first. It is less frequent or disappears
with the onset of exocrine insufficiency and/or diabetes,
Fig. 25.1: Patient with fibrocalculous pancreatic diabetes (FCPD)
which is known as the “burn out” effect.46 In about 10% of
patients, the pain persists even after diagnosis of diabetes.
1968.32 The symptoms begin with recurrent abdominal A study from Lucknow has demonstrated abdominal pain,
pain in childhood; pancreatic calculi in adolescence and weight loss and insulin requirement as more common in
diabetes during early adulthood. The classical features younger patients.37
are marked emaciation, parotidomegaly, a distended
abdomen and a peculiar cyanotic hue of the lips Pancreatic Calcification
(Fig. 25.1). The clinical features of FCPD these days differ
The presence of large intraductal pancreatic calculi is
in many aspects from older description of FCPD. Nowa­
the hallmark of FCPD. Pancreatic calculi have been
days, patients with marked emaciation are seldom seen.
documented in 80–90% cases of FCPD.4,47 The calculi are
In a recently published study from Chennai, a mean of
mostly located at the right of the first and second lumbar
body mass index (BMI) 21.2 ± 3.8 kg/m2 has been shown
vertebra (L1 and L2) on a plain abdominal radiograph.48
in contrast to 19.4 ± 3.6 kg/m2 in the year 1991–1995.
They may be solitary or multiple and at times even
However, nearly 50% of the patients had a BMI of less than
the entire pancreas may be studded with calculi. The
19 kg/m2 and a few patients were overweight.39,40 There
stones are frequently large, discrete and dense with well-
has been gradual increase in the age of presentation to
defined edges in contrast to the small, speckled, ill-defined
the hospital. The average age of diagnosis ranges between
stones in alcoholic chronic pancreatitis.13 A study from
30 years and 40 years. However, the age at presentation
Bangladesh has reported that calculi are less common
may range from 7 years to 79 years.41,42 There is a male
in overweight and obese individuals.49 The severity of
preponderance with a male to female ratio of 2.5:1.
calcification has no direct correlation with the severity of
However, the field study by Balaji et al. has shown that
pain and the duration of the disease.
the female population is more affected than males.33
In contrast to several earlier reports, it has been shown
Exocrine Pancreatic
recently that 30–50% of FCPD belonged to middle and
Insufficiency (Steatorrhea)
even upper income groups. This has been attributed to an
overall improvement in the nutritional status.37,38 Steatorrhea and weight loss may occur only when there
The typical clinical presentation of FCPD includes: is a significant exocrine pancreatic insufficiency. These
• Abdominal pain patients typically complain of passing bulky, frothy
• Pancreatic calcification and foul smelling stools, three to four times per day.45
• Pancreatic exocrine deficiency (steatorrhea) However, overt steatorrhea is seen in only 20% of patients
• Diabetes mellitus. with FCPD. The low frequency of steatorrhea is attributed
376 Clinical Profile

to low intake of fat. Over 76% of these patients develop surgical intervention and from an autopsy specimen.
steatorrhea, when the fat intake in the diet is increased for Pathological findings depend on the stage at which
experimental purposes.50 the specimen is obtained. Specimens for pathological
examination are mostly obtained from the biopsy of
Diabetes the surgical specimen and autopsy material. Hence all
these findings represent well evolved and advanced cases
The onset of diabetes follows a decade or two after the of FCPD.64,65 Both early features and advanced findings
section

first episode of abdominal pain, and 80–90% of the FCPD may coexist as the disease progression is not uniform in
deve­lop diabetes by early adulthood.46 The late develo­
7

all cases.
pment in the course of disease, denotes considerable
damage to the endocrine pancreas prior to its develo­ Pathological Changes
pment. However, a study from Lucknow has shown that
Gross Pathology
33% of patients had insulin requiring diabetes at the
time of first presentation. Diabetes tends to be more The changes in the pancreas may be focal or diffuse and
severe in lean and malnourished individuals while it is of the size varies with the degree of involvement and the
insidious onset and less severe in well-nourished indivi­ stage of the disease.66 The size may be normal, enlarged or
duals.37 During presentation these patients may have a may be atrophic and finger-like in the advance stage of the
high plasma glucose level but are usually ketone negative disease. The surface is nodular and feels like a bag of
following withdrawal of insulin. Ketosis resistance is attri­ stones. An abnormally enlarged pancreas is seen in lipo­
buted to the following factors: matous atrophy where the entire pancreas is replaced by
• Residual beta-cell function adequate to prevent adipose tissue often only hypertrophic islets and ducts can
ketosis51-57 be made out to identify the pancreas. Staining with Sudan
• Loss of glucagon reserve, a major ketogenic Black can identify the changes. Magnetic resonance
hormone58,59 imaging (MRI) and computerized tomography (CT)
• Loss of subcutaneous fat and therefore reduced supply scan can also be helpful in recognizing these changes.
of non-esterified fatty acids (NEFA) the “fuel” for The changes in the pancreas are not uniform. The most
ketogenesis60 consistent and striking feature is disruption of normal
• Resistance of subcutaneous adipose tissue lipolysis to lobular architecture. The gland is usually firm, fibrous,
circulating adrenaline and gritty. The consistency depends on the presence of
• Carnitine deficiency affecting transfer of NEFA across fibrous tissue, cyst or stone and the consistency may vary
the mitochondrial membrane. in different regions of the pancreas. The cut surface of
Diabetes mellitus is usually severe with the mean pancreas shows dilated ducts and ductules with intraductal
fasting plasma glucose being 200–400 mg/dL. Most pati­ calculi or mucus plugs and early to diffuse background
ents require insulin for glycemic control. The mean daily fibrosis. Areas of dilatation and stenosis may be seen in the
dose of insulin is 40 ± 12 units/day.56,61 However, there same gland. The gland may be displaced from its normal
are a few patients in whom diabetes can be controlled location due to uneven shrinkage and fibrous adhesion.
with only diet and oral hypoglycemic drugs.62 Patients The calculi may vary in size, shape and color. The
presenting with ketosis require insulin for their survival. calculi are invariably located in the main pancreatic duct
Insulin resistance may be present occasionally in some or its branches, and are never seen in the pancreatic
patients but this is distinctly uncommon.56,63 Patients parenchyma. The size would range from small sand
with FCPD are known to have brittle or unstable diabetes particles to large stones (4–5 cm long) and weighing up
with wide swings of blood glucose. This may be attributed to 20 g with the larger ones being located near the head
to the loss of both alpha and beta cell mass. and smaller ones near the tail. The shape of calculi may
be rounded or may appear like a stag-horn. Most of the
PATHOLOGY calculi are calcified and hard. Sections of calcified stones
show epithelial debris, fibrin, and mucinous material.
Fibrocalculous pancreatitis is a chronic degenerative Color of the stones varies from chalky-white to dirty-white.
disease of the pancreas. The gross appearance of the Younger stones are soft as they are formed by non-calcified
pancreas can be made out by imaging or during any protein plugs and caseous material.
 Fibrocalculous Pancreatic Diabetes 377

Analysis of Calculi
Pancreatic calculi are predominantly composed of
calcium carbonate (95.5%) and small amounts of calcium
phosphate. In some stones, traces of magnesium, urate,
and oxalate have also been identified. Younger stones
are soft, composed of calcium carbonate and other

chapter
materials in the mucus plug. The calculi are soft, friable

25
and radiolucent. The hard calculi mainly contain calcium
carbonate, a small amount of calcium phosphate and
traces of several other materials.
X-ray diffraction studies have shown calcite as the
predominate form of calcium carbonate and vaterite has
been detected in 12% of case.67 All calculi contain a
central amorphous material, which is a constituent of
iron, chromium, and nickel and a cryptocrystalline peri­ Fig. 25.2: Nesidioblastosis. The cells at the top, forming part of the
ductal linings, have proliferated and differentiated into endocrine cells
phery containing a number of trace elements with a Source: Balaraman Nair. The pathology of fibrocalculous pancreatopa-
predominance of calcium.68 thy. In: Balakrishnan V, Harishkumar S, Sudhindran AG, Unnikrishnan
(Eds). Chronic Pancreatitis and Pancreatic Diabetes in India. The
Indian Pancreatitis Study Group: 2006. pp. 242-79.
Histopathology
The spectrum of changes that occurs in the pancreas exocrine pancreas. As the disease advances, the insulin
includes intralobular and interlobular fibrosis, degenera­ positivity of the islet cell decreases, which partly correlates
tion of ducts and inflammatory infiltrates. The earliest with the C peptide levels.70
changes are noticed in the acini. Interlobular fibrosis are
characteristic of early cases and may be focal, segmental, ETIOPATHOGENESIS
or diffuse in more advanced cases. Pancreatic ducts
show varying degrees of dilatation, hypertrophy and The etiopathogenesis of FCPD is still poorly understood.
periductal fibrosis. The duct of Wirsung and collecting Several hypotheses have been proposed based on
ducts are often dilated and contain calculi or desquamated epidemiological data. However, these hypotheses have
epithelial cells and leukocytes. Proliferative changes never been proven either in well-designed case control
are more prominent in smaller ducts and ductules. An studies or in experimental models. Over the last one
excessive proliferation of ductal epithelial cells sometimes decade, studies are focused on identifying the susceptible
leads to squamous metaplasia and dysplasia. Infiltration gene linked with FCPD. The etiological hypotheses of
of inflammatory cells is not a consistent finding of FCPD are mentioned below:
FCPD. Most of the cellular infiltrates are composed of • Malnutrition
lymphocytes and plasma cells, which have a periductal • Dietary toxins
distribution.64,69 • Micronutrient deficiency and oxidative stress
• Familial aggregation
Immunohistochemistry • Genetic factors.
The changes in islets are the most important features
of FCPD. The immunohistochemistry of islets show a
Malnutrition
decrease in islet cell number as well as a paucity of alpha Fibrocalculous pancreatitis is more prevalent in tropical
and beta cells. In some cases there may be a hypertrophy and developing countries. It is usually seen amongst
of islets.64 Nesidioblastosis involves multifocal ductuloin­ malnourished young individuals. Preliminary studies
sular proliferation consisting of all the cellular components have described malnutrition as the main underlying
of islet cells, which is also seen in some cases of FCPD etiopathological factor of FCPD.71-74 However, recent
(Fig. 25.2). Islet cell hyperplasia and hypertrophy are studies on FCPD described malnutrition as the effect
more prominent when there is a total atrophy of the rather than the cause of disease.39,75 For example, in a
378 Clinical Profile

country like Ethiopia,76 where malnutrition was at one serotonin from bananas, trace heavy metals like thorium
time widespread, the disease had never been detected and cerium from the soil have been implicated for their
and on the other hand, states like Kerala (India) had a possible role in FCPD.84,85 However, no experimental proof
higher prevalence of FCPD in spite of high literacy and is available. Balakrishnan et al. conducted an enquiry
low infant mortality rates. Moreover, FCPD is not seen in on the dietary pattern in FCPD patients and it was found
Kwashiorkor, a classic form of protein energy malnutrition. that there was no difference in protein (53 g/day) and
Similarly, there are recent reports where FCPD have been calorie intake as compared to control subjects. However,
section

noticed in obese individuals and patients from a higher fat intakes in both groups were low (27 g/day).86 It is
7

socioeconomic background. All these facts suggest that known that both low and high fat intake can predispose
FCPD is not only solely secondary to protein malnutrition to alcoholic pancreatitis.87 In an animal experiment, rats
but also due to other nutritional factors which may in that were fed on low protein diet during fetal and the
particular include micronutrient deficiencies and may early stage of life showed a poor pancreatic development,
play a contributory role in the pathogenesis. reduced beta cell size, reduced islet volume, and altered
islet vascularization.88 On the contrary, an experimental
Dietary Toxins (Cassava Toxicity) study on Bonnet Monkeys fed on low protein and high
carbohydrate diet developed inflammatory and vascular
Cassava, which is commonly known as tapioca or manihot
changes in the pancreas and heart. The experimental
is consumed as a staple food in many developing countries.
diet used in this study is somewhat identical to the diet
The McMillan and Geevarghese hypothesis links FCPD
consumed by the poor in tropical countries. The lesions in
to the consumption of cassava.77,78 This was based on an
the pancreas are similar to that of finding seen in FCPD
overlap between the geographical distribution of FCPD
patients. However, pancreatic calculi were not observed in
and the region of consumption of cassava (Kerala, India)
this study.89,90
and some experimental evidence.
Cassava contains two important cyanogenic glycosides Micronutrient Deficiency and Oxidative Stress
linamarin and lotaustralin. These glycosides get detoxified
in the body by conversion into thiocyanates, which is Heightened oxidant stress along with relative deficiency
non-toxic. This conversion requires sulfur containing of antioxidants has been proposed to be a possible
amino acids like methionine and cystine. In the setting pathogenic mechanism for FCPD. Braganza et al. had
of malnutrition, deficiency of these amino acids results shown that patients with chronic pancreatitis including
in a lack of detoxification leading to pancreatic damage FCPD had a heightened oxidative detoxification reaction
and thus diabetes sets in.79 Studies in experimental rats mediated by cytochrome P450-1.91,92 There are several
have shown that the ingestion of cyanide can lead to factors that induce cytochrome P450-1 activity of which
transient hyperglycemia but not permanent diabetes.80,81 xenobiotics (cigarettes, alcohol, occupational chemicals)
Moreover, the rats were given potassium cyanide and not are important. Bioactivation of xenobiotics leads to
cassava. Indeed, recent epidemiologic and experimental the increased production of free radicals. If the load of
xenobiotics is high, there will be an increased activity
studies have questioned the cassava hypothesis.82 FCPD is
of enzyme and more free radicals will be generated.93
even prevalent in many parts of India where no cassava
Theophylline clearance has been considered as a standard
is grown or consumed. FCPD has not been reported in
of measurement of cytochrome P450-1 activity. One study
West Africans who regularly consume cassava.83 Thus, it
demonstrated that theophylline clearance is faster in
is unlikely that cassava ingestion can explain the majority
FCPD when compared to controls.94 Antioxidants such
of cases of FCPD seen worldwide and the current thinking
as vitamin D and beta carotene levels are found to be
is that cyanogen toxicity is not a relevant factor in its
lower in FCPD patients.95 A preliminary study on FCPD
etiopathogenesis.
patients have shown a high level of malondialdehyde
and a decreased antioxidant level.96 Antioxidant therapy
Other Dietary Factors
have been found to reduce the analgesic requirement
In non-cassava areas, foods like Sorghum, Ragi, Jowar in patients with alcoholic pancreatitis.97,98 All the above
and a variety of peas contain cyanide. Other toxins such factors suggest that oxidative stress may play a role in the
as ergot-like toxins from plants and indigenous medicines, causation of FCPD.
 Fibrocalculous Pancreatic Diabetes 379

Familial Aggregation of FCPD • Genetic alterations in the trypsinogen pathway

–– Cationic trypsinogen (PRSS1)
Familial clustering of FCPD has been described by
–– Anionic trypsinogen (PRSS2)
several authors. The earliest study by Geevarghese et al.
–– Serum protease inhibitor Kazal type 1 (SPINK1)
showed that 8% of his study patients had “Familial
–– Chymotrypsinogen C (CTRC).
pancreatitis”.4 Balakrishnan reported the occurrence of
• Alteration in other genes
FCPD in three twins, mainly siblings and a father and a
–– Cystic fibrosis transmembrane conductance regu­

chapter
son.26 Pitchumoni has reported familial aggregation
lator (CFTR)
of FCPD in 17 families where two or more members

25
–– Regenerating islet-derived genes 1α (REG1A and
had evidence of pancreatitis.99 A study from Chennai
REG1B)
detected that 8% of patients with FCPD had evidence
–– Cathepsin B (CTSB)
of a familial aggregation.100 In some families, there was
–– Angiotensin converting enzyme (ACE)
evidence of vertical transmission of FCPD from parents
–– Calcium-sensing receptor (CASR).
to the offspring, while in others there was a horizontal
distribution of the disease among siblings. However,
Genetic Alterations in the Trypsinogen Pathway
many patients also had a family history of type 2 diabetes
(T2D). A familial aggregation suggests, but does not neces­ The premature activation of trypsinogen to trypsin
sarily prove, a hereditary etiology for FCPD, since several or failure to inactivate trypsin is one of the important
family members could arguably be exposed to the same mechanisms of pancreatitis. The trypsin subsequently
toxin or other environmental factors. However, recent activated by various digestive enzymes acts as an initial
studies have suggested that there is a significant genetic triggering factor for chronic pancreatitis. The process of
association with FCPD as discussed below. trypsinogen activation or failure of trypsin inactivation
can be influenced by various genetic variations. The
Genetic Factors cascade of trypsin activation and the model of chronic
Initial genetic studies on FCPD were conducted to detect pancreatitis. SPINK1 and CTRC mutation is found to be
an association with the HLA complex. A study by Kambo associated with TCP. However there is no relationship
et al. (1989) from Southern India has shown that 40% between the PRSS1/PRSS2 and TCP.
of FCPD patients share the HLA-DQ-B haplotype, which Trypsinogen gene: There are three different types of
is usually associated with type 1 diabetes mellitus. trypsinogens found in pancreatic juice such as cationic
Another 40% of FCPD patients have shown an association trypsinogen (PRSS1), anionic trypsinogen (PRSS 2),
with the class 3 allele of the insulin gene, which is and mesotrypsinogen (PRSS 3). Mutations in anionic
similar to the association seen in some type 2 diabetic trypsinogen gene (PRSS 2) are not associated with tropical
patients.101 A case control study from Cuttack has demon­ calcific pancreatitis.104-106 A mutational study on the PRSS1
strated an association between FCPD and HLA-DQ9 gene in 283 Indian patients and 43 normal subjects with
(A*0201-B*0303).102 a family history of the disease did not elucidate any
More than a century ago, it was Chiari who postulated association.107,108 Moreover, a recent study failed to detect
in 1896 that pancreatitis is caused by the premature any trypsinogen copy number variations in 268 Indian
activated trypsin resulting in autodigestion of the pan­ TCP patients.109
creas. However, identification of the PRSS-1 gene causing Chymotrypsinogen C: Chymotrypsinogen C also known
hereditary pancreatitis has led to a paradigm shift in our as caldecrin was first isolated from the porcine pancreas
understanding of the pathogenesis of pancreatitis.103 In in 1992. It has a protective effect on the pancreas by
the last two decades, a concerted effort has been made degrading inappropriately activated trypsinogen, so loss
to identify the genes associated with various types of of function of this enzyme may lead to pancreatitis. A
chronic pancreatitis. Tropical pancreatitis has many German study showed an association between the CTRC
features similar to that of hereditary pancreatitis such as variant and hereditary pancreatitis. A study from India
(a) younger age of onset; (b) presence of calcification; and has reported five different CTRC variants in 10 out of 70
(c) risk for development of cancer, which has generated (14.1%) FCPD patients. The frequency of variation was
interest among researchers to identify the genetic basis of higher in comparison to Caucasian patients.110
FCPD. The gene mutation associated with FCPD can be The serine protease inhibitor, Kazal type 1 (SPINK1):
divided into the following categories: The serine protease inhibitor, Kazal type 1 (SPINK1) also
380 Clinical Profile

known as a pancreatic secretory trypsin inhibitor (PSTI), T663C, and Ser53Gly) polymorphisms of CSTB were
is a potent anti-protease. It is produced by the pancreatic sequenced. Leu26Val was found to be significantly over-
acinar cells and acts as a first line of defense against expressed in TCP patients.115 The association appeared to
prematurely activated trypsin by binding and inhibiting be independent of SPINK1 mutation status suggesting that
its activity up to 20%. Loss of function mutations in the val26 may act as a susceptibility allele in the pathogenesis
SPINK1 gene increases the amount of activated trypsin of TCP.
which is responsible for causing pancreatitis. The N34S Calcium-sensing receptor: Mutations involving the
section

mutation of the SPINK1 has been reported to be strongly calcium sensing receptor (CASR) have been proposed to
increase the risk of chronic pancreatitis, since an elevated
7

associated with idiopathic and familial pancreatitis. A

study by Chandak et al. (2002) detected SPINK1 mutations intracellular calcium level activates trypsinogen within
in 32 out of 68 (47%) of TCP and FCPD patients. Of 43 the acinar cells. Recently, Murugaiyan et al. (2008) has
screened the complete CASR coding region by direct DNA
patients with N34S mutation, 8 were homozygous, 23 were
sequencing in 35 Indian TCP patients and 35 controls.
heterozygous and 1 was compound heterozygote with
This study has shown four different heterozygous CASR
P55S. The SPINK1 mutation frequency in FCPD patients
variants in 5/35 patients (14.9%), which was absent in
and TCP patients without diabetes showed similar trends
the controls. All CASR variant patients had normal serum
suggesting the possibility of a similar disease. 111 A genetic
calcium level and thus the functional significance of this
study on the SPINK1 mutation from two separate ethnic
variant is yet to be established.116
groups from the Indian subcontinent (Bangladesh and Diabetes is an important albeit late feature of TCP;
South India) documented a N34S variant present in 33% however, the pathogenetic pathway leading to hyper­
of 180 subjects with FCPD, 4.4% in a non-diabetic and glycemia is not clear. Type 2 diabetes-associated poly­
3.7% in type 2 diabetic subjects. This result suggests that morphisms in transcription factor 7 like protein 2
the N34S variant of SPINK1 is a susceptibility gene for (TCF7L2) were screened in TCP and subjects with FCPD
FCPD.112 A study by Bhatia et al. (2002) detected N34S but no association was found with FCPD. It has been
missense mutation in 44% of their FCPD patients. All these hypothesized that polymorphism in TCF7L2 gene may
reports suggest that TCP and FCPD are strongly associated interact with SPINK 1 and CTSB mutations and cause
with the SPINK1 N34S mutation. Other variants of the diabetes mellitus.117 Studies on REG1A, REG1B and ACE
SPINK1 alteration have also been reported. A novel G to T gene were not found to be significant in FCPD and TCP
transversion at 215 bp upstream in the SPINK1 promoter patients.118-120
region (− 215 G > T) was identified in three patients of Thus, the pathogenesis of FCPD is a complex process.
FCPD from India.107 A heterozygous SPINK1 variant, None of the previously mentioned etiological factors can
c.194 + 2T > C (IVS3 + 2T > C) was reported in a female fully explain the pathogenesis of FCPD. Like other complex
FCPD patient from Thailand.113 disorders, TCP could be an end result of the interaction
between environmental and genetic factors. It has been
Alterations in Other Genes found that Indian patients with TCP and normal controls
had very low lipase and phospholipase levels in their
Cystic fibrosis transmembrane conductance regulator: pancreatic juice as compared to French counterparts.50
Data on CFTR mutation in TCP patients is limited. A study Thus it has been proposed that there is existence of a
from India reported a CFTR mutation rate of 11.5% (2 out condition known as subclinical pancreatopathy in TCP
of 18 patients), one subject was homozygous for 5T and patients living in a developing country. Recently,
the other was heterozygous for p.R1070Q. This is the first Mahurkar et al. (2009) has proposed a two hit model for
study which has looked for the CFTR mutation in TCP the pathogenesis of FCPD. The first hit model includes
patients.114 the mutation of one or more genes, resulting in the
Cathepsin B: The CTSB is a lysosomal hydrolase, formation of supertrypsin in the acinar cell of the pancreas.
which mediates activation of trypsinogen within the The second hit probably involves certain unidentified
acinar cell of the pancreas. Mahurkar et al. (2006) has genes which may lead to one or more phenotypes such
performed a mutational analysis in 306 cases of TCP as stone formation, fibrosis and/or diabetes mellitus
and 300 controls. Genotyping of four (Leu26Val, C595T, (Flow chart 25.1).121
 Fibrocalculous Pancreatic Diabetes 381
Flow chart 25.1: Two hits or multiple hits hypothesis in pathogenesis
of TCP

chapter
25
Fig. 25.3: Plain X-ray abdomen showing pancreatic (see arrow)
calculi at the level of L1 and L2 vertebrae

(SPINK1: Serum protease inhibitor Kazal type 1; CTRC: Cathepsin B;

CTRC: Chymotrypsinogen C; TCP: Tropical calcific pancreatitis) L2 is diagnostic of FCPD in its late stages, as it takes
Source: Adapted from Mahurkar S, Reddy DN, Rao GV, et al. Genetic
several years for the calculi to develop from the onset
mechanisms underlying the pathogenesis of tropical calcific pancrea-
titis. World J Gastroenterol. 2009;15:264-9. of abdominal pain (Fig. 25.3). However, about 10% of
patients do not develop calculi. The diagnosis of FCPD is
based on the demonstration of pancreatic calcification,
INVESTIGATIONS dilatation of the main pancreatic duct and its branches
and focal or diffuse atrophy of the pancreas. EUS and CT
Fibrocalculous pancreatic diabetes is a slowly progressive scan can easily elucidate the above findings. However,
disease. It is essential to establish the evidence of chronic USG has sensitivity of only 50–80% and specificity of
pancreatitis in patients presenting with clinical features of 80–90% and thus may show problems in the presence of
FCPD. Early stages of FCPD are difficult to be diagnosed abdominal gas and artifacts. A CT scan is more sensitive
as there are no sensitive or specific blood and urine tests, and specific than USG as it can even diagnose smaller
but can be diagnosed on histopathological examination. stones and pseudocyst of pancreas122,123 (Figs 25.4A and B).
The currently available diagnostic tests are accurate in MRCP and ERCP are probably the best ways to examine
advanced disease, when obvious functional or structural ductal changes such as ductal tortuosity and dilatation,
abnormalities are present. The diagnostic test for FCPD stenosis, obstruction, cyst formation and calculi in the
can be categorized into two groups: (a) tests to study main pancreatic duct and its branches.124 ERCP plays
pancreatic morphology; and (b) tests to study pancreatic an important role in situation where a therapeutic
function. procedure is required. An endoscopic ultrasound is equally
effective in diagnosing parenchymal and ductal changes
Tests to Study Pancreatic Morphology of the pancreas. Early changes of FCPD can be assessed
• Plain X-ray abdomen by an EUS, however it is highly operator dependent.
• Ultrasonography (USG) EUS has an over all sensitivity of 85% but a low specificity
• Computerized tomography scan abdomen of 67%.125
• Magnetic resonance imaging and magnetic resonance
cholangio-pancreatography (MRCP). Tests to Study Pancreatic Function
• Endoscopic retrograde cholangio-pancreatography
(ERCP). Tests for Exocrine Pancreatic Function
• Endoscopic ultrasonography (EUS). The exocrine pancreatic function tests in FCPD can be
Plain X-ray of the abdomen demonstrating the classified into direct stimulation tests and indirect stimula­
presence of calcification at the vertebral level of L1 and tion tests.
382 Clinical Profile
section
7

A B
Figs 25.4A and B: (A) Ultrasound finding in FCPD showing multiple calcifications and thinning of the pancreatic parenchymal; (B) Computerized
tomography (CT) scan of pancreas in FCPD showing multiple intraductal calculi and parenchymal calcification, atrophy of pancreas and ductal
dilatation

Direct stimulation test: Direct stimulation tests assess reported that 93% of patients had low IRT levels.127
the pancreatic function by measuring the enzyme and Another study by the same group observed subnormal
bicarbonate output from the duodenal fluid following the IRT levels in a few patients with TCP, while IRT levels
administration of a meal or hormonal secretagogues. The were reduced in more than two-thirds of FCPD patients.128
Lundh meal test and hormonal [secretin, cholecystokinin Estimation of serum amylase and lipase levels are not
(CCK) or both] stimulation tests are the most commonly found to be useful in TCP and FCPD patients.129,130 These
performed direct stimulation tests. The direct tests tend enzyme levels were found to be normal even in acute
to be unpleasant for patients as they are time-consuming exacerbations. Qualitative estimation of stools (Sudan-
and expensive and are performed primarily in specialized III) is less reliable than quantitative 72 hour fecal fat
centers. In the Lundh test, the enzyme content of the estimations. A study by Balakrishnan et al. reported that
duodenal fluid is estimated after administration of test the daily intake of fat in TCP patients was about 27 g.
meals. This test depends on the release of endogenous However, on a high fat diet, steatorrhea (72 hour stool
secretin and CCK. So it may be unreliable in the setting fat estimation ≥ 18.43 g) was noted in 76% of patients.50
of altered anatomy or concomitant mucosal disease. Several studies have used fecal chymotrypsin (FCT) as
Punnose et al. (1976) had performed the Lundh test to a screening test for evaluating the exocrine pancreatic
determine pancreatic function in patients with TCP. function in patients with FCPD. FCT in FCPD studied
Ninety-three percent of the TCP patients with calcification by Mohan et al. has shown abnormal values in 87.5% of
have low tryptic activity as compared to 27% in the non- patients. FCT is considered abnormal if the test value
calcific variety.126 Secretin pancreozymin tests done is less than 5.8 units/gram of fecal mass. A low FCT was
by Balakrishnan et al. (1988) in TCP patient revealed detected in 23.5% with type 1 diabetes, and 4.5% with T2D.
gross reduction in volume, bicarbonate, trypsin, and The low sensitivity is a drawback with FCT as it may not
lipase content of the pancreatic secretion. Lactoferrin detect many mild cases of chronic pancreatitis although
and calcium levels of pancreatic juice were found to be its specificity is quite high.127,129,131 Another study by Mohan
considerably higher in both normal controls and TCP et al. compared two tubeless tests (FCT and NBT-PABA)
patients from India (Kerala) when compared with their to assess the exocrine function in FCPD patients. FCT
French counterparts.50 is found to be less sensitive than the NBT-PABA test;
Indirect stimulation tests: Indirect stimulation tests however it is a more cost effective test. NBT-PABA/p-
assess pancreatic function by measuring pancreatic enzy­ amino salicylic acid test is a more efficient test to diagnose
mes in blood or stool. A study on serum immunoreactive TCP as it has a very high sensitivity and specificity. The
trypsin (IRT) levels in FCPD patients by Yajnik et al. NBT-PABA/PAS test has shown a sensitivity of 75% and
 Fibrocalculous Pancreatic Diabetes 383

a specificity of 81% in tropical pancreatitis.132 PABA/PAS Complications Related to Chronic Pancreatitis

excretion index (PEl) shown a sensitivity of 75% and a
Chronic pancreatitis can be associated with a variety of
specificity of 92%. Newer fecal tests such as fecal elastase
complications. Pancreatic pseudocyst, mechanical obstruc­
and immunoreactive lipase are promising simpler tests
tion of the bile duct and duodenum are the common
but they have a low sensitivity in mild disease and their
complications of FCPD. Pancreatic abscesses, pancreatic
utility in FCPD have yet to be evaluated. Fecal elastase has
ascitis or pleural effusion, splenic vein thrombosis with
significant advantages over fecal chymotrypsin, in that it

chapter
portal hypertension and pseudoaneurysms are less freq­
is much more stable in stool and is easier to measure.133,134
uent complications. The obstruction of the common bile

25
However, it is quite expensive.
duct and carcinoma of the pancreas can be associated
with obstructive jaundice.
Tests for Endocrine Pancreatic Function
Endocrine insufficiency and clinical diabetes develops Pancreatic Cancer
in the advanced stages of TCP. The loss of beta cell mass
Patients with FCPD have increased the risk of pancr­eatic
in FCPD is attributed to parenchymal fibrosis. Beta cell cancer. Several prospective and retrospective studies
reserve can be assessed by measuring serum C-peptide have described FCPD as a premalignant condition. The
and insulin levels. The absence of ketoacidosis on insulin risk of developing pancreatic cancer is 16.5-fold higher in
withdrawal suggests the presence of partial beta cell chronic pancreatitis patients as compared to age matched
function in FCPD.51 Mohan et al. showed that FCPD controls.135 Chari et al. followed 185 cases of FCPD at
patients have better beta cell preservation in comparison Dr Mohan’s Centre at Chennai over a period of 4.5 years,
with type-1 diabetic patients and this protected them out of which 25 died during follow-up and 6 (25%) cases
from ketoacidosis.51 Yajnik et al. (1990) measured the of death were due to pancreatic carcinoma. When this
endocrine metabolic profile in 28 FCPD patients by data was compared with the background pancreatic
oral glucose tolerance test (OGTT) and found that beta cancer rate (Chennai Cancer Registry) the relative risk of
cell function was severely diminished, while alpha cell pancreatic cancer among FCPD patients were found to be
function was preserved.60 Yajnik et al. also reported that 100 (95% confidence interval 37 to 218).136 Augustine and
beta cell function correlated well with the glycemic status Ramesh reported 22 cases of pancreatic cancer among
of the TCP patients. TCP patients with a normal glycemic 266 patients with FCPD during a period of 8 years. In
status or impaired glucose tolerance has a better beta cell this cohort, the factors associated with a higher risk of
function as compared to subject with diabetes.57 Subjects cancer were aged more than 40 years, a shorter duration
with diabetes showed a variable beta-cell function but it of symptoms and a mass on ultrasound. Intractable pain,
was severely diminished in more than 75% of subjects. weight loss, worsening of diabetes and jaundice were
Plasma glucagon responses have been shown to be the common presenting symptoms in FCPD patients
blunted in patients with FCPD. Mohan et al.58 and Yajnik with pancreatic carcinoma.137 Adenocarcinoma is the
et al.59 showed that in response to a glucose load, plasma most common type of pancreatic carcinoma in FCPD
glucagon levels rose sharply in subjects with primary and occurs predominantly near the head of the pancreas
forms of diabetes, whereas glucagon response was blunted and is locally invasive in nature. Pancreatic carcinoma
in FCPD. is more common in FCPD than in alcoholic pancreatitis.
Hereditary pancreatitis has a similar risk of cancer when
COMPLICATIONS compared with FCPD. The exact reason as to why FCPD
patients are prone for a higher risk of cancer is not known.
Complications in FCPD can be classified into four broad A longer duration of disease, exposure to inflammation
categories: and smoking have been speculated as the major factors
1. Complications related to chronic pancreatitis. that are responsible for the transformation of cases
2. Complications related to diabetes. of FCPD into malignancy. FCPD patients should be
3. Complications related to exocrine insufficiency. monitored with CA-19.9 and imaging (USG or CT scan) for
4. Pancreatic osteodystrophy. the early diagnosis of pancreatic cancer.
384 Clinical Profile

Complications Related to Diabetes Diabetic Neuropathy

Diabetic Retinopathy Diabetic neuropathy is the most common micro­vascular
complication of FCPD. Symptoms suggestive of peri­
Earlier studies have presumed that patients with FCPD pheral neuropathies are reportedly more common than
do not develop long-term complications of diabetes. This objective evidence of neuropathy. The prevalence of
has been based on the assumption that patients with neuropathy varies from 10% to 90% in different studies.
secondary diabetes have a shorter term of survival and do
section

Studies done to determine peripheral neuropathy by

not live long enough to develop diabetes related complica­ nerve conduction velocity have a higher prevalence rate
7

tions. This no longer appears to be the case, as several when compared to clinical studies.142 Barman et al. repor­
studies in the last decade had reported microvascular ted a 21% prevalence of neuropathy in subjects with
complications in FCPD. Geevarghese in his monograph FCPD.139 Nutritional deficiencies and the additive effect
mentioned the occurrence of both mild background diabetic of alcohol consumption might increase the occurrence of
retinopathy (BDR) and sight-threatening proliferative neuropathy. Autonomic neuropathy is quite common in
diabetic retinopathy (PDR) in FCPD.4 However, it was FCPD.143 A study from Chennai showed a prevalence rate
the pioneering studies of Dr Rema Mohan from Chennai of over 60% in patients with duration of diabetes more
that established beyond doubt with the help of retinal than 15 years as compared to 16% in those with a shorter
photography that diabetic retinopathy occurs in FCPD duration of diabetes (0–5 years).144 In a recently published
patients.37 Rema et al. observed diabetic retinopathy in study by Nanaiah et al. from Vellore using state of the art
13 out of 40 patients, 3 patients had proliferative retino­ technology has shown that 63.1% had cardiac autonomic
pathy and 1 patient had maculopathy.138 This pioneering neuropathy, 42.3% parasympathetic dysfunction and
work along with others in the literature around the same 13.3% had combined sympathetic and parasympathetic
time, led to a fundamental change in the prevailing dysfunction.145 Macro­vascular complications are uncom­
concept at that time that microvascular complications do mon in FCPD. This has been attributed to three factors:
not occur in secondary forms of diabetes. Indeed, a line (1) a younger age of patients; (2) a lower body mass index;
to this effect in Harrison’s Textbook of Medicine in the and (3) absence of other risk factors of cardiovascular
late 1970’s was deleted in subsequent editions of the Text disease such as dyslipidemia.146 Data on the association
book. A subsequent and larger study from Mohan’s group between FCPD and macrovascular complications are
by Barman et al. reported a 30% prevalence of retinopathy currently based only on anecdotal case reports.147,148
in FCPD, which was similar to that seen in a matched However, reports of macrovascular complications such as
group of patients with T2D (32%).139 Other microvascular stroke, peripheral vessel disease (PVD), coronary artery
complications like neuropathy were reported in 20.9% disease (CAD), and hypertension have been more freq­
and nephropathy in 10.1% in the same cohort. A study uently reported.149,150 A study from Chennai has shown
from Pune reported various patterns of retinopathy such that 4.7% of patients with FCPD had PVD and about 5%
as background retinopathy, maculopathy and PDR in had CAD.139 Insulin resistance and hyperinsulinemia are
patients with FCPD. Patients with PDR have long standing important predictors of cardiovascular disease in diabetes.
diabetes, the median duration being 5 years (1.5–30 years), Several studies were reported regarding co-existence of
two patients had PDR requiring laser photocoagulation
insulin resistance in patients with FCPD, however data
and one patient was blind in an eye as a result of central
was limited. Thus it requires further studies to determine
retinal artery occlusion.45
the presence of insulin resistance in patients with FCPD.
In a study, 15 normotensive FCPD patients with a normal
Diabetic Nephropathy electrocardiogram (ECG) (rest and exercise) were asse­
Earlier studies have reported that 21–23.8% of patients ssed for their left ventricular (LV) function by means of
with pancreatic diabetes had overt nephropathy, while systolic time intervals. Abnormal PEP/LVET ratios were
33% had microalbuminuria.140 A study from Chennai observed in 5/13 (38%) patients based on which it was
by Mohan’s group has shown a 10% prevalence of overt suggested that the LV dysfunction may be due to diabetic
nephropathy in FCPD subjects.138 Nephropathy is possibly cardiomyopathy. However, further studies are required
one of the leading causes of death among these patients.141 to establish this hypothesis.146
 Fibrocalculous Pancreatic Diabetes 385

Complications Related to a low bone mineral density in FCPD.154 Thus it has been
Exocrine Insufficiency suggested that osteodystrophy in chronic pancreatitis
is an under-recognized disorder that requires further in
Malnutrition is quite common in patients with FCPD. depth evaluation.
The pathogenesis of malnutrition in FCPD is probably
multifactorial in nature and can be precipitated by CRITERIA FOR DIAGNOSIS OF FCPD
chronic inflammation, exocrine pancreatic insufficiency

chapter
(steatorrhea, fat soluble vitamins deficiencies) and under The most commonly used and followed criteria for FCPD

25
nutrition. Patients with FCPD prefer to consume low is that proposed by Mohan et al. and are as follows:10,86
fat diets since there may be an increased frequency of • The patient should originate from a tropical country
steatorrhea and abdominal pain following a fatty meal. • Diabetes should be present
Patients with FCPD are insulinopenic and hence are • Evidence of chronic pancreatitis must be present
prone to have poor glycemic control and weight loss. (pancreatic calculi on abdominal X-ray or at least three
Beyond steatorrhea and malabsorption, under nutrition of the following (i) abnormal pancreatic morphology
and a lean body weight has been attributed to a restricted on sonography/CT scan; (ii) recurrent abdominal pain
calorie and protein intake as advised by some physicians since childhood; (iii) steatorrhea; (iv) abnormal pan­
for achieving good glycemic control. An associated low creatic function tests; and (v) absence of other causes
socio-economic status deprives those patients of a balan­ of chronic pancreatitis.
ced and nutritious diet.151
LIFE EXPECTANCY, SURVIVAL AND
Pancreatic Osteodystrophy CAUSES OF MORTALITY
Pancreatic osteodystrophy in patients with chronic In the 1960s and 1970s, the clinical characteristics of
pancreatitis comprises osteopenia, osteoporosis and FCPD had been described as pain in childhood, diabetes
osteomalacia. In chronic pancreatitis, factors that are mellitus at puberty and death in the prime of life.4 Death
associated with an increased risk of bone loss may be due in FCPD patients were mainly due to complications
to chronic inflammation, low body mass index, under of chronic pancreatitis and partly related to diabetes
nutrition, co-existing diabetes, poor sunlight exposure mellitus. Today, patients with FCPD survive longer due to
and decreased physical activity due to a chronic illness. better glycemic control assisted by insulin, easily available
Vitamin D deficiency in chronic pancreatitis is attributed glucose monitoring and improved nutritional support.
to pancreatic exocrine insufficiency and steatorrhea.152 Mohan et al. analyzed the survival time in a cohort of
The deficiency of Vitamin D leads to reduced calcium 370 FCPD patients. The occurrence of the first episode of
absorption, bone formation and remodeling, which abdominal pain and the time of onset of diabetes were
ultimately leads to osteopenia, osteoporosis and considered as two reference points. About 80% of patients
osteomalacia. Sudeep et al. performed a study on bone were alive for 35 years after the first episode of abdominal
mineral density, biochemical parameters and 72-hr fecal pain. The mean survival time after the diagnosis of
fat in 31 patients (20 FCPD patients and 11 idiopathic diabetes was 25 years. Majority of deaths were attributable
pancreatitis) which were compared with 35 healthy to diabetes related complications. Diabetic nephropathy
controls. The median vitamin D level was 19 ng/mL, 64% of was one of the major causes of the death that accounted
the subjects had vitamin D deficiency, among which 24% for 40% of cases. Other causes of death were due to severe
had severe vitamin D deficiency as per Hollick’s criteria. infections, pancreatitis and pancreatic cancer.141 Earlier
Osteoporosis (T-score minus 2.5) was detected in 29% of diagnosis, better glycemic control and pancreatic enzyme
the subjects while 32% had osteopenia (T-score between supplements ensure better survival and improve the
prognosis and quality of life n FCPD.
minus 1 and minus 2.5). Subjects with steatorrhea had a
significantly reduced bone mineral content when com­
pared to patients without steatorrhea.153 This study has
Energy Expenditure in FCPD Patients
shown a high prevalence of vitamin D deficiency, osteo­ A study by KK Behera et al. from Vellore (2012, unpub­
penia and osteoporosis amongst patients with chronic lished) measured the energy expenditure (resting energy
pancreatitis. A similar study from Lucknow has shown and total energy) in 21 patients with FCPD, compared
386 Clinical Profile

with 15 patients with T2D and 12 healthy controls. There patients do not secrete this antigen due to their Lewis
was no difference in resting energy expenditure between antigen status.160 Moreover in asymptomatic cases and
FCPD and other groups. Total energy expenditure was patients with a smaller tumor size, CA 19.9 levels may be
lowest in FCPD, intermediate in T2D and highest in within the normal range and is often elevated in benign
healthy controls.155 This is first such study conducted to biliary or pancreatic conditions such as acute cholangitis
estimate energy expenditure in FCPD and thus there is a or chronic pancreatitis.161 Among the imaging modalities,
need for further research in this field. CT scan is more valuable in predicting malignancy than
section

USG and ERCP.

MANAGEMENT
7

Surgical Procedures
Diabetes Mellitus
The main indications for surgery in FCPD are intractable
The primary goal of management of diabetes is to control pain, obstructive jaundice, gastric outlet obstruction,
hyperglycemia and its complications. The principles of leaking pseudocyst and suspicion of malignancy.162-164
diet and exercise therapy are similar to that of other
types of diabetes. Liberal calorie and protein intake are Pattern of Surgical Procedures in TCP and FCPD
advisable in case of associated undernutrition. Insulin is
Carcinoma in tropical calcific pancreatitis
essential for glycemic control in the majority of patients.
• Classical whipple
However, oral diabetic agents can be tried in milder cases
• Pylorus-preserving pancreaticoduodenectomy (PPPD)
of diabetes and in the early phase of the disease.
• Distal pancreatectomy (Duval procedure)
Steatorrhea • Palliative biliary drainage alone
• Biliary drainage
Pancreatic enzyme supplementation reduces steatorrhea • Celiac ganglion block/nerve ablation
and improves the quality of life in patients with FCPD.156 It • Subtotal pancreatectomy
can be helpful in reducing abdominal pain and improving • Local resection of the head of pancreas
glycemic control. Benign tropical calcific pancreatitis
• Longitudinal pancreatico jejunostomy (LPJ) (Puestow
Abdominal Pain
procedure)
Non-opioid analgesics should be the first choice and • Distal pancreatectomy
opioids should be avoided wherever possible for fear of • Frey’s procedure (local resection of head + LPJ)
addiction. Opioids and octreotide may be considered in • Subtotal pancreatectomy.
case of intractable abdominal pain. Advanced procedures Improvement in general health and quality of life are
like nerve ablation or celiac ganglion block may be useful. seen in patients with intractable abdominal pain following
Surgical procedures may sometimes be required in surgical procedures. There are some reports suggesting
intractable abdominal pain.157,158 transient improvement in the glycemic status following
surgical procedures; however the long-term outcome is
Fat Soluble Vitamin Deficiencies still unknown. The morbidities of surgical procedures are
Fat soluble vitamin deficiencies are common in FCPD. postoperative bleeding, pancreatic leak, delayed gastric
emptying, wound infection and adhesive small bowel
A study by Bhatia et al. reported that an intramuscular
obstruction. Recurrent pain postsurgery may be due to
injection of vitamin D (6,00,000 IU) once in 6 months
stenosis of the anastomosis, retained calculi causing
was adequate to maintain vitamin D status in FCPD
cysts or abscesses and internal postoperative herniations
patients.159 Intramuscular injections are preferred over the
sometimes twisting the roux-en-Y loop used for the
oral route as intestinal absorption is poor due to pancreatic
pancreatico jejunal anastomosis. However, pancreatic
enzyme deficiencies.
carcinoma is one of the most important causes of recurrent
abdominal pain.
Monitoring for Early Detection
The indications of endotherapy in TCP patients are
of Pancreatic Cancer pain, stones and strictures. The most commonly performed
CA 19.9 is the most widely used tumor marker, however procedures are endoscopic pancreatic sphincterotomy
it has limited value as a screening tool because 10–15% (EPS), extracorporeal shock wave lithotripsy (ESWL),
 Fibrocalculous Pancreatic Diabetes 387

endoscopic stone extraction, and endoscopic stenting. 6. WHO Study Group Report on diabetes mellitus. WHO
However, removal of stones may not guarantee relief Technical Report Series No.727. Geneva: WHO; 1985.
7. Report of the Expert Committee on the diagnosis of classifi­
of pain.165,166
cation of diabetes mellitus. Diabetes Care. 1997;20:1183-97.
8. Assan R, Assan D, Thiebaut MF, et al. Diabetogenic tropical
CONCLUSION pancreatitis. Diabete Metab. 1988;14:299-312.
9. Mohan V, Premalatha G. Fibrocalculous pancreatic
Fibrocalculous pancreatic diabetes is a distinct form of diabetes. Int J Diabetes. 1995;3:71-82.

chapter
diabetes secondary to TCP diabetes mellitus. Recent 10. Mohan V, Alberti KGMM. Diabetes in the tropics. In: Alberti
KGMM, Defronzo RA, Keen H, Zimmet P (Eds): Interna­

25
studies have shown the evidence of the changing clinical
tional Textbook of Diabetes Mellitus. John Wiley and Sons
profile, natural history and long-term survival in these
Ltd; Chichester:1999. pp. 177-96.
patients. The role of genetic factors in the etiopathogenesis 11. Anand BS. Clinical profile of chronic pancreatitis in
of FCPD has been emerging strongly during the last two Delhi. In: Balakrishnan V (Eds): Chronic Pancreatitis in
decades. Further studies are needed to elucidate the India. Trivandrum: Indian Society of Pancreatology. 1987.
etiopathogenesis and long-term prognosis of FCPD. pp.15-22.
12. Chari ST, Mohan V, Jayanthi V, et al. Comparative study of
the clinical profile of alcoholic pancreatitis and tropical
further reading chronic pancreatitis in Tamilnadu, South India. Pancreas.
1991;7:2-58.
1. Balakrishnan V, Sauniere JH, Hariharan M, Sarles H. Diet, 13. Chari ST, Jayanthi V, Mohan V, et al. Radiological appear­
pancreatic function and chronic pancreatitis in South ances of pancreatic calculi in tropical and alcoholic chronic
India and France. Pancreas. 1988;3:30-5. pancreatitis. J Gastroenterology Hepatology. 1992;7:42-4.
2. Mittal N, Mehrotra R, Agarwal G,et al. The clinical spectrum 14. Zuidema PJ. Cirrhosis and disseminated calcification of the
of fibrocalculous pancreatic diabetes in north India. Natl pancreas in patients with malnutrition. Trop Geogr Med.
Med J India. 2002;15:327–31. 1959;11:70-4.
3. Kanta Barman K, Padmanabhan M, Premalatha G, Deepa 15. Azad Khan AK, Banik NG, Mahtab H, Malnutrition Related
R, Rema M, Mohan V.Prevalence of diabetic complications Diabetes Mellitus in Bangladesh. In: Rifkin H, Colwell JA,
in fibrocalculous pancreatic diabetic patients and type Taylor SI (Eds). Proceedings of 14th IDF Congress. Amster­
2 diabetic patients: a cross-sectional comparative study. dam: Elsevier Sciences Publishers; 1991. pp. 944-9.
J Diabetes Complications. 2004;18:264-70. 16. IIIangovekara V. Malnutrition related diabetes in Sri Lan­
4. Mahurkar S , Reddy D N, Rao G V , Chandak GR. Genetic ka: fact or fiction? J Ceylon College of Physicians. 1995;
mechanisms underlying the pathogenesis of tropical cal­ 28:16-25.
cific pancreatitis. World J Gastroenterol. 2009;15:264-269. 17. Shaper AG. Chronic pancreatic disease and protein
5. Papita R, Nazir A, Anbalagan VP, et al. Secular trends of malnutrition. Lancet .1960;1:1223-4.
fibrocalculous pancreatic diabetes and diabetes second­ 18. Kinnear TWA. Patterns of diabetes in a Nigerian teaching
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pancreatic diabetes. Acta Diabetol Lat. 1989;26:345-9. 166. Ong WC, Tandan M, Reddy V, et al. Multiple main

148. Sastry NG, Mohan V. Hemiplegia in a patient with
pancreatic ducts stone in tropical pancreatitis: safe
fibrocalculous pancreatic diabetes. J Assoc Physicians clearance with extracorporeal shockwave lithotripsy. J Gas­
India. 2000;48:1129. troenterol Hepatol. 2006:21:1514-8.
 Chapter 26
Secondary Diabetes
Dukhabandhu Naik, Nihal Thomas

Secondary Diabetes

Chapter Outline
♦♦ Diseases of the Exocrine Pancreas ♦♦ Viruses and Diabetes Mellitus
♦♦ Endocrinopathies and Diabetes Mellitus ♦♦ Drug Induced Diabetes
♦♦ Syndromes of Primary Insulin Resistance ♦♦ Immune Mediated Diabetes
♦♦ Lipodystrophic Syndromes ♦♦ Secondary Diabetes in Children
♦♦ Genetic Syndromes Associated with Diabetes Mellitus

INTRODUCTION of certain drugs). In the remainder of cases, diabetes

may be associated with a number of genetic syndromes.
The term secondary diabetes generally refers to diabetes Another complex feature in the evolution of secondary
or glucose intolerance associated with other disorders and diabetes is that there may be a coexistence of primary
conditions. Presumably, diabetes can be reversed if the
diabetes which needs to be ruled out prior to classifying
disease or condition is cured. This kind of diabetes usually
it as secondary diabetes.
is precipitated by another primary disease or condition.
According to the classification system developed by
The textbook of Secondary Diabetes by Podolsky and
the Expert Committee on the Diagnosis and Classification
Viswanathan still remains a classic in this field and is
of Diabetes Mellitus, diabetes is classified into four broad
perhaps the only comprehensive book on this subject.1
categories:3
Based on the Diagnosis and Classification of Diabetes
1. Type 1 diabetes mellitus (T1DM)
Mellitus by the Expert Committee, Secondary diabetes
has now been redefined as “Other Specific forms of 2. Type 2 diabetes mellitus (T2DM)
Diabetes”.2 Secondary diabetes constitutes about 1–2% 3. Other specific types of diabetes
of the total cases of diabetes mellitus. There is no precise 4. Gestational diabetes mellitus.
way to estimate the true prevalence of secondary diabetes In the above classification, secondary diabetes is
as most data are based on the clinical studies and case categorised under other specific type of diabetes.
reports which are subjected to referral bias. The other specific forms of diabetes are as follows:
The glycemic status of secondary diabetes varies widely 1. Genetic defects of beta cell function
from impaired glucose intolerance to insulin requiring 2. Genetic defects in insulin action
overt diabetes mellitus. In most cases of secondary 3. Diseases of the exocrine pancreas: Pancreatitis, pan­
diabetes, the etiology is known (e.g. diabetes secondary to createctomy, neoplasia, cystic fibrosis (CF), hemo­
pancreatic disease, endocrine disease or administration chromatosis, fibrocalculous pancreatitis
 Secondary Diabetes 393

4. Endocrinopathies: Acromegaly, Cushing’s syndrome, shown in Table 26.1. The pathophysiology of pancreatic
glucagonoma, pheochromocytoma, hyperthyroidism, diabetes is predominantly related to beta cell failure and
somatostatinoma, aldosteronoma reduced insulin secretory capacity. However, insulin
5. Drug or chemical induced: Glucocorticoids (GCs), vacor resistance may also be present in certain cases.5,6
pentamidine, nicotinic acid, diazoxide, adre­nergic ago­
nists, thiazides, hydantoins, asparaginase, interferon Acute Pancreatitis
(IFN), protease inhibitors, antipsychotics and epineph­ Acute pancreatitis is an acute inflammatory process of the

chapter
rine pancreas. It usually presents with acute upper abdominal

26
6. Infections: Congenital rubella, cytomegalovirus (CMV), pain which is associated with nausea and vomiting.
coxsackievirus Alcoholism and gallstones are the most common causes
7. Uncommon forms of immune-mediated diabetes: Stiff- of acute pancreatitis while other causes are shown in
Person syndrome, anti-insulin receptor antibodies Table 26.2.7 Pain is usually episodic in nature and gets
8. Other genetic syndromes sometimes associated with aggravated by food intake and supine posture and it’s
dia­b etes: Wolfram’s syndrome, Down’s syndrome, partially relieved by sitting up and leaning forward.
Kline­felter’s syndrome (KS), Turner’s syndrome (TS), The diagnosis of acute pancreatitis is usually established
Friedreich’s ataxia (FRDA), Huntington’s chorea, by the detection of an increased level of serum amylase
Laurence-Moon-Biedl syndrome, Myotonic dystrophy, and lipase. However, there is no direct correlation between
Porphyria, Prader-Willi syndrome (PWS). the severity of pancreatitis and the level of elevation
This chapter will focus on sections 3 to 8 of the above of enzymes. Computerized tomography (CT) scans
classification, constituting “secondary diabetes”. may confirm the clinical diagnosis of pancreatitis. CT
findings such as loss of normal pancreatic enhancement
DISEASES OF THE EXOCRINE PANCREAS and pancreatic edema are suggestive of acute pancreatitis.8

The metabolic abnormalities commonly found in
Pancreatic diabetes accounts for 0.5–1.2% of all patients acute pancreatitis are hyperglycemia, hypocalcemia,
with diabetes mellitus. Pancreatic diabetes is usually a hyperlipidemia, hypoalbuminemia and coagulation
complication of pancreatic disorders.4 Several pancreatic disorders. The incidence of glucose intolerance varies
disorders are responsible for pancreatic diabetes as from 9% to 70%.9 Hyperglycemia in acute pancreatitis

Table 26.1: Pancreatic disease associated with glucose intolerance Table 26.2: Cause of acute pancreatitis
and diabetes • Disease of biliary tract: Gall stones, choledochal cysts
Inflammatory • Alcohol
• Acute pancreatitis • Pancreatic duct obstruction (tumor, pancreatic divisum)
• Chronic pancreatitis • Infection: Mumps, coxsackievirus, human immunodeficiency
virus (HIV), mycoplasma pneumoniae
– Fibrocalculous pancreatic diabetes
• D
 rugs and toxins: Didanosine, sulfonamides, tetracyclines,
– Hereditary chronic pancreatitis
valproate, asparaginase, azathioprine, valproic acid, pentava-
– Alcohol lent antimonials, pentamidine, mercaptopurine, mesalamine,
– Autoimmune pancreatitis estrogen preparations, opiates, tetracycline, cytarabine,
steroids, sulfasalazine, furosemide and sulindac
Infiltration
• Endocrine and metabolic disorders: Hypercalcemia, hypertriglyc-
• Hereditary hemochromatosis
eridemia, diabetic ketoacidosis
• Secondary hemochromatosis • Vascular disease (vaculitis)
• Very rare causes: sarcoidosis, amyloidosis, cystinosis • Post-traumatic
Neoplasia • P
 ostsurgical [endoscopic retrograde cholangiopancreatography
• Adenocarcinoma of the pancreas (ERCP)]
• Miscellaneous:
• Glucagonoma
– Hereditary relapsing pancreatitis
Postpancreactectomy: Partial or total
– Reyes syndrome
Trauma – Pancreatic carcinoma
Cystic fibrosis – Connective tissue disorders
394 Clinical Profile

Table 26.3: Causes of chronic pancreatitis parenchyma and degeneration of ducts. Nesidioblastosis
• Alcohol may also be present. In immunohistochemistry, the find­
• Tropical calcific pancreatitis
ing of CP includes generalized reduction in the islet cell
number accompanied by the overall decrease in beta-cell
• Disease of the biliary tract (gall stones)
mass.
• S
 ystemic disease (systemic lupus erythematosus,
hypertriglyceridemia and hyperparathyroidism)
The prominent symptoms for which patients seek
medical attention are recurrent abdominal pain, steat­
• Cystic fibrosis
section

orrhea and weight loss. Pancreatic calcification on

• Hereditary chronic pancreatitis
7

abdominal X-ray is characteristic; however it is less

• Autoimmune pancreatitis
common and is seen in advanced stages of the disease.
• Idiopathic pancreatitis
CT scan and Endoscopic Retrograde Cholangiopancrea­
tography (ERCP) are considered as the gold standard.
is usually transient in nature and is mostly related to Over 80% of patients require insulin, however the required
hyperglucagonemia and relative hypoinsulinemia. doses are typically low (30–40 units/day). Malabsorption
Hyperglycemia is usually mild and resolves within days can be effectively treated with a low-fat diet and
to weeks.10 However, about 11% of the patients may have pancreatic enzyme supplementation. Diabetes control is
severe hyperglycemia and ketoacidosis and thus require often difficult to be achieved due to recurrent episodes of
insulin for glycemic control. Frequent monitoring of hypoglycemia. The subject of fibrocalculous pancreatitis is
blood glucose (BG) is essential for diagnosis of severe described in detail in Chapter 25 in this book and therefore,
hyperglycemia and occasionally hypoglycemia during it has not been considered here.
treatment. The degree of hyperglycemia is an indicator of
the severity of pancreatitis. BG level more than 200 mg% Pancreatic Carcinoma
during the first 24 hours indicates a poor prognosis.11
Pancreatic carcinoma is the fifth most common cause
Permanent diabetes is rare and mostly seen in cases with
of cancer related death and the incidence of pancreatic
a fulminant form of pancreatitis.12 Glycemic status needs
cancer has increased significantly over the last two
to be assessed 2–3 months following an episode of acute
decades. About 80% of the patients with pancreatic cancer
pancreatitis.
have glucose intolerance or frank diabetes.16 The majority
of patients with diabetes associated with pancreatic
Chronic Pancreatitis
cancer are diagnosed either concomitantly at the time
Chronic pancreatitis (CP) is characterized by progressive of diagnosis or 2 years prior to the detection of cancer.17
inflammatory changes in the pancreas that results in The mechanisms by which pancreatic cancer leads to
permanent structural damage which can lead to impair­ diabetes are as follows:18,19
ment of exocrine and endocrine functions of pancreas. • Insulin resistance
A number of etiologies may be responsible for CP as • Islet cell dysfunction (reduced insulin release)
shown in Table 26.3. However, alcohol abuse has been • Destruction of islet cells (reduced beta-cell mass)
reported to be seen in 70–80% of the cases with CP in • Tumor related obstructive pancreatitis.
Western countries. Non-alcoholic or tropical pancreatitis In patients with pancreatic cancer, the level of islet
is considered as one of the most common causes of CP amyloid polypeptide (IAPP) has been found to be elevated;
in developing countries like India.13 The incidence of however its relationship with diabetes is unclear.20
diabetes ranges from 40% to 60% in CP and it depends Diabetes as a risk factor for pancreatic cancer has
upon the etiology, the extent of calcification and the remained a controversial issue.21 A meta-analysis of 20
duration of disease. The occurrence of diabetes in CP is epidemiological studies has shown a two-fold increase
about 55–70% while in non-calcific pancreatitis it is more in the risk of pancreatic cancer in patients with diabetes
than 30%.14 The loss of secretory function of beta cells leads with a greater than 5 years duration, which suggests that
to diabetes in CP. In parallel to loss of insulin secretion, diabetes, is a risk factor for pancreatic cancer.22 A large
glucagon secretory function also declines progressively in prospective study has displayed a progressive increase
these patients.15 The histological findings of CP includes in the risk of pancreatic cancer with an increase in
moderate to severe atrophy of the pancreas, fibrosis of the hyperglycemia, however many epidemiological studies
 Secondary Diabetes 395

have refuted the theory that diabetes is a risk factor for and the frequency varies from 1 in 2,000 to 3,000 live
pancreatic cancer.23,24 It is not clear as to whether pan­ births. The CFTR protein is a single polypeptide chain
creatic carcinoma is related to hyperglycemia per se or containing 1,480 amino acids which regulate chloride
whether hyperglycemia is related to an increase in insulin- channel function across the epithelial surface. There are
like growth factor-1 (IGF-1) levels. There is substantial five major classes of mutations out of which deletion of the
evidence to show that long standing hyperinsulinemia may phenylalanine residue at position delta F508 (F508 del)
lead to cancer, however a large number of experimental is the most common type. This defect leads to thick and

chapter
studies have shown inconsistent results. The diagnosis of viscid pancreatic secretion resulting in pancreatic ductular

26
pancreatic carcinoma should be suspected in any patient obstruction, ductal dilatation and pancreatic insufficiency.
with T2DM who complain of unexplained weight loss CF is a multisystem disorder involving the pancreas, upper
despite insulin therapy and apparently good control of and lower respiratory tract, gastrointestinal tract and
diabetes, back pain or jaundice.
the male reproductive tract. The most common manifes­
tations of CF are recurrent chest infections, steatorrhea,
Pancreatic Surgery and Diabetes growth failure, fat soluble vitamin deficiency, biliary
Diabetes mellitus is frequently found as a sequelae of cirrhosis with portal hypertension, recurrent pancreatitis
pancreatic resection. The incidence and severity of diabetes and infertility. The sweat chloride test is the primary test
mellitus are therefore related to the extent of resection.25 for the diagnosis of CF. A sweat chloride concentration of
Distal pancreatectomy is an accepted and safe procedure more than 60 mmol/L is diagnostic of CF. Deoxyribonucleic
for lesions of the body and tail of the pancreas. Diabetes acid (DNA) analysis for genetic mutations of CFTR can
occurs more frequently following distal pancreatectomy, confirm the diagnosis when the sweat chloride report
as the islet cells are more abundant in the tail of pancreas. is equivocal, moreover it also has significant prognostic
Long-term follow-up studies have shown an increased implications.30
incidence of diabetes with a frequency as high as 70%
Cystic fibrosis-related diabetes (CFRD) is the most
following distal pancreatectomy.26 Patients with primary common comorbidity in subjects with CF. CFRD is a
diagnosis of CP are more prone to develop new onset part of a continuum of glucose tolerance abnormalities
diabetes.27 ranging from normal glucose tolerance to overt diabetes

The incidence of diabetes following Whipple’s resec­ mellitus.31 The incidence of diabetes is 2–3% during
tion ranges from 20% to 50%.28 Diabetes is inevitable childhood. The incidence progressively rises with age,
following total pancreatectomy. The diabetes that occurs and ranges from about 20% in the adolescents and 40–
is a clinical forme fruste of insulin dependent diabetes. The 50% during adulthood.32 CFRD share the features of both
most significant challenge in these patients is recurrent T1DM and T2DM. The reduced beta-cell mass leading
attacks of hypoglycemia and brittleness of diabetes which to insulin insufficiency is the hallmark of CFRD. The
are attributed to the significant loss of glucagon related development of ketosis is rare in CFRD, presumably due
function.29 Small frequent meals and multiple small to low glucagon levels. Insulin resistance in these patients
doses of insulin can minimize these problems to a large may occur in some and is probably related to chronic
extent. The continuous subcutaneous insulin infusion illness and inflammation.33,34 Diabetes is more common
(CSII) pump is a better alternative in some patients. Islet in patients with homozygosity for delta F508 (F508 del)
cell transplantation is another therapeutic option for than in heterozygotes. The frequency of diabetes related
this group of patients although not freely available. Pan­ complications is similar to that of type 1 diabetes (T1D).
creatic enzyme therapy can be helpful in controlling More than 95% of CF patients die due to lung infections
diarrhea and stabilizing BG levels. and respiratory failure. Treatment of lung disease has
improved the survival in these patients. Nutritional
Cystic Fibrosis support is an essential part of the management of CF. Oral
Cystic fibrosis is an autosomal recessive disorder resulting pancreatic enzyme supplementation improves steatorrhea
from mutations in the CF transmembrane conductance and absorption of nutrition. Insulin is ultimately required
regulator (CFTR) gene located in the long arm of chrom­ in almost all patients while glycemic control can be
osome 7. The disease is more common in caucasians achieved with sulfonylurea at the initial stages.35,36
396 Clinical Profile

Hemochromatosis Phlebotomy can improve glycemic control, however

ultimately requires insulin for diabetes control. End stage
Hemochromatosis is a common inherited disorder of
liver failure is an indication for liver transplantation in
iron metabolism in which there is an abnormal increase
HH. Immunosuppressive agents can worsen the glycemic
in the absorption of iron from the intestine that results
status in patients following liver transplantation.41,42
in excess deposition of iron in various tissues. This is the
most common autosomal recessive disorders among
Secondary Hemochromatosis
section

caucasians with a prevalence of 4–5 per 1,000.

The most important causes of secondary hemochro­
7

Hereditary Hemochromatosis matosis are related to chronic transfusion therapy. The

spectrums of iron-loading anemia include both hereditary
Hereditary hemochromatic is most often cause by the and acquired disorders of erythropoiesis.43 The congenital
mutation of the gene (HFE-gene) located in chrom­ diseases in this category include various types of thala­
osome-6. A homozygous G to A mutation at C282Y ssemia, sickle-cell anemia, pyruvate kinase deficiency,
(cysteine to tyrosine substitution) is the most common congenital dyserythropoietic anemia (CDA), hereditary
occurring anomaly.37,38 H63D mutation (substitution spherocytosis and X-linked sideroblastic anemia (XLSA).
of histidine to aspartic acid at codon 63) is the second Among the acquired disease, the most important causes
most common mutation of HFE-gene. The primary defect are idiopathic sideroblastic anemia, myelodysplastic
in HH is due to deregulation of iron absorption from syndrome, idiopathic myelofibrosis and aplastic anemia.
the small intestine which preferentially gets deposited The most common causes of secondary hemochro­
in the liver, pancreas (exocrine tissues as well as islet matosis are thalassemia major and sideroblastic anemia.
cells), pituitary, heart and parathyroid. The classical triad The carrier frequency of hemoglobinopathies (thalassemia
of symptoms associated with HH is hepatic cirrhosis, and its variant) disorders varies from 3% to 17% in different
diabetes and bronzed hyperpigmentation. The prevalence population groups in India.44 A population based study
of glucose intolerance and diabetes mellitus in HH can from six cities in India have shown a 2.78% prevalence
be positively correlated with the degree of iron overload rate of b-thalassemia wand it was varied from 1.48% to
and the stage of chronic liver disease. Both insulin resis­ 3.64% in different states.45 b-thalassemia is seen in almost
tance and beta-cell failure are responsible for diabetes all Indian populations with the highest prevalence among
mellitus. Progressive iron deposition in the islet cell the Sindhis, Gujaratis, Bengalis, Punjabis and Muslims.46,47
causes beta-cell dysfunction and decreases the insulin b-thalassemia is most widely prevalent in the tribal
production. Insulin resistance is probably caused by an population with highest frequency in Andhra Pradesh,
alteration in the metabolism of insulin or glucose in the Gujarat and Odisha.48-50
liver. Diabetes is present in approximately 40–50% of the
Secondary hemochromatosis occurs in these condi­
patients with HH.39,40 tions as a consequence of repeated blood transfusions

The diagnosis of HH requires high index of suspicion which lead to an increase in hepatic and total body iron.
in patients with clinical features of diabetes, cirrhosis and Excessive deposition of iron in the liver and pancreas
skin pigmentation. The total body iron stores can be best results in insulin resistance, decreased insulin secretion
assessed by serum ferritin and percentage of transferrin and diabetes mellitus. The degree of glucose intolerance
saturation. Liver biopsy is not essential for diagnosis; depends upon the number of transfusions and the dura­
however, it is helpful in determining the severity of liver tion of disease. The prevalence of impaired glucose
disease. The availability of genetic tests can support tolerance (IGT) is 60% while diabetes is seen in 16%
the diagnosis even at early stages. All first degree adult patients with thalassemia major.51 A longitudinal study
relatives are required to be screened for genetic mutations by Gamberini et al. has shown that the incidence and
(C282Y and H63D) for early detection of the disease. prevalence of insulin dependent diabetes have decreased
Phlebotomy is the simplest, cheapest and most effective over the last decade.52 Iron chelating agents are the
way to remove accumulated iron. Therapeutic phlebotomy cornerstone of treatment in transfusion related secondary
started at an early stage may prevent the development hemo­chromatosis. Parenteral deferoxamine has been used
of cirrhosis and diabetes. Iron chelating agents are more as chelating therapy since 30 years. However, long-term
costly, less effective and lack the safety of phlebotomy. therapy with deferoxamine has shown to be associated
 Secondary Diabetes 397

Table 26.4: Effect of counter regulatory hormones in glucose homeostasis

Hormone Insulin secretion Insulin action Liver Skeletal muscle Adipose tissue
defect Gluconeogenesis Glycogena Amino acid release Fatty acid release
Glucagon + ++ + transient effect – ? ?
acute effect
Growth hormone + ++ delayed + fasting state + feed state ? +++
effect

chapter
Catecholamine – + + – – +

26
Thyroid hormone + + – 0 +
Glucocorticoids + + + + + +

+, stimulation; –, inhibition; 0, no effect; ?, uncertain

a
net effect on glycogen content by glycogenolyis and glycogen synthesis
Source: Ganda OP. Secondary forms of diabetes. In: Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ. (Eds). Joslin’s Diabe-
tes Mellitus, 14th Edition. Boston, Massachusetts: Lippincott Williams & Wilkins. 2004. pp. 478-92.

with several side effects such as: ototoxicity and visual Acromegaly
loss. Oral drugs like deferiprone (DFP) and deferasirox
Acromegaly is a clinical syndrome resulting from excess
are safer and effective chelating agents as compared to
deferoxamine.53 Combination of chelating therapy (like of GH secretion. GH secreting pituitary macroadenoma is
combining subcutaneous deferoxamine) with one of the the most common cause of acromegaly. In few patients,
oral drugs has been found to be more efficacious than acromegaly is caused by growth hormone-releasing
monotherapy alone.54 hormone (GHRH) secreting tumors like hypothalamic

Therapeutic approaches to patient with diabetes gangliocytoma and carcinoid tumors from the lung and
secondary to pancreatic disease: A patient with pancreatic pancreas. A small percentage of patients with acromegaly
diabetes needs specialized nutritional support which are associated with multiple endocrine neoplasia type
includes: (1) Liberal protein and calorie intake, (2) Small 1 (MEN-1), an autosomal dominant syndrome with
frequent meals, (3) Low neutral fat intake and (4) High associated tumors of the parathyroid, pituitary and
intake of complex carbohydrates. Alcohol intake should be pancreas. Acromegaly is a rare disorder with a prevalence
avoided. Pancreatic enzyme supplementation improves of 40–70 cases per million and an annual incidence of
digestion and decreases steatorrhea. Multiple doses of 1–3 new cases per million.55,56 Figure 26.1A shows a man
short-acting insulin are preferred for glycemic control due with typical facial features of acromegaly and magnetic
to the brittle nature of the diabetes. resonance imaging (MRI) of pituitary shows GH secreting
pituitary macroadenoma (Fig. 26.1B).
ENDOCRINOPATHIES AND Metabolic effects of growth hormone: Human GH is
a 191-amino acid, 22-kDa polypeptide secreted from
DIABETES MELLITUS
pituitary. GH is secreted episodically with a major surge
Several hormones like growth hormone (GH), cortisol, occurring at the onset of slow wave sleep. GH mediates its
glucagon, epinephrine and thyroid hormone antagonize effects via the cell surface receptors of the Janus Kinase/
insulin action. The major sites of action of various counter Signal Transducer and Activator of Transcription (JAK/
regulatory hormones on target organs and the principal STAT) cytokine receptor super family. GH has a direct
mechanisms of action are listed in the Table 26.4. Secon­ effect on many target tissues however the majority of
dary diabetes is observed in various endocrinological its effects is mediated by IGF-1 which is predominantly
disorders among which Acromegaly and Cushing’s produced in the liver. GH is an anabolic hormone and
syndrome are the most common. These forms of hyper­ in its basal state, it stimulates the protein synthesis and
glycemia typically resolve when the excess hormone decreases the breakdown of amino acids. GH stimulates
producing tumor is removed. the release and oxidation of free fatty acid (FFA). In the
398 Clinical Profile
section
7

Figs 26.1A to C: (A) Typical facial features of acromegaly: prog-

nathism, malocclusion of teeth and frontal bossing; (B) 38-year-
male with clinical and biochemical features suggestive of acro-
megaly. Magnetic resonance imaging (MRI) of pituitary showing
growth hormone (GH) secreting pituitary macroadenoma in:
(left image) T1-weighted MRI with gadolinium in coronal section
28 × 31 mm size tumor and (right image) T2-weighted MRI sag-
ittal section showing a hypointense lesion; (C) Mechanism of
hyperglycemia and diabetes in acromegaly
(NEFA: Non-esterified fatty acids; IGT: Impaired glucose toler-
C ance; MRI: Magnetic resonance imaging).
 Secondary Diabetes 399

GH excess state, GH impairs the muscle glucose uptake The effect of medical treatment in diabetes with
and non-oxidative glucose metabolism. GH antagonizes acromegaly by using somatostatin analogs (SAs) and GH
the action of insulin at the hepatic and the extrahepatic receptor antagonist is more complex. SAs had shown
site and increases the hepatic glucose output. This variable effects on glycemic control. In the early part of
increased hepatic glucose production is mainly due to treatment with SA, the glucose level may be increased
glycogenolysis and partly due to gluconeogenesis.56 due to suppression of insulin secretion. During long-
term treatment with SA glycemic control may either

chapter
Diabetes in Acromegaly improve or worsen thus patients on SA require regular

26
Glycosuria occurring in a pituitary tumor was first glucose monitoring and strict follow-up.60,61 Ronchi
observed by Loeb in 1884. It was Marie in 1886 who et al. suggested that the most important predictor of
first reported the occurrence of diabetes mellitus in deterioration of glucose control was increased weight gain
acromegaly. IGT and diabetes are more frequent in while octreotide treatment did not have any impact. Most
acromegaly. The prevalence of diabetes mellitus and patients on SA may require treatment with insulin and/or
that of IGT in acromegaly is reported to range between sulfonylureas for their glycemic control. Pegvisomant is a
19–56% and 16–46% in different series.57,58 Most patients specific GH receptor antagonist that blocks the action of
with acromegaly have some degree of insulin resistance GH at the GH receptor level to reduce the production of
and hyperinsulinemia. GH induces insulin resistance IGF-1. Pegvisomant is currently preferred as a treatment
by several mechanisms which include reduced insulin in octreotide resistant cases and patients with coexisting
receptor number, reduced tyrosine phosphorylation of diabetes mellitus. Pegvisomant improves the glycemic
the receptor and postsignaling defects. Fasting hyper­ control in acromegaly which has been attributed to
glycemia in acromegaly is due to increase in hepatic normalization of IGF-1 level, improvement of insulin
glucose output in post absorptive states. The degree of sensitivity and reduction in fatty acid production.62,63
glucose intolerance is found to have correlation with GH
level, higher age group and longer duration of disease. Cushing’s Syndrome
Family history of diabetes and pre-existing hypertension
Cushing’s syndrome comprises a group of symptoms and
are important risk factors that are associated with
signs resulting from prolonged exposure to inappropriately
diabetes mellitus. Diabetes is more common in females
high levels of GCs. Iatrogenic Cushing’s syndrome is
than males in various series. Patients with overt diabetes
more common than endogenous Cushing syndrome and
requiring insulin for glycemic control generally have low
it occurs as a result of prolonged exposure to exogenous
endogenous insulin levels. Diabetes ketoacidosis as a
GCs. The endogenous causes of Cushing’s syndrome
result of relative insulin deficiency is a rare presentation
include adrenocorticotropic hormone (ACTH) excess
of acromegaly. Figure 26.1C shows the pathogenic mech­
(pituitary or other ectopic tumors) or independent
anism of diabetes in acromegaly.
Acromegaly is a disease developing slowly and adrenal cortisol overproduction. 90% of ACTH dependent
insidiously and hence diagnosis is usually delayed for Cushing’s syndrome is due to pituitary corticotrope
variable years. The major causes of mortality in acromegaly adenomas, which are usually sporadic in nature but are
are due to various systemic complications such as 60% rarely associated with MEN-1. Ectopic ACTH secreting
due to cardiovascular diseases, 25% related to respiratory tumors are predominantly carcinoids and are mostly
disease and 15% due to malignancy.59 Early diagnosis located in the lung, thymus and pancreas.64 Figures 26.2A
and treatment can reduce the mortality in acromegaly. and B show the clinical features of Cushing syndrome
The important determinant of mortality in acromegaly and Figure 26.2C shows an MRI of the pituitary with a
includes age, pre-existing hypertension, GH and IGF-1 microadenoma.
levels. Normalization of GH and IGF-I levels can improve Metabolic effects of excess glucocorticoids: Gluco­
the glycemic control in acromegaly. Surgical removal of corticoids are primarily secreted from the zona fasciculata
GH secreting tumors improves the glucose intolerance of the adrenal cortex. Cortisol is secreted in a pulsatile
and diabetes. Although surgery showed consistent results, fashion with a circadian rhythm. Its level peaks in the
patients may develop diabetes due to lack of complete early morning and falls during the day and it reaches its
cure or recurrence of disease. nadir at midnight. Cortisol biosynthesis and secretion
400 Clinical Profile
section
7

A B

C1 C2

D
Figs 26.2A to D: (A) Characteristics facial features of Cushing’s syndrome: moon face, hyperpigmentation and hirsutism; (B) Classical striae of
Cushing’s syndrome; (C) 37-year-old female with clinical features and biochemical evaluation are suggestive of Cushing syndrome. Magnetic
resonance imaging (MRI) of pituitary showing: (left image) T1 with sagittal section 5.7 × 14.7 mm sellar and suprasellar homogenous lesion and
(right image) T2-weighted coronal section hypointense mass causing mild superior elevation of chiasma; (D) Mechanisms of hyperglycemia and
diabetes in Cushing’s syndrome
(GCs: Glucocorticoids; NEFA: Non-esterified fatty acids).
 Secondary Diabetes 401

is primarily regulated by the hypothalamic-pituitary- control can be achieved by administration of cortisol

adrenal axis. Stress is an important regulator of GCs lowering drugs like metyrapone, ketoconazole or in rare
synthesis and release. The primary action of GCs is to occasion by mitotane. In addition to this either metformin
increase the level of glucose production by stimulating alone or its combination with insulin may be required to
hepatic gluconeogenesis. GCs stimulate the process achieve glycemic control. Transsphenoidal resection of
of lipolysis and protein breakdown thereby increasing the pituitary tumor is the treatment of choice in ACTH
the level of FFAs and amino acids which are essential dependent Cushing’s disease. Pituitary irradiation and

chapter
substrates for gluconeogenesis. GCs are also essential for stereotactic radiotherapy are the next line of therapy,

26
the normal glucagon and epinephrine induced lipolysis, opted for patients in case of failure to surgical treatment.70
glycogenolysis and gluconeogenesis. Insulin resistance Surgical adrenalectomy is a definite form of treatment
is invariably present in corticosteroid excess state and in adrenal related Cushing’s syndrome.71 In the chronic
is either due to direct effect of GCs on insulin signaling setting, where diabetes prevails due to incomplete control
pathway or indirect effect of GCs by altering the insulin of hypercortisolemia, glycemic control can be achieved
function through an increase in FFA level.65,66 Moreover, by oral antidiabetic agents alone or in combination with
the peculiar excess deposition of visceral adipose insulin. Among all oral anti-diabetes agents, metformin
tissue significantly contributes to worsening of insulin is preferred as the first choice as it acts by improving the
resistance.67 Finally, GCs excess acts by suppressing the insulin resistance. Glycemic control can also be achieved
beta-cell function and inhibiting the insulin secretion. with other agents such as sulfonylureas and peroxisome
proliferator-activated receptor-g (PPAR-g) agonists.
Diabetes in Cushing’s Syndrome Rosiglitazone is a PPAR-g agonist which was being used
Glucose intolerance is quite common in Cushing’s previously in the management of T2DM and was also found
syndrome. Beyond diabetes mellitus, the other important effective in lowering corticosterone levels by suppressing
manifestations of endogenous Cushing’s syndrome are ACTH secretion in Cushing syndrome. The effects of
central obesity, hypertension, dyslipidemia, hyperin­ rosiglitazone are primarily mediated through the PPAR-g
sulinemia and the metabolic syndrome. The prevalence receptor which is highly expressed in corticotrophs tumor.
of diabetes mellitus in Cushing’s syndrome ranges from Although these effects are well-demonstrated in animal
20% to 50%. The prevalence of prediabetes may be close models, the PPAR-g agonist is shown to have limited
clinical efficacy in Cushing syndrome.72-75
to 70% if the presence of impaired fasting glucose (IFG)
or IGT is considered.64-68 Fasting hyperglycemia is found
to be more common in subclinical Cushing’s syndrome
Hyperthyroidism and Diabetes Mellitus
and high fasting glucose levels have been reported both in The term hyperthyroidism refers to a clinical syndrome re­
those with active disease as well as those in remission. sulting from overproduction of thyroid hormones. Graves’
There is also a relatively high prevalence (ranges from 0% disease is the most common cause of thyrotoxi­ cosis.
to 9.4%) of unsuspected Cushing’s in T2DM. In general, the Graves’ disease occurs in approximately 2% of women and
severity of hypercortisolemia correlates with the severity 0.2% of men.76 The classical clinical triad of Graves’ disease
of insulin resistance and diabetes mellitus. However, the are diffuse goiter, thyrotoxicosis and Graves’ ophthal­
reports are inconsistent and probably under assessed. mopathy. It is essential to distinguish Graves’ disease from
There is wide inter-individual variability which can be other transient causes of thyrotoxicosis such as subacute
explained by individual susceptibility for development thyroiditis, silent thyroiditis, drug induced thyroiditis and
of diabetes and decline in beta cell reserve. Diabetic Hashitoxicosis. Most patients with overt hypothyroidism
ketoacidosis is rather uncommon in Cushing syndrome. have low thyroid stimulating hormone (TSH) (< 0.01mU/L)
Figure 26.2D shows mechanisms of hyperglycemia and with elevation of free T4 and/or total T3 concentration.
diabetes in Cushing’s syndrome. The twenty-four hours radionuclide uptake study can
Treatment of diabetes mellitus can be categorized easily distinguish the high uptake of Graves’ disease from
into two: (1) acute setting (preoperative setting) and (2) the low uptake of thyroiditis.
chronic setting (when diabetes prevails due to incom­ The association between T1DM and Graves’ disease
plete control of hypercortisolemia following surgery or is well-known. Both diseases can co-exist with each
radiotherapy).69 In the preoperative setting, diabetes other. However on most occasions, one disease usually
402 Clinical Profile

precedes the other. Development of hyperthyroidism artery), carotid and glomus jugulare bodies, bladder wall
in T1DM patients is associated with worsening of and mediastinum. Approximately 90% of PHE or PGL are
hyperglycemia, increased insulin requirement and at believed to be sporadic in nature. These tumors also occur
times may precipitate diabetic ketoacidosis.77,78 Impaired as a part of several genetic syndromes: (1) Von Hippel-
glucose intolerance and diabetes mellitus is common Lindau (VHL) disease, and MEN-2A and 2B, (2) the
in hyperthyroidism. IGT is found in about one-third familial PGL syndromes (PGL 1–4), (3) neurofibromatosis
of the cases whereas diabetes mellitus occurs in 8% of (NF) type 1 and (4) MEN-1 and tuberous sclerosis
section

cases of hyperthyroidism. Hyperthyroidism can impair complex. The clinical presentations of PHE or PGL are
7

the glucose homeostasis by several mechanisms such as sustained or paroxysmal hypertension, severe headaches,
(1) increased intestinal hexose absorption, (2) impaired palpitations and sweating and these symptoms are
insulin action, (3) decreased half-life of insulin due to attributed to catecholamine excess. The diagnosis of PHE
increased degradation and excess release of inactive (catecholamine excess) is based upon measurements of
insulin precursors and (4) increased hepatic glucose 24 hours urinary and plasma fractionated metanephrines
output due to increased hepatocyte glucose transporter and catecholamines. Anatomical localization of tumors
2 (GLUT-2) expressions, increased fatty acid production is usually done either by CT scan or MRI, followed by
and gluconeogenesis. Insulin resistance is found to be 131 I-metaiodobenzylguanidine scintigraphy. Figures
more prominent in overweight patients. Increased levels 26.3A and B showing CT scan of abdomen and Figure
of GH, catecholamine and glucagon can also contribute to 26.3C showing iodine-131 metaiodobenzylguanidine
(131I-MIBG) scinitigraphy.
glucose intolerance in hyperthyroidism. 79-84
Glucose abnormalities occur in about 50% of cases of

The thionamides (neomercazole and propylthiouracil)
PHE. The prevalence of diabetes mellitus is approximately
are the primary drugs used to treat Graves’ hyperthy­
about 35.6%. Hyperglycemia, as a presenting symptom
roidism. Neomercazole is preferred because of its longer
in PHE also has been described. There are several mecha­
duration of action and thus can be administered once
nisms by which epinephrine excess can lead todiabetes
daily.85,86 The starting dose of neomercazole is between
mellitus such as: (1) a2 receptor-mediated inhibition
10 mg and 45 mg and it depends upon the severity of
of insulin release, (2) b2 adrenergic receptor-mediated
thyrotoxicosis. The common side effects of thionamides
impairment of insulin action and glucose uptake and
(neomercazole and propylthiouracil) include pruritus,
(3) b2 adrenergic receptor-mediated stimulation of
rash, urticaria, arthralgias, arthritis and fever. Neomer­
glyco­genolysis and gluconeogenesis.90-93 Epinephrine
cazole is found to be having teratogenic effects like aplasia
stimulates the production of precursors (lactate, fatty
cutis, choanal atresia and tracheoesophageal fistulas
acids, alanine and glycerol) in gluconeogenesis by increa­
when given during the first trimester of pregnancy. One
sing the process of muscle glycolysis and lipolysis.
of the rare side effects of neomercazole is insulin antibody
Diabetes ketoacidosis is a rare presentation in pheochro­
mediated hypoglycemia. This syndrome is also known
mocytoma. The presence of diabetes in a young hyper­
as Hirata’s syndrome which is characterized by fasting
tensive patient with normal weight raises the suspicion of
hypoglycemia, hyperinsulinemia and detectable insulin-
pheochromocytoma.94
binding antibodies and is commonly seen among oriental
Surgical resection is the treatment of choice in pheo­
population.87,88 Radioiodine and subtotal thyroidectomy
chromocytoma.95 Preoperative preparation of the patient
are equally effective in the management of Graves’
is essential to prevent hypertensive crisis during manipu­
thyrotoxicosis.85 Glucose intolerance and insulin resistance
lation and cardiovascular collapse following the removal
usually improves with restoration of the euthyroid state.89
of tumor. This can be achieved by initial administration of

Pheochromocytoma and paraganglionomas: Pheoch­
b-receptor blocker like dibenzyline followed by a-recep­
romocytomas (PHE) and extra-adrenal paraganglionomas
tor blockers. Removal of the tumor can improve or cure
(PGL) are rare neuroendocrine tumors that arise from
diabetes and hypertension in pheochromocytoma.96-98
neuroendocrine derived cells. Pheochromocytoma
usually occurs in adrenal medulla; however, PGL may
Glucagonoma
be located anywhere from the base of the skull to the
pelvis. The common locations for PGL are the organ of Glucagonoma is a rare neuroendocrine tumor that
Zuckerkandl (close to origin of the inferior mesenteric arises from a-cell of the pancreas. In 1942, Becker et al.
 Secondary Diabetes 403

chapter
26
A B

C
Figs 26.3A to C: CT scan of abdomen (A) coronal view (B) axial view showing right adrenal mass (C) showing iodine-131 metaiodobenzylguani-
dine (131I-MIBG scan showing uptake at the right supra-renal region suggestive of pheochromocytoma

reported the first case of glucagonoma. The origin of neuroendocrine tumors, only 7% had a documented
the pathology has remained unknown until 1966 and it glucagonoma.99 Most cases occur sporadically however,
was then McGavran et al. who first identified glucagon only a small percentage of them (about 10%) are linked to
hypersecretion as the cause of this syndrome. Fewer MEN-1. These tumors are most often located in the tail of
than 250 cases of glucagonoma have been described pancreas and are usually encapsulated, firm to nodular,
in literature. In a series of 340 cases of pancreatic varying in size from 2 cm to 2.5 cm. Glucagonoma is a
404 Clinical Profile

slow growing tumor and most of the patients have non- The most common symptoms of somatostatinoma
specific symptoms at the beginning of the disease.100 are weight loss and abdominal pain. The classical triad of
The average delay in diagnosis is approximately 3 years symptoms associated with somatostatinoma is diabetes
and nearly about 50% of them present with metastasis at mellitus, steatorrhea or diarrhea and cholelithiasis. Ganda
the time of diagnosis. Glucagonoma is characterized by et al. first reported a case of somatostatinoma in 46-year-
“4D’s”: (1) diabetes, (2) dermatitis (rash), (3) deep vein old lady during cholecystectomy and interestingly this
thrombosis and depression. The other manifestations patient had diabetes for 8 years.109 Diabetes in somato­
section

of glucagonoma are weight loss, diarrhea, cheilosis or statinoma is attributed to the inhibitory effect of somato­
7

stomatitis. The necrolytic migratory erythema (NME) statin in insulin secretion. Hyperglycemia is of mild to
rash is seen in 60–70% of the cases mainly involving the moderate severity and requires insulin for glycemic control.
face, perineum and extremities and it has a remitting and The occurrence of ketoacidosis is uncommon.110 Non-
relapsing course.101 The prevalence of diabetes mellitus functional somatostatinomas are either asymptomatic or
has been variable but it ranges between 25% and 95% in present with obstructive symptoms. These tumors turn
different reports. Hyperglycemia may be mild or moderate malignant by the time they are detected and nearly
and may require either oral antidiabetic drugs or insulin two-thirds have already metastasized to the regional lymph
for glycemic control. Hyperglycemia is largely due to nodes or the liver. The tumors are best localized either
glucagon stimulated hepatic gluconeogenesis.102,103 by CT scan, MRI, selective angiography of celiac tripod,
The diagnosis of glucagonoma is established by the endoscopic retrograde cholangiopancreatography or by
detection of a high fasting glucagon level in the absence functional scan (octreotide scintigraphy).111 Diagnosis
of other causes of hyperglucagonemia (e.g. severe stress, needs to be confirmed by documentation of high-fasting
hepatic and renal failure, poorly controlled diabetes, small plasma somatostatin levels. Surgical resection of tumor is
bowel malabsorption and synthetic androgenic drugs) the treatment of choice in somatostatinoma. Treatment
and location of pancreatic mass on imaging (CT and MRI mainly depends on the site and size of the tumor and
scan).104 Surgical resection is the treatment of choice. the extent of the disease at the time of diagnosis. In the
However, about 50% have metastasis in the liver at the case of advanced disease, the treatment includes tumor
time of diagnosis.105 Surgical debulking is considered as the debulking and chemoembolization of the primary tumor.
best treatment option in metastatic tumor if it is feasible. Other treatment modalities like chemotherapy, Octreotide
The other options are hepatic embolization, somatostatin and IFN-a can also be used.112,113
therapy and chemotherapy. Nutritional support and
anti-coagulation therapy are the important aspects of VIPoma
treatment. The data on long-term survival is limited. In a VIPoma (Verner-Morrison syndrome) is a rare neuro­
recent series, 9 out of 21 patients died during the follow-up endocrine tumor that secretes vasoactive intestinal
period of 4.9 years since the time of diagnosis of metastatic polypeptide (VIP). This tumor primarily originates from
disease.106 the pancreas. VIPomas are usually occur as a solitary
tumor but in 5% of the cases, they are multicentric in
Somatostatinoma nature.114 Approximately 5% of the VIPomas are associated
Somatostatinomas are rare neuroendocrine tumors of with MEN-1. In 1985, Verner and Morrison first described
D cell origin. The frequent sites of location of tumors the symptoms of VIPoma. The classical features of VIPoma
are duodenum and pancreas but may rarely be found in syndrome include watery diarrhea, hypokalemia and
jejunum, lung and liver. These tumors occur sporadically achlorhydria (WDHA). Hyperglycemia occurs in about
in 93% of cases and about 7% of these cases have been half of patients, diabetes is mild to moderate in severity.
associated with MEN-1, VHL syndromes and NF-1.107,108 The hyperglycemia in VIPoma is probably secondary
Tumors that originate from the pancreas are mainly to glycogenolytic effect of VIP. Hypokalemia can partly
responsible for the somatostatinoma syndrome. However, contribute to hyperglycemia either by impairing insulin
the tumors that originate from duodenum contained secretion and/or insulin sensitivity.115
only immunoreactive granules without any functional
The diagnosis of VIPoma is established by docum­
significance. entation of a high serum VIP level (> 75 pg/mL). Most
 Secondary Diabetes 405

VIPomas are more than 3 cm at the time of presentation due to parathyroid hyperplasia. Clinical presentation
and thus CT can easily identify the pancreatic mass in of PHPT is mainly related to severity of hypercalcemia.
most of the cases. Approximately 60–80% of the cases However, recently, more patients are either asymptomatic
are detected to have metastasis at the time of diagnosis. or even normocalcemic. Approximately, 40% of patients
The first goal in the management of VIPoma is correction with PHPT have IGT and about 8% have diabetes
of fluid deficit and hypokalemia followed by the control mellitus.122,123 The prevalence of diabetes is about threefold
of diarrhea either by octreotide and/or GCs. Surgical higher as compared to general population.124 Diabetes is

chapter
resection is the treatment of choice in benign lesions. often a presenting complaint in 39.4%. Hypercalcemia in

26
Debulking surgery in advanced cases may reduce the PHPT impairs the insulin mediated glucose uptake which
symptoms. However, hepatic embolization, IFN-a and in turn leads to insulin resistance and an increase in insulin
chemotherapy (doxorubicin and streptozotocin) may be requirement. Hypercalcemia can cause pancreatitis
used as palliative therapy.116 which may subsequently lead to diabetes mellitus.
Several studies have also demonstrated that hypopho­
Primary Hyperaldosteronism sphatemia can induce insulin hypersecretion and impair
peripheral glucose uptake. Parathyroidectomy has been
Primary hyperaldosteronism (PHA) is the most common
followed by regression of diabetes and IGT in some but
cause of endocrine hypertension and accounts for more
not all patients. This is probably related to the severity of
than 10% of all hypertensives.117 In 1955, Jerome W Conn
hypercalcemia and duration of the disease. 125-127
originally described a case of hypertension, hypokalemia,
neuromuscular symptoms associated with aldosterone
secreting adrenocortical adenoma. The most common
Polycystic Ovarian Syndrome
types of PHA are due to aldosterone producing adenomas Polycystic ovarian syndrome (PCOS) occurs in 5–10%
and bilateral adrenal hyperplasia and the rare causes of women of the reproductive age group. The diagnostic
include familial hyperaldosteronism, adrenal carcinoma criteria of PCOS include clinical or biochemical evidence
and ectopic aldosterone producing tumors. Glucose of hyperandrogenism with oligo or anovulation while
intolerance has been reported in approximately 50% other definite causes have been excluded.128 In 1921,
of patients. Conn’s registry reported a 23% prevalence Achard and Thiers reported the co-existence of diabetes
of diabetes mellitus in their cohorts. Patients requiring mellitus with clinical signs of androgen excess in a
higher number of antihypertensives are at more risk of postmenopausal women, the so called Achard-Thiers
developing diabetes mellitus. Diabetes is usually mild and syndrome or diabetes of the bearded women. Both lean
overt diabetes is unusual. Patients with aldosteronism and obese women are found to have insulin resistance
have a high risk of developing metabolic syndrome and hyperinsulinemia.129 The prevalence of IGT and type 2
and the prevalence is about 41%. In aldosterone excess diabetes (T2D) is 23–35% and 4–10%, respectively. The risk
state, aldosterone itself can cause insulin resistance by of development of diabetes is largely mediated via insulin
inhibiting the biosynthesis and affinity of the insulin resistance. Patients with IGT have greater tendency to
receptor. Aldosterone also down regulates GLUT in develop type 2 diabetes when compared with patients
adipose tissue and muscles, thus decreases the tissue without PCOS.130 PCOS patients have 3 fold increased
glucose uptake.118,119 Hypokalemia is partly responsible risk for developing gestation diabetes mellitus.131,132
for decreased insulin secretion and insulin resistance.120
However, it is not clear that whether potassium repletion SYNDROMES OF PRIMARY
can improve glycemic status or not. Surgical resection of INSULIN RESISTANCE
the tumor can improve the glycemic status in PHA.121
Insulin resistance has been broadly defined as a state
in which a greater than normal amount of insulin is
Primary Hyperparathyroidism
required to elicit a quantitatively normal response. There
Primary hyperparathyroidism (PHPT) is a disorder are several conditions that are described to be associated
characterized by over production of parathyroid hormone with insulin resistance and they include obesity, polycystic
(PTH) by the parathyroid gland. Parathyroid adenoma ovarian disease, T2DM and metabolic syndrome. In
is the most common cause of PHPT and is less commonly addition, there are a number of rare inherited syndromes
406 Clinical Profile
section
7

Fig. 26.4: Mutations in insulin receptor gene and insulin resistance

Table 26.5: Genetic syndrome of insulin resistances

Onset Clinical features Acanthosis Androgen PCOS Etiology
nigricans excess
Donohue’s syndrome/ Congenital (infant) IUGR, dimorphic features, Yes +++ Yes Mutation of insulin
leprechaunism hypertrichosis death in teenage receptor
Rabson-Mendenhall Congenital Dental dysplasia, pineal Yes ++ Yes Mutation of insulin
(0–10 years) hyperplasia, death in childhood receptor
Type A insulin Adolescence Female Yes +++ Yes Mutation of insulin
receptor
Type B Adult (Autoim- Female > Male Yes ++ Yes Anti-insulin recep-
muneddisease) tor antibody

(PCOS: Polycystic ovarian syndrome; IUGR: Intrauterine growth restriction).

that are characterized by severe insulin resistance.133 The insulin resistance, and acanthosis nigricans (HAIR–AN)
site of defect in these various severe insulin resistances syndrome. The alternation of glucose homeostasis is
is due to the mutation affecting the insulin receptors, quite variable from extremely abnormal (either diabetes
postreceptor signaling pathways134 (Fig. 26.4). The most or hypoglycemia) to normoglycemia.136 The affected
common conditions associated with insulin receptor individual has identifiable heterozygote mutation of the
gene mutation are Type A insulin resistance, Leprecha­ insulin receptor and is autosomal dominant. The less
unism, Rabson-Mendenhall syndrome (Table 26.5). There frequent features of this syndrome include short stature,
can be a considerable overlap in the clinical features acral hypertrophy, accelerated linear growth, muscle
between these syndromes which include hyperinsu­ cramps and retinitis pigmentosa.137,138
linemia, acanthosis nigricans, ovarian hyperandrogenism
and disturbances in glucose homeostasis.135 Leprechaunism
Leprechaunism (Donohue syndrome) is an autosomal
Type A Insulin Resistance Syndrome recessive disorder caused by a homozygous mutation
The major clinical features of Type A insulin resistance of the insulin receptors.139 This syndrome was originally
syndrome are severe insulin resistance, acanthosis reported by Donohue and Uchida in 1954. The disease is
nigricans, severe ovarian hyperandrogenism with poly­ characterized by severe prenatal and postnatal growth
cystic ovarian disease. This syndrome was originally retardation, acanthosis nigricans, lipoatrophy, genito­
described in a lean adolescent female patient. This megaly, insulin resistance and abnormal glucose
disease is often recognized as hyperandrogenism, homeostasis.140 This is known as Leprechaunism because
 Secondary Diabetes 407

the infants with this disease show an elf-like face and ovaries). Lipodystrophies can be further classified as
dwarfism. The dysmorphic features in the neonates follows:145,146
include large forehead, broad nose, low set ears, globular Inherited:
eyes, hypertelorism and micrognathia. Episodes of fasting • Congenital generalized lipodystrophy
hypoglycemia, hyperglycemia with marked hyperin­ • Familial partial lipodystrophy
sulinemia are seen in these patients due to extreme • Mandibuloacral dysplasia
insulin resistance. These patients do not develop diabetic Acquired:

chapter
ketoacidosis. The disease is usually fatal by 1 year. • Lipodystrophy in human immunodeficiency virus

26
(HIV) patients
Rabson Mendenhall Syndrome • Acquired generalized lipodystrophy (AGL)
• Acquired partial lipodystrophy
Rabson Mendenhall syndrome (RMS) is a rare autosomal
• Localized lipodystrophy.
recessive inherited insulin receptor disorder. The
degree of insulin resistance is less severe as compared Congenital Generalized Lipodystrophy
to Leprechaunism. Presence of certain specific clinical
features like premature and dysplastic dentition (which Congenital generalized lipodystrophy is a rare autosomal
is sometimes observed at birth), coarse senile facies and recessive disorder characterized by near absence of
pineal hyperplasia (no functional significance) can help in subcutaneous fat from the birth or infancy. The clinical
differentiating RMS from Leprechaunism.141 At the time of triad of lipoatrophy, hepatomegaly, acromegaloid feat­
childhood, they usually present with acanthosis nigricans, ures and hypertriglyceridemia are more prominent.
hirsutism, and lack of subcutaneous body fat, short Diabetes mellitus generally develops during the second
stature, enlarged genitalia and precocious puberty. Other decade; however insulin resistance is present since birth.
manifestations of RMS include medullary sponge kidney Accumulation of fat in liver can lead to hepatic steatosis
and nephrocalcinosis. At infancy, they usually present and cirrhosis. Other clinical features include hyperan­
with hyperinsulinemia, paradoxical fasting hypoglycemia drogenism and clitoromegaly in women. The mutation of
and postprandial hyperglycemia. However by 5–6 years, AGPAT2 (acylglycerol-3-phosphate O-acyltransferase 2)
these patients develop frank diabetes with recurrent is responsible for type 1 while mutations of BSCL2 gene
episodes of ketoacidosis. Patients remain insensitive to (encodes a 398 protein called seipin) causes type 2,
insulin and require a high dose of insulin for reversal of Berardinelli–Seip syndrome.147,148 Recombinant leptin
ketoacidosis.142,143 Leptin therapy was found to be partially therapy is able to reverse metabolic complications in
effective in improving the glycemic status and insulin Berardinelli-Seip congenital lipody­strophy (BSCL) but the
tolerance.144 Role of insulin sensitizers like metformin data is limited.149
and pioglitazone may be helpful but their effects are
limited. RMS patients mostly survive beyond one year Familial Partial Lipodystrophy
but death usually occurs before puberty. Death in RMS
Familial partial lipodystrophy (FPLD) are heterogenous
patients occurs mainly due to intractable ketoacidosis and
autosomal dominant disorders with several distinct
infections.
phenotypes. The two main subtypes result from muta­
tions of LMNA (encodes nuclear envelope protein lamins
LIPODYSTROPHIC SYNDROMES
A and C) and PPAR-g.150 Familial partial lipodystrophy
Lipodystrophies are clinically heterogeneously acquired (Dunnigan lipodystrophy) is associated with LMNA
or inherited disorders characterized by the selective loss mutations.151,152 This disease is characterized by loss of
of adipose tissue. Acquired lipodystrophies are more subcutaneous fat in the trunk and lower extremities with
common than the inherited varieties. These disorders sparing of the face and neck region. Other clinical features
are often characterized by insulin resistance, acanthosis include acanthosis nigricans, hepatic steatosis and features
nigricans, dyslipidemia, hepatic steatosis and diabetes of PCOS (hirsutism, irregular periods and polycystic
mellitus. Females present with features of polycystic ovaries). Hypertriglyceridemia is more common and
syndrome (hirsutism, oligomenorrhea and polycystic occasionally associated with pancreatitis. Diabetes usually
408 Clinical Profile

develops following the second decade. Cardiovascular • Increase in the production of cytokines [TNF-a and
diseases are the main cause of mortality. Familial partial interleukin 6 (IL-6)] which increases insulin resistance.
lipodystrophies resulting due to the PPAR-g mutation Metabolic derangement associated with lipodystrophy
has similar clinical features as the LMNA mutation. may predispose patients to accelerated atherosclerosis.
Hypertension is more common. Thiazolidinediones and The treatment strategies so far used for treatment of HIV
leptin replacement therapy can improve the metabolic associated lipodystrophy and its metabolic abnormalities
parameters in familial partial lipodystrophy; however, the has shown only mild to modest effect. Switching from one
section

data is limited.153,154 offending drugs [protease inhibitor to a non-nucleoside

7

reverse transcriptase inhibitor (NNRTI) have shown no

Acquired Generalized Lipodystrophy (AGL) significant improvement in the lipoatrophy. Therapeutic
(Lawrence Syndrome) intervention with drugs such as thiazolidinediones,
metformin, recombinant leptin, GH releasing factor
Acquired generalized lipodystrophy was initially described
analog (tesamorelin) and recombinant human GH (rhGH)
by Lawrence in 1984. The onset of disease usually occurs
have shown some success in reducing lipoatrophy and
in the childhood and adolescence and is found to have
improvement in the metabolic parameters; however, the
3:1 female preponderance. The disease is characterized
effects are ill-sustained.166,167
by generalized loss of subcutaneous fat (face, arms, and
legs) even in the palm and sole. The other manifestations
GENETIC SYNDROMES ASSOCIATED
include acanthosis nigricans, non-ketotic diabetes melli­
tus, hyperlipidemia and hepatic steatosis.155 The diabetes
WITH DIABETES MELLITUS
is typically followed by the onset of lipodystrophy by an Overall, there are more than 100 distinct genetic disorders
average of 4 years. Cirrhosis is late sequelae of hepatic associated with glucose intolerance. Genetic syndrome
steatosis and is seen in one-fifth of the patients. Serum associated with diabetes accounts for less than 1% of the
levels of leptin and adiponectin are found to be low in total diabetes mellitus. Some of these disorders are due to
these patients.156,157 chromosomal defect such as Down syndrome, KS and TS.
Certain genetic disorders are shown to be associated with
Human Immunodeficiency Virus obesity, insulin resistance and diabetes mellitus, which
Associated Lipodystrophy include Laurence-Moon-Biedl syndrome, Bardet-Biedl
syndrome and PWS. Hereditary neuromuscular disorders
Human immunodeficiency virus associated lipodystrophy
such as Huntington chorea, FRDA and DIDMOAD
is a syndrome that develops in HIV infected patients who
(diabetes insipidus, diabetes mellitus, optic atrophy,
are being treated with highly active antiretroviral therapy
deafness) syndrome are also linked with diabetes mellitus.
(HAART) therapy.158,159 Lipodystrophy in an HIV patient
There are several mitochondrial disorders like Kearns-
is characterized by loss of subcutaneous fat in the face,
Sayre syndrome, Leber hereditary optic neuropathy,
arms, legs and buttock while some patient concomitantly
myoclonic epilepsy with ragged red fibers (MERRF) and
develop lipohypertrophy in the neck, upper back and in the
myopathy, encephalopathy, lactic acidosis and stroke-
trunk region.160 Lipodystrophy develops in approximately
like episodes (MELAS) syndrome that are associated
40% of patients receiving protease inhibitors for more than
with diabetes mellitus. Mutation of mitochondrial DNA
1 year duration. Patients with features of lipodystrophy are
(A-to-G point mutation at position 3243) leads to mater­
often associated with dyslipidemia, insulin resistance,
nally inherited diabetes and deafness (MIDD) syndrome.
hyperglycemia and/or frank diabetes.161,162 The mechanism
of metabolic abnormalities in lipodystrophy is not clear.
Down Syndrome
The probable mechanisms are as follows:163-165
• Inhibition of activation and differentiation of the Down syndrome (trisomy 21) is the most common
preadipocytes to adipocytes due to decrease in the chromosomal abnormality in the live born. The Down
expression of adipogenic transcription factor like sterol- syndrome patient exhibits characteristic dimorphic facial
regulatory-element-binding-protein 1 (SREBP-1). features, learning disability, congenital cardiac disorders
• Decrease in the expression of insulin responsive| and gastrointestinal abnormalities. Patients with Down
GLUT-4 transporters. syndrome have a three-fold increased risk for developing
 Secondary Diabetes 409

T1DM as compared to the general population.168 Other body composition with increased total body fat and
autoimmune disorders such as thyroid and celiac disease visceral fat.176 In a study, metabolic syndrome was reported
are also common in Down syndrome.169,170 in approximately half (44%) of the patients but it was about
10% in the control group. KS patients were found to have
Turner Syndrome hyperinsulinemia and decreased insulin sensitivity.177
In a study by Bardsley MZ et al., 24% of KS patients had
Turner syndrome is the most common sex chromosomal
insulin resistance and 37% had elevated low-density

chapter
abnormality caused by the loss of a part of X chromosome.
lipoprotein (LDL) cholesterol level.178 Recent studies have
Approximately half of patients have 45, X karyotype and

26
shown that T2D is more common in hypogonadism.179
nearly about 20% have 45, X/46, XX mosaicism. The TS
Testosterone therapy can improve the insulin sensitivity in
is characterized by short stature, streak gonads, primary
obese T2D while no studies had yet examined the effect of
amenorrhea and multiple congenital abnormalities.171
testosterone therapy on diabetes, body composition and
T2DM is 3–4 times more common in TS as compared to
metabolic syndrome in KS patients.
the general population and they tend to develop it at
a younger age. Impaired glucose intolerance is more
Prader-Willi Syndrome
common and is detected in 10–30% of patients. Intrinsic
defect in the beta-cell function is the main defect in Prader-Willi syndrome (PWS) a complex multisystem
TS. Development of obesity and aging leads to insulin genetic disorder that results from lack of expression of
resistance which causes further decline in the beta-cell paternally inherited imprinted genes on chromosome
function, ultimately leading to IGT and T2DM. TS patients 15q11–q13. The disease is characterized by hypotonia,
with haploinsufficiency of Xp genes (45X, delXp and I Xq) short stature, fish-shaped mouth, morbid obesity, hypogo­
are more prone for T2DM.172 Many studies have shown nadism, learning disability and behavioral problems. The
a relative increase in the insulin resistance during GH obesity in PWS occurs as a result of hyperphagia and
treatment but there is no increased incidence of glucose excess intake of calories. T2DM is found in approximately
intolerance. Combination of GH and oxandrolone induces 25% of the cases, the mean age of onset being 20 years.180
more pronounced insulin resistance than GH alone.173 Obesity related cardiovascular disorders are the most
Effect of estrogen therapy used for puberty induction is important cause of mortality in PWS. Diet control, weight
found to improve insulin sensitivity; however long-term reduction, exercise are essential part of management in
effect of hormone replacement therapy (HRT) on TS is
PWS with obesity and diabetes. Insulin-sensitizing agents
not yet clear.174,175 Patients with TS are at increased risk of
such as metformin or thiazolidinediones are considered
various autoimmune disorders. Bakalov et al. have shown
as first line of therapy in PWS with diabetes.181
that 12.4% of their study subjects were antiglutamic acid
decarboxylase (anti-GAD) positive and none of the
Wolfram’s Syndrome
patients were positive for islet cell antibodies. Among the
patients who were anti-GAD positive only one patient had Wolfram’s syndrome is a rare cause of a neurodegenera­
T1DM. However, a study by Gravholt et al. reported an tive disorder. The disease is characterized by DIDMOAD
11.6% increased risk for developing T1DM.171,172 and neurological manifestations. Mutation of WFS1
gene (coding for Wolframin) is the most common cause of
Klinefelter Syndrome Wolfram’s syndrome and has autosomal recessive inheri­
Klinefelter syndrome is the most common sex chrom­ tance. The patients usually presents with non-immune
osomal disorder in male. The most common karyotype mediated T1DM occurring during the first decade of
in KS is 47 XXY with at least one extra X chromosome life.182 The other manifestations of Wolfram syndrome
while approximately 10% have mosaic forms with 46, include cardiomyopathy, renal related disorders, constipa­
XY/47, XXY. The KS is characterized by small testes, tion, depression, psychosis, peripheral neuropathy and
hypergonadotrophic hypogonadism, gynecomastia, infer­ autonomic manifestations. Life-threatening problems
tility and cognitive impairment in a phenotypic male. The such as central apnea and central respiratory failure are
association between KS and diabetes is well-known. In common. Death usually occurs prematurely as a result
1969, Nielsen et al. reported a 39% prevalence of diabetes of respiratory failure and recurrent pneumonia due to
mellitus in glucose tolerance test. KS patients have altered bulbar dysfunction.183
410 Clinical Profile

Friedreich’s Ataxia such as Coxsackie virus, rubella virus and mumps virus
are able to directly infect and lyses the insulin producing
Friedreich’s Ataxia is the most common autosomal reces­
beta-cells which suggests the direct cytopathic effect
sive ataxia. It is mainly caused by homozygous expansion
and death of the beta-cells.191,192 The other important
of the guanine-adenine-adenine (GAA) trinucleotide
mechanisms include immune mediated destruction of
repeat in intron 1 of the frataxin gene located on chromo­
beta-cells.193 Following viral infection, there is an incre­
some 9q13.184 The clinical features of FRDA include pro­
ased production of various IFNs which upregulate the
section

gressive ataxia, weakness, decreased sensation, absent

expression of major histocompatibility complex (MHC)-
reflexes in the lower extremities, dysarthria, blindness due
7

class I molecule on the beta-cells thereby unmasking

to retinitis pigmentosa, hypertrophic cardiomyopathy and
the immune attack. The role of molecular mimicry is one
deafness. The onset of disease usually occurs in childhood
mechanism that encompasses a cross-reactive immunity
and adolescence but sometimes in adulthood. Diabetes
against epitopes shared between viral structure and
mellitus occurs in about 8–32% of the patients and most
beta-cell antigens.194 Another mechanism by which viral
of the patients ultimately require insulin for survival.185,186
infections can trigger autoimmunity and contribute to
T1DM pathogenesis is mediated through by-stander
Huntington’s Disease
activation of unrelated T-cells which leads to production
Huntington’s disease (HD) is a rare neurodegenerative of inflammatory mediators and beta-cell destruction.195
disorder with autosomal dominant inheritance. The
The evidence of association between viral infection and
disease is caused by an elongated cytosine-adenine- diabetes has been mainly based on seroepidemiological
guanine (CAG) repeat (36 repeats or more) of the and experimental studies. The best example of association
Huntington gene located in the short arm of chromosome between viral infection and diabetes mellitus is Congenital
4 (4p16.3).187 The clinical features of HD include chorea Rubella syndrome (CRS). Several earlier studies findings
and dystonia, inco-ordination, cognitive decline and were primarily based on serological prevalence among
behavioral difficulties. The mean age of onset of the T1DM and controls. However, systemic review showed
disease is mostly between 20 years and 60 years; however, too much heterogeneity in methodology and results. The
the disease can occur at any age. A study by Bjorkqvist et viral infections which are implicated in the pathogenesis
al. reported that there is a decrease in beta-cell mass and of T1DM include: enterovirus (EV), coxsackie virus,
exocytic insulin secretion in a R6/2 mouse HD model.188 encephalomyocarditis (EMC) virus, rubella virus, retro­
IGT is detected in approximately 10–25% of the HD viruses, rotavirus, mump virus, meningo virus, foot and
patients.189 However, a recent study by Boesgaard et al. mouth disease virus, CMV, Epstein-Barr virus, varicella
found that HD patients are at less risk for development of zoster virus, Kilham rat virus (KRV) and parvovirus.196,197
diabetes mellitus as earlier reported.190 Experimental studies have shown the association between
various virus infections and the occurrence of T1D in
VIRUSES AND DIABETES MELLITUS animal models. Human EV causes diabetes mellitus in
Type-1 diabetes is a multifactorial disease caused by non-obese diabetes (NOD) mouse, D variant of EMC
autoimmune destruction of beta-cells of the pancreas. (EMC-D) virus in mice and KRV in biobreading (BB) rats.
Environmental factors such as viral infections and Despite the excellent association between viral infec­
nutritional factors have been implicated as important tions and T1DM in animal models, the evidence of casual
triggering factors for the initiation and autoimmune- association between viral infection and human T1DM is
mediated destruction of the beta-cell in a genetically still lacking. Some studies had shown the increased risk of
susceptible individual. The association between the viral T1DM in children when the mother had an EV infection
infection and the risk of developing of T1DM is known during pregnancy. These studies were primary based on
for more than 100 years. However, the immunological the serum antibodies level and viral ribonucleic acid
processes which link the viral infection to the disease (RNA). In more recent studies, reverse transcriptase
onset and progression still remain elusive. Table 26.6 polymerase chain reaction (RT-PCR) method has been
shows viral infections associated with diabetes mellitus. used to detect EV specific RNA in the sera or circulating
There are several possible mechanisms by which viral mononuclear cells of patients with newly diagnosed
infections can lead to diabetes mellitus. Several viruses T1DM.197,198 Children with diabetes have been observed
 Secondary Diabetes 411

Table 26.6: Viral infections associated with the induction of type 1 diabetes mellitus (T1DM) and the possible mechanisms
Spices Genetic Effects
factor
RNA virus
Coxsackie B Human, mice, ND Associated with induction of islet autoantibodies , cytolytic destruction of β-cells
non-human primates Virus isolated pancreas of diabetes animal
Enterovirus Mice Yes Virus-induced β-cell lysis

chapter
Molecular mimicry

26
Virus-induced bystander damage
Encephalomyocarditis Mice Yes High dose: virus-induced β-cell lysis
virus Low dose: infection of β-cells, activation of macrophage and destruction of β-cells
Toga virus Human Yes Associated with development islet cell autoantibodies
Rubella virus Human/Hamsters ND T-cell cross-reactivity between rubella antigens and GAD
Infection of β-cell without cytolytic effects
Paramyxovirus family Human ND Induction of islet autoantibodies
(Mumps virus) Infection of β-cells without cytolytic effect
Increased expression of HLA class I and II on β-cells
Rota virus Mice Yes Infection of β-cells
Molecular mimicry
Reovirus Human ND Infection of β-cells
DNA viruses
Parvovirus Human/Rat ND Associated with induction of autoimmune disease
Virus associated macrophage—breakdown of tolerance
Th-1 type immune response is enhanced
Cytomegalovirus Human/Rat ND Associated with induction of islets autoantibodies
Infection of β-cells but without cytolytic effects
T-cell cross reactivity between HCMV and GAD-65
Epstein-Barr virus Human Induction of autoimmunity mediated by recognition of epitope by HLA-DQ8
Varicella Zoster Human Indirect evidence of association
Kilham rat virus Rats ND No β-cell infection. Autoimmune mediated development of diabetes

Source: van der Werf N, Kroese FG, Rozing J, et al. Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev. 2007;23:
169-83.
(RNA: Ribonucleic acid; DNA: Deoxyribonucleic acid; HLA: Human leukocyte antigen; GAD: Glutamic acid decarboxylase; HCMV: Human CMV).

to test positive for viral RNA more frequently than the childhood is associated with development of immunity
control subject. Several researches have shown that which is found to be protective against T1DM.200 A recent
Coxsackieviruses are capable of infecting isolated human study has observed that exposure to fecal pathogens
pancreas. In situ hybridization studies on postmortem such as hepatitis E virus (HEV) (one or more specific
pancreatic tissue of T1D patients showed EV-positive variant) among children has been greatly minimized
cells in the islet cells.198 Similarly, immunohistochemistry which resulted in failure to develop immunity against
studies also demonstrated the presence of enteroviral HEV virus. This potentially increases the risk for severe
capsid protein VP1 in beta-cells of the pancreatic HEV infection and T1DM to develop. Furthermore there
specimens.199 is increasing evidence to support the contribution of
Epidemiological evidence has also documented viral infection in the occurrence of T1DM. However, the
the constant rise in the incidence of T1DM worldwide currently available literature does not explain its causal
which has been attributed to the lack of exposure to association or the pathogenic mechanisms involved.
microbial pathogen at an early childhood which is also There are other viruses like the human cardiovirus
known as hygiene hypothesis. Exposure to fecal-oral (Saffold virus) which is widespread among humans
transmission of micro-organisms and viruses in the early but its impact on T1D is completely unknown.201 Even
412 Clinical Profile

Table 26.7: Drugs that cause diabetes mellitus early interventions. Table 26.7 shows drugs that can cause
Drugs that cause diabetes by interfering with insulin-synthesis and
diabetes mellitus.
secretion:
Phenytoin L-asparaginase Drugs that Cause or Exacerbates
Pentamidine Tacrolimus Hyperglycemia
b-blockers Didanosine Antihypertensives: Thiazides
section

Diazoxide Opiates
Thiazides are recommended as the first line antihy­
Calcium channel Blockers
7

pertensive drug associated with increased risk of diabetes

Drugs that cause diabetes by interfering insulin action:
mellitus. Long-term studies have shown that the diabetes
Glucocorticoids β-adrenoreceptor agonist mellitus is slow in onset with a lag period of 2 years.202
Megasterol acetate Clonazepine, olanzapine In Antihypertensive and Lipid-Lowering Treatment
(antipsychotics) to Prevent Heart Attack Trial (ALLHAT) study, about
Oral contraceptives SSRI 11.6% of the patients developed new onset diabetes in 4
Growth hormone Protease inhibitors years of study period. Hypokalemia is a well-characterized
Drugs that causes diabetes by interfering with insulin secretion and side effect of thiazide diuretics.203 The diuretic related
insulin action: glucose intolerance is mainly related to hypokalemia
Thiazide diuretics Cyclosporine which acts by impairing the pancreatic insulin secretion.
Diazoxide Atypical antipsychotic The severity of glucose intolerance is found to be
Drugs that cause diabetes independent of insulin: correlated with the degree of hypokalemia. Glucose
Nicotinic acid
intolerance can be minimized or reversed once hypoka­
lemia gets corrected.204
Statin
Aspirin Beta-Blockers
Total parental nutrition
The effect of beta-blockers in glucose homeostasis is quite
(SSRI: Selective serotonin reuptake inhibitor). complex. In the Atherosclerosis Risk in Communities
(ARIC) study, hypertensive patients on beta-blockers had
a 28% increased risk of new onset diabetes mellitus.205
the role of vaccinations in the prevention of T1DM is
Similarly, a meta-analysis on 55,675 hypertensive patients
not clear. Further prospective studies are required to
on beta-blockers reported that 31% of them had increased
establish the association.
risk of new onset diabetes.206 Treatment with beta-
blockers can impair the pancreatic insulin secretion.
DRUG INDUCED DIABETES Patients on beta-blockers are found to have increased
Drug induced hyperglycemia is a growing concern in weight gain which is proposed to be the mechanism that
view of increasing polypharmacy. Many drugs can induce is responsible for increased insulin resistance. Patients
glucose intolerance or diabetes mellitus in a previously who are on longer duration of beta-blockers and those
normoglycemic individual or worsen hyperglycemia in a who are in combination with thiazides are at more risk.
patient with diabetes mellitus. The exact mechanism by In patients on beta-blockers, the factors which are also
which drugs can cause disturbances in glucose intolerance responsible for increased incidence of diabetes mellitus
remains uncertain in many occasions, however the includes: (1) longer duration of therapy (2) combination
diabetogenic mechanism of the drugs can be classified therapy with thiazides (3) overweight and obese at the
into four board categories: (1) impairment of insulin base line.207,208 All beta-blockers are not the same and
synthesis and secretion, (2) impairment of insulin action, the risk of new onset of diabetes is 30% greater with
(3) impairment of both insulin secretion and insulin atenolol and 34% greater with metoprolol when com­
action and (4) independent of insulin action. The most pared with other agents.209 In the Glycemic Effects in
important aspect of drug-induced diabetes is early Diabetes Mellitus: Carvedilol-Metoprolol Comparison in
identification of the altered glucose metabolism, modifi­ Hypertensives (GEMINI) trail, however Carvidelol had
cation or stoppage of offending drug, monitoring and shown favorable effects on glycemic status.210
 Secondary Diabetes 413

Other Antihypertensives and of diabetes in 1.1% for non-users, 1.7% of individuals

New Onset Diabetes Mellitus treated with 200–399 defined daily doses per year and
2.3% for those with more than or equal to 400 defined
Calcium channel blockers (CCBs) can alter glucose daily doses.221 Use of antidepressants such as tricyclic
metabolism by impairing insulin secretion. The deleterious antidepressants and selective serotonin reuptake
effects of CCBs on insulin secretion are dose dependent. inhibitors are associated with increased risk of weight
Antihypertensive drugs such alpha-blockers (doxazosin), gain and diabetes. A study by Andersohn et al. reported an

chapter
angiotensin-converting enzyme (ACE) inhibitors and incidence rate ratio of 1.77, 95% confidence interval (CI) =

26
angiotensin receptor blockers can improve the insulin 1.21–2.59 in tricyclic antidepressant group and incidence
sensitivity and decrease the risk of developing T2DM.211,212 rate ratio of 2.06, 95% CI = 1.20–3.52 in selective serotonin
reuptake inhibitors group.222 Conversely, treatment with
Antipsychotics antidepressants can relieve the depression, improve the
Atypical antipsychotic drugs are considered to be safe and compliance of the drugs and hence improves the glycemic
effective. In fact, these drugs have less extrapyramidal control.223 These drugs are also helpful in reducing weight
side effects even on long-term therapy. Recently, several gain by suppressing the appetite. An integrated treatment
studies had shown that the atypical antipsychotic drugs approach is found to be more effective in the management
are associated with increased risk of weight gain, diabetes, of patient with diabetes and depression.224
hypertension and hyperlipidemia. This is of great con­
cern as patients with psychiatric disorders per se have Glucocorticoids and Diabetes
increased risk of diabetes because of sedentary lifestyle
Glucocorticoids have been widely used because of their
and excess eating. The exact mechanism by which the
anti-inflammatory, immunosuppressive and chemothe­
atypical antipsychotic promotes hyperglycemia and
rapeutic effects. GCs are the most common cause of drug
diabetes mellitus is unknown. Atypical antipsychotic drugs induced diabetes and worsening of hyperglycemia.225,226
are associated with increased body weight and abdominal Although the extent of hyperglycemia induced by these
obesity which can lead to fasting hyperglycemia, insulin agents is not clearly known; it probably ranges between
resistance and diabetes mellitus.213-215 A meta-analysis 1.5% and 47%.227 This wide range can be due to variation
by Allison et al. had shown that patients on clozapine of the patient population, individual risk of development
and olanzapine gained an average weight of 4.45 kg of diabetes, dose and duration of corticosteroid
and 4.15 kg over a period of 10 weeks duration.216 The therapy.228 Alternation of glucose intolerance and diabetes
other possible mechanisms by which the atypical anti­ is quite common when steroid dose is equivalent to
psychotic can promote diabetes mellitus includes 30 mg or more with that of prednisolone. Hyperglycemia
(1) clozapine and olanzapine mediated anticholinergic is also quite common in hospitalized patients. A hospital
effect which can impair the cholinergic regulated insulin based study showed that 86% of subjects had at least
release, (2) antagonism of serotonin (5HT2C) receptors one BG more than 8 mmol/L and 70% had one BG more
which regulates appetite and (3) antagonism of central than 10 mmol/L when dose of steroids were 25 mg
histamine H1 receptors.217-219 prednisone or its equivalent dose of dexamethasone or
hydrocortisone. Ninety-four percentage of subjects devel­
Antidepressants oped hyperglycemia within 48 hours.229
Depression is common among patients with both T1DM
Several mechanisms are responsible for development
and T2DM.220 Concurrent depression in diabetes mellitus of steroid induced diabetes mellitus which includes
can impair the metabolic control due to poor adherence to (1) impairment of insulin action (postsignaling defect)
diet and drugs by the patient. Antidepressants are one of and (2) increased hepatic glucose output. Patients with
the most common groups of drugs prescribed worldwide. decreased beta-cell secretory reserve are more prone for
Several recent studies have raised the possibility of development of diabetes.230 All GCs cause dose-dependent
development of diabetes in patients with long term insulin resistance at dosages greater than the equivalent
anti-depressants. A prospective study, by Kivimaki et al. of 7.5 mg/day of prednisolone. The GCs related side effect
over a period of 5 years in patients with depression is more common with oral steroids. Patients who are
observed that there was an absolute risk of development on steroid inhalation have a far lower risk of developing
414 Clinical Profile

diabetes. Diabetes is not common with topical steroids effect. The important risk factor of NODAT includes
but when applied in large volumes such as over eroded older age, obesity, ethnicity (African-Americans and
parts of skin, it may be associated with diabetes. Drugs like Hispanics), pre-existing impaired glucose intolerance
deflazacort cause less hyperglycemia when compared to and family history of diabetes.238 The other risk factors like
other GCs.231 human leukocyte antigen (HLA)-type (HLA-A30, B27 and

The typical pattern of hyperglycemia in individuals Bw42) and cadaveric donor kidney are also associated
on GCs shows a minimal increase in fasting glucose but with increased risk of diabetes but the effects are less
section

an exaggeration of postprandial hyperglycemia. Most consistent.

In 1964, Starlz first described the contributory role of
7

patients with GC induced diabetes require insulin for

their glycemic control. It is always difficult to achieve corticosteroids in NODAT in renal transplant recipients.
a glycemic goal with diet and oral antidiabetic agents The diabetogenic effects of corticosteroids are dose
alone except in mild hyperglycemia or in patients who dependent.239 The incidence of steroid induced diabetes
are on low doses of GCs. Steroid induced diabetes can be has reduced significantly following the introduction
of cyclosporine in the 1980s. Steroid sparing or steroid
improved following the tapering of steroid and usually
withdrawal protocols in the early post-transplant period
resolves on stoppage of steroid but diabetes can persist in
has significantly reduced the incidence of diabetes.240,241
some patients.232
Patients needing GCs either as pulse therapy or main­
tenance dose to prevent acute rejection has increased risk
New-Onset Diabetes after Transplantation
of diabetes.
New-onset diabetes after transplantation (NODAT) is Hepatitis C virus (HCV) infection is an important
one of the serious metabolic complications after solid problem in post-transplant patients. Glucose intolerance
organ transplantation. This can adversely affect the and diabetes are more frequent in patients who are
long-term graft survival, patient survival and quality of found to be positive for HCV than negative ones.242,243
life.233 Before 2003, de novo diabetes that developed after A meta-analysis by Fabrizi et al. showed that patients
transplantation had been described in various terms and with anti-HCV seropositive are nearly four times more
most frequently as post-transplantation diabetes mellitus. likely to develop diabetes mellitus as compared to anti-
In 2003, The International Expert Panel published a HCV seronegative. The link between CMV infection and
guideline regarding the definition and diagnosis of development of NODAT was first reported in a renal
diabetes mellitus in NODAT and recommended that transplant patient.244 Both asymptomatic CMV infection
the diagnosis of NODAT should be based on the World and CMV disease are independently associated with
Health Organization (WHO) and American Diabetes development of NODAT.245
Association (ADA) criteria for diabetes.3 In 2010, ADA

The mechanism of development of NODAT is multi­
endorsed a emoglobin A1c (HbA1c) level more than 6.5% factorial in nature and occurs due to complex interactions
between the diabetogenic effect of immunosuppressants
as a diagnostic criteria for diabetes. However, it cannot
and host factors. These mechanisms include islet cell
be used in post-transplant patients because of high
toxicity, diminished insulin synthesis or release and
chances of spurious results due to anemia and immuno­
decreased peripheral insulin sensitivity. The diabetogenic
suppressants.234,235
effect of GCs is mediated by impairment of insulin

The incidence of NODAT is variable as it depends upon
mediated glucose uptake in the peripheral tissues and
the duration of follow-up, the type of immunosuppressants increased hepatic glucose output. Calcineurin inhibitors
used and the criteria used in diagnosis. Prior to consensus (cyclosporine and tacrolimus) can induce diabetes by
statement, the incidence of NODAT reported was reversible islet cell toxicity and inhibition of insulin
between 7–46%.234 The true increase in incidence of gene expression. Simultaneously tacrolimus can also
NODAT is more common within 6 months after trans­ cause severe swelling and vacuolization of islet cell which
plantation.236 Patients on tacrolimus are more prone can lead to marked reduction or absence of beta-cell
to develop NODAT than patients with cyclosporine granules. Serum tacrolimus level is shown to be strongly
(14% vs 7%).237 Newer immunosuppressants like sirolimus associated with severity of glucose abnormality. A study
have been associated with increased risk of diabetes by Maes and colleagues showed that a high tacrolimus
however drugs like azathi­ oprine and mycophenolate level (> 15 ng/mL) in the first month after transplant has
mofetil (MMF) doesn’t have independent diabetogenic been associated with an increased risk of developing
 Secondary Diabetes 415

persistent IFG in 15% and diabetes mellitus in 32% of the Statin-induced Diabetes Mellitus
individuals beyond the first year after transplantation.246
The statins are the most commonly prescribed drugs
The development of NODAT can adversely impact the
to treat high cholesterol level that acts by inhibiting the
long-term survival in transplantation patients. These
HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A)
patients have two-fold to three-fold increased risk of
reductase, a rate limiting enzyme in cholesterol biosyn­
death due to cardiovascular disease.
thesis pathway. Statins are found to be beneficial for

chapter
primary and secondary prevention of cardiovascular
Management of New-Onset
disease. Many recent reviews have shown that statins

26
Diabetes after Transplantation can modify glucose metabolism and increase the risk of
Pretransplantation risk assessment is essential in all development of new onset diabetes. The intervention
patients undergoing organ transplantation to identify trail [Justification for the Use of Statins in Primary
the subjects with a high risk of acquiring NODAT. Oral Prevention: An Intervention Trial Evaluating Rosuvastatin
glucose tolerance should be performed in all cases as (JUPITER)] evaluating the effect of rosuvastatin showed
it has a better predictive value for identifying the high- 3% of patients in the statin arm developed new onset
risk subjects for diabetes and cardiovascular disease. diabetes after 2 years of follow-up.250 A meta-analysis
Blood glucose monitoring should be done at a regular by Sattar et al. which included 13 trials (91,140 patients)
showed an overall increased risk for new onset diabetes
interval for early detection. Recent guideline recommends
was 9% [odd ratio (OR) of .09; 95% CI 1.02–1.17] in statin
weekly monitoring of fasting plasma glucose (FPG), oral
group, however there was no clear difference among
glucose tolerance test (OGGT) and/or HbA1c for initial
individual statins.251 Experimental studies have shown
4 weeks followed by every month for 1 year and ann­
that lipophillic statins such as atorvastatin is associated
ually thereafter.234 HbA1c levels must be looked at with
with a decreased glucose uptake in the adipocytes but not
caution in patients with anemia. The most important pravastatin. A recent meta-analysis by D Preiss and his
aspect is to identify the patients at high risk for acute colleagues included five statins trails (32,752 participants
rejection and thus correct immunosuppressive agents without diabetes) in which diabetes developed in 2,749
must be initiated to minimize the risk of rejection and subjects among whom 1,449 subjects were in intensive
development of diabetes.247,248 In patients with high statin therapy and 1,300 assigned moderate-dose therapy.
immunological risk, tacrolimus is preferred as the first The risk of development of diabetes is more in the intensive
choice and in patients with low immunological risk and statin arm as compared to moderate statin arm (OR 1.12,
high risk for NODAT either cyclosporine or belatacept- CI 1.04–1.22). The number needed to harm is one in every
based immunosuppressive regimen should be preferred. 498 subjects treated with intensive statin therapy.252 All
In patients who develop NODAT, the dose of calcineurin these data clearly indicates that statin therapy definitely
inhibitors and GCs should be carefully tapered or in a rare increases the risk of diabetes. However, the beneficial
case it can be switched over to an immunosuppressant effects of statins in reducing cardiovascular disease far
with less risk of diabetes like cyclosporine. Patients with outweigh the risk for development of diabetes.253
IGT prior to transplantation should get advice for life
style modification. A step care approach is recommended IMMUNE MEDIATED DIABETES
in NODAT. First step of management includes lifestyle Stiffman Syndrome (Stiff Person Syndrome)
medication: exercise, weight control. Second step includes The Stiffman syndrome was first described by Moersch
oral antidiabetes agents (monotherapy or combination) and Woltmann in 1956. The SMS is rare a neurological
therapy depending upon the glycemic status. Almost all disorder characterized by fluctuating muscle rigidity,
types of oral agents can be used except first generation painful muscle spasm, task-specific phobia, an exagg­
sulfonylureas. Metformin should be avoided if the erated startle response and ankylosing deformities such
estimated glomerular filtration is less than 60 mL/minute. as fixed lumbar hyperlordosis. The pathogenesis of SMS
Initiation of insulin should be considered with or was originally thought to be autoimmune in origin since
without oral agents and if there is failure to achieve the disease is shown to be associated with variety of
glycemic control with oral agents or if there is metabolic autoimmune diseases such as: T1DM, thyroiditis, vitiligo
decompensation.234,249 and pernicious anemia.
416 Clinical Profile

The association between SMS and T1DM is extremely the age ranges between 10 years and 50 years. The type
interesting from the immunological point of view as B insulin resistance is characterized by severe insulin
both the diseases share a common antigen, the enzyme resistance, acanthosis nigricans and hyperglycemia.257
GAD.254 The enzyme GAD is a rate limiting enzyme of Along with the above features, women often presented
gamma-aminobutyric acid (GABA) synthetic pathway with hirsutism, polycystic ovarian disease and elevated
located primarily in the GABAergic nerve terminals in testosterone level. Type-B insulin resistance syndrome
the central nervous system (CNS) and peripheral nervous often coexist with other autoimmune disorders such
section

system and also located in the pancreatic beta-cells. as Hashimoto’s thyroiditis, primary biliary cirrhosis,
7

Approximately 60% of SMS patients may have antibodies systemic sclerosis, Sjögren’s syndrome, and SLE at
against the two isoforms of GAD: (1) GAD-65 and (2) presentation. Less commonly, patient can present with
GAD-67. Autoantibodies to GAD are found in approxi­ hypoglycemia which has been attributed to agonistic
mately 70–80% of new onset T1D. Up to 30% of patients activity of the insulin receptor antibody. Mortality is
with Stiff person syndrome developed diabetes mellitus quite high in this syndrome. A case series by Arioglu
however SMS is a rare occurrence in patient with T1D. The et al. reported a 54% death rate over 10 years period from
SMS has been classified into three major variants based the diagnosis.258,259 Immunosuppressive therapy such as
upon the presence or absence of specific autoantibodies azathioprine, cyclosporine, rituximab, prednisolone and
which include: (1) Autoimmune variant (2) Paraneoplastic cyclophosphamide showed variable efficacy and are often
variant and (3) Idiopathic variant. The patients that are associated with side effects and toxicity.
included under autoimmune variant group are found to
be positive for anti-GAD, anti-islet cell, and other organ- SECONDARY DIABETES IN CHILDREN
specific autoantibodies and are also at increased risk of
To date, most researches have a focus on secondary
other autoimmune diseases. The patients with parane­
diabetes in adult population; however, there is little data
oplastic SMS are associated with neoplasm and also posi­
available regarding the prevalence, risk factors and etiology
tive for certain non-organ specific autoantibodies. The
of secondary diabetes mellitus in children.260 Secondary
patients included in idiopathic variants are neither posi­
diabetes has been of a great concern in childhood due to
tive for autoantibodies nor associated with any systemic
recent advance in the management and survival among
disorders. The clinical variant of SMS includes symptoms
the patients with malignant disorders, leukemia, CF and
confined to only a single limb known as Single Limb
other life-threatening disorders.261,262 Post-transplant
syndrome (SLS). The other variant include progressive
diabetes is one of important cause of secondary diabetes
encephalomyelitis with rigidity and myoclonus (PERM).255
in children. Early recognition and treatment of secondary
The SMS can be even present in early childhood with hyper-
diabetes can improve the outcome of the underlying
reflexia and rigidity also known as Stiff Baby syndrome.256
disease, prevention of transplantation rejection and long-
Benzodiazepine and baclofen are the most common
term complications of hyperglycemia.
drugs used for symptomatic treatment. Immunomo­
The diagnostic criteria of secondary diabetes in child­
dulation drugs such as corticosteroids, immunoglobulin
ren are similar to that of other diabetes. A thorough
and plasmapheresis can be considered in patients with
history regarding the drugs (immunosuppressants, GCs
severe disease and poor response to benzodiazepine
or chemotherapeutic agents) and environmental factor
however the effects are quite variable.
exposure such as viral infection and toxin must be
elicited.263 Over last one decade, there has been a sharp
Insulin Receptor Antibodies and Diabetes
rise in the incidence of both T1DM and T2DM and thus it
In 1975, Flier and colleague first discovered the antibodies is essential to rule out the underlying diabetes mellitus.264
against insulin receptor. The insulin resistance syndrome Clinical and laboratory evidence of autoimmunity can
associated with insulin receptor antibody is also known be helpful in identifying concomitant T1DM. Family
as type B insulin resistance syndrome. Insulin receptor support has significant impact in the management of
antibodies can cause diabetes by binding to the insulin diabetes in children. It is essential to either taper the
receptor there by blocking the binding of insulin to the drugs doses or its modification with other drugs having
target tissues. Most of the patients have been female and less risk for diabetes. Insulin therapy is the main stem of
 Secondary Diabetes 417

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1980. RA, Keen H (Eds). International Textbook of Diabetes Mel­
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haemoglobinopathies in India. Natl Med J India. 1999;12: 189-212.
234-38. 15. Larsen S, Histed J, Tronier B, et al. Metabolism control
3. Genuth S, Alberti KG, Bennett P, et al. Expert Committee and beta cell function in patients with insulin dependent
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Follow-up report on the diagnosis of diabetes mellitus. Dia­ 1987;36:964-7.
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 Chapter 27
Neonatal Diabetes
Poovazhagi Varadarajan, Viswanathan Mohan

Neonatal Diabetes

Chapter Outline
♦♦ Classification of Neonatal Diabetes Mellitus ♦♦ Case Study
♦♦ Genetic Studies of Neonatal Diabetes Mellitus in India ♦♦ Prognosis and Long-term Outcome in Neonatal Diabetes
♦♦ Pathophysiology of Neonatal Diabetes Mellitus Mellitus
♦♦ Clinical Presentation and Diagnosis of Neonatal
Diabetes Mellitus

INTRODUCTION (PNDM). Insulin production is inadequate and therefore

exogenous insulin therapy is required although some
Diabetes mellitus (DM) presenting as hyperglycemia neonates with specific mutations in the ABCC8 or KCNJ11
during the first 6 months of life is a rare disorder that genes may respond to sulfonylurea agents. Hyperglycemia
affects all races and ethnic groups and is increasingly in a neonate could be due to other factors like sepsis,
being recognized as a separate entity. This form of insulin higher infusion rates of glucose or prematurity. However,
sensi­ tive hyperglycemia has been termed “congenital
these conditions are transient and usually resolve with
diabetes mellitus” or “neonatal diabetes mellitus (NDM)”
correction of the underlying process and do not need
and is usually of genetic origin. Though technically, the
insulin therapy for long. The incidence, etiopathogenesis,
neonatal period limits itself to the first 4 weeks of life, the
presentation and management of NDM are discussed in
term NDM has been used for diabetes with onset up to
this chapter.
6 months of life and most of these cases appear to have
a monogenic form of inheritance due to a single gene
CLASSIFICATION OF NEONATAL
mutation.1-4 Although rarely NDM may present after 6
months of age, we propose the term infantile onset for
DIABETES MELLITUS
those with onset more than 6 months of age. NDM pre­ Neonatal diabetes is classified into two types: (1) TNDM
sents as hyperglycemia, failure to thrive and in some and (2) PNDM. In addition, there are other forms with
cases, dehydration and ketoacidosis, which may be other genetic syndromes.
severe often with coma in an infant and occurs within the
first few months of life.5 NDM is rare with an incidence Transient Neonatal Diabetes Mellitus
of 1:100,000–300,000 newborns.5-9 Neonatal diabetes is Transient neonatal diabetes mellitus usually presents
heterogeneous and can be transient neonatal diabetes within the first few weeks of life. It needs insulin for
mellitus (TNDM) or permanent neonatal diabetes mellitus at least 2 weeks and resolves by a median 12 weeks.
 Neonatal Diabetes 427

Table 27.1: Mutations in transient neonatal diabetes mellitus Permanent Neonatal Diabetes Mellitus
Chromosome 6q related
• Paternal uniparental disomy This is a form of NDM which does not go into remission.
• Duplication defects Unlike western literature, in our series of 33 NDM children
• Hypomethylation related from India, we noted that 61% had PNDM and only 5% had
ABCC8 (SUR) mutation TNDM.6 About 60–75% of the PNDM with onset less than
KCNJ11 (Kir6.2) mutation 6 months of age were found to be of genetic origin.2 Based

chapter
on the genetics of neonatal diabetes, they could be either

27
Rarely, it lasts until 12 months of age. In the west, TNDM syndromic or non-syndromic. The etiology of PNDM is
represents 50–60% of cases of neonatal diabetes.5 In our summarized in Table 27.2.
series of NDM, 5% had TNDM.6 The commonest genetic
mutation is the chromosome 6q24-related (PLAGLI, ABCC8 Gene
HYMAI, ZFP57 gene), which accounts for nearly 70% of
all the TNDM cases.10-12 Two imprinted genes ZAC (zinc The adenosine triphosphate (ATP) binding cassette sub
finger protein associated with apoptosis and cell cycle family C member 8 (ABCC8) gene which encodes the
arrest) and HYMAI (imprinted in hydatidiform mole) four sulfonylurea receptors of the ATP sensitive potas­
present in the 6q region were identified as potential sium channels that regulates insulin secretion. It is
candidates for this imprinting disorder. Paternal unipa­ located at 11p 15.1. Mutations in ABCC8 can lead to both
rental disomy of chromosome 6, duplication of 6q24 hyperinsulinism and hypoinsulinism. Activating muta­
region on the paternal allele and hypomethylation of tions of the ABCC8 gene lead to decreased insulin secre­
the maternal differentially, methylated region (a CpG tion and neonatal diabetes. About 20% of permanent
island overlapping exon 1of ZAC/HYMAI) account for neonatal DM is due to ABCC8 mutation, which is inherited
the 6q related TNDM.12 KATP channel mutations account either as autosomal dominant or recessive pattern.
for 25% of TNDM.13-17 The mutations seen in TNDM are ABCC8 gene mutations that cause permanent neonatal
summarized in Table 27.1. DM result from single amino acid changes in the protein
The cardinal features of TNDM are severe intrauterine sequence, leading to KATP channels that do not close and
growth retardation, hyperglycemia, dehydration, and reduced insulin secretion from beta cells. Babies with
absence of ketoacidosis. Neonates may present with this mutation usually present with low birth weight and
breathlessness, lethargy and poor feeding. Insulin is DM during the first 6 months of life. Neurological dysfunc­
required for fetal growth, and severe growth retardation tion may be a key feature in some with PNDM due to
could be due to insulin deficiency. Hyperglycemia is ABCC8 mutation.16,17 Transient hyperglycemia in neonatal
usually identified during routine investigations. Infants period may be followed by permanent diabetes later in life.
with 6q 24 related mutations may have macroglossia.
Though transient, DM may recur in the pediatric age KCNJ11 Mutations
range, or later in adulthood in over 50% of cases. Annual
KCNJ11 is the potassium inwardly rectifying channel
evaluation for hyperglycemia is therefore mandatory in
subfamily J member 11 gene located at the 11p 15.1
all children with TNDM during the remission phase.
chromosome. Mutations in the KCNJ11 gene encoding
During relapse initial management may be by diet
the Kir6.2 subunit of the beta-cell KATP channel accounts
modification but subsequently, they may need insulin, for the majority of children with diabetes diagnosed in the
as the response of oral sulfonylurea is uncertain. Women first 6 months of life.18 The mutations are predominantly
who have had 6q24-TNDM are at risk of relapse of spontaneous but may be due to autosomal dominant
diabetes during pregnancy. Thus, the “transient” form of inheritance and paternal mosaicism. Nearly, 30% of them
the disease is most likely a permanent β-cell defect with present with ketoacidosis and developmental delay is
variable expression during growth and development. reported in 20–40% of children.6,18,19 In a few patients,
Considerable overlap occurs between TNDM and PNDM KCNJ11 mutations cause a triad of developmental delay,
and hence they cannot be distinguished based on clinical epilepsy, and neonatal diabetes which is called DEND
features alone and can only be differentiated based on syndrome. It probably results from mutated KATP channels
genetic testing. However, in general, those with TNDM in muscle, nerve and brain. The variant without epilepsy
have lower insulin requirement in comparison to PNDM.5 is called iDEND.6 Studies have been performed to identify
428 Clinical Profile

Table 27.2: Types of permanent neonatal diabetes mellitus based on genetic mutations
Genetic defect Associated features
Heterozygous mutations of the ABCC8 gene (SUR) Developmental delay
KCNJ11 (Kir6.2)
Wolcott-Rallison syndrome with EIF2AK3 mutation Epiphyseal dysplasia, renal and hepatic failure
IPEX syndrome with autoimmunity with FOXP3 mutation Diarrhea, eczema, thyroiditis
Homozygous glucokinase mutation Heterozygote parents
section

IPF mutation Heterozygote parents

7

PTF1A mutation Cerebellar hypoplasia, pancreatic involvement

GLIS3 mutation Hypothyroidism, glaucoma
HNF 1β mutation Renal cysts, genital malformations
Enteroviral related diabetes
Others type A Insulin resistance syndrome Features of androgen excess with hyperinsulinemia
Leprechaunism
Rabson-Mendenhall syndrome

(IPEX: Immune dysregualtion polyendocrinopathy enteropathy X-linked)

the association between potassium inwardly-rectifying Glucokinase Mutation

channel, subfamily J, member 11 (KCNJ11) gene and
type 2 diabetes mellitus (T2DM) and the results have Glucokinase (GCK) mutation accounts for 5–10% of
been inconsistent.20 PNDM.21 Glucokinase is a key regulating enzyme in
Treatment with oral sulfonylurea results in good regulating pancreatic beta cell insulin synthesis. Being
glycemic control and improvement in epilepsy and the glucose sensor, it plays a major role in insulin release.
psychomotor abilities. Hence there is a need for a definitive Mutations in the gene encoding GCK can lead to hypo or
genetic diagnosis in children with neonatal DM. hyperglycemia. Heterozygotic mutation leads to milder
phenotype presenting as MODY and the homozygotic
INS Gene mutations are with severe phenotype with presentation
as PNDM.22 Children with neonatal diabetes born of
Mutations in the insulin gene (INS gene) account for consanguineous parents, who have hyperglycemia, must
another 20% of permanent neonatal DM. The genetic be screened for GCK mutations. They present in the first
location of this gene is 11p 15.5. The precursor form of few days of life with hyperglycemia with ketoacidosis
insulin, pro insulin is produced as single chain of amino usually requiring insulin therapy. Though sulfonylureas
acids, which is cleaved chains A and B, bound by the can enhance insulin release the response is not satis­
disulfide bonds, forming insulin. The mutation in INS factory. It may be used to reduce the insulin requirement.23
gene disrupts the cleavage or the binding of the two chains
leading to hypoinsulinemia and diabetes. These muta­ Syndromes of Insulin Resistance
tions are inherited in an autosomal dominant pattern. The
homozygous mutations of INS gene account for the most Rarely insulin resistance syndromes like type A insulin
common type of PNDM among consanguineous families. resistance, Leprechaunism, Rabson-Mendenhall synd­
They manifest with severe intrauterine growth retardation rome and lipodystrophy can present with diabetes in the
and diabetes within few days or weeks of life. Some may first few months of life. Generalized lipodystrophy in
present later, from 6 months to 1 year of age. Patients insulin resistance manifest by acanthosis nigricans, hyper­
with INS mutations do not have other associated extra- androgenism, muscular hypertrophy, hepatomegaly, glu­
pancreatic features. Some patients have complications cose intolerance or diabetes and hypertriglyceridemia.
secondary to longstanding diabetes such as neuropathy In the generalized form, both subcutaneous and visceral
and retinopathy. Mutations in INS gene may have diverse adipose tissues are nearly absent. The congenital form is
phenotypes from hypoinsulinemia and hyperinsulinemia called the Berardinelli-Seip Congenital Lipodystrophy
to neonatal diabetes. (BSCL). Berardinelli-Seip syndrome is a rare autosomal
 Neonatal Diabetes 429

recessive disease. Two loci for BSCL have been identified and heterozygous siblings of WRS patients do not have
recently on chromosome 9 (AGPAT2) and chromosome any distinctive features. Management includes close
11 (Seipin). The high degree of insulin resistance makes monitoring for hypoglycemia and ketoa­cidosis as both
metabolic control of diabetes very difficult despite high are frequent. Insulin pumps may be useful because of
doses of insulin.24 We have identified a novel mutation the brittle nature of diabetes. However, one should not
Val67Met in AGPAT2 gene in one of our NDM patient with target a very tight metabolic control in these children.
Berardinelli-Seip syndrome.6 Early diagnosis is recommended, in order to ensure rapid

chapter
intervention for episodes of hepatic failure, which is the

27
Wolcott-Rallison Syndrome most life-threatening complication. Clinical course of this
Wolcott-Rallison Syndrome (WRS) is the most common disease is variable due to the variable age of onset, varied
cause of permanent neonatal DM seen in children born clinical involvement and the associated complications.
of consanguineous parents.25 It was named after Wolcott Prognosis is poor and these children usually die at a
and Rallison, who first described this syndrome in three young age although a few can survive up to the age of 35.
affected siblings. WRS is a rare autosomal recessive Death often results from multiorgan failure with renal
condition characterized by early onset diabetes, epiphyseal dysfunction and hepatic failure sometimes associated
dysplasia with multisystem involvement in the form of with encephalopathy.
renal impairment, acute hepatic failure, developmental
delay and hypothyroidism. Central hypothyroidism is Immune Dysregulation, Polyendocrinopathy,
usually noted during the acute presentation; it may be a Enteropathy, X-linked Syndrome
reflection of euthyroid sick syndrome occurring during
stress and is not part of the syndrome. They may have The FOXP3 gene defect leading to immune dysregualtion,
associated exocrine pancreatic dysfunction. WRS is polyendocrinopathy, enteropathy, X-linked (IPEX) syn­
associated with mutations in the Eukaryotic initiation drome is an autoimmune endocrinopathy associated with
factor 2 alpha kinase 3-EIF2AK3 (PKR like endoplasmic diarrhea, anemia, eczema and thyroiditis.29,30 It is inherited
reticulum kinase PERK).26-28 EIF2AK3 regulates the protein as an X-linked disorder affecting only boys. Presentation
synthesis during stress by phosphorylating the α subunit is most commonly the clinical triad of watery diarrhea,
of the eukaryotic initiation factor 2 (e IF 2). Four protein eczematous dermatitis, and endocrinopathy (most
kinases: phosphorylate eIF2: GCN2, Heme regulated commonly type 1 DM). Coombs-positive anemia, hypo-
inhibitor, Double stranded RNA activated protein kinase or hyperthyroidism, autoimmune thrombocytopenia,
(PKR) and EIF2AK3/PERK. autoimmune neutropenia, and tubular nephropathy
Though WRS commonly presents as neonatal diabetes, are some of the other autoimmune manifestations.
it can present as late as 30 months of age. EIF2AK3 Molecular testing confirms the diagnosis. Bone marrow
mutations are considered as the most common cause transplantation can resolve clinical symptoms. Majority
of NDM in regions where consanguineous marriages of the affected males die in the first few years of diagnosis
are more prevalent. In our experience, five families with due to sepsis or severe metabolic derangements. Milder
different EIF2AK3 mutations were identified. As the inher­ phenotypes survive into second or third decade. Children
itance is recessive, children with homozygous mutations presenting in late childhood have been reported.31
were affected whereas their unaffected parents were
heterozygous. Skeletal dysplasia is usually diagnosed by 2 GLIS 3 Syndrome
years and hepatic failure can occur at any time. Defective
mineralization or dysplastic changes affect the long Permanent neonatal diabetes mellitus can present
bones, pelvis and vertebra. The skull is usually spared. due to mutations in GLIS 3 associated with congenital
Hepatic involvement can be mild with hepatomegaly or hypothyroidism, congenital glaucoma, hepatic fibrosis and
severe and life threatening. Other features include renal polycystic kidneys. It is rarely associated with osteopenia,
dysfunction, exocrine pancreatic insufficiency, hypothy­ bilateral sensorineural deafness and pancreatic exocrine
roidism, neutropenia and recurrent infections. WRS must insufficiency.32,33 Gli-similar (GLIs) 1-3 proteins constitute
be suspected in any child with diabetes onset at less a subfamily of Krüppel-like zinc finger proteins and the
than 2.5 years who presents with hepatic failure. Parents mutations have been implicated in many disorders.
430 Clinical Profile

Table 27.3: Glycemic levels of Indian children before and after sulfonylurea treatment6
S. no Gene Mutation Zygosity HbA1c Levels Fasting plasma glucose levels
Before SU After SU Before SU After SU
treatment treatment treatment treatment
1. KCNJ11 Cys42Arg Heterozygous 14.3% 7.0% 461 mg/dL 120 mg/dL
2. KCNJ11 Arg201Cys Heterozygous 10.8% 7.4% 275 mg/dL 110 mg/dL
3. KCNJ11 Arg201Cys Heterozygous 11.0% 7.2% 300 mg/dL 105 mg/dL
section

4. ABCC8 Val86Ala Heterozygous 7.8% 6.4% 250 mg/dL 92 mg/dL

7

5. ABCC8 Asp212Tyr Heterozygous 7.0% 6.2% 235 mg/dL 100 mg/dL

(SU: Sulfonylurea)

GENETIC STUDIES OF NEONATAL with the disease which will help in predicting the risk for
DIABETES MELLITUS IN INDIA subsequent pregnancies.

Neonatal diabetes mellitus is thus a form of monogenic PATHOPHYSIOLOGY OF NEONATAL

diabetes where genetic testing currently has clinical DIABETES MELLITUS
application. KCNJ11 and ABCC8 mutations have been
identified in Indian NDM children with onset of diabetes While a few do not respond to oral suphonylurea, the
below 6 months of age (Table 27.3).6 Children who are not majority of neonates respond to oral sulfonylurea therapy.
harboring mutations in KCNJ11 and ABCC8 should be The diagrammatic representation of the patho­physiology
considered for screening of INS, GCK, PDX1 and HNF4A in pancreatic cells is shown in Figures 27.1 and 27.2.
genes, as the mutations in these genes were previously
seen in children with neonatal diabetes.34 Screening of CLINICAL PRESENTATION AND DIAGNOSIS
additional clinical features is very important in case of OF NEONATAL DIABETES MELLITUS
NDM children because some of the syndromic features
present in the later part of neonatal period. Hence, a Neonatal DM in the immediate newborn period is usually
proper diagnosis will help in appropriate genetic testing diagnosed incidentally. Hyperglycemia in the neonatal
to aid for treatment regimen. Screening of EIF2AK3, period is more common and this usually resolves once
GCK, SLC2A2, SLC19A2, IPF1, PTF1A, HNF1B, FOXP3, the underlying disease process is treated. Differentiating
ZFP57, GLIS3, GATA6, NEUROD1, NEUROG3, IER31P1, this stress hyperglycemia from that of neonatal DM is
PAX6 and RFX6 genes should be considered in case of challenging. One needs to wait for the resolution of the
NDM children with clinical features like hepatic failure, underlying diseases process and the C peptide levels may
give some useful information. Neonatal DM can present
skeletal abnormalities, optic atrophy and developmental
delay etc.35 A number of homozygous mutations have as diabetic ketoacidosis with classical features of acidosis
been identified in children with syndromic forms of dia­ with hyperglycemia especially in KCNJ11 mutations.18
betes (Arg1065X in EIF2AK3, Val67Met in AGPAT2, and It is not uncommon to misinterpret this acidosis as
Leu19Arg in SLC2A2 etc.) in Indian children.6 Splice and sepsis related lactic acidosis and delay the management
frame shift mutations were identified in the genes asso­ of DM. In older infants, beyond 6 months of age, history of
ciated with NDM in Indian children and these mutations polyuria and polydipsia may be elicitable and a diagnosis
are certainly pathogenic as they can disturb the normal of type 1 diabetes may be considered. This is usually
protein synthesis mechanism (unpublished data). confounded by presence of insulin autoantibody like the
As the KATP mutations are sulfonylurea (SU) responsive, glutamic acid decarboxylase (GAD) antibody. Missed
children with KCNJ11 (Cys42Arg and Arg201Cys) and diagnosis of diabetes in not uncommon in diagnosis
ABCC8 (Val86Ala, Asp212Tyr and Pro254Ser) gene muta­ of DKA in infants. Since autoimmune etiology is less
tions have been successfully shifted to oral SU drugs common in infants, all infants with diabetes should be
from insulin injections.17 Family genetic studies should carefully examined for any syndromic features and should
be conducted to check the co-segregation of mutation undergo genetic evaluation for monogenic diabetes.
 Neonatal Diabetes 431

chapter
27
Fig. 27.1: Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations
(ATP: Adenosine triphosphate; cAMP: Cyclic adenosine monophosphate; GLP1: Glucagon like peptide 1; GLUT: Glucose transporters)
Pearson ER, et al. N Engl J Med 2006; 355:467-77

Fig. 27.2: Proposed model of the action of sulfonylurea (SU) on beta cells expressing mutations in the Kir6.2 subunit of the KATP channel
(ATP: Adenosine triphosphate; cAMP: Cyclic adenosine monophosphate; GLP1: Glucagon like peptide 1)
Pearson ER, et al. N Engl J Med 2006; 355:467-77
432 Clinical Profile

Confirmation of blood glucose more than once is in attempting to alleviate the neurological symptoms in
mandatory to diagnose neonatal diabetes. A thorough infant with this mutation. A successful dose is likely to
clinical examination should include anthropometry, dys­ be much higher than the adult dose of the drug.39-41 The
morphic features, features of androgen excess, evidence process of switch to oral medications can be done as a
of bony abnormalities, features of hypothyroidism and rapid in-hospital procedure over a period of one week
a detailed developmental assessment. Laboratory evalua­ or it can be done as a slow process as outpatient therapy
tion should include serum C-peptide levels, HbA1c, over a period of 4 weeks. Infants may need very high
section

thyroid function tests, serum uric acid, serum ammonia doses of sulfonylurea for switch. In view of altered renal
7

levels, ultrasonogram of the abdomen and genetic studies. clearance of sulfonylurea in infants, they may develop
It may not be feasible to obtain fasting and post-meal hypoglycemia during subsequent days of switch therapy.
C-peptide samples as the feeding schedule in infants Hence, out patient protocol for transfer done over a
are inconsistent. Genetic studies are mandatory in all few weeks would be better if home circumstances are
infants with onset of diabetes below 6 months of age and if appropriate for therapy. Prior to the switch, the following
pos­sible in all children with DM whose onset is less than parameters are recorded—HbA1c levels, general physical
one year of age. It is prudent to evaluate all children with examination including height and weight, develop­
onset at less than 2.5 years of age with history of liver mental age, gross motor, fine motor, verbal, neurological
failure for WRS. examination if any developmental delay (ideally with a
quantitative, repeatable method), IQ (age appropriate
Management of Neonatal Diabetes Mellitus test), electroencephalogram (EEG) if epilepsy and MRI if
The specific management includes insulin therapy and neurological features are present. A complete neurological
in genetic mutations responsive to oral sulfonylurea oral evaluation is mandatory. To initiate the switch process
medications are used. The inconsistent feeding pattern begin with 0.1 mg/kg of the sulfonylurea given twice daily.
and the requirement of insulin in very small doses pose The increment of dosage is to be done with simultaneous
difficulty in day to day management. However, if the reduction of the insulin until the infant or the child is free
requirement is very low, once or twice a day dose of of insulin. The commonest known side effects are skin
intermediate acting insulin may be useful. Insulin pumps allergies in 1.5% and they usually resolve, GI side effects
have been successfully used in neonatal DM as early as including diarrhea in 1–2% and hematological features
the first month of life.36,37 In case of requirement of insulin like anemia, leucopenia and thrombocytopenia.42 Short
being less than 0.5 units/dose it is ideal to use the insulin term follow-up in these children has not revealed any
diluent provided by the insulin manufacturers. Caution untoward complications, however long term follow-up
must be provided as accidental overdose of insulin can is awaited. Periodic monitoring of complete blood
be hazardous. Some infants may be very sensitive and counts and liver function tests are advised. Table 27.4
develop rapid hypoglycemia with rapid or short acting summarizes the different switch protocol.43
insulin. Analog insulin like Glargine has been successfully While insulin therapy in these genetic mutations can
used in extremely low birth weight neonates with DM.38 only control the hyperglycemia, studies have shown that
oral sulfonylurea therapy can also bring some improve­
Switching over to Oral Drugs in ment in the neurological impairment.44 This switch over
Neonatal Diabetes Mellitus from insulin to oral sulfonylurea can be done at any age
irrespective of the duration of diabetes. However, the
Most of the KCNJ11 and ABCC8 mutations are res­ chances of successful switch to oral therapy are reduced
ponsive to oral sulfonylurea therapy. Drugs that have in adults especially if over 30 years where there has been
been successfully tried include oral glibenclamide and poor glycemic control prior to switch. The dose required
oral gliclazide. The SUR 1 selective sulfonylurea drugs will in neonatal diabetes may range from 0.5 mg/kg/day
close β-cell KATP only while the non-selective sulfonylurea to 1.0 mg/kg/day.39,41 Among the infants with Kir6.2
drugs like glibenclamide will also act on muscle and brain mutation and SUR mutations, the insulin requirement
KATP channels. The mutated channels in nerve, muscle and later sulfonylurea requirement was found to be
and brain are responsible for the neurological symptoms. significantly lower in the SUR mutation group.5,45,46 The
Thus, a non-selective sulfonylurea may be a better choice role of oral therapy is presently limited to the KCNJ11 and
 Neonatal Diabetes 433

Table 27.4: Summary of the switch protocol from insulin to oral sulfonylurea
Slow out-patient switch protocol Rapid out-patient switch protocol
Height, weight and complete neurological examination to be Height, weight and complete neurological examination to be
documented prior to switch documented prior to switch
Day 1: Fasting HbA1c, C peptide levels. Give 0.1 mg/kg/dose of oral Day 1: Fasting HbA1c, C-peptide levels taken. Give 0.1 mg/kg/dose
glibenclamide with breakfast. Continue evening dose with insulin, of oral glibenclamide with breakfast. Continue evening dose with
if blood glucose is more than 126 mg/dL insulin if blood glucose is more than 126 mg/dL

chapter
Reduce the insulin slowly keeping the sulfonylurea constant for Day 2: Omit the isophane insulin and continue only short or rapid

27
1 week acting insulin throughout therapy. Oral sulfonylurea is increased to
0.2 mg/kg/dose given twice daily and reduce insulin by 50%
Increase sulfonylurea to 0.2 mg/kg/dose twice daily during week Day 3: Increase the sulfonylurea to 0.3 mg/kg/dose given twice daily
2 with decreasing insulin doses with reduction of insulin if the blood glucose is more than 126 mg/dL.
Do not increase sulfonylurea, if sugars are less than 126 mg/dL
Increase the sulfonylurea to 0.3 mg/kg/dose in the 3rd week and Increase sulfonylurea to 0.3 mg/kg/dose on Day 4 and then to 0.4
to 0.4 mg/kg/dose in the 4th week and later up to 0.5 mg/kg/dose mg/kg/dose to a maximum of 0.5 mg/kg/dose (1 mg/kg/day). Doses
twice daily up to 2 mg/kg/day have been used in literature
Continue to monitor the blood glucose with every meal until the Continue to monitor the blood glucose with every meal until the
switch is complete by coming off insulin switch is complete by coming off insulin
Subsequent follow-up at 3 months with height, weight, a complete Subsequent follow-up at 3 months with height, weight, a complete
neurological assessment with HbA1c levels and serum C-peptide neurological assessment with HbA1c levels and serum C-peptide
levels levels

ABCC8 mutations. The same has been successfully used that the weight gain was very minimal despite being
in transient neonatal DM and in relapse of TNDM at exclusively breast fed. The infant was initially evaluated
15 years of age in a child (glimepiride).47,48 Sulfonylurea by a physician and was referred to a tertiary care facility
therapy has not been found to be useful in homozygous as suspected bronchopneumonia. Clinical examina­
GCK mutation, Wollcott Rallison syndrome and other tion at the emergency room revealed that the child
types of neonatal diabetes. However, there are some recent was afebrile with lethargy, tachypnea and tachycardia
reports where homozygous GCK mutation had showed with hepatomegaly of 7 cm. Other systems were
partial responsiveness to repaglinide, glibenclamide or normal. The infant was admitted with a provisional diag­
glyburide.32,49 The associated co-morbid states like pan­ nosis of sepsis with bronchopneumonia. The investi­
creatic dysfunction, hypothyroidism, anemia and eczema gations revealed normal chest X-ray, serum sodium of
need to be treated. Parental evaluation for heterozygote 130 mEq/dL, potassium of 5 meq/dL, and a bicarbonate
status may help to plan future pregnancies and antenatal of 10 mEq/dL. His urea was 98 mg/dL and creatinine was
genetic counseling and diagnosis. As the mother is the 2.1 mg/dL. Routine blood sugar done at the bed side was
immediate caregiver in NDM, the role of these painful high. The blood glucose was subsequently confirmed
injections being given by the mother with whom the in the laboratory to be 550 mg/dL. Urine sugars were
infant is developing bonding, needs to be addressed. +++ and ketones were mildly positive. Retrospectively,
a history of polyuria was obtained, which the mother
CASE STUDY was not able to recognize as abnormal being a neonate.
There was also a history of white patches over the
A 45-day-old male child was brought to the emergency external genitalia, which were noticed for 2 weeks prior
room with a history of breathlessness of 1 day duration, to the illness. There was no dehydration clinically but
lethargy and refusal of feeds noted since 8 hours. The blood gases revealed metabolic acidosis with a wide
child was the first born of consanguineous parents and anion gap. The child was treated as per DKA protocol
was delivered as a full term baby by Cesarean section and stabilized after 72 hours of hospital stay and
with a birth weight of 2.3 kg and had an uneventful switched over to subcutaneous insulin injections. His
neonatal period. The baby was exclusively breast fed and HbA1c level was 9%. Serum C-peptide was low and GAD
the present weight was 3 kg; the mother was concerned antibodies were negative. Baby required 1 unit/kg/day
434 Clinical Profile

of insulin to start with and was stabilized after 10 days reports the long-term outcome for WRS is poor. Some
on 1 unit of intermediate insulin in the morning and of the PNDM may require replacement therapy for the
0.5 units of intermediate acting insulin in the evening. exocrine functions of the pancreas as well. Finally, the level
Genetic analysis was done 2 weeks later and the child of metabolic control determines the timing of appearance
was found to have a homozygous ABCC8 mutation. Both of the long-term complications like any other diabetes.
the parents were heterozygous carriers for the mutation. The management in insulin resistance syndromes is much
Following genetic reports, the baby was readmitted for an difficult. The impact of insulin sensitizers is very limited in
section

in-hospital transfer process to oral sulfonylurea. The severe insulin resistance states. In partial lipodystrophy,
7

child had a successful switch over to oral glibenclamide metformin may be useful. In total lipodystrophy, leptin
at the dose of 1.5 mg/kg/day given in two divided therapy may be useful though presently it is for research
doses. There was no episode of hypoglycemia and after purposes only.50 Response of NDM subjects with Kir6.2
3 months of the switch, the HbA1c reduced to 7.8% and and SUR–1 (ABCC8) mutations to sulfonylurea therapy
at the end of 6 months, to 6.5%. The serum C-peptide represents one of the best examples of the benefits of
levels improved. At 3 years of age, the child had good genetic testing in the field of medicine.
metabolic control and normal growth and development.
ACKNOWLEDGMENT
PROGNOSIS AND LONG-TERM OUTCOME
We thank Dr Radha Venkatesan, Executive Scientific
IN NEONATAL DIABETES MELLITUS
Officer & Head Molecular Geneticist, Madras Diabetes
Neonatal diabetes is very different from other forms of Research Foundation and Mrs S Jahnavi, Research Fellow,
diabetes in that the course of disease is variable. In some Madras Diabetes Research Foundation, Chennai for their
infants it is transient, in some it remits after varying help with the genetic studies of neonatal diabetes. The
periods of insulin dependency only to recur later in website www.neonataldiabetes.in is recommended as a
life, in some infants it continues to be permanent DM. resource material on this subject.
Outcome in the immediate neonatal period depends on
the presentation, severity of dehydration and acidosis FURTHER READING
and how early it is recognized and treated appropriately. 1. Development of the pancreas and neonatal diabetes. Shield
In the post neonatal period the prognosis is determined JPH, Scharfmann R (Eds). Endocrine Development. Basel:
by associated conditions like neurological involvement or Karger; 2007. pp. 86-98.
hepatic involvement. 2. Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endo-
Though it resolves in a few weeks, transient neonatal crine Reviews 2008;29:265-91.
3. Edghill EL, Flanagan SE, Ellard S. Permanent neonatal
diabetes can later lead to diabetes over the years. Some
diabetes due to activating mutations in ABCC8 and KCNJ11.
of these genetic mutations predispose the pregnant Rev Endocr Metab Disord. 2010;11:193-8.
mother who had TNDM in the past to develop DM during 4. Støy J, Steiner DF, Park SY, et al. Clinical and molecular
pregnancy. Hence, the infants with TNDM need to be genetics of neonatal diabetes due to mutations in the
followed up for relapse later. Follow-up studies on children insulin gene Rev Endocr Metab Disord. 2010;11:205-15.
on oral sulfonylurea has shown good metabolic control 5. Karges B, Meissner T, Icks A, et al. Management of diabetes
and improvement of developmental delay and are safe mellitus in infants. Nat Rev Endocrinol. 2012;8:201-11.
in the short term.2,19 Reports from literature mention the
incidence of hypoglycemia with oral medications to be REFERENCES
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2007;2:12. pancreas and brain. Neurology. 2007;69:1342-9.
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2013;83(5):439-45. als. Mol Biol Rep. 2012;39:645-59.
7. Stanik J, Gasperikova D, Paskova M, et al. Prevalence of 21. Borowiec M, Mysliwiec M, Fendler W,  et al. Phenotype
permanent neonatal diabetes in Slovakia and successful variability and neonatal diabetes in a large family with
replacement of insulin with sulfonylurea therapy in KCNJ11 heterozygous mutation of the glucokinase gene. Acta
and ABCC8 mutation carriers. J Clin Endocrinol Metab. Diabetologica. 2011;48:203-8.
2007;92:1276-82. 22. Osbak KK,Colclough K,  Saint-Martin C,  et al. Update on
8. Slingerland AS, Shields BM, Flanagan SE, et al. Referral mutations in glucokinase (GCK), which cause maturity-
rates for diagnostic testing support an incidence of perma- onset diabetes of the young, permanent neonatal diabetes,
nent neonatal diabetes in three European countries of at and hyperinsulinemic hypoglycemia. Hum Mutat.  2009;
least 1 in 260,000 live births. Diabetologia. 2009;52:1683-5. 30:1512-26.
9. Russo L, Iafusco D, Brescianini S, et al. Permanent diabetes 23. Turkkahraman D, Bircan I, Tribble ND, et al. Permanent
during the first year of life: multiple gene screening in neonatal diabetes mellitus caused by a novel homozygous
54 patients. Diabetologia. 2011:54:1693-701. (T168A) Glucokinase (GCK) mutation: initial response to
10. Temple IK, Gardner RJ, Mackay DJ, et al. Transient neonatal oral sulfonylurea therapy. J Pediatr. 2008;153:122-6.
diabetes: widening the understanding of the etiopathogen- 24. Poovazhagi V, Shanthi S, Jahnavi S, et al. Berardinelli
esis of diabetes. Diabetes. 2000;49:1359-66.
Seip congenital lipodystrophy presenting with neonatal
11. Diatloff-Zito C, Nicole A, Marcelin G, et al. Genetic and epi-
diabetes mellitus due to a mutation in the AGPAT2 gene. Int
genetic defects at the 6q24 imprinted locus in a cohort of
J Diabetes Dev Ctries. 2013;33:66-8.
13 patients with transient neonatal diabetes: new hypoth-
25. Rubio-Cabezas O, Patch AM, Minton JA, et al.  Wolcott-
esis raised by the finding of a unique case with hemizygotic
Rallison syndrome is the most common genetic cause of
deletion in the critical region. J Med Genet. 2007;44:31-7.
permanent neonatal diabetes in consanguineous families.
12. Mackay DJ, Temple IK. Transient neonatal diabetes mel-
J Clin Endocrinol Metab. 2009;94:4162-70.
litus type 1. Am J Med Genet C Semin Med Genet.
26. Iyer S, Korada M, Rainbow L, et al. Wolcott-Rallison syn-
2010;154:335-42.
drome: a clinical and genetic study of three children, novel
13. Flanagan SE, Patch AM, Mackay DJ, et al. Mutations in ATP-
mutation in EIF2AK3 and a review of the literature. Acta
sensitive K+ channel genes cause transient neonatal dia-
betes and permanent diabetes in childhood or adulthood. Paediatr. 2004;93:1195-201.
Diabetes. 2007;56:1930-7. 27. Senée V, Vattem KM, Delépine M, et al. Wolcott-Rallison Syn-
14. Edghill EL, Flanagan SE, Patch AM, et al. Insulin mutation drome: clinical, genetic, and functional study of EIF2AK3
screening in 1,044 patients with diabetes: mutations in the mutations and suggestion of genetic heterogeneity.
INS gene are a common cause of neonatal diabetes but a Diabetes. 2004;53:1876-83.
rare cause of diabetes diagnosed in childhood or adult- 28. Delépine M, Nicolino M, Barrett T, et al. EIF2AK3, encod-
hood. Diabetes. 2008;57:1034-42. ing translation initiation factor 2-alpha kinase 3, is mutated
15. Gloyn AL, Cummings EA, Edghill EL, et al. Permanent neo- in patients with Wolcott-Rallison syndrome. Nat Genet.
natal diabetes due to paternal germline mosaicism for an 2000;25:406-9.
activating mutation of the KCNJ11 Gene encoding the Kir6.2 29. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation,
subunit of the beta-cell potassium adenosine triphosphate polyendocrinopathy, enteropathy, x-linked  syndrome: a
channel. J Clin Endocrinol Metab. 2004;89:3932-5. paradigm of immunodeficiency with autoimmunity. Front
16. Gonsorcikova L, Vaxillaire M, Pruhova S, et al. Familial Immunol. 2012;3:211.
mild hyperglycemia associated with a novel ABCC8-V84I 30. d’Hennezel E, Bin Dhuban K, Torgerson T, et al. The immu-
mutation within three generations. Pediatr Diabetes. nogenetics of immune dysregulation, polyendocrinopa-
2011;12:266-9. thy, enteropathy, X linked (IPEX) syndrome. J Med Genet.
17. Patch AM, Flanagan SE, Boustred C, et al. Mutations in the 2012;49:291-302.
ABCC8 gene encoding the SUR1 subunit of the KATP chan- 31. Bae KW,  Kim BE,  Choi JH,  et al. novel mutation and
nel cause transient neonatal diabetes, permanent neonatal unusual clinical features in a patient with immune
diabetes or permanent diabetes diagnosed outside the neo- dysregulation, polyendocrinopathy, enteropathy, X-linked
natal period. Diabetes Obes Metab. 2007;9:28-39. (IPEX) syndrome. Eur J Pediatr. 2011;170:1611-5.
436 Clinical Profile

32. Dimitri F, Warner JT, Minton JA  et al. Novel GLIS3 muta- 43. Transferring Patients with Diabetes due to a KIR6.2 Muta-
tions demonstrate an extended multisystem phenotype. tion from Insulin to Sulfonylureas. [online] Available form
Eur J Endocrinol. 2011;164:437-43. http://www.diabetesgenes.org/content/transferring-pa-
33. Lichti-Kaiser K, ZeRuth G, Kang HS, et al. Gli-similar pro- tients-diabetes-due-kir62-mutation-insulin-sulfonylureas[
teins: their mechanisms of action, physiological functions, Accessed August 2013].
and roles in disease. Vitam Horm. 2012;88:141-71. 44. Slingerland AS,  Nuboer R,  Hadders-Algra M, et al.
34. Suzuki S, Makita Y, Mukai T, et al. Molecular basis of neona- Improved motor development and good long-term
tal diabetes in Japanese patients. J Clin Endocrinol Metab. glycaemic control with sulfonylurea treatment in a patient
section

2007;92:3979-85. with the syndrome of intermediate developmental delay,

35. Senniappan S, Shanti B, James C, et al. Hyperinsulinaemic early-onset generalised epilepsy and neonatal diabetes
7

hypoglycaemia: genetic mechanisms, diagnosis and man- associated with the V59M mutation in the KCNJ11 gene.
agement. J Inherit Metab Dis. 2012;35:589-601. Diabetologia. 2006;49:2559-63.
36. Bharucha T, Brown J, McDonnell C, et al. Neonatal diabetes 45. Rafiq M,  Flanagan SE,  Patch AM,  et al. Neonatal Diabe-
mellitus: insulin pump as an alternative management strat- tes International Collaborative Group. Effective treat-
egy. J Pediatr Child Health. 2005;41:522-6. ment with oral sulfonylureas in patients with diabetes due
37. Begum-Hasan J, Bruce AA, Koster J. Case Study: Experience to sulfonylurea receptor 1 (SUR1) mutations. Diabetes
in Insulin Pump Therapy During the Neonatal Period. Clin- Care. 2008;31:204-9.
ical Diabetes.  2010;28:30-3. 46. Wagner VM, Kremke B, Hiort O, et al. Transition from insu-
38. Barone JV, Tillman EM, Ferry RJ. Treatment of transient lin to sulfonylurea in a child with diabetes due to a mutation
neonatal diabetes mellitus with subcutaneous insulin glar- in KCNJ11 encoding Kir6.2--initial and long-term response
to sulfonylurea therapy. Eur J Pediatr. 2009;168:359-61.
gine in an extremely low birth weight neonate. J Pediatr
47. Loomba-Albrecht LA, Glaser NS, Styne DM, et al. An oral
Pharmacol Ther. 2011;16:291-7.
sulfonylurea in the treatment of transient neonatal diabetes
39. Hattersley AT. Molecular genetics goes to the diabetes clin-
mellitus. Clin ther. 2009;31:816-20.
ic. Clin Med. 2005;5:476-81.
48. Schimmel U. Long-Standing sulfonylurea therapy after
40. Massa O, Iafusco D, D’Amato E, et al. KCNJ11 activating pubertal relapse of neonatal diabetes in a case of uniparen-
mutations in Italian patients with permanent neonatal dia- tal paternal isodisomy of chromosome 6. Diabetes Care.
betes. Hum Mutat. 2005;25:22-7. 2009;32:e9.
41. Zung A, Glaser B, Nimri R, et al. Glibenclamide treatment in 49. Bennett K, James C, Mutair A, et al. Four novel cases of
permanent neonatal diabetes mellitus due to an activating permanent neonatal diabetes mellitus caused by homozy-
mutation in Kir6.2. J Clin Endocrinol Metab. 2004;89:5504-7. gous mutations in the glucokinase gene. Pediatr Diabetes.
42. Codner E, Flanagan S, Ellard S, et al. High-dose glibencla- 2011;40:949-51.
mide can replace insulin therapy despite transitory diar- 50. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insu-
rhea in early-onset diabetes caused by a novel R201L Kir6.2 lin resistance and hepatic steatosis in patients with severe
mutation. Diabetes Care. 2005;28:758-9. lipodystrophy. J Clin Invest. 2002;109:1345-50.
 Chapter 28
Early Onset
Type 2 Diabetes
Viswanathan Mohan

Early Onset Type 2 Diabetes

Chapter Outline
♦♦ Epidemiology ♦♦ Criteria
♦♦ Pathophysiology of Early Onset T2DM ♦♦ Treatment and Management
♦♦ Risk Factors of Early Onset T2DM ♦♦ Prevention of T2DM in Children

INTRODUCTION now started moving to younger age groups, especially

in ethnic minority populations in the developing world.
Diabetes mellitus is one of the commonest endocrine and Indeed, since the 1990’s, there has been a striking increase
metabolic diseases of childhood. Till recently, diabetes in the incidence and prevalence of T2DM in children and
in children, adolescent and young adults was almost adolescents.1-3 The potential cumulative morbidity and
exclusively type 1 diabetes mellitus (T1DM), which is mortality resulting from early onset T2DM is worrisome as
caused by autoimmune destruction of the insulin pro­ the period of exposure to glycemia can be considerable,
ducing beta cells. Today this scenario has changed, as if one develops the disorder at a young age. The available
there is increased recognition of a number of different data on the pathophysiology, management, complications
forms of “non-type 1 diabetes” in the young. This includes and long-term outcomes of children with T1DM and T2DM
type 2 diabetes mellitus (T2DM), maturity onset diabetes suggests that there are important differences in the clinical
of young (MODY), fibrocalculous pancreatic diabetes profile of these two populations.4 The limited amount of
(FCPD), gestational diabetes mellitus (GDM) and diabetes information about the epidemiology of T2DM in children
due to genetic disorders. This shift to other types of diabetes is in part due to the relatively recent recognition of its
that has also coincided with the increasing epidemic of emergence in this age group and in part because screening
T2DM along with a shift of the age at onset of T2DM, which for diabetes in children is not generally recommended.
has now started affecting the youth and even children and Historically, the first cases of childhood onset T2DM
adolescents. This chapter will focus exclusively on the were reported in 1979 and 1984 among Native Americans
epidemiology, clinical profile and management of early and Canadian First Nation People, who were regarded as
onset T2DM. homogenous groups with a greater genetic susceptibility
to T2DM.5,6 The second wave of reports appeared in the
EPIDEMIOLOGY mid-1990s and involved predominately ethnic minorities,
namely blacks and Hispanic Americans and some
International white populations in the United States.6 At about the
Although T2DM has been traditionally viewed as an adult same time, reports began to appear from Japan as well.
disease, with the epidemic of T2DM spreading fast, it has About a decade later, cases from Europe were reported.6
438 Clinical Profile

Table 28.1: Prevalence of T2DM in children and adolescents

Study/Location Year of study Prevalence Age group studied Ref. No
Africa (PS)
Tanzania 1989 0.7% 15–24 9
Europe (CS)
Austria 1999–2001 *1.5% of all DM < 15 years 10
France 1993–1998 *2.0% of all DM < 17 years 11
section

Germany 1991–2004 *0.90% of all DM < 20 years 12

7

Hungary 1989–2001 *10.7% of all DM ≤ 19 years 13

Italy 1994–2001 *0.1% of all DM 6–18 years 14
United kingdom 2000 *1.8% of all DM < 20 years 15
North America (CS)
Cincinnati 1994 *16% of all DM 0–19 years 16
Canada 1994–2002 *4.3% of all DM < 18 years 5
U.S.A (PS) 2001 Native Americans 1.74/1000 10–19 years 17
SEARCH African Americans 1.05/1000
Asian/Pacific islander 0.54/1000
Hispanics 0.48/1000
California 1994 Non-Hispanic whites 0.19/1000 0–17 years 18
Arizona 1992–1996 *45% of all DM 10–14 years 7
22.3/1000 15–19 years
50.9/1000
*  Prevalence within the specific populations.
  (DM: Diabetes mellitus; PS: Population study; CS: Clinic based study)

The North American experience with youth-onset T2DM the 10–18‑year‑olds.19 One study has reported children as
was reviewed by Fagot-Campagna et al. in 2000.7 Table young as 8 years being affected with T2DM.20 An excellent
28.17,9–18 shows the reported prevalence of early onset review on T2DM in children highlights the increasing
T2DM in North America, Europe and Africa. trends and high prevalence of diabetes in the young espe­
From a worldwide perspective, there appears to be a cially in the minority groups and indigenous populations
close relation between rising rates of T2DM in adults and that are undergoing rapid economic and social transition.21
the eventual appearance of the disorder in adolescents.
Indeed T2DM in children was reported earliest in Studies from Asia and India
those countries with the highest rates of adult T2DM.6 Table 28.222-36 presents the reports on early onset T2DM
Thus attention to the epidemiology of T2DM in adult from Asia Pacific region. The prevalence of T2DM in Asia is
populations may be helpful in predicting the emergence amongst the highest worldwide37 and is increasing rapidly
of T2DM in adolescents and children. These observations particularly in urban India.38 According to the national
appear to have great implications for screening programs ICMR-INDIAB study, currently in India, there are an
for T2DM among children and adolescents. estimated 62.4 million individuals with diabetes and this
It is estimated that as many as 15–46% of children with is expected to increase to over 100 million by 2030. This
newly diagnosed diabetes in the United States may now study showed the take-off point for increasing prevalence
have T2DM.5 Similar increases have been documented of diabetes was at 25–34 years of age as shown in
worldwide. The SEARCH study which is one of the largest Figure 28.1.39 However, population based estimates for
studies on diabetes in children reports an incidence per diabetes in children and adolescents are lacking in our
100,000 person years of 0.8 in the 5–9 year olds, 8.1 in country as most population based studies are done on
10–14 years and 11.8 in 15–19 years.8 Another large study adults aged 20 years and above. Available data from clinic
from Canada, reports an incidence of 0.27 per 100,000 in based reports suggests that there is a shift of age at onset of
children less than 10 years and 3.1 per 100,000 per year in T2DM towards younger age groups.
 Early Onset Type 2 Diabetes 439

Table 28.2: Prevalence and incidence of T2DM in children and adolescents in Asia Pacific region (Pinhas-Hamiel O6)
Asia Pacific Year of Prevalence/ Age Group Ref. No.
Region Study Incidence Studied
Japan 1976 0.2/100,000 Primary School Children 22
1995 2.0/100,000 Primary School Children
1995 13.9/100,000 Junior high school children 23
Taiwan 1992–1999 6.5/100,000 6–18 years 24

chapter
Singapore 1997 10 cases 12 years 25

28
2000 > 50 cases 26
Hong Kong 1996 0.1/100,000 < 15 years 27
Bangkok 1987–1996 5% 0–14 years 28
1997–1999 17.9%
China 2001 2.4% < 18 years 29
New Zealand 1997–1999 12.5% Age at diagnosis–15 years 30
2000–2001 35.7% 31
Auckland, NZ 1995–2007 0.5 to 2.5/100,000 < 15 years 32
Australia 1999–2001 5% Mean age 14.2 ± 2.0 years 32–34
2001–2002 2.5/100,000 35
Bangladesh 1995 5.7% 15–29 36
1997 0.04% 15–19 37

Fig. 28.1: Age- and sex-specific weighted prevalence of diabetes39 Fig. 28.2: Young diabetes (YD) cases as a percentage of total
ICMR INDIAB study diabetes patients seen at our center (1992–2009)45

The increasing trend of T2DM occurring in Asians, We recently reported on one of the largest series
including Indian children and adolescents, is linked closely of diabetes in the young (n=2630) seen at our center,
to the increasing prevalence of obesity and increased which is a tertiary diabetes center in Chennai in South
insulin resistance (IR) in association with low birth weight India.45 “Diabetes in the young” was defined as those
and sedentary lifestyle on a background of a strong family with first diagnosis of diabetes at or below 25 years of age.
history of T2DM.27,40-43 As the prevalence of diabetes in Figure 28.2 shows that the overall proportion of diabetes
youth increases, there is a risk that micro and macro­ in the young at our center rose from 0.55% during the period
vascular complications of diabetes may develop by early 1992–95 to 2.5% in 2009. Among the total of 2,630 subjects
adulthood, i.e. during the height of their productivity with diabetes in the young, 1,262 (48.0%) had T2DM, 1,135
which potentially could affect the economy of the nation (43.2%) had T1DM, 118 (4.5%) had GDM and 115 (4.4%)
apart from posing a large burden to an individual and had other forms of diabetes including FCPD and genetic
his/her family.44 syndromes of diabetes.45 Thus at our center, T2DM is
440 Clinical Profile

already more common than T1DM. However, this may well again possibly reflecting a socio economic bias, due to the
reflect referral bias in private diabetes centers which not free supply of insulin provided at these hospitals.
surprisingly, would attract patients from the more affluent Till recently, T2DM mellitus was considered rare
sections of society who tend to have higher obesity rates. In in children. A study from Chennai published in 1995
most government hospitals, T1DM is still more common, reported a “zero” prevalence for diabetes in children after
screening 3,515 school children.46 Other studies from
Chennai have reported on type 1 as well as T2DM based
section

on clinic data. Figure 28.3 shows that there is a gradual

increase in childhood and adolescent T2DM (CAT2DM)
7

defined as onset of T2DM at or below 19 years of age. The

figures, which are presented as a proportion of the total
patients registered at our center during that period show
that the prevalence of CAT2DM rose from 0.01 % in 1992 to
0.35% in 2009 (p for trend < 0.001).47 Young-onset T2DM
has also been reported from other parts of India48,49 in
addition to China, Korea, Malaysia and Singapore50 and the
highest prevalence of type 2 in children has been reported
from Japan.51 In one multicenter study from India48 done
over a period of 2 years, 603 subjects were evaluated, of
whom 535 (89%) had a diagnosis of T1DM, 36 (6%) had
Fig. 28.3: Prevalence of childhood and adolescent onset T2DM T2DM, 18 (3%) had FCPD and 14 (2%) had other subtypes
(CAT2DM) shown as proportion of total subjects registered at our of diabetes. Table 28.352-60 shows the percentage of T2DM
center (1992–2009)47 in children and adolescents reported in India.

Table 28.3: Percentage of T2DM in children and adolescents reported in India

S. No. Place, Author and Center name Year or Number of T2DM in child- Total Age group Ref.
Period of ren reported and given sample studied No.
study as % where applicable screened
Population based studies
Chennai:
1 Bai et al. 1994 0.00 3515 5–19 years 46
2 Mohan et al. (Dr Mohan’s Diabetes Specialities Centre) 2012 4 (0.3%) 1519 6–19 years 52
Clinic based studies/Case series
1 Chennai:
Venkatraman et al. (Madras Medical College) 1979–89 2 (1.2%) 160 < 20 years 53
Mohan et al. (Diabetes Research Centre) 1981–83 219 (4.8%) 4560 < 25 years 54
Ramachandran et al. (Diabetes Research Centre) 1988 314 (57.7%) 545 < 30 years 55
Ramachandran et al. (Diabetes Research Centre) 2002 18 cases < 15 years 42
Mohan et al. (Dr Mohan’s Diabetes Specialities Centre) 2006 116 (26.7%) 434 < 16 years 43
Mohan et al. (Dr Mohan’s Diabetes Specialities Centre) 1992–2009 1262 (48.0%) 2630 < 25 years 45
Mohan et al. (Dr Mohan’s Diabetes Specialities Centre) 1992–2009 368 (26.8%) 1372 < 20 years 47
Poovazhagi et al. (Institute of Child Health and Hospital 1999–2010 2 (0.5%) 432 < 12 years 56
for Children)
2 Hyderabad: Sahay et al. (Sahay’s Diabetic Clinic and 1999–2002 339 (7.0%) 4833 < 30 years 57
Research Centre) 19 (0.4%) < 20 years
3 Kolkata: Banerjee et al. (NRS Medical college) 2004 13 (19.4%) 67 6–25 years 49
4 New Delhi (Multisite case control study): Vikram et al. 2006 51 cases < 30 years 58
(All Indian Institute of Medical Sciences)
5 MEDI study: Unnikrishnan et al. (Amrita Institute of 2006–2008 36 (6%) 603 < 20 years 48
Medical Sciences)
6 Lucknow: Bhatia et al. (SGPIMS) 2004 13 (8%) 160 < 18 years 59
7 Varanasi: Jyotsna et al. (Institute of Medical Sciences) 2002 12 (17.11%) 70 < 30 years 60
 Early Onset Type 2 Diabetes 441

Drawbacks in present population based and clinic based PATHOPHYSIOLOGY OF EARLY ONSET T2DM
reports on childhood and adolescent onset T2DM are:
• The age ranges studied are usually inconsistent. The Beta Cell Function and Insulin Resistance
age group studied by different ethnic group varies and As the information on the pathophysiology of T2DM in
this leads to underestimation and a large proportion of the young is sparse, projections from adults becomes
patients may have been missed. In future, if researchers necessary. T2DM is characterized by disorders of insulin
could adopt a standard age range limit like 0–11 years, action and insulin secretion, either of which may be the

chapter
12–19 years and 20–29 years etc. it would be helpful in predominant feature.63 The development of alterations in

28
segregating children, adolescents and young adults. glucose metabolism results from a gradual deterioration
• Lack of uniformity in classification of diabetes types. of beta cell function occurring on a background of IR.
Some of the adolescents who were originally diagnosed T2DM is a progressive disorder and the most important
as having type 1 diabetes were later found to have factor responsible for this, is a continuing decline in beta
T2DM and vice versa. When new cases of adolescents cell function. Several studies have demonstrated that
with diabetes are analyzed for classification, diagnosis diabetes and prediabetes do not develop until the beta
could not be made initially which might be due to cells fail to compensate appropriately to the peripheral
unavailability of glutamic acid decarboxylase (GAD) IR state.64 One of our study done in youth, showed both
antibody and C-peptide assays. Another problem is IR and beta cell function [measured by oral disposition
migration of patients to other centers. index-(DIo)] are associated with T2DM-Y and prediabetes
• The growing awareness of adolescent T2DM over time, however only DIo remained significant after adjusting for
among the physicians, may have affected prevalence body mass index (BMI), waist circumference and parental
rates. Clinicians in urban areas have become more history of diabetes showing that it is more strongly linked
adept at identifying and treating T2DM in children with T2DM-Y and prediabetes than IR in this ethnic
and adolescents, and hence only few of them are now group.65 The ability of the beta cell to secrete sufficient
being referred to academic centers. This may have led insulin to adequately respond to the peripheral IR state
to an underestimation of T2DM in prevalence studies depends on multiple factors including beta cell mass and
at diabetes centers in major teaching hospitals. secretory capacity,66 which are influenced by genetic and
• Finally, the studies presented in Table 28.3 are almost environmental factors.67 Indeed, although the progressive
exclusively diagnosed cases of T2DM. However, if loss of beta cell function could be due to different
pediatric T2DM mirrors the adult pattern of T2DM, metabolic derangements (IR, lipotoxicity) several studies
many affected children with T2DM may be undiag­ have suggested that beta cell dysfunction depends also
nosed. This assumption is supported by a recent study on a pre-existing, and most likely, genetically determined
of obese children, wherein asymptomatic T2DM was risk, which appears to be crucial for beta cell dysfunction
identified in 4% of obese adolescents at screening.61 to occur.64,67
A small number of population-based studies in Although the pathophysiological mechanisms of
the United States, Australia, and Canada suggest that T2DM are not commonly understood, it is clear that IR
the true prevalence T2DM in children is at least twice plays an important role in its development. Evidence for
that of the known cases, a proportion similar to that this comes from longitudinal studies demonstrating that
seen in adults.62 IR occurs 10–20 years before the onset of the disease and
Despite all the above limitations, one must admit that it is the best predictor of whether or not an individual
that T2DM is rapidly emerging as a health problem in will develop diabetes later.68 In addition, IR, by placing
children and adolescents, following the same pattern as an increasing demand on the beta cell to hyper secrete
in adults. Since the life-time risk of developing diabetes- insulin, influences the progressive beta cell failure of
associated complications can be expected to be higher in T2DM.65 The precise mechanism by which IR leads to
this age group due to the long disease duration and greater beta cell failure remains unknown. A possible hypothesis
duration of glycemic response, it is particularly important is that the cause of IR is also directly responsible for
that appropriate screening measures be implemented to the beta cell failure (i.e. lipotoxicity).64-66 Flow chart 28.1
diagnose early onset T2DM at an early stage to prevent summarizes the pathophysiology and risk factors of
progression to the stage of complications of diabetes. T2DM in youth.
442 Clinical Profile

Flow chart 28.1: Risk factors of T2DM in youth

section
7

Clinical Presentation of Early Onset of T2DM groups. In addition, C-peptide, insulin antibodies, and
ultrasonography of the abdomen are all useful. It must
As in adults, T2DM is largely asymptomatic in children, be emphasized that it is difficult to classify some patients
and often is diagnosed during routine clinical examination into a distinct type, for example, those with overlap of
or when complications develop. The early symptoms features of T1DM and T2DM so-called “double diabetes”
include polyuria, nocturia, polydipsia, polyphagia, weight or “hybrid diabetes”. Flow chart 28.2 summarizes the
loss and fatigue. Often the child complains of frequent diagnostic approach to classify diabetes in youth in India.
infections, excessive tiredness and irritability or injuries
take a long time to heal. Although these symptoms are very RISK FACTORS OF EARLY ONSET T2DM
typical, the possibility of diabetes is often not considered
because of a lack of awareness. A family history of diabetes Ethnicity
is a strong pointer to T2DM. Acanthosis nigricans (AN)
Ethnicity/race is an important non-modifiable risk factor
and skin tags are other important clues. An adolescent girl
in the development of T2DM in adults. The influence of
with polycystic ovarian syndrome (PCOS) is highly likely
this appears to be even stronger among youth onset T2DM.
to be having glucose intolerance or even overt T2DM.
However, high prevalence rate have been noted in Asians,
The clinical features distinguishing early onset T2DM,
Hispanics, indigenous peoples (USA, Canada, Australia)
T1DM and MODY are summarized in Table 28.4.
and African Americans, with the highest rates in the world
being observed in Pima Indians.69-71 A number of studies
Algorithm for Differential Diagnosis of
comparing African-American and European-American
Diabetes in Youth in India children suggest a genetic basis for the apparently greater
Using a simple questionnaire, which involves family susceptibility to T2DM in certain ethnic groups.71-73 It has
history of diabetes, response to therapy, presence of keto­ been known for several years that Asian Indians, despite
sis, and abdominal X-ray, we have evolved an algorithm having lower body mass index and lower prevalence
(Flow chart 28.2) by which the majority of cases of youth- of traditional risk factors for diabetes, are more insulin
onset diabetes in India can be classified into different resistant and more susceptible to T2DM, than whites.74-77
 Early Onset Type 2 Diabetes 443

Table 28.4: Clinical features differentiating between type 1, early onset T2DM and MODY
Clinical features Early onset T2DM Type 1 DM MODY
Ethnicity Hispanic, African American, Asians, Caucasians Caucasians
Native Americans
Parents affected Usually both (45–80%) 5–10% Either one or both affected (90–100%)
Age of onset At Puberty Throughout childhood < 25 years
Obesity Common Uncommon Uncommon

chapter
Acanthosis Nigricans Yes No No

28
Family history of DM Yes Less common Yes (Autosomal dominant)
Onset of DM Chronic, insulin required to correct Acute, severe insulin Subtle, insulin not required
glucotoxicity required
Severity of DM Mild Severe Mild
Ketosis/Coma Unusual Yes Unusual
Causative factor Insulin resistance β cell Destruction leading ↓ Insulin secretion
to insulin deficiency
Autoimmunity No Yes No
(T2DM: Type 2 diabetes mellitus; DM: Diabetes mellitus; MODY: Maturity onset of diabetes)

Flow chart 28.2: Algorithm for differential diagnosis of diabetes in youth (Mohan et al.)43

(OHA: Oral hypoglycemic agents; MODY: Maturity onset of diabetes; GDM: Gestational diabetes mellitus; DM: Diabetes mellitus;
FCPD: Fibrocalculous pancreatic diabetes)
444 Clinical Profile
section
7

A B
Figs 28.4A and B: Acanthosis nigricans

Puberty and Polycystic Ovarian Syndrome base of neck, in the axilla (Figs 28.4A and B) and anoge­
nital area. It is a well established clinical sign of IR and is
Polycystic ovarian syndrome is being increasingly
reported to occur in up to 60–90% of youth with T2DM.81
recognized in adolescents as part of the IR syndrome.
However in our study, only 21.2% had this marker47
Adolescent females with T2DM should be assessed for
and it is also uncommon in Japan.82 One study showed
symptoms and signs of PCOS-like menstrual irregularities
that apart from AN, other phenotypic markers like buffalo
and hirsutism. The mean age at diagnosis in all studies
hump and double chin are associated with metabolic
of T2DM in children is approximately 13.5 years corres­
syndrome in adult Asian Indians.83 Thus, even though
ponding to the time of peak adolescent growth and
occurrence of AN when present is a useful clue to suspect
development.3,78 A significant percentage of girls develop
T2DM before the age of 15 years in different ethnic T2DM, it cannot be relied on as a diagnostic marker of
groups.18,69,79 Our clinic based study revealed that girls IR and T2DM.
10–14 years old have a much higher risk of developing
diabetes than boys even after adjusting for BMI, parental Obesity
history, serum cholesterol and blood pressure.47 A recent The rising occurrence of T2DM has been attributed to
population based study from our group, shows that the the increasing rates of obesity in children.84 Obesity is
prevalence of glucose intolerance among girls was higher the most important modifiable risk factor for the develop­
(4.2%) when compared to boys (3.2%).52 Approximately, ment of IR, independent of sex, age and ethnic
30% of adolescent girls with PCOS have been found to background.85 Overweight and obesity are now becoming
have impaired glucose tolerance (IGT), with 4% having major pro­ blems in adolescents around the world.
T2DM.80 It is well known that the onset of puberty Secular increases in the prevalence of obesity in children
leads to increased IR and that hormonal change due to have also been recorded in China,86 Hong Kong,87 the
puberty could be a triggering factor for developing T2DM UK88 and Australia.89 The problem of obesity now also
in girls.81 IR in youth typically occurs during puberty extends to developing nations, particularly in relatively
and is thought to coincide with occurrence of T2DM. affluent urban areas. In India, a study conducted in 2002
Pancreatic beta cells of some adolescents cannot over­ found that the age adjusted prevalence of “overweight”
come the physiologic rise in IR and therefore a relative among 13–18 years old was 18% in boys and 16% in girls
insulin deficiency develops, eventually leading to T2DM. correlating positively with age and socioeconomic status
and negatively with physical activity.90 Another Indian
Acanthosis Nigricans study showed an increasing trend in prevalence of over­
Acanthosis nigricans is a cutaneous marker characterized weight and obesity in urban Asian Indian adolescents
by velvety hyperpigmented patches typically seen at the associated with male gender and high socio economic
 Early Onset Type 2 Diabetes 445

status.91 In children, as in adults, visceral fat appears to In Utero Exposure to Undernutrition

be the best predictor of T2DM.92 The presence of both obe­
Undernutrition in fetal and infant life followed by over
sity and IR confer greater risk for cardiovascular disease
nutrition later in life have been shown to predispose
(CVD) in young type 2 diabetic patients compared with
individuals to diabetes and the metabolic syndrome.110
that expected with either obesity or IR alone.93
India is one of the countries with the highest incidence
of infants with low birth weight. This is most likely due to
Diet and Physical Activity poor maternal nutrition. A particular pattern of being born

chapter
Obesity is linked to recent changes in the diets of small for gestational age (SGA), followed by accelerated

28
children.94,95 Fast foods and high fat/high carbohydrate/ weight gain in early childhood has been associated with
high sugar consumption has increased, while the concept increased risk for both IGT and T2DM in adulthood.111,112
of family meals has declined in many societies. While diet
composition may contribute to obesity, it is likely that Systemic Inflammation
the most important aspect in the development of IR and Several inflammatory markers, such as interleukin 6,
type 2 in youth is excess calorie intake which is not on par C-reactive protein, other cytokines and acute-phase
with the expenditure of calories. This imbalance between reactants, such as fibrinogen and plasma activator in­
excess intake and reduction in the energy expenditure hibitor-1 (PAI-1), have been associated with T2DM
coupled with large portions and high-calorie diets with and its metabolic precursor, IR.113,114 Elevated C-reactive
a sedentary lifestyle have led to an epidemic of obesity protein, inflammatory cytokines and white blood cell
among youth.96,97 Indeed, physical inactivity has been counts in obese adolescents have been associated with
identified as an important predictor of excess weight gain increased risk for CVD in adults.115 Adiponectin, a hor­
and evolution of the T2DM epidemic.98 mone released by adipocytes, has insulin sensitizing,
anti-inflammatory and anti-atherogenic properties. Adi­
Family History of Diabetes ponectin levels are decreased in obese individuals.116
Many studies show a strong family history among affected One study has reported that insulin-sensitive obese ado­
youth with 45–80% having at least one parent with diabetes lescents have higher levels of adiponectin as compared
and 74–100% having a first or second degree relative with insulin-resistant obese adolescents.117 In addition,
with T2DM.99 History of diabetes in one or both parents adiponectin levels decrease in parallel to progression
was seen in over 80% of our T2DM in children and adoles­ through puberty, with pubertal stage being the strongest
cents in our clinic47 and it corroborates a previous study independent predictor of adiponectin levels in adoles­
done in children, adolescents and young adults from cent boys.118 Therefore low levels of adiponectin in obese
North India.58 Parental history of T2DM mellitus increases individuals may play a critical role in the development of
the risk of not only glucose intolerance, but also other T2DM. We have recently showed that adiponectin levels
cardiometabolic risk factors like overweight, low high- can be used as a marker to differentiate T1DM and T2DM
density lipoprotein, high cholesterol and high blood pres­ with a cut off value of 5.1 μg/mL.119
sure in Asian Indian adolescents.100
Genetics
In Utero Exposure to Maternal Diabetes Understanding the genetics of childhood T2DM poses
The intrauterine environment influences the risk of a challenge owing to a relatively low prevalence of
developing T2DM. Since the 1970’s, several human studies disease, large variation in the ethnic background and the
have found striking long-term effects of the diabetic underlying complex genetic traits of diabetes. Recently,
uterine environment on growth and development, genome wide association studies in adult onset T2DM
including higher rates of obesity,101-103 impaired glucose have contributed substantially to our understanding.
tolerance104,105 and T2DM106 as well as diagnosis of diabetes It is of interest that of the 24 genetic loci that have been
at a younger age.107,108 The increasing frequency of exposure associated with T2DM, the majority of genes effect insulin
to diabetes in utero has been hypothesized to account secretion rather than sensitivity.120 There is a paucity of
for atleast some of the increase in diabetes prevalence in studies examining T2DM susceptibility genes in children
Pima Indian children.109 and adolescents. The TCF7L2 gene has recently been
446 Clinical Profile

implicated in the development of IGT in obese children.121 symptoms of hyperglycemia or hyperglycemic cri­
The only gene mutation confirmed to increase the risk of sis, a random plasma glucose more than or equal to
T2DM in children and adolescents is the unique single- 200 mg/dL (11.1 mmol/L).
nucleotide polymorphism (SNP-G319S) in hepatocyte
nuclear factor (HNF) 1α gene, which has been described TREATMENT AND MANAGEMENT
in the Oji-Cree population in Canada. We have also
Treating T2DM in children and adolescents can be as
shown that the Ala98 Val polymorphism of HNF 1α gene
(or even more) challenging than treating type 1 diabetes,
section

is associated with MODY and with earlier age at onset of

because the cornerstone of therapy is lifestyle modi­
7

T2DM.122 More genetic studies of T2DM in children and

fication achieved through diet and physical activity. In
adolescents are urgently needed.
developed countries, pediatric T2DM disproportionately
affects segments of the population with fewer resources,
Diagnostic Criteria
both at the family and community levels, to implement
Testing for T2DM in asymptomatic children.123 these changes. Conversely, in developing countries, at
present, the more affluent groups tend to get childhood
CRITERIA onset T2DM. The goals of treatment are weight loss plus
A consensus panel of the American Diabetes Association normalization of glucose, blood pressure and lipids.
(ADA) recommended that individuals who are overweight These goals are best accomplished through a combination
(as defined below) and with any of the other risk factors of education, medical nutrition therapy, exercise and
indicated below should be tested every 3 years, starting pharmacotherapy. Behavior change is critical to the
at age 10 or at the onset of puberty, if that begins earlier. management of T2DM in children and it is important to
Overweight is defined as (BMI ≥ 85th percentile for age impress on the whole family unit regarding need for
and sex, or weight for height ≥ 85th percentile, or weight healthy food choices and the benefits of increasing
≥ 120% of ideal for height). physical activity.
Lifestyle modification includes attainment and main­
Other risk factors for T2DM:
tenance of a healthy bodyweight, increased exercise levels,
• Family history of T2DM in first- or second-degree
normalization of blood glucose levels, minimization of
relative
hypoglycemia and the prevention of not only the complica­
• Race/ethnicity (Native American, African American,
tions of diabetes but also, hypertension, hyperlipidemia
Latino, Asian American, Pacific Islander)
and non-alcoholic fatty liver disease. Education should be
• Signs of IR or conditions associated with IR (AN,
age-appropriate and culturally sensitive, and must focus
hypertension, dyslipidemia, polycystic ovary syndrome
on lifestyle and health behaviors of the entire family in
PCOS or SGA birth weight)
order to be effective.125 This should be continued in addi­
• Maternal history of diabetes or GDM during the child’s
tion to pharmacologic treatment, the primary aim of
gestation.
which is to decrease IR, preserve insulin secretion, or to
Criteria for the Diagnosis of Diabetes*124 slow postprandial glucose absorption.
Type 2 diabetes mellitus can be controlled with oral
1. HbA1c more than or equal to 6.5%. The test should
hypoglycemic agents (OHA) at least for the first 2–5 years.
be performed in a laboratory using a method that is
Treatment should be started with metformin and moni­
NGSP certified and standardized to the DCCT assay*or
tored frequently until control is achieved. If control is not
2. Fasting plasma glucose (FPG) more than or equal to
achieved with metformin, a sulphonylurea can be added.
126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric
Very often, insulin may be required at least in the early
intake for at least 8 h.*or
stages to control symptoms and later, if secondary failure
3. Two-h plasma glucose more than or equal to 200 mg/dL
to OHA develops.
(11.1 mmol/L) during an oral glucose tolerance test
(OGTT). The test should be performed as described
Biguanides
by the World Health Organization, using a glucose
load containing the equivalent of 75 g anhydrous Metformin is the drug of choice for children and adole­
glucose dissolved in water, or in a patient with classic scents with T2DM. Metformin acts on insulin receptors
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be
confirmed by repeat testing.
 Early Onset Type 2 Diabetes 447

in liver, muscle and fat tissue with a predo­minant action prolonged use of pioglitazone, this drug should be avoided
on the liver.126 The following are some of the effects of in children. Among the newer therapeutic options that
metformin: may prove beneficial for pediatric patients with T2DM
• Hepatic glucose production is reduced by decreasing are the incretin-based therapies like GLP-1 analogues
gluconeogenesis. (Exenatide and Liraglutide) and dipeptidyl peptidase-4
• Insulin stimulated glucose uptake is increased in inhibitors (DPP4) like sitagliptin, vildagliptin, saxagliptin
muscle and fat. and linagliptin. However, data in pediatrics is almost non-

chapter
• An initial anorexic effect may promote weight loss. existent and their approval for use in children is awaited

28
• Long-term use is associated with a 1–2% reduction in once the ongoing trials are completed.
HbA1c.
• Gastrointestinal side effects (transient abdominal pain, Complications of Early Onset of T2DM
diarrhea, nausea) may occur. These can be eliminated
Type 2 diabetes mellitus in children and adolescents may
in most patients with slow dosage titration over
place the individuals at risk for increased morbidity and
3–4 weeks and instructions to always take the medica­
mortality during their most productive life years, however
tion after food. The side effects may also be attenuated
only limited long-term studies on follow-up were available
by the use of extended release formulations.
on secondary complications.
• The risk of lactic acidosis with metformin is extre­
As with adults, it can be expected that youth with T2DM
mely low. Metformin should not however be given to
will also develop diabetes-related complications. Long-
patients with renal impairment, hepatic disease, car­
term complications may be microvascular (retinopathy,
diac or respiratory insufficiency, or who are receiving
nephropathy, and neuropathy) or macrovascular (ische­
radiographic contrast materials. Metformin should be
mic heart disease, peripheral vascular disease and stroke).
temporarily discontinued during any acute illness.
Microvascular complications may develop in puberty or
• Metformin may normalize ovulatory abnormalities in
early adulthood whereas macrovascular complications
girls with PCOS and thereby increase pregnancy risk.
usually occur in later years. The longer the duration of
• Metformin should be started at a low dose (either 250 diabetes, the greater the risk of complications, which incr­
or 500 mg twice daily depending on their glycemic ease significantly following puberty. The risk of developing
levels along with meals) and slowly titrated to reach a complications may also be increased by poor glycemic
total daily dose of 2 g. control, hypertension, dyslipidemia and behavior such as
smoking, in addition to genetic factors.
Insulin
Despite hyperinsulinemia and IR, relatively small doses of Retinopathy
supplemental insulin are often effective to achieve eugly­ Dilated eye examinations and retinal photography should
cemia in T2DM. If there is inadequate glycemic control be performed in adolescents with T2DM according to the
on oral agents, a long acting insulin analogue without a ADA’s standards of medical care.125 Even though overall
peak action may provide satisfactory therapy without meal retinopathy remains more frequent in patients with type 1
related therapy. Metformin should be continued to improve diabetes (matched for duration), it may be present in
insulin sensitivity. If postprandial hyperglycemia persists, adolescents with T2DM at the time of diagnosis, and hence
rapid or short acting insulin can be substituted. The side the need for screening at the time of diagnosis itself.127
effects of insulin are hypoglycemia and weight gain, which The earliest sign of diabetic eye disease is the develop­
could be a substantial problem if dietary measures and ment of background or non-proliferative diabetic retino­
physical activity are not attended to.126 pathy (NPDR), which consists of microaneurysms and
Sulphonylurea agents (glibenclamide, gliclazide, hemorrhages with exudates which do not involve the
glipizide or glimipiride) may be used to control diabetes. macula. NPDR is usually asymptomatic and does not
However, other class of drugs, such as glinides (repaglinide damage vision. It may stabilize, regress with improved
and nateglinide), glucosidase inhibitors (acarbose) and glycemic control or progress if poor control continues.
thiazolidinediones compounds (glitazones like pio­ gli­ NPDR however may progress to proliferative diabetic
tazone) are not approved in childhood onset T2DM.
126
retinopathy (PDR). This can be successfully treated in its
Indeed, with the recent reports of bladder cancer with early stages with laser photocoagulation therapy. Macular
448 Clinical Profile

edema is the result of fluid accumulation in the retina adolescents with diabetes. The prevalence of neuro­
secondary to capillary leakage and/or microaneurysms128 pathy was 3% in those with diabetes duration of less
and can develop at all stages of retinopathy.129 Cataract is than 5 years and increased to 49.2 % (30 of 61) in those with
very rare under the age of 20 years. more than 15 years duration in our study.47 Limited data
Up to 9% of patients diagnosed with T2DM before age suggest that rates of peripheral and autonomic neuro­
30, have evidence of retinopathy at diagnosis and nearly pathy do not differ among adolescents with type 1 and
13% develop proliferative retinopathy before age 35.130 T2DM, although, adolescents with T2DM appear to deve­
section

In our study the prevalence of retinopathy rose from lop neuropathy at a more rapid rate.127,133 Prevalence of
diabetes complications in early onset T2DM is detailed in
7

4.2% among those with diabetes duration of less than

or equal to 5 years to 81.5% in those more than 15 years Table 28.5.134-139 Prevalence of microvascular complications
duration.47 According to one study,131 retinopathy was less in childhood and adolescent onset at our center stratified
common in youth onset than in adult onset groups at all by duration of diabetes is presented in Figure 28.5.
durations of diabetes. Metabolic risk factors or other characteristics of the IR
syndrome are commonly seen at diagnosis or appear early
in the course of T2DM and should be tested for sooner
Nephropathy
than in type 1 diabetes, as in the latter these disorders
Screening for microalbuminuria should be done at dia­ are complications of the diabetes, rather than comorbid
gnosis and at yearly intervals thereafter.123 Nephro­pathy conditions. Thus, dyslipidemia and hypertension should
is preceded by the development of persistent microal­ be assessed at the time of onset of diabetes itself, in early
buminuria which affects approximately 10% of children onset T2DM.
and adolescents.132 Microalbuminuria is defined as an
albumin excretion rate of 30–300 mg/24 hours in two out of Hypertension
three timed collections. Timed collections may be difficult Blood pressure should be monitored and treated aggres­
to collect in children and an alternative screening tool is sively with angiotensin converting enzyme (ACE)
the measurement of the albumin creatinine ratio in the inhibitors, if either the systolic or diastolic pressure is above
first voided morning urine sample which has been shown the child’s usual percentile or above the 85th percentile for
to correlate closely with the timed overnight albumin age and sex. In our study, raised blood pressure was seen
excretion rate. Nephropathy was equally common in all among 27.2% of boys and 21.4% of girls.47 Hypertension
the age groups and was not related to age of diabetes onset is estimated to account of 35–75% of both microvascular
(at < 5 years duration of T2DM, nephropathy incidence and macrovascular complications.140 Diabetes or IGT
per 1,000 person years was 13/1,000 youth, 8/1,000 young doubles the risk of developing hypertension.141 Confirmed
adults and 7/1,000 older groups).131 In our clinic based hypertension or albuminuria should be treated with
study, the prevalence of microalbuminuria increased an angiotensin receptor blocker or an ACE inhibitor.
from 8.7% in those with diabetes duration of less than Combination therapy may be required if hypertension or
or equal to 5 years to 29.5% in those more than 15 years, albuminuria does not normalize on a single agent.
whereas the prevalence of overt nephropathy increased
from 9% in those with diabetes duration of more than Dyslipidemia
5 to less than or equal to 10 years to 34.4% in those with Hypertriglyceridemia and decreased high density lipo­
duration of more than 15 years.47 protein (HDL) cholesterol are the hallmarks of T2DM
dyslipidemia. We found 40.3% boys and 36.2% girls have
Neuropathy hypertriglyceridemia, while 61.1% and 69.2% respec­
The earliest symptoms include numbness and paresthesia tively have low HDL cholesterol.47 Dyslipidemia is very
of the feet or hands with evidence of decreased vibra­ common, with raised cholesterol and triglyceride concen­
tion sense, loss of ankle jerk reflexes and a diminution trations in 33–60% of younger adults aged less than
in sensation to pinprick on clinical examination. Clinical 18 years with T2DM.16,127,142,143 These rates are higher than
neuropathy in adolescence is rare, although subclinical those found in non-diabetic obese individuals, suggesting
neuropathy demonstrated by abnormalities of vibration that the presence of diabetes has an additive impact on
perception threshold have been reported in 20–57% of dyslipidemia.
 Early Onset Type 2 Diabetes 449

Table 28.5: Diabetes complications in early onset T2DM

S.No. Country, Author and Centre name Year or Age at onset in Retinopathy Nephropathy Neuropathy Ref
period of years (Duration n (%) n (%) n (%) no.
study of diabetes in
years)
1 India
• Mohan et al. (Diabetes Research 1985 ≤ 25 (≥ 15) 26/60 (43.3%) 12/60 (20%) 27/60 (45%) 54

chapter
Centre)
• Ramachandran et al. (Diabetes 1988 ≤ 30 (> 15) 31/56 (55.0) 19/31 (61.0) 37/75 (49.0) 55

28
Research Centre)
• Mohan et al. (Dr Mohan’s Diabetes 2011 ≤ 25 (≥ 15) 100/139 (71.9%) 38/172 (22.1%) 57/165 45
Specialities Centre) (34.5%)
• Mohan et al. (Dr Mohan’s Diabetes 2012 < 20 (>15) 44/54 (81.5%) 21/61 (34.4%) 30/61 47
Specialities Centre) (49.2%)
• Jyotsna et al. (Institute of Medical 2002 < 30 41% — — 60
Sciences)
2 South African Indians
• Omar et al. 1986–2006 < 30 (15) 37/103 (35.9) 16/103 (15.5) — 134
3 USA
• Farah et al. 2001–2003 — 1/40 (2.5) 9/40 (22.5) — 135
• Pavkov et al. (given as age sex — < 20 (decades — ESRD-25 — 136
adjusted incidence rate) of age) cases/1,000
person years
• Krakoff et al. 2003 < 20 (15–20) 9 cases 10 cases — 131
4 UK
• Song et al. 2009 ~ 32 (10–20) 55 (35.5) — 51 (32.9) 137
5 Japan
• Yokoyama et al. (given as 1965–1990 < 30 (15–19) — 31.4/1,000 — 138
Incidence density) person years
1997 — 9.3% — — 130
6 Malaysia
• Wan Nazaimoon et al. 1999 < 30 (> 10) 82/191 (42.9) 57/197 (28.9) — 139

The hyperlipidemia could improve with exercise,

weight loss and glycemic control. Nutritional changes
include a reduced fat diet and changing to complex
carbohydrates. However, should such attempts to norma­
lize lipids fail after 6 months of intensive efforts, use
of lipid lowering medications would be indicated. The
most commonly used lipid lowering agents are the HMG
CoA reductase inhibitors (statins).

PREVENTION OF T2DM IN CHILDREN

In high-risk cases, e.g. those with strong family history,
obesity, acanthosis nigricans or polycystic ovarian disease,
screening for diabetes seems to be justified in youth. Early
Fig. 28.5: Prevalence of complications stratified according to duration detection and treatment are the cornerstones to reduce
of diabetes among childhood and adolescent onset T2DM (CAT2DM)47
morbidity and mortality due to youth-onset T2DM.43
450 Clinical Profile

The increasing prevalence of T2DM in the young may ACKNOWLEDGMENTS

be arrested by increasing physical activity and following
traditional dietary habits. Interventional programs should I would like to thank Dr A Amutha, Research Associate,
be considered to address the underlying cause, with an MDRF who helped with the writing of this manuscript.
emphasis on diet, weight, exercise and lifestyle issues. It This paper is largely based on numerous studies, carried
is far better to put our public health efforts on primordial out by her as part of her PhD thesis and now published.
and primary prevention of diabetes, rather than dealing The author also wishes to thank Dr Ranjit Unnikrishnan,
section

with diabetes and its late stage complications. Lifestyle Dr RM Anjana and Dr Ranjani Harish for their help.
7

modification should be encouraged and implemented for

all children and adolescents at the school level.
Further reading
Physical activity plays a critical role in the prevention 1. American Diabetes Association. Type 2 diabetes in children
of early onset T2DM. Increased physical activity results in and adolescents. Diabetes Care. 2000;23:381-9.
improved insulin sensitivity and increased glucose uptake 2. Ramachandran A, Snehalatha C, Satyavani K, et al. Type 2
diabetes in Asian-Indian urban children. Diabetes Care.
at the level of the muscle and a decreased need for insulin
2003;26:1022-5.
therapy.144 3. Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial
changes in childhood body-mass index to impaired glu­
What can be Done to Prevent the cose tolerance in young adulthood. N Engl J Med. 2004;350:
Epidemic of T2DM in Children? 865-75.
4. Dabelea D, Bell RA, D’Agostino RB Jr, et al. Incidence of
1. Screening methods should target the high-risk youth diabetes in youth in the United States. JAMA. 2007;297:
population which can be identified by simple clinical 2716-24.
5. Unnikrishnan AG, Bhatia E, Bhatia V, et al. Type 1 Diabetes
clues: presence of overweight or obesity and a positive and Type 2 Diabetes with Onset in Persons younger than
family history of diabetes/AN and/or polycystic ovarian 20 Years of Age Results from an Indian Multicenter study.
disease. An OGTT is ideal in these children. If this is not Ann NY Acad Sci. 2008;1150:239-44.
feasible, at least FPG should be done, which however, 6. Bell RA, Mayer-Davis EJ, Beyer JW, et al. Diabetes in non-
has a much lower sensitivity. Hispanic white youth:prevalence, incidence, and clinical
characteristics: the SEARCH for Diabetes in Youth Study.
2. We should find ways to help people to be more physically
Diabetes Care. 2009;32:S102e11.
active and eat healthier diets. This requires an integrated
approach, and should involve other sectors outside of
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 Chapter 29
An Approach to Management of
Diabetes Mellitus
Mala Dharmalingam

Approach to Management

Chapter Outline
♦♦ Individualization of Therapy and Treatment Goals ♦♦ Approach to Management
♦♦ Type 2 Diabetes ♦♦ Type 1 Diabetes

INTRODUCTION: IMPORTANCE Table 29.1: Ominous Octet—Newer insights in pathogenesis of

AND OVERVIEW diabetes mellitus
• Decreased insulin secretion
Diabetes is a growing epidemic in India with a prevalence • Increased and non-suppressible glucagon secretion
of 61 million and expected to reach 100 million by 2030.1 • Increased hepatic glucose output
The morbidity and mortality associated with this disorder • Neurotransmitter dysfunction
is mainly because of cardiovascular (CV) events. Type 2 • Decreased glucose uptake by cells
• Increased glucose reabsorption by kidney tubules
diabetes and its complications have a major impact on
• Increased lipolysis
the financial resources of the country and the individual.
• Decreased incretin effect
A holistic approach is required for successful preven­
tion and management of diabetes mellitus (DM) as in all
chronic diseases.2,3 study showing that the microvascular and cardiovascular
Type 2 diabetes management does not consist of disease (CVD) risk continued to be lower even after
control of blood glucose alone, but also associated comor­ 10 years in the intensive treatment group. This was due to
bidities like hypertension (HTN) and dyslipidemia. the “metabolic memory” or the “legacy effect”.6
Additionally, a good diet counseling and diabetes educa­ The Action to Control Cardiovascular Risk in
tion is essential. Glycemic management in type 2 DM Diabetes (ACCORD),7 Action in Diabetes and Vascular
has become incre­ asingly complex with the improved Disease: Preterax and Diamicron Controlled Evaluation
understanding of the multifactorial pathogenesis of DM4 (ADVANCE),8 and Veterans Affairs Diabetes Trial (VADT)9
(Table 29.1) and the accumulated scientific evidence from brought in a new perspective and skepticism about
recent studies. intensive glycemic control. For the first time concern
With the publication of the United Kingdom Pros­ regarding safety of the intensive treatment surfaced parti­
pective Diabetes Study (UKPDS)5 results there is now little cularly based on the ACCORD results. However, further
doubt that early glycemic control is of prime importance analysis of these studies revealed that tight glucose control
in the management of diabetes. This is further corro­ was detrimental in the subgroup that had a previous
borated by the publication of the 10-year post UKPDS CV incident contributing to increase in morbidity and
456 Clinical Profile

Table 29.3: Various groups of type 2 diabetes for purpose of indivi­

dualization of treatment
1. Newly diagnosed individuals with type 2 diabetes with no
complications
(i) Overweight or obese
(ii) Lean individuals
2. Individuals who are known diabetic and with history of
inadequate glycemic control
section

(i) No complications
(ii) With complications
7

(a) History of cardiovascular disease

(b) History of chronic kidney disease
3. Individuals at increased risk of hypoglycemia
4. Elderly individuals
5. Comorbidities
(i) Liver dysfunction

of glycemic variability is also important and has to be

factored in when planning management.
Fig. 29.1: Individualizing glycemic targets in type 2 diabetes mellitus
(T2DM) INDIVIDUALIZATION OF THERAPY AND
Source: ADA and EASD guidelines 2012.10
TREATMENT GOALS
Type 2 Diabetes
Table 29.2: Factors to be considered while individualizing treatment
• Duration of diabetes mellitus For the purposes of individualization of therapy, patients
• Stage of disease, presence of complications with type 2 diabetes can be categorized into various
• Age of the patient groups (Table 29.3). Flow chart 29.1 gives the general
• Life expectancy of the individual approach to management of diabetes.
• Weight of the patient
• Risk of hypoglycemia Newly Diagnosed Individuals with Type 2
• Cardiovascular disease
• Psychosocial factors including motivation of patient
Diabetes with No Complications
• Economic considerations “Overweight or obese” patients should be counseled
on therapeutic life style changes (TLC) which include a
mortality. This was partly explained by hypoglycemia healthy diabetic diet, exercise and stress management.
but there appear to be other unknown mechanisms. Glycated hemoglobin (HbA1c) in the range of 6.5–7%
With this data it becomes increasingly important to should be targeted. HbA1c as close to normal should be
have a proper approach to management of diabetes and achieved, if possible, but without causing hypoglycemia
individualization of treatment. or weight gain. Ideally HbA1c should be monitored every
The recent American Diabetes Association (ADA) 3–6 months. The therapeutic choice should be such that
guidelines have laid down certain patient-centric glycemic individuals achieve good glycemic control with either
targets.10 The guidelines have taken into consideration weight loss or without weight gain (weight neutral).
various factors including the co-operation of the patient Metformin is the preferred drug followed by combination
for individualizing targets and tailoring treatment therapy with glucagon-like peptide-1(GLP-1) analogs,
(Fig. 29.1)11 and (Table 29.2). Although these guidelines dipeptidyl peptidase (DPP-4) or a-glucosidase inhibitors,
may sound relatively straightforward, confusion exists in if inadequately controlled.
the healthcare community regarding how this information However if there are financial constraints, pioglitazone
can be translated into clinical practice.12 The concept or sulfonylureas may be considered as a combination
 An Approach to Management of Diabetes Mellitus 457
Flow chart 29.1: Algorithm for Type 2 Diabetes tested to see for pancreatic reserve if LADA is suspected.13
Approach to diabetes Patients with LADA will invariably need insulin within
months or first one or certainly 2 years after diagnosis of
diabetes.

Individuals with Known Diabetes and History

of Inadequate Glycemic Control

chapter
No Complications

29
The patients with known diabetes are likely to be older
in age with a longer duration of diabetes. The factors that
influence the goals of glycemic control will be same as in
Figure 29.1. It is important to assess potential reasons for
inadequate glycemic control, such as overly conservative
management (including delay in introducing combination
therapy), inappropriate choice of agents (e.g. agents that
do not address the underlying pathophysiology) and
most importantly poor compliance of patients towards
medications and diet. A more gradual reduction in HbA1c
should be attempted as compared with newly diagnosed
individuals and near-normal HbA1c should be targeted.
Patients need to be motivated to take an active role in
(HbA1c or A1c: Glycated hemoglobin; OADs: Oral antidiabetic drugs;
DPP: Dipeptidyl peptidase) their glycemic control. It is important to achieve the glyce­
mic control without hypoglycemia or increased glycemic
variability.
therapy. Both these treatments will cause weight gain
and sulfonylureas may cause hypoglycemia and should
be avoided in those patients with an HbA1c of around
Individuals at Risk of Hypoglycemia
7–7.5%. In older patients with type 2 diabetes, hypoglycemia is
An ideal drug should have good efficacy and be free an important safety concern. The other individuals who
of side effects, mainly weight gain and hypoglycemic are at high risk of hypoglycemia include individuals who
events. It should be safe in all comorbid conditions have had prior hypoglycemia, renal impairment, previous
especially in cardiac patients. Above all it should be CV events and those with very erratic lifestyles with
affordable for the patient. Metformin is a drug which has variations in their time of eating and activities. Patients
almost all of the above properties. should be made aware of the symptoms of hypoglycemia.
“Lean” adults have more marked beta-cell dysfunction They should also be taught how to manage hypoglycemia.
as compared with overweight or obese individuals who are Elderly individuals and patients with repeated hypog­
more insulin resistant. Thus lean individuals may require lycemia may also have hypoglycemic unawareness. This
agents which preserve b-cell function. These individuals entity is very hazardous and needs appropriate dosage
may require combination therapy early. They may also adjustment to maintain less tight control. Patients need
require early insulin therapy. to be counseled on the increased risk of hypoglycemia
Latent autoimmune diabetes in adults (LADA), which with irregular lifestyles or eating patterns and need for
constitutes around 10% of all patients diagnosed to have compliance to prescribed regimens. The importance of
type 2 diabetes, should be considered in this population regular self-monitoring of glucose wherever appropriate,
of lean patients. Antibodies such as islet cell antibodies, should be stressed. Less stringent HbA1c goals (7.5–8.0%
antibodies to glutamic acid decarboxylase, and insulin or even slightly higher) are appropriate for patients with
auto antibody should be tested. C-peptide should also be a history of severe hypoglycemia.
458 Clinical Profile

Patients who can have a less stringent HbA1c target may be on multiple drugs for various other conditions, it
include the following: is important to keep in mind the co-prescription to avoid
• Children drug interactions.
• Limited life expectancy Hypertension: Hypertension (HTN) is a common
• Advanced complications comorbid condition in diabetes with as many as 39%
• Extensive comorbid conditions patients having HTN at the time of diagnosis of diabetes.16
• Those in whom the target is difficult to attain despite In India about 50% of diabetic individuals have HTN.17
section

intensive self-management education, repeated coun­ Hypertension increases micro- and macrovascular
7

seling, and effective doses of multiple glucose-lowering complications in diabetes. HTN and diabetes both affect
agents, including insulin. the same target organs via vascular mechanism putting
patient at risk of developing atherosclerosis, retinopathy,
Elderly Individuals renal failure, non-traumatic amputations and CVD. Thus
control of HTN is of paramount importance in diabetic
Elderly patients have their unique requirements. This pop­
patients. Blood pressure measurement must be made at
ulation has higher risk of hypoglycemia, they may be on a
each visit with initiation of lifestyle modification when
larger pill load with tablets for different disorders which
blood pressure is more than 120/80 mm Hg. The first
may lead to drug interactions. They may also have some
step in the management of HTN is lifestyle interventions.
diabetes-related complications either micro­ vascular
A healthy life style with low salt diet, reducing sodium
or macrovascular. Hypoglycemia can lead to unsteadi­
intake (to below 1,500 mg/day), plenty of fruits which
ness which can result in falls and fractures.14 Glycemic
are suitable to diabetics and exercise to avoid excess
goals should be achieved without hypoglycemia and with
bodyweight. Increasing consumption of fruits, vegetables
a good quality of life. This means a patient should not
(8–10 servings per day), and low-fat dairy products
experience any side effects of the medicine or hypo­
(2–3 servings per day); avoiding excessive alcohol con­
glycemia. The targets of glucose control are also set with
sumption (no more than two serving 90 mL per day for
this in mind. A patient should not have nocturia due
men and no more than one serving 45 mL per day for
to osmotic diure­sis, should not get recurrent infections
women); and increasing activity level should be initial
because of the poor glycemic control or feel tired. A glyce­
advice. Those requiring anti-hypertensive therapy should
mic target of an HbA1c of 7.5–8.0% is acceptable. While
aim for target blood pressure of < 140/90 mm Hg (< 130
lifestyle modification can be successfully implemented
mm Hg systolic if young patient). Angiotensin-converting-
in elderly, the choice of antihyperglycemic agent should
enzyme (ACE) inhibitors or angiotensin receptor blockers
be such that it minimizes hypoglycemia. The drugs
(ARBs) are the first choice of antihypertensives except in
used should have CV safety. The other considerations are
pregnancy. Most patients require more than two antihy­
renal dysfunction, bone fractures, and drug-drug interac­
pertensives. The hypertensives should preferably be given
tions which are common in the elderly.
both morning and night.
Dyslipidemia: Lipid abnormalities are common in
With Complications diabetes, the characteristic triad being increased trigly­
History of cardiovascular disease: Studies have shown that ceride, decreased high-density lipoprotein (HDL) and
diabetic patients with a prior cardiac event have poorer increased low-density lipoprotein (LDL) with a predo­
prognosis with very tight glycemic control. Hence less rigid minance of small and more atherogenic LDL. Each
control with less glycemic variability should be attempted. component is related to atherogenesis and adds on to
The morbidity and mortality associated with glycemic risk for adverse cardiovascular (CV) outcome. Benefit
control follows a U curve pattern with very low and very of 9% proportional reduction in all-cause mortality and
high blood glucose levels having the highest incidence 13% reduction in vascular mortality, for each mmol/L
of complications.15 Prevention of complications should (mg/dL) reduction in LDL cholesterol has been shown.18
be balanced against the need to ensure patient safety. All diabetic patients should be annually screened for lipid
The most important factor is to prevent hypoglycemia. profile. Dyslipidemic patients should be recommended
Other CV risk factors like HTN and dyslipidemia should reduction of saturated fat, trans fat and cholesterol intake;
be addressed and effectively managed. As many patients increase of n-3 fatty acids, viscous fiber (14 gm/1000 Kcal),
 An Approach to Management of Diabetes Mellitus 459

and plant stanols or sterols; weight loss (if indicated); and rarely, cases of lactic acidosis have been described in
increased physical activity. Statin therapy should be added patients with renal failure.22 Most insulin secretagogues
to all diabetic patients with CVD and patients without like sulfonylurea undergo significant renal clearance
CVD over age 40 years and risk factors like family history (exceptions include repaglinide and nateglinide) and the
of CVD, HTN, smoking, dyslipidemia, or albuminuria. risk of hypoglycemia is therefore higher in these patients.
The aim is to keep LDL <100 mg/dL in patients without Pioglitazone is not eliminated renally. However because
CVD and < 70 mg/dL in those with CVD or multiple risk of fluid retention, it may cause or worsen the existing

chapter
factors. Statin therapy remains the preferred strategy edema hence it is not preferred in CKD. The newer class

29
and combination with other lipid lowering agent is not of drugs the DPP-4 inhibitors, sitagliptin, vildagliptin,
recommended. and saxagliptin have significant renal elimination, and
Tobacco consumption: Smoking is a risk factor for need dosage reduction in advanced CKD. However
diabetes. It is known to cause insulin resistance and linagliptin, a newer DPP-4 gets eliminated enterohe­
deterioration of glucose metabolism.19 It is also toxic patically and is not renally excreted and hence can be
to pancreas. The risk of complications associated with used in renal failure without any dose change. GLP-1
tobacco use and diabetes in combination is nearly 14 times receptor agonist exenatide is contraindicated in CKD
higher than the risk of either smoking or diabetes alone.20 stage 4–5 as it is renally eliminated; the safety of liraglutide
Hence routine and thorough assessment of smoking is not established in CKD. Insulins are the treatment of
is an important part of diabetes care. All the diabetic choice in a patient with CKD. However, because of the
patients should be asked not to smoke or use tobacco slower elimination of insulin in severe renal functional
products. For the patient motivated to quit, the addition impairment, the insulin dose needs to be titrated carefully.
of pharmacological therapy to counseling is more effective A short acting insulin may act as an intermediate acting
than either treatment alone. Special considerations should insulin in the presence of renal failure.
include assessment of level of nicotine dependence, which Liver dysfunction: The management depends on the
is associated with difficulty in quitting and relapse. type and degree of liver damage. In patients with mild
Obesity: Obesity and overweight [body mass index hepatic disease the management of diabetes is by and
(BMI) > 23kg/m2] is an important risk factor for both large same as those without liver disease.23 Hepatosteatosis
diabetes and CVD. Weight loss is recommended for all is frequently seen in type 2 diabetics. There is some
overweight or obese individuals who have or are at risk for evidence that patients with fatty liver may benefit from
diabetes. For weight loss, either low-carbohydrate, low-fat treatment with metformin or pioglitazone. This should
calorie-restricted, or Mediterranean diets may be effective in not be used in an individual with active liver disease or an
the short term. Physical activity and behavior modification alanine transaminase level above 2.5 times the upper limit
are important components of weight loss programs and of normal. Insulins remain the drug of choice in patients
are most helpful in maintenance of weight loss. with moderate to severe liver disease.

History of Chronic Kidney Disease APPROACH TO MANAGEMENT

Approximately 20–30% of patients with diabetes may in Management of diabetes requires a good physical exami­
their lifetime develop moderate to severe renal functional nation and history.
impairment [estimated glomerular filtration rate (eGFR)
History
<60 mL/min].15,21 Patients with chronic kidney disease
(CKD) have an increased risk of hypoglycemia. This is The history should include complaints related to hyper­
because of various reasons including delayed clearance glycemia and hyperosmolar symptoms and symptoms
of oral antidiabetic drugs (OADs). Thus, dose reduction related to the different systems. Family history and per­
may be necessary. Moreover, the consequences of sonal history of lifestyle (diet and exercise) and smoking
hypoglycemia and that of fluid retention require careful has to be taken. In women history of menstrual irregulari­
evaluation. It is generally advocated to avoid metformin ties indicating polycystic ovaries or associated disorders
in men with serum creatinine more than 1.5 mg/dL and like hypothyroidism should be asked for. History of hypo­
in women more than 1.4 mg/dL although these are not glycemia is also to be elicited. A detailed review of systems
absolute values. Metformin is eliminated renally, and (or direct questioning) must be done regarding symptoms
460 Clinical Profile

Table 29.4: Summary of evaluation of patient with diabetes (Patient evaluation consists of history, physical examination and blood tests)
History Physical examination
• Age and characteristics of onset of diabetes (e.g. DKA, hyperos- • Height, weight, BMI, Blood pressure determination, including
molar asymptomatic) orthostatic measure
• Eating patterns, physical activity habits, nutritional status, and • Fundoscopic examination
weight history; growth and development in children and adoles- • Thyroid palpation
cents • Skin examination (for acanthosis nigricans and insulin injection
• Diabetes education history sites)
section

• Review of previous treatment regimens and response to therapy • Comprehensive foot examination including:
7

(HbA1c records) – Inspection

• Current treatment of diabetes, including medications, medication – Palpation of dorsalis pedis and posterior tibial pulses
adherence and barriers to adherence, meal plan, physical activity – Presence or absence of patellar and achilles reflexes
patterns, and readiness for behavior change – Determination of proprioception, vibration, and monofilament
• Results of glucose monitoring and patient’s use of data sensation
• DKA frequency, severity and cause
• Hypoglycemic episodes
• Hypoglycemia awareness
• Any severe hypoglycemia: frequency and cause
• History of diabetes-related complications
• Microvascular: retinopathy, nephropathy, neuropathy (sensory,
including history of foot lesions; autonomic, including sexual
dysfunction and gastroparesis)
• Macrovascular: CHD, cerebrovascular disease, and PAD
• Other: psychosocial problems, dental disease
(DKA: Diabetic ketoacidosis; BMI: Body mass index; A1c: Glycated hemoglobin; CHD: Coronary heart disease; PAD: Peripheral arterial disease).

related to eyes, skin, cardiorespiratory, gastrointestinal Investigations

(GI), neurological, genitourinary and endocrine systems.
Blood glucose: Concept of self-monitoring of blood glucose
A history of medications being used currently, in the
recent past and remote past must be elicited. (SMBG) should be encouraged. The blood glucose testing
can be as frequent as possible and feasible for the patient.
Physical Examination However, certain groups do not need SMBG; for example
a type 2 diabetic controlled on lifestyle interventions. On
A detailed physical examination must include general the other hand a type 1 diabetic or a pregnant diabetic
examination for pedal edema, pallor, xanthelasma to see may require frequent testing. The blood glucose testing at
for dyslipidemia, signs of insulin resistance like acan­ various times of the day, pre- and postmeals, occasionally
thosis nigricans, and skin tags and nails to see for fungal at bed time and 3 am should be performed.
infection, pulse should be taken of all peripheral arteries, Other blood investigations should be performed as in
blood pressure of both upper and lower limbs if possible Table 29.5.
should be taken. The blood pressure should be recorded
after 5 minutes of rest and both in the sitting and supine
TYPE 1 DIABETES
position to detect autonomic dysfunction. Anthropometric
measurements like BMI, and waist circumference should It is characterized by absolute insulin deficiency due to
be noted. A waist circumference of more than 80 cm in autoimmune destruction of beta-cells of pancreas. It
women and 90 cm in men will be considered abnormal. accounts for about 2–5% of diabetes cases in India.15
A proper foot examination to identify high risk foot Patient presents with polyuria, polydipsia, polyphagia,
should be done. This testing should include a monofila­ weight loss and fatigue. The most dreaded presentation
ment and vibration test. is diabetic ketoacidosis (DKA) in which patient presents
Evaluation of CV, respiratory and neurological system with vomiting, abdominal pain, dehydration, acidotic
should be performed (Table 29.4). breathing and coma. The usual precipitating causes of
 An Approach to Management of Diabetes Mellitus 461

Flow chart 29.2: Algorithm for Type 1 Diabetes

Table 29.5: Investigations
S. No. Blood investigations Frequency Approach to diabetes

1. Glycated hemoglobin (HbA1c) Every 3–4 months

2. Lipid profile Every year
3. Creatinine Every year
4. Urine analysis Every year
5. Microalbuminuria Every year

chapter
29
DKA are acute infections, acute vascular event, trauma,
stress, surgery and missed doses of insulin. Type 1 diabetes
patients can occur with other autoimmune diseases like
Addison’s disease, hypothyroidism and vitiligo; hence,
these should be considered as additional diagnosis.

Recognizing the Problem

As type 1 diabetes can have different presentations, its
early recognition is important especially in a country like
India where subtle symptoms of the disease are ignored or
attributed to other etiology. Very often poor growth, loss of
weight, frequent urination are ignored and hence pose a
problem for early detection, education, and management (ABG: Arterial blood gas; DKA: Diabetic ketoacidosis: IV: Intravenous;
of type 1 diabetes. Health education holds the key to make SC: Subcutaneous; HbA1c or A1c: Glycated hemoglobin;

people aware about the problem.

CONCLUSION
Diagnosis
Planned management of diabetes is of paramount impor­
It is diagnosed clinically based on age of presentation,
tance and individualization of therapy is the key to its
phenotype and ketoacidosis. Antibodies to glutamic acid
success. Various factors have to be taken into conside­
decarboxylase, islet cells and insulin help to substantiate
ration when setting glycemic targets. Glycemic targets
the diagnosis. C-peptide helps us to gauge the pancreatic
should be reached with as few side effects as possible.
insulin reserve.
The preservation of the beta-cell is also an important
consideration in the management of diabetes. Drugs with
Approach to Management
the same mechanism of action should not be combined.
Insulin is the mainstay of therapy. Patient should be Finally, the patient’s comfort, safety and economic status
taught the technique of insulin administration and stor­ need to be considered while treating people with diabetes.
age. Education on various topics like sick day rules and
FURTHER READING
adverse events like hypoglycemia should be given. Mul­
tiple insulin injections are required for adequate gly­ 1. Harris M, Zimmet P. Classification of diabetes mellitus and
other categories of glucose intolerance. In: Defronzo RA,
cemic control. Persons with type 1 diabetes should be Ferrannini E, Keen H, Zimmet P (Eds). International Text­
educated on how to match prandial insulin dose to car­ book of Diabetes Mellitus, 2nd edition. Chichester: John
bohydrate intake, premeal blood glucose, and anticipated Wiley and Sons Ltd; 1997.
activity (Flow chart. 29.2).24 Insulin analogs may be used 2. Holt RIG, Cockram C, Flyvbjerg A (Eds), et al. Textbook of
Diabetes, 4th edition. Blackwell Publishing Ltd; 2010.
to reduce hypoglycemia risk. Continuous insulin infu­
3. Wass JAH, Stewart PM, Stephanie AA (Eds). Oxford Text­
sion by pump is a useful tool for insulin delivery in type 1 book of Endocrinology and Diabetes, 2nd edition. Oxford:
diabetic patients. Oxford University Press; 2011.
462 Clinical Profile

REFERENCES on behalf of the Global Partnership for Effective Diabetes

Management. Int J Clin Pract. 2010;64:295-304.
1. International Diabetes Federation. Diabetes Atlas, 5th 13. Bera C, Pratyush DD, Tiwari S, et al. Study on insulin
edition. Brussels, Belgium: International Diabetes Federa­ resistance and beta cell dysfunction in lean type 2 diabetes
tion; 2011. mellitus. J Assoc Physicians India. 2009;57.
2. World Health Organization. Preparing health care work­ 14. Nelson JM, Dufraux K, Cook PF. The relationship between
force for the 21st century. The challenge of chronic condi­ glycemic control and falls in older adults. J Am Geriatr Soc.
tions. Geneva; 2005. 2007;55:2041-4.
section

3. Wagner EH. The role of patient care teams in chronic 15. Huang ES, Liu JY, Moffet HH, et al. Glycemic control,
disease management. BMJ. 2000;320:569-72. complications, and death in older diabetic patients: the
7

4. DeFronzo RA. From the triumvirate to the ominous octet: a dia­betes and aging study. Diabetes Care. 2011;34:1329-36.
new paradigm for the treatment of type 2 diabetes. Diabe­ 16. Turner R, Stratton I, Fright V, et al. Hypertension in Diabetes
tes. 2009;58:773-95. Study (HDS): I. Prevalence of hypertension in newly
presenting type 2 diabetic patients and the association
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive
with risk factors for cardiovascular and diabetic complica­
blood glucose control with sulphonylureas or insulin com­
tions. J Hypertens. 1993;11:309-17.
pared with conventional treatment and risk of complica­
17. Singh RB, Beegom R, Rastogi V, et al. Clinical characteristics
tions in patients with type 2 diabetes (UKPDS 33). Lancet. and hypertension among known patients of non-insulin
1998;352:837-53. dependent diabetes mellitus in North and South Indians.
6. Ceriello A, Ihnat MA, Thorpe JE. Clinical review 2: the J Diabetic Assoc India. 1996;36:45-50.
‘‘metabolic memory’’: is more than just tight glucose con­ 18. Kearney PM, Blackwell L, Collins R, et al. Cholesterol
trol necessary to prevent diabetic complications? J Clin Treatment Trialists (CTT) Collaborators. Efficacy of cho­
Endocrinol Metab. 2009;94:410-5. lesterol-lowering therapy in 18,686 people with diabetes
7. Gerstein HC, Miller ME, Byington RP, et al. Effects of in 14 randomized trials of statins: a meta-analysis. Lancet.
intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;371:117-25.
2008;358:2545-59. 19. Fagard RH, Nilsson PM. Smoking and diabetes–the double
8. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glu­ health hazard. Prim Care Diabetes. 2009;3:2005-9.
cose control and vascular outcomes in patients with type 2 20. Haire-Joshu D, Thomas J. Gambling with addiction: dan­
diabetes. N Engl J Med. 2008;58:2560-72. gerous beliefs about smoking and diabetes. Diabetes Voice
9. Duckworth W, Abraira C, Moritz T, et al. Glucose control Smoking and diabetes special issue. 2005;50:15-8.
and vascular complications in veterans with type 2 diabe­ 21. Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use
tes. N Engl J Med. 2009;360:129-39. and prevalence of chronic kidney disease among patients
with type 2 diabetes mellitus in the United States. Clin Ther.
10. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management
2009;31:2608-17.
of hyperglycemia in type 2 diabetes: a patient-centered
22. Holstein A, Stumvoll M. Contraindications can damage
approach: position statement of the American Diabetes
your health. Is metformin a case in point? Diabetologia.
Association (ADA) and the European Association for the 2005;48:2454-9.
Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-79. 23. Tolman KG, Fonseca V, Dalpiaz A, et al. Spectrum of liver
11. Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing disease in type 2 diabetes and management of patients
glycemic targets in type 2 diabetes mellitus: implications with diabetes and liver disease. Diabetes Care. 2007;30:
of recent clinical trials. Ann Intern Med. 2011;154:554-9. 734-43.
12. Del Prato S, LaSalle J, Matthaei S, et al. Tailoring treatment 24. Raha O, Chowdhury S, Dasgupta S, et al. Approaches in
to the individual in type 2 diabetes practical guidance from type 1 diabetes research: a status report. Int J Diabetes Dev
the Global Partnership for Effective Diabetes Management Ctries. 2009;29:85-101.
Section 8

MANAGEMENT
Section Editor: Viswanathan Mohan
 Chapter 30
Nutrition Management of
Diabetes Mellitus
Rekha Sharma, Swapna Chaturvedi

Nutrition Management

Chapter Outline
♦♦ Goals ♦♦ Realistic Diet Prescription Strategies
♦♦ Basic Principles for Planning Diet for Diabetics ♦♦ Additional Nutritional Considerations to
♦♦ Nutrition Recommendations Reduce Cardiac Risk
♦♦ Goals of Medical Nutrition Therapy ♦♦ Meal Planning

INTRODUCTION The third step, nutrition intervention, must incorporate

a variety of meal planning and nutrition education reso­
The epidemic of overweight and obesity among affluent urces that the patients can easily understand and use.
nations is fueling the increasing prevalence of the The fourth step is evaluation, which reassesses how the
metabolic syndrome and type 2 diabetes. Metabolic goals have been accomplished and indicate the area
syndrome encompasses a cluster of abnormalities inclu­ for future self-management education. The goals of diet
ding insulin resistance, central obesity, hypertension therapy are to maintain and prolong a healthy, productive
and dyslipidemia. Both type 2 diabetes and the insulin and satisfying life.
resistance syndrome are associated with a marked
increased risk for cardiovascular disease (CVD). Contri­ GOALS
butors to these conditions are improper nutrition and
inadequate physical activity; thus weight management • To improve health through optimum nutrition
is the cornerstone of treatment and prevention. Medical • To provide calories for reasonable body weight (BW),
nutrition therapy (MNT) for insulin resistance and dia­ normal growth and development
betes requires the application of nutritional, medical and • To maintain glycemic control
behavioral sciences. This can be accomplished using a • To achieve optimal blood lipid levels
four pronged approach. The first step is a comprehensive • To minimize nutrition related chronic degenerative
nutrition assessment that includes metabolic, nutrition complications
and lifestyle parameters. The second step is setting Adapting diet therapy to the specific needs of an
goals with the patient and these goals must be practical, individual patient is most essential; however, there are few
achievable and acceptable for the patient with diabetes. basic principles that are to be followed.
466 Management

Table 30.1: Standard height and weight chart (Men) Table 30.2: Standard height and weight chart (Women)
Height (cm) Height Weight (kg) Weight (lbs) Height (cm) Height Weight (kg) Weight (lbs)
152.3 5 feets — — 152.3 5 feets 50.8 – 54.4 112 – 120
154.8 5 feets 1 inch — — 154.8 5 feets 1 inch 51.7 – 55.3 114 – 122
157.3 5 feets 2 inches 56.3 – 60.3 124 – 133 157.3 5 feets 2 inches 53.1 – 56.7 117 – 125
159.9 5 feets 3 inches 57.6 – 60.3 127 – 136 159.9 5 feets 3 inches 54.4 – 58.1 120 – 128
section

162.4 5 feets 4 inches 58.9 – 63.5 130 – 140 162.4 5 feets 4 inches 56.3 – 59.9 124 – 132
165.0 5 feets 5 inches 60.8 – 65.3 134 – 144 165.0 5 feets 5 inches 57.6 – 61.2 127 – 135
8

167.5 5 feets 6 inches 62.2 – 66.7 137 – 147 167.5 5 feets 6 inches 58.9 – 63.5 130 – 140
170.0 5 feets 7 inches 64.0 – 68.5 141 – 151 170.0 5 feets 7 inches 60.8 – 65.3 134 – 144
172.26 5 feets 8 inches 65.8 – 70.8 145 – 156 172.6 5 feets 8 inches 62.2 – 66.7 137 – 147
175.1 5 feets 9 inches 67.6 – 72.6 149 – 160 175.1 5 feets 9 inches 64.0 – 68.5 141 – 151
177.7 5 feets 10 inches 69.4 – 74.4 153 – 164 177.7 5 feets 10 inches 65.8 – 70.3 145 – 155
180.2 5 feets 11 inches 71.2 – 76.2 157 – 168 180.2 5 feets 11 inches 67.1. – 71.7 148 – 158
182.7 5 feets 12 inches 73.0 – 78.5 161 – 173 182.7 5 feets 12 inches 68.5 – 73.9 161 – 163
185.3 5 feets 13 inches 75.3 – 80.7 166 – 178 185.3 5 feets 13 inches — —
187.8 5 feets 14 inches 77.6 – 83.5 171 – 184 187.8 5 feets 14 inches — —
190.4 5 feets 15 inches 79.8 – 85.6 176 – 189 190.4 5 feets 15 inches — —

BASIC PRINCIPLES FOR Table 30.3: Criteria for obesity

PLANNING DIET FOR DIABETICS WHO (Kg/m2) Asian Indians1 (Kg/m2)
Normal: 18.5 – 24.9 18 – 22.9
• Age, sex, activity, height, body weight (BW), cultural
Overweight: 25 – 29.9 23 – 24.9
factors
Obese: More than 30 More than 25
• Type of diabetes, mode of treatment, control of diabetes
• Aggravating factors; infections, gastrointestinal dis­
orders, cardiovascular disorders, pregnancy. 2. Around hips (pear-shaped)
Based on these factors, the primary consideration is of Being apple-shaped (more fat around the waist)
calorie requirements, to achieve one’s ideal body weight places them in higher risk category than the pear-shaped
(carrying more fat on hips).
(IBW) with a balanced wholesome meal. Over the recent
The measure of the two is called:
years, overweight and obesity are escalating rapidly to
• Waist-hip ratio
epidemic proportion in many parts of the world including
–– Waist measure below the ribcage above the naval
India, reflecting increasing consumption of high energy
–– Hip measure at its maximum.
diets rich in fats and sugars, compounded by declining
• Waist circumference is another quick measure to
levels of physical activity. determine obesity especially in Indian population, due
Obesity can be defined by body mass index (BMI) to more marked central obesity.
Table 30.3, i.e. Healthy cutoff1
Weight in kilogram
WHR = Men Less than 0.88
Height in meter 2 Women Less than 0.80
Obese persons are 10 times more likely to develop Waist circumference = Men 90 cm
type 2 diabetes and obesity is the principal risk factor Women 80 cm
especially when it is central obesity [higher waist circum­ Table 30.1 and 30.2 depict safe limits of BW for height.
ference or higher waist-hip ratio (WHR)]. The formula for calculating the IBW (kg) is:
Most people store their body fat in two distinct ways: Men: Height (in cm) – 100
1. Around middle (apple-shaped) Women: Height (in cm) – 105
 Nutrition Management of Diabetes Mellitus 467

NUTRITION RECOMMENDATIONS • Percentage and distribution vary with insulin regimen

and treatment goals.
Calories
• Sufficient to attain and/or maintain a reasonable
Sweeteners
BW for adults, normal growth and development for • Nutritive sweeteners (fructose, sugar and alcohols)
children and adolescents, and increased to meet needs have no advantage over sucrose.
during pregnancy and lactation or for recovery from • Non-nutritive sweeteners approved by the Food and

chapter
catabolic illness. Drug Administration (acesulfame-K, aspartame, sucra-

30
• Reasonable BW is defined as the weight an individual lose, saccharin) are safe to consume.
and health care provider acknowledges, as achievable
and maintainable, both in the short-term and long- Fiber
term. • About 25–40 g/day, same as general population
• Basal calorie requirements are 20 calories per kilogram (15 g/1,000 kcal)
of the IBW: • Generally not beneficial for glycemic control at lesser
–– Add 5 cal/kg of IBW for moderate activity amounts.
–– Decrease 5 cal/kg IBW, if overweight
–– Give basal calories, if overweight and sedentary
Sodium
–– Increase 5 cal/kg of IBW, if underweight • Five grams per day, same as general population
–– Increase 10 cal/kg of IBW, if underweight and • Less than 2400 mg/day, in mild-to-moderate hyper­
moderate activity. tension
• Less than 2,000 mg/day, with nephropathy, hyper­
Proteins tension and edema.

Twelve to fifteen percent of daily calories, not less than Alcohol

adult recommended dietary allowances (RDA); adjust to The same precautions apply regarding alcohol consump­
0.8 g/kg/day with evidence of microalbuminuria; adjust tion in diabetes and non-diabetics. Abstention from
in reduced glomular filtration rate (GFR) (0.6 g/kg/day); alcohol should be advised for people with a history of
adjust for very young children, pregnant and lactating alcohol abuse or dependence; for women during preg­
women and some elderly. nancy; and for people with medical problems such as liver
disease, pancreatitis or advanced neuropathy. If individual
Fats choose to drink alcohol, daily intake should be limited, to
one drink or less for adult women and two drinks or less
Individualized, based on the nutrition assessment and
for adult men (1 drink = 12 oz beer, 5 oz of wine, or one
treatment goals for those older than 2 years of age.
and a half oz of distilled spirits). Each drink contains ~15 g
Total fat: 15–30% energy alcohol. The type of alcoholic beverage consumed does
Saturated fat: Less than 10% energy; less than 7% with not make a difference.
elevated low-density lipoproteins (LDLs)
Polyunsaturated fats (PUFA): Less than 10% energy; Vitamins/Minerals
n-6/n-3 ratio (5–10) (n-6, linoleic acid; • Same as general population
n-3, alpha linolenic); n-6, 3–7% energy; • Magnesium replacement possibly needed, if at high
n-3, more than 1% energy risk of deficiency due to glycosuria ketoacidosis
Monounsaturated fat (MUFA): 10–15% energy • If high risk of deficiency, determine if replacement
Carbohydrates: 55–60% energy is necessary based on laboratory test.
Cholesterol: Less than 300 mg/day
GOALS OF MEDICAL NUTRITION THERAPY
Carbohydrates
For Type 1 Diabetes
• Individualized based on the patient’s eating habits
• Difference of total minus protein and fat For patients with type 1 diabetes, MNT should emphasize
• Total amount more important than the source the inter-relationships among food, exercise, and insulin.
468 Management

Flow chart 30.1: Consistency in food, exercise and insulin intake for type 1 diabetic patient
section
8

Those receiving conventional insulin therapy must overweight patients with diabetes. This recognizes the fact
maintain consistency in the timing and amount of food that modification of fat intake, spacing and size of meals,
intake. Ideally, the insulin plan should be designed to match exercise, and reasonable weight loss can be effective in
the patient’s preferred eating pattern. Earlier the nutrition achieving blood glucose and lipid goals in patients with
recommendations were for total calories and carbohydrate type 2 diabetes.
to be “fractionated” between meals and snacks based The primary goal for patients with type 2 diabetes
on the insulin regimen. This is no longer recommended should be to achieve and maintain near normal blood
because it does not promote individualization. Because glucose levels. Making healthy food choices, especially
of the limitations of a conventional insulin regimen modifying calorie intake, can be beneficial. Current
(i.e. 1–2 insulin injections per day), patients on such a recommendations aim to promote good glycemic control
regimen may need to alter their usual eating habits in and maintain IBW while reducing the risk of coronary
incorporating consistency with timing and amounts of heart disease (CHD) through improved lipid profiles.
food (Flow chart 30.1). People with diabetes find it more difficult to lose weight
Nutrient requirements for children and adolescents and maintain the loss compared to those without the
with diabetes appear to be similar to those of children and disease. It is now clear that they do not need to reach their
adolescents without diabetes. Individualized meal plans
IBW in order to improve their metabolic status; as little as
along with insulin regimens using basal (background) and
5–10% reduction in BW is sufficient to result in clinically
bolus (mealtime) insulins are required. Insulin pumps
relevant benefits.3
can provide flexibility for children with type 1 diabetes.
This approach accommodates irregular meal times, and
For Gestational Diabetes
schedules and varying appetites and activity levels.4
Patients receiving intensive insulin therapy, i.e. mul­ Diabetes is diagnosed in some women during pregnancy.
tiple daily injections or pump infusions, have consi­derable MNT for gestational diabetes mellitus (GDM) primarily
flexibility, in when and what to eat. Nevertheless, they too involves a carbohydrate-controlled meal plan that
need to integrate their insulin regimen with their lifestyle promotes optimal nutrition for maternal and fetal health
and adjust the insulin dose when they deviate from their with adequate energy for appropriate gestational weight
usual eating and exercise patterns. These patients can gain, achievement and maintenance of normoglycemia,
adjust their premeal insulin dose to compensate for and absence of ketosis. The pattern of weight gain during
departures from their meal plan and exercise program. pregnancy for women with GDM should be similar to that
Even with the increased flexibility, the more consistent of women without diabetes. Weight loss is not recom­
they are with their eating and physical activity, the easier mended for overweight and obese women with GDM;
is the overall management. however, modest energy and carbohydrate restriction may
be appropriate (ADA 2007).8 CHO should be distributed
For Type 2 Diabetes throughout the day into 3 small-to-moderate size of
Blood glucose and lipid goals along with weight loss meals and two to four snacks. All women require a mini­
to attain an ideal weight are the focus of therapy for mum of 175 g of CHO daily (Institute of Medicine, 2002).
 Nutrition Management of Diabetes Mellitus 469
Flow chart 30.2: Strategy to promote metabolic control for type 2 No single dietary approach will be suitable for all
diabetic patient
patients. Meal plans and dietary modifications need to
be tailor made to suit each patient’s needs and lifestyle.
Current medical status (HbA1c, blood lipid levels, home
blood glucose monitoring results, nutritional status,
BW, medication, blood pressure, renal function) needs
to be assessed before any dietary modifications are

chapter
recommended. Dieticians should reinforce that the dietary

30
and exercise prescription is an essential component of
diabetes management irrespective of medicine. Other
than the quantity we need to change the diet to make it
more balanced and, composition and quality of major
ingredients in the diet need to be taken care of.

An evening snack is usually needed to prevent accele­

Carbohydrates
rated ketosis overnight. Although caloric restriction must
be viewed with caution, in obese women with GDM a Carbohydrates (CHO) constitute a major proportion of
30% caloric restriction (an intake about 1,700–1,800 kcal human diet. CHO rich food items are easily digested,
daily) may reduce hyperglycemia without ketonemia and relatively inexpensive, provide ready energy and sense of
reduce the rate of maternal weight gain. Intake below filling. These are also considered more suitable for the sick
these levels is not advised. and at the extremes of age.
The amount of CHO in daily diet cannot be fixed as a
For Pre-diabetes general rule. This has to be decided for individual patients
taking physical features, metabolic status and treatment
These persons should be monitored closely because they
goals into account. CHO may account for 45–60% of the
have an increased risk of developing diabetes.
total energy provided. The relationship of CHO inges­
tion and changes in blood glucose has been known
REALISTIC DIET PRESCRIPTION STRATEGIES
for a long-time. Hence, the need for counting from
• Emphasize on low saturated fat, low GI complex CHO calories in meals and snacks. This is addressed by
carbohydrate foods to promote satiety and reduce providing equivalent content of CHO in different food
hyperinsulinemia items in day-to-day meals.
• Modest caloric restriction, not extreme restrictions An important priority for food and meal planning is
prevent excessive hunger. A moderate caloric modi­ the total amount of CHO that the person with diabetes
fication (250–500 calories less than the average daily chooses to have for meals or snacks. A variety of methods
intake) and increased physical activity may lead to can be used to estimate the nutrient content of meals,
improved weight control including carbohydrate containing, exchange lists, and
• Distribution of carbohydrate intake throughout the day, experience. For carbohydrate counting food portions
more frequent smaller meals to reduce postprandial contributing 15 g of CHO (regardless of the source) are
hyperglycemia considered to be one CHO serving. Testing premeal and
• Increased physical activity to promote higher energy postmeal glucose levels is important for making adjust­
expenditure ments in either food intake or medication to achieve
• Support from family and other professionals to increase glucose goals. For several decades, it has been appre­
compliance ciated that all CHO containing food items do not raise
• Behavior modification techniques and relaxing activities blood glucose to a similar extent within the same period
to reduce stress-related eating. of time. Ingestion of simple sugars raises plasma glucose
The strategies that have been discussed to promote faster and higher than food consisting of complex CHO
improved metabolic control for patients with type 2 such as starch. Even among starchy foods distinction
diabetes are highlighted in Flow chart 30.2. has been made between refined raw rice and potato on
470 Management

one hand and whole mill wheat flour and pulses on the Table 30.4: Glycemic index (GI) of certain food items (GI: White
other. Quantization of these differences has been possible Bread × 100)
following introduction of procedures for estimate of Food items GI
glycemic index (GI) by Jenkins et al. (1981).5 White rice (raw) 90–120
Wheat and brown bread (brown) 98
Glycemic Index Whole wheat bread 71
Brown parboiled rice 67
section

Glycemic index is meant to measure the change in blood

glucose following the ingestion of food containing a Comflakes and breakfast cereals 119
8

specific amount of CHO and compare it with a reference High GI biscuits cookies 105
standard such as glucose or white bread. GI is the ratio Baked potato 121
between the increase in blood glucose over the fasting French fries 102
levels observed for 2 hour following ingestion of a set Sucrose 92
amount of carbohydrate (50 g) in the test food and the Honey 104
response to glucose or white bread containing similar Banana 75
amount of carbohydrate in the same individual. The Apple 51
increments are calculated from the measurement of area Orange 61
under the curve (AUC) in the graph drawn as in glucose Low GI chick peas 47
tolerance test (GTT). GI = AUC following the test meal/ Lentils (Dal) 40
AUC after 50 g of glucose or equivalent amount of white Kidney beans 38
bread × 100. Whole milk 38
Glycemic index values for commonly consumed
Fructose 33
carbohydrate rich-food items have been determined in
Nuts including peanuts 35
numerous laboratories across the world. There was wide
variability in the results due to both intrinsic and extrinsic
factors. Of late, the procedures have been standardized.
Whatever differences still exist may be similar to varia­ • Physical characteristics of foods/starch:
tions in GTT values in such situations. GI calculations –– Form: Raw and large particles are better than cooked
for a large number of dietary ingredients have been pub­ and homogenized particles
lished recently by Foster-Powell.6 Values for few items –– Size: Large particles size is better than small particle
are listed in the Table 30.4. Food prepared from whole size (Size of wheat starch = 20 to 22 micron, potato
grains products as whole wheat (flour), Oats, Jowar, Rye starch = 15, rice starch = 5.0).
• Fiber content of food: Many whole grains are often
and Ragi have low GI. In addition, these are rich in fibers,
processed into refined products, like maida, suji rice,
antioxidants and phytochemicals. Legumes (grams) and
sago, corn and arrowroot. During this processing,
beans have low GI and higher protein as well as viscous
the useful fiber present in the unprocessed foods is
soluble fiber contents. Food items with GI of 60 or below
removed to varying extent. The beneficial effects of food
are preferred for patients with diabetes or prediabetes. fiber include reduction of blood glucose, reduction of
Several prospective studies have found an inverse asso­ serum cholesterol and reduction of BW. The common
ciation between whole grain consumption and incidence sources of dietary fiber are whole cereals, ragi, whole
of diabetes and CHD. dals and grams, kottu and jowar. Viscous soluble
Glycemic index of a CHO containing food item may be fiber increases the viscosity of intestinal contents and
influenced also by the following factors: this slows down the interaction between starch and
• Nature of starch and its digestibility: Amylopectins enzymes, so sugar release is slow.
are rapidly digested and amylose is slowly digested. • Acidity: Acids in foods slows down gastric emptying,
Therefore foods with higher amylose content are thereby slowing the rate of digestion. Vinegar, lemon,
recommended (Amylose content of Bengal gram = oranges, foods fermented with curds, lactic acid are
33%, wheat = 25%, potato = 23%). beneficial.
 Nutrition Management of Diabetes Mellitus 471

• Fats and proteins: Slows rate of stomach emptying. of CHO in diabetic diet, despite the fact that source
• Degree of starch gelatinization on cooking: Larger the and nature of CHO profoundly influence postprandial
particles size, lower the GI. glycemic values both in normal and diabetic subjects.
By now several prospec­tive, observational studies have
Sucrose established that overall GI and GL of diet but not total
carbohydrate content are independently related to risk
It is a general, long standing advice to patients of
of development of type 2 diabetes and CVD. In view

chapter
diabetes mellitus not to take either free sucrose or sweets
of the above, ADA has issued a statement on dietary
containing sucrose. They are also cautioned to avoid

30
carbohydrate (Amount and Type) in the prevention and
such other food preparations that are sweetened with management of diabetes.11
added sucrose. ADA continues to state that sucrose in In short-term and relatively long-term studies, use
amounts of some 20 g per day may not disturb glycemic of low GI carbohydrate items in diet have yielded posi­
control when taken along with mixed meals. This is not tive results on glycemic control while some studies are
acceptable in our circumstances as Indian diet is already inconclusive. These doubts are set to rest by meta-
high in carbohydrate. Further cane sugar provides only analysis of all available controlled studies by Brand Miller
empty calories practically devoid of trace elements such et al.12 and a report on multicentric trial by Buyken et al.
as minerals, vitamins as well as fibers. Substituting 20 g in Europe.13 The beneficial effect of low GI items in diet
of sucrose for more useful CHO rich ingredients results on glycemia, lipidemia and obesity reported by these
in reduced fiber intake and other useful ingredients. studies have been cited in the ADA statement.
Further, free sugar promotes hypertriglyceridemia which Reducing amount of CHO in diabetes diet below a
is quite common in diabetic patients of Indian origin. It certain level is not recommended as the components
is therefore unwise to liberalize sucrose in diabetic diet. are important sources of energy, water-soluble vitamins,
Sucrose can certainly be allowed to some lean patients minerals and fibers. The National Academy of Science—
(especially with T1DM) on multiple doses of insulin Food and Nutrition Board recommends CHO to consti­
especially on sick days when consumption of usual diet is tute between 45% and 65% of total calories and not below
severely restricted. 130 g per day in any case. High CHO diet (60%) with low
Glycemic response of an equicalorie amount of CHO GI has been found to be as good as high monounsaturated
taken in isolation may be different from the same amount fat (MUFA) diet, better for its lower cost and higher
in a mixed meal. Fat in the meal may retard digestion and preference in developing countries. The GI selection has
absorption of CHO and protein-induced insulin secretion to be more strict in cases with high serum triglyceride.
modifies the postprandial glucose level. While these The problem with exchange list is that it indicates
concerns are relevant, it has been observed that the GI equivalent amounts of carbohydrate without reference
of a mixed meal can be predicted by calculating the GI of to their source and nature. ADA, for a period, preferred
individual components.7 exchange lists to GI as the latter was thought to
be too complex to be practiced. On the other hand,
Gilbertson et al.14 in one of the longest and largest studies
Glycemic Load
have documented that children with type I diabetes
Until recently ADA dietary recommendations empha­ considered it more convenient to choose from a flexible
sized on the quantity of CHO that has to be taken care list of low GI food items than the use of exchange lists.
of7 despite the fact that source and nature of CHO pro­ Recommendations for choice of diet ingredients are to
foundly influence postprandial glucose values.8 Of late be made keeping in view the individual’s culture, habits
Salmeron et al.9 have most appropriately brought in and preferences. On the whole, modest amount of brown
the concept of glycemic load (GL) of meals by taking parboiled rice and/or whole wheat flour (chapatti) is
both the GI and total amount of CHO contained in the prescribed in specified quantities; higher proportion of
meals. GL of a food item is to be calculated by GI/100 × pulses (legumes) as well as, liberal intake of vegetables,
CHO content in grams. While the European Association fruits and salad have to be clearly detailed in the dietary
for Study of Diabetes recommends the use of low GI advice. Common high GI items to avoid are sugar, sweets,
CHO in MNT for diabetes,10 until recently the ADA has jaggery, honey, potato, yam, sweet potato, white bread,
been laying emphasis on regulating only the total quantity biscuits, cookies, puffed rice, cornflakes, breakfast cereals,
472 Management

raw polished rice, preparations from refined wheat flour Proteins

(maida, pasta) as well as South Indian foods such as idli
Since current scientific evidence does not support either
and dosa.
higher or lower intake of protein by patients with diabetes,
the recommendation for intake is 10–15% of total calories,
Fibers similar to that for the general population.
Fiber is an integral part of human diet. It was considered In patients with type 1 diabetes and overt diabetic
synonymous with roughage and was considered dis­ nephropathy, restriction of dietary proteins has been
section

advantageous ever until Burkett and Trowell published shown to retard the progression to renal failure. There
8

their observations in the 1970s.15 is some evidence that this may also be true for people
Dietary fiber is defined as plant material in diet that with type 2 diabetes. Therefore, a protein intake of
cannot be digested by the human alimentary digestive approximately 0.8 g/kg BW per day (generally equivalent
tract. These may be better described as non-starch to 15% of daily total calories), is recommended for patients
polysaccharides. A complex mixture of substances, fibers with evidence of microalbuminuria. However, it has
have a wide range of effects on the function of the GI tract been suggested that once the GFR begins to fall, further
mainly mobility and absorption. restriction to 0.6 g/kg/day may prove useful in showing
Fibers can be insoluble or soluble. Cellulose, a glucose the decline of GFR in selected patients. On the other hand,
polysaccharide is the predominant insoluble fiber. Leafy nutritional deficiency may result in some individuals
vegetables, brans of cereals, vegetables, fruits and legumes and may be associated with muscle weakness. Nutrition
are dietary sources of cellulose. Soluble or partially soluble recommendation for patients with renal insufficiency
fiber are pectin, plant gums and mucilage. These are requires an individualized approach. In patients with
mixtures of polysaccharides that combine with water to type 1 and type 2 diabetes and microalbuminuria, there
form gels. Soluble fibers are essential contents of fruits, is inconclusive evidence that a low-protein diet slows the
progression of nephropathy.
vegetables and seeds including legumes.
There are some evidences that the protein source,
Insoluble fibrous fibers provide bulk and satiety after a
whether animal or vegetables; in origin, may be important
meal and increase colonic movements and fecal volume.
in affecting the progression of renal disease. However,
The soluble fraction may delay gastric emptying, reduce
the studies are preliminary. If beneficial renal effects of
rate of absorption from the small intestine and help in
vegetables proteins are confirmed, less drastic dietary
control of rapid rise of blood glucose. Further soluble
protein restriction may be required in the treatment of
fibers are effective in lowering total and LDL cholesterol
diabetes nephropathy. Additional research is needed
through increased bile acid excretion and decreased
in this area. At least 50% of the total protein should be
hepatic synthesis of cholesterol and fatty acids (FA).16
acquired from the group containing 1st class proteins.
Refinement of cereals removes fibers from the natural
First class proteins: Milk, cheese, curd, buttermilk,
products. Numerous studies have shown that high fiber
eggs, meat, fish and chicken.
intake reduces risk of type 2 diabetes and CHD.17 More Second class proteins: Soybeans, pulses, grams, peas,
recent studies suggest better results from cereal fibers beans. Since the cost of foods in the first class protein
emphasizing the need of materials from whole grain group is high biological value of proteins can be further
cereals. Fiber content of carbohydrate foods lower GI improved by mixtures of second class proteins, e.g.
and/or GL. For example, water melon and carrot in Cereals: Grams mixtures in ratio 4:1.
spite of sugar content offer low GL because of high fiber
content. On these grounds, emphasis has to be given on Fats
whole grain cereal derivatives, legumes, fruits, vegetables Fats in the dietary sense include edible oils used for
and nuts. High fiber content fully mitigates the hyper­ cooking; fats in milk, meat, fish and eggs.
glycemic and triglyceridemic effect of high carbohydrate Fatty acids, the principal components of fats and oils
diet that compares well with low CHO, high MUFA diet apart from having variable chain length can be either:
in the above respects. • Saturated (C4-18)—SFA
The average fiber content of western diet is estimated • Unsaturated (C16-22)—USFA
at 10–12 g per day while at least 25 g/day or 12–15 g/ –– USFA may be:
1000 kcal is considered desirable for maintenance of ǃǃ Monounsaturated (MUFA)
good health. ǃǃ Polyunsaturated (PUFA)
 Nutrition Management of Diabetes Mellitus 473

Table 30.5: Fatty acid composition of commonly used edible oils and fats (Values are percentage of total methyl ester of fatty acid)
S No. Oil/Fats Total SFA Total MUFA Linoleic 18:2 (n-6) Alfa-linolenic 18:3 (n–3) Total PUFA
1. Coconut oil 89.5* 7.8 2.0 — 2.0
2. Corn oil 12.7 29.6 57.4 — 57.4
3. Cotton seed oil 25.9 22.9 50.9 — 50.9
4. Groundnut oil 20.9 49.3 29.9 — 29.9
5. Mustard or rapeseed oil 10.7 56.0 †
18.1 14.5 32.6

chapter
6. Olive oil 14.8 74.5 10.0 — 10.0

30
7. Palm oil 46.3 43.7 10.0 — 10.0
8. Palmolein 47.7 41.4 10.3 0.3 10.6
9. Rice bran oil 22.1 41.0 34.3 1.4 35.7
10. Safflower oil 10.7 16.7 73.5 — 73.5
11. Gingelly oil 13.7 41.3 44.5 — 44.5
12. Soybean oil§ 13.1 28.9 50.7 6.5 57.2
13. Sunflower oil 9.1 25.1 66.2 — 66.2
14. Butter 69.4* 28.0 2.5 — 2.5
15. Lard 46.2* 45.2 11.0 — 11.0
16. Tallow 54.9* 40.9 4.2 — 4.2
17. Canola oil 6 62 22 10 32
*
Includes lower chain fatty acid
†
Includes 46.5% of erucic acid (22:1)
§
Most suitable as cooking oils.
(SFA: Saturated fats; MUFA: Monounsaturated fats; PUFA: Polyunsaturated fats).

• Trans fatty acids (TFA): These are formed when vege­ Coconut—SFA, Walnuts n-3 PUFA
table oils are partially hydrogenated. TFA are also MUFA is the best fatty acid for diabetics, as it not
formed when the best of oils are reused for more than only keeps blood lipids under check, but also improves
6 hours at 180°C. glycemic control by replacing CHO. It is considered a good
Polyunsaturated fatty acid includes essential fatty replacement for CHO.
acids, i.e. linoleic acid (LNA), a-linolenic acid (ALNA),
arachidonic acid (20.4) (AA), eicosapentaenoic acid
(EPA) and decosa hexaenoic acid (DHA) which are basic
Visible Fats
components of cell membrane. Dietary PUFA may be of Fats (solidify in cool temperature): Lard, butter, ghee,
two types: hydrogenated vegetable oils (vanaspati) coconut and
• Omega 3 (n-3) with first double bond at the 3rd carbon palmoline oils rich in SFA. Hydrogenated oils, vanaspati
atom and margarine—contain TFA, all these increase LDL
• Omega 6 (n-6) with first double bond at the 6th carbon
cholesterol.
atoms.
Oils (liquid)
Sources of Dietary Fat (Invisible)
Animal sources • Peanut, sesame, olive, canola oils are rich in MUFA
• Sunflower, safflower corn oils—n-6 PUFA
• Milk and meat fats provide SFA • Mustard, rapeseed, canola—MUFA, n-6 and n-3 PUFA
• Egg yolk, lean meat, chicken—both SFA and USFA Proportion and types of USFA in common sources of
• Fish is the main source of n-3 PUFA (EPA and DHA). dietary fats are listed in Table 30.5.

Plant sources Fats in Nutrition Therapy

Cereals, pulses, millets (low), nuts and seeds. Mainly The total amount of fat in daily diet of diabetic subjects
MUFA and n-6 PUFA. has not been specified by the ADA, but the proportion
474 Management

is set to be between 25% and 35% of total calories. In and DHA) in the cell membrane exert useful anti-inflam­
general, energy from fat should be limited to 30% of matory effect in contrast to proinflammatory cytokines
the total. Out of this saturated fat, calories has to be generated from n-6 arachidonic acid.18
restricted to below 10% (7% for persons with adverse At least 2–4 g of n-3 fatty acids providing 1–2% of total
history or excess cholesterol) while PUFA can be given calories is recommended in the daily diet. Fish, mustard,
maximum up to 10% although 7% may be a better option. canola oil (10%), soybean oil (7%), flax seeds, walnuts and
Within the PUFA fraction the ratio of n-6 to n-3 ought certain spices are good sources of n-3 FA.
section

not to go below 4–5:1. The balance of 12–16% can be

profitably assigned to MUFA which is safe even at higher Trans Fatty Acids
8

proportion. Food items offering trans fatty acids are by

Formed from hydrogeneration of USFA in vegetable
and large interdicted.
oils, trans fatty acids, as in case of SFA, on consumption
The major concerns in defining the fat component
results in increase in serum total cholesterol, LDL chole­
of diet are maintenance of desirable BW and leveling of
sterol and triglycerides while there is decline in HDL
serum lipids primarily total and LDL cholesterol. While
cholesterol levels. Higher intake of TFA is associated
the role of restriction of fat compared to that of the total
with elevated risk of CHD as well as adverse effects on
calories is uncertain, substitution of SFA by MUFA and
glucose metabolism with high-risk for development of
PUFA has been convincingly shown to reduce cholesterol
type 2 diabetes.19 The major sources of trans fatty acids
levels.
are vanaspati (vegetable ghee), margarine, commercially
The greater concern for fat intake in control of BW is
available baked products (biscuits, pastries) deep fried
because it is most calorie dense, generating above 9 kcal/g
fast food, chips and similar snacks.
compared to 4 kcal in the other categories. Further, fat
lends palatability to food and hence fatty foods are more
Cholesterol
attractive. For limiting calories in diet, care has to be taken
to select low fat foods as well as limit the use of cooking fat. Dietary cholesterol has only a minor effect on serum
Use of low fat toned milk or low-fat butter milk, amounting lipid levels in general except in case of high SFA in diet.
to around 400 mL in non-vegetarians and 650 mL for But the general dictum of limiting daily cholesterol to 300
vegetarians appears appropriate. Avoidance of red meat mg/day (200 mg in case of dyslipidemia/CHD) is more
(beef, mutton, pork) and substitution of the same by appropriate for diabetic subjects. In diabetic subjects,
chicken (skin removed), turkey and fish needs emphasis. cholesterol transport is distorted because of lower plasma
In view of the usual (20–25 g) content of invisible levels of apo E and raised levels of apo C. Unrestricted
fat in usual dietary ingredients cooking oil is better limited consumption of eggs, a rich source of dietary cholesterol,
to 20–30 mL per day for adults. Appropriate low fat items has been documented to be associated with increased risk
are to be selected when eating out. of CHD among persons with diabetes but not so in general
population. In diabetic men and women taking one egg
Omega 3 (n-3) Fatty Acids (cholesterol, 250 mg) per day, the relative risk of CHD is
1.86 and 1.99 respectively.20 Cholesterol is available in
Keen interest on n-3 fatty acids LNA, EPA, DHA has been food products of animal origin, not so in plant products.
evinced since high intake of fish and marine products Instead, plant oil contain stanol esters which were been
were found to greatly reduce the incidence of CHD found to have the beneficial effect on serum cholesterol.
and diabetes in Eskimos and Netherlanders taking fish
around 3 times per week. Further observation have
Recommendation on Choice of Fat in Diet
confirmed the usefulness of dietary n-3 FA or fish oil
capsules to lower incidence of myocardial infarction As per general consensus, dietary fats are to provide
and ischemic stroke. Initially used high doses of fish oil between 25% and 30% of total calories. Any further lower­
(9–12 g/d) was associated with hyperglycemia. More ing would lead to increase the proportion of CHO in diet
recently convincing evidence from meta-analysis of beyond acceptable limits.
around 50 studies reveal no such adverse effect with use For vegetarians, raising the milk quota is not without
of fish oil supplements in moderate doses of 3–6 g/d. On risk. In addition to some innocuous short chain fatty acids
the other hand, there is a decrease in levels of triglycerides milk fat contains high proportions of highly atherogenic
while HDL remains unaffected. In addition, n-3 FA (EPA fats. Hence, the need for consumption of low fat milk.
 Nutrition Management of Diabetes Mellitus 475

Coconut oils and palm oils are both rich sources of Other sources of ALNA (n-3) are:
SFA. Yet the former is more atherogenic. • Wheat, bajra, black gram, lobia, rajmah, soy
A larger proportion of MUFA is preferred.21 The predo­ • Green leafy vegetables
minantly n-6 PUFA containing sunflower and safflowers • Fenugreek, mustard
oils are not to be preferred as cooking media. Further, • Oils—mustard, soybean
these as well as peanut, sesame and cotton seed oils are • Source of EPA and DHA (n-3)—Fish (fat).
devoid of any n-3 fatty acids. High n-6 sources includes safflower, sunflower, corn

chapter
Both olive and mustard/canola oils are rich in MUFA and cottonseed (55–70%) oils. Excess of these oils are

30
(73 and 64%). Mustard oil has the added advantage of likely to upset n-6: n-3 proportions and retard conversion
having 10% of n-3 PUFA. Soybean oil has adequate n-6 and of LNA (LNA to EPA and DHA).
around 7% of n-3 PUFA. Therefore, mustard and soybean
oils in combination should be the most preferred choice Micronutrients
for use as cooking fats. Addition of fish in non-vegetarians
and fish oil capsules for vegetarians would then fulfill the The vitamin and mineral needs of patients with diabetes,
n-3 requirements. The proportion of n-6 to n-3 FA is best who are healthy, appear to be adequately met by RDAs.
kept at 4–5: 1 as contained in breast milk. Furthermore, a patient’s response to vitamin and mineral
Saturated fatty acid content of meat fat (46%) is double supplement is largely determined by nutritional state, so
that in fish oils while it is intermediate in chicken (35%), only patients with micronutrient deficiencies respond
hence the preference for fish. Further, as fish is practically favorably. People who are at greatest risk of micronutrient
only dietary source of EPA and DHA (except mother’s deficiency and who may require evaluation for vitamin/
milk) in common human diet at least 2–3 servings of fish mineral supplements include those on extreme weight
per week should be strongly recommended. reducing diets, strict vegetarians, the elderly, pregnant
In cases, where elevated LDL cholesterol is the and lactating women, those taking medications known to
primary problem lowering the SFA content in diet to alter micronutrient metabolism, patients in poor meta­
below 7%, cholesterol to below 200 mg/day and other bolic control (e.g. with glycosuria) patients with a malab­
such recommendation of Adult Treatment Panel III (2001) sorption disorder or in a critical care environment, and
have to be strictly followed. On the other hand, where patients with a congestive heart failure or myocardial
elevated triglycerides and low HDL cholesterol persists infarction. There is no clear evidence of benefits from
after adequate glycemic control strict avoidance of sugars vitamins or mineral supplementation in people with dia­
and low amylose starch in diet as well as alcoholic drinks betes who do not have underlying deficiencies. Exception
are needed. Use of additional amount of MUFA in diet includes folate for prevention of birth defects and calcium
to replace some CHO calories may be helpful. Instead for prevention of bone disorders. Magnesium depletion
desired results may be achieved by choice of fiber rich has been associated with insulin insensitivity, which may
sources of CHO ingredients such as whole grain cereal, improve with oral supplementation. Magnesium should
legumes, beans and fresh fruits (rich in pectin) in place of be replaced only if hypomagnesemia is demonstrated.
high GI, low fiber items in diet. Routine supplementation of diet with antioxidants is
Indian diets provide 20 g of invisible fat. To provide not advised because of uncertainties related to long-term
20 g of visible fat (cooking oil)—the first option should efficacy and safety when administered in this form.
include oils rich in MUFA and those that provide some n-3
FA. Hence, the first choice is to include mustard oil and Miscellaneous
soy oil, in proportion of 2:1, the next option is to include,
rice bran oil, sesame oil or peanut oil along with mustard
Alcohol22
oil. If diabetes is well-controlled, moderate use of alcohol is
The fatty acid composition of some important edible unlikely to have adverse effect on blood glucose. However,
oils and fats is given in Table 30.5. it is important to verify this through blood glucose moni­
High in MUFA includes olive oil (76%), mustard (64%), toring. Patients who take insulin should limit their intake
canola (61%), rapeseed (53%), til (42%) and rice bran to not more than two drinks per day (one drink equals
(41%). High n-3 sources includes mustard (10%), rapeseed 360 mL beer, 150 mL wine, or 45 mL distilled alcohol).
(10%) and soybean (7%). In the fasting state alcohol may produce hypoglycemia.
476 Management

Table 30.6: Composition of common alcoholic beverages

Alcoholic drinks Measure Grams of alcohol Calories (ranges) Average calories
Whisky (Irish, Rye, 1 peg (1 oz, 30 mL) 10.5 – 12 75 – 85 80
Scotch) or Feni
Brandy, Gin, Rum 1 brandy peg (1 oz, 30 10.5 – 13 70 – 90 80
mL)
Liqueurs and Cordials 1 cordial (2/3 oz, 20 mL) 4–7 50 – 80 60
section

Ale, Beer, Porter, Stout 1 glass (250 mL) 7 – 14 80 – 150 120

8

Sweet wine 1 wine glass (100 mL) 13 – 15 140 – 165 150

Dry wine 1 wine glass (100 mL) 10 – 11 75 – 90 80
Vodka 1 peg (30 mL) 16 – 18 100 – 120 110
Source: Chandalia HB, Modi SV (EDs). Conquest of Diabetes: By Diet and Exercise. Diabetes Endocrine Nutrition Management and Research
Society, Grant Medical College; 1987.

This is because alcohol cannot be converted to glucose, to less than 3 g/day. In hypertensive patients or edematous
inhibits gluconeogenesis, and augments or increases the patients with nephropathy, sodium restriction is required
effect of insulin by interfering with the counter regulation and sodium intake should not exceed 2 g/day.23
of insulin-induced hypoglycemia.
Alcohol is metabolized in a manner similar to fat. Even Sweeteners
though extra calories are consumed, total food intake Nutritive Sweeteners24
should not be reduced. When calorie intake is being
restricted, as in individuals trying to reduce their BW, Nutritive sweeteners include fructose, honey, corn syrup,
alcohol may be substituted for fat (one drink equals two molasses, fruit juice or fruit juice concentrates, dextrose,
fat exchanges, or about 100 kcal that would have been maltose, mannitol, sorbitol, xylitol, hydrogenated starch
consumed as fat). hydrolysates as well as sucrose. Research has shown no
Composition of common alcoholic beverages is given significant advantage or disadvantage of any of these
in Table 30.6. nutritive sweeteners over sucrose.
Here are some guidelines for alcohol use: Fructose, which occurs naturally in fruits, vegetables
For insulin users and honey, provides 4 kcal/g, as do other CHO, but causes
• Limit two small drinks per day a smaller rise in plasma glucose than do sucrose and other
starches. For this reason, it has been a popular sweetener
• Drink only with food
in meal plans for people with diabetes. However, there is
• Do not cut back on food except fat in case of the obese.
no reason to recommend people to avoid consumption of
For non-insulin users
fruits and vegetables, in which fructose occurs naturally,
• Substitute for fat calories
or moderate consumption of fructose-sweetened foods.
• Limit to promote weight loss or maintenance
Sorbitol, mannitol and xylitol are common sugar
• Limit if triglycerides are elevated.
alcohols (polyols) that cause a lower glycemic response
than do sucrose and other CHO. They are used as binding
Sodium22 agents and sweeteners in food. Their energy value is
There is an association between hypertension and both 2–3 kcal/g. The main disadvantage of their use is osmotic
type 1 and type 2 diabetes, especially for people who diarrhea if consumed in large amounts. Polyols do not
are obese. There is also evidence that people with type 2 appear to have significant advantage over other nutritive
diabetes are more salt-sensitive than the general popu­- sweeteners. When 30 g sorbitol (the amount in 10 pieces
l­ation. of small hard candy) or more is ingested in a single dose,
Sodium intake recommendations for people with the result may be abdominal gas, discomfort, and osmotic
diabetes are the same as for the general population: diarrhea, depending on the individual’s gastrointestinal
Salt should be less than 5 g/day.11 For person with sensitivity. An individual’s tolerance level may be as low
hypertension and diabetes, the intake should be reduced as 10 g.
 Nutrition Management of Diabetes Mellitus 477

Non-nutritive Sweeteners24 disease and its beneficial effects are also seen in people
with type 2 diabetes.
Aspartame, acesulfame K, sucralose and saccharin are
currently approved for use. Each of these products under­ Traditional Indian Foods in Diabetes Mellitus
went rigorous testing by the manufacturer and scrutiny
from the FDA before it was approved for consumption. All Several studies have shown that barley, buck wheat,
can be used safely by people with diabetes. legumes, peanuts, soybean and certain herbs, and spices,
like onions, garlic, ginger, fenugreek seeds, cinnamon, taiz

chapter
The average intake of all the non-nutritive sweeteners
is much less than the acceptable daily intake (ADI), which patta, lemon, curry leaves, tulsi, pepper and vinegar have

30
is determined by the FDA. The ADI represents the amount hypoglycemic activity.
of a food additive that even if consumed on a daily basis
throughout an individual’s lifetime, is still considered safe MEAL PLANNING
by a 100-fold safety margin. It is not a toxic threshold, and
Considerations for meal planning include:
even if an individual occasionally ingested a substance
• A practical meal depending on one’s socio-economic
in amounts greater than the ADI, it would not pose a
status, cultural pattern, eating habits
health risk. For example, aspartame consumption (14-day
• Calorie needs
average) in a person with diabetes is 2–4 mg/kg BW per
day—well below the ADI of 50 mg/kg BW. • Type of treatment, diet alone, with oral drugs or insulin.
The meal plan must provide a balanced meal in terms
Additional NUTRITIONAL Considerations of all essential constituents of foods including vitamins
and mineral, and for this it is essential to follow “Food
TO REDUCE CARDIAC RISK
Groups” pattern.
Fish and Omega 3 Fatty Acids
Diabetics should be encouraged to include oily fish in the Food Groups
diet, ideally 2–3 times a week. Fish oils are increasingly • Cereal and cereal products
available in capsule or liquid form. These should provide • Milk and milk products
approximately 0.5–1.0 g of n-3 fatty acids per day. Vege­ • Meat and meat products
tarians, or those allergic to fish, can optimize their n-3 • Pulses and legumes
intakes by using vegetable n-3 sources (rapeseed, canola, • Green leafy and other vegetables
linseed and flax oils), but the conversion rate to EPA and • Fruits
DHA is low and other polyunsaturates (n-6) can compete • Fats and oils.
when in excess.
All the above given food groups have an essential role
to play in a balanced meal. To make the diet more flexible
Stanols and Sterols25
each food group is divided into “exchanges” to form an
Inhibit the absorption of cholesterol and reduces LDL “Exchange List” (Table 30.7). The exchanges from each
cholesterol. Plant sterols occur naturally in vegetables oils group are distributed into different meals depending upon
such as soybean and rapeseed oil. Manufactured products the calorie level of the diet. Example of a 1700 calorie diet
containing these products include spreads, cereal bars, is given in Table 30.7.
cheeses, milk, ice-cream and yogurt. The optimal dose It is preferable to distribute the daily ratio of calories
appears to be 1.6–2.0 g/day which equates to ~20 g spread. into three major meals: Breakfast, lunch, dinner and
For these products to be effective, the recommended three snacks mid morning, teatime and bedtime. The
intake should be consumed daily. This results in a
recommended calorie break-up for Indian situations of
9–14% decrease in LDL-cholesterol. Patients should be
practice may be:
encouraged to eat foods containing stanols and/or sterols
Breakfast—350 kcal
daily to reduce LDL-cholesterol.
Mid morning snack—100 kcal
Lunch—550 kcal
Soy Protein, Flavonoids and Phytoestrogens Teatime—200 kcal
About 25 g of soy protein a day, as part of a diet low in Dinner—400 kcal
saturated fat and cholesterol may reduce the risk of heart Bedtime—150 kcal
478 Management

Table 30.7: Exchange list of measured food ingredients

• Cereal exchange • Fruit exchange
Carbohydrates 15 g Carbohydrates 10 g
Proteins 2g Calories 40 g
  Calorie 70
Chapatti (20 g atta, 30 g chapatti) Pear 90 g,1 medium
Cooked rice 75 g (3 tsp) Apple 90 g,1/2 medium
Idli 1 medium Banana 40 g,1/2 small
section

Bread (30 g)—1 large slice Mango 60 g,1/2 small

8

(4² × 3.1/2² × 0.4²)

Cornflakes (20 g) (3 tsp) Ber 70 g, 5–6 medium
Porridge (cooked) 120 g—¾ cup Watermelon 300 g, 1 large slice
Biscuits 2–3 Papaya 120 g, 1 medium slice
• Milk exchange Grapes 55 g, 10 medium
Carbohydrates 12 g Guava 100 g, 1 medium
Proteins 8g Loquat 100 g, 4–5 Nos.
Fats 7g Tomato 1 glass juice (240 mL)
Calories 145 Dry fruit 5 g, 5–6 medium
   Dates dry 12 g, 4–5 Nos.
Milk (120 mL)
Curds 1 glass (3% fat, DMS) 240 g 2 bowls 30 g 2² × 3² × 1² cube • Vegetable exchange
Butter milk 750 mL—3 glasses Group A
Skimmed milk powder 45 g (3 tsp) Carbohydrates 3g
• Legume exchange Proteins 2g
Carbohydrates 15 g Calories 20 kcal
Proteins 5g Cabbage, Spinach, 100 g
Calories 80 kcal Cauliflower, Mustard
Moong greens, Brinjal,
25 g (raw wt)
Capsicum, Lauki, torai
Urad 25 g
Group B
Arhar 25 g2
Carbohydrates 6g
Rajmah 25 g2 Proteins 2g
Lobia 25 g2 Calories 32 kcal
Bengal gram 25 g2 Peas, Beans, Carrot, 100 g
Nutrinuggets 25 g2 Pumpkin, Bhindi, Onions,
• Meat exchange Radish, Roots and Tubers
Proteins 7g Carbohydrates 5g
Fat 5g Calories 20 kcal
Calories Potato, Sweet potato, 25 g
70 kcal
Colocasia, Beet root, Yam
Egg 40 g (one)
Mutton 30 g • Fat/oil exchange
Chicken 30 g Fats 5g
Fish Calories 45
30 g
Sunflower, Soya, Peanut, 5 g (1 tsp)
Pork 30 g
Mustard, Corn, Til oil
Sausage 20 g (2 cocktail links)
Vanaspati 5 g (1 tsp)
Ham 20 g Cream (Med) 10 g (2 tsp)
Cheese 20 g Butter 7 g (1 tsp)
Cottage cheese 30 g

(tsp: Tea spoon)

 Nutrition Management of Diabetes Mellitus 479

Table 30.8: Description of 1,700 calories vegetarian diet

Food groups Breakfast Midmorning Lunch Evening tea Dinner Bed-time snack
Cereals (No. of exchanges) 2 1 3 1 3 1
Milk low fat 1 1/2 1/2 1/2 1
Legumes (No. of exchanges) — — 1 — 1 —
Fruit (No. of exchanges) — — 1 — 1 —

chapter
Oil (No. of exchanges) — — 2 — 1 —

30
Veg. B (No. of exchanges) — — 1 — — —
Veg. A (No. of exchanges) — — — — 1 —
Carbohydrates = 275 (65%); Proteins = 69 (16.2%); Fats = 35 (18.5%); Calories = 1700

Table 30.9: Dietary Guidelines for healthy living and prevention of obesity, the metabolic syndrome, diabetes and related disorders in Asian
Indians26
Nutrients Recommendations
Energy Method of calculation of energy need has been provided
Carbohydrates 50–60% of total energy
Proteins 10–15% of total energy
Total fats Less than 30% of total energy
Saturated fatty acids Less than 10%
Trans fatty acids Less than 1%
Fats Essential poly-unsaturated acids (PUFAs) PUFA should be 5–8% of total energy
Alpha linolenic acid (ALA) 1–2% of total energy
Mono-unsaturated fatty acids (MUFAs) 10–15% of total energy
Linoleic: a Linolenic acid 5:1
Salt Less than 5 g per day
Sugar Less than 10% of total energy
Artificial sweeteners Moderate use, FDA approved sweeteners
Water 1.5–2 liters/8–10 glasses per day
Alcohol Intake of small quantity should not be discouraged

A total of 1,750 kcal/day for a 60 kg standard weight ground wheat (Dalia), whole wheat flour along with Bengal
patient with modest physical activities. Broadly, gram flour (Besan) (Chhatu). White bread, cornflakes,
CHO to provide 1,000 kcal (55–60%); fat 450–500 kcal refined breakfast cereals and cookies are to be avoided in
(25–30%) and protein up to 250–300 kcal (10–15%). general.
Among CHO ingredient high preference is to be given One egg per day thrice a week and a cup of toned
for whole grain preparations of wheat, parboiled rice, milk on rest of the days may be provided, if calorie count
with liberal provision of pulses (legumes) fruits and permits.
vegetables. The fat provision is to constitute of mustard oil, Dietary Guidelines for healthy living and prevention
soybean oil, fish or fish oil and nuts (except for the of obesity, the metabolic syndrome, diabetes and related
overweight). For vegetarians, protein supply has to be met disorders in Asian Indians (Table 30.9).26
by increasing the quantity of milk and milk products and
providing more legumes and beans—including soybean.
Further Reading
Notes on Meal Planning in the Indian Context
1. Chandalia HB, Modi SV (Eds). Conquest of Diabetes: By
It may be preferable to plan breakfast with ingredients Diet and Exercise. Diabetes Endocrine Nutrition Manage­
principally of pulses (legumes), porridge of oat meal or ment and Research Society, Grant Medical College; 1987.
480 Management

2. Medical nutrition t\therapy for diabetes mellitus and 12. Brand-Miller JC, Hayne S, Petocz P, et al. Low-glyce­
hypoglycemia on non-diabetic origin. In: L Kathleen mic index diet in the management of diabetes: a meta
Mahan, Sylvia Escott-Stump (Eds). Krause’s Food & Nutri­ analysis of randomized control trials. Diabetes Care. 2003;
tion Therapy, 12th edition. WB Saunders Copmany; 1996. 26:2261-7.
3. Dietary Guidelines for Indians. National Institute of Nutri­ 13. Buyken AE, Toeller M, Heitkamp G, et al. Glycemic index
tion. 1998. in the diet of European Out Patients with type 1 diabetes:
4. Gopalan C, Rama Sastri BV, Balsubramanian SC. Nutritive relation to glycated hemoglobin and serum lipids. AmJ Clin
Value of Indian Foods. NIN 2004. Nutr. 2001;73:514-81.
section

14. Gilbertson HR, Brand-Miller JC, Thorburm AW, et al.

The effect of flexible low glycemic index dietary advice
8

REFERENCES versus measured carbohydrate exchange diets on glyce­

mic control in children with type 1 diabetes. Diabetes Care.
1. Misra, P Chowbey, BM Makkar, et al. FEBRUARY 2009
2001;24:1137-43.
Consensus Statement for Diagnosis of Obesity, Abdomi­
15. Trowell H, Southgate DA, Wolever TM, et al. Letter: Dietary
nal Obesity and the Metabolic Syndrome for Asian Indians
fiber redefined. Lancet. 1976;1:967.
and Recommendations for Physical Activity, Medical and
16. Anderson JW, Smith BM, Gustafson NJ. Health benefits
Surgical Management. JAPI. Vol. 57.
and practical aspects of high-fibre diet. Am J Clin Nutr.
2. American Diabetes Association. Nutrition principles and
1999;59:1242S-7S.
recommendation in diabetes. Diabetes Care. 2004;27:
17. Chandalia M, Garg A, Lutjohann D, et al. Beneficial effects
S36-46.
3. Frost G, Dornhorst A, Moses R (Eds). Nutritional Manage­ of high dietary fiber intakes in patients with type 2 diabetes
ment of Diabetes Mellitus, illustrated edition. John Wiley mellitus. N Engl J Med. 2000;342:1392-8.
and Sons Ltd; 2003. 18. Friedberg CE, Janssen MJ, Heine RJ, et al. Fish oil and gly­
4. American Diabetes Association. Standards of Medical care cemic control in diabetes. A meta-analysis. Diabetes Care.
in Diabetes. Diabetes Care. 2007;30:s4-s41 1998;21:494-500.
5. Jenkins DJ, Wolever TM, Jenkins AL, et al. The glycemic 19. Christiansen E, Schnider S, Palmvig B, et al. Intake of a diet
index of foods tested in diabetic patients: a new basis of car­ high in trans monounsaturated fatty acids or saturated
bohydrate exchange favouring the use of legumes. Diabeto­ fatty acids. Effects on postprandial insulinemia and glyce­
logia. 1983;24:257-64. mia in obese patients with NIDDM. Diabetes Care. 1997;
6. Foster-Powell K, Holt SHA, Brand Miller JC. International 20:881-7.
table of glycemic index and glycemic load values. Am J Clin 20. Hu FB, Stampfer MJ, Rimm EB, et al. A prospective study
Nutr. 2002;76:5-56. of egg consumption and risk of cardiovascular disease in
7. Bornet FR, Costagliola D, Rizkalla SW, et al. Insulinemic women. JAMA. 1999;281:1387-94.
and glycemic indexes of six starch-rich foods taken alone 21. Garg A. High-monounsaturated fat diets for patients
and in a mixed meal by type 2 diabetics. AM J Clin Nutr. with diabetes mellitus: a meta-analysis. Am J Clin Nutr.
1987;45:588-95. 1998;67:577S-82S.
8. American Diabetes Association. Evidence-based nutrition 22. Beilin LJ. Alcohol, hypertension and cardiovascular disease.
principles and recommendation for the treatment and pre­ J Hypertens. 1995;13:939-42.
vention of diabetes and related complications. Diabetes 23. Law MR, Frost CD, Wald NJ. By how much does dietary salt
care. 2002;25:202-12. reduction lower blood pressure? I–Analysis of observation­
9. Salmeron J, Manson JE, Stampfer MJ, et al. Dietary fibre al data among populations. BMJ. 1991;302:811-24.
glycemic load, and risk of non-insulin-dependent diabetes 24. Powers MA. Handbook of Diabetes Medical Nutrition
mellitus in women. JAMA. 1997;277:472-7. Therapy, 2nd edition. Gaithersburg Maryland: An Aspen
10. Recommendations for the nutritional management of Publications; 1996.
patients with diabetes mellitus. Eur J Clin Nutr. 2000; 25. Law M. Plant sterol and stanol margarines and health.
54:353-5. BMJ. 2002;320:861-4.
11. Sheard NF, Clark NG, Brand-Miller JC, et al. Dietary carbo­ 26. Misra A, Sharma R, Gulati S, et al. Consensus dietary guide­
hydrate (amount and type) in the prevention and manage­ lines for healthy living and prevention of obesity, the meta­
ment of diabetes: a statement by the American Diabetes bolic syndrome, diabetes and related disorders in Asian
Association. Diabetes Care. 2004;27:2266-71. Indians. Diabetes Technol Ther. 2011;13:683-94.
 Chapter 31
Nutrition Management in
Special Situations
Sonal V Modi

Nutrition in Special Situations

Chapter Outline
♦♦ Nutrition Management in Undernutrition and Obesity ♦♦ Nutrition Management in Various Life Situations
♦♦ Nutrition Management Through Journey of Life ♦♦ Nutrition Management in Complications of Diabetes
♦♦ Nutrition Management in Various Treatment Modalities ♦♦ Food Labeling and Interpretation

NUTRITION MANAGEMENT IN Das studied the dietary habits of a cohort of 146 newly
UNDERNUTRITION AND OBESITY diagnosed lean type 2 diabetics.2 Their anthropometric,
biochemical and dietary measurements were done at the
Undernutrition baseline and dietary intervention was done with changes
in caloric intake according to their BMI and physical
Type 2 diabetes mellitus (T2DM) is a heterogeneous dis­
activity. A follow-up after 1 year revealed that the low body
ease. Type 2 diabetes starts a decade earlier in Indians
weight subjects required a hypercaloric diet (i.e. augmen­
than their counterparts in the developed countries. There
tation by 500 kcal/day), with the usual propor­ tion of
exists a subset of type 2 diabetic patients who are charac­
carbohydrate, protein and fat intake. The normal body
teristically lean and undernourished with a body mass
weight subjects required a reduction in the intake of
index (BMI) of less than 18 kg/m2. They are different from
carbohydrate but an increase in the amount of fat intake
the individuals who lose weight at the onset of diabetes. was required in order to maintain the total calories. The
Attention to this specific type of underweight type 2 dia­ overweight group required a hypocaloric diet (reduc­
betes was first drawn by Tripathy and Kar in 1965 when tion of 900 kcal) with the usual proportion of carbo­
they reported that 28% of their patient population were hydrate, protein and fat intake. On calculation of the
underweight.1 actual caloric intake of low body weight subjects, it
Lean diabetics are characterized by a different was found to be only 4.5% less than recommended
chemical, biochemical, hormonal and longevity profile. It allowances. Their protein and carbohydrate intake was
was observed that risk factors for atherosclerosis were appropriate but average fat intake was less by 9.6 gm/day.
less prevalent as compared to well-nourished indivi­ The biochemical parameters of fasting blood glucose
duals, whereas peripheral neuropathy and infection were (FBG) and postprandial blood glucose (PPBG) improved
increased in this group. Also, their β-cell reserve was with treatment in all three groups. However, the low
preserved and there was a low prevalence of islet cell body weight group still showed the highest mean values
antibodies and other immunological markers of auto­ for both. This indicated that in this group, carbohydrate
im­mune β-cell damage. They have a hyperactive hepatic metabolism was impaired to a greater extent. Hence,
function with brisk futile cycles in carbohydrate and better treatment strategies are required in low body weight
homocysteine metabolism. diabetics.
482 Management

Low body weight can also be due to pancreatic dia­ most type 2 diabetics can easily lose 5–10% of their body
betes, often associated with exocrine pancreatic defici­ weight if provided appropriate guidance.5
ency. Besides administration of pancreatic enzymes, these
patients do well on a relatively low fat diet (15–20% of total Medical Nutrition Therapy for
calories). This fat can be in the form of coconut oil, which Weight Reduction
provides medium chain triglycerides (MCTs). MCTs can
be absorbed in the form of fatty acids without the help of The target in any weight reduction program would initially
section

pancreatic lipase. be a 10% loss of body weight. A desirable rate of weight loss
by caloric restriction is 2 kg/month. This can be achieved
8

Severe peripheral neuropathy, associated with unbe­

arable tingling, numbness and burning of feet is seen only by a reduction of approximately 500 kcal/day from the
in undernourished diabetics. It requires a hypercaloric current total caloric intake. This amounts to about a 20%
diet besides meticulous control of diabetes, preferably reduction from the average daily energy intake.
with insulin. Undernutrition will also be seen in diabetics Usually an overall restriction in calories is advised by
with tuberculosis. A nutritious diet is indicated but over­ reducing dietary fat and direct sugar intake. The earlier
nutrition should be avoided. Modern antitubercular drugs concept of “ideal body weight (IBW)” is now superseded by
are highly efficacious in controling tuberculosis; hence, the concept of “desirable body weight (DBW)”. Desirable
it is not necessary to promote excessive weight gain while body weight is the lowest stable weight of the individual
treating tuberculosis. in young adulthood which was maintained for a period of
2 years or more.
Obesity
The link between diabetes and obesity has been recognized Low Calorie Diet
for decades. This close association between obesity and A low calorie diet (LCD) is traditionally a diet of
type 2 diabetes is seen in all ethnic groups, in both sexes 1,200 kcal/day or lower. This works more efficiently on
and all ages. An obese diabetic may show more insulin a long-term basis. Weight loss may be slower than that
resistance and impaired glucose metabolism due to the achieved by very low calorie diet (VLCD), but a LCD is more
excessive body fat. Heritability of obesity is also a complex likely to induce healthier eating habits, hence improved
situation, similar to the heritability of type 2 diabetes. weight maintenance and adherence. Ad-libitum low-fat
Both diseases are polygenic and in fact, it is possible that diets reduce the caloric density of the diet yet maintain
they share some susceptibility genes. An excessive caloric satiety by their high content of complex carbohydrate and
intake in the form of a high fat, low fiber diet and sedentary protein.
lifestyle are among the most important environmental An interesting study was conducted on the effect
factors which produce obesity in individuals with genetic of different hypocaloric diets on the hormones and
susceptibility.3 interleukin (IL) secretion from the adipose tissue of obese
Obesity is a common accompaniment of type 2 dia­ women. A 10-week hypocaloric (600 kcal/day) diet with
betes. At the Diabetes Endocrine Nutrition Manage­ment moderate fat and moderate carbohydrate or low fat and
and Research Center (DENMARC), out of a group of high carbohydrate content was prescribed. Effect of these
consecutive 800 type 2 diabetics, 36% were moderately diets on the production of leptin, tumor necrosis factor
obese (BMI > 25) and 16% severely obese (BMI > 30).4 alpha (TNF-α) and IL-6 was compared. Both diets showed
Lifestyle changes with marginal weight loss (5–10%) can similar results with a reduction in body weight by 7.5%.
prevent or delay development of type 2 diabetes in the In both groups, the rate of leptin secretion decreased
high-risk group. Lifestyle modification in diet and physical by approximately 40% and circulating levels of leptin
activity can reduce the risk of diabetes by as much as decreased by 30%. Thus, the caloric restriction and not
40–60%, by curbing obesity. Weight management is the key macronutrient composition appeared to influence the
to good management of type 2 diabetes. Weight loss and production and secretion of leptin.6
long-term weight maintenance improves blood glucose Meals with similar energy densities but rich in one of
(BG) control in type 2 diabetics. It also has a beneficial the macronutrients (protein, fat, carbohydrate) or alcohol
effect on other risk factors of cardiovascular disease were tested in normal healthy subjects.7 Alcohol was
(CVD). Although it is difficult to normalize body weight, noted to stimulate energy expenditure, but suppress
 Nutrition Management in Special Situations 483

fat oxidation and leptin production more than isoener­ Table 31.1: Fat mimetics and fat replacers
getically dense protein or carbohydrate or fat rich meals. Name Source
Very low fat and low-fat diets usually derive between Fat mimetics
10% and 19% of calories from fat. Both are high in carbohy­ • Carbohydrates: non-caloric
drate and moderate in protein. The popular Dean Ornish fat replacers (≤ 2 kcal/gm)
diet and Pritikin diet are well-known examples of such – Cellulose gel Synthetic microcrystal of celulose
diets. Initially, these diets were prescribed for prevention – Cellulose gum Wood pulp

chapter
– Pectin Apple, citrus fruits
and reversal of heart disease, but now the focus has shift­
– Sugar gum Seeds

31
ed toward their use in weight loss programs. These very – Carrageenan Red sea weed
low-fat diets primarily consist of vegetables, fruits, whole – Xanthan gum Microorganism
grains, beans and moderate amounts of egg-white, non- – Bran Wheat, oats, rice
fat dairy and soy products, small amounts of white flour • Carbohydrates: caloric fat
and sugar. Usually, the diet is a part of a multicomponent replacers (4 kcal/gm)
weight loss program which also includes stress reduction – Maltodextrin Potato, tapioca
techniques, exercise and emotional support. – Dextrin Wheat, corn
– Modified foods Potato, tapioca
The Lifestyle Heart Trial conducted by Ornish8 was
– Starch, corn, rice
undertaken for 1 year with a follow-up at 5 years. The fat – Polydextrose Starch polymer
intake was significantly different between two groups at – Oatrim Oats
1 year and 5 years. The control group consumed 28.8% – Corn syrup solids Corn
fat at year 1 and 25% fat at year 5, whereas the experi­ • Proteins: caloric fat replacers
mental group consumed 6.22% fat at year 1 and 8% fat (4 kcal/gm)
at year 5. Weight loss in both these groups was also mark­ – Microarticulated egg-white Egg and milk
and milk protein
edly different. The control group did not show much
– Whey Milk
weight change from their baseline, whereas the experi­
– Zein Maize
mental group lost 10.9 kg in 1 year and maintained a
Fat replacers
5.8 kg weight loss in 5 years. However, there were many • Low calorie fats (5 kcal/gm)
confounding factors in this study, like physical activity, – Caprenin Palm kernel, coconut oil
inaccuracies of the diet diary and a small sample size. – Salatrim Canola, soy
The importance of monounsaturated fatty acids • Fat substitutes (negligible
(MUFA) in diet has undergone extensive scrutiny. MUFA calories)
produce a favorable influence on the lipid profile in type 2 – Olestra Sucrose polyester
– Sorbestrin Sorbitol polyester
diabetes.
– EPG Vegetable oil, glycerol esters
A study compared a high MUFA diet (37–40% fat,
comprising of 20% MUFA, 43–46% carbohydrate) versus a (EPG: Esterified propoxylated glycerol).
high carbohydrate diet (containing 54–57% carbohydrate
and 27–30% fat comprising of 10–13% MUFA) in type 1 Most weight loss strategies usually adopt a reduction
diabetics.9 The subjects on the high MUFA fat diet had a in the dietary fat in a prescribed diet. Efforts are made to
low-density lipoprotein (LDL) cholesterol level 7% lower replace fat with low-calorie or calorie-free fat mimetics
in comparison with low MUFA diet at the end of treatment. or fat replacers. A fat replacer should have the same
This group also displayed a lowering of triglycerides by flavor, mouth-feel, creaminess and palatability as the
18% and of very low-density lipoprotein (VLDL) by 26%. natural fat. Certain carbohydrate and protein foods for
Thus, high MUFA diet produced a favorable effect on the example, dextrin, maltodextrin, egg-white and whey
lipoprotein profile of type 1 diabetics. mimic the properties of fat. They may provide 2–4
Ad-libitum, low carbohydrate and high fat diets calories/gm as compared to 9 calories/gm provided by
achieve short-term weight loss effectively by reducing natural fat. Certain fats serve as low-calorie fats providing
appetite. A low carbohydrate, high protein and low fat diet 5 calories/gm, e.g. caprenin, salatrim. Other fats which
may be more effective in the short-term. There is a concern may provide negligible calories are called fat-substitutes,
over low carbohydrate diets inducing an unbalanced e.g. olestra, sorbestrin.10 All these fat replacers may permit
metabolism of fat (ketosis) and calcium losses from an obese diabetic to continue to enjoy the taste of fat with
the bones. a reduction in caloric intake (Table 31.1).
484 Management

The role of sugar consumption in the etiology of obesity management of obesity. A study was conducted on
is not very well-established and no direct correlation is seden­tary, overweight women put on a 1,500 kcal diet.
seen. However, non-nutritive sweeteners play a crucial Qualitatively, one diet was high carbohydrate (71%) and
role in weight management strategies. It is a Herculean another was high fat (32%). The weight loss achieved
task to cut down 500 calories while prescribing a weight was approximately 8.6 kg, being a 10% reduction in body
reduction diet. An omission of direct sugar from the diet weight. Weight loss in both groups was not significantly
by replacing it with an artificial sweetener reduces about different.14 Heilbronn et al.15 studied type 2 obese patients
section

100 calories, which is one-fourth the battle won. If this on three isocaloric diets for 12 weeks. One diet was high
is done daily for about 2 months, weight loss of approxi­ carbohydrate (72%), very low fat; second one was high
8

mately 1 kg is achieved. It further helps in improving monounsaturated fat (32%), low carbohydrate; third being
the adherence to the diet program. Hence, the artificial high saturated fat (32%), low carbohydrate. The subjects
sweeteners play a very important role in obesity as well as lost an average of 6.6 kg on all three diets.
diabetes. In case diabetes is associated with obesity, it is
The Atkins diet, a low carbohydrate, high protein, important to prescribe a low glycemic index diet. A few
high fat diet seems to work well for achieving weight loss. very interesting new approaches have been described for
Newer studies have shown that those on Atkins-type diet this purpose.16 For example, it is possible to add fructose
lost more weight than those on a traditional diet for the rich fruits instead of polysaccharides or starches with
first 6 months. Long-term implications of this diet have considerable blunting of PPBG peak. Increasing the
not yet been firmly researched and established. The side proteins to 30% of total calories also blunts the prandial
effects of high protein intake such as kidney damage BG rise.
and high fat intake such as high cholesterol are yet to be An optimum combination would be a program with a
evaluated. Hence, obese diabetics on oral hypoglycemic nutritionally balanced dietary regimen and weekly meet­
agents (OHA) or insulin therapy should not try this diet. ings for behavioral therapy. The maintenance of weight
Atkins or other low carbohydrate diets are often tried loss is a more challenging task than the short-term weight
without permission and supervision of the doctors. The loss.
curtailment of carbohydrate intake without adjustments
in the medications could cause severe hypoglycemia.11 Very Low Calorie Diets
Literature suggests that high protein, low fat diets A variety of other dietary measures have been proposed to
promote a greater degree of weight loss compared to high achieve and maintain weight loss. VLCD may contain 800
carbohydrate, low fat diets, but the mechanism of this or even lesser kcal/day. A very rapid weight loss may occur
enhanced weight loss is unclear. A study compared the on any such diets in the first week of strict dieting. This loss
meal-induced thermogenesis on a high protein, low fat is not sustainable because it is a loss of water. The metabolic
diet versus a high carbohydrate, low fat diet. Postprandial rate also tends to drop with a decrease in body mass and
thermogenesis at two and a half hours postmeal was hence the rate of weight loss will decline progressively
about two-fold higher on the high protein diet as on the same diet. Combination of an exercise regimen
compared to the high carbohydrate diet.12 This difference with a VLCD is the most effective way to promote weight
was significant after breakfast and dinner. loss of adipose tissue while maintaining muscle mass.
The speed of protein digestion has a major effect on A cyclical VLCD or refeeding regimen with a 3 week or
protein anabolism after one single meal. In comparison 1 week alternating cycle has been advocated, but episodic
with carbohydrate metabolism, slow and fast proteins eating with oscillations in body weight may not be safe and
modulate the postprandial metabolic response differently. may cause an increased risk of vascular disease.17 Side
The effect of whey protein on metabolism is short lived effects of VLCDs are well-known, yet it may be acceptable
as it is digested and absorbed quicker as compared to as a short-term or medium-term strategy. A well-planned
casein. But, casein resulted in a 34% reduction of protein VLCD may improve hyperglycemia, hyperinsulinemia,
breakdown due to its slow rate of absorption.13 Hence, dyslipidemia and essential hypertension in type 2 dia­
whey protein may work well just before a physical activity betics. VLCDs should not only contain adequate protein
session whereas casein may work well for the extended of high biological value but also include multivitamin and
period between main meals to maintain an anabolic state. mineral supplements.18
Equicaloric diets with varying proportions of carbo­ A 5-year follow-up of an intensive weight loss program
hydrate, protein and fat have been evaluated in the in type 2 diabetes with a BMI more than 30, illustrated
 Nutrition Management in Special Situations 485

the following.19 One group was put on a VLCD whereas type 1 patients due to potential hypoglycemia. VLCD
the second group was put on an intensive conventional shows decreased compliance over a period of time.
diet and exercise regimen. The results showed a slower Addi­tionally, VLCDs do not modify eating behavior,
weight loss in the conventional diet and exercise group nutritional knowledge and skills which are the key to
than in the VLCD group, but the conventional group long-term weight maintenance. VLCD is to be undertak­
maintained the weight loss better than VLCD group over en under medical supervision. The modern VLCD is an
5 years. Long-term effect on high-density lipoprotein increasingly balanced diet as compared to the traditional

chapter
(HDL) cholesterol and diastolic blood pressure was VLCD and may have better application in weight reduc­

31
also better in the conventional diet and exercise group tion programs (Tables 31.2 and 31.3).
as compared to the VLCD group. The use of VLCD on Effectiveness of Medical Nutrition Therapy (MNT)
outpatient basis was found to be safe but not as effective in diabetes is adequately established.20 This has made
as the conventional diet and exercise therapy on a long- reimbursement of a nutritionists’ consultation possible.
term basis. Weight regain is inevitable after treatment with The nutrition recommendations in obese or overweight
VLCD. The conventional diet and exercise group may also diabetics have been proposed by the American Diabetes
require anti-obesity medications in addition to nutrition Association (ADA).
and exercise therapy.
VLCD is contraindicated in obese type 2 diabetics with Medical Starvation Diets
vascular disease. VLCD is not recommended in obese On rare occasions, when obesity is extreme, some harsh
measures, like total medical starvation can be employed
Table 31.2: Diet for obesity management. Very low calorie diet to initiate rapid weight loss. This should only be practiced
(VLCD): a hypocaloric, hypolipidemic, low salt, high fiber, high
protein diet (vegetarian)
Table 31.3: Diet for obesity management. Very low calorie diet
Approximately contains: 800 calories, 142 gm carbohydrate, 40 gm
(VLCD). A hypocaloric, hypolipidemic, low salt, high fiber, high
protein, 5 gm fat, low salt
protein diet (non-vegetarian)
• Breakfast
Approximately contains: 800 calories, 129 gm carbohydrate, 56 gm
– ½ glass skimmed milk (in tea or coffee) without sugar protein, 6 gm fat, low salt
– 1 handful roasted chana, 1 fruit unit • Breakfast
• Lunch – ½ glass skim milk (in tea or coffee) without sugar
– 1 chapati (30 gm) – 1 egg-white (hard-boiled or scrambled or omelette)
– 1 vati veg A cooked in minimal amount of oil or boiled only – 1 fruit unit (from exchange list)
– 1 vati dal (thin)
• Lunch
– 1 vati dahi (skim)
– 2 chapatis (60 gm)
– Salad plenty (veg A)
– 1 vati veg A cooked in minimal amount of oil or boiled only
• Snack
– Lean meat (60 gm) (chicken without skin; fish)
– ½ glass skim milk (in tea or coffee) without sugar
– 1 vati dahi (skim) or 1 vati dal (thin)
– 1 vati sprouts
– Salad plenty (veg A)
– 1 fruit unit (from exchange list)
• Snack
• Dinner
– ½ glass skim milk (in tea or coffee) without sugar
– 1 chapati (30 gm)
– 1 handful roasted chana
– 1 vati veg A cooked in minimal amount of oil or boiled only
– 1 fruit unit
– 1 vati dal (thin)
• Dinner
– 1 vati dahi (skimmed)
– Salad plenty (veg A) – 2 chapatis (60 gm)

• Bedtime – 1 vati veg A cooked in minimal amount of oil or boiled only

– ½ glass skim milk – Lean meat (60 gm) (chicken without skin; fish)
– 1 fruit unit – 1 vati veg B cooked in minimal amount of oil or boiled only
– Salad plenty (veg A)
Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL (1/4
liter); for examples of vegetables or fruits, see exchange list, Chapter 30 Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL (1/4
(i.e. Nutrition Management of Diabetes Mellitus). liter); for examples of vegetables or fruits, see exchange list, Chapter 30.
486 Management

under medical supervision for a period of 1–2 weeks. The Table 31.4: Behavioral modifications
patient is permitted to eat salads and 2–3 fruit units/day Innovative behavioral strategies22
to ensure intake of micronutrients. Low calorie density • Divide your day’s diet into 4–6 meals rather than having two
foods like skimmed buttermilk and clear soups are also large meals
permitted. The patient tends to be constipated on this • Overall reduce the intake of food
– Eat slowly, pause between bites and chew well before swal-
regime and there is substantial loss of potassium through
lowing
kidneys and a rise in uric acid. These side effects require – Fix meal timings, place of eating and cutlery for daily meals
section

appropriate corrective measures. – Preferably use small size plates

8

• Do not skip any meal in the day

Behavioral Approaches • “Fasting or feasting” should be avoided. Do not try to adjust your
schedule to accommodate a rich meal
Behavioral therapy is now a standard component of weight • Do not sleep immediately after a meal. Preferably keep a gap of
loss programs. The hallmark of behavioral therapy in 1–2 hour between the last meal and bedtime and a gap of
obesity is self-monitoring of eating behavior, techniques 1 hour between a meal and exercise
of stimulus control, self-reward, nutrition education • Drink at least 8–10 glasses of water daily
and physical activity. An intensive behavioral treatment • Avoid eating food while watching television or reading. Choose
program alone manages to achieve short-term weight loss low calorie snacks when tempted to eat
• Fix attainable targets. Reward yourself suitably to sustain the
but weight regain tends to occur in the long run. This can
program
be overcome by supplementing the behavioral therapy
with other modalities like VLCDs and medications.
Additionally, an attempt has to be made to identify the changing relationship between the patient and practi-
patients with eating disorders, e.g. binge eating. Specific tioners. The term adherence has recently replaced “com­
approaches should be adopted to tackle such situations. pliance”, thus shifting the focus from a restricted, submis­
Use of behavioral therapy alone is insufficient. Yet, sive patient to a more free, empowered patient. A greater
it plays an important adjunctive role for many patients. involvement of the patient in his own health affairs will
Differences in efficacy of short and long-term weight loss actually facilitate more systematic and improved medical
were studied in a large group of individuals. They were put care. A paradigm shift from “compliance” or “non-com­
on a series of 12 behavior modification group programs pliance” to “adherence” helps in better understanding of
(n = 125) and compared to 28 individual programs. patient behavior and thereby improving glycemic con­
Information was collected directly and via questionnaire trol. Gene­rally, the term “treatment adherence” is now
during the program and after 10–36 months. In neither used as an intermediate one between compliance and
case, the type of program (group vs individual) played adherence.23
any significant role in weight loss. Instead, several other The factor which influences and enables patients to
factors emerged as being significantly related to weight adhere to treatment is the first step in designing effective
loss. Those patients who had participated in other weight interventions. Patient participation in medical decision-
programs earlier had less weight loss during this program. making may affect self-care positively or negatively.
Men participating in group sessions and women in Hence, the components of patient participation which
individual sessions achieved greater weight loss. Use of the affect adherence to self-care have to be identified and then
behavioral technique of slowing the rate of eating resulted specific behavioral strategies developed.24
in significant weight loss21 (Table 31.4).22 Overall, the adherence rates are 50% or lower for
lifestyle intervention prescriptions and other behavioral
Dietary Education, Implementation modification regimens. Enhancing adherence to long-
term regimens requires a combination of information
and Adherence
about the regimen, counseling on the importance of
Adherence to any mode of treatment is an important adherence, ability to organize one’s schedule, rewarding
aspect to consider. The term “adherence” characterizes and recognizing patients efforts and enlisting social
the patient’s independent, intelligent and autonomous support from family and friends. These interventions
decision to follow the program. It indicates a more active may be labor intensive but ultimately may prove to be
role of the patient in achieving the goals of therapy and cost-effective.25 Adherence to the treatment regimen and
 Nutrition Management in Special Situations 487

improvement in glycemic control and quality of life is An important fact of behavioral therapy is to assess the
achieved by adequate psychosocial therapies. ability of the internal diabetes locus of control and social
An interesting study was conducted on the effect of support to predict adherence to a weight control regimen
behavioral intervention on the treatment adherence in in type 2 diabetics. Data on a large sample of about
adolescents with type 1 diabetes. Twelve intervention 465 patients interviewed revealed that in a high social
sessions were applied which consisted of different support group, the internal locus of control was not related
procedures like instruction, BG discrimination training, to weight control. These two factors are important when

chapter
role playing, self-instructions, problem-solving strategies promoting treatment adherence.30

31
and homework. The control groups were given routine The potential barriers to dietary adherence among a
medical care. The experimental group showed a signi­ficant low-income, urban black type 2 patient population were
change in their knowledge related to diabetes information evaluated. A few problem areas were identified. Most
(patient and parents), adherence, daily hassles, social patients felt that the recommended meal plans were
interactions and negative family support. No real effect was lacking in taste and the cost of low fat and sugar-free items
seen on their diet, physical activity or glycemic control. In a was a major impediment. Lack of family support and
1 year follow-up improvement in the patients’ information increased pressure to use fat containing seasonings posed
on diet, physical exercise, barriers to adherence, severity a problem. Patients had difficulty following the exchange
of daily hassles and degree of uneasiness in social system and analyzing food labels. An attempt to involve the
interactions was maintained.26 patient’s family provides an appropriate menu. Patients
should be suggested to have healthy food choices.31
In another study, type 1 diabetic youths were assessed
Certain selected factors influence patient’s use of diet
for their psychological maturity and its impact on self-
regimens for diabetes. It was realized that demographic
care autonomy. The results showed that the excessive
characteristics were required to be considered to design
self-care autonomy group demonstrated less favorable
education sessions and improve communication with
treatment adherence, diabetes knowledge and glycemic
patients to increase understanding of diabetes. It showed
control. This shows that due caution has to be observed
that increased education promoted adherence to dietary
while encouraging maximal self-care autonomy among
recommendations.32
youth with type 1 diabetes. Also, parental involvement
may provide a better outcome in management of disease
NUTRITION MANAGEMENT
in these individuals.27
THROUGH JOURNEY OF LIFE
Research has also been conducted on the efficacy
of different methods of educating patients. A group of Medical nutrition therapy is an integral part of the care
112 patients were divided into two subgroups. One-half and management of diabetes and is essential in achieving
underwent group consultations in groups of nine or ten optimal glycemic control.
individuals (experimental group). The other half went
through individual consultations plus support education Youth
(control group). On review after 2 years, it was seen that A young diabetic needs to be carefully guided regarding
glycosylated hemoglobin (HbA1c) levels were lower in his or her nutrition through each stage of childhood.
patients in the test group than the control group. Interest­ A detailed nutrition management plan is required at every
ingly, HDL cholesterol and triglyceride (TG) levels were step with constant revision. The meal plan also has to be
modified favorably in the experimental group. Patients based on food preferences and daily schedule of the child.
who had undergone group visits had improved knowledge The ultimate goal in the treatment of a young diabetic
of diabetes, quality of life and experienced more appro­ is the overall well-being and normal health of the
priate health behaviors. The group therapy is easy to con­ individual with reduced risk of long-term complications.
duct without being additionally time consuming. Another It is essential that all children grow and develop normally.
study supported the finding that a good social support The insulin treatment plan has to be one which takes
to type 2 diabetics with amputations is instrumental into account the appropriate phase of growth, nutrition
in improving their adherence to diet.28 It is possible to con­ plan, physical and sports activity, yet maintaining a strict
vey simple principles of nutrition management to semi­ glycemic control. Likewise, a good diet plan is one which
literate or illiterate diabetics effectively.29 is synergistic with the insulin regimen.
488 Management

In the preadolescence period, the requirement of person without diabetes. Children need to be consistent
calo­ries is different. Overall, a 1,000 kcal plan with an in the timing and quantity of their food intake and under­
increment of 100 kcal for each year of age is considered stand the onset, peak and duration of their insulin dose in
adequate. For example, a 5-year-old child would need relation to meals and snacks. An intensive insulin therapy
1,500 kcal daily. This caloric requirement usually takes or insulin pump is useful in achieving strict glycemic
care of the requirement for routine activity and sports control in young diabetics. Almost 95% of young diabetics
activity of the children.33 are type 1 with a small fraction being type 2 diabetics.
section

During puberty, when the growth rate is increased, The former are always treated on an insulin regime.
8

larger doses of insulin are needed. Boys show this growth Young type 2 diabetics are usually children who are often
spurt at around 14 years of age and girls at about 12 years obese. In this group, once the growth is complete (age 18
of age. Boys require higher doses of insulin during puberty years for boys and 13 years for girls), a caloric restriction
as compared to girls. An increased caloric requirement may be undertaken. On the other hand, if they are still
would be necessary. In the adolescent phase, most in the growth phase, use of a prudent diet is advisable.
individuals would need an intake of 2,200–2,400 kcal/day. Hence, a mild restriction of fats, omission of sweets and
This high caloric intake warrants a systematic division of junk foods is advised. More importantly, it would be
the day’s meal into breakfast, mid-morning snack, lunch, advisable to make them undertake an exercise program to
mid-afternoon snack, dinner and bedtime snack. This is to control weight.36,37
minimize the postmeal hyperglycemia. Any intensive therapy has its limitations. A few impor­
A study conducted on the evaluation of linear tant factors hinder the adherence to insulin and diet regi­
growth in prepubertal type 1 diabetic children revealed men. It can be the fear of weight gain, eating dis­orders,
interesting data.34 A group of 89 type 1 patients with onset (binge eating, anorexia nervosa), history of severe hypo­
of diabetes in the prepubertal period were examined. In glycemia, psychological and social pressures. Children on
this group, 17 patients were at the prepubertal stage. Their insulin treatment are more likely to experience hypogly­
height-centiles and height-velocity were determined. cemia. Many a time, the child is hypoglycemic just before
These patients were under fair metabolic control. Bone a meal. A child may refuse to eat total or part of the
age was evaluated in 11 type 1 patients. The data showed meal after insulin is injected. Night time hypo­glycemia
a height velocity of 5.6 ± 1.9 cm/year (height velocity can be avoided by eating a bedtime snack like whole-
> 5 cm/year is optimal in prepubertal period). It was wheat sandwich, fruit and milk, especially if the BG is
interesting to see that the percentile height, height- 110 mg/dL or less.38
velocity and skeletal maturation were marginally advan­ The “diabetic foods” found in health shops and markets
ced as compared to chronological age. It is possible are unsuitable for children in their growth period. These
that prepubertal children have a higher height-centile, “sugar-free” foods contain artificial sweetening agents
especially if obese at the time of onset of their disease. which are harmful when ingested in large amounts. Also,
The insulin therapy may also influence their growth, these products are occasionally zero or low fat, which is
partly through glycemic control. This study showed that detrimental to their health.
in this particular age group a reasonable glycemic control Children show the highest intake of artificial sweet­
allowed normal growth pattern in children. eners because of high food and beverage consumption.
After puberty, the insulin requirements decrease to Sweetened drinks, fruit drinks have high fructose and
an adult level.35 Accordingly, the calorie intake is tapered sorbitol content and may cause non-specific diarrhea
off so as to prevent undue weight gain and obesity. In in children. Aspartame is restricted in children as this
young diabetics, monitoring of BG and HbA1c is extremely compound diffuses easily across the blood-brain barrier
important; so also is monitoring their linear growth and and high level of phenylalanine derived from aspartame
sexual maturation. They exhibit the same growth pattern causes alteration in brain activity. Hence, the consump­
as non-diabetics, if metabolic control and nutrition tion of diet drinks by youngsters needs to be restricted.
management is good. Take, for example, the case of a youngster of around
In children, the insulin regimens and food intake are 60 kg weight who replaces water with diet colas. The daily
adjusted to each other. The insulin therapy is planned to consumption of cola may reach up to 10–12 cans/day.
mimic the endogenous insulin secretory pattern seen in a Each 12-ounce can of cola contains 54 mg of aspartame.
 Nutrition Management in Special Situations 489

Hence, the total consumption may be 540–600 mg daily. gastroenteritis. This reduces the requirement of insulin.
Although this falls well below the acceptable daily intake Suitable beverages like a regular cola, tea with sugar, juice,
(ADI) of 40–50 mg/kg body weight/day, it is yet a high oral-rehydration solution in small and frequent doses
consumption of aspartame. Therefore, it is advisable can be given. Once the child is able to retain food, solid
to curb the consumption of these beverages. Sucralose foods can be started. Milk and milk products are excluded
apparently has no adverse effect and is considered safe.39 for a week or two if the child continues to have diarrhea;
Young diabetic children more often face difficulty in however, curds are allowed.

chapter
following a strict diet plan owing to their likes and dislikes,

31
peer pressure and the availability of a large variety of “junk Pregnancy and Lactation
food” or “fast food” in the market. Fast foods or junk foods
contain high calories in the form of fat and carbohydrate, Pregnancy produces changes in eating habits, exercise
with low amounts of protein and fiber. Moreover, they pattern, emotional state, insulin sensitivity and hormone
rarely include fruits and vegetables. Hence, these foods secretions. This further alters glucose control and insulin
are devoid of much needed micronutrients. “Fast food” is requirements.
increasingly emerging as a staple diet for many youngsters. In India, the most common association of pregnancy
It is not desirable, but consuming it once in a while with and diabetes is seen in type 2 diabetes or gestational
parallel adjustment of insulin dosage is acceptable. diabetes mellitus (GDM). Type 1 diabetes is uncommon in
Importantly, the ingredients and composition of the mixed India and its association with pregnancy is even rarer. The
meal either as fast food or otherwise should be known.40 nutritional approach in these three different situations is
Young children are constantly engaged in their own different. Most type 2 diabetics and gestational diabetics
activities and sports. The food intake has to be adjusted are obese and/or hypertensive. Type 1 diabetics are usually
normal weight or even undernourished. These factors call
according to their exercise routine. It is possible to expe­
for appropriate dietary modification.
rience hypoglycemia few hours after vigorous exercise as
the muscles have increased insulin sensitivity for several
hours after a bout of exercise. In the event of a long Normal Pregnancy
outdoor exercise schedule (more than 1 hour), the child
In the first trimester of pregnancy, there is a decreased food
has to consume an extra snack half-an-hour before and
intake due to nausea and vomiting (morning sickness). A
half hourly during the exercise regimen. In case of a weight
palatable, high carbohydrate food may be permitted in
loss program undertaken by obese children, the insulin
the morning in such situations. The requirement of
dosage is reduced according to the time action profile of micro- and macronutrient are similar for diabetic and
the insulin used and the time of the exercise regime.41,42 non-diabetic women. A weight gain of 1–2 kg (2–4 lbs) is
A few basic guidelines have been suggested for diet and desired in this trimester. This can be done by an increment
exercise in type 1 diabetes. An individual with blood sugars of 100 kcal/day. During the second and third trimesters,
of more than or equal to 80 mg/dL undertaking exercise for there should be adequate intake of food along with a
a short duration should consume 15 gm of carbohydrate steady weight gain. In the second trimester, weight gain
every half an hour, like a fruit or carbohydrate exchange. of ¼ kg/week (½ lb) and third trimester weight gain of
An individual undertaking moderate exercise with ½ kg (1 lb)/week is sought. This is achieved by an incre­
blood sugars between 80 mg/dL and 180 mg/dL, should ment of 300 kcal/day. Thus, an overall weight gain of
also consume 15 gm carbohydrate per hour of exercise. 10–12 kg is expected in normal weight pregnant women.
Whereas a person with blood sugars of 80 mg/dL and 180 An increase in the protein requirement is required, of
mg/dL undertaking strenuous exercise should consume which 50% should be from the high biological value (HBV)
about 30–50 gm of carbohydrate per hour, depending on type. Thus, 1.3 gm of protein/kg body weight per day is
the intensity and duration of physical activity.43 prescribed. Adequate intake of complex carbohydrate
In case of an infection, diarrhea, fever or other (fruits, vegetables and cereals) and dietary fiber is
intercurrent illness a sick-day routine needs to be followed. advised. Supplemental iron, folic acid and calcium are
There is decreased appetite and decreased food intake in recommended.
490 Management

Diabetes with Pregnancy 36–40 kcal/kg/day for women less than 90% DBW.46
The main purpose of the diet is to maintain normal BG
Overweight pregnant women should gain less than half
levels and meet the nutritional requirements. Regularity
the normal amount of weight gain. Although pregnancy is
of meals and snacks (divided into three meals and three
not the appropriate occasion to institute a vigorous weight
snacks) is important to prevent hypoglycemia.
reduction plan, the weight gain can be restricted to almost
The nutritional quality of the diet during the post­
5–6 kg without any untoward consequences. In order to do
partum period is important because the mother has to
section

so, a 1,500 kcal diet can be used without any adverse effect
deal with the additional demands of the newborn baby
on the fetal growth.
8

along with her own physiological stress. Breastfeeding is

A modest caloric restriction (1,600–1,800 calories/day)
recommended and an additional 500 kcal/day is allowed
results in normal mean glucose without an increase in
for this reason. To prevent hypoglycemia while feeding,
free fatty acids (FFA) or ketones in the urine.44 The quality
the mother needs to consume a carbohydrate and protein
of carbohydrate is important. Complex, unrefined carbo­
containing snack before or during breastfeeding. A bed­
hydrates are preferred, as they seem to produce lower
time snack is of utmost importance.
glycemic responses. Breastfeeding is encouraged.
Generally recognized as safe (GRAS) sweeteners
A woman with known type 1 or type 2 diabetes plan­
ning to undertake pregnancy needs to do so with a strict are accepted in pregnancy. Saccharin is restricted
metabolic control before attempting conception. There in pregnancy as the placenta concentrates it avidly.
should be good glycemic control and optimal body weight As-partame was found to have no adverse effect on the
in the prenatal period. Poorly controlled diabetes is life- fetus but it is restricted in pregnant women and individuals
threatening to the fetus and newborn and at times to the with hyperphenylalaninemia. Sucralose is found in low
mother. It has been established that congenital anomalies concentrations in the placenta. It is considered safe in
are related to hyperglycemia during the first 6 weeks of pregnancy. Acesulfame-K and stevioside need more
pregnancy. Incidence of birth defects reduces from 10% studies to ascertain their safety in pregnancy.
to 2% (this is at par with the general population), if strict
glycemic control and weight control is obtained before Elderly
conception and maintained after conception.45
In general, a person aged 65 years or more is considered
About 2–4% of women develop diabetes during preg­
as elderly. An elderly diabetic may also face problems of
nancy (GDM). This generally reverses after delivery. These
decreased physical activity, obesity, decreased muscle
women are more likely to develop diabetes during
subsequent pregnancies or later in life. An excellent glyce­ mass, other concomitant illnesses like heart disease,
mic control and weight control has to be achieved to osteo­arthritis, hypertension, neuropathy, nephropathy
reduce maternal and fetal morbidity and fetal mortality. and retinopathy. The elderly have multiple biochemical
The risk factors for GDM include occurrence of abnormalities like impaired insulin secretion, decreased
GDM during an earlier pregnancy, delivery of a previous action of insulin, an increased hepatic glucose output
macrosomic infant (> 9 lbs birth weight), family history of and peripheral insulin resistance. A multidisciplinary
diabetes and maternal obesity (> 120% DBW). approach is required.47
Many type 2 diabetics with pregnancy and women A well-balanced, nutritious diet with adequate calorie
with GDM have edema, hypertension and toxemia of intake from a wide variety of foods is recommended.
pregnancy. Nutritional modification is essential to alle­ The dietary fat component should be restricted to 25% of
viate these conditions. Usually, a salt-restricted diet is total calories with restricted saturated fat and cholesterol
mandatory in this situation. intake. The carbohydrate intake can be in the complex
Insulin therapy is always needed in type 1 DM carbohydrate form so as to also maintain adequate intake
and usually needed in type 2 DM with pregnancy. GDM of fiber and prevent constipation.
may be controlled by diet and exercise, but may also In cases, where the elderly are dependent for day-to-
need insulin. Hence, the risk of hypoglycemic episodes in day care, the nutrition plan should be simple, practical and
pregnancy is to be discussed with the patient. A suggested easy to implement. The texture and consistency of food
guideline is about 30 kcal/kg/day for women at DBW, may vary depending on the dental health of the individual.
24 kcal/kg/day for women more than 120% DBW and Soft food may be required in diabetics with loss of teeth.
 Nutrition Management in Special Situations 491

A restricted diet may be an additional burden on the If a diabetic is hypoglycemic before the meal he
patients and lead to non-compliance. Yet, restrictions should take the scheduled insulin injection but not wait
according to the complications have to be introduced. 30–45 minutes before eating or withhold the injection
Calorie-dense food may be recommended for under­ until it is time to eat or inject just before the next meal.
nourished patients. New rapid-acting insulin analogs, e.g. lispro, aspart
An overall healthy diet with adequate micronutrients and glulisine insulin can be injected just before or even
especially calcium, iron, vitamin D and vitamin C is after a meal. This will synchronize the insulin effect and

chapter
required to ensure optimal health and immunity. Vitamin entry of glucose from the food into the blood stream.

31
D deficiency is now known to be highly prevalent in urban Mild hypoglycemic episodes are common with insulin
areas of India because of exclusion of ultraviolet rays from therapy. At times, these episodes are serious. Fear of
the sun by the pollutants. hypoglycemia can motivate the patient to increase calorie
Elderly diabetics are likely to have more hypoglycemic intake, hence resulting in weight gain. A prudent approach
episodes due to poor food intake or mild kidney and liver would be to readjust and lower the insulin or medication
dysfunction causing slow excretion of oral medication. dosage than to increase food intake.
If an elderly patient is living alone, hypoglycemia may
be fatal as the awareness may be impaired especially in Intensive Insulin Therapy and
type 1 diabetics. A bed time snack is advisable to avoid
Insulin Pump Therapy
nocturnal hypoglycemia.
Water intake may also need monitoring in mentally The insulin pump therapy or intensive insulin therapy is
obtunded, elderly subjects. Reduced water intake may usually undertaken for type 1 diabetes but occasionally
result into severe hyperglycemia and a hyperosmolar, also for type 2 diabetes. This regime allows tremendous
hyperglycemic, non-ketotic state. flexibility of diet as the premeal dosage of insulin can be
altered every time. On pump therapy, basal rates can also
NUTRITION MANAGEMENT IN VARIOUS be varied as desired.
TREATMENT MODALITIES A crucial meal planning concept to be understood
in this regime is counting of carbohydrates for every
Nutrition management of diabetes essentially remains the meal and snack in the daily diet. This is important, as
same with various treatment modalities except for small
carbohydrate is the fundamental macronutrient, which
modifications.
has maximum effect on the PPBG. The two main methods
of counting carbohydrates are (1) “carb-counting” and (2)
Insulin Therapy
“carbohydrate gram counting”. Carb-counting uses the
A variety of insulin regimes are being used in both type 1 exchange list for meal planning as the basis for counting
and type 2 diabetes. These regimes can be single or two- of carbohydrates. The carbohydrate gram counting system
dose insulin per day or more intensive therapies with adds the carbohydrate gram values for all foods eaten to
3–4 doses per day. The onset, peak and duration of action
obtain the total carbohydrate of a meal. Then, the bolus is
of different insulins have to be understood carefully.
calculated by dividing the total grams of carbohydrate in a
Regular insulin usually shows peak effect at about 2
meal by the carbohydrate to insulin ratio.
hours after injection. The Neutral Protamine Hagedorn
In general, three levels of pump settings have been
(NPH) and Lente insulin peak at about 6–10 hours after
injection. Hence, a mid-afternoon snack would be advis­ identified based on increasing levels of complexity:
able for a person taking NPH or Lente in the morning • Level one is basic and introduces individuals to the
and a bedtime snack, if a patient is taking NPH or Lente concept of carbohydrate counting.
at dinner time. • Level two or intermediate level focuses on the rela­
Certain maneuvers help in delaying the rate of gastric tionships among food, diabetes medications, physical
emptying; for example, large amounts of fluid intake activity and blood glucose level. It also introduces the
at the end of the meal. Also, high fat content of the food steps needed to manage these variables based on pat­
will slow down the gastric emptying rate. Diabetic gast­ terns of BG levels.
ropathy can delay gastric emptying considerably with • Level three or advanced level is designed to teach
bizarre BG profiles. individuals with type 1 diabetes who are using multiple
492 Management

Table 31.5: Counting carbs on exchange basis at a meal and the number of units of rapid-acting or
Food (1 exchange) Carbohydrate content (gm) Carb-count short-acting insulin needed to attain desirable BG levels.
Starches or Breads 15 1
For example, if a person consumes 72 gm carbohydrate
Fruits 15 1 at a meal and requires 9 IU of insulin to reach the target
Milk 12 1 BG, he has a ratio of 1 IU insulin to 8 gm carbohydrate.
Vegetables 5 1/2 Typically, one unit of regular insulin is required to handle
Fats 0 0 10–15 grams of carbohydrate. Food specific doses may
section

Meat or Proteins 0 0
also be required, e.g. for foods like spaghetti, pizza. If the
meat or fat content of the meal is high, adjustment in the
8

daily injections or insulin infusion pumps how to

timing of dose is required. Patients on insulin pump may
match short-acting insulin to carbohydrate, using the
use a square-wave form of bolus to cover a high protein-
carbohydrate-to-insulin ratios.
fat meal. If the serving of fiber is more than 5 gm, it is
All three levels emphasize portion control and offer
subtracted from the total carbohydrate content, as fiber
opportunity for using creative teaching methods.
is not an available source of glucose and, in fact, retards
The exchange list for meal planning is also widely
the absorption of the available carbohydrate.48 The grams
used for planning food intake. It forms the basis for
of protein in a meal is multiplied by a factor of 0.6, i.e. 60%
carb-counting. It consists of starch, fruit, milk and other
and the value is added to the carbohydrate grams to obtain
dessert-type or snack-food type. This system also expands
the total.
the meat group into the lean, medium-fat and high-fat
Weight gain is a very important aspect of any treatment
categories. It gives detailed serving size and accurate food
regime for diabetes. Usually, the body tends to move
content. The food and nutrient intake can be assessed by
towards its stable weight.49 Certain modes of therapy do
nutritionists and patients alike. It offers great flexibility
cause weight gain. Insulin therapy and oral hypoglycemic
toward the menu planning but is a less precise method for
agents like sulfonylurea cause maximum weight gain.
counting carbohydrates (Table 31.5).
On the other hand, metformin has an anorectic effect
The carb-counting system is easier to understand
and prevents weight gain in type 2 diabetics. There is
once the exchange system is mastered. It focuses on
tremendous weight gain with rosiglitazone and piogli­
the total amount of carbohydrate and not the source
tazone, at times up to 15 kg in 3 months. Therefore, while
of carbohydrate. Emphasis is laid on eating consistent
following the basic principles of the diabetic diet, a watch
amounts of carbohydrates at meals and snacks.
has to be kept on the weight gain trend in the individual.
High carbohydrate foods that have to be taken into
Any undesired weight gain has to be combated with
account in carbohydrate counting are cereals, pulses,
appropriate nutrition management.
fruits, milk and sweets. Starchy vegetables are taken into
account, if eaten in servings more than 15 gm. The amount
of insulin can be worked out for a certain amount of
NUTRITION MANAGEMENT IN
carbohydrate to produce the target BG value. This helps VARIOUS LIFE SITUATIONS
work out a carbohydrate-insulin ratio. This carbohydrate- There are various situations in the life of a diabetic
insulin ratio is expressed as the number of grams of where adjustments in his treatment schedule, timing of
carbohydrate covered by one unit of regular insulin. It can meals, dosage and timing of medication are required.
be calculated by dividing the total grams of carbohydrate Nutrition management needs to be suitably altered in
consumed in a day by the total insulin taken in a day. This
these situations. A diabetic should be able to carry out
can vary for different individuals and also in the same
the daily recreational activities and duties, at work and
individual for different meals, at different times of the
home and also handle a variety of changing situations. The
day and presence of other nutrients in the meal. This ratio
diabetologist, nutritionist and diabetes educator need to
is usually low at breakfast time compared to lunch and
guide the patient towards self-reliance in these situations.
dinner time. Carb-counting does not take into account the
glycemic index (GI) but a low GI food will automatically
Travel
require less insulin to reach the target glucose.
This system empowers the patient to learn the relationship A diabetic has to feel confident to travel anywhere.50
between food, insulin, physical activity and BG levels. A mild diabetic may be able to manage, if he eats sensibly
It involves determining the grams of carbohydrate eaten outside the house at altered timings, whereas a patient on
 Nutrition Management in Special Situations 493

an insulin regime should always keep a ready snack in his understand the exchange system of menu and utilize the
or her carry-on bag in case the next meal is not available flexibility offered by it. Complex dishes should be avoided
at the right time. Packed ready snacks such as non-sweet as their ingredients are difficult to figure out. Order the
biscuits, nuts or pulses mixture (e.g. peanuts and chana), food carefully, e.g. a clear soup instead of a thickened
or a cheese sandwich should be carried. A packet of toffees soup and main course which has non-fried options. One
or candies (hard candies) should be on person in case of a should consume fresh fruit instead of a fat-rich or cream-
hypoglycemic episode. based dessert. One should order non-fried food, i.e.

chapter
To avoid gastroenteritis and other waterborne diseases, broiled, baked or boiled food. For example, plain steamed

31
one can carry bottled water and avoid under-cooked, raw rice is preferred to greasy pulao or biryani and chapati or
foods, unpurified water and ice and unpasteurized milk. phulka over puri or paratha. One can order a diet cola or
a glass of dry wine or whisky with water or soda-water to
Road Travel drink instead of fresh or canned fruit juices or cocktails.
During road travel a diabetic should try and figure out the Other options are: dhokla, idli-sambhar with green mint
timing and availability of meal on the route before hand or coriander chutney, bajra-jowar based chapatis, whole-
and try to stick to a regular schedule. He should stop-by wheat based chapatis, missi roti, pastas (preferably durum
at any restaurant at meal timings. One should not risk wheat) in tomato based gravy and not containing white
hypoglycemia while driving, as it can result in impaired sauce. Salads with dressing of lime juice, vinegar and
judgment and cause an accident. It is always advisable spices are better options than oily salad dressings.
to carry some food and water in a handbag in the vehicle In India, one has to be cautious about the hygiene of
itself. the food. Raw salads and fresh coriander as a garnishing
is taboo, as it may carry a variety of infections. Even fresh
Air Travel fruit should be eaten at a place where it is either peeled or
cut in front of you or the restaurant has a good reputation.
When traveling by air especially on domestic flights, try Sweets are anyway not allowed for diabetics. Milk-based
and work out the timing of meals and type of food suitable sweets are especially avoided when made on a mass-scale.
to you. In case, a special diabetic meal is not provided one Milk is difficult to preserve and can cause severe food
can choose intelligently from the regular meal. One can poisoning. The golden rule is to go for well-cooked, fresh
opt for healthier alternatives such as clear soup instead of and warm food.
a thickened soup, tandoori rotis instead of naan, plain rice
instead of fried rice, fresh fruit platter instead of a cream- Religious Fasts
based dessert, diet cola or a dry wine or whisky with soda
India is a country with tremendous diversity of culture,
instead of a cocktail.
beliefs, customs and religions. Each community has its
When on international travel and traveling across roots entrenched in particular customs and traditions. A
2 hours or more hours of time zone, it is necessary to large number of people worldwide and in India undertake
make changes in medication and food intake. If the time various religious fasting regimens. For devout individuals,
difference is less than 2 hours, no adjustment is necessary. this is a period of austerity, self-discipline and charity.
The insulin doses need to be planned in advance and During any fasting period, there may be considerable
understood well. Traveling eastward shortens the day and change in meal timings, frequency and type of diet
decreases the requirement for snacks and medication. ingested. Additionally, altered carbohydrate, fat and pro­
Traveling westward lengthens the day and increases the tein intake affect the metabolic control of diabetes. The
requirement for snack and medication. Most airlines will main purpose of all fasting regimes is to develop restraint
accept a special diabetic meal request up to 48 hours in eating. If such restrained behavior is adopted in a
before the flight departure. day-to-day nutrition plan, it would be highly beneficial.

Eating Out Hindu Fast

When eating out, a diabetic has to choose wisely from Fasting in Hindus is done in the months of Shravan. In
the menu so as to approximately stick to his daily calorie, the day, omission of cereals and pulses is undertaken
carbohydrate, fat, protein and fiber intake. He also has to and subsistence is mainly on fruit and milk products.
494 Management

In the evening, a single regular meal is consumed. The food meal. Besides, these fasting regimes, general restraint and
intake is somewhat lower in calories but high in its diminished food intake termed Unnodari is promoted in
carbohydrate content due to fruit and milk. This possibly Jainism. This is eminently suitable for obese diabetics.
prevents hypoglycemic episodes. No major alteration in There is paucity of data on the effect of various reli­
the insulin or medication is called for in this fast. gious fasts on the metabolic control of type 1 and type 2
diabetics. This poses a major question whether religious
Muslim Fast fasts are safe and/or beneficial. Usually, type 1 diabetic
section

The Ramazan or Ramadan fasting (Roza) is undertaken patients or type 2 on multiple insulin doses are not per­
8

by Muslims the world over. The length of the fast may mitted to undertake these fasts. However, some of these
vary amongst the community from different regions since fasts can be of tremendous therapeutic value in selected
the duration of the fast is defined from sunrise to sunset. type 2 patients.
Food intake occurs mainly as two major meals, i.e. Iftehar
in the evening and Shiyori in the morning. It is believed Shift Duties
that a larger than usual food intake occurs after sunset in Many diabetics may hold jobs and positions where
this fast. This may be attributed to higher consumption a shift duty system may exist. Shift duties of different
of fat and infrequent, larger meals. The word “fasting” types pose considerable difficulty in medication and
medically and nutritionally could be inappropriate for nutrition management of diabetes. A fixed schedule
diets during Ramazan and some other fasts. However,
shift is preferred, e.g. evening to midnight or midnight to
a study of Ramazan fast showed that patients ingested
morning. This is practical as the individual can reorient
significantly less calories, more carbohydrate and less fat.
his schedule of diet, medication and exercise on a long-
The metabolic control judged by BG and HbA1c remains
term basis. Weekly or biweekly changing duties are best
unchanged at the end of the fasting period. Dose of insulin
avoided by a diabetic. Diabetics on oral medication may
or OHA was not altered, but morning and evening doses
find it easier to maintain shift duty schedules compared to
were interchanged.51 A population-based study from
those treated on insulin. If on insulin, multiple small doses
13 countries has described the characteristics of diabetes
of insulin would offer more flexibility for diet planning
in Ramadan fasting.52 Based upon similar studies appro­
and implementation rather than the single dose insulin
priate recommendations have been made for the manage­
regimen.
ment of diabetes during Ramadan.53
Reorientation of the diet and meal timings is required
Jain Fast on shift duty. The appropriate meal is a tiffin with an
accompaniment of healthy snacks that can be easily car­
Jain fasts are of various types. The total fast allows only ried, e.g. whole-wheat vegetable sandwich with a low fat
water intake and this fast may last from 1 day up to cheese slice and salads. For snacks, roasted chana, plain
1 month. A similar fast of 8 days at the main religious
khakra, mumra (puffed rice) may be carried.
festival period called Paryushan is undertaken annually.
Other interesting fasting schedules in Jains consist of Sick Day Routine
1 year of a total day fast (only water) alternating with
another day of two meals. When meals are consumed it Intercurrent illness like cold, cough, diarrhea and vomiting
is always during daylight. The Ayambil is a fast where one assume increased importance in a diabetic. Those condi­
single meal is eaten sometime during midday. This meal tions though minor, upset the metabolic balance consi­
is salt-free and fat-free. The meals usually omit green leafy derably. Hypoglycemia as well as diabetic keto­acidosis
vegetables and fruits completely. Hence, the antioxidant (DKA) can occur. Usually, gastrointestinal (GI) disease
intake may be low. The regimen of Ayambil is also done in causes maximum metabolic disturbance due to a change
a row of 9 days (called Oli), which may be extended up to in the food intake. Yet, skin or respiratory tract infection
15–20 days. There is increased consumption of cereal and may be equally responsible for causing hyper­glycemia.
pulses thus increasing the fiber content from cereal-pulse A diabetic should not omit insulin in spite of omission
origin. The lack of salt may produce a beneficial effect on of food. The insulin regime should continue under medical
the blood pressure. Yet, there may be an overall decrease supervision. The patient can attempt to consume small
in total calories. The dose of oral hypoglycemic agents is amount of liquids every hour. Soft, non-spicy foods can
usually halved and administered at the time of the single be eaten, if tolerated. If the patient has excessive nausea,
 Nutrition Management in Special Situations 495

vomiting and is unable to retain food, immediate action (CAD). Additionally, diabetics have dyslipidemia, obesity
has to be taken to stop nausea or vomiting. If one is too ill and hypertension. These risk factors tend to cluster in the
then they have to try retaining whatever is palatable, e.g. diabetic population.54 The combined effect of these risk
a glass of fluid every hour, water, fruit juices, regular soft factors is an increased risk of atherogenesis and coronary
drinks, tea, clear soup or broth. Buttermilk is preferable in artery disease. Modification of diet in hypertension,
case of diarrhea. Once recovery starts, a switch-over to soft dyslipidemia and obesity is required. Thus, a hypocaloric,
and later a solid diet is done. hypolipidemic, low salt and high fiber diet will be appro­

chapter
If a type 1 diabetic or insulin requiring type 2 diabetic priate. The components of diet in these different situations

31
has nausea or vomiting, high carbohydrate snack can be are further described in this section.
given to combat the ketone body formation effectively.
An approach like “no food-no insulin” does not work as Coronary Artery Disease Risk Factors
starvation is not the road to recovery. In case of severe
Obesity
vomiting, oral feeds are stopped and intravenous fluids
may be started in order to maintain fluid and electrolyte Presence of excess weight or obesity along with diabetes
balance. and coronary artery disease compounds the problem.
In case of a type 2 diabetic on oral medication, a Strategies for weight reduction by diet modification is
different approach is taken. In case of minor colds and essential, to reduce further risk of coronary heart disease.
coughs, no change in treatment is called for. But in the A low calorie, low fat and high fiber diabetic diet is
event of a severe illness, e.g. GI upset, the medication recommended. Effectively, a reduction of 500 calories from
is stopped and insulin therapy initiated. A program of the present diet could be done with focus on maintaining
fractional meals and fractional insulin therapy is most normal protein intake. Behavioral therapy in conjunction
appropriate, as it offers the desired flexibility. with a hypocaloric diabetic diet is an important weight
management strategy.
NUTRITION MANAGEMENT IN
COMPLICATIONS OF DIABETES Dyslipidemia
Clinical and epidemiological data in humans suggest that Lipid abnormalities occur more frequently in type 2
the magnitude and duration of hyperglycemia in diabetes diabetes patients. Characteristically hypertriglyceridemia,
are strongly associated with the severity of microvascular, low HDL-cholesterol and normal or mildly elevated total
macrovascular and neuropathic complications. Not all and LDL-cholesterol levels are seen. Small, dense LDL
patients with hyperglycemia develop complications. Other particles which are strongly related to vascular risk also
factors including age, sex, race, ethnicity, socio-economic predominate in type 2 diabetics. This dyslipidemia is
status and comorbid conditions (hypertension, hyperli­ characteristic of “Syndrome X” too. Lipoprotein (a) [Lp(a)]
pidemia) have a modifying influence. levels have also been found to correlate to atherosclerosis
The Stockholm Diabetes Intervention Study and the and is considered a potent risk factor for CAD.
Diabetes Control and Complications Trial (DCCT) are Lipid abnormalities concomitant with diabetes and
landmark studies done in type 1 diabetes and its progre­ cardiovascular disease can be treated by dietary modifi­
ssive complications. The United Kingdom Prospective cations of total fat intake, cholesterol intake and, saturated
Diabetes Study (UKPDS) is another landmark study done and unsaturated fat intake. The dietary principles also
in type 2 diabetes and its complications. Through all these have to include a high fiber, weight maintenance or
studies, the importance of strict, long-term glycemic hypocaloric weight loss diet. A diet for hyperlipidemia
control and parallel strategy of treating the associated works well for a diabetic as the increased fiber intake also
conditions or complications has been established. helps maintain good glycemic control. Caution has to be
observed not to prescribe a very high carbohydrate diet
Cardiovascular Disease and its Risk Factors as this will exacerbate the hypertriglyceridemia further.
Coronary Artery Disease A balance can be struck by increasing the protein intake of
Diabetes mellitus is associated with an increased risk the diet. Caution has to be observed regarding protein, salt
of macrovascular diseases like coronary artery disease and potassium intake in patients of diabetic nephropathy.
496 Management

The Dean Ornish diet is a very popular diet in coronary Table 31.6: Guidelines for fat restriction: simple dietary modifications
artery disease. It recommends a plant-based diet of fruits, to cut-down total fat intake
vegetables, grains, legumes (beans) with an option of Avoid
supplementing the diet with a moderate amount of non- • Deep-fried foods of all types such as sev, ganthia, puris
fat dairy products and egg-white. This plant-based diet • Oily salad dressings, mayonnaise, peanut butter, grated
was advised, as it was a zero cholesterol diet and was low in coconut, coconut-based chutney
total and saturated fats. It was additionally low to normal in • Dried fruits and nuts, olives
section

oxidants like iron and high in antioxidants like β carotene, • Sweetmeats, cakes, pastries, puddings, chocolate, cookies
8

Vitamins A, C and E. A high fiber intake would occur • Cream soups, meat or chicken soups
automatically in such a diet. Intake of moderate amounts • Whole milk and its products, e.g. ice-cream, cheese, ghee,
of complex carbohydrate and low fat consumption (10% of butter, margarine, cream, evaporated and condensed milk
total calories) were the mainstay of Dean Ornish diet.8 • Egg yolk, egg yolk containing products are especially rich in
cholesterol, e.g. waffles, pancakes, French toast

Recommendations for lowering total fat, saturated fat
and cholesterol can be achieved by following the National • Beef, pork, bacon, cold cuts, sausage, salami, frankfurters,
hot-dog, mutton, cream sauces and gravies, organ meats
Cholesterol Education Program (NCEP) guidelines. These
• Skin and fat of poultry, fatty fish, e.g. tuna, mackerel, salmon,
guidelines advocate a two-step diet which is as follows:
trout, sardine, Bombay duck, pomfret, rohu. They do contain
1. In step 1 diet, 30% of total calories should be obtained omega-3 fatty acid, but calories have to be accounted for
from total fat. Out of this, 8–10% of total calories should • Lard, shortening, cooking oils such as palm, coconut, corn,
be derived from saturated fat, 10% from polyunsaturated olive, peanut, sesame seeds
fat and 12% of total calories from monounsaturated fat. • Sea foods rich in cholesterol, e.g. crab, prawns, lobster, oyster,
Intake of cholesterol is limited to 300 mg/day. squid and shrimp

2. In step 2 diet, the percentage of total calories from fat, • Junk or fast foods have a high caloric value, but poor nutritive
value and should not form or replace any main meals as they
polyunsaturated fat and monounsaturated fat remains
are high in carbohydrate and fat, but lower in protein, vitamin
the same as in step 1. But, saturated fat is reduced to and minerals
7% of total calories. The cholesterol intake is further Choose and prepare low fat foods
restricted to less than or equal to 200 mg/day. • Eat plenty of vegetables as raw salad and fruits with skin
Both these diets emphasize the intake of grains, whenever possible. This provides dietary fiber
legumes, vegetables, fruits, lean meats, poultry, fish and • Eat moderate amounts of whole grain cereals, legumes and
non-fat dairy products.55 pulses

The maneuvers to reduce total fat intake can be • Opt for skimmed milk and its products (ice-cream, curds,
achieved easily by certain simple modifications: Avoid fats cottage cheese)
as spreads for flavoring; reduce the consumption of meat; • Egg white and products containing egg-white
consume lean meats, like chicken without skin; replace • Eat lean meats (e.g. chicken without skin), lean fish and seafood
high fat foods with low fat foods, like substitute whole milk such as halibut, pike, shark, clams, mussels, octopus; also
remove all trimmings from meat
with skimmed milk. A rich source of saturated fat is animal
• Use lemon juice, herbs, vinegar, spices, fat free curd and green
fats. High fat choices have to be omitted and are replaced
chutneys as salad dressing
by low fat choices. For example, one has to avoid intake of
• Make gravies and curries using fat free curd or buttermilk,
organ meats, ground meats, poultry with skin, egg yolks, tomato puree, ginger, garlic, grated onion, skimmed milk
fried fish and whole milk (Table 31.6).
• Prefer cooking methods, such as boiling, broiling, steaming,
Soluble fiber intake is encouraged in the step 1 and step stewing, baking, grilling and roasting. In case of frying, always
2 diets. This can be achieved by including legumes, oat use a non-stick frying pan with just a few drops of oil
bran, fresh fruits and vegetables in the diet. Salt intake
needs to be kept under check at about 2400 mg/day. This
could be difficult to maintain, as many low fat processed Hypertension and Edema
foods contain high amounts of salt. Hypertension is seen as much as 1.5–2 times higher in
General guidelines and dietary management plan to diabetic people than non-diabetic people. Hypertension is
be followed in CVD is outlined in Tables 31.7 to 31.11. also one of the primary risk factors for CVD. Diabetics also
 Nutrition Management in Special Situations 497

Table 31.7: General instructions for cardiovascular disease

Food preparation
• Dal and vegetables may be prepared along with the rest of the family’s meals, but the patient’s portion should be removed before adding
extra fat, flour, sugar or jaggery
• Chapatis should be prepared from unrefined (whole) flour without using oil, ghee or butter
• Fruits should be eaten whole preferably with the skin, instead of fruit juices
• Milk should be boiled, refrigerated overnight and the cream removed before use

chapter
• Use direct sugar sparingly. Use artificial sweeteners such as saccharin (sweetex, hermesetes) or aspartame (equal, canderal, sugar-free)

31
or stugar (stevia) or sucralose (zero, sugarite, sugar-free natura) liberally as a sweetener
• Fish, chicken and eggs should be boiled or baked
Foods to be avoided
• Deep fried foods such as sev, ganthia, puris
• Jams, jellies, cakes, cookies, puddings, sweetmeats, sweetened canned fruits, alcohol
• Whole milk and its products (cheese, cottage cheese, ice-cream)
• Soups thickened with starch, fat, cream, or egg yolk
• Dried fruits and nuts.
• Vegetables like potato, sweet potato
• Sweetened and carbonated drinks, colas (except diet drinks)
• Oily salad dressings, mayonnaise, peanut butter
• Beef, pork, sausage, mutton and gravies, chicken skin, fatty fish, egg yolk
Foods allowed in liberal amount
• Spices and condiments
• Healthy drinks like water, lemon juice (without sugar), plain soda, tea and coffee (with the prescribed quota of milk, without sugar), raw
salads and vegetables (Group A)

Table 31.8: Diet for cardiovascular disease. Low calorie diet (LCD): a hypocaloric, hypolipidemic, low salt, high fiber diabetic diet (vegetarian)
Approximately contains: 1200 calories, 191 gm carbohydrate, 44 gm protein, 20 gm fat, low salt
• Breakfast
– ½ glass skimmed milk without sugar
– 1 bread slice (whole wheat) or 1 khakra or 2 small idlis or 1 chapati or 1 vati upma or 1 vati poha or 1 vati dalia (30 gm)
• Midmorning
– 1 fruit unit
• Lunch
– 1 bowl clear soup (no potato, onion, cornflour)
– 2 chapatis (60 gm) or 2 bread slices (whole wheat) or 1 chapati (30 gm) + 1 vati brown rice
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati veg group B cooked in minimal amount of oil or boiled only
– 1 vati dal (thin)
– 1 vati dahi (skimmed) or 1 glass buttermilk or 20 gm paneer (from skimmed milk)
– Salad plenty (veg A)
• Snack
– 1 glass skimmed milk (in tea or coffee) without sugar
– 1 khakra (30 gm) or 1 bread slice (whole wheat) or 2 small idlis or 1 vati upma or 1 vati poha or 3 pieces dhokla
• Mid-evening
– 1 fruit unit
Contd...
498 Management

Contd...
• Dinner
– 1 bowl clear soup (no potato, onion, cornflour) 2 chapatis (60 gm) or 2 bread slices (whole wheat) or 1 chapati (30 gm) + 1 vati khichdi
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati veg group B cooked in minimal amount of oil or boiled only
– 1 vati dal (thin)
– 1 vati dahi (skimmed) or 20 gm paneer (from skim milk)
section

– Salad plenty (veg A)

8

• Bedtime
– 1 glass milk (skimmed)
– 1 fruit unit

Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL (1/4 liter); for examples of vegetables or fruits, see exchange list, Chapter 30.

Table 31.9: Diet for cardiovascular disease. Very-low calorie diet (VLCD): a hypocaloric, hypolipidemic, low salt, high fiber diabetic diet
(vegetarian)
Approximately contains: 800 calories, 130 gm carbohydrate, 30 gm protein, 15 gm fat, low salt
• Breakfast
– ½ glass skimmed milk (in tea or coffee) without sugar
– 1 bread slice (whole wheat) or 1 khakra or
– 2 small idlis or 1 chapati (30 gm) or 1 vati upma or 1 vati poha
• Mid-morning
– 1 fruit unit
• Lunch
– 1 bowl clear soup (no potato, onion, cornflour)
– 1 chapati (30 gm) or 1 bread slice (whole wheat) or 1 vati brown rice
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati veg group B cooked in minimal amount of oil or boiled only
– 1 vati dahi (skim) or 1 vati dal (thin)
– Salad plenty (veg A)
• Snack
– ½ glass skimmed milk (in tea or coffee) without sugar
– 1 khakra (30 gm) or 2 small idlis or 1 vati upma or 1 vati poha or
– 3 pcs dhokla or roasted chana (with skin)
• Mid-evening
– 1 fruit unit
• Dinner
– 1 bowl clear soup (no potato, onion, cornflour)
– 1 chapati (30 gm) or 1 bread slice (whole wheat) or 1 vati khichdi
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati dal (thin) 1 vati dahi (skim)
– Salad plenty (veg A)
• Bedtime
– 1 exchange nuts

Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL (1/4 liter); for examples of vegetables or fruits, see exchange list, Chapter 30.
 Nutrition Management in Special Situations 499

Table 31.10: Diet for cardiovascular disease. Low calorie diet (LCD): a hypocaloric, hypolipidemic, low salt, high fiber diabetic diet (non-vegetarian)
Approximately contains: 1200 calories, 177 gm carbohydrate, 53 gm protein, 26 gm fat, low salt
• Breakfast
– ½ glass skimmed milk (in tea or coffee) without sugar
– 1 bread slice (whole wheat) or 1 khakra or 2 small idlis or
– 1 chapati (30 gm) or 1 vati upma or 1 vati poha or 1 vati dalia

chapter
– 1 egg-white (hard boiled or poached or omelette)

31
• Mid-morning
• 1 fruit unit
• Lunch
– 1 bowl clear soup (no potato, onion, cornflour)
– 2 chapatis (60 gm) or bread slices (whole wheat) or 1 chapati (30 gm) + 1 vati brown rice
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati veg group B cooked in minimal amount of oil or boiled only
– 1 vati dal (thin)
– 1 vati (skimmed) or 1 glass buttermilk or 20 gm paneer (from skimmed milk)
– Salad plenty (veg A)
• Snack
– 1 glass skimmed milk (in tea or coffee) without sugar
– 1 khakra (30 gm) or 1 bread slice (whole wheat) or
– 2 small idlis or 1 vati upma or 1 vati poha or 3 pieces dhokla
• Mid-evening
– 1 fruit unit
• Dinner
– 1 bowl clear soup (no potato, onion, cornflour)
– 2 chapatis (60 gm) or 2 bread slices (whole wheat) or 1 chapati (30 gm) + 1 vati khichdi
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati veg group B cooked in minimal amount of oil or boiled only
– 60 gm lean meat/fish/chicken cooked in minimal amount of oil or roasted or baked or grilled
– Salad plenty (veg A)
• Bedtime
– ½ glass milk (skimmed)
– 1 fruit unit

Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL (1/4 liter); for examples of vegetables or fruits, see exchange list, Chapter 30.

Table 31.11: Diet for cardiovascular disease. Very-low calorie diet (VLCD): a hypocaloric, hypolipidemic, low salt, high fiber diabetic diet
(non-vegetarian)
Approximately contains: 800 calories, 118 gm carbohydrate, 35 gm protein, 13 gm fat, low salt
• Breakfast
– ½ glass skimmed milk (in tea or coffee) without sugar
– 1 bread slice (whole wheat) or 1 khakra or 2 small idlis or
– 1 chapati (30 gm) or 1 vati upma or 1 vati poha
Contd...
500 Management

Contd...
• Mid-morning
– 1 fruit unit
• Lunch
– 1 bowl clear soup (no potato, onion, cornflour)
– 1 chapati (30 gm) or 1 bread slice (whole wheat) or 1 vati brown rice
– 1 vati veg group A cooked in minimal amount of oil or boiled only
section

– 1 vati veg group B cooked in minimal amount of oil or boiled only

8

– 1 vati dahi (skimmed) or 1 vati dal (thin)

– Salad plenty (veg A)
• Snack
– ½ glass skimmed milk (in tea or coffee) without sugar
– 1 khakra (30 gm) or 2 small idlis or 1 vati upma or 1 vati poha or
3 pieces dhokla or roasted chana (with skin)
• Mid-evening
– 1 fruit unit
• Dinner
– 1 bowl clear soup (no potato, onion, cornflour)
– 1 chapati (30 gm) or 1 bread slice (whole wheat) or 1 vati khichdi
– 1 vati veg group A cooked in minimal amount of oil or boiled only
– 1 vati veg group B cooked in minimal amount of oil or boiled only
– 30 gm lean meat or fish or chicken cooked in minimal amount of oil or roasted or baked or grilled
– Salad plenty (veg A)
• Bedtime
– ½ glass milk (skimmed)

Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL (1/4 liter); for examples of vegetables or fruits, see exchange list, Chapter 30.

have edema due to many diseases like heart failure, kidney • The second “fruit and vegetable” diet tested the effect
failure, poor nutrition, cancer and at times liver disease. of fruits and vegetables alone. The 8 week study
The lifestyle modifications for hypertension prevention showed a significant blood pressure lowering effect of
and management include attaining and maintaining combination diet by 5.5 mm Hg systolic and 3.0 mm Hg
normal weight, increased physical activity (30–45 min/ diastolic. In contrast, the latter diet reduced blood
day), reduced dietary sodium intake to less than 4 gm pressure by about half this amount, i.e. 2.8 mm Hg
sodium (6 gm NaCl), adequate dietary potassium intake, diastolic and 1.1 mm Hg systolic. The diets were more
reduced intake of dietary saturated fat and cholesterol, effective in hypertensive patients (29% of total group),
smoking cessation.56 where a reduction of 11.44 mm Hg/5.5 mm Hg was
The Dietary Approach to Stop Hypertension (DASH) observed for the combination diet and about 7.2 mm
trial was a multicentric, randomized controlled trial, Hg/2.8 mm Hg for the fruit and vegetable diet.
studying dietary patterns rather than single nutrients. Two The therapeutic effect of the combination diet in the
dietary patterns were tested. hypertensives was comparable to that of pharmacological
• One was a “combination diet” high in fruits, vegetables, treatment. It was summarized that a high intake of vege­
whole-grain cereal products, low-fat dairy products, tables and fruits accounted for approximately 50% of
fish, chicken and lean meats. This was designed to the lowering effect of the combination diet. Fruits and
reduce saturated fat, total fat and cholesterol yet vegetables are high in potassium, magnesium, fiber and
remain moderately high in protein, minerals and fiber. other nutrients which help reducing pressure effectively.57
 Nutrition Management in Special Situations 501

The epidemiologic evidence for the role of sodium in Congestive Cardiac Failure
the pathogenesis of essential hypertension is indirect as
The Framingham study demonstrated an increased risk of
many genetic and other environmental factors come into
congestive heart failure (CHF) in diabetics. This risk was
play. A well-planned population study (the Intersalt study)
four times higher among young diabetic men and eight
was conducted in 200 people.58,59 A threshold relation
times higher among females with diabetes, as compared
between sodium intake and hypertension was found.
to the non-diabetic population. Hence, diabetes and CHF
Low intake of sodium prevented development of hyper­
is a common combination and are interrelated.61

chapter
tension whereas high intake of sodium caused preci­
The prognosis of patients with heart failure and

31
pitation of high blood pressure, especially with an existing
genetic susceptibility. Once, beyond the threshold level diabetes is related to the degree of metabolic control. The
of 50–100 mmol NaCl/day (3–6 gm NaCl/day) this effect UKPDS showed a significant independent relationship
was found to be linear. between a reduction in HbA1c and development of heart
Preventive studies like the Trials of Hypertension Pre­ failure. A 1% reduction of HbA1c reduced the development
vention Phase (TOHP) study demonstrated that a mode­ of heart failure by 16%.
rate reduction of dietary sodium intake significantly Dietary manipulation would be of great benefit in
reduced the evidence of hypertension in people with a treating this condition. A moderate salt restriction is
high-normal blood pres­sure.60 required in patients with severe heart failure. Excess fluid
In the diabetic population, sodium restriction has not intake is to be avoided and in fact fluid restriction is also
been systematically tested by controlled clinical trials. required. Potassium replenishment may also be required
Studies done in essential hypertension have shown a if diuretics are being used. A lipid lowering, salt restricted,
reduction in blood pressure with moderate sodium hypocaloric diet with restriction of fluid intake may be
restriction (2,300 mg/day). followed.
Concomitant use of salt restriction and a pharmaco­
logic agent produces better response. Simple instruc­ Diabetic Nephropathy
tions of omitting foods containing large amount of salt Diabetic nephropathy is a common microvascular
may achieve the goal of partial salt restriction. Foods complication of both type 1 and type 2 diabetes. Treatment
containing small amounts of salt can be eaten freely even of diabetic nephropathy requires attention to be paid to
under severe salt restriction. blood pressure control as well as control of hyperglycemia.
A severe salt restriction is usually not recommended on
Diabetes is now the most common single cause of
long-term basis except in conditions of edema, congestive
end-stage renal disease (ESRD) in USA and Europe.
cardiac failure and nephropathy. Severe salt restriction
This is due to an increasing prevalence of type 2 dia­
finds reduced acceptability due to reduced palatability
betes, longevity of diabetic patients and acceptance of
of the food. A salt substitute like “LoNa (low sodium)”
more patients into ESRD treatment programs. The earli­
may be used in such situations. These substitutes contain
est clinical evidence of nephropathy is the appearance
19.6% Na as compared to 39.3% Na found in regular edible
of low yet above normal levels (30 mg/day) of albu­
salt. The remaining is salt of potassium chloride which
may be beneficial in lowering high blood pressure. Such min in the urine. This is called microalbuminuria and is
salt substitutes have to be used with caution in conditions indicative of an incipient nephropathy. Once overt
of nephropathy and are usually contraindicated. nephropathy occurs, the glomerular filtration rate (GFR)
A normal individual may consume up to 10 gm of gradually falls over a period of several years. About 40% of
salt daily. Salt intake may be up to 15 gm of salt daily to type 1 diabetics are seen to evolve eventually into ESRD.
compensate for the excessive salt loss in the sweat in Type 2 diabetics can have microalbuminuria at the time of
tropical countries. In most of the edema states, patients diagnosis or shortly after diagnosis of their disease. Almost
are advised to restrict salt partly. A severe salt restriction 20% of this group progress to overt nephropathy. Detec­
is impractical and can be harmful. A partial salt restriction tion of microalbuminuria is also indicative of generalized
in the diet usually brings the salt-content of food to about endothelial damage. The key to reducing risk of complica­
half, i.e. 5 gm/day. Usually, the therapeutic benefits are tions is to maintain good glycemic control.62
seen with partial salt restriction. But in severe edema Just as in chronic renal failure of other etiologies,
states and hospitalization, a stringent salt-restriction may reduction of protein intake has been also advocated in
be required. diabetic nephropathy. Data on diabetic patients with less
502 Management

severe impairment of renal function show that reduc­ long-term effect of a particular level of dietary protein in
tion in protein does retard the progression of diabetic the progression of renal disease still remains open.67
nephropathy in type 1 diabetes. Long-term studies using A meta-analysis of five studies was conducted by Pedrini
reliable markers of GFR showed favorable results. In where 108 patients with type 1 diabetes were followed
a 5-year study, there was a significant reduction in the up for an average of 9–35 months. A low protein diet
rate of decline in GFR when the protein intake was (0.6 to 0.5 gm/kg body weight/day) significantly slowed
reduced from 1.13 gm/kg body weight/day to 0.67 gm/kg the increase in urinary albumin excretion rate (AER)
section

body weight/day. The effect of the diet was indepen­ in individuals with normo-albuminuria or microalb­
8

dent of blood pressure. Another 5-year prospective uminuria. Also reduction in the rate of decline in GFR was
study in type 1 diabetics with nephropathy showed that seen in individuals with diabetes and microalbuminuria.
50% of the patients receiving dietary therapy resulted in Yet, there was no consistency on the amount and type of
no decline in GFR.63 protein used in these studies. Also, foods were prepared
A protein restriction to 0.5–0.6 gm/kg protein/day at home (unsupervised) and adherence to food intake was
seemed to have no long-term detrimental effect on the not assessed. No such studies, short-term or long-term
nutritional status. A 50% reduction in dietary protein is have been reported in type 2 diabetes.68
seen to reduce the excretion of albumin in patients with A new emerging school of thought suggests that
microalbuminuria. At a very early stage, type 1 diabetics restriction of protein may be detrimental to the general
show a stage of hyperfiltration. This is also reduced by well-being, nutrition and muscle mass of the patient
protein restriction. Short-term studies of the physiologic with diabetic nephropathy. Brodsky et al. concluded that
mechanism of action of low protein diets in diabetics with type 1 patients adapt to the protein restriction (0.6 gm/kg
nephropathy indicate that such diets lead to a reduction body weight/day) and a period of “undernutrition” may
in the fractional clearance of albumin, IgG and broad- occur in states of poor glycemic control.69
sized neutral dextrans. This leads to an improvement of It has been hypothesized that higher protein diets may
the selective permeability of the glomerular membrane be detrimental to renal function as it causes increased
without affecting GFR.64 glucagon production and/or increased concentrations
The optimal diet for diabetic nephropathy in terms of of specific amino acids. Rudberg et al. observed that an
macronutrients (especially protein) and micronutrients is increase in GFR on a diet with 20% energy contribution
still under evaluation. Evidence to recommend restriction from protein was significantly correlated with an increase
in dietary protein for diabetic patients with overt nephro­ in glucagon and branched-chain amino acids such as
pathy is insufficient in terms of gross proteinuria, dimi­ isoleucine, valine.70 Hence, this poses the fundamental
nished renal function or both. The effect of dietary protein question: which type and source of protein (e.g. animal
on glycemic control has been carefully examined over the vs. plant) reduces the risk or slows the progression of early
past decade. The studies have suffered from flaws in their diabetic nephropathy? A small number of studies (one-
experimental design, small sample size and insufficient meal length) and three other short-term crossover studies
short-term and long-term data. Usually, a single meal generated interest in this area. These studies show that
effect (added protein compared with other macro­ the plant-based protein when eaten in amounts similar to
nutrients) on the postmeal BG and insulin concentrations animal-based protein may be beneficial in the reduction
is studied. These studies show either none or mild increase of hyperfiltration and AER.
in postprandial insulin, but no changes in glucose.65 An interesting study by Pecis et al. compared 3 weeks
Gulliford et al. showed that the co-ingestion of a of 1.4 gm/kg body weight/day red meat protein-rich diet
single dietary protein with a carbohydrate load or fat versus 3 weeks of 1.2 g/kg body weight/day chicken and
load modi­fied the glycemic index of the former.66 Gannon fish protein-rich diet. The latter slowed decline in GFR
et al. examined the effect of different types of protein: significantly in type 1 diabetics with normal albuminuria
high protein (30% of total calories) and lower protein and hyperfiltration.71
(15% of total calories) with differences in carbohydrate Several mechanisms are suggested for the beneficial
intake (40% compared to 55%) of total calories but not fat effect of plant versus animal protein. It is postulated that
(30% in both diets). The high protein diet resulted in 40% the different hormonal responses exist. Individuals with
reduction of plasma glucose and HbA1c. The issue of the type 1 diabetes have impaired hemodynamic response to
 Nutrition Management in Special Situations 503

a meat meal. Therefore, there is a failure in rise of gluca­ For a diabetic in the initial phase of kidney disease,
gon. Secondly, it is dependent on the differential plasma usually a mild restriction of salt in the diet with normal
amino acid levels. Glycine, arginine, and alanine are protein intake may be advised. General guidelines towards
implicated in renal hemodynamics and induce a rise mild salt restriction are given in Tables 31.12 to 31.14.
in glucagon and GFR. These amino acids are found in Additionally, one can choose foods without sauces and
decreasing amounts in red meat < tuna < bean curd. Also gravies and instead use vinegar, lemon juice, red pepper,
branched chain amino acids (valine, leucine, isoleucine) tabasco sauce or garlic as salad dressing.

chapter
are found to be higher in bean curd than tuna.72 As the kidney disease advances, kidney failure sets

31
Because of these persistent questions and issues, in and waste products like urea and creatinine start to
standard recommendations of protein intake in diabetics accumulate which are toxic to the body. At this stage a
are difficult to make. Yet, a dietary recommendation for protein restriction of approximately 20–40 gm/day is
protein restriction to 0.6–0.8 gm/kg/day might be advised advisable. This protein should be of high biological value
in selected diabetic patients. The contentious issue is (HBV). The HBV protein spares the breakdown of the
whether the reduction of protein should be total protein body protein for energy, thus preventing muscle wasting.
(animal and plant) or just animal protein. Exchanging The vegetable protein is also known to be of benefit in
some of the animal protein for plant protein may not be retarding the progression of kidney disease, as discussed
harmful and may also help to reduce total and saturated above. Hence, division of protein intake equally between
fat intake plus increase dietary fiber. For years and even these sources seems prudent and practical.
currently, it is recommended that at least 50% of the total When there is renal failure, both edema and high blood
protein is high biological value based protein. pressure coexist and it requires salt restriction. Once the

Table 31.12: Instructions for salt-restricted diets

General instructions
• Avoid salt completely in cooking unless it is prescribed by a physician
• Avoid use of soda-bicarbonate or baking soda in the preparation of meals or snacks, e.g. dhoklas or idlis or in preparation of vegetables
• Avoid Chinese foods (contains Ajinomoto)
Foods to be avoided (0.2 gm salt and above per 100 gm)
• Baked products such as bread, cakes, pastries, doughnuts, biscuits
• Salted nuts and salted snacks such as chiwda, sev, bhajia, vada, bhel-puri
• Salted butter and processed cheese
• Vegetables such as knol-khol (bandh gobi), amaranth (chaulai sag), field beans (val), red gram tender (kutcha arhar)
• Fruits such as litchies and musk melon (kharbuza)
• Organ meats such as liver, kidney, brain and seafood such as crab, lobster, prawn, dry fish and shellfish
• Papad, pickle, chutney, sauces and all canned, brined, preserved and seasoned products unless they are declared to be salt free
Foods to be taken in moderate amounts (0.1–0.2 gm salt per 100 gm)
• Rice flakes, corn flakes, maize tender
• Black gram dal, red gram dal, bengal gram dal, green gram dal and lentil
• Vegetables such as lettuce, beetroot, pink radish, spinach (palak), broad beans (bakla) and snake gourd (chahchinda)
• Fruits such as apple, banana, mango, water-melon (kalinger) and pineapple
• Mutton, eggs
• Milk, ice-cream, milkshakes, condensed milk and curds
Foods which can be taken freely (0.03–0.1 gm salt per 100 gm)
• Rice, wheat, jowar, ragi, bajra
• Vegetable such as peas, cabbage, cauliflower, white radish, brinjal, cucumber, French beans, ladiesfinger, pumpkin, ridge gourd (torai)
and bitter gourd (karela)
• Fruits such as amla, guava, orange, papaya, peach, pear, plum and sapota (chickoo)
504 Management

Table 31.13: Instructions for potassium-restricted diets Table 31.14: Diet for diabetic nephropathy
General instructions Approximately contains: 1,750 calories, 276 gm carbohydrate,
• Drain the water after boiling vegetables, dals and pulses to 60 gm protein (24 gm HBV), 35 gm fat, salt or potassium restriction
leach out the potassium • Morning
• Avoid using low sodium (LoNa) salts or salt substitutes. They – ½ glass skimmed milk (as tea or coffee) without sugar
are very high in their potassium content • Breakfast
Avoid low sodium canned foods where sodium chloride is – ½ glass skimmed milk (as tea or coffee) without sugar
section

replaced by potassium chloride

– 3 bread slices (whole wheat) or 3 kora khakras (90 gm) or
8

Foods to be avoided (4–6 mEq or 285–430 mg and above of

– 2 vatis poha or 2 vati upma
potassium/100 gm)
• Mid-morning
• Whole grain cereals like bajra, maize, ragi, wheat, wheat germ,
wheat flour, bran – 1 fruit unit (papaya)
• All dals, pulses, legumes and soyabean • Lunch
• Green leafy vegetables and other vegetables such as potato, – 2 chapatis (60 gm) + 1 vati rice
sweet potato, mushroom – 1 vati (veg A group) pumpkin or bitter or ridge or bottlegourd
• Fruits and juices of citrus fruits, banana, plum, figs, melons (leached)
(honeydew, musk), peach, gooseberry, phalsa and coconut – 1 vati veg B (leached)
water
– 1 vati dal or 1 vati curd (skimmed milk)
• Dry fruits and nuts such as dates, apricot, raisins, prunes
– Salad veg A (cucumber and tomato)
• Meat and poultry products
• Snack
• Coffee, colas, cocoa, chocolate
– ½ glass skimmed milk (tea or coffee) without sugar
Foods which can be taken in moderate amounts (2–4 mEq or
– 2 vatis sago porridge or khichdi
145–285 mg of potassium/100 gm)
• Mid-evening
• Maize tender, rice flakes
– 1 fruit unit (guava or apple or peach or pear or papaya)
• Vegetables such as celery, bitter gourd, brinjal, drumstick,
tomato, coriander leaves • Dinner

• Fruits such as amla, litchi, mango, watermelon, chickoo, – 2 chapatis (60 gm) + 1 vati rice
strawberry, cherry – 1 vati (veg A group) pumpkin or bitter or ridge or bottlegourd
• Milk and milk products, cheese, cottage cheese (leached)

• Fish such as bhekti, cod, hilsa, katla, koi, magur, prawn, rohu, – 1 vati dal or 1 vati curd (skimmed)
salmon, sardine, singhi – 1 vati veg B (leached)
• Tea • Bedtime
Foods which can be taken freely (1–2 mEq or 72–143 mg of potas- – 1 glass skimmed milk (as tea or coffee) without sugar
sium/100 gm)
Note: Vati: measures 125 mL (1/8 liter); Glass: measures 250 mL
• Jowar, semolina, vermicelli, rice, barley, wheat flour and its
(1/4 liter); for example of vegetables or fruits, see exchange list in the
products (maida, pasta, spaghetti, white bread), arrowroot flour
Chapter 30.
• Vegetables such as broad beans, cauliflower, cucumber, field
beans, French beans, ladies finger, onion stalks, parwal, pink A balanced diabetic nephropathy diet with appropriate
beans, pumpkin, gourds (bottle, ridge, round, snake), restrictions of salt and potassium needs intelligent
• Tinda planning and implementation. A very important aspect of
• Fruits such as apple, guava, jambu, papaya, pear, pineapple, managing diabetes with renal failure is to concentrate on
pomegranate, grape dealing with the renal failure as first priority. In this event,
• Eggs the carbohydrate intake (complex and simple sugars) may
be liberal as compared to that in a diabetic without renal
kidney progressively fails, its excretion of the potassium disease.
ion is hampered. The diet also requires to be low in The blood sugar control can be maintained strictly by
potassium which can be achieved by avoiding potassium using insulin therapy, which allows greater flexibility of
rich foods. treatment. Patient should not curtail fat intake, as it will
 Nutrition Management in Special Situations 505

affect overall caloric intake. However, the type of fat used microparticulated egg-white and milk protein. Fats as
should be of the appropriate type. fat replacers are caprenin, olestra (olean) and salatrim
(benefat).75
Diabetic Neuropathy A diabetic should be able to read between the lines
and utilize products containing sugar and fat substitutes
The increasing duration of diabetes and severity of hyper­
judiciously. Some of these substitutes are not calorie-free
glycemia increases the risk of developing peripheral
and the calories have to be taken into consideration as

chapter
polyneuropathy in type 1 and type 2 diabetics. The
well as the right proportion incorporated when planning a
pathogenesis of neuropathy is vascular and metabolic in

31
diabetic diet.
nature.73 Abnormalities occur in the nerve fibers due to The food label has a revised nutrition panel which says
alterations in structure and function. The polyol pathway “nutrition facts”. A set of dietary components appears on
is accelerated because of hyperglycemia. Overall, there is the nutrition panel (Table 31.15).76
an accumulation of glucose, fructose and sorbitol in the There are mandatory and voluntary components which
nerve. Simultaneously, there is a decrease (about 25%) must be specified in the order given. If the food claims
in the myoinositol concentration. Once this compound any beneficial effect of a nutrient or if the food is fortified
is affected, further pathways involved in the formation or enriched with it, it must be listed accordingly. Data
of the integral cell membrane and other enzymes are for each of the nutrients is represented as grams (or
affected. Pathway of Na+/K+ ATPase activity is inhibited, milligrams) per serving and as a percentage of daily value.
impairing peripheral nerve function. This occurs due to All the data in the nutrition label are presented on the
obstruction in Na+ extrusion, so increasing intracellular basis of serving size. “Calories” is the number of calories
Na+ concentration. This in turn inhibits depolarization, in that particular serving. A serving with 20 calories or
thus slowing nerve conduction velocity. Disturbances in less is called a “free food”. If it has more than 20 calories
omega-6 fatty acid and prostaglandin metabolism result then one has to look further at the label. The grams of
in alterations in nerve membrane structure.74 total carbohydrate are inclusive of the grams of sugar.
Diabetic neuropathy patients require a hypercaloric Hence, one counts only the grams of total carbohydrate
diet with emphasis on supplementation of myoinositol, for calculation. The amount of total carbohydrate for a
antioxidants, potassium and magnesium. A high calorie particular serving is counted as per in Table 31.16.
nutritious diet is recommended as most diabetics with
neuropathy are undernourished and have experienced
Table 31.15: Representative nutrition facts label
significant weight loss.
Nutrition facts
Serving size: (mL)
FOOD LABELING AND INTERPRETATION Serving per container:
An understanding of the labeling procedures of “diabetic Amount per serving

foods” is of interest to a diabetic as it allows him to intro­ Calories _______________   Calories from fat _________ %
Daily value*
duce these products in the meal plan. Usually these foods
Total fat _____ gm
would contain substitutes of sugar or fat. This substitution
Saturated fat _____ gm
is routinely done to render products “sugar free”, “low-fat”
Cholesterol _____ mg
and “zero-cholesterol”. The sugar substitutes commonly
Sodium _____ mg
used in the industry are aspartame, saccharin, acesul­ Total carbohydrate _____ gm
fame-K, sucralose, maltodextrin, polydextrose, erythri­ Dietary fiber _____ gm
tol, lactitol, maltitol, mannitol, xylitol and hydrogenated Sugar _____ gm
starch hydrolysate (HSH). Protein _____ gm
Fat replacers may be carbohydrate, protein or fat- Vitamin A Vitamin C
based. Carbohydrates used as fat replacers are cellulose Calcium iron Vitamin D
gum, corn syrup solids, guar gum, maltodextrin, modi­ *Percent daily values are based on a 2,000 calorie diet. Your daily
fied food starch, pectin, polydextrose and xanthan gum. values may be higher or lower depending on your total caloric
Proteins as fat replacers are whey protein concentrate, allowance.
506 Management

Table 31.16: Carbohydrate and fat content per serving 6. Gannon MC, Nutall FQ, Saeed A, et al. An increase in
dietary protein improves the blood glucose response in
Carbohydrate (in gm) Count as persons with type 2 patients. Am J Clin Nutr. 2003;78:734-4.
0–5 gm Do not count 7. Chandalia HB, Lamba PS, Chandalia SH, et al. Weight gain
6–10 gm ½ carbohydrate serving in type 2 diabetics with different treatment modalities.
11–20 gm 1 carbohydrate serving Metabol Syndr Relat Disor. 2005;3:157-63.
The grams of total fat are considered for calculation as follows: 8. Chandalia HB, Modi SV. Nutrition management through
One fat serving is based on 5 gm of fat journey of life. In: Conquest of diabetes by diet and
section

exercise. Mumbai: DENMARC; 2010.

Fat (in gm) Count as
8

0–2 gm Do not count

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 Chapter 32
Physical Activity and
Exercise in Diabetes Mellitus
Uday K Phadke

Physical Activity in Diabetes

Chapter Outline
♦♦ Physiology of Fuel Metabolism in Exercise in ♦♦ Recommendations for Exercise Therapy in Diabetes
Healthy Individuals ♦♦ Specific Considerations in Type 2 Diabetes Mellitus
♦♦ Effects of Regular Training on Fuel Metabolism ♦♦ Special Considerations in People with Long-term
♦♦ Effects of Exercise in Type 1 Diabetes Mellitus Complications of Diabetes
♦♦ Effects of Exercise in Type 2 Diabetes Mellitus ♦♦ Mind Body Therapies
♦♦ Cardiovascular Adaptations to Exercise Training ♦♦ Role of Exercise in Diabetes Prevention

introduction About 80–90% energy produced in the resting muscles

comes from fatty acids whilst the rest comes from glucose
It has long been recognized that exercise is an impor­
oxidation.
tant tool in the treatment of diabetes. This is more so in
With the onset of exercise, blood flow to the muscles
patients with type 2 diabetes where exercise can improve
increases resulting in increased uptake of glucose and
insulin sensitivity and helps in reducing or maintaining
weight in obese patients. Exercise helps to improve oxygen.2
glycemic control and control cardiovascular risk factors. Blood glucose levels are essentially constant as hepatic
The definition and meaning of various terms used in glucose production keeps pace with the muscle glucose
exercise physiology are presented in Table 32.1.1 uptake. If exercise continues for long periods of time, non-
esterified fatty acids (NEFA) becomes the main source
PHYSIOLOGY OF FUEL METABOLISM IN of fuel. Once exercise stops, increased muscle and liver
EXERCISE IN HEALTHY INDIVIDUALS glucose uptake continues to rebuild muscle and liver
stores of glycogen.
There is an increased demand for energy during exercise,
If exercise is continued for several hours without
and several hormonal, cardiovascular and neurological
caloric intake, hepatic glucose production cannot keep
responses enable the body to adapt to this increased
pace with increased muscle utilization and hypoglycemia
demand.
might result.
In the resting fasted state, blood glucose levels are
maintained by a balance between hepatic glucose pro­
duction and peripheral glucose uptake (50% by brain,
Control of Fuel Homeostasis During Exercise
15–20% by muscles and the rest by blood cells, kidneys The main arbiters of fuel homeostasis during exercise
and other tissues). Glycogenolysis is the main source for are the sympathoadrenergic system3 and the endocrine
this glucose while gluconeogenesis contributes only a system particularly via modulation of insulin, cortisol and
small component. growth hormone.
510 Management

Table 32.1: Summary of terms

1. Physical activity The expenditure of energy above that of resting by contraction of skeletal muscles to produce bodily
movement
2. Exercise A type of physical activity that involves planned, structured and repetitive bodily movement
performed for the purpose of improving or maintaining physical fitness
3. Cardiorespiratory fitness, cardiores- This refers to the ability of circulatory and respiratory systems to provide oxygen during sustained
piratory endurance, aerobic fitness exercise
section

4. Aerobic exercise Exercise that uses primarily aerobic energy producing systems and involves the repeated and
continuous movement of the same large muscle groups for extended periods of time (at least 10
8

minutes at a time). If performed with sufficient intensity and frequency, this type of exercise
increases cardiorespiratory fitness. Aerobic activities include walking, jogging, cycling, swimming
and similar exercises
5. Anaerobic exercise This type of exercise is short, high intensity exercise involving anaerobic energy producing
systems. If performed with sufficient intensity and frequency this type of exercise can increase the
body’s ability to tolerate acid-base imbalance during high intensity exercise
6. Intensity of aerobic exercise The intensity of aerobic exercise is generally described in relation to an individual’s maximum aerobic
capacity (VO2max) as measured using direct calorimetry during a graded maximal exercise test. An
activity level corresponding to 40–60% of VO2max is generally considered to be “moderate” in intensity,
while “vigorous” aerobic activities consist of those performed at greater than 60% of VO2max
7. Muscular fitness This term describes the force, the muscle can exert (strength) and the ability of the muscle to
perform continuously without fatigue
8. Resistance training This is also known as weight training or strength training. Resistance training involves the use of
muscular strength to work against a resistive load or move a weight. Examples include lifting free
weights, or using weight machines. Exercise at sufficient (moderate to high) resistance increases
muscular fitness
9. Intensity of resistance exercise The intensity of resistance exercise is often considered “moderate” if the resistance provided is
50–74% of the maximum that can be lifted a single time (one repetition maximum). High intensity
exercise involves resistance more than 75% of one repetition maximum
10. Repetition This describes number of times a resistance exercise is repeated during each set
11. Set A grouping of repetitions of a specific resistance exercise

Sympathetic Nervous System Glucagon

The sympathetic nervous system is activated at the Glucagon is an important counter regulatory hormone,
onset of exercise: this results in increased heart rate and and its effects oppose the action of insulin on fuel
vasoconstriction of vessels supplying the splanchnic bed metabolism. The level of glucagon increases in exercise
and non-exercising muscles. This results in increased and helps glycogenolysis and also gluconeogenesis.
blood supply to exercising muscles. The resulting increase
in catecholamines, stimulates lipolysis, suppresses insulin Cortisol and Growth Hormone
secretion and stimulates glycogenolysis. These processes
Although not the primary mediators of fuel metabolism,
increase the availability of fuel to the exercising muscles.
these act as counter-regulatory hormones and block the
effect of insulin especially in non-exercising tissues. They
Insulin Levels
thus act in conjunction with glucagon and synergistically
Insulin is one of the main controls of modulating carbo­ increase the availability of glucose for the exercising muscles.
hydrate and fat metabolism. At the beginning of exercise, Apart from the above primary controls, several addi­
insulin secretion is suppressed. This allows the liver to tional factors affect the fuel metabolism during exercise.
increase glucose output and lipolysis is also stimulated. Level of physical training greatly changes the way an
Muscle glucose uptake during exercise is not dependent individual handles exercise. Trained athletes tend to utilize
on insulin, and hence a reduction in insulin level does not free fatty acids more than glucose as fuel. This enhances
affect the uptake of glucose in exercising muscles. endurance because muscle glycogen levels are relatively
 Physical Activity and Exercise in Diabetes Mellitus 511

spared. The intensity of exercise itself also modulates the This is particularly more important after the age of
fuel metabolism during exercise. 50 years.
As the intensity rises, the importance of glucose as Regular resistance exercise can increase muscle
the source of energy increases progressively and the role strength by up to 30% and the muscle mass by 5–10%.
of lipolysis decreases progressively. The duration of exer­ There is also the added benefit of improvement in post­
cise will determine, what kind of fuel is used as energy ural stability, and hence a decrease in the risk of falls and
during exercise. For short stints of exercise, glycogen related injuries and fractures. These facts suggest that

chapter
breakdown alone can provide the necessary fuel supply. some form of resistance training is beneficial even in the

32
As the duration of exercise increases, glycogen stores get elderly, and its practice need not be restricted only to the
depleted after several hours and lipolysis becomes the younger population.
main source of fuel.
Since exercise results in consumption of large quan­ Effects of Exercise/Physical
tities of glucose, the composition of diet preceding exercise Activity on Diabetes Mellitus
also becomes important. A high carbohydrate diet is
associated with greater rate of glucose oxidation, and The general effects of exercise fuel metabolism in healthy
muscle glycogen stores. This results in greater endurance. individuals have been discussed. We now look at the
specific effects of exercise in diabetic individuals.
EFFECTS OF REGULAR TRAINING
ON FUEL METABOLISM EFFECTS OF EXERCISE IN
TYPE 1 DIABETES MELLITUS
Trained athletes without diabetes mellitus (DM) have
low fasting and post glucose challenge insulin levels and Individuals with type 1 DM do not have any endogenous
increased insulin mediated glucose uptake. Lipid and insulin production, and depend entirely on the therapeu­
lipoprotein profiles become less atherogenic with an tically administered insulin doses. In these individuals,
increase in high-density lipoprotein (HDL) and some the normal drop of insulin levels at the onset of exercise
reduction in triglycerides. Low-density lipoprotein (LDL) cannot occur, and hence hepatic glucose production
levels may remain unchanged, but particle diameter remains low in the face of increased glucose consumption
increases. These quantitative and qualitative changes by exercising muscles. Hence unless pre-exercise insulin
would prove beneficial for the cardiovascular status of doses are reduced, there is a serious risk of hypoglycemia
an individual. occurring during exercise. Moreover increased insulin
sensitivity may occur up to 24 hours after stoppage of
Effect of Regular Anaerobic Exercise exercise resulting in hypoglycemia several hours after
Regular anaerobic training improves the availability of exercise cessation.4 These effects are particularly promi­
ATP and phosphocreatine levels in the muscle allowing nent in individuals who generally have a good glycemic
higher exercise intensities for longer periods of time. control. In fact, exercise done regularly may help in
inducing or prolonging remission in a newly detected type
Fuel Metabolism During Anaerobic Activity 1 diabetic.5 On the other hand, a paradoxical rise in blood
glucose occurs in type 1 diabetics after short bursts of high
With very intense exercise (> 80% VOmax
2
), glucose produc­ intensity exercise. The resultant rise in blood glucose is
tion in liver may exceed the rate of glucose utilization usually evident within 15 minutes to 1 hour postexercise
resulting in increase in blood glucose levels. During
and is believed to be due to the dramatic elevation in levels
recovery from exercise, glucose utilization decreases
of counter-regulatory hormones during exercise. This
more rapidly than glucose production, and hence hyper­
occurs particularly in individuals with poorly controlled
glycemia can occur; this is restored to baseline in about
diabetes and may be accompanied by ketosis.
45 minutes by an increase in the insulin levels.
In type 1 diabetics, these changes may have major
implications in advice about time, duration and intensity
Effects of Regular Resistance Training of exercise; insulin dosing and carbohydrate intake before,
Advancing age causes a 10–15% reduction in muscle during and after exercise, and the appropriate recom­
strength and a 6% reduction in muscle mass per decade. mendations will be considered later.
512 Management

Effects of Exercise in Overall Health and to compromise on the tightness of glycemic control if
Glycemic Control in Type 1 Diabetes Mellitus they wish to participate in competitive sports and high
intensity activities.
Moy et al.6 have reported that higher habitual physical
activity is associated with decreased incidence of diabetes Resistance Exercise in Type 1 Diabetes Mellitus
related complications and mortality in individuals with
There is little information regarding the outcomes of only
type 1 DM.
resistance training in individuals with type 1 diabetes.
section

In this study of 548 patients with type 1 DM, it was

Durak et al.11 have conducted a study with a cross
observed that the risk of microvascular complications
8

over design with 10 weeks of heavy resistance exercise

varied inversely with self-reported activity. Sedentary
performed three times a week followed by 6 weeks of no
individuals were three times more likely to die than active
resistance training or vice versa. Mean HbA1c was 6.9 ±
ones even after adjusting for age, body mass index, smok­
1.4% at the end of no resistance exercise period versus
ing and diabetes related complications.
5.8 ± 0.9% at the end of 10 weeks of resistance exercise.
In a longitudinal study of 1,680 type 1 diabetics,
Serum cholesterol and self-monitored glucose levels
Waden et al.7 reported a beneficial effect of exercise on
were also lower at the end of the exercise period.
glycemic control. In a more recent randomized study,
Balducci et al.8 reported that the onset of peripheral neuro­ Several studies have shown the effects of combined
pathy can be prevented or delayed over a 4-year period aerobic and resistance-training programs in individuals
by regular exercise. In a study of 1,945 indivi­duals with with type 1 diabetes.12-14 These studies have shown gene­
type 1 diabetes, Waden et al.9 reported that individu­ rally positive effects including lower HbA1c, reduction in
als who had little physical activity were more likely to blood pressure (BP), improved cardiorespiratory fit­ness,
have impaired renal function, proteinuria, retinopathy greater muscle strength, improved lean body mass and
and cardiovascular disease when compared to individuals improvements in lipid profiles. There were however no
who engaged in more frequent and more vigorous physi­ concomitant diabetic control groups without exercise, and
cal activity. hence these results are difficult to interpret.

Aerobic Exercise in Type 1 Diabetes Mellitus EFFECTS OF EXERCISE IN

TYPE 2 DIABETES MELLITUS
Exercise done regularly does improve insulin sensitivity
and may help in inducing or prolonging remission in a Due to the differences in pathophysiologic factors invol­
newly detected type 1 diabetic; but the effects of regular ved, physical activity would be expected to be much more
aerobic activity on glycemic control in established type 1 beneficial in type 2 diabetes than type 1 diabetes in terms
diabetes is difficult to ascertain. Some studies have shown of both glycemic control and cardiovascular protection.
some improvement (albeit not statistically significant) in A large body of evidence supports the beneficial role of
HbA1c, but most studies have shown either no benefit or exercise in type 2 diabetes.
an increase in HbA1c. This could also be due to the drastic
reduction in insulin doses, or excess carbohydrate loading Aerobic Exercise in Type 2 Diabetes Mellitus
prior to exercise to avoid hypoglycemia. However, the Several studies have demonstrated an association between
participants in these studies still showed other benefits regular exercise and a reduction in morbidity and mortality
like lower body fat percentage, increased musclemass, in type 2 diabetics. Smith et al.15 have reported in a 10-year
increased aerobic capacity and improved lipid profiles prospective study of 347 individuals with type 2 diabetes
and a need for reduced exogenous insulin doses.10 and 1,317 non-diabetic controls that the lowest age-
adjusted all-cause death rate was seen in diabetics who
Anaerobic Exercise in Type 1 Diabetes Mellitus walked a mile or more daily. Wei et al.16 followed-up 1,263
The literature on the effect of regular anaerobic training men with type 2 diabetes over 12 years, and reported that
in type 1 diabetics is still sparse. Individuals with type 1 compared with the least fitness (bottom 20% on maximum
diabetes, who engage in competitive sports, often treadmill testing), those with moderate fitness had a
experience a worsening of glycemic control, and this 60% lower risk of cardiovascular and overall mortality.
aspect needs further research. At this point of time, it In one of the most well-documented prospective
appears that individuals with type 1 diabetes will have cohorts (the Nurses’ Health Study), Hu et al.17 observed a
 Physical Activity and Exercise in Diabetes Mellitus 513

lower risk of cardiovascular disease in women performing Till lately, resistance training was not considered
greater habitual exercise. advisable in a diabetic individual. However it is now
recognized that there is an age related reduction in muscle
Effects of Regular Aerobic Training in mass, and this may reduce insulin sensitivity. Resistance
Type 2 Diabetes Mellitus training can improve muscle mass and has been shown
to improve insulin sensitivity and glucose metabolism.
Regular exercise in type 2 diabetes will help in reducing There is also a modest improvement in lipid profiles.

chapter
both glycemic burden and help preventing atherosclerotic Regular resistance exercise also increases resting energy

32
cardiovascular disease by several mechanisms. expenditure in all age groups, and hence seems a valid
Enhanced post-receptor insulin signaling, increased intervention even in older individuals with type 2 diabetes.
glucose transporter activity, increased activity of glyco­ Studies have shown that post-exercise body weight does
gen synthase, decreased release of free fatty acids, incre­ not change significantly, suggesting that exercise as an
ased muscle capillary density and change in muscle intervention is beneficial in its own right, and this is not
composition all favor enhanced glucose disposal. mediated through weight reduction.
A decrease in visceral fat will also result in decreased Several studies have now shown an additional benefit
release of tumor necrosis factor (TNF) alpha and NEFA, of combining aerobic and resistance training over aero­
thus leading to reduction in insulin resistance. bic activity alone. Snowling and Hopkins18 reported in
Exercise also promotes better lipid profiles, a reduction a meta-analysis that HbA1c reduced by 0.8% in the com­
in BP, favorable change in coagulation parameters and bined exercise group versus 0.7% in the aerobic alone
inflammatory markers, thus reducing the risk of athero­ and 0.5% in the resistance training alone group. Studies
sclerosis. There is also improvement in endothelial func­ using combined exercise training have also reported
tion, and improvement in flow mediated dilatation. improvement in body composition and cardio­vascular
risk profile.19 Even in older individuals with type 2 diabetes
Fuel Metabolism during Activity in aged 60–70 years, regular exercise at least three times a
Type 2 Diabetes Mellitus week showed a significant change in body composition,
lipid profile and a decreasing trend in requirement of
Type 2 diabetics have both hepatic and peripheral insulin medications as compared to a group of diabetics who were
resistance. With moderate intensity aerobic exercise, peri­ sedentary.
pheral glucose uptake increases, hepatic glucose output In the DARE (Diabetes Aerobic and Resistance
and insulin levels fall, and there is also a reduction in Exercise) trial,20 251 previously sedentary individuals with
the circulating triglyceride levels. There is an overall reduc­ type 2 diabetes were randomized into four arms: aerobic
tion in blood glucose levels because peripheral glucose exercise training, resistance exercise training, combined
uptake exceeds the hepatic glucose output, but in patients exercise training, or a non-exercising control group.
not on exogenous insulin, the risk of hypoglycemia is Improvements in glycemic control was found in all exer­
relatively small. cise groups, and the improvement in the combined aero­
The effects of exercise on glucose and insulin levels bic and resistance training group was significantly greater
are similar, whether the exercise is performed in single than aerobic or resistance training alone.
versus multiple bouts as long as the duration of exercise The Italian Diabetes and Exercise study21 recruited
remains the same. This has great clinical importance 606 patients with type 2 diabetes, and randomized them
because this implies that just staying active the whole day to a year of exercise counseling alone or supervised facility
will still benefit a type 2 diabetic as much as a single bout based combined aerobic and resistance training twice a
of exercise. Strenuous prolonged physical activity (> 80% week plus exercise counseling. The group receiving super­
VO2max) will result in enhanced peripheral and hepatic vised training had significantly more favorable outcomes
insulin sensitivity that remains so for 12–16 hours after the for glycemic control, lipid profiles, body com­position, BP
exercise is over. Glycogen stores are depleted, and there and cardiovascular risk estimation than the group which
is a risk of development of hypoglycemia particularly received exercise counseling alone. This study makes
in usually well controlled patients even if not on insulin a strong case for supervised exercise training in type 2
therapy. diabetes rather than exercise counseling alone.
514 Management

Effect of Diabetes on Exercise Capacity Table 32.2: Comparison of responses to exercise in healthy
controls and type 2 diabetics
The effect of exercise on diabetes is now well known and Peak responses Healthy controls Type 2 diabetes mellitus
documented. However, it is not very well known that
• VO2max (mL/kg/min) 22.3 ± 4.2 18.7 ± 2.3
diabetes itself causes a reduction in the ability to exercise.
• Respiratory
Both in adults and teenagers with type 2 diabetes, 1.14 ± 0.05 1.8 ± 0.05
exchange ratio
there is an important finding that even in people who have • Perceived exertion 17.1 ± 1.4 16.6 ± 1.8
section

had diabetes for just about 3–5 years, there are substantial • Watts 123 ± 27.5 110 ± 21.1
effects on the ability to perform exercise. These effects
8

• Heart rate max/min 166 ± 15 169 ± 8

come partly from the heart. The reduction in exercise
• Cardiac output
capacity is believed to be about 20%.22 Ground breaking 13.1 ± 2.8 12.6 ± 1.6
(L/min)
work has already established that lack of exercise causes • Cardiac index
7.3 ± 1.4 6.8 ± 0.5
low cardiorespiratory fitness, and this predicts cardiovas­ (L/min)
cular disease and all-cause mortality in diabetics. About • Arteriovenous
12.8 ± 2.2 12.3 ± 1.3
20% reduction may not sound much especially in young oxygen difference
individuals, but as age advances and the window and • Pulmonary capillary
wedge pressure 15.7 ± 3.7 23.5 ± 3.9
the margins for physical activity narrow, it may be a real
(mm Hg)
problem. So if a person is unable to exercise and also if the
Ref: Regensteiner JG, Bauer TA, Reusch JE, et al. Cardiac
person does not exercise, the metabolic health and the
dysfunction during exercise in uncomplicated type 2 diabetes. Med Sci
heart status get worse and the vicious cycle is perpetuated. Sport Exe. 2009;41:977-84.
Regensteiner22 has reported that people with type 2
diabetes perceived much greater effort in performing perfusion of the heart. There was a correlation between
what might seem very low workload tasks to non-diabetic. the wedge pressure finding and the perfusion index. One
The situation is especially worse in women than in men. of the causes of heart stiffness could be under perfusion
Hence, exercise in diabetics may have to be initiated of the heart.
at much lower workloads than usual if patients’ persistence Nadeau et al.24 studied adolescents with type 2 diabetes
with exercise has to be ensured. Even at submaximal and found exactly the same abnormalities in exercise
exercise levels, diabetics show a 20% lower VO2max a marker tolerance and a reduced VO2max. This VO2max correlated
of cardiorespiratory fitness. positively with insulin sensitivity. Thus individuals with
To analyze the reasons for the above abnormalities greater insulin resistance had the greatest reduction
Regensteiner et al. designed a very elaborate study. They in VO2max.
took 10 non-diabetic mildly obese women and compared All the above studies show that diabetes itself without
them to 10 diabetic women who had a median duration the presence of other complications significantly reduces
of diabetes of 3.6 years. They had no complications at all an individual’s capacity to exercise.
in the echocardiogram, autonomic function testing and
urinary protein excretion. The cholesterol levels were also CARDIOVASCULAR ADAPTATIONS
not significantly different.
TO EXERCISE TRAINING
The following Table 32.2 shows that the VO2max was
lower in diabetics, but cardiac output was not significantly To test the question of whether exercise therapy itself
different; the arteriovenous oxygen difference, the marker would improve the capacity to exercise, Regensteiner
of peripheral extraction of oxygen also did not differ. set up a study in diabetic women aged median 59 years
However, on catheterization of the right heart, there and randomized them to 10 weeks of exercise versus
was a significantly higher capillary wedge pressure control. Exercise was performed thrice a week and was a
(a marker of stiffness of the heart) and diastolic dysfunc­ combination of aerobic and resistance training. Peak O2
tion in the diabetic group. consumption, LV filling dynamics, arterial compliance,
In another study, Regensteiner compared seven diabe­ lipids, insulin sensitivity were studied.
tics and seven controls by a nuclear sestamibi stress test. Among exercisers, the peak oxygen consumption
Analysis of the data showed that diabetics had a lower increased by 15% (P < 0.05) and the large artery comp­
total myocardial perfusion index, i.e. a reduction in the liance increased (P < 0.05). There was no change in other
 Physical Activity and Exercise in Diabetes Mellitus 515

Table 32.3: General guidelines: Exercise therapy in diabetes Table 32.4: Exercise therapy specific considerations in type 1
diabetes mellitus
• Patients with diabetes should exercise as part of their medical
management Avoid hypoglycemia during exercise by:

• There is good evidence to suggest benefits of exercise training • Avoiding heavy exercise during peak insulin action
extend to the cardiovascular consequences of the disease • Using non-exercising sites for insulin injection
• Exercise used to reduce weight should be combined with • If using multiple daily injections reducing pre-exercise insulin
dietary measures dosages by 20–50% or more if necessary. If using an insulin

chapter
• Moderate intensity aerobic exercise and resistance training pump, decrease basal rate and/or amount of last bolus before

32
should be part of the exercise regimen exercise. These reductions should be individualized and based
on blood glucose monitoring; not all individuals will require an
• Multiple shorter exercise sessions lasting at least 10 minutes
insulin dose reduction
each in the course of a day are probably as useful as a single
longer session of equivalent length and intensity • Monitor glycemia before, during and after exercise as necessary

• Include low intensity warm-up and cool-down periods especially • Taking extra carbohydrate before and hourly during exercise.
if vigorous exercise is undertaken This amount should be individualized and based on blood glu-
cose monitoring
• Exercise should be appropriate to the person’s general physical
• After prolonged exercise, monitor glycemia and take extra
condition and lifestyle
carbohydrate to avoid hypoglycemia. The quantity required can
• Use proper footwear and, if appropriate, protective equipment be estimated using the semi-quantitative technique (1 g carbo-
• Avoid exercise in extreme heat or cold hydrates/kg body weight/hour of activity) or by consulting tables
of energy requirements for particular activities
• Inspect feet before and after exercise
• Use extra caution in monitoring glycemia if exercise is being
performed within 24 hours of a hypoglycemic episode
• Intensive exercise should be avoided by type 1 diabetics espe-
variables and in controls no significant changes were seen cially when the glycemic control is poor in view of the possibility
in any parameters. This seems to suggest that exercise of paradoxical rise in blood glucose accompanied by ketosis
itself can improve the cardiovascular adaption to exercise • It is also important to note that insulin is considered a banned
and improve exercise capacity.23 substance by the World Anti-Doping Agency, and that elite-level
Not all studies have shown a similar improvement. athletes with diabetes will be required to apply for a Therapeutic
Use Exemption certificate prior to competition
There is a thinking that if the duration of diabetes is long,
the diastolic dysfunction may not improve. Hence exercise
therapy should be started early on in the course of the
Patients taking sulfonylureas or insulin may need to
disease. reduce the doses of these medications during days when
they exercise. Such adjustments should be guided by
RECOMMENDATIONS FOR glucose monitoring.
EXERCISE THERAPY IN DIABETES
Most types of exercise can be recommended to individuals
Aerobic Training
with type 1 and type 2 diabetes (Tables 32.3 and 32.4). It is generally recommended that all individuals accumu­
Exercise does not need to be strenuous and even regular late at least 150 minutes of moderate aerobic activity,
walking has beneficial effects. Specific recommendations and/or at least 90 minutes of vigorous aerobic exercise
and guidelines for exercise in individuals with diabetes every week, and that this activity be spread over at least
have been published by the American Diabetes Association 3–5 days. A day’s activity need not occur in a single session
and the American College of Sports Medicine.25 but may be accumulated in bouts of 10 or more minutes
at a time. Performing progressively greater amounts of
SPECIFIC CONSIDERATIONS IN moderate activity (in excess of the minimum 150 minutes)
TYPE 2 DIABETES MELLITUS is associated with progressively greater benefits. Studies
have also shown that group exercise environments can
Hypoglycemia is less common during exercise in type 2 DM provide motivation, social support and enjoyment for
as compared to type 1 diabetes, and extra carbohydrate is individuals starting and maintaining exercise training
therefore usually unnecessary. programs.
516 Management

Table 32.5: Caloric expenditure of 30 minutes of different activities

• Activity 40 kg 45 kg 50 kg 55 kg 65 kg 72 kg 77 kg
• Aerobic dancing 104 115 127 138 161 184 195
• Badminton 135 150 165 180 210 240 255
• Cycling 16 kmph 112 125 138 150 175 200 213
• Gardening 81 90 99 108 126 144 153
• Hiking (backpack) 180 200 220 240 280 320 340
section

• Housework 81 90 99 108 120 144 162

• Jogging 8 kmph 167 185 203 222 254 296 333
8

• Skipping rope 257 285 313 342 399 456 513

• Swimming 108 120 132 144 168 192 216
• Stair climbing 126 140 154 168 196 224 252
• Tennis 140 160 176 192 224 256 288
• Walking 5 kmph 72 80 88 96 112 128 142
• Weight training 230 255 280 306 357 408 439

Table 32.6: Target heart rate zones by age and breathing techniques to improve benefits and avoid
Age Target heart rate Predicted max heart injury. Use of weight machines is recommended initially
zone (60–85%) rate before moving on to free weights to avoid injury. Warming
20 120–170 200 up before each training session with low-intensity aerobic
25 117–166 195 exercise also helps to minimize injury. When multiple
30 114–162 190 exercises are performed in a workout, exercises involv­
35 111–157 185
ing the use of larger muscle groups (lunges or pull downs)
40 108–153 180
should be performed before exercises requiring the use
45 105–149 175
of smaller muscle groups (calf raises or biceps curls).
50 102–145 170
Multiple joint exercises, such as squats, chest presses
55 99–140 165
or seated row, should precede single joint exercises like
60 96–136 160
65 93–132 155
leg extensions or triceps extensions.
70 90–123 150
The best results are obtained with three sets of each
exercise performed on three non-consecutive days per
week. It is recommended that eight different muscle
Resistance Training groups be exercised at relatively high intensity (eight
repetitions performed at the maximum weight that can be
Braith et al.26 have shown in a recent meta-analysis that
lifted eight times).
resistance exercise can be safe and effective even for
vulnerable cardiac patients. High intensity weightlifting It is now recognized that the best effects are obtained
in healthy older men (mean age 64 years) caused less by combining 3–5 days of aerobic training with 2–3 days of
circulatory stress than walking up 192 stairs. Weightlifting resistance training as described above.
was not associated with increased proliferative retino­ The caloric expenditure associated with 30 minutes
pathy risk in the Wisconsin Epidemiologic Study of of some common daily activities and exercises have been
Diabetic Retinopathy, although the statistical power of presented in Table 32.5.
the study was limited.27 When properly performed, resis­ Maximum benefit of exercise is obtained at the least
tance training can be safe and enjoyable, and also offers risk when a person exercises in the target heart rate zone.
significant health benefits. Usually this is when the exercise pulse rate is 60–80% of
Resistance exercise training programs should be the maximum heart rate (calculated as 220 - age in years).
progressive in nature. Previously sedentary individuals Sometimes the target heart rate zone may be kept at 50%
should always start with a low intensity workload. Indi­ to begin with. The target heart rate zone for people of
viduals should receive proper instruction on lifting different age groups has been described in the Table 32.6.
 Physical Activity and Exercise in Diabetes Mellitus 517

SPECIAL CONSIDERATIONS IN PEOPLE WITH A large number of elderly people with diabetes will
LONG-TERM COMPLICATIONS OF DIABETES also suffer from osteoarthritis. The pain resulting from
this condition often makes these patients reluctant to exer­
Some advanced long-term complications of diabetes may cise, and this inactivity leads to weight gain and further
limit the individual’s ability to exercise but should not stiffness of joints. Swimming and other water activities
prevent them from becoming active at all. are excellent for these patients. Swimming has minimal
When proliferative or severe non-proliferative retino­ impact on joints and allows exercise with minimal pain.

chapter
pathy is present, it has been suggested that vigorous Water exercises can also help to reduce the stress on the

32
activity (both aerobic and resistance) be avoided because spine. Swimming laps, walking in the water and water
of the risk of precipitating vitreous hemorrhage or retinal aerobics are safe and effective for these people.
detachment.28 The American College of Sports Medicine recommends
Prior recommendations have advised non-weight- avoiding strenuous activity during periods of inflammation
bearing exercise for patients with severe peripheral neuro­ and working slowly upwards to a goal of up to 30 minutes
pathy. However, studies have shown that moderate-inten­ of moderate intensity aerobic exercise for 3–5 days a week.
sity walking may not lead to increased risk of foot ulcers If joint pain after exercise lasts longer than 2 hours, the
or re-ulceration in those with peripheral neuropathy.29 intensity and duration of future exercise sessions should
All individuals with peripheral neuropathy should wear be adjusted.
proper footwear and examine their feet daily to detect
lesions early. Anyone with a foot injury or open sore should
MIND BODY THERAPIES31-37
be restricted to non-weight-bearing activities. People with
autonomic neuropathy have associated unpredictable Chronic stress and negative affective states can contribute
carbohydrate delivery from gastroparesis, predisposing significantly to development and worsening of diabetes.
them to hypoglycemia. Autonomic neuropathy is also In response to this, there is interest in “mind body thera­
strongly associated with cardiovascular disease in people pies”, especially accepted is “yoga”—the traditional Indian
with diabetes. It is therefore recommended that people exercise method.
with diabetic autonomic neuropathy should undergo There are a large number of studies in literature
cardiac investigation before beginning physical activity about the efficacy of yoga in diabetes.31 There have been
more intense than that to which they are accustomed.30 more than 20 randomized controlled studies to evaluate
Physical activity can acutely increase urinary protein the effect of yoga. There is however great variation in
excretion. However, there is no evidence that vigorous design, duration, frequency and these studies are largely
exercise increases the rate of progression of diabetic kidney underpowered to detect significance of treatment effects.
disease, and there is likely no need for any specific exercise In studies carried out in India by Sahay et al.32,33
restrictions for people with diabetic kidney disease. patients with diabetes showed a fall in fasting and post­
prandial blood glucose values and HbA1c and a reduction
Cardiac Screening in the requirement of oral hypoglycemic agents and
All diabetics do not require to have cardiac screening tests insulin. In patients with brittle type 1 diabetes, there was
before starting exercise, especially if the activity planned an improvement noted with the practice of yoga.
is low to moderate intensity. However, cardiac assessment There was also some improvement in lipid profiles
with maximal exercise stress test is recommended in the with a decrease in cholesterol and triglycerides and an
following situations: increase in HDL.
• Electrocardiography is abnormal, atypical chest Certain “asanas” or postures such as “dhanurasana”
symptoms or “ardhamatsyendrasana” have been identified as being
• Peripheral or carotid occlusive arterial disease useful in the control of diabetes (Figs 32.1 and 32.2).
• Two or more of the following risk factors: These asanas have also been shown to improve lean
–– Low-density lipoprotein > 160 mg/dL, Total chole­ body mass and reduce body fat content. Long-term
sterol > 240 mg/dL, High-density lipoprotein follow-up of patients practicing these asanas regularly
< 35 mg/dL (> 5 years mean follow-up) has shown that the benefits are
–– Blood pressure >140/90 mm Hg sustained. Yogic practices like “pranayama”(breathing
–– Family history of premature coronary artery disease exercises) have been shown to produce a reduction in
–– Smoking plasma cortisol in patients with type 2 diabetes. Yogic
518 Management
section
8

Fig. 32.1: Dhanurasana Fig. 32.2: Ardhamatsyendrasana

practices have also been shown to increase the number of exercise and lifestyle modification on the prevention of
of insulin receptors leading to better insulin utilization. type 2 diabetes. The Da Qing Study38 enrolled 577 Chinese
Graded exercise tolerance in healthy volunteers showed a patients with impaired glucose tolerance and divided
significant reduction in oxygen consumption and lactate them into four groups: a control group, diet therapy alone,
levels after 90 days of yoga and pranayama therapy. exercise therapy alone, diet and exercise therapy. All the
Diabetics also showed an improvement in their exercise treatment groups had a significant drop in incidence of
tolerance (without an increase in oxygen consumption). diabetes over 6 years compared with the control group.
There is other short-term controlled and uncontrolled The group with only exercise as the intervention showed
data to show that yogic exercises can reduce BP, trigly­ the highest reduction in incidence of diabetes.
cerides and heart rate and also markers of oxidative stress The second study, the Finnish Diabetes Prevention
and fibrinogen. A comprehensive program of diet/stress study39 divided patients with impaired glucose tolerance
management and yoga in people with type 2 diabetes has into two groups: lifestyle changes with diet and exer­
shown reduction in LDL, BP and coronary lesions after cise and a non-treatment control group. After an average
one year. The possible mechanisms of effect include follow-up of 3.2 years, the incidence of diabetes in the
increased parasympathetic and reduced sympathetic tone, treatment group was reduced by 58%. The risk reduction
reduced systemic inflammation, possible improvement in was most significant in those who exercised for more than
endo­thelial function, skeletal muscle activation: increased 4 hours every week.
glu­cose metabolism similar to other forms of exercise. The Diabetes Prevention Program,40 a large multicenter
Overall yogic practices do seem to have a useful role clinical trial, examined the incidence of DM in patients
in the therapy of diabetes but more extensive research with impaired glucose tolerance who were randomized to
is necessary. placebo, lifestyle intervention and metformin treatment
groups. The lifestyle treatment group had a 58% reduction
ROLE OF EXERCISE IN in the incidence of diabetes as compared to controls. This
was significantly better than the 31% reduction achieved
DIABETES PREVENTION
with metformin.
Numerous studies have evaluated the effectiveness of
exercise in the prevention of type 2 diabetes. It has been SUMMARY
observed that the beneficial effect of exercise is independent It is now clearly established that exercise therapy has
of the correction of the risk factors of diabetes. Recently, a significant role both in the prevention and treatment
three important clinical trials have evaluated the effects of DM.
 Physical Activity and Exercise in Diabetes Mellitus 519

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21. Balducci S, Zanuso S, Fernandos F, et al. The Italian
34. Jain SC, Uppal A, Bhatnagar SO, et al. A study of response
diabetes and exercise study. Diabetes. 2008;57:A306-7.
pattern of non-insulin dependent diabetics to yoga therapy.
22. Regensteiner JG, Bauer TA, Reusch JE, et al. Cardiac dys­
Diab Res Clin Pract. 1993;19:69-74.
function during exercise in uncomplicated type 2 dia­betes.
35. Singh S, Malhotra V, Singh KP, et al. Role of yoga in
Med Sci Sport Exe. 2009; 41:977-84.
modifying certain cardiovascular functions in type 2
23. Brandenburg SL, Reusch JE, Bauer TA, et al. Effects of
exercise training on oxygen uptake kinetic responses in diabetic patients. JAPI. 2004;52:203-56.
women with type 2 diabetes. Diabetes Care. 1999; 22: 36. Pederson O, Beck-Nielsen H, Heding L. Increased insulin
1640-6. receptors after exercise in patients with insulin-dependent
24. Nadeau KJ, Zeitler PS, Bauer TA, et al. Insulin resistance diabetes. N Engl J Med. 1980;302:886-90.
in adolescents with type 2 diabetes is associated with 37. Surwit RS, van Tilburg MAL, Zucker N, et al. Stress manage­
reduced exercise capacity. J Clin Endocrinol Metab. 2009; ment improves long-term glycemic control in type 2
94:3687-95. diabetes. Diabetes Care. 2002;25:30-4.
25. Sheri R, Sigal RJ, Fernhall B, et al. Exercise and type 2 38. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise
diabetes. The American College of Sports Medicine and the in preventing NIDDM in people with impaired glucose
American Diabetes Association : joint position statement. tolerance: the Da Qing IGT and Diabetes study. Diabetes
Diabetes Care. 2010;33:e147-67. Care. 1997;20:537-44.
26. Braith RW, Beck DT. Resistance exercise: training adapta­ 39. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention
tions and developing a safe exercise prescription. Heart of type 2 diabetes by changes in lifestyle among subjects
Failure Rev.2008;13:69-79. with impaired glucose tolerance. N Engl J Med. 2001;344:
27. Cruickshanks KJ, Moss SE, Klein R, et al. Physical 1343-50.
activity and the risk of progression of retinopathy or the 40. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduc­
development of proliferative retinopathy. Ophthalmology. tion in the incidence of type 2 diabetes with lifestyle inter­
1995;102:1177-82. vention or metformin. N Engl J Med. 2002;346:393-403.
 Chapter 33
Yoga and Relaxation
Techniques in
Diabetes Mellitus
GR Sridhar

Yoga in Diabetes

Chapter Outline
♦♦ Stress Response and Relaxation Response ♦♦ Mindfulness-Based Stress
♦♦ Mind-Body Techniques Reduction
♦♦ Yoga in Diabetes Mellitus ♦♦ Meditation and Prayer
♦♦ Role of Yoga in Prevention of Diabetes ♦♦ Basis of Relaxation Response
♦♦ Biological Basis for Effectiveness of Yoga ♦♦ Stress Reduction Techniques

INTRODUCTION STRESS RESPONSE AND

RELAXATION RESPONSE
There is now adequate evidence that stress leads to insulin
resistance, obesity and type 2 diabetes mellitus; in addition, If stress is considered as a process whereby demands are
stress also hampers their management.1 Efforts are made more than what an individual can cope with relaxation
to combat stress. Relaxation and relaxation response is response is characterized by decreased arousal of the
one major area of intervention. From the early proof of sympathetic nervous system, or a “wakeful hypometabolic
concept studies on small samples in the early 1990s,2 state” that allows an individual to maintain optimal stress
relaxation methods have been employed in improving level.6
outcomes of diabetes mellitus, along with other medical
methods. Shortly afterwards, other studies reported that MIND-BODY TECHNIQUES
relaxation was non-inferior to physical exercise in lower­ Relaxation techniques fall under the umbrella of mind-
ing glycosylated hemoglobin.3 Evidence from real-world body phenomenon, where a confluence of mind, body and
setting also showed that stress management was cost- behavior is believed to influence one another and thereby
effective when applied to groups in providing clinically health and disease. Attempts are made to synchronize
significant benefits for subjects with type 2 diabetes them to improve physical and emotional health. They may
mellitus.4 It is essential to be reminded that these methods be used alone, in combination and along with conven­
complement and do not replace conventional treatment tional treatment methods. A variety of methods exist such
of diabetes.5 These techniques are safe, practical and cost- as breathing techniques to reduce tension and induce
effective methods to cope with the stress of living with relaxation and progressive muscle relaxation; where
diabetes. sequential tightening and relaxation of muscle groups
522 Management

aims to make one aware of the effects of stress on muscles; Table 33.1: Beneficial effects of yogic practices
the individual is taught to then relax muscles in times of • Improves glycemic control
stress. In guided imagery or visualization, the power of • Reduction of blood pressure
imagination is invoked to evoke positive responses in • Correction of dyslipidemia
physical or emotional spheres; during times of stress, these • Reduction of insulin resistance and correction of
hyperinsulinemia
images are used. Meditation is also an important mind-
• Elimination of stress
body technique in which the intention is to focus attention
section

and calm the mind. Meditative practices as used to help

also been shown to increase the lean body mass and
8

in health are independent of spiritual or religious beliefs,

in which a state of concentrated attention is practised decrease the body fat content. Long-term follow-up of
on a single subject. The purpose is to focus and calm the subjects practicing these asanas regularly (greater than
mind. Other methods include yoga, Tai Chi and clinical 5 years mean follow-up) has shown that these benefits
biofeedback. are sustained and the drug requirements are lower with
lower rates of infections, ketoacidosis, hypoglycemia and
YogA in Diabetes Mellitus improvement in exercise tolerance.8-10

Yogic practices particularly pranayama have been
Yoga has a long history and is a term derived from Sans­ shown to produce a decline in plasma cortisol levels
krit, meaning “to join together”. It combines stretching, in patients with type 2 diabetes. In contrast, in normal
practising poses, breath control and meditation. A variety individuals and also in subjects with bronchial asthma,
of yogic forms are practiced: Hatha yoga, which is a the cortisol levels are increased.
relaxing and restorative form, Ashtanga yoga consists of These practices have been shown to increase the
strenuous poses and Anusara yoga or slow free-flowing number of insulin receptors, while bringing about a dec­
movements. Considering that diabetes is increasing line in insulin levels and improvement in insulin-glucose
in India and its medical management is bound to be ratio. Plasma-free fatty acid levels have also been shown
expensive, yoga has been included in the management of to decrease. This suggests that the regular practice of
diabetes. The chief advantages are that it is inexpensive, yoga improves the insulin sensitivity and leads to better
and more importantly, it is holistic: as physical exercises utilization of insulin.
are combined with lifestyle and behavior modifications Graded exercise tolerance in normal healthy volun-
teers showed a significant decrease in the oxygen con-
such as diet, relaxation and stress management.7 More
sumption and the blood lactate levels after 90 days of
recently several well-planned studies have demonstrated
pranayama and yoga training.11 Individuals with dia­betes
the beneficial effects of yogic practices in diabetes.
also showed improvement in their exercise tolerance
Table 33.1 lists the beneficial effects of yogic practices
following yogic practices. After yoga training the lactate
in patients with diabetes.
levels did not rise significantly and the patients showed
Patients with diabetes demonstrated a significant fall
an increase in their ability to perform exercise for longer
in fasting, postprandial blood glucose values and hemo­
periods, suggesting that their anaerobic threshold was
globin A1c (HbA1c) with reduction in the requirements postponed.11
of oral hypoglycemic agents and insulin. (Patients with In comparison, physical training exercises also improve
type 1 diabetes showed marked improvement with prac­­ exercise tolerance and postpone anaerobic threshold but
tice of yoga). There was a salutary effect on the lipid yogic practices seem to do so without increasing the oxygen
profile, with a fall in serum cholesterol, triglycerides and consumption.12 Skinfold thickness was also significantly
an increase in high density lipoprotein (HDL) cholesterol reduced with an increase in the lean body mass after yogic
fraction. Certain asanas have been identified as useful in practices.13
the control of diabetes.8-10 A number of recent studies have demonstrated the
Other asanas such as Dhanurasana, Ardha Matsyendra­ beneficial effects of yogic practices in diabetes and obesity:
sana, Bhujangasana, Naukasana, Halasana, Vajrasana yogic breathing (Sudarshan kriya yoga and pranayama)
and Paschimottanasana have been found to have improved well-being in the physical, psychological and
beneficial effects in terms of glycemic control, reduction social domains and quality of life.14 Similarly practice of
in requirements for medications, insulin kinetics and yoga over 40 days at a yoga camp improved well-being,
also producing a sense of well-being. These asanas have reduced anxiety and lowered body mass index (BMI).15
 Yoga and Relaxation Techniques in Diabetes Mellitus 523

Yoga-nidra, practiced up to 90 days by subjects with type Sr. No. Yoga

2 diabetes was shown to flatten blood glucose fluctuations 1. Prayer—Omkar
and improve symptoms.16
Among individuals without diabetes, women who
had mental distress showed improved measures of stress
and psycho­logical outcomes after a 3-month yoga class.17 2. Trikonasana
When compared with supine rest, 20 minutes of yoga-

chapter
based deep relaxation reduced the anxiety score.18 Thus,

33
yogic practices have a useful role in the control of diabetes
and prevention of its long-term complications. 3. Katichakrasana

Role of Yoga in
Prevention of Diabetes 4. Suryanamaskar

Yogic practices also are likely to play a role in the preven­

tion of type 2 diabetes. Studies in diabetic patients (type 1
and 2), and patients with hypertension and obesity 5. Ardha-vakrasana/Ardha-
have shown a reduction in the fat percentage of the body matsyendrasana
with an increase in the lean body mass. Upregulation
of the insulin receptors and the normalization of the 6. Pawanmuktasana
insulin/glucose ratios also occur following yogic practices.
The practice of Shavasana and Makarasana, help in
elimination of stress and decrease the output of counter-
7. Bhujangasana
regulatory hormones. Therefore, yogic practices bring
about an improvement in insulin sensitivity and reduc­
tion in insulin resistance which is the major abnormality
underlying the development of type 2 diabetes and which 8. Dhanurasana
antedates the development of type 2 diabetes by several
years. Therefore, it is postulated that these beneficial
effects on the insulin kinetics, prevent beta-cell exhaustion 9. Padachakrasana
and thereby prevent the development of type 2 diabetes.7-11
Some useful commonly practiced yogic exercises and
pranayama are illustrated in Figure 33.1. A preliminary
study from Pittsburgh suggested that a yoga program 10. Prashantha asana
could be an option to reduce risk of type 2 diabetes
in high-risk adults, as well as to lower cardiometabolic Pranayama
risk factors.19 1. Rechaka, puraka

BIOLOGICAL BASIS FOR

EFFECTIVENESS OF YOGA 2. Bhastrika

Studies are being conducted to understand how yoga

exerts its beneficial effects. There is evidence that
physical exercise, changes in biochemical, physiological 3. Nadi shodhana (alterna-
and endocrine profile, along with stress elimination tive breathings)
and inculcation of self-discipline is responsible for the
benefits. In addition, yoga is reported to stabilize the
sympathetic and parasympathetic nervous system and
Fig. 33.1: Yogic exercises and pranayama
downregulate the hypothalamo-pituitary-adrenal axis.20
524 Management

Relaxation response, of which yoga has a component, Prayer is another method by which stress of coping
has been shown to change gene expression response. with chronic diseases is addressed. It is defined as an
Both short-term and long-term practitioners of relaxation “active process of communicating with and appealing to
response had “constitutive changes in gene expression” a higher spiritual power”.26 Prayer can be employed for
which may be related to the relaxation response.21 wellness and also for specific health conditions, although
patients rarely discussed prayer with their physicians. The
MINDFULNESS-BASED STRESS REDUCTION beneficial effects of prayer may be attributed to its action as
section

Mindfulness meditation and Hatha yoga can be taught in a relaxation response, a placebo, an expression of positive
8

a structured clinical program. Mindfulness-based stress emotions or as a channel for supernatural intervention.
reduction (MBSR) is an integrative therapy of the mind
and body.22 It focuses on cultivating enhanced moment- BASIS OF RELAXATION RESPONSE
to-moment non-judgmental awareness of surroundings. Relaxation response has been called “a state rather than
Relaxation in this method is obtained by developing
a specific technique”, which can be approached by many
mental discipline that leads to deeper awareness and
paths such as breath awareness, guided imagery, progres­
movement, a state of physiological relaxation and of non-
sive muscle relaxation, transcendental meditation and
judgmental perspective. Diabetes is associated with a
yoga. Engagement in repetitive or sustained mental or
variety of stress involving anxiety, depression and social
physical action and disregarding distracting thoughts
isolation. Early studies show that MBSR can be useful in
leads to a break in the routine of everyday thinking, where
type 2 diabetes mellitus.
both body and mind are quieted.
It can be a facilitator to adapt to chronic illness, acting
through relieving stress, and thereby influencing anxiety
and depression. The aim is a “non-judgmental acceptance STRESS REDUCTION TECHNIQUES27
of the present experience rather than ruminations on Progressive Muscle Relaxation
previous or anticipated events”.
The subject tenses and relaxes muscle groups sequentially,
with closed eyes; tension is placed for 10 seconds followed
MEDITATION AND PRAYER
by a release of muscle tension for 20 seconds. Mentally
There is overlap among different methods classified as there is a focus on the different feelings while tense and
medication: an Evidence Report on Meditation Practices while relaxed. With practice, it is possible to effectively
for Health published by the Agency for Healthcare and relax on demand.
Research Quality (AHRQ) categorized meditation into
five categories23 (1) mantra meditation (transcendental Autogenic Training
meditation technique); (2) relaxation response; (3) clinically This is a self-relaxation method in which relaxation res­
standardized meditation; (4) mindfulness meditation ponse is elicited. The subject learns directions by which the
(Vipassana, Zen Buddhist meditation, MBSR, mindfulness- body is allowed to relax; six standard exercises comprise
based cognitive therapy) and (5) yoga, Tai Chi and Qigong. visual imagination and verbal cues.
In general, all these had use of breathing as a universal
component along with techniques to anchor attention. Relaxation Response
Spiritual or belief component was not universal. Although
most published studies were not scientifically robust, Relaxation response is simple to learn and practice in
the commonly studied methods involved transcendental which a word, sound or prayer is repeated to achieve
meditation and relaxation response, followed by other concentration and dispel intruding thoughts.
mantra practices, yoga and mindfulness meditation.
Spirituality and religion have long been recognized
Guided Imagery
to be effective coping methods to deal with stress of non- A trained professional can teach this technique, which
communicable diseases such as diabetes.24 They were is practiced for 10 minutes a day. The subject employs
shown to improve treatment compliance and to help in personalized images through a variety of adaptable
lowering stress due to managing diabetes. A pilot Indian techniques such as relaxation/stress reduction. A link
report showed that women tended to believe that religion is created with the image when a stressful situation is
and faith could help in glycemic control.25 encountered.
 Yoga and Relaxation Techniques in Diabetes Mellitus 525

Transcendental Meditation 3. Van Rooijen AJ, Rheeder P, Eales CJ, et al. Effect of exer-
cise versus relaxation on haemoglobin A1c in black females
Maharishi Mahesh Yogi introduced this method, which is with type 2 diabetes mellitus. QJM. 2004;97:343-51.
simple and needs to be practiced 20 minutes a day. The 4. Surwit RS, van Tilburg MA, Zucker N, et al. Stress man-
eyes are closed and a sound or a sequence of sounds are agement improves long-term glycemic control in type 2
repeated which shifts ones mind to a wakeful but restful diabetes. Diabetes Care. 2002;25:30-4.
5. McGrady A. The effects of biofeedback in diabetes and
state, called transcendental consciousness. It allows one
essential hypertension. Cleve Clin J Med. 2010;77:S68-71.

chapter
to adapt to environmental stressors. 6. Park ER, Traeger L, Vranceanu AM, et al. The development

33
of a patient-centered program based on the relaxation
SUMMARY response: the Relaxation Response Resiliency Program
(3RP). Psychosomatics. 2013;54:165-74.
In summary, relaxation techniques and yoga have a 7. Aswathy S, Unnikrishnan AG, Kalra S. Effective manage-
positive effect, albeit for a short term on diabetes out­ ment of type 2 DM in India: looking at low-cost adjunctive
comes; long-term positive benefits are yet to be clearly therapy. Indian J Endocrinol Metab. 2013;17:149-52.
defined. Nonetheless, associated aspects of diet regula­ 8. Sahay BK. Yoga and diabetes. J Assoc Physicians India.
1986;34:645-8.
tion and stress response, along with inculcation of self-
9. Sahay BK, Ramanand Y, Raju PS, et al. The effect of yoga in
control have a beneficial effect in the management
diabetes. In: Bajaj JS (Ed). Diabetes Mellitus in Developing
of diabetes, with low cost and few or no side effects.28 Countries. New Delhi: Interprint; 1984. pp. 379-81.
There is sufficient scientific evidence to warrant a critical 10. Sahay BK, Murthy KJR, Raju PS, et al. Long-term follow-up
review.29 Replication studies of beneficial effects in larger on effect of yoga in diabetes. In: Kobe BS Baba S (Kobe)
samples for longer duration using robust experimental (Ed). Diabetes Research and Clinical Practice. Abstracts of
methods are under way. In addition, the mechanisms for XIII Congress of IDF. POS-004;293:655.
11. Raju PS, Kumar KA, Reddy SS, et al. Effect of yoga on exer-
effectiveness of such techniques are being identified using
cise tolerance in normal healthy volunteers. Indian J Physi-
genomic and transcriptomic changes in peripheral blood. ol Pharmacol. 1986;30:121-32.
A recent study identified that relaxation response was 12. Sahay BK, Murthy KJ, Raju PS, et al. Effect of yogic practices
associated with overexpression of genes associated with on the exercise tolerance in diabetics. Diabetes. 1991;40
energy metabolism, mitochondrial function and insulin Abstract 1590:398.
secretion. Simultaneously, there was a reduction of genes 13. Madhavi S, Raju PS, Reddy MV, et al. Effect of yogic exercises
related to stress-related pathways.30 on lean body mass. J Assoc Physicians India. 1985;33:465-6.
14. Jyotsna VP, Joshi A, Ambekar S, et al. Comprehensive yogic
breathing program improves quality of life in patients with
Further READING diabetes. Indian J Endocrinol Metab. 2012;16:423-8.
1. Longevity, regeneration and optimal Health. Ann NY 15. Kosuri M, Sridhar GR. Yoga practice in diabetes improves
AcadSci. 2009;1172. physical and psychological outcomes. Metab Syndr Relat
2. Aljasir B, Bryson M, Al-sheri B. Yoga practice for the manage­ Disord. 2009;7:515-7.
ment of type 2 diabetes mellitus in adults: a systematic review. 16. Amita S, Prabhakar S, Manoj I, et al. Effect of yoga-nidra
Evid Based Complement Alternat Med. 2010;7:399‑408 on blood glucose level in diabetic patients. Indian J Physiol
3. Field T. Yoga clinical research review. Complement Ther Pharmacol. 2009;53:97-101.
Clini Pract. 2011;17:1-8 17. Michalsen A, Grossman P, Acil A, et al. Rapid stress reduc-
4. Telles S, Bhat R. Yoga: physiology and applications in ther- tion and anxiolysis among distressed women as a conse-
apy and rehabilitation. In: Tandon OP, Tripathi Y (Eds). quence of a three-month intensive yoga program. Med Sci
Best & Taylor’s Physiological Basic of Medical Practice. New Monit. 2005;11:CR555-61.
Delhi: Wolters Kluwer; 2012. pp. 1217-30. 18. Khemka SS, Rao NH, Nagarathna R. Immediate effects of
two relaxation techniques on healthy volunteers. Indian J
Physiol Pharmacol. 2009;53:67-72.
REFERENCES
19. Yang K, Bernardo LM, Sereika SM, et al. Utilization of
1. Sridhar GR, Madhu K. Stress in the cause and course of 3-month yoga program for adults at high risk for type 2
diabetes. Int J Diab Dev Countries. 2001;21:112-20. diabetes: a pilot study. Evid Based Complement Alternat
2. McGrady A, Bailey BK, Good MP. Controlled study of Med. 2011;2011:257891.
biofeedback-assisted relaxation in type 1 diabetes. Diabetes 20. Sengupta P. Health impacts of yoga and pranayama: a state-
Care. 1991;14:360-5. of-the-art review. Int J Prev Med. 2012;3:444-58.
526 Management

21. Dusek JA, Out HH, Wohlhueter AL, et al. Genomic counter- 27. Varvogli L, Darviri C. Stress management techniques:
stress changes induced by the relaxation response. PLoS evidence-based procedures that reduce stress and promote
One. 2008;3:e2576. health. Health Sci J. 2011;5:74-89.
22. Whitebird RR, Kreitzer MJ, O’Connor PJ. Mindfulness- 28. Alexander GK, Taylor AG, Innes KE, et al. Contextualizing
based stress reduction and diabetes. Diabetes Spectr. the effects of yoga therapy on diabetes management: a
2009;22:226-30. review of the social determinants of physical activity. Fam
23. Meditation Practices for Health: State of the Research 2007. Community Health. 2008;31:228-39.
AHRQ Publication No. 07-E010. 29. Bushell WC, Theise ND. Toward a unified field of study:
section

24. Sridhar GR. Diabetes, religion and spirituality. Int J Diab

longevity, regeneration, and protection of health through
Dev Countries. 2013.
8

medication and related practices. Ann N Y Acad Sci.

25. Sudha GR. Well-being, religiosity and social support in
type 2 diabetes. Dissertation submitted for award of MPhil 2009;1172:5-19.
(Psychology and Parapsychology) to Andhra University, 30. Bhasin MK, Dusek JA, Chang BH, et al. Relaxation response
Visakhapatnam, 2004. induces temporal transcriptome changes in energy meta­
26. Jantos M, Kiat H. Prayer as medicine: how much have we bolism, insulin secretion and inflammatory pathways. PLoS
learned? Med J Aust. 2007;186:S51-3. One. 2013;8:e62817.
 Chapter 34
Insulin Secretagogues
Rakesh K Sahay

Insulin Secretagogues

Chapter Outline
♦♦ Role of Insulin Secretagogues in Management of ♦♦ Timing of Secretagogue Administration
Type 2 Diabetes Mellitus ♦♦ Comparison of Various Secretagogues
♦♦ Classification of Insulin Secretagogues ♦♦ Newer Insulin Secretagogues
♦♦ Insulin Secretagogues and Cardiovascular Disease

INTRODUCTION ROLE OF INSULIN SECRETAGOGUES

IN MANAGEMENT OF TYPE 2
Type 2 diabetes mellitus (T2DM) has now been described
to be caused by eight different pathophysiological mecha­
DIABETES MELLITUS
nisms of which the two most important defects remain Defects in both insulin secretion and sensitivity are
insulin resistance and a defect in insulin secretion. While described in the pathogenesis of type 2 diabetes. Fasting
insulin resistance starts several years before the deve­ glucose levels are basically determined by hepatic glucose
lopment of diabetes, the presence of an insulin secretory output, which is controlled by insulin and glucagon levels
defect is essential for the development of diabetes. The in the portal circulation whereas postprandial glucose
defect in insulin secretion therefore determines not levels are dependent on the composition of the diet and
only the development of type 2 diabetes but also its pro- insulin mediated peripheral glucose uptake. While the
gression. maintenance of hepatic glucose output, i.e. fasting glucose
The recent management guidelines suggested by requires significantly lower levels of insulin, enhancement
various professional bodies across the world advocate of the peripheral glucose uptake, which is reflected as the
the initiation of treatment of type 2 diabetes with medical postprandial glucose level requires much higher levels of
nutrition therapy along with metformin. However, when insulin. It is therefore logical that the sequence of abnor­
metformin alone is not sufficient to maintain glycemic mal glucose metabolism starts from impaired glucose
control the addition of an insulin secretagogue is the tolerance, progresses to minimal fasting hyperglycemia
next available option. The use of insulin secretagogues with significant postprandial hyperglycemia and finally to
may also be considered earlier when the patient with fasting hyperglycemia with marked postprandial hyper­
type 2 diabetes has difficulty in tolerating metformin or glycemia. All patients with type 2 diabetes with hyper­
has contraindication to metformin or in those in whom glycemia have some deficiency in insulin secretion and
defective β-cell function is thought to be the predominant the higher the degree of fasting hyperglycemia, greater is
pathology. the insulin deficiency. Therefore, insulin secretagogues
528 Management
section
8

Fig. 34.1: Chemical structure of the sulfonylurea compounds

which act by improving β-cell function and augment Table 34.1: Classification of insulin secretagogues
insulin secretion are powerful tools in the management of
Sulfonylureas:
type 2 diabetes. Apart from type 2 diabetes, several types of
First generation: Tolbutamide, chlorpropamide, tolazamide,
diabetes like maturity onset diabetes of the young (MODY)
Second generation: Glipizide, glicazide, glibenclamide
are also characterized by defects in insulin secretion and
Third generation: Glimepiride
respond to the secretagogues.
Glinides: Repaglinide
CLASSIFICATION OF INSULIN Nateglinide
SECRETAGOGUeS
available in the 1950s. It was later withdrawn from the
The classification of insulin secretagogues is shown in market due to bone marrow toxicity. The chemical struc­
Table 34.1. ture of sulfonylureas in use now is shown in Figure 34.1.
Their pharmacokinetics and dosage are depicted in
Sulfonylureas Table 34.2. First generation sulfonylureas are no longer
Sulfonylureas were discovered serendipitously while look­ available, however, compounds from the subsequent
ing for newer sulfonamides. The first sulfonylurea to be gene­rations are currently used in practice (e.g. glibencla­
used in clinical practice was carbutamide, which became mide, glipizide, gliclazide and glimepiride).
 Insulin Secretagogues 529

Table 34.2: Dosage requirements and duration of action of different insulin secretagogues
Drug Starting Maximum total Number of Duration of
dose daily dose doses action in hours
Tolbutamide 500 mg 2 gm 3 + HS 6–12
Chlorpropamide 100 mg 500 mg 1 Up to 60
Tolazamide 100 mg 1,000 mg 1–2 10–14
Glibenclamide 1.25 mg 20 mg 1–3 10–24

chapter
Glipizide 1.25 mg 15 mg 2–3 4–6

34
Gliclazide 40 mg 240 mg 1–3
Glimepiride 1 mg 8 mg 1 12–24
Repaglinide 0.5 mg 4 mg 3–4 4–5
(one per meal)
Nateglinide 60 mg 180 mg 3–4 4–5
(one per meal)

Structure of Sulfonylureas
Basically sulfonylureas have a benzene ring + sulfonyl
group + urea. The individual compounds in this group
differ in the para position of benzene ring and the group
attached to the urea moiety (Fig. 34.1).

Mechanism of Action
Glucose stimulates insulin secretion by elevating the
intracellular ratio of adenosine triphosphate (ATP) to
adenosine diphosphate (ADP) in the pancreatic β-cell,
which causes closure of ATP-sensitive potassium (K+)
(KATP) channels, resulting in membrane depolarization
and influx of calcium into the β-cell. This increase in Fig. 34.2: Mechanism of action of sulfonylurea
intracellular calcium causes release of insulin from β-cell (ATP: Adenosine triphosphate; SU, sulfonylurea) The first step in phys­
iological insulin release is glucose entry into the β-cell, which leads to
secretory granules (Fig. 34.2). increased production of adenosine triphosphate (ATP). ATP binds to
Sulfonylureas and meglitinides (another class of insu­ and shuts off the K+ channels. The insert in the bottom right corner
lin secretagogues) bind to the sulfonylurea receptor (SUR) shows the mechanism of action of sulfonylureas at this step. The sulfo­
nylureas bind to the sulfonylurea receptor (SUR) component, which
on the β-cell membrane, which causes closure of the closes the K+ channel and depolarizes the cell membrane. This leads
KATP channels, ultimately resulting in release of insulin. to opening of Ca+ channels and Ca+ pours in. This leads to release of
Sul­fonylureas may have an additional method of action. preformed insulin from the storage granules by a process of exocytosis

Up to 90% of sulfonylurea binding proteins (Fig. 34.2)

are located in the intracellular membranes including the after mixed meals containing protein and carbohydrate,
secretory granules storing insulin. So, they may potentiate the beneficial effect is generally preserved.
exocytosis of insulin containing granules by direct Chronic administration of sulfonylureas in type 2
action on these binding proteins. Insulin synthesis is not diabetes also decreases glucagon levels. This may be due
enhanced by sulfonylureas, in fact it may even be reduced. to increased release of insulin as well as somatostatin both
It is only the release of insulin after a meal that is increased. of which impair glucagon release.
It is seen that after prolonged administration, even the The KATP channels consist of two subunits: (1) a SUR
postglucose tolerance test (post-GTT), insulin levels are and (2) the K+ pore (Kir 6.2), where ATP binds and closes
not increased and may be decreased by sulfonylureas. But, the channel (Fig. 34.2). Apart from pancreatic β-cells, KATP
530 Management

Table 34.3: Extrapancreatic effects of sulfonylureas to its prolonged action and relative lack of specificity on
different KATP channels. Glibenclamide can rarely cause
Site of Direct action Indirect action
action (i.e. through insulin)
flushing with ethanol ingestion and it causes slight diu­
resis. Glibenclamide is contraindicated in patients with
Liver Increases fructose 2,6- Increases hepatic
hepatic or renal failure. The micronized formulation of
biphosphate glycogen synthesis
Increases glycolysis Increases hepatic lipid glibenclamide has a faster onset of action due to its
Decreases gluconeogen­ synthesis increased rate of gastrointestinal absorption.
section

esis Glipizide: Glipizide has the shortest half-life (2–4 hours)

Decreases oxidation of long
8

among the potent sulfonylureas and is hence the

chain fatty acids
preferred drug when hypoglycemia has to be avoided.
Skel­ Increases glucose Potentiates insulin-
The recommended initial dose is 5 mg and up to 15 mg
etal transport mediated glucose uptake
muscle Increases fructose
can be given in a single dose. Maximum therapeutic
2, 6-biphosphate effect is seen with 20 mg in two divided doses. Extended
Adi­ Increases adenosine Potentiates insulin-
release preparations of glipizide are also available which
pose monophosphate (AMP) mediated glucose can even be used once a day. At least, 90% of glipizide is
tissue diesterase and inhibits transport and inhibition of metabolized in the liver to inactive products and 10%
increase in glycogen lipolysis is excreted unchanged in the urine. Hence, glipizide is
synthase Glucose transporter also contraindicated in patients with hepatic or renal
4 (GLUT-4) translocation
insufficiency.
channels are present in various other tissues in the body. Gliclazide: Gliclazide has a duration of action of up to
The cardiac muscle shares a common Kir 6.2 unit with 20 hours and once daily dosing may be sufficient. It is uni­
the pancreatic β-cell, but the SUR subunit is slightly que in that it has a favorable action over platelet aggre­
different: (1) SUR1 in the β-cell and (1) SUR2 in the cardiac gation and fibrinolysis. So, it might provide extra protection
cells. Some sulfonylureas bind to SUR1 only and others against the vascular complications of diabetes. Weight
to both the SURs. gain is less compared with other sulfonylureas because
The sulfonylureas have some extrapancreatic effects this drug causes comparatively less hyperinsulinemia.
also. It is seen that the insulin action on target tissues is A modified release (MR) formulation of gliclazide is also
potentiated by sulfonylurea therapy. This is probably available. Interestingly, the 30 mg preparation of gliclazide
a secondary beneficial metabolic effect resulting from MR gives equivalent efficacy as 80 mg of the unmodified
reduced glycemia and free fatty acids. The number of gliclazide with a lower risk of severe hypoglycemia.
insulin receptors is increased and there is an augmented Glimepiride: Glimepiride is the most potent among
postreceptor effect. The extrapancreatic actions of sulfo­ sulfonylureas and hence used in the smallest dose. A single
nylureas are summarized in Table 34.3. daily dose of 1 mg is effective and maximum recom­
mended daily dose is 8 mg. Half-life is 5 hours. It is com­
Currently Available Sulfonylureas pletely metabolized in the liver to inactive products.
Glimepiride is supposed to have several benefits over
The currently available sulfonylureas include the second
the other sulfonylureas, including rapid onset and longer
generation drugs glibenclamide, glipizide and gliclazide
duration of action, lower insulin levels and reduced
and the third generation sulfonylurea, glimepiride. cardiovascular side effects.1 It binds to a different subunit
Glibenclamide (Glyburide): This is the most commonly (65 kDa subunit) of the SUR which renders it with unique
used sulfonylurea due to its low cost. It is metabolized in kinetics: the drug rapidly associates and dissociates with
the liver to inactive products. The usual starting dose is the receptor, making its action short enough to prevent
2.5 mg or less once daily which is gradually up titrated over unnecessary hypoglycemia, yet long enough to correct
a few weeks. The maximum daily dose is 20 mg. It is also hyperglycemia. It has a unique extrapancreatic effect of
available as micronized form with good bioavailability. reducing the insulin resistance. This decrease in insulin
It is a highly potent sulfonylurea and its efficacy on resistance is thought to be due to increased levels of
glycemic lowering is similar to other sulfonylureas, but plasma adiponectin and decreased levels of tumor
has a greater risk of hypoglycemia and weight gain due necrosis factor-alpha (TNF-α).2
 Insulin Secretagogues 531

It has been suggested that glimepiride is more cardio factor for cardiovascular disease. In view of these adverse
friendly as it does not have dangerous interaction with effects of sulfonylureas, and the availability of alternative
the cardiac SUR, however, this has not been established drugs which have lower risk of causing hypoglycemia
conclusively. and weight gain, there are many clinicians who consider
that their use should be restricted. However, the large
Indications and Contraindications body of evidence showing the benefit of sulfonylureas in
the management of type 2 diabetes in terms of reducing

chapter
Sulfonylureas have been widely used as monotherapy and
the risks of microvascular complications indicates that
in combination with metformin or a thiazolidinedione.

34
they will continue to have an important role to play in the
They can also be used with an α-glucosidase inhibitor, and
management of type 2 diabetes.
there are individuals who can benefit from combination of
The recent American Diabetes Association and the
a sulfonylurea with an incretin or dipeptidyl pepti­dase-4
European Association for the Study of Diabetes (ADA-
(DPP-4) inhibitor or insulin. Combination of a sulfo-
EASD) algorithm has suggested that sulfonylureas should
nylurea with a different type of antidiabetic agent usu­
be used as a second line drug once therapeutic lifestyle
ally produces an additive glucose-lowering effect, at least
changes and metformin are unable to maintain adequate
initially. However, this happens with an increased risk of
glycemic control. Sulfonylurea therapy should be started
hypoglycemia. Since the meglitinides also increase insu­
at a low dose, preferably with self-monitoring of blood
lin secretion by acting on the β-cell via the SUR1 complex,
glucose by the patient at least once daily during the first
similar to sulfonylureas, combination of sulfonylureas
few weeks. This is especially recommended where there
with these drugs does not offer any extra benefit.
are strong concerns about the potential consequences of
Although most clinicians would stop the sulfonylurea
hypoglycemia (e.g. in elderly patients, those living alone,
when insulin is added to patients with poor response to
operating machinery or driving). In general, patients who
a combination of oral antidiabetic drugs, there could be
have responded to some extent (but still inadequately)
some who would prefer to continue the sulfonylurea. The
with lifestyle measures and have less marked fasting
pharmacologic basis for this combination of sulfonylurea hyperglycemia are more likely to incur hypoglycemia
(or other insulin secretagogue) to insulin therapy for with a sulfonylurea. The dose should be uptitrated at
patients with T2DM is that subcutaneous insulin injections 2–4 week intervals as required. Hypoglycemia or early
do not mimic the normal endogenous delivery of more hypoglycemic symptoms are the main limitations to dose
insulin to the liver than to the periphery and therefore escalation of sulfonylureas. If evidence of hypoglycemia
where there is residual endogenous β-cell function, a occurs before the glycemic target is achieved, or if a
stimulus to increase delivery of endogenous insulin to the dosage increment produces no further glycemic benefit,
liver should assist in reducing hepatic glucose production it is advisable to return to the previous dose. Adjustment
particularly during digestion of a meal. This also forms the of the administration regimen may assist or an alternative
basis for the very popular bedtime insulin with daytime class of insulin secretagogue may be more suitable.
sulfonylurea (BIDS) therapy, which could significantly Where sulfonylurea is taken as monotherapy and the
reduce the insulin dose requirements for some period of glycemic target is not achieved, then addition of an agent
time in the natural history of diabetes.3,4 to reduce insulin resistance or an α-glucosidase inhibitor
is the usual recourse. It should be noted that the maximal
Current Positioning of Sulfonylureas blood glucose—lowering effect of a sulfonylurea is usually
With the availability of several newer classes of antidiabetic achieved at a dose that is well below the recommended
drugs, there has been a lot of debate regarding the use of maximum, indicating that maximum stimulation of
insulin secretion has already been achieved.
sulfonylureas in the management of type 2 diabetes. The
major concerns have been that sulfonylureas cause weight
gain, hypoglycemia and accelerated β-cell loss. The results
Efficacy
of the Action to Control Cardiovascular Risk in Diabetes As monotherapy in patients inadequately controlled by
(ACCORD) trial and the Veterans Affairs Diabetes Trial lifestyle measures, sulfonylureas are generally expected to
(VADT) have highlighted the risks of hypoglycemia and reduce the fasting plasma glucose by about 35–50 mg/dL,
recently hypoglycemia is also being considered as a risk translating to a decrease in hemoglobin A1c (HbA1c) of
532 Management

1–2%.4–6 The glucose-lowering effect of sulfonylureas sulfonylurea-induced hypoglycemia is reported to be

is immediate and sulfonylureas are particularly very 0.014–0.033 per 1,000 patient-years.10 Factors which can
effective in the short term. Efficacy of sulfonylureas be associated with greater frequency of hypoglycemia
depends upon the presence of sufficient reserve of β-cell with sulfonylurea use include use of longer acting sulfony­
function. Considering the fact that patients with diabetes lureas, older age, irregular meals, use of other antidiabetic
have a gradual and inevitable decline in β-cell function, it drugs especially insulin, excessive alcohol consumption,
can be expected that the dose of sulfonylurea may need near normal glycemia prior to initiation of sulfonylureas
section

escalation in order to achieve the same degree of glucose and use of other drugs which could interact to increase the
8

lowering. In view of this, the durability of glucose-lowering potency of sulfonylurea.

effect of sulfonylureas is lowest as compared to other Patients treated with sulfonylureas should be given
antidiabetic drugs and this has also been shown in the A instruction on the prevention and recognition of hypo­
Diabetes Outcome Progression Trial (ADOPT) study.5,6 glycemia and the prompt actions required (described
“Secondary Sulfonylurea Failure” is defined as a chapter on hypoglycemia).
rapid deterioration of glycemic control, in those subjects Sulfonylurea-induced hypoglycemia requires prompt
who were earlier well-controlled with the same dose admission to hospital. Intravenous glucose infusions are
of sulfonylurea. This occurs in approximately 5–10% needed for prompt treatment and this may need to be
of patients per year.6 Although this may probably vary continued for more than a day to guard against the tend­
between compounds it largely reflects the progression of ency for a recurrence of hypoglycemia where long-acting
β-cell failure.4,5,7 Early intervention in patients with a better sulfonylureas were used.11 The vasodilator diazoxide
β-cell function usually produces a greater and longer and the somatostatin analog octreotide have been used
response to sulfonylureas, although not without risk of successfully (but with extreme caution) to inhibit insulin
hypoglycemia, whereas late intervention in patients with secretion in severe sulfonylurea—induced hypoglycemia.
very poor β-cell function is less effective. Use of glucagon in patients with T2DM should be avoided
Although sulfonylureas generally have no significant as this is itself an insulin secretagogue.
effect on blood lipids, they can occasionally cause a small Drug interactions: Salicylates, sulfonamides and mono­
decrease in plasma triglycerides or increase in high- amine oxidase inhibitors can displace sulfonylureas from
density lipoprotein (HDL) cholesterol. protein binding sites and potentiate their actions.

Adverse Effects Weight gain: Weight gain, typically in the range of 1–4 kg,
is common after initiation of sulfonylurea therapy; it
Hypoglycemia: Hypoglycemia is the major side effect of stabilizes by about 6 months.1,5,9 The weight gain probably
the use of sulfonylureas. They can produce prolonged reflects the anabolic effects of increased plasma insulin
hyperglycemia especially in the elderly. This is more concentrations together with reduced loss of glucose in the
often seen with the longer acting preparations like gliben­ urine. Weight gain may have adverse impact on diabetes
clamide. Hypoglycemia is the most common and poten­ and cardiovascular disease.
tially most serious adverse effect of sulfonylurea therapy. Less common side effects include headache, gas­
Although it is only rarely life-threatening in patients with trointestinal disturbances, skin rashes and rarely thro­mbo­
type 2 diabetes, even mild impairment of neural or motor cytopenia, agranulocytosis and aplastic anemia. Although
function can endanger the patient and others, and may pre­ structurally related to sulfonamides, people allergic to
dispose to a poor prognosis after a myocardial infarction sulfonamides need not be allergic to sul­fonylureas.
(MI).5,8 In the United Kingdom (UK) Prospective Diabetes
Study (UKPDS), about 20% of sulfonylurea-treated Glinides (Meglitinides)
patients reported one or more episodes of hypoglycemic
symptoms annually. Other studies have suggested simi­ The meglitinide analogs are non-sulfonylurea compounds
lar rates.9,10 Severe hypoglycemia (requiring third party derived from the benzamido non-sulfonylurea portion
assistance) during sulfonylurea therapy occurred in about of glibenclamide. The chemical structure of meglitinides
1% of patients annually in the UKPDS and lower rates along with that of glibenclamide for comparison is given
(approximately 0.2–2.5 episodes per 1,000 patient-years) in Figure 34.3. Daily dosage requirements and duration of
have been reported elsewhere. The mortality risk from action are given in Table 34.2.
 Insulin Secretagogues 533

gliclazide on the basis of change in HbA1c. Although it is

thought that repaglinide does not cause hypoglycemia,
hypoglycemic events were reported in 16% of repaglinide-
treated patients and 15–20% of sulfonylurea-treated
patients.14 Repaglinide can be safely combined with
insulin sensitizers and insulin.
Nateglinide, a derivative of the amino acid pheny­

chapter
lalanine derivative, sensitizes β-cells to ambient glucose,

34
reducing the glucose concentration needed to stimulate
insulin secretion. The pharmacokinetics of nateglinide are
characterized by rapid absorption and elimination, with
good (73%) bioavailability.
Nateglinide is more rapidly absorbed when given
0–30 minutes prior to meal ingestion.
Nateglinide is extensively metabolized in the liver,
Fig. 34.3: Chemical structure of meglitinides in comparison with that primarily by cytochrome P450 2C9 and eliminated prima­
of glibenclamide rily by the kidney. With increasing nateglinide doses, the
risk of hypoglycemia also increases, but its incidence is
low. As in the case of repaglinide, even if a meal is missed
Structure and Mechanism of Action and the patient skips the dose of nateglinide (as reco­
This group of drugs, called prandial glucose regulators act mmended in the event of a missed meal), the incidence
on a non-SUR, but their ultimate mechanism of action is of subsequent hypoglycemia remains low compared with
quite similar (Fig. 34.2) i.e. they also block K+ efflux from long-acting agents. The postprandial insulinotropic effects
the β-cell, leading to the cascade of events that ultimately of nateglinide are more rapid than those of repaglinide
result in insulin secretion.5 and more rapid and greater than those of glibenclamide
These drugs mimic the physiological insulin secretion, (glyburide), while producing less prolonged insulin
i.e. insulin is released only in the presence of glucose exposure and less risk of delayed hypoglycemia.15
thus minimizing the risk of hypoglycemia. They have a
rapid onset and a short duration of action lasting about Side Effects
1–2 hours; hence they are good at controlling postprandial Hypoglycemia is much less common than with sulfo-
hyperglycemia or the glucose peaks that occur in blood nylureas. Rarely, they can produce rash, itching and
soon after a meal (prandial glucose regulator). However, urticaria.
this short-lived effect means that they do not adequately
control fasting blood glucose levels. INSULIN SECRETAGOGUES AND
Nateglinide, although largely similar to repaglinide has CARDIOVASCULAR DISEASE
slightly better absorption kinetics, rendering it a slightly
better prandial glucose regulator.12,13 The two major areas of concern that have been raised
Repaglinide, a carbamoylmethyl benzoic acid deri­ about the potential adverse cardiovascular effects of
vative is rapidly absorbed, metabolized by the liver and secretagogues are that the high levels of insulin produced
eliminated primarily via the bile. Oral bioavailability by the use of sulfonylureas may promote atherosclerosis
is about 65%. It is especially effective in insulin-naïve and that sulfonylureas might have cardiotoxic effects
patients. It can be safely used in renal failure. It can be because they might bind to the SUR isoforms SUR2A or
combined with insulin sensitizers. It causes an average SUR2B present on cardiac and vascular smooth muscle
reduction in HbA1c by 1.6%. The insulin-stimulating effect cells respectively and may interfere with the ischemic
of repaglinide has been found to be 10–20 times more preconditioning.16-19
potent than that of glibenclamide. In one study, repag­ In-vitro, insulin has been shown to have several poten­
linide was more effective than glipizide at maintaining tially proatherogenic effects, including stimulation of
glycemic control and was equivalent to glibenclamide and cellular cholesterol accumulation and stimulation of
534 Management

vascular smooth muscle cell proliferation.13 In vivo, glimepiride).26-31 Sulfonylureas without a benzamido group
hyperinsulinemia is associated with increased very-low- (e.g. tolbutamide, chlorpropamide and gliclazide) would
density lipoprotein (VLDL) cholesterol levels, decreased show very little interaction with the cardiac and vascular
HDL-cholesterol levels, decreased low-density lipoprotein SUR receptors. In cardiomyocytes, it has been shown
(LDL)-cholesterol particle size (so-called small, dense that KATP channels mediate ischemic preconditioning.2,16
LDL) and hypertension. Insulin can also stimulate Ischemic preconditioning is the condition in which
proliferation of the arterial smooth muscle cells. Therefore, exposure of cardiomyocytes to episodes of ischemia
section

a concern has been raised that sulfonylureas by increasing induces cellular adaptations that make these cells resistant
the concentration of circulating insulin may potentiate
8

to damage during subsequent episodes of ischemia.10

the adverse cardiovascular effects of hyperinsulinemia. The effects of the KATP channel opener nicorandil (an
However, the levels of circulating insulin reached are antianginal drug with cardioprotective properties) are
seldom as high as the levels present in non-diabetic blocked by sulfonylureas that have a benzamido group.
individuals or those with prediabetes. Although compounds with a benzamido group could
Moreover, evidence from clinical trials shows that theoretically interfere with ischemic preconditioning and
intensive insulin therapy actually decreases, rather than
increase vascular contractility at a time when this might
increases, cardiovascular risk in patients with T2DM.9,20,22
be undesirable (e.g. severe myocardial ischemia), there
A landmark study, the Diabetes Insulin and Glucose in
is no clear evidence that therapeutic concentrations of
Acute Myocardial Infarction (DIGAMI) trial, which rando­
sulfonylureas exert such an effect in-vivo. Hyperglycemic
mized type 2 diabetes patients with acute MI to either
states have themselves been shown to obviate ischemic
usual care or intensive insulin therapy has suggested that
preconditioning and therefore the role of sulfonylureas
intensive insulin therapy confers cardiovascular benefit
in causing this seems unclear. However, many authorities
(rather than harm) in diabetic patients presenting with
acute MI.23 Compared to the usual care group, patients restrict wider use of sulfonylureas in patients with overt
randomized to the insulin or glucose infusion group had coronary artery disease.32
30% lower mortality at one year and 28% lower mortality
at 3.4 years.24 TIMING OF SECRETAGOGUE
The UKPDS was a 20-year study involving 23 centers ADMINISTRATION
and more than 5,000 patients with type 2 diabetes in
The conventional sulfonylureas are best taken about
the UK. The study found that improved control of blood
20–30 minutes before meals as food may interfere with their
glucose or blood pressure while significantly reducing the
absorption. In contrast, the prandial glucose regulators
risk of the microvascular complications had little or no
have a more rapid onset of action and need to be taken
effect on reducing macrovascular events.25 Nevertheless
just before or even soon after starting a meal. The prandial
there was no evidence of any major detrimental effect of
glucose regulators are an attractive option in patients who
the drugs or insulin on survival or outcome other than the
expected risk of hypoglycemia. The subsequently pub­ lead erratic lifestyles. They offer flexibility of dosing, i.e.
lished follow-up of the UKPDS has shown that the initially if the meal is delayed, then the tablet too can be delayed.
intensively controlled arm did go on to have a reduction However, this strategy of advising the patient to “pop a
of major macrovascular events; demonstrating that early pill and take the meal” and to skip the tablet, if a meal is
aggressive control with the use of even sulfonylureas skipped should be strongly discouraged. This is because
is beneficial in reducing long-term microvascular and such advice contradicts the basic principles of therapeutic
cardiovascular outcomes. lifestyle modification advised for management of diabetes
Studies have shown that there are two isoforms of the which urges the patient to eat proper meals at proper times
SURs, SUR2A and SUR2B, which are expressed in cardiac in order to maintain 24-hour normalcy of glucose levels.
muscle and vascular smooth muscle, respectively. These The use of extended release sulfonylureas is increasing,
isoforms lack the sulfonylurea binding site but retain and long-acting formulations of glipizide and glicla­
the benzamido binding site. Therefore, these receptor zide are available. These are useful drugs, especially in
isoforms present on cardiac and vascular smooth patients keen on once-daily medication. At the same time,
muscles, SUR2A/B can only bind those sulfonylureas that these formulations can cause hypoglycemia, thus the
contain a benzamido group (glibenclamide, glipizide and advantage over the much cheaper glibenclamide is lost.
 Insulin Secretagogues 535

When a sustained release preparation does not result in • The second generation sulfonylureas have a shorter
normoglycemia, the patient may still respond to a multiple duration of action and are in common use.
dose regimen. • Hypoglycemia is the major side effect.
• Glimepiride binds to a different subunit of the SUR,
COMPARISON OF VARIOUS making its action short enough to prevent unnecessary
SECRETAGOGUES hypoglycemia.31 This SUR is not present on the cardiac
muscle and hence glimepiride does interfere with

chapter
With the advent of the newer secretagogues like the ischemic preconditioning. Gliclazide has also been

34
meglitinide derivatives, it is inevitable that comparisons shown to have no effect on ischemic preconditioning.
are drawn between them and the sulfonylureas.33 Repag­ • Meglitinides act on a non-SUR leading to the cascade
linide and nateglinide have earlier onset and shorter of events that ultimately result in insulin secretion.
duration of action than the conventional sulfonylureas. Repaglinide and nateglinide are the two drugs in
Head-on comparisons between nateglinide and gliben­ this group. Since they have a rapid onset and a short
clamide have shown that earlier stimulation of insulin duration of action, they are good at controlling post­
release with nateglinide results in slightly faster glucose prandial hyperglycemia but cause negligible or no
disappearance with a smaller increase in total insulin hypoglycemia.12
secretion, i.e. earlier insulin release reduced the insulin • Sulfonylureas are taken 20–30 minutes before a meal.
requirement to respond to a meal challenge. Randomized Meglitinides are taken immediately before food.
trials have shown that repaglinide and sulfonylureas are Extended release preparations of sulfonylureas are
equally effective in reducing HbA1c and that nateglinide is also available.
less effective. Preliminary data also shows that since the • Repaglinide and nateglinide have earlier onset and
meglitinide derivatives cause less of hypoglycemia, there shorter duration of action than the sulfonylureas.
is reduced dietary intake, which can translate into less • Randomized trials have shown that repaglinide and
weight gain. sulfonylureas are equally effective in reducing HbA1c
and that nateglinide is slightly less effective. Prelimi­
NEWER INSULIN SECRETAGOGUES nary data also shows the meglitinide derivatives cause
less weight gain.
Incretin based therapies can broadly be categorized
• Secretagogues can be combined with metformin and
in two categories: GLP-1 receptor agonists and DPP-4
glitazones.
inhibitors. These newer agents lower blood glucose levels
• Combination therapy with a secretagogue and met­
by stimulating glucose dependent secretion of insulin
formin targets both β-cell dysfunction and insulin
from the b-cells. Several clinical studies have shown that
resistance early on in the disease.
therapeutic use of GLP-1 receptor agonists is associated
• Sulfonylureas are preferable when there is both fasting
with the benefit of substantial weight loss. Comparatively,
and postprandial hyperglycemia, while meglitinides
minimal or no weight loss has been observed with
are good for postprandial hyperglycemia alone. Nate­
the use of DPP-4 inhibitors. A major advantage of this
glinide can possibly reverse defects in the first phase of
novel treatment approach is an absolute minimal risk
insulin release.
of hypoglycemia, which is a significant adverse effect
• Even if ischemic preconditioning is a clinically relevant
of insulin secretagogues. This topic has been further
phenomenon, there should be little concern about the
discussed in chapter 36 in this book.
use of newer insulin secretagogues in patients with
type 2 diabetes.
SUMMARY
• Insulin secretagogues act by improving β-cell function Further Reading
and therefore augmenting insulin secretion. They are
1. Cleveland JC, Meldrum DR, Cain BS, et al. Oral sulfonylurea
mainly classified into sulfonylureas and meglitinides.
hypoglycemic agents prevent ischemic preconditioning in
• The sulfonylureas are the most commonly prescribed human myocardium: two paradoxes revisited. Circulation.
secretagogues. They act by binding to SUR on the 1997;96:29-32.
pancreatic β-cell plasma membrane causing closure of 2. UK Prospective Diabetes Study (UKPDS) Group. Intensive
KATP channels. blood-glucose control with sulphonylureas or insulin
536 Management

compared with conventional treatment and risk of com­ 15. Gomis R. Repaglinide as monotherapy in type 2 diabetes.
plications in patients with type 2 diabetes (UKPDS 33). Exp Clin Endocrinol Diabetes. 1999;107:S133-5.
Lancet. 1998;352:837-53. 16. McLeod JF. Clinical pharmacokinetics of nateglinide: a rap­
3. Carroll MF, Gutierrez A, Castro M, et al. Targeting postpran­ idly absorbed, short acting insulinotropic agent. Clin Phar­
dial hyperglycemia: a comparative study of insulotropic macokinet. 2004;43:97-120.
agents in type 2 diabetes. J Clin Endocrinol Metab. 2003; 17. Noma A. ATP regulated [K+] channels in cardiac muscle.
88:5248-54. Nature. 1983;305:147-8..
4. McLeod JF. Clinical pharmacokinetics of nateglinide: a 18. Standen NB, Quayle JM, Davies NW, et al. Hyperpolarizing
section

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8

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19. Speechly-Dick ME, Grover GJ, Yellon DM. Does ischemic
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2001;358:1709-16. 28. Garratt KN, Brady PA, Hassinger NL, et al. Sulfonylurea
13. Riddle MC. Sulfonylureas differ in effects on ischemic drugs increase early mortality in patients with diabe­
preconditioning—is it time to retire glyburide? J Clin Endo­ tes mellitus after direct angioplasty for acute myocardial
crinol Metab. 2003;88:528-30. infarction. J Am Coll Cardiol. 1999;33:119-24.
14. Saloranta C, Guitard C, Pecher E, et al. Nateglinide im­ 29. Klepzig H, Kober G, Matter C, et al. Sulfonylureas and
proves early insulin secretion and controls postprandial ischemic preconditioning: a double-blind, placebo-con­
glucose excursions in a prediabetic population. Diabetes trolled evaluation of glimepiride and glibenclamide. Eur
Care. 2002;25:2141-6. Heart J. 1999;20:439-46.
 Insulin Secretagogues 537

30. Ovünç K. Effects of glibenclamide, a K(ATP) channel blocker, 32. Wilson SH, Kennedy FP, Garratt KN. Optimization of the
on warm-up phenomenon in type II diabetic patients with management of patients with coronary heart disease and
chronic stable angina pectoris. Clin Cardiol. 2000;23: 535-9. type 2 diabetes mellitus. Drugs Aging. 2001;18:325-33.
31. Mocanu MM, Maddock HL, Baxter GF, et al. Glimepiride: a 33. Hu S, Wang S, Dunning BE. Tissue selectivity of antidia­
novel sulfonylurea, does not abolish myocardial protection betic agent nateglinide: study on cardiovascular and beta-
afforded by either ischemic preconditioning or diazoxide. cell K (ATP) channels. J Pharmacol Exp Ther. 1999;291:
Circulation. 2001;103:3111-6. 1372-9.

chapter
34
 Chapter 35
Insulin Sensitizers: Metformin
and Thiazolidinediones
Sudip Chatterjee

Insulin Sensitizers

Chapter Outline
♦♦ Metformin ♦♦ Thiazolidinediones

METFORMIN
History
Galega officinalis, a plant found in Europe was known
for the last 1,000 years to reduce polyuria (Fig. 35.1). The
usefulness of extracts of this plant in modern clinical
medicine was limited by gastrointestinal (GI) side effects.
It was realized in the 1930s that the active compound in
the plant was a guanidine residue. Eventually, diguanides
(or biguanides as they are now called) were synthesized
where two guanidine residues were connected by a NH
chain. Several pharmacologically active biguanides were
produced, but only one, i.e. metformin continues to be
available for clinical use.
Metformin has enjoyed widespread popularity since
the 1960s and has been widely used in India since that
time. However, unfounded fears of lactic acidosis led
the US Food and Drug Administration (FDA) to with­
hold permission for its use in the US till 1994. From
1995 onwards, particularly with the publication of United
Kingdom Prospective Diabetes Study (UKPDS) data
there has been a major resurgence in the study and use
of metformin. Today, there is universal acceptance that it
is the pharmacological agent of choice in initiating treat­ Fig. 35.1: Galega officinalis
Source: Wikipedia
ment of type 2 diabetes.1
 Insulin Sensitizers: Metformin and Thiazolidinediones 539

both of which result in decreased protein synthesis and

decreased cell survival.
The atypical PKC-CBP pathway is downstream of AMP
kinase (AMPK) which is stimulated by metformin. It has
been shown in rat models that neurogenesis and genesis
of glial cells are enhanced by metformin. The same effect
was seen in human stem cells that were differentiated to

chapter
Fig. 35.2: Structure of Metformin form neural cells. Also mice pretreated with metformin in

35
a human dose equivalent of 1,550 mg per day, performed
better on maze tests, an effect that was lost on co-treatment
Chemical Structure with temozolomide [an alkylating agent used in treating
central nervous system (CNS) malignancy that selectively
Metformin consists of two guanidine residues linked by
an ammonia bond. One of the residues has a methyl side destroys replicating cells].7
chain (Fig. 35.2).
Usefulness of Metformin in Type 2
Mechanism of Action Diabetes Mellitus (T2DM)
Metformin is lipophilic and binds to membrane phospho­ All professional bodies presently recommend metformin
lipids in the cell wall and mitochondria. The cellular as the drug of choice for control of hyperglycemia once
targets are the hepatocyte and skeletal muscle cell and to lifestyle measures prove inadequate. A usual dose is
a lesser extent the adipocyte. The primary enzyme target 500 mg once or twice daily. Metformin can be added to
is adenosine monophosphate protein kinase or activated all other oral antidiabetic agents and can be used with
protein (AMP) kinase.2 This enzyme is a major regulator insulin. Failure rates with metformin as monotherapy
of intracellular energy production via its effects on glucose are fairly steep and approach 20% per year.8 Reduction of
and fat metabolism. Although the detailed cellular glycated hemoglobin (HbA1c) with monotherapy is around
pathways are yet to be elucidated, in simplistic terms, the 1.5%, a figure that cannot be bettered by any other agent
target cell appears to suffer an energy deficit. The action except insulin and sulphonylurea.
is mediated through the Peutz Jeghers protein liver kinase Metformin is “lipid friendly” in that reduction of trigly­
(LK) B1.3 Activation of this pathway has tumor suppressor ceride levels occurs independent of its glucose lowering
effects, as will be discussed later. effect.
However, other pathways of action are possible as mice Metformin does not cause weight gain. Some studies
deficient in AMP kinase and LKB1 can still have hepatic have shown it to be weight neutral while others have found
glucose output reduced by metformin. In the hepatocyte a modest weight loss.
the main effect is reduced glucose output while in the
skeletal muscle it promotes glycogen synthesis.4 There may Side Effects
be a mild enhancement of intes­tinal glucose utilization. The major side effect is GI, leading to abdominal cramps,
Metformin has a direct stimulatory effect on the tyro­ bloating, loose stools, anorexia and altered taste sensation.
sine kinase pathway of insulin secretion by its action on In majority of patients the side effects, if experienced,
the beta sub unit of the insulin receptor.5 It also increases wear off within 2 weeks. However, there are patients in
glucose transporter activity (GLUT 1) in cell culture. whom the drug has to be withdrawn due to side effects.
Metformin has a dose dependent suppressive effect in Use of the extended release form appears to reduce side
vitro on plasminogen activator inhibitor-1 (PAI-1) produc­ effects especially bloating, nausea, flatulence—which
tion, which may account for its vasoprotective property.6 can be ascribed to the upper GI tract.
The major action of metformin appears to be through Plasma Vitamin B12 lowering occurs in up to 30% of
activation of AMP kinase. AMP kinase activation has subjects. The cause is unknown but it can be prevented
multiple effects throughout the cell especially on the LKB1 by administration of calcium carbonate or vitamin
system and on mammalian target of rapamycin (mTor), supplements.9
540 Management

Contraindications
Extensive review of the literature suggests that metformin
is associated with lactic acidosis only in clinical situations
that in themselves are likely to cause lactic acidosis,
e.g. sepsis or poor tissue perfusion states. Renal disease
with a serum creatinine of over 1.5 mg/dL in men and
section

1.4 mg/dL in women is the main clinically relevant

contraindication. This would correspond to an estimated
8

glomerular filtration rate (eGFR) of below 50 mL/min.

Conditions likely to predispose to lactic acidosis or
renal compromise like coronary angiography, metabolic
instability like sepsis, diabetic ketoacidosis (DKA), poor
tissue perfusion states (e.g. postsurgery) are contraindica­
tions. Heart failure remains a contraindication, although Fig. 35.3: The metformin cohort in the United Kingdom Prospective
it has been extensively used in such situations without Diabetes Study (UKPDS), showing beneficial effect on myocardial
infarction (MI) and sudden death.13
harm.

Safety in Pregnancy (ER) preparation has a 20% lower plasma peak—which

is reached later. Upper GI side effects are less with the
The US FDA has assigned a category B status to metformin.
ER preparation but some studies have shown increased
This means that safety in pregnancy has been established
lower GI side effects with the ER tablets. The maximum
in animal studies. It can be used in human pregnancy
dose for the standard preparation is 2,550 mg/24 hours
if the situation warrants but there is an inadequacy of
and for the extended release preparation is 2,000 mg/
satisfactory controlled studies. Metformin crosses the
24 hours, although higher doses are allowed by some
placenta. Beneficial fetal effects may include reduction
regulatory bodies.11
of fetal adiposity and birth trauma. However, it may be
detrimental in situations where there is intrauterine
Cardiovascular Protective
growth restriction (IUGR) or poor placental perfusion.
An Australian randomized trial called metformin in
Effects seen in Diabetes
gestational diabetes: the offspring follow-up (MiG:TOFU) The UKPDS data was the first to show a cardioprotective
which is yet to report, has looked at outcome in offspring effect of metformin. Patients allocated to metformin had
where the mothers have received metformin.10 a 32% risk reduction for any diabetes related end point
(p = 0.002), 36% risk reduction for all cause mortality
Safety in Young Children and the Elderly (p = 0.011) and 42% for diabetes related deaths12 (p = 0.017).
Metformin is permitted for use in children aged 10 years This has since been confirmed in several observational
or more. In patients over 80 years, maximum doses should studies. A Cochrane review looked at 29 trials with a total
of 5259 participants. Obese patients allocated to met­
not be used. Caution is needed so that eGFR is not below
formin showed greater benefit compared to sulfonylureas
50–60 mL/min in these patients.
or insulin for any diabetes related outcome (p = 0.009),
all cause mortality (p = 0.01) and diabetes related death
Formulations
(p = 0.03) or myocardial infarction (MI) (p = 0.02).13
Along with the standard tablet, a liquid formulation Although randomized controlled trial (RCT) data is
which has similar properties is available. There is also a lacking on this subject, metformin is now established as
widely used extended release formulation. The efficacy cardioprotective. A post–UKPDS follow-up study showed
in glucose lowering and the drug area under curve (AUC) continued reduction of risk in the metformin treated
are similar for both preparations. The extended-release subjects (Fig. 35.3).14
 Insulin Sensitizers: Metformin and Thiazolidinediones 541

Metformin decreases the expression of many genes

involved in mitosis. It has a pro-senescence and anti-
immortalizing effect on many cell lines. Human epidermal
growth factor receptor 2 (HER-2), which is a specific
oncogene found in some breast cancers can be blocked
by metformin.
Cancer preventive effects of metformin have been

chapter
shown in a retrospective study of breast cancer where

35
there was a 56% decrease in risk in diabetic patients
receiving metformin. An inhibitory effect on some sub­
Fig. 35.4: Showing effects of metformin on various pathways
including anti-cancer pathways populations of cancer stem cells has been shown.
The conclusion that may be drawn from current data
is that metformin has anticancer effects both preventive
Role in Cancer Prevention and therapeutic. Its use as a specific anticancer agent on
Evans in 2005 noted a dose dependent reduction in cancer its own will depend on the outcome of several ongoing
in patients treated with metformin. A Dutch study looked studies.
at 1,300 patients of which 289 were treated with metformin
Use in Conditions other than Type 2 Diabetes
for 9.6 years. There was a 42% decrease in the probability
of mortality for every 1 gm of daily dose of metformin. Use in Prediabetes: The Diabetes Prevention Program
A meta-analysis found a 31% reduction in the cancer (DPP)—use of metformin resulted in 31% lower incidence
rate in patients taking metformin. Subsequent studies on of diabetes in a susceptible population compared to
cancers of the colon, breast, pancreas and prostate have placebo.16
demonstrated consistent beneficial effects of metformin. Use in PCOS: Insulin resistance plays a central role
These studies are primarily retrospective observational in polycystic ovary syndrome (PCOS). Metformin has
studies and are likely to suffer from selection bias. been shown to increase ovulation rates and fertility
This is because cancer patients receiving metformin are in this condition, though not as much as clomiphene
likely to be significantly different from other cancer citrate. Variable results have been achieved with the
patients, a fact that can affect the findings.15 However, combination of both agents. The consensus is that the
the basic science underpinning the clinically observed combination is superior to either agent alone depending
anticancer effect of metformin is compelling. Metformin on the subject’s body mass index (BMI) and sensitivity to
exerts its effects primarily by activation of AMP kinase, as
clomiphene.17
noted earlier (Fig. 35.4). The cascade of events associated
Use in patients of HIV: Highly Active Antiretroviral
with this activation modulates LKB1, which is a tumor
Therapy (HAART) has been shown to increase insulin
suppressor protein. Genes such as ataxia telangiectasia
resistance and small studies have shown that metformin
mutated (ATM) are known tumor suppressor genes.
reduces adverse metabolic features of the HAART.18
Activities of these genes are required for metformin
to exert its full anti-glycemic effect. Thus, patients on
whom metformin is effective, benefit from its tumor supp­
THIAZOLIDINeDIONES
ressor activity. Introduction
Mammalian target of rapamycin is a protein that plays
an important role in tumorigenesis and its activation Thiazolidinediones or glitazones, are a group of antidia­
correlates with a worse prognosis. AMP kinase activation betic agents that act by stimulation of peroxisome proli­
inhibits mTOR activity. One of the effects of metformin ferator activated receptors (PPAR). Of the agents in this
is reduced lipogenesis. Several tumor cells produce class, troglitazone was banned because of its adverse
high levels of fatty acids and experiments where fatty effects on the liver. Rosiglitazone has fallen into disfavor
acid synthesis has been blocked have shown increased because of its adverse effects on the cardiovascular
apoptosis of tumor cells, leading to the speculation that system. Rosiglitazone has also been removed from the
metformin may have similar activity. Indian market. The only drug in this class that is available
542 Management

Pioglitazone in Type 2 Diabetes

Pioglitazone used as monotherapy causes a 0.8% fall in
HbA1c levels. It is recommended to be used as a second
Fig. 35.5: Structure of Pioglitazone
line agent and various combinations with sulfonylureas
and metformin are available. It can be used with insulin,
is pioglitazone (Fig. 35.5) and it will be the one discussed although this is not advisable due to its propensity to cause
fluid retention and weight gain. The recommended dose
section

in this chapter. With recent upsurge in reports of bladder

cancer in pioglitazone treated patients, it has been is 15–30 mg per day when used in combination with other
8

withdrawn in France and Germany. oral antidiabetic agents, and 45 mg/day as monotherapy.24
There is an increase in body fat and weight gain associated
Mechanism of Action with the treatment, with pioglitazone. Preadipocytes are
converted into adipocytes in subcutaneous tissue.25 There
Peroxisome proliferator activated receptors are of two is no increase in visceral fat and there is reduction of HbA1c
types: (1) α and (2) γ, and pioglitazone binds to both, inspite of weight gain. Low-density lipoprotein (LDL)
though mostly to γ. PPAR gamma is found in adipocytes, cholesterol levels rise. However, small dense LDL particles
vascular endothelium, CNS, macrophages, skeletal muscle which are more atherogenic are replaced by larger LDL
and beta cells in the pancreas. The ligand, i.e. piogli­
particles and there is no rise of apo-B lipoprotein levels.19
tazone binds to its receptors and the activated receptor
binds to intranuclear deoxyribonucleic acid (DNA) with Relation of Pioglitazone with Cancer
the help of the Retinoid X Receptor. Multiple effects are
Peroxisome proliferator activated receptors gamma ago­
produced including a fall in insulin resistance and
nists suppress several human cancer cell lines like those
increased appetite, perhaps by reducing levels of leptin.
of breast, colon, pancreas and prostate. There is some
There is also inhibition of vascular endothelial growth
evidence that by inhibiting angiogenesis, these com­
factor (VGEF) induced angiogenesis, differentiation of
pounds can inhibit metastatic cancer.26 However, there
preadipocytes to adipocytes and fall of interleukin (IL)
6 levels.19 Conceptually, the most interesting action is are no clinical series where a glitazone was shown to
its ability to raise adiponectin levels. Adiponectin levels have a beneficial effect.
are low in diabetes and this has a negative correlation On the other hand, the prospective pioglitazone clini­
with BMI, insulin and triglyceride levels and there is a cal trial in macrovascular events (PROactive study) found
positive correlation with high-density lipoprotein (HDL) an increased incidence of bladder cancer, i.e. 8 versus
cholesterol.20 19 cases per 10,000 patient years in patients on piogli­
The exact biochemical pathways of pioglitazone tazone. Rat studies using the equivalent of 45 mg/day
action have not yet been elucidated. Nor is it certain why human dose of pioglitazone also found an increased
peak effect is reached as late as 4–6 weeks after initiation incidence of bladder tumors. A meta analysis of clinical
of therapy. trials showed 19 cases of bladder cancer versus 7 in cont­
The fall of insulin resistance appears to be a peripheral rols with an hazard ratio (HR) of 2.64 (1.11–6.31). The
effect with increased insulin sensitivity and increased risk appeared to be related to the dose and duration of
glucose uptake in the peripheral adipocytes being the exposure. This finding makes it quite likely that there
main driver. There is likely to be a direct effect of pioglita­ is indeed a small but valid increased risk of bladder
zone on the beta cell. Subjects treated with pioglitazone cancer.27 Meta analyses of published data on piogltazone
had higher insulin responses to oral glucose. Surrogate show an increased risk of bladder cancer which goes
markers of beta cell function like homeostatic model up with dosage and duration of use.28 Three recent large
assessment (HOMA) and the insulin or proinsulin ratio studies have clearly shown that pioglitazone is associated
have shown improvement after glitazone treatment.21,22 with bladder can­cer in men although the absolute risk
The exact mechanism by which glitazones increase may be low.29-31 Hence it has been advised that patients
insulin secretion is not known. Apparently there is with a history of bladder cancer should not receive
activation of the phosphoinositol pathway and there is no pioglitazone. All patients on the drug should be monitored
enhancement of glucose-mediated insulin secretion.23 for hematuria and unexplained hematuria should be
 Insulin Sensitizers: Metformin and Thiazolidinediones 543

worked up thoroughly in these patients. Finally, it appears the same system and can alter the effectiveness of piogli­
preferable to use low dose pioglitazone 7.5 mg/day, if at all tazone as can inhibitors of the system like itraconazole.
the drug is to be used.
Side Effects
Relation of Pioglitazone to Fractures
Edema is one of the main side effects, affecting up to 7.5%
The glitazones appear to divert stromal cells in bone of patients. It is worse in patients receiving simultaneous
from forming osteoblasts to forming adipocytes.19 This is insulin. This is perhaps the reason why clinical studies

chapter
likely to lead to a loss of bone strength as has been with the glitazones have consistently reported high rates

35
confirmed in clinical studies with both rosiglitazone and of congestive heart failure. The mechanism is unknown.33
pioglitazone. The fractures were more likely to be in the Weight gain has been seen consistently in trials with
distal end of the extremities and involve the long bones the glitazones. A weight increase of up to 2.8 kg–4 kg over
and more likely to occur in women.32 6 months has been reported with pioglitazone although
anecdotally some patients may gain up to 15 or 20 kg in
Relation to Cardiovascular Protection weight. How much of the weight increase is due to fluid
In vitro studies on atherosclerosis have shown promising retention is not known.
results. PPAR agonists have effects on vascular smooth Other side effects include anemia (perhaps due to
muscle cells inhibiting their migration to the intima. They hemodilution), headache, myalgia and upper respiratory
have inhibitory effects on the monocyte macrophage infections. Hypoglycemia is not expected to occur with
system by reducing their adhesiveness to the vascular monotherapy. The association with fractures and cancers
endothelium. There is a further effect on the endothelial has been outlined above.
cells themselves, reducing their activation of pro
atherogenic molecules like PAI-1. Safety in Special Populations
The largest human clinical study, PROactive, was Pioglitzone has a category C labeling from the US FDA.
designed to test the beneficial effects of pioglitazone in This means that animal studies have demonstrated harm
high risk individuals. In this study, all patients received to the fetus and well controlled human studies are not
their usual medication and the study group received available. It is not recommended for use in pregnancy as
45 mg/day of pioglitazone in addition. There was no several established treatment options are available.
difference in the primary end points of all cause mortality, Use in chronic liver disease Child Grade B and C is
non-fatal MI, stroke, revascularization, amputation or not advised. In view of the experience with troglitazone,
acute coronary syndrome. However, if a different combi­ regulatory agencies earlier advised regular liver function
nation of end-points, designated secondary end-points, monitoring and discontinuation if transaminases rise to
all cause mortality, MI and Stroke were used, which were over 2.5 times upper limit of normal. However, widespread
not included in the initial trial design, the differences clinical experience suggests that pioglitazone has no liver
were significant. However, if congestive heart failure and toxicity and may actually be of use in non-alcoholic fatty
silent MI were added to these end-points, the statistical liver disease.34
significance was lost. A lowering of blood pressure (BP) Pioglitazone is safe in chronic renal disease, having
occurred as has been consistently reported in several been used in patients with creatinine clearance below
studies.26 30 mL/min.
It has to be concluded that in the clinical setting the Pioglitazone is effective in the elderly; however the
net cardiovascular benefit of pioglitazone is small. It is increased risk of congestive heart failure in this population
possible that potential CVS benefits are compromised by should be recognized. It is not officially recommended
fluid retention and the likelihood of causing congestive for use in patients below 18 years age although there are
heart failure. studies documenting its use in this age group.

Drug Interactions CONCLUSIONS

Pioglitazone is metabolized by the cytochrome cDNA Metformin continues to be the first line drug for all patients
expressed P450 isoforms. A large number of drugs, like with type 2 diabetes and has been in wide clinical use from
erythromycin, simvastatin, diltiazem are metabolized by the 1960s. It was over 30 years later that its mechanism
544 Management

of action was worked out and still later, came the data on 8. Zeitler P, Hirst K, Pyle L, et al. A Clinical Trial to Maintain
its cardioprotective and anticancer effects. On the other Glycemic Control in Youth with Type 2 Diabetes. N Engl
J Med. 2012;366:2247-56.
hand, the glitazones were developed in the laboratory with
9. de Jager J, Kooy A, Lehert A, et al. Long term treatment
a plethora of beneficial effects shown in animal studies with metformin in patients with type 2 diabetes and risk of
and in vitro. Once they were put in clinical use, they failed vitamin B-12 deficiency: randomised placebo controlled
to live up to their promise. The enthusiasm arising out trial. BMJ. 2010;340:c2181.
of basic science data has not been upheld in the clinical 10. Brown FM, Wyckoff J, Rowan JA, et al. Metformin in
section

Pregnancy. Diabetes Care. 2006.29485-6.

setting. The drug continues to be used, although recent
11. Joshi SR. Metformin: old wine in new bottle-evolving
data, particularly with reference to bladder cancer has
8

technology and therapy in diabetes. J Assoc Phys India.

somewhat diminished its standing in the clinical setting 2005.53;964-72.
and if at all it is used, it should be done so with caution and 12. UK Prospective Diabetes Study (UKPDS) Group. Effect
in very small doses. of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes
(UKPDS 34). The Lancet. 1998;352:854-65.
FURTHER READING 13. Saenz A, Fernandez-Esteban I, Matuix A, et al. Metformin
monotherapy for type 2 diabetes mellitus. Cochrane Data­
1. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996; base of systematic Reviews, 2005;3:CD002966.
334:574-9. 14. Holman RR, Paul SK, Bethel MA, et al. 10-Year Follow-up of
2. Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004; Intensive Glucose Control in Type 2 Diabetes. N Engl J Med.
351:1106-18. 2008;359:1577-89.
3. Esposito K, Chiodini P, Bellastella G, et al. Proportion of 15. Del Barco SD, Alejandro Vazquez-Martin AV, Cufí S, et al.
patients at HbA1c target <7% with eight classes of Metformin: Multi-faceted protection against cancer. Onco­
antidiabetic drugs in type 2 diabetes: systematic review target. 2011;2:896-917.
of 218 randomized controlled trials with 78 945 patients. 16. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction
Diabetes Obes Metab. 2012;14:228-33. in the incidence of type 2 diabetes with lifestyle interven­
tion or metformin. N Engl J Med. 2002;346:393-403.
17. Misso ML, Teede HJ, Hart R, et al. Status of clomiphene
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29. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone function in type 2 diabetic patients during clinical trials:
and the risk of bladder cancer in people with type 2 evidence that rosiglitazone does not cause hepatic dysfunc­
diabetes: nested case-control study. BMJ. 2012;344:e3645. tion. Diabetes Care. 2002;25:815-21.
 Chapter 36
Incretin-Based Therapy
Ajay Kumar

Incretin-Based Therapy

Chapter Outline

♦♦ Incretin Physiology ♦♦ Incretin mimetics or analogs

♦♦ Development of glp-1 based treatment ♦♦ Incretin-based treatment and risk of pancreatitis
♦♦ Pleiotropic effects of glp-1 ♦♦ Liraglutide and risk of c-cell hyperplasia or cancer
♦♦ Dpp-4 inhibitors

INTRODUCTION INCRETIN PHYSIOLOGY

Type 2 diabetes mellitus (T2DM) is a complex metabolic Knowledge about incretins dates back to several decades.
disease characterized by inexorable decline in beta cell However, major breakthrough in this arena came from
function and persistent insulin resistance throughout the seminal work of Creutzfeldt from Germany. He
its natural history.1 Several other pathophysiological identified and characterized the secretion of two intestinal
mechanisms contribute to the altered glycemic milieu hormones in response to meal as part of “entero-insular
and its consequences (Fig. 36.1).2 Conventional treatment axis” (Fig. 36.2).3 They were named glucose dependent
modalities including metformin, thiazolidinediones, insulinotropic peptide (GIP) and glucagon-like peptide-1
insulin secretagogues, alpha glucosidase inhibitors and (GLP-1). Both these hormones demonstrated insulino­
insulin are quite effective in achieving glycemic control. tropic properties. However, insulinotropic effect of GIP
However, optimum metabolic control largely remains was found to be extremely weak. Whether GIP resistance
elusive on account of several limitations including treat­ could account for this phenomenon remains to be pro­
ment induced hypoglycemia, weight gain and other side ven. On the other hand, GLP-1 demonstrated meaning­
effects of individual drugs. Furthermore, none of them ful efficacy in stimulating both first phase and maximal
effectively address the underlying pathophysiological insulin secretory response.4 GLP-1 was also found to
mechanisms particularly the progressive decline in beta suppress inappropriately elevated glucagon secretion from
cell function. Abnormalities of incretin hormones secre­ alpha cells of pancreas in a glucose dependent manner.
tion has emerged as an important therapeutic target in Subsequently, Michael Knock demonstrated the classic
subjects with type 2 diabetes. Incretin-based treatment “incretin effect” depicting bigger insulin secretory res­
modalities are likely to address majority of underlying ponse with oral glucose as compared to intravenous (IV)
pathophysiological mechanisms, if not all. glucose (Figs 36.3A to D).5 “Incretin effect” was attributed
 Incretin-Based Therapy 547

chapter
36
Fig. 36.1: From triumvirate to the ominous octet
Defronzo RA. From the Triumvirate to the ominous octet: a new para-
digm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;
58:773-95. Fig. 36.2: Entero-Insular axis as basis of Incretin therapy concept.3

A B

C D
Figs 36.3A to D: Graphs showing the incretin effect in health and type 2 diabetes5
548 Management

to the insulinotropic effects of gut hormones. This “incretin could provide pharmacological concentration of
effect” was found to be attenuated in type 2 diabetic GLP-18 as compared to DPP-4 inhibitors which could
subjects resulting in blunted insulin secretory response achieve only physiological concentration of GLP-1.9 It is
to food.5 These two observations paved way for further well understood that only pharmacological concentration
research into harnessing the therapeutic potential of of GLP-1 could restore insulinotropic effect in type 2
GLP-1 in treatment of type 2 diabetes. diabetics close to that seen in non-diabetic individuals.4,10
Furthermore, robust pleotropic effects of GLP-1 on human
section

DEVELOPMENT OF GLP-1 BASED TREATMENT physiology could be demonstrated effectively only with
8

pharmacologic concentrations. DPP-4 inhibitors on the

To achieve normoglycemia, 24 hours therapeutic concen­ other hand provide only physiological concentration of
tration of GLP-1 is warranted.6 GLP-1 unfortunately has GLP-1 and have minimal pleiotropic effects on human
a very short half-life of less than 2 minutes.7 It is rapidly physiology.
degraded by a ubiquitous serine protease enzyme,
dipeptidyl peptidase-4 (DPP-4) almost immediately after
PLEIOtropic EFFECTS OF GLP-1 (FIG. 36.4)
its secretion from L-cells of small intestine.7 As a natural
corollary, to realize the therapeutic potential of GLP-1, Glucagon-like peptide-1 is secreted in response to food
either its half-life has to be prolonged by molecular from mucosal L-cells in the ileum of small intestine.
engineering techniques or DPP-4 enzyme ought to be When used therapeutically, it acts through specific cyclic
blocked. Both could be successfully realized leading to adenosine monophosphate (C-AMP) based receptors in
development of two classes of drugs: (1) GLP-1 analogs the islet cells of pancreas producing glucose-dependent
or mimetics, and (2) DPP-4 inhibitors respectively. It insulin secretion from pancreatic beta cells and glucose-
soon became apparent that GLP-1 analogs or mimetics dependent glucagon suppression from pancreatic

Fig. 36.4: Effects of Glucagon-like peptide-1 (GLP-1)16

 Incretin-Based Therapy 549
• GLP-1 receptor (GLP-1R) expression more varied in human vs rat pancreas
• Co-localization of GLP-1R protein with insulin is similar

chapter
36
• GLP-1R is localised in the core of human islets
• No co-localization of the GLP-1R protein with glucagon or somatostatin
•   GLP-1R may be expressed in a small subset of alpha- and delta-cells
•   GLP-1 may have indirect effect on alpha- and delta-cells
Fig. 36.5: Glucagon-like peptide-1 receptor (GLP-1R) colocalization with insulin in human beta-cells12

alpha cells.11 These pharm­ acological effects result in weight loss. Another interesting phenomenon with these
glucose utilization by different tissues and decreased agents is altered preference for healthy food as compared
hepatic glucose production, both regulating the glucose to unhealthy foods at least in rat models.17 It is well known
homeostasis. Colocalization of messenger ribonucleic that sustained weight loss of approximately 5% can lead
acid (mRNA) protein of GLP-1 with insulin secreting to about 0.6% reduction in glycated hemoglobin (HbA1c).
beta cells in pancreas could explain this phenomenon In addition, it can reduce the requirement of antidiabetic
(Fig. 36.5). This has been demonstrated both in rats and medications and favorably impact cardiovascular risk
humans.12 The obvious advantage of this phenomenon is factors like hypertension and dyslipidemia. Weight gain of
avoidance of hypoglycemia with these agents when used more than 40% above ideal target weight can increase the
in clinical practice. risk of mortality by as high as 8-fold in type 2 diabetics.18
Cyclic adenosine monophosphate mediated insulin One of the most promising effects of GLP-1 is
mediated through its actions on receptors situated in
secretion prevents endo­ plasmic reticulum stress and
cardiomyocytes and vascular endothelial cells. The former
therefore is unlikely to accelerate beta cell fatigue.13 This
leads to improved myocardial contraction and reduced
holds promise for long-term beta cell protection with
infarct areas following ischemic myocardial damage.19 Its
these agents. Both in animal models and in humans;
effect on vascular endothelium leads to increased availa­
GLP-1 has demonstrated efficacy in preventing beta cell
bility of nitric oxide and consequent vasodilatation.20 This
apoptosis and stimulating neogenesis and replication of
could lead to reduction in atherosclerosis, endothe­
beta cells.14,15 lial dysfunction, inflammation and level of cardiac bio­
Glucagon-like peptide-1 receptors are situated in markers.21-24 This is eminently beneficial in subjects with
several tissues within the human body. Naturally, this type 2 diabetes with concomitant hypertension and vas­
molecule exerts potent pharmacologic effect on various cular diseases.
organ systems.16 Its action on stomach leads to delayed Furthermore, its effect on liver might have beneficial
gastric emptying resulting in early satiety and fullness. implications in relation to gluconeogenesis, glycoge­
This translates into weight loss which is so very desirable nolysis and lipogenesis. Many of these effects remain
in majority of type 2 diabetic subjects. Similarly, GLP-1 speculative; nevertheless hold great promises. Small but
exerts important effect on these receptors in the area significant improvement in insulin sensitivity is another
postrema of the hypothalamus again leading to improved bonus that accrues with the use of GLP-1 through its
satiety, reduced appetite and consequently significant actions on muscles and adipose tissues.
550 Management

Table 36.1: DPP-4 inhibition and binding of different DPP-4 Table 36.2: DPP enzyme selectivity of different DPP-4 inhibitors
inhibitors Linagliptin Sitagliptin Saxagliptin Vildagliptin

Linagliptin Sitagliptin Saxag­liptin Vildag­liptin DPP-4 selectivity

> 100,000 fold > 5,500 over > 50,000 over > 50,000 over
DPP-4 > 80% OD 80% OD 70% OD 80% as BD over DPP-2 DPP-2 DPP-2 DPP-2
inhibition dosing
40,000 fold > 2,660 over 390 over 270 over
> 100 12.4 over DPP-8 DPP-8 DPP-8 DPP-8
Half-life 2.5 hours 2–3 hours
section

hours hours
10,000 fold > 5,500 over 77 over 32 over
DPP-4 Fast Fast Slow Slow
8

over DPP-9 DPP-9 DPP-9 DPP-9

Binding and Slow Fast Slow Slow (DPP: Dipeptidyl peptidase)

dissociation

(DPP: Dipeptidyl peptidase) amino acid. Second terminal NH2 amino acid in GLP-1 is
alanine. Native GLP-1 has a very short half-life because
this cleavage is very rapid. Inhibition of this enzyme
DPP-4 INHIBITORS
by various techniques has led to the development of a
Classification of DPP-4 Inhibitors new class of antidiabetic agents called DPP-4 inhibitors
(Table 36.1). Initial concern that DPP-4 inhibitors might
They can be classified on the basis of their binding
cleave all other bioactive peptides with alanine or proline
properties with the substrate DPP-4 enzyme.
as the second amino acid from NH2 terminal leading to
• Non-covalent bonds at catalytic sites: serious adverse events has not been substantiated either
–– Sitagliptin in animal studies or in humans (Table 36.2).26
–– Alogliptin
–– Linagliptin Pharmacological Characteristics
• Two step reversible covalent binding resulting in
of DPP- 4 Inhibitors
enzyme inhibitor complex with slow equilibrium:
–– Vildagliptin DPP-4 inhibitors act by suppressing the degradation of
–– Saxagliptin GLP-1 by DPP-4 enzyme and thereby extend its biological
DPP-4 inhibitors can also be classified on the basis of activity. They improve both insulin secretion and insulin
their molecular structure into peptidomimetic and non- sensitivity leading to improvement in “disposition
peptidomimetic inhibitors. index” or “adaptation index”.27 DPP-4 inhibitors provide
• Peptidomimetic DPP-4 inhibitors physiological concentration of GLP-1 and thus provide
(Those which mimic dipeptide structure of DPP-4 modest reductions in glycosylated hemoglobin. Like all
substrates): GLP-1 based treatment they cause glucose dependent
–– Sitagliptin insulin secretion and also glucose dependent glucagon
–– Vildagliptin suppression. Consequently, they cause minimal hypo­
–– Saxagliptin glycemia. They are weight neutral or occasionally lead
• Non-peptidomimetic DPP-4 inhibitors: to mild weight loss. They can cause minor reduction in
–– (Modified pyrinodinedione) systolic blood pressure and have some effect on beta cell
Alogliptin preservation.28 Pleotropic effects of DPP-4 inhibitors are
–– (Xanthine based) minimal as they provide only physiological level of GLP-1.
Linagliptin These compounds are orally active and rapidly absorbed.
They inhibit plasma DPP-4 activity by almost 100% at
15–30 minutes after oral administration. At least 80%
DPP-4 Enzyme
inhibition of DPP-4 activity persists for about 16 hours.29
This enzyme cleaves GLP-1 to a truncated inactive form DPP-4 inhibitors differ from GLP-1 agonists in several
called GLP-1 (9-36).25 DPP-4 owes this property to its respects.
ability to cleave two NH2 terminal amino acids of bioactive They have different binding affinity for other DPP
peptides having either alanine or proline as the second substrates including DPP-2, DPP-8, DPP-9 and others
 Incretin-Based Therapy 551

Table 36.3: Selectivity of gliptins to DPP-4 inhibition: Off target inhibition

All have good selectivity to DPP-4 enzyme and non-selectivity to DPP-8 and DPP-9
Inhibitor Selectivity QPP/DPP-2 PEP FAPa DPP-8 DPP-9
• Sitagliptin High > 5,550 > 5,550 > 5,550 > 2,660 > 5,550
• Vidagliptin Moderate > 100,000 60,000 285 270 32
• Saxagliptin Moderate > 50,000 Not reported > 4,000 390 77

chapter
• Alogliptin High > 14,000 > 14,000 > 14,000 > 14,000 > 14,000

36
• Linagliptin Moderate > 100,000 > 100,000 89 40,000 > 10,000

(QPP: Quiescent cell proline dipeptidase; PEP: Prolyl endopeptidase; FAPa: Fibroblast activation protein-a; DPP: Dipeptidyl peptidase)

Table 36.4: Pharmacodynamic properties of five dipeptidylapeptidase-4 (DPP-4) inhibitors

Parameters Sitagliptin Vidagliptin Saxagliptin Alogliptin Linagliptin
• Therapeutic dose 100 100 5 25 5
(mg/day)
• Administration Once daily Twice Once daily Once daily Once daily
• In-vitro DPP-4 inhibition 19 62 50 24 1
(IC50 nmol/L)
• In-vitro selectivity for DPP-4 vs High Moderate Moderate High Moderate
other DPP-4 family members
• Effect on plasma DPP-4 activity 80 80 70 80 80
(% inhibition over 24 hour)
• Increase in active GLP-1 levels 2-fold 3-fold 1.5 to 3-fold 2- to 3-fold 4-fold (25 mg)
• Dose reduction in renal Yes (25/50) Yes (50) Yes (2.5) Yes (12.5) No
impairment
• Dose reduction in hepatic No No No No No
impairment
• Dose reduction if CYP3A No No Yes (2.5) No No
inhibitors
• Drug-drug interaction potential Low Low Mild-moderate Low Low

(GLP-1: Glucagon-like peptide-1)

(Table 36.3).2 All substrates for DPP enzyme influence Clinical Data with DPP-4 Inhibitors
various organ functions. This could be responsible for
“Glycemic control” with these agents is rather modest with
putative benefits with these classes of drugs in preventing an average HbA1c reduction of 0.5–0.8%.31 In combination
cardiovascular complications. On the other hand, off with metformin and other oral antidiabetic agents
target inhibition through binding to DPP-8 and DPP- they cause further reduction in HbA1c by another 0.5%.
9 could be responsible for certain serious side effects Combination treatment with metformin provides greater
including gastrointestinal (GI), immunological reactions, concentration of GLP-1 than either of these agents given
alopecia and skin reactions.30 alone.32 This suggests a synergistic effect. Like all other
Several DPP-4 inhibitors are available for therapeutic antidiabetic agents they can cause greater reduction in
use; these include Vildagliptin, Sitagliptin, Saxagliptin, HbA1c in subjects with higher baseline values.
Linagliptin and Alogliptin. Pharmacokinetic and clinical DPP-4 inhibitors are inferior in efficacy as compared
differences amongst various DPP-4 inhibitors are shown to metformin monotherapy. They lead to smaller decrease
(Table 36.4). in HbA1c and also lesser probability of achieving the target
552 Management

HbA1c of less than 7%. As compared to sulfonylureas they Regulatory agencies have mandated long-term trials to
achieve smaller reduction in HbA1c but have comparable ensure cardiovascular safety of these agents. These results
probability of achieving target HbA1c of less than 7%. They are likely to be available after 2014.
are comparable in efficacy regarding HbA1c reduction DPP-4 enzyme physiologically cleaves cytokines,
to pioglitazone. However, subjects on pioglitazone had chemokines and neuropeptides involved in inflamma­
greater probability of achieving target HbA1c of less than tion, immunity and vascular function.34 Therefore, DPP-4
7%. DPP-4 inhibitors were inferior to GLP-1 agonists both inhibitors hold promise for cardiovascular protection.
section

in terms of HbA1c reduction and probability of achieving They reduce inflammation by reducing the level of inter­
8

target HbA1c of less than 7%. These differences are leukin 6 (IL-6), tumor necrosis factor (TNF)-a and mono­
particularly robust in favor of GLP-1 agonists.33 cyte chemoattractant protein-1 (MCP-1).34
“Weight reduction” with DPP-4 inhibitors was inferior
to metformin as monotherapy. In combination with DPP-4 Inhibitors and Risk of Malignancy
metformin, GLP-1 agonists were far superior to DPP-4 DPP-4 enzymes suppress certain malignancies. They
inhibitors in achieving weight loss. However, in similar particularly limit the tissue invasion of certain tumors. As
set of individuals DPP-4 inhibitors had a favorable weight a natural corollary, DPP-4 inhibitors as a class can lead
profile (weight neutral or led to small weight loss) as to progression of these cancers. In one study conducted
compared to sulfonylureas or pioglitazone. Sulfonylureas on subjects with non-small cell lung carcinoma (NSCLC)
and pioglitazone led to modest weight gain.33 DPP-4 inhibitors led to loss of growth control in NSCLC
“Hypoglycemia” was comparable in subjects receiving cells. As DPP-4 functions as tumor suppressor, its
DPP-4 inhibitors, metformin and pioglitazone as shown downregulation might explain these findings.32
in a pooled analysis from various trials recruiting
type 2 diabetics to compare efficacy and safety of DPP- Vildagliptin
4 inhibitors and other antidiabetic agents. However, it Vildagliptin was the first DPP-4 inhibitor developed
was significantly more with sulfonylureas as compared for clinical use. It makes a two-step covalent bond with
to DPP-4 inhibitors. Incidence of severe hypoglycemia DPP enzyme forming a reversible tight enzyme-inhibi­
with DPP-4 inhibitors was 6 out of 6,615 subjects. Com­ tor complex.35 The enzyme slowly equilibrates between
parative figures with metformin were 1 out of 1647, active and inactive forms. The catalytic activity of the
sulfonylureas 51 out of 3,873 and GLP-1 agonists 1 out of enzyme is inhibited even after free drug is cleared from
381. None of the subjects on pioglitazone had severe the circulation. Vildagliptin binds fast and dissociates
hypoglycemia.33 slowly as compared to competitive inhibitors like sitag­
Side effects: By and large, DPP-4 inhibitors are free of liptin providing longer duration of active GLP-1. In one
side effects and very few subjects had to be withdrawn study vildagliptin was found to sustain high intact GLP-1
during clinical trials. Minor GI disturbances including level and higher glucagon suppression as compared to
nausea, vomiting and diarrhea occurred in few cases sitagliptin; thus promising tighter glucose control.36 It is
with these agents as compared to metformin and GLP-1 rapidly absorbed after oral administration and achieves
agonists. Gastrointestinal side effects were similar with peak concentration at 1–2 hours. Its plasma half-life
these agents as compared to sulfonylureas and piogli­ with once and twice daily dosing is 1.68 hours and 2.54
tazone. Increased risk of nasopharyngitis, upper respira­ hours, respectively. However, because of its association
tory tract infection and urinary tract infection reported and dissociation kinetics it inhibits DPP-4 activity for
earlier has not been confirmed in subjects treated with longer than its relatively short half-life would suggest. It
DPP-4 inhibitors as compared to active comparators. has 85% bioavailability and is only 9.3% protein bound.
Skin rashes are reported in few and occasionally may be It is metabolized by hydrolysis quickly into an inactive
troublesome. Alopecia and bone marrow suppression has metabolite. Twenty-two percent is excreted unchanged
been reported in few cases. in the urine. The metabolite is excreted 85% through
“Cardiovascular safety” is universally seen with all kidneys and 15% through feces.35 It is recommended in
DPP-4 inhibitors. In clinical trials, Major Adverse Cardio­ doses 50 mg once or twice daily.
vascular Events (MACE) was reported less frequently with Vildagliptin has shown improvement in insulin sensi­
these agents as compared to other antidiabetic agents.32 tivity most likely as a consequence of reduced glucagon
 Incretin-Based Therapy 553

levels. This was demonstrated both by the hyperinsuline­ dangerous and warrants immediate withdrawal of medica­
mic euglycemic clamp test or using indirect measure of tion. Incidence of pancreatitis is not more than that with
insulin sensitivity including homeostatic model assess­ other antidiabetic agents.
ment insulin resistance (HOMA IR) and proinsulin/ Vildagliptin has been studied in subjects undergoing
insulin ratio.37 Ramadan fasting. It was found to cause less hypoglycemia
Direct comparison amongst various DPP-4 inhibitors as compared to sulfonylureas and also led to fewer missed
is very scanty and not sufficient to draw any meaningful doses in these subjects.43

chapter
conclusion regarding their efficacy and safety with respect

36
to one another. In a Japanese study, vildagliptin was found Sitagliptin
to have superior efficacy as compared to sitagliptin.38
Sitagliptin is a peptidomimetic DPP-4 inhibitor that acts
In another study, mean amplitude of glucose excursion
by non-covalent binding with DPP-4 enzyme through
(MAGE) was found to be less in subjects treated with
competitive inhibition. Its half-life is 12 hours and is
vildagliptin as compared to sitagliptin.39 This effect was
approved for use in a dose of 100 mg once daily. Sitag­
demonstrated by continuous glucose monitoring system
liptin is rapidly absorbed with a peak concentration at
(CGMS). Reduced glycemic variability could have impact 1–4 hours. It has 87% bioavailability and is 38% protein
in reducing future cardiovascular complications. bound. Its plasma half-life is 12.4 hours and is to be admi­
DPP-4 inhibitors are generally lipid neutral when nistered once daily. It is excreted unchanged in the urine
studied in fasting state. However, in one study, triglyceride (79%) and is partly metabolized in the liver through CYP
response to ingestion of a fat-rich meal was significantly 450 3A4 and 2C8 pathways.44
inhibited with vildagliptin given 50 mg twice daily for It reduces HbA1c by approximately 0.7% when used as
4 weeks. There was 91% reduction in chylomicron apoli­ monotherapy versus placebo. In combination with met­
poprotein B-48 and chylomicron cholesterol.40 This effect formin the mean reduction in HbA1c is 0.75 and in combi­
on postprandial lipemia might have beneficial effect on nation with pioglitazone it is 0.9%.45 It is also approved for
cardiovascular diseases. use in combination with other oral antidiabetic agents.
Vildagliptin can be taken with or without food and is Side effect profile is comparable to placebo. Several
excreted through kidney. Dose adjustment has to be made cases of pancreatitis were reported during the clinical trials
in presence of various degree of renal impairment. In mild with sitagliptin.46 However a cause and effect relationship
renal impairment no adjustment is needed. However in has not been proven.
moderate to severe renal impairment, maximum recom­ In presence of mild renal impairment no adjustment is
mended dose is 50 mg daily. Its safety in elderly subject required. In moderate renal impairment the dose has to be
has been established in clinical studies.41 It is contrain­ reduced to 50 mg daily and in severe renal impairment the
dicated in any degree of hepatic impairment, in type 1 dose recommended is 25 mg daily.44
diabetes, diabetic ketoacidosis (DKA), pregnancy, breast­ It has not been studied in children and adolescents. It
feeding and moderate to severe heart failure. It has to be is category B drug in pregnancy and is not recommended
used with caution in subjects with mild heart failure. As during breastfeeding.
vildagliptin contains lactose, it should not be taken by Sitagliptin has also been studied in Ramadan fasting
people with lactase deficiency, which is a rare hereditary subjects and was found to cause lesser hypoglycemia
problem of galactose intolerance.42 Its efficacy and safety (6.7% vs 13.2%) as compared to sulfonylureas.47
in children and adolescents under 18 years of age has Drug interaction with sitagliptin is not very significant.
not been studied and therefore it is not recommended for Cyclosporine causes approximately 68% increase in sitag­
use in this population. liptin concentration which may not be clinically relevant.
Side effects include headache, dizziness, tremor, Similarly, plasma level of digoxin may be increased by 18%
hypoglycemia particularly when used in combination with which does not necessitate dose adjustment.44
sulfonylurea or metformin, nausea, vomiting, diarrhea
and arthralgia. Very rarely it can cause hepatic function Saxagliptin
abnormalities, nasopharyngitis, allergic reactions called Saxagliptin is an adamantyl derivative with potent DPP-4
angioedema involving face, tongue or throat, difficulty inhibition properties. Because of its high microsomal
in swallowing or breathing, rash or hives. This could be turnover rate it is quickly converted into active metabolite,
554 Management

5-hydroxy Saxagliptin. It is used in a dose of 2.5 mg and inhibition of DPP-4 enzyme and was developed by repla­
5 mg daily. It reaches its peak concentration in 2 hours cing quinazolinone with pyrimidinedione. It does not
after oral administration. Neither Saxagliptin nor its active inhibit CYP 450 enzymes. Its selectivity for DPP-4 is 10,000
metabolite has significant protein binding. Therefore its fold higher than that of other DPP isoenzymes DPP-2 or
disposition is not affected in presence of renal or hepatic 8 or 9.53
disorders causing alteration in blood protein levels.48 It is It is rapidly absorbed after oral administration and is
metabolized by CYP 450 3A4/5 pathway. Significant drug minimally protein bound. It is a non-covalent binder to
section

interaction can occur with strong CYP3A4/5 inhibitors DPP-4 enzyme and is administered in dose of 12.5 mg and
and inducers. Significant increase in Saxagliptin concen­ 25 mg daily. Its half-life across all dose ranges is 12.4–21.4
8

tration can be induced by strong CYP 3A4/5 inhibitors hours. It is primarily excreted unchanged through the
like ketoconazole, itraconazole, atazanavir, indinavir, nel­ kidney. No significant drug interaction has been reported.
finavir, ritonavir, saquinavir and clarithromycin. When
administered concomitantly with these drugs the dose of INCRETIN MIMETICS OR ANALOGS
Saxagliptin should be reduced to 2.5 mg daily.48
Saxagliptin is eliminated both by renal and hepatic
Introduction
pathways. No dose adjustment is necessary in presence of Incretin mimetics or incretin analogs were the first
mild renal impairment. However, the dose has to be redu­ amongst the incretins to be used in clinical practice. They
ced to 2.5 mg daily in moderate to severe renal impair­ provide pharmacological concentration of GLP-1 and
ment. No dose adjustment is required for subjects with thereby exert the pleotropic effects of the native molecule.
hepatic impairment. They have robust effect on glycemic control and cause
significant weight loss without causing hypoglycemia.
Linagliptin They have shown great promise towards beta-cell protec­
Linagliptin is a non-peptidomimetic DPP-4 inhibitor with tion both in animal and human studies as manifested by
unique xanthine based structure. It directly binds to the improvements in surrogate markers. They are superior
active site of the enzyme through non-covalent bonding. in achieving composite end-points of HbA1c reduction
As compared with vildagliptin and sitagliptin, linagliptin and weight loss without hypoglycemia as compared to
(xanthine based compound) demonstrates superior effi­ all other treatment modalities including insulin, sulfony­
cacy, long lasting DPP-4 inhibition and long lasting lureas, pioglitazone and DPP-4 inhibitors.54
improvement in glucose control.49,50
After oral administration it is rapidly absorbed and Exenatide
remains protein bound to the tune of 95% and is slowly Exenatide was first incretin mimetic approved for
eliminated. Unbound fraction is rapidly eliminated via therapeutic use. Its naturally active form Exendin 4 is
bile and gut if protein binding sites are saturated. It has resistant to enzyme DPP-4 and was isolated from the
a long terminal half-life of approximately 25 hours. It saliva of a lizard Gila monster (Heloderma suspectum).55
achieves steady state concentration after third dosing and This has 53% homology to the native GLP-1 molecule.56 It
provides 91% DPP-4 inhibition at peak concentration and has a life of 2–3 hours and therefore has to be administered
80% inhibition for 24 hours.51 This has the advantage of parentally twice a day. Exenatide administration restores
stable 24 hours glycemic control even after a missed dose first phase insulin secretion in humans.57 Exenatide
or after double dosing at steady state. It has the highest demonstrated reduction in HbA1c to the tune of 0.8–0.9%
DPP-4 selectivity within the family of DPP-4 inhibitors.51 in phase 3 clinical trials at a dose of 5–10 µg bid and were
Off target inhibition is minimal. approved for human use in 2005.58,59 It exerts its major
Because of limited excretion through renal route (5%), effect on postprandial hyperglycemia. Glycemic control
no adjustment is required in any degree of renal or hepatic is sustained for prolonged period of time reflecting its
impairment.52 It has not shown any significant drug to potential in protecting the beta-cell function. Exenatide
drug interaction.51 has the potential to augment beta-cell proliferation and
islet neogenesis from precursor cells in different models
Alogliptin of diabetes. Notwithstanding difficulties in assessing
Alogliptin is a potent reversible, durable and highly selec­ beta-cell mass and function in humans, several surrogate
tive DPP-4 inhibitor. Alogliptin shows excellent selective markers have been demonstrated to be favorably affected
 Incretin-Based Therapy 555

by exenatide. These include HOMA beta, proinsulin/insu­ (ACE) inhibitors, Digoxin, 3-hydroxy-3-methyl-glutaryl-
lin ratio and 30 minutes oral glucose test measuring area CoA (HMGCoA) reductase inhibitors (Statins), Warfarin
under curve for the glucose.59 as it has no significant drug-drug interaction. However,
In addition to the glycemic benefits, exenatide showed drugs requiring rapid GI absorption should be used with
remarkable impact on weight reduction (1.6–2.8 Kg) after caution along with exenatide as delayed gastric emptying
30 weeks of administration and modest impact on reduc­ might lead to loss of efficacy of the coadministered drug.64
tion in systolic blood pressure.58 Both these effects could They should either be administered an hour before the

chapter
have long-term impact in mitigating the cardiovascular exenatide injection or should be taken with meals which

36
complications in these subjects. Several studies in animals are not preceded by exenatide administration.
and humans clearly showed improvement in left ventri­
cular function, reduction in infarct size and reduction of Exenatide QW (Exenatide LAR)
cardiac biomarkers.60 Weekly administration of exenatide long-acting release
Most important limiting factor with exenatide is mode­ (LAR) has now been approved by several regulatory agen­
rate to severe nausea particularly in first 10–12 weeks. cies. It has been developed by incorporating exenatide
Persistent and prolonged nausea might be attributed to into biodegradable polymeric microspheres. It offers the
the fluctuating peaks and troughs levels of GLP-1 with advantage of better glycemic control and greater weight
twice daily administration of exenatide. However, it usu­ loss than twice daily administration of exenatide.65 In
ally settles in 12–16 weeks time, except in few cases where head to head studies it has been found to be superior to
the drug has to be withdrawn permanently. sitagliptin but inferior to liraglutide and pioglitazone. Its
Acute pancreatitis was reported in excess during efficacy was similar to metformin and SU.66
Exenatide approval trials as compared to comparators.61 However, reconstitution before administration is
However subsequent analysis failed to demonstrate incre­ quite cumbersome and is likely to affect acceptability by
ased hazard ratio with the use of Exenatide as compared patients in general who have now become used to pre­
to metformin and sulfonylureas. Nevertheless this promp­ filled syringes. Antibody formation is even higher with
ted the regulatory agencies to issue warning to practicing exenatide LAR and injection site nodules are also quite
physicians to stop the drug in subjects complaining of common. Nausea is less common than with daily exena­
symptoms suggestive of pancreatitis unless excluded by tide administration.
further relevant investigations.
Exenatide has only 53% homology to the native GLP-1 Dulaglutide
molecule. This has the potential of producing neutralizing
It is another promising weekly injection of similar nature.
antibodies. Significance of these antibodies remains
It is produced by fusion of GLP-1 to a larger carrier moiety
to be ascertained particularly with reference to their
[modified immunoglobulin G4 (IgG4) Fc fragment].67
neutralizing properties. However, there is clear possibility
This reduces the in-vivo clearance. Reconstitution is not
of these antigen antibody complexes getting deposited into
required for administration and antibody formation is
the glomerular basement membrane. This has led to the
less likely.
warning for restraining the use of Exenatide in presence of
renal dysfunction.62 Liraglutide
Exenatide can be combined with other oral antidia­
betic agents including metformin, sulfonylureas, piogli­ Liraglutide is the first human GLP-1 analog. It has been
tazone, alpha-glucosidase inhibitors (AGIs) and insulin. developed by molecular engineering in the native GLP-1
The risk of hypoglycemia is likely to increase when Exena­ molecule by addition of Myristic acid at terminal seven
tide is combined with sulfonylurea (SU). Exenatide in and switching the amino acid 1 to position 2. Further
combination with insulin provides additional reduc­ protraction in the half-life to 13 hours has been achieved
tion in HbA1c without leading to any significant weight by albumin binding. This makes it eminently suitable for
gain.63 Another bonus is a reduction in the dose of insu­ once daily administration.68 Liraglutide achieves steady
lin by adding Exenatide to existing insulin treatment.63 state concentration within a week of initiating treat­
No adjustment is required when Exenatide is coadmini­ ment. It effectively restores beta-cell sensitivity to glucose
stered with agents like angiotensin-converting-enzyme with single administration.69 Liraglutide reduces HbA1c
556 Management

by approxi­mately 1.1–1.6%.70 Glycemic control with Lira­ clinical trials. However, the incidence of pancreatitis has
glutide was found to be superior to Glimepiride, Rosiglita­ not been found to be more than that in the background
zone, Insulin Glargine, Exenatide, Exenatide LAR and population of type 2 diabetics. Excess incidence of pan­
Sitagliptin.71-74 Impressive weight loss was observed in creatitis in these patients might be the result of reporting
three quarters of these subjects. Weight loss was found to bias during clinical trials. Besides several causative factors
be greater in those subjects with a higher baseline body like associated gall stones disease, hypertriglyceridemia,
mass index (BMI). Glycemic control was independent of obesity and many concomitant antihypertensive and
section

weight loss as subjects with lowest and highest quartiles of other medications could account for the reported cases
weight loss demonstrated similar reductions in the HbA1c.
8

of pancreatitis.61 Temporal relationship of drug exposure

Liraglutide has the potential to protect beta-cell and development of pancreatitis also does not support
function and mass. Notwithstanding the fact that real life a cause and effect relationship. However, pharmacovigi­
assessment of beta-cell function is extremely difficult; its lance in this respect in subjects taking incretin based treat­
effect on surrogate markers of beta-cell function including ments should ensure the safety of these classes of drugs.
HOMA b and proinsulin/insulin ratio has been found
to be quite impressive. In this context it was found to be
LIRAGLUTIDE AND RISK OF C-CELL
superior to rosiglitazone, exenatide and sitagliptin.75 This
could explain prolonged glycemic control up to 3 years
HYPERPLASIA OR CANCER
with liraglutide. Clinical development program with liraglutide showed
Another advantage with liraglutide is its potential increased incidence of c-cell hyperplasia and c-cell cancer
to reduce the systolic blood pressure by approximately in mice and rats.78 This appears to be limited to rodents; as
3–7 mm Hg. Systolic blood pressure is an important humans have extremely low numbers of c-cell receptors.
surrogate for cardiovascular complications and this might Furthermore use of liraglutide in humans did not lead
improve long-term cardio vascular outcomes. Impressive to activation of c-cell receptors as manifested by C-AMP
reduction in cardiac biomarkers including brain natri­ activation, nor did it lead to an increase in the serum
uretic peptide (BNP), plasminogen activator inhibitor 1 calcitonin, which is the biomarker of c-cell activation.78
(PAI-1) and highly sensitive C-reactive protein (hS CRP)
has also been observed with liraglutide.76 Liraglutide also
showed improved myocardial contraction, improved left
CONCLUSION
ventricular function and reduced infarct size in animal Incretin-based therapies have revolutionized the thera­
models.77 peutic paradigm for management of type 2 diabetes.
A novel approach of combining liraglutide with Clinical practice guidelines have promoted these agents to
ultralong acting basal insulin analog, degludec has been second line therapy along with sulfonylureas, pioglitazone
tested in phase III trials. Complementary action of each and insulin.79 Subjects failing on lifestyle modification and
other is likely to provide a new paradigm for management
metformin have to be judged individually regarding the
of type 2 diabetes. Hypoglycemia and weight gain caused
best therapeutic option. Incretin-based therapies have
by insulin is counter balanced by liraglutide. Insulin
the advantage of providing comparable glycemic control
degludec takes care of fasting plasma glucose where
without causing hypoglycemia. They have the additional
as liraglutide controls post prandial glucose. β-cell
advantage of either being weight neutral or can lead to
protection by liraglutide is may be a further bonus. As this
weight loss. They have also shown great promise towards
new molecule comes into pre filled syringe, it is likely to be
beta cell protection. They seem to address the basic
extremely convenient in clinical practice.
Significant nausea is reported with liraglutide in underlying pathogenetic mechanisms involved in type 2
first 8–12 weeks of treatment. However, it is usually diabetes. They have already been available for clinical use
self-limiting. for more than 7 years and have demonstrated consistent
and durable efficacy. Initial concern regarding the risk of
INCRETIN-BASED TREATMENT AND pancreatitis and c-cell hyperplasia has largely died down.
Long term safety and effect on cardiovascular outcomes
RISK OF PANCREATITIS
are likely to be addressed by long term outcome trials.
Pancreatitis has been reported in number of subjects They certainly have proved to be a valuable addition to
exposed to incretin mimetics and DPP-4 inhibitors in the the therapeutic armamentarium to treat type 2 diabetes.
 Incretin-Based Therapy 557

FURTHER READING 8. Degn KB, Juhl CB, Jacobsen G, et al. One weeks treatment
with long acting glucagon-like peptide-1 derivative
1. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the liraglutide (NN2211) markedly improves 24-h glycemia
treatment of type 2 diabetes: a comparative review. and alpha- and beta-cell function and reduces endogenous
Diabetes, Obes Metabo. 2011;13:7-18. glucose release in patients with type 2 diabetes. Diabetes.
2. Garber AJ. Long-acting glucagon-like peptide-1 receptor 2004;53:1187-94.
agonists; a review of their efficacy and tolerability. Diabetes 9. Marie A, Sallas WM, He YL, et al. Vildagliptin, a dipeptidyl
Care. 2011;34:S279-84. peptidase-IV inhibitor, improves model-assessment beta

chapter
3. Aroda VR, Henry RR, Han J, et al. Efficacy of GLP-1 receptor cell function in patients with type 2 diabetes. J Clin Endo­

36
agonists and DPP-4 inhibitors: meta-analysis and syste­ crinol Metab. 2005;90:4888-94.
matic review. Clin Ther. 2012;34:1247-58. 10. Højberg PV, Vilsbøll T, Rabøel R, et al. Four weeks of near
4. Karagiannis T, Paschos P, Paletas K, et al. Dipeptidyl pepti­ normalization of blood glucose improves the insulin
dase-4 inhibitors for treatment of type 2 diabetes mellitus response to glucagon-like peptide-1 and glucose-
dependent insulinotropic polypeptide in patients with type
in the clinical setting: systematic review and meta-analysis.
2 diabetes. Diabetologia. 2009;52:199-207.
BMJ. 2012;344:e1369.
11. Nauck MA, Kliene N, Orskov C, et al. Normalization of
5. Ahren B. Incretin therapy for type 2 diabetes: GLP-1 recep­
fasting hyperglycemia by exogenous glucagon-like peptide
tor agonist and DPP-4 inhibitors. EDN Spring. 2013;10:31-6.
1 (7-36 amide) in Type 2 (non-insulin dependent) diabetic
6. Angeli FS, Shannon RP. Incretin based therapies: can we
patients. Diabetologia. 1993;36:741-4.
achieve glycemic control and cardioprotection? J Endo­
12. Tornehave D, Kristensen P, Rømer J, et al. Expression of
crinol. 2013. JOE-13-0195.
the GLP-1 receptor in Mouse, Rat and Human pancreas.
7. Burgmaier M, Heinrich C, Marx N. Cardio vascular
J Histochem Cytochem. 2008;56:841-51.
effects of GLP-1 and GLP-1 based therapies: implications
13. Eizirik DL, Cardozo AK, Cnop M. The Role for endo­
for the cardiovascular continuum in diabetes? Diabet Med. plasmic reticulum Stress in diabetes mellitus. Endocr Rev.
2013;30:289-99. 2008;29:42-61.
8. Calanna S, Christensen M, Holst JJ, et al. Secretion of 14. Furman B, Ong WK, Pyne NJ. Cyclic AMP signaling in
glucagon-like peptide-1 in patients with type 2 diabetes pancreatic islets. Adv Exp Med Biol. 2010;654:281-304.
mellitus: systemic review and meta-analysis of clinical 15. Farilla L, Bulotta A, Hirshberg B, et al. Inhibition of b-cell
studies. Diabetologia. 2013;56965-72. apoptosis by GLP-1 in isolated human islets. Endocri­
nology. 2003;144:5149-58.
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 Chapter 37
Nutrient Blockers and
Bromocriptine
Jitendra Singh

Miscellaneous Antidiabetic Agents

Chapter Outline
♦♦ Bromocriptine ♦♦ Amylin Mimetics
♦♦ a-Glucosidase Inhibitors ♦♦ Anti-Obesity Drugs
♦♦ Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors

BROMOCRIPTINE
Bromocriptine mesylate, an ergot derivative, is a sym-
path­olytic dopamine D2 receptor agonist that exerts
inhibitory effects on serotonin turnover in the central
nervous system (CNS) (Fig. 37.1).1
The idea for using bromocriptine for the treatment
of type 2 diabetes mellitus (T2DM) originated from the
research on metabolism of migratory birds.2,3 Migratory
birds develop seasonal changes in body fat stores and
insulin sensitivity.2 Similarly, mammalian species living
in the wild have the ability to alter their metabolism from
the insulin sensitive glucose tolerant state to the insulin
resistant glucose intolerant state at appropriate times of
the year to survive long periods when food is sparse.3 Fig. 37.1: Chemical structure of Bromocriptine
In these animals, during transition from the insulin
sensitive to the insulin-resistant state, the basal lipolytic The seasonal metabolic changes in migratory birds
activity increases to spare glucose utilization by peripheral and hibernating animals are governed by changes in
(muscle) tissues, fat oxidation becomes predominant, and monoaminergic concentrations and activity in the supra­
hepatic glucose production and gluconeogenesis rise to chiasmatic nuclei (SCN) of the hypothalamus and in the
supply glucose to the CNS during these prolonged periods ventromedial hypothalamus (VMH).3
of food deprivation. At the end of the season, animals In these animals, it has been observed that there is an
revert back to their insulin sensitive glucose tolerant increase in serotonin and noradrenergic levels and activity
state.3 during the insulin-resistant state and decrease to normal
 Nutrient Blockers and Bromocriptine 561

Table 37.1: The insulin-resistant state3

• Insulin resistance in muscle and liver
• Accelerated hepatic glucose production or gluconeogenesis
• Hyperglycemia
• Adipocyte insulin resistance
• Increased lipolysis
• Enhanced fat oxidation

chapter
• Increased plasma free fatty acids (FFA) and triglyceride levels

37
• Obesity

with return to the insulin-sensitive state. Conversely,

dopamine levels are low during the insulin-resistant state
and increase to normal following return of the insulin- Fig. 37.2: The relationship between metabolic syndrome, insulin resis­
sensitive state.2 tance, hyperinsulinemia and hyperglycemia (overt type 2 diabetes).
These neurogenic and metabolic changes seen in An insulin-resistant state following nuclear peroxisome proliferator
activated receptors (PPAR) deactivation is the key phase of meta­
birds and animals have been compared to the thrifty gene bolic syndrome initiation. Afterwards, there are two principle pathways
hypothesis, which proposes that conversion to the obese, of metabolic syndrome development: (1) with preserved pancreatic
insulin-resistant state during periods of inadequate food beta- cells function and insulin hypersecretion which can compensate
for insulin resistance. This pathway leads mainly to the macrovascu-
supply provides a survival advantage.3,4
lar complications of metabolic syndrome; (2) with massive damage
of pancreatic beta-cells leading to progressively decrease of insulin
The Link with Insulin Resistance in Humans secretion and to hyperglycemia (e.g. overt type 2 diabetes). This path-
way leads both to microvascular and macrovascular complications.
It is now believed that the development of type 2 diabetic
state of insulin resistance observed in people with the
insulin resistance syndrome and type 2 diabetes is akin to
night, during sleep. In contrast, obese insulin-resistant
the insulin-resistant state in the animals during periods of
individuals have elevated (2-fold) day time plasma pro­
seasonal change (Table 37.1 and Fig. 37.2).3
lactin levels, consistent with a reduced dopaminergic
tone.1
The Role of Bromocriptine As a sympatholytic dopamine D2 receptor agonist,
Based on data available from the seasonal changes bromocriptine exerts inhibitory effects on serotonin
observed in animals and birds, studies were conducted turnover in the CNS. Consequently, bromocriptine can
in animal models. In these studies, selective destruction reverse many of the metabolic alterations associated with
of dopaminergic neurons in the SCN resulted in severe obesity by resetting central (hypothalamic) circadian
insulin resistance. Chronic infusion of norepinephrine organization of monoamine neuronal activities.3
and/or serotonin into the VMH of insulin-sensitive Indeed, bromocriptine, if administered systemically
animals caused severe insulin resistance, glucose intole­ or into the cerebral ventricle during the early hours of the
rance, and accelerated lipolysis in hamsters and rats.2 It
light cycle, prevents or reverses seasonal fattening, insulin
is now suggested that a decreased hypothalamic dopa-
resistance, and decreased endogenous (hepatic) glucose
mi­nergic tone may be involved in the pathogenesis of
production in mammals.3 Moreover, timed bromocriptine
insulin resistance.
treatment decreased body weight and improved glucose
In humans, the normal circadian cycle that results in
a leaner body in the summer and heavier body in winter tolerance in obese individuals who were instructed
is disrupted because of the abundant caloric intake year to follow a hypocaloric diet.3 Bromocriptine has also
round resulting in the absence of a lean phase.1 been shown to reduce mean day long plasma glucose,
Type 2 diabetic individuals are believed to have an triglyceride, and free fatty acid (FFA) levels in the absence
early morning dip in the dopaminergic tone, which leads of a change in body weight in obese non-diabetic women.4
to increased sympathetic activity.5 Bromocriptine also reduced body fat stores, improved
In lean, normal, glucose-tolerant, insulin-sensitive glycemic control, and diminished the need for oral hypo­
humans, the plasma prolactin concentrations peak at glycemic agents in obese patients with type 2 diabetes.4
562 Management

60 minutes. Absorption is delayed by food and peak plasma

levels are achieved at 120 minutes in a fed state. Also,
the relative bioavailability of the drug is increased under
the fed as compared to fasting conditions, by an average
of approximately 55–65%. Bromocriptine is 90–96%
bound to plasma proteins. The major route of excretion
of bromocriptine is in the bile, with the remaining
section

approximately 2–6% of an oral dose excreted via the urine.

8

The elimination half-life is approximately 6 hours.2,7

No pharmacokinetic studies have been conducted in
subjects with renal and hepatic impairment, and it should
be used with caution in such patients.2,7
Bromocriptine is metabolized in the liver by the
CYP3A4 cytochrome system. Medications that inhibit this
pathway, such as macrolide antibiotics, protease inhi­
bitors or antifungal therapies will raise circulating levels
of bromocriptine. Inducers of CYP3A4 activity, such as
phenytoin or St John’s wort, decrease bromocriptine
levels and can lead to ineffectiveness of therapy.7

Fig. 37.3: Proposed mechanism of action of Bromocriptine to improve Dosage

glucose homeostasis and insulin sensitivity
(HGP: Hepatic glucose production; TG: Triglyceride; FFA: Free fatty The recommended dose is 1.6–4.8 mg, administered
acid; SNS: Sympathetic nervous system). once daily, within 2 hours after waking in the morning. It
should be taken with food to potentially reduce the gastro­-
The proposed mechanism of action of bromocriptine intesti­nal (GI) side effects such as nausea. Bromocriptine
to improve glucose tolerance is summarized in Figure 37.3. mesylate should be initiated at one tablet (0.8 mg) and
increased by one tablet per week until a maximum daily
Therapeutic Use of Bromocriptine-QR6 dose of six tablets (4.8 mg) or until the maximal tolerated
number of tablets, between two per day and six per day, is
Bromocriptine-quick release (QR) was designed to provide reached.1
a short duration pulse of this dopamine agonist to centers
in the brain that regulate peripheral fuel metabolism. Contraindications
Bromocriptine-QR is administered in the morning, within
2 hour of waking, to effectuate an increase in central Contraindications to bromocriptine include type 1 dia­
dopaminergic tone at the time of day it normally peaks in betes, syncopal attacks and psychosis. It can precipitate
healthy individuals.5 hypotension in patients with syncopal migraines and
By resetting the circadian clock, bromocriptine actu­­ inhibit lactation in nursing women. It should not be used
ally resets the abnormally elevated hypothalamic drive in patients with hypersensitivity to ergot-related drugs or
for increased plasma glucose, triglycerides, and FFA levels bromocriptine. It can cause orthostatic hypotension and
in fasting and postprandial states in insulin resistant syncope, particularly upon initiation or dose escalation
patients.1 so caution is advised in patients taking antihypertensive
medications. It should not be used in patients with severe
Pharmacokinetics psychotic disorders.1,8,9
When administered orally, approximately 65–95% of the
drug is absorbed. Due to extensive hepatic extraction
Clinical Efficacy of Bromocriptine
and first-pass metabolism, approximately 7% of the dose Bromocriptine represents a novel agent with a unique
reaches the systemic circulation. Under fasting conditions mechanism of action in the management of type 2 dia­
the time to maximum plasma concentration is about betes mellitus (T2DM). Both as monotherapy and in
 Nutrient Blockers and Bromocriptine 563

combination with other oral hypoglycemic agents, timed

bromocriptine causes a 0.6–0.7% reduction in glycated
hemoglobin (HbA1c) and reduces plasma triglyceride
and FFA concentrations in type 2 diabetic patients. In a
52-week safety study, bromocriptine decreased the
cardiovascular (CV) composite end point by 40%. The
other advantages of bromocriptine include absence of

chapter
hypoglycemia since insulin secretion is not stimulated,

37
weight neutrality, no need for dose adjustment in patients
with moderate renal insufficiency, lack of edema and con­
gestive heart failure (CHF) and good side effect profile.1,2,6,7
Presently, however, it is not clear how bromocriptine
would fit in the current recommended strategy for
medical treatment of diabetes. It is being speculated that
bromocriptine may have optimal effects if used early in
the course of the disease, possibly in combination with
other potential disease-modifying therapies such as
metformin, thiazolidinediones, or GLP-1 agonists. It may
have utility later in the course of T2DM as well. Publi-
cations of larger trials are awaited to confirm the potential
benefits of bromocriptine for diabetes patients.1,2,7

Fig. 37.4: Acarbose competitively inhibits the enzymatic hydrolysis of

α-GLUCOSIDASE INHIBITORS oligosaccharides by α-glucosidases in the small intestine.

The three a-glucosidase inhibitors, currently available

are: (1) acarbose; (2) miglitol and (3) voglibose. secretion rates. a-glucosidase inhibition results in an
improvement of the insulin-resistant state.11
Mechanism of Action
a-glucosidase inhibitors do not target any specific Efficacy and Clinical Use
patho­­physiologic aspect of diabetes. This class of oral The blood glucose lowering effect of a-glucosidase
hypoglycemic agents competitively inhibit enzymes in
inhibitors is less than that of most of the other classes of
the small intestinal brush border that are responsible for
oral hypoglycemic agents (Table 37.2).10
the breakdown of oligosaccharides and disaccharides into
Compared with placebo, clinical trials have demons­
monosaccharides suitable for absorption (Fig. 37.4).10
trated an average HbA1c lowering effect of about 0.5–1.0%,

Inhibition of a-glucosidase, an enzyme, found predo­
with a greater improvement in postprandial plasma
minantly in the proximal half of the small intestine, delays
glucose levels than fasting levels. A small reduction in
the intestinal absorption of carbohydrates and shifts it to
triglyceride levels has also been demonstrated. Given
more distal parts of the small intestine and colon. This,
the relatively poor efficacy compared with other antihy­
consequently, retards glucose entry into the systemic
perglycemic agents (OHAs), a-glucosidase inhibitors are
circulation and lowers postprandial glucose levels.10
a-glucosidase inhibitors act locally at the intestinal rarely used alone and are not recommended as initial
brush border and different compounds are absorbed to a therapy for moderate to severe hyperglycemia (HbA1c
variable extent. They are excreted in feces.10 concentration ≥ 9.0%).10
Secondary to the suppression of postprandial hyper­
glycemia, a-glucosidase inhibition significantly reduces
Side Effects, Cautions and Contraindications
the postprandial increment in plasma insulin levels. This The main side effects of a-glucosidase inhibitors are gastro­-
action is most prominent in individuals with high insulin intestinal. Specifically, bloating, abdominal dis­comfort,
564 Management

Table 37.2: Orally administered antihyperglycemic agents (OHAs) for the treatment of diabetes10
Drug class Mechanism of Dosage Decrease in Main side effects Contraindications
action hemoglobin
A1c concentra-
tion*
α-Glucosidase Delays intestinal Acarbose: 25 mg once 0.5–1.0% Gastrointestinal Irritable bowel syndrome,
inhibitor (miglitol carbohydrate daily, titrated to 100 mg severe kidney or liver
acarbose, voglibose) absorption three times daily dysfunction
section

Voglibose: 0.2–0.3 mg
8

TDS, before meals

Miglitol: 50–100 mg TDS,
before meals
Biguanide† Increases 500 mg once daily, titrated 1.0–1.5% Gastrointestinal, Moderate to severe liver or
(metformin) liver and muscle to 1000 mg twice daily lactic acidosis cardiac dysfunction, mild renal
insulin sensiti­ (rare) dysfunction‡
vity; decreases
hepatic glucose
production
Insulin secretagogue Increases insulin Gliclazide: 40–160 mg 1.0–1.5% Hypoglycemia, Moderate to severe liver
Sulfonylureas secretion, acute twice daily, 30–120 mg Repaglinide: weight gain dysfunction; adjust dose in
(gliclazide, glimepiride, increase of insu- once daily (MR form) 1.0–1.5% the presence of severe kidney
glyburide) lin secretion Glimepiride: 1–8 mg Nateglinide: dysfunction. Avoid use of
Non-sulfonylureas once daily Glyburide: 0.5–1.0% glyburide in elderly patients or
(repaglinide, ≤ 5 mg once daily, titrated patients with kidney dysfunction.
nateglinide) to > 5 mg twice daily Severe liver or kidney dysfunc-
Repaglinide: 0.5 – 4 mg tion; avoid concomitant use of
three times daily repaglinide with gemfibrozil
Nateglinide: 60 –120 mg
3 times daily
Insulin sensitizer or Increases Rosiglitazone: 2–8 mg 1.0–1.5% Weight gain, Severe liver dysfunction, NYHA
thiazolidinedione§ adipose and once daily edema, anemia, class II–IV CHF
(rosiglitazone, muscle insulin Pioglitazone: 15–45 mg pulmonary edema,
pioglitazone) sensitivity once daily CHF
DPPIV inhibitors Increases insulin Sitagliptin 100 mg OD, Pharyngolaryngitis History of pancreatitis,
(sitagliptin, vildagliptin, secretion, Vildagliptin 50 BD, Nausea Renal dysfunction, (modified
saxagliptin, linagliptin) decreases Saxagliptin 5 mg OD, dosage allowed)
glucagon, Linagliptin 5 mg OD, Severe liver dysfunction
delayed gastric
emptying,
increases satiety
Intestinal lipase Decreases 120 mg three times daily 0.3–0.9% Gastrointestinal, Malabsorption syndrome,
inhibitor (orlistat) intestinal fat reduced absorp- cholestasis
absorption tion of fat-soluble
(weight loss) vitamins
(MR: Modified release; CHF: Congestive heart failure, NYHA: New York Heart Association).
Keys: *Indicated average decreases in hemoglobin A1c concentrations after 3–6 months of monotherapy.
†
Preferred primary agent for overweight patients.
‡
Use with caution or avoid in the presence of any elevation in serum creatinine levels.
§
6–12 weeks are required to achieve the full glucose-lowering effect. Suitable for obese patients only.

diarrhea and flatulence occur in about 20% of patients. alone, in patients who are using it in combination with
Initiation of therapy at a low dose with slow titration another OHA or with insulin, hypoglycemia must be
upward may minimize these side effects, and symptoms treated with glucose itself (e.g. dextrose tablets) instead
may diminish with continued use. Although hypogly- of complex carbohydrates, since absorption of the latter is
cemia does not occur when a drug in this class is used delayed.10
 Nutrient Blockers and Bromocriptine 565

chapter
37
Fig. 37.5: Chemical structure of Miglitol Fig. 37.6: Chemical structure of Acarbose

a-Glucosidase inhibitors are contraindicated in pati­ whom metabolic control was suboptimal despite dietary
ents with irritable bowel syndrome, severe kidney or liver and pharmacological intervention.12
dysfunction. Inflammatory bowel disease is a relative As monotherapy, miglitol is not associated with hypo­
contraindication.10 glycemia, but concomitant use with other oral antidiabetic
agents may necessitate dosage adjustment of the other
Miglitol agents. Miglitol had no significant effects on renal, CV,
respiratory or hematological parameters in long-term
Miglitol, the first pseudomonosaccharide alpha-gluco­
studies. No dosage adjustments are required in elderly
sidase inhibitor, smoothens postprandial peak plasma
patients, in those with hepatic impairment or in those with
glucose levels and thus improves glycemic control, which
mild to moderate renal insufficiency.12
is reflected in a reduced HbA1c level. Miglitol is generally
Most adverse events associated with miglitol treat­-
well tolerated and, unlike the sulfonylurea agents, is not
ment involve disturbances of the GI tract (most common
associated with body weight gain or hypo­glycemia when
effects are flatulence, abdominal pain and diarrhea). These
administered as monotherapy. The drug is systemically
symptoms are usually dose dependent, mild to moderate
absorbed but is not metabolized and is rapidly excreted
in severity, occur at the onset of treatment, decline with
via the kidneys (Fig. 37.5).12
time and resolve promptly on discontinuation of the drug
Clinical trials with miglitol (usually 50 mg or 100 mg
or with dosage adjustment.12
three times daily) in patients with T2DM consistently
This agent is a useful first-line therapy in patients
demonstrated a significant improvement in glycemic
with T2DM insufficiently controlled by diet alone and as
control for periods of 6–12 months. There were also mar­
second-line or as adjuvant therapy in those insufficiently
ked reductions in post-prandial serum insulin levels,
controlled with diet and sulfonylurea agents. Miglitol
although miglitol generally had no effect on fasting
may prove particularly beneficial in elderly patients and
insulin levels. In comparative studies miglitol had simi­
those with hepatic impairment or mild to moderate renal
lar efficacy to acarbose, but at lower therapeutic doses
impairment, in which other oral antidiabetic agents are
(50 mg and 100 mg three times daily, respectively). In
contraindicated or need to be used with caution.12
addition, although sulfonylurea agents provided superior
reductions in HbA1c levels, miglitol provided similar or
Acarbose
superior reductions in fasting and postprandial plasma
glucose levels.12 Of the three a-glucosidase inhibitors, the benefits of
Indeed, in long-term, well designed trials miglitol acarbose are best documented (Fig. 37.6).
reduces fasting and postprandial plasma glucose levels, Insulin resistance and an increasing decline in pan­
thus improving glycemic control, which is reflected in a creatic beta-cell function result in the progression from
reduced HbA1c level in patients with T2DM.12 impaired glucose tolerance (IGT) to diabetes. Acarbose
In combination with other oral antidiabetic agents or therapy increases insulin sensitivity in patients with
insulin, miglitol improved glycemic control in patients in type 2 diabetes13 and in individuals with IGT.14
566 Management
section
8

Fig. 37.7: The effect of Acarbose on developing cardiovascular events in individuals with impaired glucose tolerance (IGT) during STOP-NIDDM
(CV: Cardiovascular; STOP NIDDM: Study to prevent non-insulin dependent diabetes mellitus).

Furthermore, studies also suggest that acarbose the­ is associated with inflammation, leading to the develop­
rapy may attenuate deterioration of beta-cell function. In ment of endothelial dysfunction and atherosclerosis.20
acarbose treated patients, with type 2 diabetes, C-peptide Acarbose reduces the levels of coagulation markers in
levels remained unchanged15 and proinsulin to insulin patients with type 2 diabetes. Indeed, the use of acarbose
ratios were low16 thereby reflecting normal insulin proces­ has been shown to reduce postprandial fibrinogen levels
sing by the pancreas. substantially in these patients.21
These results were further strengthened by the study There is also evidence to show that acarbose improves
to prevent non-insulin-dependent diabetes mellitus lipid profiles by reducing levels of low-density lipoprotein
(STOP-NIDDM) trial. This study concluded that acarbose (LDL), leading to significant improvements in the high-
could be used, either as an alternative or in addition density lipoprotein (HDL)/LDL ratio.22 The same trial also
to changes in lifestyle, to delay development of type 2 found that the reduction in postprandial hyperglycemia
diabetes in patients with IGT. In this trial involving indivi­ with acarbose therapy was associated with a 34% relative
duals with IGT, there was a 25% reduction (p = 0.0015)
risk reduction in the incidence of new cases of hypertension
in the incidence of type 2 diabetes when subjects were
(p = 0.006).22
diagnosed with one positive oral glucose tolerance test
A substudy of STOP-NIDDM found that acarbose
(OGTT), and a 36% reduction (p = 0.0017) when subjects
slows the progression of intima media thickening (IMT)
were diagno­sed with two consecutive OGTTs.17
in individuals with prediabetes; compared with placebo,
Current available evidence also indicates that acar­
bose, by reducing postprandial hyperglycemia, positively acarbose treatment reduced the annual increase in carotid
affects a number of cardiovascular disease (CVD) risk IMT by approximately 50% (p = 0.027).23
factors, including progressive dysglycemia, endothelial In contrast to other oral antidiabetes agents, acarbose
dysfunction, dyslipidemia and hypercoagulability.18 is not associated with weight gain.23
In a study involving individuals with IGT, acarbose The above benefits on CV risk factors, offer an advan­
therapy lowered postprandial blood glucose levels and t­
age in reducing cardiovascular events. In individuals
improved flow mediated vasodilation (FMVD) compared with IGT, in the STOP-NIDDM trial, there was a 49%
with placebo (p = 0.046).19 relative risk reduction in the development of CV events
In another study, acarbose decreased the activity of (p = 0.03) over a mean follow-up of 3.3 years (Fig. 37.7).22
the transcription factor nuclear factor kappa B (NFkB) In a meta-analysis of seven randomized, double-blind
in peripheral blood mononuclear cells, compared with acarbose trials involving 2,180 patients, of whom 1,248
placebo, in patients with type 2 diabetes. NF-kB activation received acarbose, the prevalence of CV events was 6.1%
 Nutrient Blockers and Bromocriptine 567

among patients treated with acarbose, compared with

9.4% among patients receiving placebo (p = 0.0061). After
a mean duration of 400 days of acarbose therapy, the risk
of any CV event was reduced by 35% (p = 0.0061), and
the risk of myocardial infarction (MI) by 64% (p = 0.0120).24
Thus, the impact of post-prandial hyperglycemia
appears to be attenuated by the use of acarbose. The

chapter
results from the STOP-NIDDM trial and other trials and

37
meta-analysis appear to suggest that acarbose can red­
uce the risk of CVD across the diabetes continuum. These
studies support a scientific rationale for the early use Fig. 37.8: Chemical structure of Voglibose
of acarbose to reduce the progression from IGT to estab­
lished type 2 diabetes and to reduce the risk of CVD.18
Voglibose, in addition to standard care with diet and
Dosage exercise, has been shown to be effective in preventing the
progression of IGT to type 2 diabetes and in facilitating the
Although acarbose is not significantly absorbed, but its
normalization of the OGTT in high-risk Japanese subjects
metabolites are absorbed and can accumulate in renal
failure. In patients with severe renal failure (creatinine with IGT.28-30
clearance < 25 mL/min/m2) five times the serum concen­ As seen with acarbose, studies also suggest that vogli­
tration of acarbose is seen.25 The recommended starting bose lowers the daily glycemic excursions and inhibits
dosage of acarbose is 25 mg orally three times daily overwork of the pancreatic beta-cells.31
(t.i.d.) at the start of each main meal. A more gradual By improving postprandial hyperglycemia voglibose
dose titration of 25 mg once per day and subsequently has been shown to reduce oxidative stress markers and
increasing the frequency of administration to achieve soluble intercellular adhesion molecule 1 (sICAM-1).32
25 mg t.i.d. is recommended to minimize gastrointestinal The administration of voglibose resulted in a significant
side effects. reduction of total cholesterol and triglyceride concen­
Once a 25 mg t.i.d. dosage regimen is reached, dosage trations, as well as an increase in HDL cholesterol concen­
of acarbose is adjusted at 4–8 week intervals from 25 mg tration suggesting the beneficial effects of voglibose in
t.i.d. to 50 mg t.i.d. Some patients may benefit from further progression of IMT.33
increasing the dosage to 100 mg t.i.d. The maintenance Currently, voglibose has been tested extensively in
dose ranges from 50 mg t.i.d. to 100 mg t.i.d.26 combination therapy with conventional oral antidiabetic
agents, including metformin and the gliptins.
Voglibose
Voglibose is a new, potent glucosidase inhibitor, approved Dosage
by the Japanese Ministry of Health, Labor and Welfare,
Voglibose is scarcely absorbed and is safe to use in renal
in the year 2009, for the prevention of new-onset type
failure.25 Voglibose is recommended as a single dose of
2 diabetes, in patients with impaired glucose tolerance
0.2 mg t.i.d., just before each meal. If the effect is not
(Fig. 37.8).27,33
sufficient, the single dose may be increased up to 0.3 mg,
The inhibitory actions of voglibose were assessed on
under close observation of the course of disease.
porcine small intestine-derived maltase and sucrase, and
were found to be about 20–30 times as strong as acarbose,
SODIUM GLUCOSE COTRANSPORTER 2
respectively, while the inhibitory actions of voglibose on
rat small intestine-derived maltase and sucrase are about
(SGLT-2) INHIBITORS
270 times and 190 times as strong as those of acarbose, Sodium glucose cotransporter 2 (SGLT-2) inhibitors are
respectively. On the other hand, the inhibitory actions of a novel therapeutic class of antidiabetic drugs.
voglibose on porcine and rat pancreatic a-amylase are The transport of glucose into epithelial cells is medi­
about 1/3,000 of those of acarbose, and voglibose pro­ ated by an active cotransport system, the sodium glucose
duces no inhibitory action on b-glucosidase.28 co-transporter (SGLT).34 Two SGLT isoforms have
568 Management

been identified, namely SGLT-2, which is exclusively

expressed in the brush border of epithelial cells in S1
and S2 segments of proximal renal tubules, and SGLT-1,
which is expressed primarily in the small intestine,
S3 segment of the proximal tubule of the kidney, and
myocardium.35 SGLT-2 accounts for 90% of the glucose
reabsorption in the kidney.35
section

Selective inhibition of SGLT-2 therefore increases

8

urinary glucose excretion by inhibiting renal glucose

reabsorption in an insulin independent manner.34 SGLT-
2 inhibitors offer a considerable advantage as potential
antidiabetic medications because of their ability to
increase urinary glucose excretion and subsequent
plasma glucose-lowering effect without inducing excessive
insulin secretion. An increase in urinary glucose excretion
leads to a negative energy balance, making it a unique
therapeutic class that reduces body weight in diabetic
patients.35 The inhibition does not hamper glucose trans­
port in other major organs of the body such as the brain,
liver, and muscle.35
Effects of SGLT-2 inhibitors include reduction of HbA1c,
fasting and postprandial blood glucose level and some
reduction in body weight and systolic blood pressure.36 Fig. 37.9: Overview of central and peripheral functions associated with
antiobesity pharmacotherapies
The most common adverse events are genital mycotic
and urinary tract infections. Dapagliflozin and canag­
imbalance between energy intake and expenditure, is
liflozin are the first agents of this class, approved by the
widely recognized as the largest and fastest growing
European Medicine Agency and US Food and Drug
public health problem in the developed and developing
Administration (FDA), respectively.36
world. It has been estimated that in 2005, 400 million
adults worldwide were obese, with a total of 1.6 billion
AMYLIN MIMETICS being overweight. Obesity is associated with substantial
Deficient amylin secretion is a well-recognized pheno­ increases in morbidity, premature mortality and impaired
menon in type 1 diabetes mellitus (T1DM) and in later- quality of life. One of the most common comorbidities is
type 2 diabetes.39
stage T2DM patients, in whom pancreatic insulin produc­
A pathogenic relationship exists between type 2
tion is markedly reduced.37
diabetes and obesity.40 Over the last decade, the escalation
Amylin suppresses glucagon secretion from pancreatic
in diabetes cases has paralleled the rapid increase in
a-cells, thereby attenuating hepatic glucose production. It
obesity rates, constituting a global health crisis. Both
also delays gastric emptying. It has also been shown to
diabetes and obesity confer an elevated risk of developing
have a central effect to enhance satiety.37
a range of complications and comorbidities, including
Pramlintide is a synthetic analog of human amylin,
CVD, hypertension and stroke, which can complicate
(also referred to as an amylinomimetic) for therapeutic
disease management.40
use in T1DM and T2DM patients. Pramlintide mimicks the Drugs that have been prescribed or evaluated for obe-
physiological effects of amylin.37 sity may reduce fat absorption or regulate satiety via their
Pramlintide significantly reduces HbA1c and body weight action on serotonin, noradrenergic or dopaminergic or
in patients with T1DM and T2DM.38 the cannabinoid receptor systems in the brain (Fig. 37.9).41

ANTI-OBESITY DRUGS Orlistat

Obesity, most often defined as a body mass index (BMI) Orlistat is a GI lipase inhibitor. It was approved by the
of more than and equal to 30 kg/m2 and caused by an US FDA for the treatment of obesity in 1998.39 It is a
 Nutrient Blockers and Bromocriptine 569

chapter
37
Fig. 37.10: Chemical structure of Orlistat Fig. 37.11: Chemical structure of Lorcaserin

synthetic drug derived from a naturally occurring lipase The US FDA received 32 reports of serious liver injury
inhibitor. It does not directly act on appetite as other obe­ in patients using orlistat between 1999 and October
sity pharmacotherapies, rather it decreases fat absorption 2008, including six cases of liver failure. This prompted
by binding to pancreatic lipase, the principle enzyme that the US FDA to undertake a review of the safety of orlistat
hydrolyses triglyceride thereby reducing fat absorption treatment. The review identified a total of 13 cases of
from the gut by approximately 30% (Fig. 37.10).39,41 severe liver injury [12 foreign reports with orlistat 120 mg
Weight loss is relatively modest circa 3 kg at 12 months, and a US report with the lower dose OTC product (orlistat
but of sufficient magnitude to have beneficial effects on 60 mg)] and in May 2010 led to a label revision and the
CV risk, as reflected by a lowering of LDL cholesterol, addition of a warning of severe liver injury.41
blood pressure and glycemia.39
The long-term efficacy of orlistat (120 mg three Lorcaserin
times daily) for weight loss has been demonstrated in Lorcaserin is a novel selective agonist of the 5-HT(2C)
several randomized controlled trials of 2–4-year therapy receptor for weight loss therapy (Fig. 37.11).43
compared to placebo, as well as improvements in blood Preclinical and clinical studies indicate lorcaserin is
pressure, insulin resistance, and serum lipid levels. well tolerated and not associated with cardiac valvulopathy
Several systematic reviews in adults have demonstrated or pulmonary hypertension suggesting that lorcaserin
significantly more weight loss with orlistat than placebo, is a selective 5-HT(2C) receptor agonist and has little or
6.2 kg [95% confidence interval (CI), 1.7–14.0 kg]. no activation of the 5-HT(2B) and 5-HT(2A) receptors,
The most commonly experienced side effects of respectively.43
orlistat are GI and include diarrhea, flatulence, bloating, Lorcaserin acts to alter energy balance through a
abdominal pain, and dyspepsia.39,41 reduction in energy intake and without an increase in
In 2007, the US FDA approved orlistat 60 mg capsules energy expenditure.43
for over-the-counter (OTC) use in the United States, for Clinical trials with lorcaserin have demonstrated
use by overweight adults in conjunction with a reduced- effective weight loss compared to placebo along with a good
calorie, low-fat diet. Studies indicate that orlistat 60 mg safety profile. Results from two recently presented pivotal
helps people lose 50% more weight than with diet alone. Phase III trials, behavioral modification and lorcaserin
Orlistat 60 mg is the only FDA-approved weight-loss for overweight and obesity management (BLOOM) and
product available to consumers without a prescription, behavioral modification and lorcaserin second study
and it is the first clinically-proven OTC product to be com­ for obesity management (BLOSSOM) indicated greater
bined with a comprehensive support program.42 weight loss with lorcaserin than with placebo.44
Reduced-calorie, low-fat diet in conjunction with orli­- Pooled data from these two studies showed a weight
stat 60 mg leads to a modest, gradual weight loss, offering loss at 52 weeks of 5.8% in the lorcaserin group and 2.5%
the triple benefits of efficacy, safety and consequently in the placebo group (p <.0001). Weight loss was main­
compliance, thereby providing significant health benefits tained in 67.9% of lorcaserin patients in 2nd year and
to an overweight patient.42 50.3% of placebo (p <.001). The most frequent adverse
570 Management

events reported were headache, dizziness and nausea, but 9. Misdrahi D, Chalard R, Verdoux H. Postpartum mania
these were not significantly different between treatment induced by Bromocriptine: a case report. J Gynecol Obstet
Biol Reprod (Paris). 2006;35:79-81.
groups.44
10. Cheng AY, Fantus IG. Oral antihyperglycemic therapy for
Lorcaserin, as monotherapy, was however initially type 2 diabetes mellitus. CMAJ. 2005;172:213-26.
rejected in 2010 owing to concerns about tumour growth 11. Rupp Markus. Diabetes Mellitus: a fundamental and clini-
in preclinical studies but, following re-file, was approved cal text, 3rd edition. Lippincott Williams & Wilkins; 2004.
by the US FDA in June 2012.39 Available at http://www.msdlatinamerica.com/diabetes/
section

sid1418338.html [Accessed September 2013]

12. Scott LJ, Spencer CM. Miglitol: a review of its therapeu-
Further Reading
8

tic potential in type 2 diabetes mellitus. Drugs. 2000;59:

1. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment 521-49.
and the risk of cardiovascular disease, and hypertension in 13. Meneilly GS, Ryan EA, Radziuk J, et al. Effect of acarbose
patients with impaired glucose tolerance: the STOP-NID- on insulin sensitivity in elderly patients with diabetes. Dia­
betes Care. 2000;23:1162-7.
DM trial. JAMA. 2003;290:486-94.
14. Laube H, Linn T, Heyen P. The effect of acarbose on insu-
2. Inzucchi, SE, McGuire, DK. New Drugs for the Treatment
lin sensitivity and proinsulin in overweight subjects with
of Diabetes, Part II: Incretin-Based Therapy and Beyond.
impaired glucose tolerance. Exp Clin Endocrinol Diabetes.
Circulation. 2008;117:574-84.
1998;106:231-3.
3. Defronzo, RA. Bromocriptine: a sympatholytic, D2-dopa-
15. Delgado H, Lehmann T, Bobbioni-Harsch E, et al. Acar-
mine agonist for the treatment of type 2 diabetes. Diabetes
bose improves indirectly both insulin resistance and
care. 2011;34:789-94. secretion in obese type 2 diabetic patients. Diabetes Metab.
4. Choudhary N, Kalra S, Unnikrishnan AG, et al. Preven- 2002;28:195-200.
tive pharmacotherapy in type 2 diabetes mellitus. Indian 16. Hanefeld M, Haffner SM, Menschikowski M, et al. Different
J Endocrinol Metab. 2012;16:33-43. effects of acarbose and glibenclamide on proinsulin and
5. Chandalia HB. Oral anti-diabetics in presence of hepatic & insulin profiles in people with type 2 diabetes. Diabetes Res
renal disease. In: Samar Banerjee (Ed). Oral anti-diabetics. Clin Pract. 2002;55:221-7.
Gurgaon: Macmillan’s Reference Series; 2013. pp. 59-71. 17. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for preven-
tion of type 2 diabetes mellitus: the STOP-NIDDM ran-
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18. Båvenholm PN, Efendic S. Postprandial hyperglycaemia
1. Shivaprasad C, Kalra S. Bromocriptine in type 2 diabetes and vascular damage—the benefits of acarbose. Diab Vasc
mellitus. Indian J Endocrinol Metab. 2011;15:S17-S24. Dis Res. 2006;3:72-9.
2. Defronzo, RA. Bromocriptine: a sympatholytic, D2-dopa- 19. Wascher T, Schmolzer I, Stuehlinger M, et al. Hypergly-
mine agonist for the treatment of type 2 diabetes. Diabetes cemia-induced endothelial dysfunction in patients with
care. 2011;34:789-94. impaired glucose tolerance is prevented by acarbose [Abs­
3. Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel tract 3020]. European Society of Cardiology Congress, 2004.
approach to the treatment of type 2 diabetes Diabetes Care. 20. Rudofsky G, Reismann P, Schiekofer S, et al. Reduction of
2000;23:1154-61. postprandial hyperglycemia in patients with type 2 diabe-
4. Speakman JR, Westerterp KR. A mathematical model of tes reduces NF-kappaB activation in PBMCs. Horm Metab
weight loss under total starvation and implications of the Res. 2004;36:630-8.
genetic architecture of the modern obesity epidemic for the 21. Tschoepe D. Decreased fibrinogen by treatment with the
thrifty-gene hypothesis. Dis Model Mech. 2012;6:236-51. alpha-glucosidase inhibitor acarbose [ADA abstract 766].
5. Bernardi L, Ricordi L, Lazzari P, et al. Impaired circadian Diabetes. 2004;53:A189.
modulation of sympathovagal activity in diabetes. A possi- 22. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment
ble explanation for altered temporal onset of cardiovascu- and the risk of cardiovascular disease, and hypertension in
lar disease. Circulation. 1992;86:1443-52. patients with impaired glucose tolerance: the STOP-NID-
6. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized DM trial. JAMA. 2003;290:486-94.
clinical trial of quick-release bromocriptine among patients 23. Hanefeld M. Cardiovascular benefits and safety profile of
with type 2 diabetes on overall safety and cardiovascular acarbose therapy in prediabetes and established type 2 dia-
outcomes. Diabetes Care. 2010;33:1503-8. betes. Cardiovasc Diabetol. 2007;6:20.
7. Via MA, Chandra H, Araki T, et al. Bromocriptine approved 24. Hanefeld M, Cagatay M, Petrowitsch T, et al Acarbose
as the first medication to target dopamine activity to reduces the risk for myocardial infarction in type 2 dia­betic
improve glycemic control in patients with type 2 diabetes. patients: meta-analysis of seven long-term studies. Eur
Diabetes Metab Syndr Obes. 2010;3:43-8. Heart J. 2004;25:10-6.
8. Sicuteri F, Boccuni M Fanciullacci M, et al. A new non- 25. Chandalia HB. Oral anti-diabetics in presence of hepatic &
vascular interpretation of syncopal migraine. Adv Neurol. renal disease. In: Samar Banerjee (Ed). Oral anti-diabetics.
1982;33:199-208. Gurgaon: Macmillan’s Reference Series; 2013. pp. 59-71.
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26. RxList: The Internet Drug Index. (Year). Precose: indica- 34. Piya MK, Tahrani AA, Barnett AH. Emerging treatment
tions, dosage and administration. [online] RxList website. options for type 2 diabetes. Br J Clin Pharmacol. 2010;
Available from http://www.rxlist.com/precose-drug/indi- 70:631-44.
cations-dosage.htm [Accessed September, 2013]. 35. Ghosh RK, Ghosh SM, Chawla S, et al. SGLT2 Inhibitors: a
27. Choudhary N, Kalra S, Unnikrishnan AG, et al. Preven- new emerging therapeutic class in the treatment of type 2
tive pharmacotherapy in type 2 diabetes mellitus. Indian J diabetes mellitus. J Clin Pharmacol. 2012;52:457-63.
Endocrinol Metab. 2012;16:33-43. 36. Andrianesis V, Doupis J. The role of kidney in glucose
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29. Kawamori R, Tajima N, Iwamoto Y, et al. Voglibose for Diabetes, Part II: Incretin-Based Therapy and Beyond. Cir-
prevention of type 2 diabetes mellitus: a randomised, dou- culation. 2008;117:574-84.
ble-blind trial in Japanese individuals with impaired glu- 38. Younk LM, Mikeladze M, Davis SN. Pramlintide and the
cose tolerance. Lancet. 2009;373:1607-14. treatment of diabetes: a review of the data since its intro-
30. Matsumoto K, Yano M, Miyake S, et al. Effects of voglibose duction. Expert Opin Pharmacother. 2011;12:1439-51.
on glycemic excursions, insulin secretion, and insulin sen- 39. Rodgers JR, Tschop MH, Wilding, JP. Anti-obesity drugs:
sitivity in non-insulin-treated NIDDM patients. Diabetes past, present and future. Dis Model Mech. 2012;5:621-6.
Care. 1998;21:256-60. 40. Colagiuri S. Diabesity: therapeutic options. Diabetes Obes
31. Satoh N, Shimatsu A, Yamada K, et al. An alpha-glucosidase Metab. 2010;12:463-73.
inhibitor, voglibose, reduces oxidative stress markers and 41. Ioannides-Demos LL, Piccenna L, McNeil JJ, et al. Pharma-
soluble intercellular adhesion molecule 1 in obese type 2 cotherapies for obesity: past, current, and future therapies.
diabetic patients. Metabolism. 2006;55:786-93. J Obes. 2011;2011:179674.
32. Yamasaki Y, Katakami N, Hayaishi-Okano R, et al. 42. US Food and Drug Administration. (2007). alliTM: read me
first--keys to successful weight loss. [online] Available from
Alpha-glucosidase inhibitor reduces the progression of
http://www.accessdata.fda.gov/drugsatfda_docs/label/
carotid intima-media thickness. Diabetes Res Clin Pract.
2007/021887lbl.pdf [Accessed September, 2013].
2005;67:204-10. 43. Redman LM, Ravussin E. Lorcaserin for the treatment of
33. Takeda Pharmaceutical Company Limited. (2008). voglibose obesity. Drugs Today (Barc). 2010;46:901-10.
(BASEN®) for the prevention of type 2 dia-betes melli- 44. Anderson CM, Sanchez M, Krolikowski J, et al. A selec­-
tus: a randomized, double-blind trial in japanese sub- tive 5-HT2C agonist is efficacious for weight loss across
jects with impaired glucose tolerance. [online] Takeda patient subgroups. American Diabetes Association 70th
website. Available from http://www.takeda.com/news/ Scientific Meeting, 2010. [http://professional. diabetes.org
2008/20080526_3621.html [Accessed September, 2013]. Abstracts].
 Chapter 38
Insulin Therapy

Sunil M Jain

Insulin Therapy

Chapter Outline
♦♦ History of Insulin Development ♦♦ Insulin Therapy in Type 2 Diabetes Mellitus
♦♦ Method of Insulin Production ♦♦ Insulin Therapy in Type 1 Diabetes Mellitus
♦♦ Types of Insulin ♦♦ Practical Information on Insulin
♦♦ Pharmacology of Available Insulin Preparations ♦♦ Adverse Effects of Insulin
♦♦ Indications for Insulin Therapy ♦♦ Continuous Subcutaneous Insulin Infusion, Insulin Pump
♦♦ Insulin Regimens ♦♦ What’s New and Future?

HISTORY OF INSULIN DEVELOPMENT insulin and the injected material, which lowered his blood
sugar. This was the first step towards insulin therapy.
Insulin was the first treatment discovered for managing Only short-acting insulin was available in first few
diabetes mellitus (DM) and still it is considered most years after discovery. Efforts to prolong the action of
effective and safest therapeutic option. “Insulin” term insulin were initiated in 1923 and Neutral Protamine
was coined in English from insula or “island”, so called Hagedorn (NPH) insulin was first introduced in 1946 by
because the hormone is secreted by the islets of Langer­ efforts of Hagedorn. Hallas-Moller et al. of Novo Nordisk
hans in the pancreas. The history of insulin begins at the developed insulin zinc suspension commonly known as
beginning of the twentieth century. In 1920, the patho­ Lente insulin, another widely used intermediate-acting
logist Barron1 recognized that pancreatic duct obstruction insulin. The NPH and regular insulin were combined to
causes atrophy of the exocrine pancreas while endocrine obtain premixed insulin.
pancreas remains unaffected. This information was uti­ J Erik Jorpes (Sweden) showed that re-crystallization
lized by Frederick G Banting. He ligated pancreatic duct of insulin reduces allergy towards it. In 1970, chromato­
in dog and thus atrophy of acinar cells was induced and graphically purified insulin was introduced using
this led to isolation of islet hormones without their destruc­ technology developed by Jorjen Schlichtkrull. The earlier
tion by digestive enzymes.2 soluble insulin preparations could be manufactured only
Insulin was finally discovered in 1921 by joint work at acidic pH, which was required to solubilize foreign
of Frederick Banting, Charles Best, James Collip and JJR proteins and protect insulin from degradation. With
MacLeod. They received the Nobel Prize in 1923 for this development of purification methods, it became possible
discovery. On January 23, 1922 at the Toronto General to produce neutral insulin solution.
Hospital, Leonard Thompson, a 14-year-old boy received Frederick Sanger first described the structure and
the first dose of an extract from ox pancreas containing amino acid sequence of insulin including species related
 Insulin Therapy 573

molecular differences in 1955. He was awarded the To produce such insulin, pancreas are selectively picked,
Nobel Prize for this discovery in 1958. Berson and Yalow and deep frozen. Acid ethanol/water extraction ensures
introduced the high sensitivity radioisotope method for high solubility of insulin, low solubility of proteolytic
detecting antigen-antibody complexes. This discovery enzymes and other proteins and provides protection
led to the development of radioimmunoassays and sub­ against enzymatic degradation. The extract is then neutra­
sequent great strides in the field of endocrinology. For this lized to remove unwanted pancreatic proteins, acidified
discovery, Rosalyn Yalow received the Nobel Prize in 1978. again and evaporated to increase the rather low insulin

chapter
The insulin gene was cloned in 1977 by Ulrich, Rutter, content (0.02%), recover ethanol, and remove fatty

38
Goodman and coworkers leading to the development of substances. The next step is addition of 2–3 mol/L sodium
human insulin and introduction of a new field of molecular chloride, a process commonly referred as salting out. This
biology and genetic engineering. The first commercially leads to separation of unwanted proteinaceous and non-
available human insulin was made by a biosynthetic proteinaceous compounds. The product is then subjected
method developed by Jan Markussen and associates to purification process.
of Novo Nordisk in 1981. In 1982, the first genetically Bovine insulin is extracted from cattle pancreas. It
engineered human insulin was introduced by Eli-Lilly as a differs from human insulin in three amino acids, namely
result of work carried out in Genentech Laboratories using A8, A10 and B30. Because of these differences even
Escherichia coli as the host cell. Genetically engineered when purified it exhibits antigenicity. On subcutaneous
second generation human insulin was introduced by administration, absorption is slower and its duration of
Novo Nordisk in 1984 using a method to produce a single effect is slightly longer than porcine or human insulin.
chain insulin precursor using Saccharomyces Cerevisiae as Porcine insulin is extracted from pig pancreas. It
the host cell. differs from human insulin at only one position, i.e. the
Insulin therapy has significantly evolved since 1922, B30 position, hence is relatively less antigenic compared
with major improvements in insulin purification, produc­ to bovine insulin. When purified, its antigenicity is quite
tion, formulation, regimens, and delivery systems. Since low. Absorption is quicker and duration of effect is slightly
1980s, insulin replacement strategies have been incre­ shorter than bovine insulin but slightly longer than
mentally optimized, with the development of structurally human insulin. Mixture of bovine and porcine insulin is
modified, so-called designer insulin analo­gues;3,4 the eval­ more antigenic than single species bovine when both are
uation of alternative delivery routes (e.g. nasal, pulmo­ purified to the same level. The pharmacokinetic profile is
nary, oral, peritoneal insulin formulations);5 continuous similar to bovine insulin.
subcutaneous insulin infusion (CSII) therapy (i.e. insulin
pumps);6,7 and most recently the potential to use conti­ Human Insulin
nuous glucose monitoring with glucose sensor technology Human insulin became available for treatment in 1981,
(i.e. closed loop insulin delivery), also referred to as the initially as semi-synthetic, and a year later as the first
artificial pancreas.8,9 genetically engineered product.
Semi-synthetic human insulin or human insulin,
METHOD OF INSULIN PRODUCTION as it was called earlier, was made by modifying porcine
Animal Insulin insulin, i.e. enzymatically replacing the B30 alanine with
threonine, thus converting pork insulin to human insulin.
Animal insulin is not available now. But up to a decade Human insulin was the first genetically engineered
ago, it saved millions of lives. Insulin from two animal protein used in therapy and its method of production is
sources was used, i.e. bovine and porcine, as meat from now widely used. Genetic engineering is a process by
these animals is widely consumed. Earlier, no distinction which genetic characteristics of a selected host cell
was made between bovine and porcine pancreas and (microorganism) are altered by inserting foreign DNA
batches of insulin contained varying proportions of bovine sequences (gene), which enable the host cell and its prog­
and porcine insulin. The knowledge that porcine insulin eny to synthesize peptides encoded by the foreign gene.
had a molecular structure closer to human insulin and Genetic engineering is now being employed to produce
caused less immunogenicity, particularly when purified, a number of protein substances, which were earlier diffi­
led to the development of monospecies porcine insulin. cult to synthesize.
574 Management

One method uses two sets of Escherichia coli bacteria After advent of human insulin, animal insulin was
coded to produce either the “A” chain or the “B” chain, losing its utility and hence animal insulins have been
which are extracted and chemically combined by inser­ discontinued. Insulin analogs were developed from 1995
ting disulfide bridges. Insulin so obtained is called onwards which resulted in discontinuation of lente and
human insulin chain recombinant bacterial (CRB). This ultra lente insulin. Thus, following types of insulin are now
method has been largely replaced by methods wherein available:
human proinsulin or human mini-proinsulin is produced
section

by genetically engineered micro-organisms, E coli or Meal Time Insulins

S Cerevisiae (Baker’s yeast). Use of yeast has certain
8

advantages—its cultures are easier to maintain, the culture • Regular human insulin
medium is simple, the organism does not inherently • Analogues (lispro, aspart, glulisine)
produce toxins (unlike the E coli bacteria) and secretes the
protein into the culture media. The proinsulin produced Basal Insulins
by either method is then enzymatically cleaved and is • Intermediate: NPH, lente
purified. Insulin produced by these methods is referred to • Analogues: Glargine, detemir
as genetically engineered human insulin (HMge).
Premixed
Insulin Analogs
• Regular with NPH (30/70, 50/50, 25/75)
Using genetic engineering technique, it became possible
• Analog premix (30/70, 50/50, 25/75)
to change amino acids at strategic locations to enhance
All insulin preparations have an international color
charge repulsion, increase stearic hindrance, or reduce
code and color for a specific type of insulin is printed on
hydrophobic surfaces and produce insulin analogs that
vials and pen refills. Following table (Table 38.1) mentions
have different absorption and pharmacokinetics. Thus,
characteristics of various available insulin preparations
it is possible to have fast and short-acting or long-acting
insulin analogs. The fast-acting analogs are absorbed with their international color code.
faster; achieve quicker peak and their level declines more
rapidly as compared to short-acting human insulin.
PHARMACOLOGY OF AVAILABLE
Similarly, by changing the amino acid structure, it has INSULIN PREPARATIONS
been possible to delay the breakdown of hexameric forms, Any insulin, once in circulation, will be degraded mainly
and further enhance binding to albumin; it has been by liver, which is responsible for approximately 60 to 80%
possible to produce long-acting analogs that have slower of the total insulin disposal; approximately 10–20% is
and more predictable absorption and can provide basal
accounted by the kidney and the balance in the peripheral
insulin level throughout the 24 hours as compared to the
tissue. Elimination is mainly through receptor mediated
presently available long-acting insulin. Several analogs
degradation with some amount excreted directly into
have now been marketed worldwide and several others
the urine. Of the renal elimination, two-thirds is filtered,
are in various stages of development.
the filtered insulin is reabsorbed and degraded by the
proximal tubular cells, while one-third is degraded in
TYPES OF INSULIN
the post-glomerular, peritubular vessels. Degradation of
Insulin release occurs both at a constitutive, basal rate exogenous insulin also occurs in similar manner but since
and in short-lived large bursts, secondary to physiologic exogenous insulin is given subcutaneously, its onset of
stimuli related to food intake. Thus to replace insulin, action and duration depends on rate of absorption.
there is need of insulin, which can rise rapidly in response When insulin is replaced, our objective is to replicate
to a meal as well as insulin which is released in circulation meal-stimulated and basal insulin release by the healthy
continuously at a slow rate. When insulin was discovered, pancreas. Thus, insulin replacement regimens comprises
for many years only regular or soluble insulin was avail­ of two components; a basal (fasting) and bolus (meal/
able. Later prolonged action formulations were develo­ prandial) insulin preparation. There are various insulin
ped with protamine or zinc or both, as retarding agent, to preparations developed to mimic normal insulin secretion
delay absorption and extend the duration of effect. pattern.
 Insulin Therapy 575

Table 38.1: Types of insulin with their color codes

Human Insulin and Insulin Analogs Onset Peak Duration Color code
Rapid-acting analogs
• Insulin lispro (Humalog) 10 – 15 minutes 1 – 2 hours 3 – 5 hours

• Insulin aspart (NovoLog) 10 – 15 minutes 1 – 2 hours 3 – 5 hours

• Insulin glulisine (Apidra) 10 – 15 minutes 1 – 2 hours 3 – 5 hours

chapter
38
Short-acting
• Regular 0.5 – 1 hour 2 – 4 hours 4 – 8 hours

Intermediate-acting
• NPH 1 – 3 hours 4 – 10 hours 10 – 18 hours

Long-acting analogs
• Insulin glargine (Lantus) 2 – 3 hours none 24 + hours

• Insulin detemir (Levemir) 1 hour none Up to 24 hours

• Insulin degludec (Tresiba) 1 – 2 hours none Up to 42 hours

Premixed insulins conventional

• 30/70 (30% Regular +70% NPH) 0.5 – 1 hour 2 – 10 hours 10 – 18 hours

• 50/50 (50% Regular + 50% NPH) 0.5 – 1 hour 2 – 10 hours 10 – 18 hours

• 25/75 (25% Regular + 75% NPH) 0.5 – 1 hour 2 – 10 hours 10 – 18 hours

Premixed insulins analog

• H
 umalog mix 25/75 (25% lispro + 75% lispro 10 – 15 minutes 1 – 3 hours 10 – 16 hours
protamine)
• H
 umalog mix 50/50 (50% lispro + 50% lispro 10 – 15 minutes 1 – 3 hours 10 – 16 hours
protamine)
• NovoLog Mix/Novomix 30/70 (30% aspart +70% aspart protamine) 10 – 20 minutes 1 – 4 hours 10 – 16 hours

(NPH: Neutral Protamine Hagedorn).

In this section, time action profile of all available into dimers and monomers only then it will enter in
insulin preparations is discussed below. circulation and exert its action on glucose control. This
process of conversion from hexamer to monomer takes
Short-acting or Prandial or 30–45 minutes as shown in Figure 38.1 and hence regular
Meal-related Insulin insulin should be administered 30 minutes before meals.
Regular Insulin Pharmacokinetic Profile of regular insulin: Onset of action
of regular insulin is in 30–60 minutes after administration,
Regular recombinant human insulin is identical to the
peak effect at 2–4 hours post injection and duration of
endogenous insulin polypeptide. In solution, however,
regular insulin tends to self-associate to form clumps of six action is 6–8 hours, as illustrated in Figure 38.2.
insulin molecules called as hexamer.10,11 This property is Disadvantage of regular insulin: Regular insulin phar­
due to charge at amino acids at tail end of insulin molecule. macokinetics does not match with the meal stimulated
This propensity to self-associate delays the absorption of endogenous insulin secretion12 Delayed peak and
regular human insulin from subcutaneous tissue. After longer duration of action leads to early postprandial
subcutaneous injection, the hexamers are converted hyperglycemia and late hypoglycemia.13 To overcome
into dimers and monomers before they can be absorbed. this drawback, meal time insulin analogs were developed
Thus after injection, regular insulin must first dissociate which have a faster onset of action.
576 Management
section
8

Fig. 38.1: Absorption kinetics of hexameric and monomeric insulin Fig. 38.2: Diagram of time action profile of regular insulin
after subcutaneous injection
Adapted from Brange J, Owens DR, Kang S, et al. Monomeric insu-
lins and their experimental and clinical implications. Diabetes Care.
1990;13:923-54. Glulisine: Replacement of lysine at B29 for glutamine
and aspartic acid at B3 for lysine simultaneously provides
insulin with a reduced ability to be self-associated.17-19

Pharmacokinetic Profile of Rapid-acting Analogs

All three analogs have similar pharmacokinetics. They
all are monomer insulin and hence are rapidly absorbed
after subcutaneous injection. If given intravenously,
there is no difference in regular and rapid-acting analog
insulin. All rapid-acting analogs have a faster onset of
action; 10–30 minutes post-administration, peak of action
at 30 minutes to 2 hours and a shorter duration of action
that is 3–5 hours (Fig. 38.3). This pharmacokinetic profile
Fig. 38.3: Diagram of time action profile of rapid acting analog
matches more closely with physiologic meal-stimulated
insulin release.20,21
Rapid-acting Insulin Analogs
These analogs are created by modifications in insulin Advantage of Rapid-acting Analogs
molecule. Modifications are done in a manner to achieve Major advantages of rapid-acting insulin analogs include
insulin which can exist as monomer in solution while it better post-meal glycemic control, less risk of hypogly­
should have normal binding with insulin receptor. cemia, patient can inject and eat without waiting for
Currently available rapid-acting analogs are: 30 minutes. These analogs were given postmeal and glyce­
• Lispro mic control remained equally good so ideally rapid-acting
• Aspart analogs should be injected 10–15 minutes prior to meal
• Glulisine but there are clinical data to support the concept that a
Lispro: The first rapid-acting analogue was developed patient can inject and eat or eat and inject.
in 1996. In this insulin, transposition of amino acids
proline and lysine at positions B28 and B29 is done which Basal Insulins
leads to conformational change that interferes in hexamer
Neutral Protamine Hagedorn and
formation.14,15
Aspart: Here substitution of proline at B28 is done by a
Other Intermediate-acting Insulin
negatively charged aspartic acid residue and this change First introduced in 1946, NPH insulin is a suspension
results in monomer insulin formulation.16 of insulin complexes with protamine and zinc.22 NPH
 Insulin Therapy 577

is poorly absorbed from subcutaneous tissue, leading of amino acid threonine at position B30 and acylation
to delayed onset of action (2.5–3 hours), late peak effect of a 14-carbon aliphatic fatty acid (myristic acid) to the
(5–7 hours), and prolonged duration of action e-amino group of lysine at position B29, which enhances
(13–16 hours).23 A second intermediate-acting insulin pre­ its affinity for albumin.30,31
paration is lente, a crystalline suspension of insulin with Acylation of the insulin molecule with a fatty acid
zinc and acetate. It exhibits a pharmacokinetic profile results in albumin binding and protracts absorption from
similar to that of NPH, but with a slightly later peak and the subcutaneous depot. Both insulin self-association

chapter
longer duration of action. and albumin binding leads to slow absorption of insulin

38
Lente insulin was discontinued in 2005, thus NPH detemir from the subcutaneous depot at the injection
has been the only available intermediate-acting insulin. site. Further prolongation occurs in the circulation, but
Although the delay in peak action of NPH provides a this contributes less to the overall protracted action of
means to cover lunch time glucose excursions in twice a detemir than does depot albumin binding. When insulin
day injection regimes, it makes NPH less than satisfactory detemir exits the circulation to arrive in interstitial fluid,
for overnight basal insulin replacement.24 Since NPH has it is likely that it will again bind reversibly to interstitial
a peak and does not behave like ideal basal insulin so albumin. However, detemir’s much greater affinity for
basal insulin analogs were developed which have reduced the insulin receptor than for albumin, together with the
usage of NPH in basal-bolus regimen. But NPH insulin high concentration of insulin receptors in target tissues,
is still very popular insulin preparation as all premix insu­
means that albumin-mediated protraction in the target
lins are having NPH insulin component.
tissue itself will be negligible. Detemir is characterized
by significantly greater within patient pharmacodynamic
Basal, Long-acting Insulin Analogs predictability than NPH insulin or glargine. This
An ideal exogenous basal insulin product should be predictability is likely to result from the buffering effect of
“peakless”, whereas NPH displays a pronounced peak serum albumin binding.
action profile.24-26 Moreover, the fact that NPH must be Detemir insulin treatment is associated with signifi­
evenly suspended before administration and it also has cantly less weight gain than NPH insulin in almost all
wide inter-subject variability in its absorption from the clinical trials involving people with type 1 and type 2
subcutaneous tissue depot. diabetes. Significantly less weight gain (P = 0.020) was
To design basal insulin analog, the structure of insu­ demonstrated with detemir insulin compared to NPH
lin is altered to achieve prolonged absorption following insulin (both administered as the basal component in
subcutaneous injection and a relatively peakless 24-hour similar insulin regimens), even when adjusted for changes
time-action profile, which is much more similar to in HbA1c values. Reason for this differential effect on
physiologic basal insulin release. Three such analogs are weight is not clear.
available:
Glargine Insulin: Here modifications have been Degludec Insulin
introduced both in a and b insulin chains. Specifically,
the replacement of asparagine with glycine at position Insulin Degludec is the most recently launched Ultra Long
A21 and the addition of two arginine residues at position Acting novel insulin analogue. This analogue is created
B30, respectively, are done. This structural change results by deletion of threonine in position 30 of B chain and
in an insulin molecule with isoelectric point of 5.5. This attaching lysine at B29 is attaching with a spacer molecule,
means glargine is less soluble at neutral, physiologic pH glutamic acid. A fatty acid—hexadecandioyl acid is atta­
yet stable in the acidic pH of its storage solution. Thus, ched to spacer glutamic acid (Fig. 38.4). As a result of these
when injected into the neutral milieu of the subcutaneous modifications, insulin degludec is able to self-aggregate
tissue, glargine forms an amorphous precipitate from and form large multi-hexamer complexes upon injec­
which insulin molecules are slowly released into the tion in subcutaneous tissues, which subsequently slowly
circulation.27-29 Glargine was introduced in year 2000 and dissociate into monomers that enter the circulation.33
became very popular basal insulin. Half life of degludec insulin is 25.4 hours. Insulin degludec
Detemir Insulin: In detemir, two alterations have been has an ultra long action and a peak-less basal profile. It can
introduced within the b insulin chain. First is deletion be injected once in 24 hours with variable timings.
578 Management
section
8

Fig. 38.4: Molecular structure of Insulin Degludec

and aspart (protamine crystalline aspart or insulin aspart

protamine) which are functionally identical to NPH.
Studies comparing the clinical efficacy of premixed
human insulin and premixed insulin analogue prepara­
tions suggest that premixes of insulin analogues are
superior in terms of controlling post-prandial glucose
excursions with less intrasubject variation, yet do not
show consistent improvements in HbA1c levels.34-40
Currently available insulin preparations have different
pharmacokinetics. Figure 38.541 shows a summary of onset
of action, peak, and duration of action of all available
insulin preparations. Normally, when a person takes
Fig. 38.5: Diagram showing time action profile of available insulin
preparations
meals, glucose reaches to peak by 1 hour and by 3 hour
(NPH: Neutral protamine Hagedorn). almost all is cleared. Thus to cover a meal, insulin should
rise very rapidly, should reach peak in 30–60 minutes
and should disappear in 3 hours. It can be seen from
Figure 38.4 that rapid-acting analogs serve as better
Premixed Insulin Preparations
meal time insulin. Similarly, NPH has a peak and shorter
Two main classes of premixed insulin preparations are duration of action while glargine and detemir are peakless
currently on the market: premixes of conventional insulin with a longer duration of action and hence they are
products and fixed ratio mixes of insulin analogues. considered better basal insulin preparations.
Conventional premix insulin is a combination of regular
human insulin and NPH insulin in different ratio like INDICATIONS FOR INSULIN Therapy
30/70, 25/75 or 50/50.
When premix analog insulin is prepared, it is mixture of The aim of diabetes treatment has changed with each new
rapid-acting analog with the protaminated forms of lispro development and passing time. In the preinsulin era, the
[neutral protamine lispro (NPL), insulin lispro protamine] aim was to ensure that the patient had a less painful death
 Insulin Therapy 579

Table 38.2: Indications of insulin therapy Table 38.3: Insulin therapy regimens
• Type 1 diabetes • Basal only
• Type 2 diabetes not controlled with maximal doses of oral anti- • Premixed (generally twice daily)
diabetic agents • Split mix regimen
• Type 2 patients during periods of stress • Basal-bolus regime [multiple subcutaneous insulin injections
– Acute infection (MSII)]
– Major surgery • Bolus only
– Acute myocardial infarction, stroke • Premix with bolus

chapter
– Acute fever

38
– Acute emergencies, e.g. Hyperosmolar non-ketone state,
diabetic ketoacidosis. a different pattern of insulin deficiency and insulin
• Pregnancy with diabetes
requirement. Thus, there are many regimens of insulin
– Renal failure
replacement (Table 38.3). First three treatment regimens
(HONKS: Hyperosmolar non-ketotic; DKA: Diabetic ketoacidosis).
(Table 38.3) are more often used. The choice depends
as no specific treatment was available. The discovery of on treatment goals, type of diabetes, pattern of insulin
insulin changed the aim to patient survival and prolonging deficiency, meal pattern, dynamism of physician and
life, by preventing acute complications, and subsequently motivation of patient.
also included making patients as asymptomatic as
possible. The aim of treatment in the post Diabetes
Basal Only Insulin Regimen
Control and Complications Trial (DCCT) era, has added Basal insulin therapy goes back many years to bedtime
prevention of complications and improving quality of insulin, daytime sulfonylurea (BIDS) insulin therapy,
life. In the 21st century, the aim of insulin therapy is which added NPH insulin at bedtime to the only
gradually changing to provide physiological substitution available oral therapy in the United States at the time.42,43
and pain­less administration. Another variation added 70:30 NPH regular insulin at
suppertime.44 Another variant of basal only regimen in
Indications of Insulin Therapy past was administration of one or two injections a day
of an intermediate-acting insulin. Concept of basal only
All patients with diabetes have insulin deficiency in relative insulin regimen is now based on basal insulin analogs.
or absolute sense. Following box (Table 38.2) mentions After availability of basal analogs, basal only regimen
various well-known indications of insulin. often denotes one or two shots of long-acting basal
As far as oral drugs are concerned, so many new drugs insulin analog. Generally single injection of basal insulin
are added to armamentarium and thus now it is difficult is given daily, irrespective of meal timings. Since duration
to define oral antidiabetic drug (OAD) failure in type 2 of action of basal analog is 24 hours, it is important that
diabetes. Thus, it is preferable to initiate insulin therapy insulin should be given at the same time daily. Patient
if a patient with type 2 diabetes is not controlled on maxi­ can do self-titration based on fasting glucose levels. Once
mum doses of three oral drugs. It is actually beta cell fasting glucose is normal, prandial glucose monitoring is
failure rather than OAD failure. to be done.
Insulin therapy is indicated for all women contem­
plating pregnancy, as well as for gestational diabetes. Premix Insulin Regimen
Regular, NPH, aspart, lispro and detemir insulin are
Mixtures in various ratios of soluble insulin from 10 to 50
approved to be used during pregnancy.
are available, usually the 30:70, 25:75 and 50:50 ratio
of short-acting to NPH is the most commonly used.
INSULIN REGIMENS
In patients who have both basal and prandial insulin
Physiological insulin release consists of basal and meal deficiency, premixed insulin formulations provide greater
related secretion into the portal venous system which is convenience as compared to basal-bolus regimen.
precisely regulated as per glucose level in blood. There Premixed formulations include a mixture of regular or
are many insulin preparations available to replace rapid-acting analog in combination with NPH or neutral
insulin in physiological manner. Each individual has protamine analog insulin in various proportions. Premix
580 Management

insulin regimen can be conventional premix or analog basal insulin together with regular or rapid-acting analog
premix regimen. Short-acting component of premix insulin prior to each meal, as bolus insulin. If basal insulin
insulin is expected to take care of meal related glucose analog with rapid-acting insulin analog is used than this
rise while intermediate-acting component is expected to regimen is close to ideal. It is best suited for:
take care of basal insulin requirements. Generally, premix • Type 1 diabetes
insulin is given twice a day but it has been tried thrice a • Young type 2 diabetics not at goal with premix
day also. Mixtures of 25/75 and 30/70 are traditionally • Type 2 diabetes needing intensive glucose control
section

dosed twice daily, usually two-thirds of the total daily dose • People with brittle or labile diabetes
8

before breakfast and a third of the total daily dose before • Pregnant women with diabetes or women with diabetes
supper. In patients taking two big meals, 50/50 premix is contemplating pregnancy.
a better option. Premix insulin regimen have advantages
with respect to convenience in administering the injection INSULIN THERAPY IN TYPE 2
and disadvantages with respect to the inconvenience of DIABETES MELLITUS
having to be more rigid in the timing and composition
of meals to achieve excellent control. In head-to-head Type 2 diabetes is a disorder with both insulin deficiency
studies, premixed insulin tends to reduce A1c to a greater and insulin resistance. Concept of insulin therapy in
degree than basal insulin alone, but at the expense of this disease is still evolving with no consensus. There are
more hypoglycemia and possibly weight gain.45,46 Premix many controversies like what to do with oral agents, how
regimen is most popular insulin therapy in India as well as to manage weight gain associated with insulin, any effect
most other countries. on cardiovascular (CV) risk, any risk of cancer, and how
to combine glucagon-like peptide (GLP) 1 analog and
Split Mix Regimen insulin.
There are many ways through which insulin therapy
Twice a day mixtures of intermediate and short-acting can be added in type 2 diabetes. Persons with type 2
insulin in the same syringe is split mix regimen. Major diabetes requiring insulin may be initially started on insu­
advantage is the fact that quantity of short and long- lin once a day, but as the disease progresses; they may
acting insulin can be changed as per need. This is not require two or more doses of insulin per day. Though
possible with premix insulin regimen. Based on the self- body weight alone is less correct way to determine insu­
monitoring, titration of insulin dose in split mix regimen lin dose as insulin sensitivity differs among patients but
can be done in the following manner: to initiate insulin, it serves as a guide and per recommen­
• If fasting glucose is high, the dose of predinner dations of American Diabetes Association (ADA)/Euro­
intermediate-acting insulin should be increased pean Asso­ciation for the study of Diabetes (EASD) algo­
• If pre-lunch glucose is high, the dose of prebreakfast rithm47 and many others, typical start dose is 0.2 units/kg
regular insulin should be increased of the intermediate-acting insulin (NPH or lente), pre­
• If post-lunch glucose is high, the dose of prebreakfast mixed insulin; or a basal insulin analog (glargine, detemir).
intermediate-acting insulin should be increased Following are programs for starting insulin therapy:
• If predinner glucose high, the dose of prebreakfast
intermediate-acting insulin should be increased. Basal Insulin Only
Split mix regimen cannot be used with pen devices.
This concept began many years ago as insulin therapy,
Short-acting insulin has to be taken first in syringe
where NPH insulin was added at bedtime to daytime
followed by intermediate-acting insulin. This regiemen
sulfonylurea (SU) which was the only available oral the­
is now a days often used by type 1 diabetes patients who rapy in the United States at the time.42,43 Another varia­
cannot afford basal-bolus analog therpay. tion added 70:30 NPH/regular insulin at supper time.43
Logic behind BIDS was to achieve normal fasting and thus
Basal-Bolus Regimen to ameliorate glucotoxicity.
This is also known as multiple subcutaneous insulin Later, with availability of basal analogs, basal only regi­
injections (MSII) regimen. It involves administration of men became very popular for type 2 diabetes, as it pro­
intermediate-acting or long-acting insulin once a day as vides lot of flexibility and convenience.
 Insulin Therapy 581

Interest intensified with results from the the Treat to Basal Plus Regimen
Target Study, which compared bedtime glargine versus
NPH insulin added to patients failing metformin and SU Sequential stages for therapy for type 2 diabetes including
therapy.48 The study population was large (756 patients), a step between basal insulin and basal-bolus insulin
with the kind of patients seen commonly by both primary therapy: the sequential addition of 1, then 2 prandial
care providers and specialists: A1c level average of injections if needed before moving to a full basal-bolus
8.6% on the most common combination of oral agents at program. This therapy is usually referred to as stepped

chapter
the time. prandial therapy or basal plus therapy.

38
Thus, basal insulin therapy is simple and safe and
has a high degree of success in getting patients to an A1c Basal-Bolus Regimen
level of 7% or less. A comprehensive review of published All meals are covered with rapid-acting insulin analog
randomized trials of basal insulin therapy in type 2 and one or two shots of basal insulin are given at a fixed
diabetes found on average more than 40% of patients met time. Objective of basal bolus is to mimic endogenous
that goal, with many starting with high A1c levels.49 insulin release pattern. Major problem with this regimen
is higher number of pricks. It is better to stop SU in patients
Prandial Insulin Only on basal-bolus regimen.
Another starting program is to add prandial insulin at
each meal without basal insulin. The APOLLO trial com­ Insulin Plus Glucagon-like Peptide 1 Regimen
pared once-daily glargine with mealtime lispro (three This combination takes care of both alpha and beta-cell
times daily) for 44 weeks in 418 patients failing various dysfunction. It may also help in prevention of weight
oral agents with mean A1c level 8.7%.50,51 The decrease in gain associated with insulin therapy. Additionally, it has
A1c level was the same (– 1.7% with glargine and – 1.9% been shown in clinical trials that GLP1 reduces risk of
with lispro) as was weight gain, but there was five times severe hypoglycemia. Recently, basal insulin and GLP1
the rate of hypoglycemia with the lispro program. This analogs are approved by Food and Drug Administration
strategy is responsible for more glycemic variability and (FDA). In near future combination of GLP1 analog and
useful for a small subset of patients who have predo­ basal insulin in same pen fill will become available.
minantly post­ meal hyperglycemia with normal fasting It is believed that GLP1 plus insulin combination will
glucose. be at the core of future diabetes therapy. The greatest
enthusiasm for insulin and incretin therapy is based on
Premix Insulin Therapy their complimentary effects on basal and postprandial
glucose and the hope that the weight loss and minimal
Premix insulin, one injection in morning and one in
risk of hypoglycemia with GLP1 receptor agonists would
evening is generally initiated. Patients who take three
mitigate those issues with insulin.
to five meals including morning breakfast, they are
Figure 38.6 shows stepwise approach of insulin therapy
initiated with 30/70 or 25/75 insulin at breakfast and
in type 2 diabetes.
dinner. Patients who take two large meals, 50/50 insulin
is preferred. Patients, who have a wide gap in fasting and
What to do with Oral Drugs when
post-prandial with a relatively very high post meal blood
Insulin is Initiated
glucose (BG), are generally candidates for basal-bolus or
premix regimen. Premixed insulin, particularly analogue All OAD have been tried with insulin. Metformin and
mixes, are highly effective for glycemic control, especially dipeptidyl peptidase-4 inhibitor (DPP4) inhibitors are
with high A1c values, but carry a higher risk of hypoglycemia logically good options to continue with insulin therapy.
than basal insulin alone; this same conclusion was made Metformin is useful because of its insulin sensitizing
in the previous cited comprehensive analysis of insulin effect. In basal only regimen, there seems to be a rationale
regimens in type 2 Diabetes.49 Premix insulin is tried for keeping SU onboard. The question, which has not
three times daily and it maintains the high efficacy, but been fully settled, is whether to continue SUs with basal
with fewer side effects.45,46,52,53 Giving 50/50 three times insulin; there has been a running debate on this issue for
daily is more physiological. many years.54-56 The argument for keeping them is that
582 Management

pioglitazone when insulin is added. Alpha glucosidase

inhibitors can be used with insulin to flatten the post
prandial glucose. Thus OAD to be used with caution with
insulin are SU and pioglitazone. While metformin, DPP4
inhibitors and alpha glucosidase inhibitors can be used
without additional risk of hypoglycemia, physician must
also consider rationale to add OAD and also debate the
section

question: is there a real advantage of OAD? If there is no

8

advantage then these drugs can be discontinued.

Insulin Therapy for Type 2 Diabetes in Practice

How to Initiate Insulin Therapy
Though body weight alone is less correct way to determine
Fig. 38.6: Stepwise approach for insulin therapy in type 2 diabetes insulin dose as insulin sensitivity differs considerably
among patients but to initiate insulin, it serves as a guide
and as per recommendations of ADA/EASD algorithm47
prandial component of insulin will be stimulated by SU, and many others, typical start dose is 0.2 units/kg of the
and SU if discontinued, there may be deterioration of chosen insulin.
glycemic control.57 Thus, when basal insulin is added to
the common combination of metformin and a SU with How to Titrate Insulin Dose
or without a thiazolidinedione, the only medication that
This has to be preferably done on the basis of self monito­
is directly acting on postmeal glycemia is the SU. It is
ring of plasma glucose (SMPG). For different SMPG,
also argued that the SU raises the risk of hypoglycemia
schedule differs and based on SMPG, insulin dose has to
and weight gain. Also, some believe that being able
be adjusted as mentioned in Table 38.4.
to optimize the basal insulin (i.e. fasting glucose) is
sometimes pre­vented by a normal to low daytime glucose
How to Adjust Insulin if there is Hypoglycemia
level from the SU. A post hoc analysis of a large number
of patients who were kept on metformin and where If hypoglycemia occurs due to missing a meal than instead
the issue whether to stop secretagogues was left to the of adjusting insulin, meals pattern should be properly
discretion of the investigator, reported that the patients followed. If hypoglycemia occurs without any other
who continued secretagogues had equivalent levels of A1c reason than insulin preparation, which is responsible for
but more weight gain and hypoglycemia than those taking hypoglycemia, should be reduced. It is preferable to first
only metformin.58 Thus whether SUs have a positive or rectify hypoglycemia, reduce dose of insulin responsible
negative effect with basal insulin in type 2 diabetes for hypoglycemia from next day and to take next insulin
remains an open question. dose in usual manner.
When patient is shifted on basal-bolus regimen then Table 38.4 contains a detailed summary of managing
it is preferable to stop SU. Metformin or DPP4 inhibitors Insulin therapy in type 2 diabetes.
can be continued as they do not increase risk for
hypoglycemia. Vildagliptin added for 24 weeks in patients INSULIN THERAPY IN TYPE 1
on a multishot insulin program with average A1c level 8.4% DIABETES MELLITUS
decreased the A1c level by 0.2% versus a 0.5% increase
in placebo-treated patients. Sitagliptin for 24 weeks in Patients with type 1 diabetes lack both, basal insulin
insulin-taking patients with average A1c level 8.6–8.7% secretion, as well as the ability to secrete insulin in res­
decreased the A1c level by 0.6% versus 0.0% with placebo.59 ponse to meals. Further these patients require a relatively
Pioglitazone may cause weight gain when used with small quantity of insulin initially as some beta cells are
insulin therapy. It is not licensed to be used with insulin still capable of producing insulin. In most patients, when
in many countries. The present author prefers to stop diabetes duration is more than 2 years, all beta cells are
 Insulin Therapy 583

Table 38.4: Sequence of steps for initiating basal insulin therapy

Insulin initiation in type 2 diabetes
Following is the approach followed at our center to initiate and adjust insulin dose in patients with type 2 diabetes:
• Preparing patient
– Discuss reason for insulin therapy, involve a educator to re discuss and inform barriers to physician, physician to discuss and provide
solutions to barriers
– Demonstrate pen devices, discuss affordability, understand life style and choose initial insulin regimen

chapter
• Insulin start

38
– Basal insulin: start with 10 units per day (other option: 0.2 units/kg) per day to be injected, at same time daily, ask patient to measure
fasting glucose daily or alternate day, take average of three readings and go on increasing dose of insulin till FPG < 120 mg/dL
–  Premix insulin: start 30/70 or 25/75 insulin with 12 units before breakfast and 8 units before dinner. In patients taking two large meals,
10 hours apart insulin 50/50 to be used 10 units with morning meal and 10 units with evening meal. If conventional insulin is used, it
should be injected 30 – 45 minutes prior to meals
– Ask patient to do self-monitoring of plasma glucose (SMPG)
– Self-monitoring of plasma glucose frequencies depend on type of insulin regimen. Generally fasting, prelunch, postlunch, predinner and
bed time are important tests
• Insulin dose titration
– Review SMPG and titrate insulin dose
– Educate patient how to adjust insulin dose
– Adjust basal insulin dose as needed to attain target fasting glucose that is 80 – 120 mg. If fasting is more than 121 but less than 180,
2 units are to be increased in basal insulin dose. If fasting glucose is more than 181 mg, 4 units to be increased in basal insulin dose
– Evening premix insulin dose to be increased if fasting glucose is high and morning dose to be increased if post prandial glucose is high.
In 30/70 or 25/75 regimen, morning dose cannot be increased if prelunch glucose is normal
• Switch over to next level
– If patient is on basal insulin only and if normal fasting glucose is achieved but post-meal hyperglycemia persists than there is need to
add prandial insulin. Either bolus shots to be added or switch to premix twice daily regimen
– If patient on twice premix and prelunch glucose normal while postlunch goes high than an additional short-acting insulin to be added to
cover lunch
• Basal-bolus regimen/Insulin pump
– If glucose values still uncontrolled, consider basal-bolus
– Adjust basal insulin dose on basis of fasting glucose and bolus dose on post and pre-prandial values
– If it is difficult to control or patient needs less pricks and more flexibility consider option of insulin pump

destroyed and thus there is increase in insulin requirement. • Premix

During puberty, insulin demand may rise to two to three • Split mix
times. To manage type 1 diabetes, it is important to do Each regimen has a place in practice: For well-motivated
SMPG and adjust insulin dose. In a well motivated and patients and parents, basal-bolus or CSII is the option of
educated patient, dose adjustment can be done on daily choice. For patients who can fix their carbohydrate intake
basis. and meal timings, a premixed regimen may also work.
If initial insulin therapy in children with type 1 diabetes Split mix is a good option for those patients who want to
is effective then it helps child to enter the honeymoon, take insulin with syringe and are interested in two pricks
or partial remission phase. If good glycemic control is only.
achieved initially, it helps to restore insulin sensitivity Initiating insulin therapy in type 1 diabetes mellitus:
deranged as a result of glucose toxicity. Normal glucose Patients with type 1 diabetes mellitus (T1DM) who present
with diabetic ketoacidosis (DKA) require management of
values also improve function of residual b-cells, and both
DKA in a hospital setting. At the time of discharge from
these together can prolong honeymoon period.
hospital these patients should be preferably on basal-
bolus regimen. Patients who are incidentally diagnosed
Insulin Regimen for Type 1 Diabetes Mellitus
with type 1 diabetes and are not in DKA, also should
• Basal-bolus [multiple daily injections (MDI)] be initiated preferably on basal-bolus regimen or other
• Continuous subcutaneous insulin infusion regimen which patient and parents can manage, with
584 Management

control, indicating that near normal glucose and A1c levels

should be achieved and maintained in patients with
T1DM as early in the course of the disease as possible.61,62
The DCCT and EDIC studies established basal-bolus
therapy using either MDI or CSII as the gold standard
of treatment of T1DM. However, insulin works only if
it is taken, and other factors must be addressed when
section

determining the best insulin regimen for an individual

8

patient. These factors include the availability of an adult

parent/guarding to supervise insulin administration,
ability to count carbohydrates and monitor BG levels,
and the willingness to take four or more injections of
insulin daily.

PRACTICAL INFORMATION ON INSULIN

Where and How Insulin Should Be Stored
Insulin is temperature sensitive, requiring appropriate
storage conditions. When prolonged storage is required,
insulin vials should be stored between 2°C and 8°C.
However, the vial in use can be kept at room temperature,
away from sunlight for about 4 weeks with no apparent
Fig. 37.7: Insulin injection sites loss in biological activity. Insulin formulations are
sensitive to frosting and/or freezing as also to high
starting dose of insulin around 0.5 unit/kg/day and then ambient temperature. Freezing must be avoided. Any
on basis of SMPG, dose of insulin should be adjusted. insulin frozen, must not be used. Insulin transported in
Long-term objective of insulin therapy in type 1 a check-in bag during air travel is rendered ineffective as
diabetes is to achieve age-specific glycemic targets. ADA it freezes at the low temperature in the baggage-hold.
has suggested that A1c and glucose targets should be
adjusted based on the age of the child and range from 7.5% Where to Inject Insulin
to less than 8.5% in very young children, less than 8.0% in Insulin is injected in areas having adequate subcutaneous
children aged 7–12 years, and less than 7.5% in teenagers. fat as shown in Figure 38.7. Among insulin injection
While International Society for Pediatric and Adolescent sites, absorption differs from different sites, it is fastest
Diabetes (ISPAD) guidelines 2009 recommend a target and highest from the abdominal region, slower from the
A1c of less than 7.5% for all pediatric patients, with strong brachial or gluteal areas and still slower from the femoral
emphasis placed on individual glucose targets to promote region. These regional differences are related to diffe­
normoglycemia and preventing severe or frequent hypo­ rences in tissue perfusion. The variable rate of absorption
glycemia.60 To answer the question of good glycemic from different sites can be used for therapeutic advantage;
control and prevention of diabetic complications, the
injection of soluble insulin into the periumbilical region
DCCT was initiated. DCCT established that intensive
ensures faster absorption while injection of NPH or
glycemic management leading to near normal glucose
glargine or detemir insulin in the femoral region will help
and A1c levels significantly reduced the risk of developing
to protract the insulin action even more.
long-term complications. In the Epidemiology of
Diabetes Interventions and Complications (EDIC) study,
How to Inject Insulin
the observational follow-up to the DCCT, a continued
increase in risk of complications was seen in the former Earlier a lot of emphasis was given on skin pinch to avoid
conventional treatment group years after the end of the intramuscular injection. Reason for need of skin pinch
randomized control trial despite improved metabolic was the fact that needle length was 12 mm. Now needle
 Insulin Therapy 585

ADVERSE EFFECTS OF INSULIN

Hypoglycemia
Any treatment of hyperglycemia is likely to cause
hypoglycemia so also with insulin. Hypoglycemia is the
commonest problem with insulin therapy. There are
a number of risk factors for hypoglycemia in insulin-

chapter
treated persons with diabetes. These include, excess

38
dose, mismatched meal timings, and unusually vigorous
exercise. Insulin dose has to be adjusted if there is no
cause for hypoglycemia.
Fig. 37.8: Insulin delivery in the subcutaneous tissue
Weight Gain
length is reduced to 8 mm for syringes and 4–6 mm for This is one of the limiting factors for glycemic control
pen devices. In a patient with a normal body mass index with insulin therapy. Appetite is increased with insulin
(BMI), a perpendicular injection without a skin fold is therapy, which causes weight gain. Another factor is
possible as needles are very short. Figure 38.8 shows a hypoglycemia and over-correction of hypoglycemia by
cross-section of human skin and subcutaneous tissue. eating large amount of calories also leads to weight gain.
In general, thickness of epidermis and dermis is about The issue of weight gain has been looked at differently;62
3 mm and then there is a layer of adipose tissue. In as weight gain mainly occurred in those patients who
most patients there is enough adipose tissue present so had lost weight prior to effective insulin therapy and
represented restoration of set-point weight.
insulin can be taken without any skin pinch and insulin
delivery occurs in subcutaneous tissue only.
Insulin Neuritis
How to Rotate Injection Sites Many patients develop a phenomenon of paresthesia
when insulin is added. This occurs due to osmotic changes
Absorption differs from different injection sites, it is fastest in nerve fibers. These symptoms are self-limiting and
and highest from the abdominal region, slower from generally resolve in 4–8 weeks.
the brachial or gluteal areas and still slower from the
femoral region. These regional differences are related to Insulin Edema
differences in tissue perfusion. It is important that day
Water retention and edema occasionally develop when
after day the injection should be made into predefined
insulin treatment is started.
areas and not randomly. Within the region, injection
sites may be rotated. It is preferable to rotate a particular Change in Vision
injection in the same region of body. For example, a
On initiating insulin therapy and improvement in glycemic
patient on twice premix insulin can inject all morning
control, some patients experience change in vision due
shots in abdomen and rotate them in abdomen while all
to changes in the diameter of the eye lens as result of
evening shots can be rotated in thigh region.
change in fluid content. This may require new pair of
spectacles. The change in the spectacles should be made
How to Reduce Pain of Injection only after the BG stabilizes to the new level. A very rapid
To reduce pain of injection, it is preferable that insulin decrease in glucose levels in a patient with diabetic
should be injected at room temperature since cold retinopathy may worsen retinopathy. Thus in patients with
insulin pains more. If patient is using spirit as disinfectant significant retinopathy, glucose lowering should be slow.
then insulin should be injected only when the spirit has
dried out. Injection should not be given through hair Insulin Allergy
roots. One most important recommendation to make Immune response to injected insulin is determined by
insulin shot pain less is to use a new needle for every prick. the type of insulin injected and the individual receiving it.
586 Management

Immunogenicity is determined by the species of insulin,

its purity, pH, and presence of adjuvants. In the past,
when impure insulin were used, allergy was very
common. With widespread use of purified porcine and
human insulin, the pharmacokinetic changes caused
by insulin antibodies are becoming clinically irrelevant.
There was a fear that these issues may surface again in
section

relation to insulin analogs, however, despite the long-

8

term use in large number of cases so far the issue of insulin

antibodies to insulin analogs has not caused any major
concern or problem.

Lipohypertrophy and Lipoatrophy

Use of less purified insulin results in unsightly depressions
Fig. 38.9: Insulin pump
at the site of insulin administration due to atrophy of
subcutaneous fat. It is not seen now a days as all insulin
factor (IGF)-1 receptor has been a matter of concern. Such
preparations are highly purified. More often seen
binding may cause an increased residence time at the
problem is lipohypertrophy, which results due to insulin
insulin receptor or an increased affinity for IGF-1 receptors
injection at the same site. Presence of lipohypertrophy
may lead to increased mitogenesis, growth promotion and
makes insulin absorption slower and thus affects glucose
carcinogenicity compared to human insulin. An early
control. It is very important to rotate injection sites to
analog that had these two properties B10 Asp (X10) was
avoid lipohypertrophy. If lipohypertrophy is present,
associated with carcinogenicity in female Sprague Dawley
patient must be educated about injection site rotation
rats. A two-year study in female Sprague Dawley rats
and lipohypertrophic areas must not be used for insulin
with insulin glargine showed no evidence of mammary
shots for nearly 2 months.
gland tumors. This has been explained on the basis of the
fact that the ability of insulin glargine to stimulate DNA
Controversial Issues
synthesis in non-malignant cell lines with few or no IGF-1
Cardiovascular Risk receptors does not differ from that of human insulin. The
Is insulin good or bad for the heart? To understand safety of insulin glargine has clearly satisfied regulatory
the issue of CV safety with insulin, Origin trial was authorities in many countries around the world. In the
conducted. Results were announced in 2012. In this Origin trial, there was no significant difference in cancers
study 12,537 patients (mean age, 63.5 years) with CV among glargine and standard care group (hazard ratio,
risk factors plus impaired fasting glucose, impaired 1.00; 95% CI, 0.88 to 1.13; P = 0.97). When used to target
glucose tolerance, or type 2 diabetes were randomized to normal fasting plasma glucose levels for more than 6 years,
receive insulin glargine (with a target fasting BG level of insulin glargine had a neutral effect on cancers.63
≤ 95 mg) or standard care and to receive n–3 fatty acids
or placebo. The median follow-up was 6.2 years. Rates
CONTINUOUS SUBCUTANEOUS INSULIN
of CV outcomes were similar in the insulin-glargine and INFUSION, INSULIN PUMP
standard-care groups. This study concluded that Insulin Continuous subcutaneous insulin infusion involves
glargine has a neutral effect on CV risk.63 use of a small battery driven pump that delivers insulin
subcutaneously as shown in Figure 38.9. Rapid-acting
Cancer Risk insulin, preferably analog is filled in a syringe (Reservoir),
There are reports of cancer and CV risks with insulin and the syringe is kept inside the pump. The syringe is
therapy.64,65 A change in the structure of the insulin attached to a tube called infusion set. Infusion set has a
molecule relative to native human insulin is suspected cannula at its end, which is inserted in subcutaneous
to affect receptor interaction in unexpected ways. The tissue with help of a needle and needle is removed. Now
binding capacity of insulin analogs to insulin-like growth pump can deliver small amount of insulin continuously
 Insulin Therapy 587

chapter
38
Fig. 38.10: Insulin pump with remote glucose meter device

• Recurrent hyperglycemia
• Hypoglycemia unawareness
• Dawn phenomenon
• Difficult to manage pregnancy
• Gastroparesis with brittleness
• Post-renal transplant patients

Lifestyle Indications
• Erratic schedule
• Varied work shifts
• Desire for flexibility
• Inconvenience of MDIs
Many pump models are available. A remote device with
Fig. 38.11: Sensor augmented insulin pump
an inbuilt glucose meter, as shown in Figure 38.10 is now
available in India. In such pumps, patient can control all
at different rates, which is called basal insulin delivery. pump functions with help of remote. Patient can also take
Pump can deliver meal-related insulin, which is called bolus or adjust basal rates with help of remote connected
bolus insulin. Adjustment in dose is made in response to pump through bluetooth.
to measured capillary glucose value in a fashion similar Next new development is sensor augmented insulin
to that used in basal-bolus regimen. Ordinarily, about pumps as shown in Figure 38.11. In this pump, insulin
40–50% of the total daily dose is given at the basal rate, delivery and continuous glucose monitoring, both are
the remainder being administered as pre-prandial bursts. done by one machine. A sensor is inserted in subcutaneous
There is no doubt that CSII can improve metabolic control tissue, this sensor measures glucose and this information
as compared to conventional therapy. Most persons report is transferred to pump and glucose value is displayed on
positive feelings of well-being as control improves. pump screen. Thus, pump user can adjust insulin supply
as per glucose.
Indications of Pump Therapy Lot of work was done in past and still going on to replace
insulin without pricks. Alternate route like nasal, buccal,
Clinical Indications
pulmonary and oral have been tried but unfortunately
• Type 1 Diabetes could not replace insulin shots. Insulin delivery that may
• Inadequate glycemic control inspite of MSII in type 1 allow insulin administration through the nose have been
or type 2 DM tried. Nasal insulin is absorbed and cleared rapidly, is
588 Management

administered non-invasively and has been shown to be Linjeta (Biodel) is another unique insulin formulation
effective. The problem of low bioavailability and nasal comprising regular human insulin with ethylenedia­
irritation are the stumbling blocks and given the current minetetra-acetic acid and citric acid. The latter additives
status of development it is unlikely to be made available act to chelate zinc ions and prevent self-aggregation of
commercially in the near future. Buccal insulin was also insulin molecules into hexamers on injection into the
launched in India but could not gain popularity due to subcutaneous tissue, thus maintaining insulin in a mono­
inconvenience of administration. Extensive work was meric state. As anticipated, Linjeta displays a faster onset
section

done to develop formulations of insulin that can be admi­ of action and peak effect, with reduced intra-individual
nistered as an inhalation aerosol into the lungs. Almost all variability of metabolic action compared with regular
8

the major pharmaceutical players in the insulin business human insulin and/or insulin lispro in healthy subjects
worked on development of inhaled insulin. Exubera was and patients with type 1 diabetes.63,66,67
the first inhaled insulin which got approval by FDA and PEGylated insulin: Another novel approach to delay
was made commericlly available. It was withdrawn from insulin absorption involves chemically coupling the insu­
the market due to low consumption as a result of very lin molecule to poly (ethylene glycol) PEG. A PEGylated
high cost and thus commercial non-viability. In addition, form of insulin lispro, with a flatter, extended duration of
there was a fear of increased risk of lung cancer. Looking action, has been developed by Eli Lilly and is currently
to the fate of Exubera, other major companies also entering phase III trials.
suspended their inhaled insulin program and it seems iDegASp or Degludec Plus (Rhyzodeg): Degludec is the first
that inhaled insulin is now history. basal analogue which can have a premixed formulation
As far as oral insulin is concerned, any news relating with insulin aspart.68,69 Degludec in combination with
to oral insulin delivery system continues to attract media Liraglutide, GLP1 analog is also underway which will be a
and lay press. It is a dream product for most people novel combination expected to take care of both beta and
with diabetes on insulin therapy or at least that is how alpha cell dysfunction as well as weight sparing glycemic
it is projected. While genuine attempts are also being control.
made, the development is still at an early stage and low
pH in stomach, transfer through the jejunum, effect of Closed Loop Insulin Pumps
gastrointestinal (GI) motility, absorption of insulin in Continuous glucose monitoring with CSII has made it
reproducible quantities at defined time points are major possible to have an insulin delivery like artificial pancreas.
issues and oral insulin being used as effective therapeutic The first step towards this was development of insulin
option are very low. pump with auto suspend during hypoglycemia. Now work
Thus new areas for future are to develop more is going on to develop pumps, which will deliver bolus
physiologic meal-related insulin, better basal insulin insulin as well as will modify basal rates based on glucose
and closed loop insulin pump which is a step towards value measured by sensor. These are called closed loop
artificial pancreas. insulin pumps.
Thus, insulin therapy can be optimized only when
WHAT’S NEW AND FUTURE? it mimics endogenous insulin secretary pattern. It is
impossible to replace insulin the way beta-cells secrete.
Novel Insulin Analogues Still, if insulin is replaced keeping type of insulin deficiency
The molecular structure of human insulin has been in a patient and then if the right insulin type and right
gradually refined over the past 2 decades, yielding several regimen and right insulin delivery technique is chosen
unique rapid-acting and long-acting insulin analogues then near normoglycemia can be achieved.
with pharmacokinetic properties that closely imitate
endogenous insulin profiles. Following are few of the
Further Reading
many insulin analogs under development: 1. Cryer PE. Banting lecture. Hypoglycemia: the limiting
The insulin-PH20 (Halozyme Therapeutics) formu­ factor in the management of IDDM. Diabetes 1994;43:
1378-89.
lation contains one of the commercially available meal-
2. Pickup J, Keen H. Continuous subcutaneous insulin
time insulin products mixed with recombinant human infusion at 25 years evidence base for the expanding use
hyaluronidase (rHuPH20). Hyaluronidase makes insulin of insulin pump therapy in type 1 Diabetes. Diabetes Care.
absorbed faster. 2002;25:593-8.
 Insulin Therapy 589

3. Chandalia HB, Lamba PS, Chandalia SH, et al. Weight 12. Jehle PM, Micheler C, Jehle DR, et al. Inadequate suspen­
gain in type 2 diabetics with different treatment modalities. sion of neutral proamine Hagendorn (NPH) insulin in pens.
Metab Syndr Relat Disord. 2005;3:130-6. Lancet. 1999;354:1604-7.
4. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352: 13. Cryer PE. Banting lecture. Hypoglycemia: the limiting
174-83. factor in the management of IDDM. Diabetes 1994;43:
5. Riddle MC. Combined therapy with insulin plus oral agents: 1378-89.
is there any advantage? Diabetes Care. 2008;31:S125-30. 14. Holleman F, Hoekstra JB. Insulin lispro. N Eng J Med.
6. Nathan DM, Buse JB, Davidson MB, et al. Medical man­ 1997;337:176-83.

chapter
agement of hyperglycemia in type 2 Diabetes: a conse­nsus 15. Brems DN, Alter LA, Beckage MJ, et al. Altering the associa­

38
algorithm for the initiation and adjustment of therapy. tion properties of insulin by amino acid replacement. Pro­
A consensus statement of the American Diabetes Associa­ tein Eng. 1992;5:527-33.
tion and the European Association for the Study of Dia­ 16. Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart
betes. Diabetes Care. 2009;32:193-203. (B28 asp - insulin); a fast - acting analog of human insulin:
7. Heise T, Track CJ, Cuddihy R, et al. A new-generation ultra- absorption kinetics and action profile compared with regu­
long acting basal insulin with a bolus boost compared with lar human insulin in healthy non-diabetic subjects. Diabe­
insulin glargine in insulin-naive people with Type 2 Diabe­ tes Care. .1999;22:1501-6.
tes; a randomized, controlled trial. Diabetes Care. 2011;34: 17. Barlocco D. Insulin glulisine. Aventis Pharma. Curr Opin
669-74. Investig Drugs. 2003;4:1240-4.
8. ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. 18. Becker RH, Frick AD. Clinical pharmacokinetics and phar­
Basal Insulin and Cardiovascular and Other Outcomes in macodynamics of insulin glulisine. Clin Pharmacokinet.
Dysglycemia. N Engl J Med. 2012;367:319-28. 2008;47:7-20.
19. Danne T, Becker RH, Heise T, et al. Pharmacokinetics, pran­
dial glucose control, and safety of insulin glulisine in chil­
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11. Kang S, Brange J, Burch A, et al. Subcutaneous insulin 28. Bolli GB, Owens DR. Insulin glargine. Lancet. 2000:356:
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30. Barlocco D. Insulin detemir. Novo Nordisk. Curr Opin dosing with biphasic insulin aspart 70/30 (The 1-23-3
Investig Drug. 2003;4:449-54. study), Diabetes Obes Metab. 2006;8:58-66.
31. Havelund S, Plum A, Ribel U, et al. Albumin binding of 46. Robbins DC, Beisswenger PJ, Ceriello A, et al. Mealtime
insulins acylated with fatty acids; characterization of the li­ 50/50 basal + prandial insulin analogue mixture with a
gand - protein interaction and correlation between binding basal insulin analogue, both plus metformin, in the
affinity and timing of the insulin effect in vivo. Biochem J. achievement of target HbA1c and pre- and postprandial
1995;312 (Pt 3):725-31. blood glucose levels in patients with type 2 Diabetes; a
32. Mooradian AD, Bernbaum M, Albert SG. Narrative review: multinational, 24-week, randomized open-label parallel-
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33. Jonassen I, Havelund S, Ribel U, et al. Insulin degludec ment of hyperglycemia in type 2 Diabetes: a consensus
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a unique mechanism of protraction based ultra-long consensus statement of the American Diabetes Association
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34. Yamada S, Watanabe M, Kitaoka A, et al. Switching from Trial: randomized addition of glargine or human NPH insu­
premixed human insulin to premixed insulin lispro; a lin to oral therapy of type 2 diabetic patient. Diabetes Care.
prospective study comparing the effects on glucose control 2003:26:3080-6.
and quality of life. Intern Med. 2007;46:1513-7. 49. Giugliano D, Maiorino MI, Bellastella G, et al. Treatment
35. Roach P, Yue L, Arora V. Improved postprandial glycemic regimens with insulin analogues and haemoglobin A1c
control during treatment with Humanlog Mix25, a novel target of < 7% in type Diabetes: a systematic review. Diabe­
protamine - based insulin lispro formulation. Humalog tes Res Clin Pract. 2011;92:1-10.
Mix25 Study Group. Diabetes Care. 1999;22:1258-61. 50. Bretzel RG, Nuber U, Landgraf W, et al. Once-daily basal
36. Koivisto VA, Tuominen JA, Edeiling P. Lispro Mix25 insu­ insulin glargine versus thrice-daily prandial insulin
lin as premeal therapy in type 2 diabetic patients. Diabetes
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Care. 1999;22:459-62.
agents (APOLLO); an open randomized controlled trial.
37. Malone JK, Woodworth JR, Arora V, et al. Improved post­
Lancet. 2008;371;1073-84.
prandial glycemic control with Humalog Mix 75/25 after a
51. Bretzel RG, Eckhard M, Landgraf W, et al. Initiating insulin
standard test meal in patients with type 2 Diabetes mellitus.
therapy in type 2 diabetic patients failing on oral hypogly­
Clin Ther. 2000;22:222-30.
cemic agents. Basal or prandial insulin? The APOLLO trial
38. Klio C, Mezitis N, Jain R, et al. Starting patients with type
and beyond. Diabetes Care. 2009;32 (Suppl 2):S260-5.
2 Diabetes on insulin therapy using once-daily injections
52. Clements MR, Tits J, Kinsley BT, et al. Improved glycaemic
of biphasic insulin aspart 70/30, biphasic human insulin
control of thrice - daily biphasic insulin aspart compared to
70/30, or NPH insulin in combination with metformin.
J Diabetes Complications. 2003;17:307-13. twice- daily biphasic human insulin; a randomized, open
39. Mortensen H, Kocova M, Teng LY, et al. Biphasic insu­ - label trial in patients with type 1 or type 2 Diabetes. Diabe­
lin aspart vs. human insulin in adolescents with type 1 tes Obes Metab. 2008;10:229-37.
Diabetes on multiple daily insulin injections. Pediatr 53. Farcasiu E, Ivanyi T, Mozejko-Pastewka B, et al. Efficacy
Diabetes 2006;7:4-10. and safety of prandial premixed therapy using insulin
40. Boehm BO, Home PD, Behrend C, et al. Premixed insulin lispro mix 50/50 3 times daily compared with progressive
aspart 30 vs. premixed human insulin 30 / 70 twice daily: titration of insulin lispro mix 75/25 or biphasic insulin
a randomized trial in Type 1 and Type 2 diabetic patients, aspart 70/30 twice daily in patients with type 2 Diabetes
Diabet Med. 2002;19:393-9. mellitus; a randomized, 16-week, open- label study. Clin
41. Diabetes Care, Diabetologia. 19April 2012 [Epub ahead of Ther. 2011;33:1682-93.
print] 54. Yki-Järvinen H. Combination therapies with insulin in type
42. Riddle MC. New tactics for type 2 Diabetes: regimens based 2 Diabetes. Diabetes Care. 2001;24:758-67.
on intermediate - acting insulin taken at bedtime. Lancet. 55. Riddle MC. Combined therapy with insulin plus oral
1985;1:192-5. agents: is there any advantage? Diabetes Care. 2008;31
43. Yki-Järvinen H, Kauppila M, Kujansuu E, et al. Comparison (Suppl 2):S125-30.
of insulin regimens in patients with non-insulin dependent 56. Raskin P. Why insulin sensitizers but not secretagogues
Diabetes mellitus. N Engl J Med. 1992;327:1426-33. should be retained when initiating insulin in type 2 Diabe­
44. Riddle M, Hart J, Bingham P, et al. Combined therapy for tes. Diabetes Metab Res Rev 2008;24:3-13.
obese type 2 Diabetes: suppertime mixed insulin with day­ 57. Riddle MC, Schneider J. Beginning insulin treatment of
time sulfonylurea. Am J Med Sci. 1992;303:151-6. obese patients with evening 70/30 insulin plus glimepiri­
45. Garber AJ, Wahlen J, Wahl T, et al. Attainment of glycaemic de versus insulin alone. Glimepiride Combination Group.
goals in type 2 Diabetes with once-, twice-, or thrice- daily Diabetes Care. 1998;21:1052-7.
 Insulin Therapy 591

58. Swinnen SG, Dain MP, Mauricio D, et al. Continuation 64. Currie CJ, Johnson JA. The safety profile of exogenous insu­
versus discontinuation of insulin secretagogues when ini­ lin in people with type 2 Diabetes: Justification for concern.
tiating insulin in type 2 Diabetes. Diabetes Obes Metab. Diabetes Obes Metab. 2012;14:1-4.
2010;12:923-5. 65. Smith U, Gale AM. Does Diabetes therapy influence the risk
59. Vilsbøll T, Rosenstock J, Yki-Järvinen H, et al. Efficacy of cancer. Diabetologia. 2009;52:1699-708.
and safety of sitagliptin when added to insulin therapy 66. Steiner S, Hompesch M, Pohl R, et al. A novel insulin
in patients with type 2 Diabetes. Diabetes Obes Metab. formulation with a more rapid onset of action. Diabetolo­
2010;12:167-77. gia. 2008;51:1602-6.

chapter
60. Rewers M, Pihoker C, Dongaghue K, et al. Assessment and 67. Hompesch M, McManus L, Pohl R, et al. Intra-individual
monitoring of glycemic control in children and adolescents

38
variability of the metabolic effect of a novel rapid - acting
with Diabetes. Pediatr Diabetes. 2009;10 (Suppl 12):71-81.
insulin (VIAject) in comparison to regular human insulin.
61. White NH, Cleary PA, Dahms W, et al. DCCT Research
J Diabetes Sci Technol. 2008;2:568-71.
Group, EDIC Research Group. Beneficial effects of intensive
therapy of Diabetes during adolescence: outcomes after the 68. Heinemann L, Nosek L, Flacke F, et al. U-100, pH Neutral
conclusion of the Diabetes control and complications trial formulation of VIAject ((R)): faster onset of action than
(DCCT). J Pediatr. 2001;139:804-12. insulin lispro in patients with type 1 Diabetes. Diabetes.
62. Chandalia HB, Lamba PS, Chandalia SH, et al. Weight gain Diabetes Obes Metab. 2012.
in type 2 diabetics with different treatment modalities. 69. Heise T, Track CJ, Cuddihy R, et al. A new-generation ultra-
Metab Syndr Relat Disord. 2005;3:130-6. long acting basal insulin with a bolus boost compared with
63. ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. insulin glargine in insulin-naive people with Type 2 Diabe­
Basal Insulin and Cardiovascular and Other Outcomes in tes; a randomized, controlled trial. Diabetes Care. 2011;34:
Dysglycemia. N Engl J Med. 2012;367:319-28. 669-74.
 Chapter 39
Insulin Pump Therapy
Banshi Saboo

Insulin Pump Therapy

Chapter Outline
♦♦ Principles and Theory of Insulin Pump ♦♦ Proper Selection of Site and Rotation
♦♦ The Basics of Insulin Pump Therapy ♦♦ Problems Associated with Insulin Pump
♦♦ The Mechanics of Insulin Pump ♦♦ Bolusing for Carbohydrate Containing Foods
♦♦ Indications and Consideration for Insulin Pump Therapy ♦♦ Meal Bolus Options
♦♦ Insulin Pump Formula ♦♦ Bolus Wizard Calculator
♦♦ Operating Insulin Pump ♦♦ Prevention of Acute Problem
♦♦ Types of Insulin Pump ♦♦ Training for Insulin Pump User
♦♦ Handling of Insulin Pump in Daily Life ♦♦ Limitations of Pump Therapy
♦♦ Blood Sugar Monitoring in Insulin Pump Therapy ♦♦ Future of Insulin Pump Therapy
♦♦ Benefits of Insulin Pump Therapy

INTRODUCTION history the CSII system has become very popular among
patients with diabetes mellitus (DM); there are significant
Technological advances in medicine are highly anticipated advancements in its applications, mainly because of
and valued. As these advances gain recognition, they computer technology progress and the availability of new
frequently change perspectives about appropriate treat­ rapid insulin analogs.
ments and may affect the information that physicians The combination of a CSII system with a continuous
provide to families when discussing treatment options. glucose monitoring (CGM) system is another very pro­
However, it is imperative that newer treatments are eval­ mising therapeutic option. Such an integrated CSII+CGM
uated to accurately identify treatment efficacy as well as system is an appealing approach and much effort is being
possible psychosocial effects of treatment. These issues made to make it a reality. In the Western world, and
have been particularly relevant for children and adole­scents especially in the USA, the CSII system is becoming more of
with type 1 diabetes with the advent of the insulin pump.1 a choice for type 1 DM. It is estimated that 375,000 diabetic

Continuous subcutaneous insulin infusion (CSII) patients were treated with the CSII system in the USA in
with a portable pump is an insulin therapy system first 2007.4 As a therapeutic option, the CSII system aims to
built in 1976 by Pickup and Keen for research purposes.2,3 achieve and preserve a good glycemic control, to reduce
At that time, the size of the pump was equal to that of a hypoglycemic episodes and weight gain caused by insulin
back bag. Nowadays the size of an insulin pump is no therapy, to improve the quality of life and prevent or delay
bigger than a cell phone or a credit card. During its 30-year diabetic complications.
 Insulin Pump Therapy 593

The aim behind the insulin pump system is an attempt

to imitate the natural insulin secretion from pancreatic
beta cells. Between meals and during the night a small
amount of insulin is being secreted by the pancreas in
order to sustain euglycemia. This is termed as basal insulin
secretion; during the meals beta cells secrete the necessary
insulin amount in order to lower blood glucose (BG) which

chapter
can be termed a bolus in terms of pump terminology.

39
With the insulin pump a constant prearranged insulin
amount is infused subcutaneously all day and night
along with certain rate variations. This constant infusion
corresponds to the basal insulin secretion of the pancreas.
During meals, the patient receives extra insulin loads Fig. 39.1: Basic components of Insulin pump
in accordance with the amount of food received (bolus
insulin). New insulin pumps allow applying this bolus in
which is placed inside the pump and attached to a plas­
three different ways: (1) infusion of the total dose at once
tic infusion set with a cannula on the end (Fig. 39.1). The
or splitting the dose into two boluses; (2) infusion of a
cannula, similar to an intravenous (IV) angiocatheter, has
part of the bolus in the usual manner plus infusion of the
a metal needle inside, which is removed once the can­
other part over a prolonged period of time (with a higher
nula is successfully inserted into the subcutaneous tissue.
infusion rate than the basal rate); or (3) infusion of the
The cannula and infusion set are inserted manually every
total dose in the form of an elevated basal rate. There is no
2–3 days, a procedure which takes less than 5 minutes.
question that the procedure is elaborate and the patients Infusion sets can be temporarily disconnected at the inser­
need to be familiar with insulin pharmacodynamics, tion site, leaving the cannula taped in place, while bathing,
pharmacokinetics and pump technology, to be able to swimming, or performing certain activities that require a
perform self-monitoring at least four times a day and to large amount of physical contact or jarring of the body.
know the relationship between insulin dosage needed for A variety of infusion set types, lengths, and cannula sizes
the amount of carbohydrates and maybe of lipids that they are available for the patient to choose from.7,8
consume.
Currently, more than five different companies manu­
Rapid acting analogs (Aspart, Glulisine and Lispro) facture insulin pumps. Although each pump may offer
are the insulin types mainly used for the CSII system. something unique, the overall principles of insulin
The pharm­ acodynamic and pharmacokinetic features delivery are the same. The basal rate provides a continuous
of rapid acting analogs (instant absorption, quick peak, per hour infusion of insulin, released in equally divided
fast withdrawal) make them the best choice, because of intervals every 3 minutes or more minutes, depending
better mimicking of the physiological secretion of insulin on the brand of pump.9 In the absence of food, the basal
from the b-cells. Furthermore, insulin analogs have fewer insulin should keep the BG levels within target range.10,11
tendencies to form crystals inside the plastic tubes of
The initial basal rate is calculated from the combined
pump which can lead to obstructions.5 total daily dose (TDD) of insulin before transitioning
to the pump. If the original regimen consists of Neutral
PRINCIPLEs AND THEORY OF INSULIN PUMP Protamine Hagedorn (NPH) with rapid or short acting
insulin, the TDD is reduced by 25%8 as a result of the
An insulin pump is a portable, external, battery-powe­ increase in insulin sensitivity provided by the pump.
red device programmed to deliver a continuous “basal” Pubertal patients with insulin resistance and patients with
infusion of rapid-acting insulin every 3–4 minutes and higher BG levels at the start of pump therapy may need
“boluses” or bursts of insulin on demand at meals, snacks, little to no reduction in TDD of insulin.8 In adults, half of
or other times when the BG level is elevated.3,6-8 Most the reduced insulin dose is divided by 24 hours and used
insulin pumps are approximately the size of a cell phone as basal, and the remainder is split between the meals as
and weigh between 50 g and 90 g. Insulin is drawn up into the boluses. In children and adolescents, approximately
a 2–3 mL plastic syringe called a reservoir or cartridge, 40–45% of the TDD accounts for the basal insulin, with the
594 Management

remainder as meal boluses.7,12 When meals or snacks are

consumed, a bolus of insulin is delivered to cover the rise
in BG with the goal of delivering enough insulin to return
the BG level to normal range in post-prandial phase. The
amount of insulin needed with food is calculated by using
insulin to carbohydrate ratios. The insulin to carbohydrate
ratio can be 1 unit insulin to cover 5 g of carbohydrates in
section

someone who is overweight and more insulin resistant, to

as little as 1 unit per every 30 g or more of carbohydrates in
8

an infant or child who is newly diagnosed with diabetes.8,11

The ratio may change through the years as an individual’s
body weight or insulin sensitivity changes. To estimate
the amount of carbohydrates covered by 1 unit rapid
acting insulin, the TDD of insulin is divided into 500.
Some diabetes providers may estimate the ratio based on
patient care experience. If the BG level is not within target Fig. 39.2: Insulin pump and accessories
range before or between meals, a supplemental dose of
insulin is needed. The correction or supplemental insulin
dose, determined by using the sensitivity factor, is the meal. The size of insulin bolus can then be determined.
amount of insulin needed to lower the blood glucose to This results in the ability for flexible meal timing and meal
a predetermined target range. The sensitivity factor is the size; (2) A correction bolus which is used to reduce a high
estimated drop in the blood glucose level caused by 1 unit BG level.
insulin.13 When rapid-acting insulin is used, the sensitivity
factor is calculated by dividing the TDD of insulin into THE MECHANICS OF INSULIN PUMP
1,700. Like the carbohydrate ratio, the sensitivity factor
may change through the years as insulin needs increase The pump: A battery operated computerized device about
with growth.8 the size of a cell phone that delivers insulin, stores an
individual’s specific settings and calculates bolus doses.
THE BASICS OF INSULIN PUMP THERAPY The reservoir: A cartridge, which looks like a syringe
that is filled with insulin and placed in the pump.
Insulin pumps simulate normal pancreatic function by The infusion set: A thin plastic tube connected to the
delivering fast acting insulin in two ways: (1) basal rate: reservoir through which insulin flows. The infusion set
background insulin, delivered continuously by the pump usually has a soft cannula at the end that the user places
throughout the day and night to cover the individual’s into subcutaneous tissue every 2–3 days (Fig. 39.2).
metabolic need for insulin; and (2) bolus: a calculated
amount of insulin “on demand” given by the pump INDICATIONS AND CONSIDERATION FOR
user when food is eaten or to correct for high BG values, INSULIN PUMP THERAPY
because the basal rate can be set to the individual’s
metabolic need, highs or lows at different times of day or The main advantage of insulin pump therapy over
night can be avoided. For example, the pump can be set to insulin injections is better insulin pharmokinetics.11 The
deliver more insulin in the early morning hours to correct pump uses only one type of insulin, thereby decreasing
for an increase in BG caused by hormonal activity known variability in BG levels. Insulin pump therapy is ideal
as the “dawn phenomenon”. The basal rate can also be for patients who require and desire improved diabetes
adjusted temporarily, for example while exercising to control and increased flexibility in their lifestyle. Research
accommodate the reduced need for insulin. Boluses can suggests that pump therapy provides better BG control
be delivered when immediate insulin is needed. The pump than conventional insulin regimens3,6,14 and is as better
user controls the timing and amount of the bolus. There than multiple daily injections.3,6,15 In very young children,
are two types of bolus: (1) a meal or food bolus which is diabetes control may improve less, but the flexibility
given after assessment of the carbohydrate content of the and convenience of the regimen itself is preferred by
 Insulin Pump Therapy 595

many parents and pediatric diabetes specialist.16 Insulin treatment goals and outcome measures are suboptimal,
pump is also indicated in gastroparesis, as it makes including, but not limited to:18
glucose regulation difficult. Since gastric emptying is • A1c more than 7.0–7.5%, accompanied by frequent
often delayed, a normal bolus taken before a meal may severe hypoglycemia (< 70 mg/dL).
lead to hypoglycemia immediately after eating and • Hypoglycemic events requiring third party assistance
hyperglycemia several hours later. The Square Wave® and or interfering with work, school, or family obligations.
Dual Wave® Bolus features allow the pump user to spread • Frequent and unpredictable fluctuations in BG levels.

chapter
out the bolus over an extended period of time and help to • Patient perception that diabetes management impedes

39
decrease the risk of postprandial hypoglycemia or delay the pursuit of personal or professional goals.
hypoglycemia. It takes trial and error to determine the Prospective pump users or their care givers must be
length of the extended bolus required for different foods. able to change infusion sets, fill pump cartridges and
There is no exact science to using the bolus options. It program the pump, and must demonstrate willingness
takes plenty of practice to work out what meals need which to collaborate with healthcare providers in achieving the
type of bolus and in what proportions. Pumpers should goals of diabetes therapy.18,19 In general, patients likely to
become proficient at estimating the carbohydrate content succeed on insulin pump therapy will have had sufficient
of their meals and using the normal bolus feature before education and support while using other forms of insulin
attempting to experiment with the different bolus options. therapy so that they are already competent in assessing
It is worth asking the patient to keep to their usual meal the nutritional value of meals and monitoring BG levels
size and food types in the first few days after starting pump frequently (minimum four times a day, preferably 6–8
therapy. This allows easy adjustment of the basal rate times) and checking ketone levels when appropriate.20
without the variations in BG level which can otherwise be Insulin pump therapy is contraindicated in patients
lacking the commitment or competence to perform basic
seen. This also allows the patient time to become familiar
diabetes self-management behaviors,3 however, many of
and confident with using the normal bolus feature.
recent researches have shown that such patients can see
positive results from using a pump.18,21
Indications17
Insulin pump users have the option of skipping or
• High glycated hemoglobin (HbA1c or A1c) levels despite delaying meals and flexing the amount of carbohydrates
multiple daily injections consumed at one time. When taking insulin injections,
• High level of insulin resistance patients must consume a pre-determined amount of
• Brittle diabetes food at specific times to prevent hypoglycemia from the
• Recurrent hypoglycemia, nocturnal hypoglycemia, onset and peak of the insulin injection.22 With a pump,
activity-induced hypoglycemia and hypoglycemia meal time insulin is delivered more physiologically, based
unawareness on the use of rapid acting insulin.
• Subjects with chronic kidney disease requiring renal Insulin pump is contraindicated in psychiatric
replacement therapy illness, financial constraints, and absence of at least one
• Dawn phenomenon responsible educated care giver and lack of time or comm­
• Gastroparesis itment to learn about using insulin pump.22
• Recurrent diabetic ketoacidosis (DKA) and hospitali­
zation INSULIN PUMP FORMULA
• Low insulin requirement
• Frequent travellers with varied food habits The following formulae are used in day-to-day Insulin
• Subjects on insulin seeking improved quality of life calculations. These may vary from patient to patient but
• Type 2 diabetic on multiple daily insulin injection who provide a guide to a beginner.
need more flexibility in life style.
Insulin Carbohydrate Ratio (ICR)
Consideration of Candidate for ICR is also known as Carb factor:
Insulin Pump Therapy 500
Patients should be considered for insulin pump therapy TDD (Total daily insulin dose )
when intermittent insulin injections are not meeting = Grams of carbohydrate for 1 unit insulin
596 Management

When 500 is divided by TDD of insulin [can be seen If by mistake it is taken out then it should not be
in pump], then the grams of carbohydrate which will be reused. When pump is on, it will show various icons. First
neutralized by 1 unit of insulin can be calculated. Feeding it will show a count down after which the screen goes dark
this information to Paradigm pump is must for using Bolus and then the version of the particular pump will appear on
Wizard®. the screen. Then a dark circle, a battery sign and a syringe
Example: sign will appear on the screen and the company name will
If a person’s total daily insulin dose is 40 units then his appear in the middle of the screen. Generally, the battery
section

ICR would be 500/40=12.5, this means that 12.5 grams of work up to 10–12 days, if there is a low battery alarm, then
8

carbohydrate would be neutralized by l unit of insulin. the battery should be immediately changed.
Once pump is turned on, by pressing the ‘Act’ button,
Correction Factor (1,700 Rule) the main menu can be reached to select any function of
pump by using pump guide. On pressing ‘Esc’ a summary
When 1,700 which is divided by TDD of Insulin, and then of pumps functioning is displayed and in addition, Esc
we can get the milligrams of glucose level which would be is also an exit button and is used for going back to main
lowered by 1 unit of insulin. menu, from any level. The ‘Up’ scroll is for going up the
1700 menu and for increasing the numbers. It is also used for
= Correction factor
Total daily dose(TDD) taking the easy bolus. The down scroll is for going down
the menu or for decreasing the numbers. It is also used for
Correction factor means milligrams of glucose,
switching on the light for the screen. There is also a button
lowered by 1 unit of Insulin. For example: If a person’s total
which provides a shortcut to administer a bolus. Once
daily insulin dose is 50 units then his Correction factor
after starting the pump patient can set the pump function
would be 1700/50 =34. This means in this person 1 unit
as per requirement.23
of insulin will lower BG by 34 mg. For more insulin sensi­
tive patients it may be 1800 rule while for less insulin
sensitive 1500 rule will be more appropriate.
TYPES OF INSULIN PUMP
Insulin Pump Connected with
Estimating Correction Bolus
Tubes or Infusion Sets
On the basis of correction factor, a pump user may
calculate correction bolus amount of insulin. These types of insulin pump are the most common and
the ones typically referred to when talking about pumps.
Current BG − Target BG The pump itself is about the size of a cell phone and is worn
= Units of insulin
Correction factor on the outside of the body. It delivers fast-acting insulin
Converting Millimoles (mmol) to into the body via an infusion set, a thin plastic tube ending
in a small, flexible plastic cannula or a very thin needle.
Milligrams (mg) of Glucose
Formula for conversion of glucose mmol to mg/dL: Tubeless Insulin Pumps
mmol × 18 = Blood Glucose in mg/dL
Example: 11 mmol glucose in milligrams will be: These pumps sit directly on the skin so inject insulin
11 × 18 = 198 mg/dL through the skin without the use of tubes (infusion sets).
It is also known as a Patch Pump.
OPERATING INSULIN PUMP
Insulin Pump with CGM
Insulin pump is a small device like a mobile phone, there
are four to five buttons in pump such as Act, Esc, up Insulin pump with integrated continuous glucose
scroll, down scroll and B. For starting the pump, battery monitoring system also known as a “real time insulin
has to be installed first. For this, the battery cover pump” shows the sugar level and also sugar trend on
needs to be opened and a new battery should be inserted screen with the help of glucose sensor (Fig. 39.3).
in the battery port end. After placing the battery, it should The real time trend arrow on screen reveals the
not be taken out till it is discharged. direction and degree of change in glucose levels. It is also
 Insulin Pump Therapy 597

be to keep it in the outer pocket or make an internal

pocket in the dresses.
Women: Women can wear the pump very comfortably
attached to their dresses.
School going user: Children can attach it in the uniform
either by clipping it on the belt or cloth. The pump

chapter
does not create any hindrance in the school activities.
While participating in any water sports the pump can be

39
disconnected and kept aside.
Infants and toddlers: The best way to keep the pump is
making a pocket on the inner back side of their dress.
Otherwise the pump can be kept in any part of the dress
or the pocket where it is safe and does not move around.
Fig. 39.3: Insulin pump with continuous glucose monitoring (CGM) During bath: The pump should be disconnected for
bathing. It can be suspended and disconnected by slowly
rotating the knob on cannula anticlockwise. If the bathing
designed to alarm patients when they are approaching
process takes longer time, then small bolus can be taken to
unsafe low or highs. Advance treatment management
prevent rise in glucose.
software comes with this pump which allows patient to
monitor their own treatment information with easy to Intimacy: Although the tape adhesive is strong, still it
read flow charts, graphs, and tables and to share data with is appropriate to remove the pump during intimacy, as
physician. It is a CGM ready insulin pump with automatic there are high chances of getting the cannula tube pulled.
insulin shut off mechanism. Low glucose suspend (LGS) It is also difficult to handle the pumps position during
is designed to automatically detect hypoglycemia and intimacy. There is no need of any extra bolus before
suspend insulin infusion prior to the onset of severe removing pump for intimacy. It should be remembered to
hypoglycemia episodes. In addition to LGS, CGM alerts reconnect pump later.
warn patients of glucose trends, aiming at minimizing the During sleep: It is very easy to handle pump while sleeping.
risk of unwanted excursions. Low glucose suspend is a key With small children, pump sized pockets can be made in
step in “closing the loop” (artificial pancreas). their night dresses anywhere near the abdomen area as
for children the pump is connected on the stomach or hip
HANDLING OF INSULIN PUMP IN DAILY LIFE region. The pump clip can be inserted in the pocket and
the cannula length allows the pump to move during the
Many patients in India are reluctant to accept pump as sleep, without getting it pulled and tampered. Sleeping
an external device, attached to the body throughout day over the pump in the night does not harm it at all. With
and night. But once a patient is on pump then same issues adults the pump can be either kept in the pockets or just
become less important as patient realizes benefits of pump near by while they sleep but only as far as the length of the
therapy. For the prospective pump user with concerns of tube attached to the body and the pump. Ladies who wear
wearing pump, we can take analogy of glasses, for good gowns can tuck the pump in the under garments or in the
vision one has to wear them all the time. In this chapter, pocket made in the gown.
common day-to-day life issues are discussed.
Travel: During travel, user should keep enough extra
insulin pen fills, infusion sets, extra batteries, and also
How to Wear the Pump?
pen or syringe to inject insulin if the pump does not
An insulin pump has a clip which can be attached to the work. Pump user should carry letter from doctor which is
clothing easily. Pump can be worn both by men, women important for security checks during air travel.
and children of any age. In different situations the pump Hiding the pump: This is a personal choice for the pump
can be worn in the following ways: wearers. In case they don’t want to show the pump and
Men: Pump can be comfortably attached in men’s clothes. disclose about diabetes then the pump can be conve­
Men can clip it on the belt or cloth. Another way would niently hidden under the clothes.
598 Management

During sports and dance: The pump is no hindrance same is provided by pump as basal rate. So if a particular
during these fast moving activities like when playing or basal rate is low, premeal glucose around that particular
dancing. All one has to take care is that the pump should that basal profile will be high, if all basal profiles are set
not be pulled from the place it is attached to. The pump low then all preprandial values will be high and all basal
can be clipped to the sports skirt, jogging pants, shorts, profiles will need increment.
etc. The clip is well fitted and does not move much while Similarly, low preprandial indicates a need for reduc­
playing. It can be kept in the pocket, inside or outside the tion in a particular profile. If a basal rate is considered
section

sports dress. low or high, then it should be changed at least 2–3 hours
8

earlier. For example, to take care of rising glucose at 5 am,

Adjusting Insulin Pump adjustment in basal profile should be done around 2 am.
Therapy During Exercise This is due to the fact that it takes nearly 2–3 hours for basal
Different exercise regimens will cause different effects insulin to show its effect on glucose levels. In practice, for
on BG, during or after the exercise. For example, well- basal rate setting, first aim is to set night basal then to set
conditioned athletes who exercise intensively on a regular morning and early noon, lastly to set late noon and evening
basis may not have a significant change in their BG in basal. If on monitoring, most premeal values, bedtime
response to exercise. On the other hand, people just glucose, 3 am value, and fasting value are in normal range,
beginning an exercise program may experience rapid then the basal rate setting is fine.
drop in BG with the effect lasting up to 24 hours following If fasting glucose is high then patient should test
the exercise. In addition, short bursts of high intensity bedtime and 3 am value as well if all the three values are
exercise can cause hypoglycemia. Remember to explain high then increment in basal rate from 10 pm till early
to the patient that the BG level will increase from exercise morning is needed. If bedtime value and 3 am value is
if there is a lack of insulin. Exercise will only decrease BG good but only fasting glucose value is high then an
levels if there is enough insulin available to efficiently increment in basal rate from 3–4 am is needed. While
utilize glucose and allow it to enter the muscle cells. If there if bedtime glucose is normal and 3 am is low with high
is a lack of insulin the BG level can increase. With heavy fasting, then a reduction in basal rate from 11 pm onwards
exertion, such as competitive sports, excessive amounts of is needed.
adrenaline may be secreted, causing the BG level to rise in
spite of adequate insulin levels. The pump user can adjust How Bolus Rate Influences Blood Glucose
the basal rate to compensate for insulin needs associated
Rapid acting analog insulin, pushed by bolus starts rising
with exercise. Feature is used to temporarily increase
in 10 minutes, reaches peak by 1 hour and it disappears
or decrease the basal rate in half an hour increments from
by three and half hours. Thus, if a bolus is taken by a user,
30 minutes to 24 hours.
it will work for nearly 4 hours. Now if a second bolus
BLOOD SUGAR MONITORING IN is given within 3 hours then there will be an overlap of
INSULIN PUMP THERAPY insulin action. Thus, bolus should be taken 3 hours apart
or if taken early, level of previous insulin bolus must be
The Objectives of Blood Glucose Monitoring considered for deciding dose of new bolus.
• To set basal rate Once basal rates are set, monitoring following values
• To decide bolus insulin daily should be a routine:
• To avoid hypoglycemia and hyperglycemia • Fasting
• To take correction dose. • Premeals (before breakfast, lunch, and dinner)
By achieving above goals, a pump user can have a • Bedtime
flexible life style with good glycemic control. In fact, Sleeping with a normal bedtime and waking with a
monitoring is the only way to get the best out of pump. normal glucose value sets the stage for the rest of the day.
Premeal glucose testing helps in bolus dose calculation,
How Basal Rate Influences Blood Glucose adding any correction dose and it is also needed to
In fasting state, there is a continuous need of small amount optimally utilize smart pump menu like bolus wizard.
of insulin to take care of glucose coming from liver. The Maintaining a log book record of glucose levels, meal
 Insulin Pump Therapy 599

details and bolus quantity and its type gives a better Reduction in Hypoglycemic Events30
guidance about boluses.
As the definition and reporting of hypoglycemia are
• Postmeal BG target recommendations:
different in different trials and guideline, it is not easy to
American Diabetes Association (ADA): Less than or equal make any direct comparisons. However, based on the
to 160 mg/dL, American Association of Clinical Endo­ available data, it appears that pump use was associated
crinologists (AACE) less than or equal to 140 mg/dL, with a decrease in the frequency of mild hypoglycemic
pregnancy less than or equal to 120 mg/dL.

chapter
episodes,9 and this was probably related to the lower
variability of BG concentrations.8 In patients prone to

39
Glucose Goals with Pump
severe hypoglycemia, the use of pump resulted in a large
The following are target ranges suggested by many health and sustained reduction in such episodes.19 In addition,
care providers: a meta-analysis of randomized controlled trials and
• Premeal or Fasting (80–120 mg/dL or 4.4–6.7 mmol/L) observational studies, conducted with pump and short-
• 2 hours after meal (less than 160 mg/dL or 8.87 acting insulin analogs in patients with severe hypoglycemia
mmol/L)
at baseline, showed that severe hypoglycemia was reduced
• Bedtime (100–140 mg/dL or 5.6–7.8 mmol/L)
by a mean of about 75% by pump treatment compared
• 2 am–3 am (100 mg/dL or 5.6 mmol/L)
with MDI in adults as well as in children.20
Aim of glucose monitoring is to find best working basal
rate most of the time. Similarly to estimate best working
Less Variability in Insulin Absorption31
bolus, users need to find the best fit and should not expect
perfection. Further, in analyzing glucose values, it is better • The insulin pump uses only shorter-acting insulin,
to observe trends rather than concentrating on one value. reducing absorption variability by over 50% compared
to longer-acting insulin given by injection.
BENEFITS OF INSULIN PUMP THERAPY • The infusion set is inserted in only one area of the body,
usually the abdomen, which minimizes variation of
Insulin pump therapy is a fast-growing choice for diabetes
management. In fact, the majority of diabetes specialists insulin absorption between different sites.
who have many type 1 diabetic patients use pump therapy • The infusion set remains in one injection site for
to manage type 1 DM in a better way.24 Less than 3% of 2–3 days, decreasing variability in insulin absorption.
pump patients ever discontinue insulin pump therapy.25
Insulin pump therapy offers clinical and lifestyle benefits. Exact Dosing of Insulin
Several studies on adults and children have proved that • The basal rate can be changed every 30 minutes. These
insulin pump therapy leads to significant improvements minute adjustments allow for insulin dosing to be
over injection therapy. matched to metabolic need.
• Bolus can be calculated based on BG levels, the
Decrease in HbA1c
carbohydrate content of the meal, and insulin sensiti­
Compared to multiple daily injections the pump gives vity. Doses are delivered immediately or over a period
better glycemic control in all population.26 Many of time to compensate for the variation in absorption of
researchers have confirmed the superiority of CSII over different types of food.
Multiple Daily Injections (MDI) in terms of HbA1c. In • The bolus can be delivered in 0.1 U increments.
the Diabetes Control and Complications Trial (DCCT),7 • The basal rate can be adjusted in 0.025 unit increments.
HbA1c levels in the intensive treatment group were • The basal rate can be lowered temporarily during
significantly lower with CSII than with MDI (ranging exercise to prevent hypoglycemia or raised temporarily
from 0.2% to 0.4%). Several researches have reported during illness to prevent hyperglycemia.
positive experiences with CSII in small cohorts of severely
obese type 2 diabetes mellitus (T2DM) patients with Increased Flexibility for a Better Quality of Life
poor glycemic control (HbA1c 10–12%) in spite of
intensified insulin therapy using high insulin dosages • There is no longer-acting insulin dictating when to take
(1.5–5.0 U/kg).27,28 Interestingly, in these particularly another injection or eat the next meal.
insulin-resistant patients, both HbA1c and insulin • Meal timing and size is determined by the individual’s
requirements were decreased with CSII.29 choice.
600 Management
section

A B
Figs 39.5A and B: Site rotation
8

allows for more rapid and consistent insulin absorption

than from other sites, especially after exercise. When using
the abdomen, help the pumper to identify a variety of
abdominal sites for adequate rotation. Imagining a clock
drawn on the abdomen can be helpful. Ask the patient
to rotate the site in clockwise position from 12 o’clock to
Fig. 39.4: Sites for Insulin pump 3 o’clock and so on (Fig. 39.5A).
• Visualize an M or a W on either side of the umbilicus.
Rotate the site starting with one point and ending at the
• Quality of life in adults and coping skills in adolescents other, staying on one side of the abdomen if possible
improve after initiating insulin pump therapy.32,33 until the rotation is complete and then switching to
the other side. This gives one side a few weeks to “rest”
Delays the Onset and Progression of before using it again (Fig. 39.5 B).
Complications • Make sure the site is convenient to insert the cannula.
The excellent BG control that is attainable with pump • The following should be considered when inserting
therapy has been shown in research settings to stop infusion sets:
and/or delay the progression of diabetic kidney disease –– Avoid the area around the belt or waistline.
and diabetic eye disease, and to improve nerve conduc­ –– Avoid the area where clothing may rub or constrict
tion velocities.34-36 the infusion set.
–– Infusion sets can be uncomfortable, if inserted
Improves Glucose Control Postrenal Transplant around the underwear or bikini line.
–– Areas of lipohypertrophy and scar tissue should be
While transplanting a healthy kidney into a person
avoided by 1–2 inches.
with diabetes who is in renal failure, BG management
–– Insert infusion sets at least 1–2 inches away from
is necessary for the patient, BG management after the
the umbilicus.
transplant may be difficult. This is due to both, the effects Some pumpers use the thigh or hip area; it is also
of surgery and the need for anti-rejection medication that possible to use areas higher on the abdomen than may
creates insulin resistance. Insulin pump therapy has been have been previously used with injected insulin. Many
shown to improve both glucose and metabolic control both prefer the hip area because it is “out of sight”. If these
immediately and several months after renal transplant.27 sites are used, make sure that cannula placement is
subcutaneous, not intramuscular.
PROPER SELECTION OF SITE AND ROTATION Make sure that your patients understand that the insulin
Patients need to change the infusion set site every 2–3 days pump will alarm only if insulin delivery is interrupted.
and should always rotate to a new site (Fig. 39.4). Some Reinforce that the pump cannot detect and will not alarm
pump users may need to change the site more often if they for certain problems at the infusion site. Explain that
notice their BG is less stable over time. The abdominal area occasionally an infusion site may temporarily cease to
is the most common site for set insertions. The abdomen absorb insulin properly, resulting in hyperglycemia.
 Insulin Pump Therapy 601

PROBLEMS ASSOCIATED WITH • If abscess occur, perform an incision, drain the area
INSULIN PUMP and culture the fluid
–– Rule out the methicillin-resistant staphylococcus
Discomfort –– Consider using antibacterial in nares weekly to
Although the insertion devices make insertion virtually minimize recurrent infections.
painless, a small percentage of pumpers will experience
discomfort when first inserting the infusion set. If Lipohypertrophy

chapter
discomfort occurs, immediately reassure the pumper that

39
there are solutions available. Some doctors recommend Frequent site changes (every 2–3 days) are also needed
placing an ice cube against the infusion set for 15–20 to avoid lipohypertrophy (hardening of the skin) which
seconds to numb the area slightly before inserting the may be related to the length of time an infusion set is left
infusion set. Some chemists now sell small gel filled pads, in one site. Lipohypertrophy causes poor insulin absorp­
designed to reduce bruising after a sprain, which can be tion and reduces the number of possible infusion sites
kept in the fridge and used for the same purpose. Another over time. Regular use of alcohol swabs can also harden
option is the use of a topical analgesic product. the skin overtime.

Skin Problem Fine-Tuning and Setting of Insulin

Clean technique, good hygiene and changing the site Pump and Its Parameters
as recommended are the best protection against skin
The initial insulin pump parameters are prescribed by
infections. Careful attention to site preparation and daily
the diabetes team based on the patient’s previous insulin
checks of the site will prevent most infections. However,
dose and sometimes weight. This prescription will be
serious consequences can occur if insertion site irritation
modified over time, first by adjusting for hypoglycemia
and infections are ignored. Suggestions for avoiding skin
and hyperglycemia and then through a process of fine-
infections at insertion sites are:
tuning for optimal control.
• Always wash hands thoroughly with soap and water
The following calculations are commonly used by the
prior to removing an used infusion set and then again
diabetes team to set up initial pump parameters:
before preparing a new set.
• Change the infusion set every 2–3 days, preferably,
after a bath or shower. Total Daily Dose
• Prepare the new infusion set on a clean surface such as The amount of insulin (basal and bolus) delivered by the
on a clean paper towel. insulin pump each day, typically, 40–50% is delivered
• Always remove an infusion set at the first sign of as basal insulin and the remaining 50–60% as bolus
abnormal discomfort at the insertion site and place a insulin. Insulin pump therapy uses rapid-acting insulin
new infusion set in a fresh site, away from the original (Tables 39.1 and 39.2).28,29
area.
At the first sign of an infection instruct the patient to Clinical Guidelines
call the doctor if any of the following are present:
• Redness or hardness around the site Use both methods and average the two values to deter­
• Oozing from the cannula site mine the starting insulin pump TDD. Example: (40 units/
• Area warm to the touch day + 35 units/day) + 2 =37.5 units/day Insulin Pump Total
• Tenderness or soreness around the site Daily Dose
• Unexpectedly high blood sugar levels • For hypoglycemia or hypoglycemia unawareness, use
If an infection occurs: the lower value
• It is usually staphylococcal in nature and typically • For consistent hyperglycemia, an elevated HbA1c, or
requires oral antibiotic treatment. in pregnancy, use the higher value
• If infections are recurrent, recommend patient to • For erratic glucose control, or if starting insulin pump
cleanse the area followed by alcohol prior to needle therapy at diagnosis or from oral medications, use the
insertion. weight-based method.
602 Management

Table 39.1: Total daily dose (TDD) for Insulin pump start28 Table 39.2: Methods for total daily dose (TDD) insulin
Example patient: Type 1 male weight: 70 kg (154 lb) Method 1 Method 2
Prepump insulin Rapid-acting: 33 units/day • Based on prepump TDD • Based on patient weight
regimen 11 units premeal × 3 • Reduce prepump TDD Weight: kg. × 0.5 or lbs.
Long-acting: 20 units/day by 25% × 0.23 = pump TDD
20 units (Bedtime) Example: Example:
Prepump total daily 53 units/day 53 units/day × 0.75 OR 70 kg × 0.5 = 35 units/day or
= 40 units/day 154 lbs × 0.23 = 35 units/day
section

dose
(*Reduce less if prepump
8

TDD is >70% rapid-acting

Basal Rate Calculations29,37 insulin)

Basal rate calculations can be calculated from prepump

total daily dose or by weight. Use lower calculation for –– The start time of the basal rate adjustment should
starting insulin pump parameters. Prepump total daily be set 2 to 3 hours prior to rise or fall in BG
dose (TDD), usually reduced by 25% (although this –– If BG increases more than 30 mg/dL: increase
figure may be adapted for special circumstances, e.g. basal rate by 10–20%
children) divided by two, (half for total bolus), divided –– If BG decreases more than 30 mg/dL (or falls
by 24 (hours in the day) = estimated hourly basal rate or below target): treat the low BG and decrease basal
to determine by weight: 0.1 units per lbs (body weight), rate by 10–20%
divided by 24 hours. –– Verify changes by re-evaluating overnight BG over
Basal rate provides a continuous infusion of insulin the next 2–3 nights.
to cover hepatic glucose production, mimics pancreatic
basal secretion and maintains glucose stability in the Two Methods of Adjusting Daytime Basal Rates
fasting state (between meals and during sleep), progra­
1. Method One (Fasting Technique)
mmed to meet patient’s individual diurnal variations.
• Choose a calm day when BG is in normal (safe) range
• STEP 1: Total daily basal requirement • Have patient skip a meal (do not try to skip more than
Divide insulin pump TDD in half one meal/day)
Example: 37.5 units/day + 2 =18.75 units/day (total daily • Have patient check BG every hour and observe for
basal insulin) symptoms
• STEP 2: Starting hourly basal rate • If BG increases or decreases more than 30 mg/dL
Divide total insulin pump basal requirement by 24 hours during the fasting period: adjust basal rate in 10–20%
Example: 18.75 units/day + 24 hours = 0.78 units/hour increments—verify change by repeating the fasting test
Starting basal rate = 0.8 units per hour • If BG drops below 70 mg/dL (or below target): have
Begin insulin pump therapy with one basal rate patient treat the low and decrease the basal rate by
delivering evenly over 24 hours. Adjust or add additional 10–20%—verify change by repeating the fasting test the
basal rates based on glucose trends over 2–3 days. next day.
2. Method Two (Post-meal to Pre-meal Technique)
Basal Rate Adjustments29,38-40 The following principles apply when evaluating
Focus on Overnight Basal Rates First basal rates in the non-fasting state: 2-hour postmeal BG
should be 30–60 mg/dL higher than premeal BG; and the
Evaluate overnight control by comparing BG and/or CGM 2-hour postmeal BG should steadily decline to fall back
values across time segments. within the next premeal target range.
• The basal rate is properly set if BG remains within • Instruct patient not to eat between meals
desired range throughout the night. • Instruct patient not to correct postmeal high BG
• Adjust or add basal rate based on rise or fall pattern of (if postmeal is corrected, do not include this post- to
blood glucose (BG) in each time segment premeal time period in your evaluation)
–– Example: bedtime to 12 am; 12 am–3 am and • Evaluate the basal rate by comparing the 2-hour
3 am–7 am postmeal BG to the next premeal BG
 Insulin Pump Therapy 603

Table 39.3: Calculation of carbohydrate meal bolus ratio28

Method 1: 500 rule OR Alternate methods
• 500/by the pump TDD = Carbohydrate ratio • Weight: kg × 6 ÷ pump TDD = Carbohydrate ratio or
Example: lbs × 2.8 + Pump TDD = Carbohydrate ratio
450 ÷ 37.5 = 12 grams 1 unit covers 12 Example:
grams of carbohydrate 70 kg × 6 ÷ 37.5 units/day = 11 grams or
154 lbs × 2.8 ÷ 37.5 = 11 grams 1 unit covers

chapter
11 grams of carbohydrate
• Fixed bolus: 1/2 Pump TDD + 3 (equal meals)

39
Example: 37.5 × 0.5 ÷ 3 = 6.3 units per meal
(Use for patients who are not yet carbohydrate counting, or who have lower
cognitive ability. Convert fixed units per meal to fixed grams of carbohydrate per
meal and provide dosing instructions for small, medium and large meals)
(TDD: Total daily dose)

–– If BG decreases more than 60 mg/dL, or falls below BOLUSING FOR CARBOHYDRATE

BG target: decrease basal rate by 10–20% CONTAINING FOODS
–– If BG decreases less than 30 mg/dL, or stays the
same, or rises: increase the basal rate by 10–20%. One of the major advantages of insulin pump therapy is
the increased flexibility it offers relative to food choice
The Temp Basal (Temporary Basal Rate) and meal timing. Carbohydrate counting by estimating
grams gives the pumper freedom in food choices and
Feature is used to temporarily increase or decrease the
portion sizes. Choosing a bolus to best match the food
basal rate in 1/2 hour increments from 30 minutes to
being eaten requires the ability to look at the food and
24 hours.
estimate its carbohydrate content. Patients who have been
counting carbohydrates prior to insulin pump therapy
Bolus Calculation (Insulin to
need to understand the differences between carbohydrate
Carbohydrate Ratio)
counting with injection and insulin pump therapy.
There are three methods of calculating an insulin to In multiple daily injection therapy long acting insulin
carbohydrate ratio: (1) 2.8 multiplied by body weight (in works slowly and may “peak” throughout the day. In
pounds) divided by total daily dose is equal to units of contrast, with insulin pump therapy, there is no longer-
insulin per grams of carbohydrate; (2) 14 or 500 divided by acting insulin covering any of the food that is eaten.
current pump total daily dose is equal to units of insulin Whenever carbohydrate containing foods are eaten, a
per grams of carbohydrate; and (3) oral third method is to bolus must be given to cover the carbohydrates.
use a food diary taken over 3–5 days, which might include
a weekend. The dietician can then calculate the average Carbohydrate Foods
total daily carbohydrate intake from this information. Insulin participates in the metabolic processes involving
The average total daily carbohydrate in grams is then all macronutrients, i.e. carbohydrate, proteins and fats.
divided by the total daily amount of food bolus insulin. However, the maximum impact on the blood glucose
The resulting figure will give the grams of carbohydrate is produced by carbohydrate foods and insulin dose is
which will be matched by 1 unit of insulin. Example such primarily determined by the carbohydrate intake. Hence,
as if the patient’s average total daily carbohydrate intake the bolus dosage in insulin pump therapy are calculated
is 170 g and the total daily bolus insulin is 10 units: 170 on the basis of carbohydrate intake. Carbohydrates also
divided by 10 is equal to 17, i.e. 17 grams of carbohydrate provide more than 50–60% of the calories and hence need
will be approximately matched by 1 unit of insulin. All to be accounted in pump therapy.
pump calculations are approximate and will need to be It is important to appreciate that although all
tailored to the individual patient’s needs over time carbohydrates are created equal, there are differences
(Table 39.3). amongst them. The differences are primarily due to
604 Management

Table 39.4: Carbohydrate-rich foods to be included in carb counting Carb Counting Based on Nutrition Facts
Polysaccharides This is a more accurate method than the exchange system.
• Cereals and Pulses (Wheat bread, rice, millets, corn, dhals,
These tables are easily available on the internet.24,42 If the
lentils)
• Vegetable (B group) Onion, Carrots, Peas, Beet root nutrition fact labels are used, it is important to subtract the
Disaccharides and monosaccharides fiber content from the total carbohydrates, although less
• Milk, yoghurt and other milk products than 5 g fiber in total serving consumed need not enter in
• Fruits, fruit juice, honey, syrup the calculation. It is important to note the fat and protein
section

content as well, as a high fat or protein content influences

8

different glycemic index of these foods. The main source the glycemic response to carbohydrate. The most common
of carbohydrate is starch (polysaccharide) contained error is to ignore the serving size on the label; it may not be
in cereals and pulses. Fruits provide direct sugar in the same as the serving size ingested by the patient.
The bolus calculations also require the following facts
form of fructose or glucose. Fiber contained in cereals
to be borne in mind:
and pulses is also a form of carbohydrate, but it is not
assimilable. Hence, while calculating carb content of a Glycemic index: Although the carb count of a high glycemic
food, amount of fiber is subtracted. Starchy vegetables index food like syrup or white bread or polished rice is
of group B (carrots, onions, peas, beet root) also contain treated with similar insulin doses as that from complex
significant amount of carbohydrates. Other important carbohydrate foods (whole wheat, pulses), there are some
source of carbohydrate is milk and dairy products, which important differences. The bolus wave used for simple
contain lactose, a disaccharide. Rarely, a diabetic on sugars should be regular type and at times, if a patient
pump therapy can indulge in a dessert containing sugar finds uncontrolled post-prandial hyperglycemia in spite of
or partake of honey or syrup, which contain simple sugars a brisk insulin bolus following ingestion of high glycemic
(mono or disaccharide) (Table 39.4). index food, such foods will need to be consumed in small
amounts or omitted. The concept of glycemic load is also
important, as a small amount of high glycemic index (GI)
Carb Counting41
food may be well tolerated.
Basically two methods are used to count carbohydrates.
Carb counting based on exchange system: The first method Effect of Dietary Protein and Fat on Insulin Bolus
is based on exchange system, where foods of similar A large amount of protein or fat in the diet influences
macronutrient composition are clubbed together, thus the glycemic response produced by carbohydrates. The
permitting exchangeability. For example, one exchange proteins and fats in gross excess of their usual proportion
portion of cereal or bread unit is equal to 15 g carbohydrate. (15% and 30% of total calories respectively) will slow the
As large amounts of pulses are used in diet in developing gastric emptying, thus causing lower glycemic response
countries, it is important to note that 1 unit of a pulse-food for about 2 hours following such meal. However, there is
provides 13 g carbohydrate (it provides 2 g of extra protein possibility of a heightened glycemic response at 4–6 hours
as compared to cereals). postmeal in this situation. A larger proportion of fat also
It is easy to remember that 1 unit of cereal (bread) confers a state of increased insulin resistance postmeal.
exchange is equal to a 30 g ready chapatti or 1 vati (120 mL) The insulin bolus for such meal should be a square wave
cooked rice or dhal or a 20 g whole wheat bread slice. bolus, extending for about 4–5 hours. This can be either
Similarly, common fruit exchanges can be remembered: achieved by a long square wave bolus or two such boluses
1 orange or 1 small apple or 1 elaichi banana or 100 g 3 hours apart. In pumps which are not versatile to deliver
papaya, each of them providing 10 g carbohydrates. such boluses, the basal rate can be increased by about
The starchy vegetable group (Group B in American 25% at 2–6 hours post-meal. Boluses for such unusual
Diabetes Association’s exchange list) also provides 10 g meals can be perfected by monitoring blood glucose at
carbohydrates. One glass (8oz, 125 mL) of milk provides 2, 4, 6 and 8 hours after the meal.
12 g carbohydrates. Many pump users find this method
of carb counting easy. However, it is not as accurate as
Effect of Alcohol on Insulin Bolus Dose
the method based on nutrition facts. To make it simpler,
a list of foods has been provided from which each item Alcohol is allowed in moderation to most diabetics. The
yields 15 g carbohydrates. amount permitted in 45 mL of distilled spirit (whiskey,
 Insulin Pump Therapy 605

vodka, rum) or 120 mL of wine or 250 mL of regular beer produce a calculation. However the resulting figure will be
in females and double this amount in males. However, in mg/dL.
the moderate amount of alcohol can produce nocturnal The patient will be given initial insulin pump para­
hypoglycemia by inhibiting gluconeogenesis in the liver. meters by the diabetes team but must be taught how to:
For this reason, a reduction in nocturnal basal rate is • Set the basal rate
advisable. Some beverages contain high carbohydrate, • Determine a meal bolus using their insulin to
for example ale, regular beer, non-alcoholic beer and carbohydrate ratio

chapter
liqueurs. However, a higher bolus insulin is not usually • Determine a correction bolus using the insulin sen­

39
advised while consuming these beverages, as alcohol- sitivity ratio.
induced hypoglycemia is likely. Insulin sensitivity factor (ISF) or correction bolus
In real life situation, the guidelines regarding bolus • Sensitivity factor: 1,700 rule
calculations make the starting point of pump therapy. • Correction dose formula
The individual response may vary considerably and most (Current BG – Target BG) + ISF = Correction dose
pump users come to recognize the differences. Frequent Example:
monitoring is the key to fine-tuning of bolus doses. Current BG = 200 mg/dL Target BG =100 mg/dL
(200 – 100) ÷ 45 = 2.2 units (correction dose)
Although it appears laborious to do carb counting, but
using these methods for a 3–6-month period the pump
users develop capability to utilize this knowledge to their
BOLUS WIZARD® CALCULATOR
great advantage. The Bolus Wizard® calculator is an optional feature of the
pump that is designed to simplify meal and correction
MEAL BOLUS OPTIONS bolus dosing. Using information such as an individual’s
predetermined insulin sensitivity factor, blood glucose
Normal Bolus: A meal bolus that is delivered at one time
levels and previous bolus insulin when applicable, the
as soon as the bolus is activated. This bolus is commonly
Bolus Wizard® calculator calculates suggested bolus doses
used for meals with normal or low fat content that are
of insulin. The patient does BG test with their usual meter
eaten over a short period of time.
and then manually enters the result into the pump to be
Square Wave Bolus®: A meal bolus that is given over used by the Bolus Wizard® calculator. The Bolus Wizard®
a 30 minutes to an 8 hours period of time in 1/2 hour calculator provides an advantage to the patient by using
increments. This bolus is often recommended for meals preset information which is stored in the pump’s memory
that contain significant fat content or meals that will be to calculate bolus dose. The patient can use this feature to
eaten over a long period of time, such as at a formal dinner set a meal bolus, correct high BG or do both at the same
party or a prolonged buffet. People with gastro paresis use time. The bolus calculation uses conservative estimation
this bolus frequently to match their slow gastric emptying. based on preset target BG, carbohydrate ratio, insulin
Dual Wave Bolus®: A meal bolus that is divided to give sensitivity and active insulin from previous bolus doses.
some of the insulin as a normal bolus and some as a The Bolus Wizard® calculator can accommodate for
square wave bolus. This bolus is used for meals that a patient’s different insulin to carbohydrate ratios and
contain carbohydrates and also have a moderate to high different insulin sensitivities throughout the day or night
fat content, such as pasta with a creamy sauce, rich curries by allowing them to set up to eight different settings for
or pizza. each.
The Bolus Wizard® calculator provides the patient with
Correction Bolus a series of advantages over traditional ways of using and
setting a bolus:
There are several suggested formulae for calculating the • Clinical advantage
insulin sensitivity which are shown below. All of them are –– More accurate dosing
approximate and will require adjustment over time. –– Tracks active insulin
The 1,700 rule for analog insulin is based on work –– Records data for therapy evaluation
done using the continuous glucose monitoring system –– Reduces hypoglycemia due to stacking
(CGMS). 1,700 is divided by the pump total daily dose to –– Prevents stacking of insulin doses
606 Management

• Ease of use Table 39.5: Bolus Wizard® calculator28

–– Instead of doing complicated math with a calculator Example settings Example of dose calculation
or in their head, at the touch of a few buttons
Wizard: On Estimate details
and using preset information, the Bolus Wizard® Carbohydrate units: Grams Estimate total: 3.0 units
calculator does the calculation. Carbohydrate ratios: 12 Food intake: 24 grams
–– The Bolus Wizard® calculator is a great advantage, Sensitivity: 42 BG: 220 mg/dL
providing individualized calculations to optimize BG target: 100–110 Food: 2.0 units
section

pump therapy. Correction: 2.6 units

Active insulin: 1.6
8

Bolus Wizard® Calculator Settings 2.0 units (food bolus)

+ 1.0 unit (suggested correction)
Once the Bolus Wizard® calculator is programmed, all the 3.0 units estimated bolus
patient needs to do is enter his or her current BG and the 24 grams
number of grams of carbohydrate to be consumed. The ÷ 12 (carbohydrate ratio)
Bolus Wizard® calculator will do the math and provide 2.0 units (food bolus)
a suggested insulin dose based on the patient’s BG, 220
carbohydrates and individual preset parameters. – 110 (target BG)
2.6 units
Determine Active Insulin Time 2.6 units (correction)
– 1.6 units (active)
Suggested settings for active insulin time: 1.0 unit (suggested correction)
• Adults: 4–5 hours Active insulin time: 5 hours
• Children: 4–5 hours
(BG: Blood glucose)
• Pregnancy: 3–4 hours
The Bolus Wizard® calculator tracks how much active
insulin remains from previous boluses. • If the current BG is lower than the target BG, the
correction bolus portion of the estimate will reduce the
How the Bolus Wizard® Calculator Works total estimate.
Important points for Bolus Wizard® (Table 39.5) • If a Dual Wave bolus is less than the estimate due to the
maximum bolus limit or user change, the square (sq)
Estimated Bolus Wizard® calculator dose portion is reduced first.
= Meal dose + (Correction dose – active insulin)
• Active insulin is only subtracted from correction insulin
PREVENTION OF ACUTE PROBLEM
• Active insulin is never subtracted from food insulin
• A correction dose is not calculated if the patient’s BG All insulin delivery involves a potential risk of hypo­
falls within the target range. glycemia, hyperglycemia and undetected hyperglycemia
leading to DKA. These risks can be minimized with good
Active Insulin glycemic control and frequent BG monitoring. It is very
Active insulin is estimated based on the timing of previous important that you discuss these risks with your patients
bolus insulin and insulin type. Four to six hours after a and review prevention guidelines and treatment protocols.
bolus, the majority of insulin has been absorbed, but a Ensure that pump users are given written guidelines for
very small amount is active for a few more hours. Based on treating hypoglycemia and hyperglycemia, which should
preset information, the Bolus Wizard® calculator calculates include a treatment protocol for high BG level.
this and subtracts the appropriate amount from its’ The best prevention against hypoglycemia and hyper­
final recommendation. The details will appear in the “esti­ glycemia and DKA is regular BG testing. By monitoring
mate details” screen during the bolus programming steps. BG levels a minimum of 4–6 times a day, and modifying
• Active insulin only reduces the correction bolus treatment accordingly serious problems can be avoided.
portion of the estimate, not the food portion. It is important to make sure the patient understands his
• If the active insulin is more than the correction bolus or her individual target BG levels that have been set by the
estimate, the correction portion of the estimate will be diabetes team and takes appropriate action when BG is
changed to zero (0). not within the suggested target range.
 Insulin Pump Therapy 607

Hypoglycemia • Monitor BG before, during and after exercise and make

appropriate adjustments in food and insulin as needed.
Hypoglycemia is present when the BG drops below
• Minimize boluses administered at bedtime and after
approximately 70 mg/dL. Hypoglycemia occurs when
exercise.
there is not enough food, too much insulin, stress hormone
• Confirm accuracy of basal rate, insulin to carbohydrate
release or increase in the usual level of activity. The goal of
ratio and insulin sensitivity factor. If hypoglycemia
treating hypoglycemia is to prevent loss of consciousness
persists, patient should be advised to contact the

chapter
and potential shock. Most pump users experience less
doctor immediately. Refer to the fine-tuning exercises

39
episodes of hypoglycemia than when using injections.
found in the insulin pump therapy workbook.
When hypoglycemia does occur the symptoms are often
• Make sure that the pump is set correctly. Check the
more subtle and less unpleasant. This is, in part, due to
time of day and all basal rate settings.
the reduction in intense blood glucose swings. The patient
• The auto off safety feature can be set to alert if a pump
needs to know how to recognize and treat hypoglycemia
button has not been pressed for a certain number of
and must be prepared to treat episodes whenever and
hours.
wherever they occur. Patients on pump therapy should
use glucose tablets or other food containing 100% simple, Hypoglycemia treatment suggestions for pump
fast acting sugar to treat hypoglycemia. These foods act fast patients:
because they do not need to be broken down into simpler • Carry fast acting carbohydrate with you at all times to
sugar like other types of carbohydrate. Fat containing treat hypoglycemia
foods such as chocolate are best avoided when treating • Follow the rule of 15, if BG is 70 mg/dL or below
hypoglycemia as the fat may slowdown the absorption –– Take 15 g of fast acting carbohydrate immediately
of the sugar. This will prolong hypoglycemia as the blood –– Check BG in 15 minutes
sugar level will not rise quickly. If not above 70 mg/dL, repeat treatment and check BG
in another 15 minutes.
Hypoglycemia Prevention • The following contain 15 g of carbohydrate:
–– Three to four glucose tablets depending on the
Suggestions for pump patients:
brand. Check the food value label for an accurate
• Monitor BG levels a minimum of 4–6 times a day.
• Always test BG before bedtime. BG of more than amount
100 mg/dL is recommended. –– 100 mL or 4 oz of fruit juice, or any non-diet drink
• Always test BG before driving and do not drive if below of fruit juice
100 mg/dL. –– One tablespoon table sugar or honey
• If drinking alcohol, monitor BG often and never drink –– Hospitalization is required if hypoglycemia
alcohol without consuming carbohydrate containing persists.
food.
• Set appropriate BG target goals. Remember to take Hyperglycemia
into account age and hypoglycemia awareness when Hyperglycemia is present when the BG is higher than
setting these targets. target and especially if above 250 mg/dL. Blood glucose
• Become familiar with the use of glucose tablets. The
can rise from several causes including illness, too much
pump user should always carry glucose tablets or
food, not enough insulin, stress hormone release, decrease
equivalent with him. Glucose tablets are convenient as
in the usual level of activity and not receiving insulin from
packets can be kept at home, work or in the car.
the pump. The goal of treating hyperglycemia is to prevent
• Wear an ID bracelet or necklace such as Medic-Alert.
Ensure it is updated to reflect pump usage. An ID card DKA and delay or prevent diabetes complications due to
should also be carried. persistent high BG levels. One of the greatest benefits of
• Call doctor if hypoglycemic events occur. insulin pump therapy is that it allows patients to easily
• Discuss raising the target BG goals with the Diabetes correct for high BG levels. By testing BG and taking a
Team if there is a history of severe hypoglycemia or correction bolus as prescribed, the BG can be brought
hypoglycemic unawareness. back into target range.
608 Management

Hyperglycemia Prevention if they are present contact your doctor for advice as
extra insulin may be needed.
Suggestions for pump patients:
–– Change the reservoir and infusion set completely.
• Monitor BG levels a minimum of 4–6 times a day and
Position the infusion set away from the old site.
always correct high blood glucose.
–– Troubleshoot the pump. During working hours the
• Whenever eating carbohydrate foods, always take a
patient may be advised to call the local technical
bolus to cover the carbohydrate content of the food.
officer.
section

• Confirm accuracy of basal rate, insulin to carbohydrate

–– Patient should be advised to drink 150–200 mL
ratio and insulin sensitivity factor. If hyperglycemia
8

sugar free fluids every 30 minutes (e.g. water or

persists, contact your doctor.
sugar free squash), if unable to drink.
• Make sure that the pump is set correctly. Check the
–– Check BG level and ketones every hour and
time of day and all basal rate settings.
continue to take correction insulin with a syringe
• Change the reservoir and infusion set as per recom­
or insulin pen as directed. If ketones are not
mendation.
decreasing, contact your doctor.
Hyperglycemia treatment suggestions for pump
–– If BG is less than 200 mg/dL and ketones are still
patients:
present, correction insulin may still be indicated.
• If the BG is over 250 mg/dL, the following steps must
Patient should advise to contact your doctor for
be taken:
individual advice.
–– Take a correction bolus via the pump immediately.
–– Recheck BG in 1 hour. If the BG has remained the Suggestions for Troubleshooting
same or is not falling, take an injection via syringe
or pump at once and not through the pump. Most • When treating hyperglycemia or DKA, always change
pumpers use their correction formula to determine the reservoir and infusion set. There may be a partial
the amount needed. occlusion in the tubing preventing the correct amount
–– Change the reservoir and infusion set completely. of insulin from being delivered. The infusion set may be
Position the infusion set away from the old site. crimped or have come out of the subcutaneous tissue.
–– Troubleshoot the pump. During working hours the • Use a different site using site rotation guidelines as
patient may be advised to call the local technical recommended. Check if the site has been overused
officer. and is not absorbing insulin efficiently. Look for signs
–– Recheck BG in another hour. If BG is still not coming of infection at the old site.
down, check for ketones and contact your doctor. • Check the infusion set tubing for bubbles.
–– It is imperative that the patient aggressively treats • Check the infusion set connections to make sure that
hyperglycemia to prevent DKA. they are not loose which can result in insulin leakage.
• Consider using a new bottle of insulin if hyperglycemia
Diabetic Ketoacidosis persists. There may be a loss of insulin potency from
degradation overtime.
Diabetic ketoacidosis is a serious medical condition
• Troubleshoot the pump. During working hours the
that results from untreated hyperglycemia. DKA needs
patient may be advised to call the local technical officer
immediate treatment. Since insulin pump therapy uses
for assistance.
only fast acting insulin, DKA can occur rapidly because
there is no longer-acting insulin in the body as back-up. Note: “These are general guidelines. Impress on your
patients the seriousness of DKA and tell them they must
Preventing and Treating DKA call their doctor for specific advice if DKA is suspected”.
Suggestions for Pump Patients
Illness
• If nausea or vomiting is present, immediately check BG
and ketones. Illness and infection put extra stress on the body, often
• If BG is above 250 mg/dL or if ketones are present: causing a rise in BG. It left untreated, hyperglycemia from
–– Immediately take an injection via syringe or insulin illness can quickly lead to DKA. Hyperglycemia during
pen and not through the pump. Check for ketones: illness is easily prevented by increasing oral fluid intake,
 Insulin Pump Therapy 609

adjustments to insulin pump doses and more frequent • Management of nutrition (carbohydrate counting or
BG monitoring. Illness is manageable with diabetes if estimation)
treatment guidelines are understood and necessary • Principles of basal or bolus therapy (including
supplies are available. It is important to teach your patient circadian variation of insulin sensitivity)
to prepare for sick-days by having necessary supplies • Insulin kinetics and self-management of insulin dosage
available at all times especially when travelling. • Preventing, detecting and treating of hypoglycemia
If high blood glucose persists during illness, the and hyperglycemia

chapter
doctor may recommend setting a temporary basal rate • Adjusting insulin in relation to physical activity and

39
on the pump to deliver more insulin per hour. Setting exercise
an increased basal rate requires extra blood glucose • Management of sick-days
monitoring to detect potential hypoglycemia. Increased • Integrating CSII in everyday life (i.e. day-care, school,
or frequent bolus doses can also be given to maintain parenting, independence in diabetes care).
BG control. The goal of insulin treatment during illness
is to keep BG within target range and for ketones to be LIMITATIONS OF PUMP THERAPY
negative.
Diabetic ketoacidosis is a concern in patients using insulin
pump therapy. In the event of a pump malfunction,
Suggestions for Pump Patients during Illness
infusion set occlusion, catheter dislodgement, battery
• Check BG and ketones every 2 hours during the day failure, or depleted insulin supply, insulin delivery will
and frequently at night. halt, and hyperglycemia will ensue. Because there is no
• Keep accurate records of BG, ketones, medications, long-acting insulin on board, individuals are susceptible
temperature and all symptoms. to DKA and need to be vigilant with routine daily testing
• Take prompt correction boluses for blood glucose over and procedures for high BG management in the event of
250 mg/dL as directed by the Doctor. hyperglycemia and ketosis. In the past, frequent episodes
• Drink sugar-free liquids to prevent dehydration. Some of DKA were more common with pumps compared with
doctors recommend drinking at least 150–200 mL insulin injections;14 however, recent studies report no
every hour if no ketones are present and every half increase in episodes of DKA with patients using pump
hour if ketones are present. therapy.8,14,16 This is likely due to improved patient
• Extra insulin and fluids are needed if ketones are education on using the pump and added features on
present, even if glucose levels are in target range. newer pump models, such as alarms for low battery, low
• Contact your doctor for nausea or vomiting. insulin, or occlusion of delivery. Infection at the cannula
insertion site is another possible concern with continuous
TRAINING FOR INSULIN PUMP USER subcutaneous insulin infusion and is a common cause
Training and education is very essential for significant for discontinuation of pump therapy. Staphylococcus or
outcome of insulin pump therapy. Depending on their Streptococcus species is usually the infecting organism,
cognitive development, diabetic patients should be warranting treatment with a course of oral antibiotic
involved in educational training of insulin pump therapy. therapy immediately. Pump wearers should pay particular
Long-term care for children and adolescent should attention to the insertion site, especially when blood
be delivered including knowledge and experience of glucose levels are elevated, and should receive instruction
technical aspects, correct dosing, and the practical aspect about assessment of infection before pump initiation. A
of implementing the pump therapy in everyday situations, third concern and possible deterrent from insulin pump
as well as continuous follow-up education for the family. initiation is the risk of weight gain.13,14,16 The weight gain
Following parameters should be included for the results from improved glycemic control and can be as
educational program on insulin pump therapy: much as five pounds within the first month. This gain
• Introduction to pump may be welcomed by some individuals. Improvement
• Skills training in pump-related technical abilities in BG control helps to compensate for these potential
• Selection and management of a catheter problems.8,11
610 Management

FUTURE of INSULIN PUMP THERAPY 2. Insulin Pump Therapy: Guidelines for Successful Outcomes
American Association of Diabetes Educators 2008 Consen­
Frequent self-monitoring of blood glucose (SMBG) sus Summit. Chicago, Illinois; 2008.
remains the foundation of optimized insulin therapy, 3. Sunil Jain. How to get most out of your pump including
carbohydrates counting. Bhopal, India: Manjul Publication
and CGM is gaining prominence in optimized CSII.
House (P) Ltd; 2008.
This paradigm shift is occurring primarily because CGM 4. Wu YP, Graves MM, Roberts MC, et al. Is insulin pump
can offer enhanced insight into glycemic patterns and therapy better than injection for adolescents with diabetes?
section

variations. SMBG captures a patient’s glucose level Diab Res Clin Prac. 2010;89:121-5.
precisely at a moment in time, much like a photograph, 5. American Diabetes Association. (year). Insulin pumps.
8

[online] ADA website. Available from http://www.diabetes.

while CGM can be compared to closed-circuit television.
org/living-with-diabetes/treatment-and-care/medication/
Measuring interstitial fluid (ISF) glucose levels with CGM insulin/insulin-pumps.html [Accessed September, 2013].
may yield values not directly comparable with SMBG
owing to lag time.43 However, CGM can enable the patient REFERENCES
and the healthcare team to make therapy adjustments to
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to diabetic patient who are on different treatment. Pump
Diab Res Clin Prac. 2010;89:121-5.
users may find CGM particularly beneficial by using the 2. Pickup JC, Keen H, Parsons JA, et al. Continuous subcuta­
data to support their diabetes management in real time.44 neous insulin infusion: an approach to achieving normo­

Continuous glucose monitoring technology has glycaemia. Br Med J. 1978;1:204-7.
improved significantly over the last decade, and research 3. Pickup J, Keen H. Continuous Subcutaneous Insulin
Infusion at 25 years: evidence base for the expanding use
continues to develop its full potential. According to the of insulin pump therapy in type 1 diabetes. Diabetes Care.
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2007;25:50-6.
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5. Triantafillos D, Fotios I. Insulin pump therapy in adults.
closed-loop system may be achieved with implantable Diab Res Clin Prac. 2011;93:S109-13.
sensors, but the technology is still under development. 6. Lenhard MJ, Reeves GD. Continuous subcutaneous insulin
A true “closed-loop” or artificial pancreas does not infusion: a comprehensive review of insulin pump therapy.
appear to be imminent but research and development Arch Intern Med. 2001;161:2293-300.
7. Torrance T, Franklin V, Greene S. Insulin pumps: a growing
efforts are underway. Trials of CGM and pump systems option in the UK for children and young adults with type 1
sophisticated enough to control glucose levels overnight diabetes. Arch Dis Child. 2003;88:949-53.
automatically, without patient intervention, may bear fruit 8. Zeitzoff L. A comprehensive review of insulin pump
within the next 10 years. Until approved by the US Food therapy for the nurse practitioner. J Nur Prac. 2005;1:201-6.
and Drug Administration (FDA) to replace SMBG, CGM 9. Diabetes Mall: health through information. (year). Com­
parison of current insulin pumps. [online] Diabetesnet
devices should be used to complement SMBG, not as a website. Available from www.diabetesnet.com/diabetes_
substitute for SMBG. technology/insulin_pump_models.php [Accessed Septem­
ber, 2013].
Acknowledgment 10. Walsh J, Roberts R. Pumping Insulin. San Diego, CA: Torrey
Pines Press; 2000.
The author is grateful to Ms Sonal V Modi for contributing 11. Skyler J. The Insulin Pump Therapy Book. Los Angeles,
part of the chapter subtitled “Carbohydrate foods, Carb Calif: MiniMed® Technologies; 1995.
12. Bode BW, Tamborlane WV, Davidson PC. Insulin pump
counting, Effect of dietary Protein, Fat and Alcohol on therapy in the 21st century. Strategies for successful use in
Insulin Bolus”. adults, adolescents, and children with diabetes. Postgrad
Med. 2002;111:69-77.
further reading 13. Boland EA, Ahern J, Grey M. A primer on the use of insu­
lin pump therapy in adolescents. Diabetes Educ. 1998;24:
1. Garg S, Zisser H, Schwartz S, et al. Improvement in glyce­ 78-86.
mic excursions with a transcutaneous, real-time continu­ 14. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R.
ous glucose sensor: a randomized controlled trial. Diabetes Insulin pump therapy. A meta-analysis. Diabetes Care.
Care. 2006;29:44-50. 2003;26:1079-87.
 Insulin Pump Therapy 611

15. Weintrob N, Benzaquen H, Galatzer A, et al. Comparison 31. Chantelau E, Schiffers T, Schutze J, et al. Effect of patient
of continuous subcutaneous insulin infusion and multiple selected intensive insulin therapy on quality of life. Patient
daily injection regimens in children with type 1 diabetes: Edu Couns. 1997;30:167-73.
a randomized open crossover trial. Pediatrics. 2003;112: 32. Boland EA, Grey M, Oesterle A, et al. A new way to lower
559-64. risk of severe hypoglycemia, improve metabolic control
16. DiMeglio LA, Pottorff TM, Boyd SR, et al. A randomized, and enhance coping in adolescents with type 1 diabetes.
controlled study of insulin pump therapy in diabetic Diabetes Care. 1999;22:1779-84.
preschoolers. J Pediatr. 2004;145:380-4. 33. Feldt-Rasmussen B, Mathiesen ER, Jensen T, et al. Effect of

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17. Kesavadev J. Continuous insulin infusion systems in type 2 improved metabolic control on loss of kidney function in

39
diabetes. J Assoc Physicians India. 2011;59:41-3. Type 1 (insulin dependent) diabetic patient: an update of
18. Insulin Pump Therapy: Guidelines for Successful Outcomes the steno studies. Diabetologia. 1991;24:164-70.
American Association of Diabetes Educators 2008 Consen­ 34. Diabetes Control and Complications Trial Research Group.
sus Summit. Chicago, Illinois; 2008. The effect of intensive treatment of diabetes on the devel­
19. American Diabetes Association. (year). Insulin pumps. opment and progression of long-term complication in
[online] ADA website. Available from http://www.diabetes. insulin-dependent diabetes mellitus. N Engl J Med. 1993;
org/living-with-diabetes/treatment-and-care/medication/ 329:977-86.
insulin/insulin-pumps.html [Accessed September, 2013]. 35. Pietri A, Ehle AL, Raskin P. Changes in nerve conduction
20. American Association of Diabetes Educators. Education for velocity after six weeks of glucoregulation with portable
continuous subcutaneous insulin infusion pumps users. insulin infusion pumps. Diabetes. 1980;29:668-71.
36. Schmitz O, Sorensen S, Alberti K, et al. Metabolic control in
Diabetes Educ. 2003;29:97-9.
newly transplanted insulin-dependent diabetes: improve­
21. Petrovski G, Dimitrovski C, Milenkovic T. Insulin pump
ment by insulin pump treatment (CSII). J Diabet Complica­
therapy with continuous glucose monitoring improves
tions. 1987;1:81-6.
metabolic control in brittle type 1 diabetes. Prilozi. 2007;28:
37. Health Professional’s guide to insulin pump therapy.
129-35.
[online] Available from http://www.diabetesclinic.ca/
22. Litton J, Rice A, Friedman N, et al. Insulin pump therapy
en/diab/5pumps/profguide_instherapy.pdf [Accessed
in toddlers and preschool children with type 1 diabetes.
September, 2013].
J Pediatr. 2002;141:490-5.
38. Adjusting your basal rates on insulin pumps.https://www.
23. Sunil Jain. How to get most out of your pump including
childrensmercy.org/library/uploadedFiles/childrensmer­
carbohydrates counting. Bhopal, India: Manjul Publication
cyorg/Clinics_and_Services/Clinics_and_Departments/
House (P) Ltd; 2008.
Endocrinology_and_Diabetes/Diabetes_Team/Adjust­
24. Graff MR, Rubin RR, Walker EA. How specialists treat their ing%20Your%20Basal%20Rates%20on%20Insulin%20
own diabetes: Findings from a study of the AADE and ADA Pumps4.pdf
membership. Diabetes Educ. 2000;26:460-7. 39. Diabetes Health: Investigate, Inform, Inspire. (year). Adjust­
25. Bode BW, Gross T, Steed D, et al. A recent assessment of ing Basal Rates and Bolus Doses. [online] Diabeteshealth
continuation rates for continuous subcutaneous insulin website. Available from http://www.diabeteshealth.com/
infusion (CSII). Diabetes. 1998;47:392. read/2002/12/01/3055/adjusting-basal-rates-and-bolus-
26. Wredling R, Hannerz L, Johansson UB. Variability of blood doses/ [Accessed September, 2013].
glucose levels in patients treated with continuous subcu­ 40. Insulin pump adjustments basal rate testing. [online] Avail­
taneous insulin infusion: a pilot study. Prac Diab. 1997; able from http://boulderendo.com/pdffiles/basalrate.pdf
14:5-8. [Accessed September, 2013].
27. Barbosa J, Menth L, Eaton J, et al. Long-term ambulatory, 41. Warshew HS, Kulkarni K. Complete guide to carb counting.
subcutaneous insulin infusion versus multiple daily injec­ Alexandria, VA: American Diabetes Association; 2001.
tions in brittle diabetic patients. Diab Care. 1981;4:269-74. 42. Diabetes Education Online (UCSF). (year). Counting
28. Anbar University College of Medicine. Insulin Pump Thera­ Carbohydrates. [online] UCSF website. Available from
py 2012. http://amc-iq.com/uploads/insulin%20pump.pdf http://dtc.ucsf.edu/living-with-diabetes/diet-and-nutri­
29. Bode BW. Pumping Protocol: a guide to insulin pump tion/understanding-carbohydrates/counting-carbohy­
therapy initiation (Medtronic). Northridge, CA: Medtronic drates/ [Accessed September, 2013].
Diabetes; 2008. [http://www.professional.medtronicdiabe­ 43. Wentholt IM, Hart AA, Hoekstra JB, et al. How to assess and
tes.com/sfc/servlet.shepherd/version/download/068C000 compare the accuracy of continuous glucose monitors?
0000IptI] Diabetes Technol Ther. 2008;10:57-68.
30. Bode BW, Steed RD, Davidson PC. Reduction in severe 44. Garg S, Zisser H, Schwartz S, et al. Improvement in glyce­
hypoglycemia with long-term continuous subcutaneous mic excursions with a transcutaneous, real-time continu­
insulin infusion in type 1 diabetes. Diabetes Care. 1996;19: ous glucose sensor: a randomized controlled trial. Diabetes
324-7. Care. 2006;29:44-50.
 Chapter 40
Glycemic Management in
Hospitalized Patients
Shaival H Chandalia

Glycemic Management in Hospitalized Patients

Chapter Outline
♦♦ Hyperglycemia in Hospitalized Patients: Need for ♦♦ Blood Glucose Targets in Hospitalized Patients
Treatment ♦♦ Strategies to achieve Blood Glucose Targets
♦♦ Insulin versus Oral Agents in Hospitalized Diabetics
♦♦ Clinical Trial Evidence

INTRODUCTION is discharged. The two conditions can be differentiated

by doing glyca­ted hemoglobin (HbA1c) test. Stress hyper­
Hyperglycemia is a very common disorder seen in 12–15% glycemia may be associated with a poorer prognosis
of hospitalized patients.1 The glycemic targets to be achi­ because it pro­ bably represents a condition of greater
eved, the complications associated with uncontrolled gravity causing decompensation in a normal individual.
hyperglycemia and the management of hyperglycemia The reason hyperglycemia requires intensive treat­
in hospitals presents certain unique features. As opposed ment is because it is associated with poorer outcomes.
to the management of diabetes in the outpatient setting Hyperglycemia has a number of adverse effects on various
the targets and strategies are different in hospi­ talized organ systems, namely the immunological system, the
patients. heart and the brain. Also, hyperglycemia, specifically
a plasma glucose more than 180 mg/dL is associated
HYPERGLYCEMIA IN HOSPITALIZED with glycosuria. Thus, a blood glucose (BG) above
PATIENTS: NEED FOR TREATMENT 180–200 mg/dL is associated with a loss of water and
electrolytes in the urine. The ensuing dehydration and
Hyperglycemia in hospitalized patients can be classified
electrolyte loss is adverse to the metabolic milieu of the
into the following categories:
body. This also gives an insight into the glycemic target to
• Hyperglycemia in a known diabetic,
be achieved in hospitalized patients. As a starting point,
• Hyperglycemia in an undetected diabetic and
this is a conve­nient and rational figure.
• Stress hyperglycemia.
Stress hyperglycemia is seen in normal individuals
Hyperglycemia and the Immunological System
who decompensate during hospitalization and return to
normal post-discharge when the underlying stress is The link between hyperglycemia and the immunological
relieved. On the other hand, hyperglycemia in an unde­ system has focused on the granulocyte. Bagdade et al.
tected diabetic does not settle to normal when the patient first demonstrated that granulocyte function improved as
 Glycemic Management in Hospitalized Patients 613

the fasting BG was reduced from 293 ± 20 mg/dL to 198 pathway. In a number of in vitro studies, an inflammatory
± 29 mg/dL in ten diabetic patients.2 Numerous defects response to acute hyperglycemia is seen.25-27 This is
have been subsequently demonstrated in various facets confirmed by in-vivo studies. Elevation of glucose to
of phagocyte function like adherence to the endothelium, 270 mg/dL for 5 hours increases interleukin (IL)-6, IL-8
chemotaxis, phagocytosis and bacterial killing by and tumor necrosis factors (TNF) alpha.28 Also the ubiqui­
respiratory burst.3-12 We are familiar with various molecular tous proinflammatory transcription factor nuclear factor
pathways mediating the complications of diabetes, viz. (NF)-kappa B is activated by acute in-vivo hyperglycemia

chapter
aldose reductase pathway, protein kinase pathyway, above 180 mg/dL.29

40
advanced glycation end products (AGE) path­ way and
reactive oxygen species pathway. The same pathways have Hyperglycemia and the Neurological System
been implicated in the neutro­phil dysfunction seen with Acute hyperglycemia is associated with increased neu­
hyperglycemia.13-14 Sato et al. showed that hyperglycemia ronal death following induced brain ischemia.30-33 The
is associated with reduced superoxide production in ischemic penumbra of the brain is susceptible to injury
neutrophils.15 Reduced super­oxide production has been from hyperglycemia.34,35 This seems to be medi­ated by
correlated with phagocyte dysfunction. tissue acidosis and increased lactate levels, consequences
Immunological dysfunction has clearly focused on the of acute hyperglycemia.36,37 This has been unequivocally
neutrophil. However, other components of the immuno­ demonstrated in animal models of stroke.
logical system (not only innate immunity) have also been Animal models have also shown hyperglycemia to be
implicated. Diabetic patients with hyperglycemia have associated with increased glutamate levels in the cere­
been found to have reduced T-cell populations, which bral cortex. A relationship exists between glutamate levels
are reversed on correction of BG levels.16 To summarize, and neuronal damage.38 Finally, the effects of hyper­
there is a body of data showing that diabetes and hyper­ glycemia on the coronary vasculature and poor cardio­
glycemia in general are associated with an immune vascular outcomes can be extended to the cerebral vascula­
suppressed state. Reversal of immune abnormalities is ture and poor cerebrovascular outcomes. Whether it is
seen with the correction of hyperglycemia. endothelial injury or increased IL-6 or increased oxida­
tive stress, the consequences are as deleterious for the
Hyperglycemia and the Cardiovascular System cerebrovascular system as they are for the rest of vasculature.
Whether hyperglycemia by itself is a risk factor for
Mechanistic evidence linking hyperglycemia and the
adverse outcomes, as suggested by the above evidence,
cardiovascular system has been documented. Hypergl­
or whether it is a risk marker of severity of disease in
ycemia can prevent ischemic pre-conditioning of the
hospitalized patients is a noteworthy point of debate.
heart17 and reduce coronary collateral blood flow.18 Acute
The above mechanistic evidence suggests that reducing
hyperglycemia can promote cardiac myocyte apoptosis
BG in the hospital is good. But does this mechanistic
as well.19 Hemodynamic changes like acute elevation of
evidence translate into good clinical outcomes in cont­
systolic and diastolic blood pressures with acute hyper­
rolled clinical trials? What are the BG targets that are
glycemia have been reported.20 Hyperglycemia promotes
recommended to be achieved in different hospital popula­
the development of a pro-coagulatory state by reducing
tions? How does one go about achieving these targets?
plasma fibrinolytic activity and increasing plasminogen
Does achieving good glycemic control in the hospital
activator inhibitor (PAI)-1 activity.21 Platelet hyperreactivity by insulin have any advantages over the use of other
and increased activation have also been demonstrated. treatment modalities? These are some of the issues that
Endothelial dysfunction is an important component deserve discussion.
of the effect of hyperglycemia on the cardiovascular
system. Endothelial dysfunction is measured by quanti­ INSULIN VERSUS ORAL AGENTS IN
fying endothelial dependent vasodilation in the brachial
HOSPITALIZED DIABETICS
artery. In-vivo studies have shown that acute hyper­
glycemia can cause endothelial dysfunction.22-24 Insulin, for all practical purposes, is the mainstay of anti-
The link between hyperglycemia and the cardio­ hyperglycemic therapy in the hospital. This is because
vascular system is also mediated by the inflammatory insulin therapy, whether it is three or four shots a day
614 Management

offers the convenience of great flexibility in controlling undergoing bypass surgery showed that if administered
BG. In the hospital, one often faces the situation where GIK infusions, they have shorter length of intubation and
oral intake is curtailed or is allowed in an unpredictable shorter length of stay.43 When used in the setting of acute
manner. Insulin can be titrated exquisitely, i.e. unit by unit myocardial infarction (AMI or MI), GIK infusions have
in regulating BG. The onset and offset of action is quick. been associated with improved short-term survival.39,40
Oral agents are quite unwieldy in this situation. The typical Initial enthusiasm for tight glycemic control in the
oral agent has a slow onset and offset of action, e.g. Piogli­ hospital specially in critically ill and MI patients was
section

tazone takes 15 days to start producing its biological driven by two large prospective studies; Van den Berghe’s
8

effects. The other oral agents may take a shorter time of study of critically ill patients in a surgical intensive care
2–7 days but this is much less than the swiftness and unit (ICU)44 and Diabetes and Insulin Glucose Infusion
flexibility with which insulin can be used. in Acute Myocardial Infarction study (DIGAMI study).45
Multiple contraindications exist to the use of various This initial enthusiasm has been tempered by more
oral agents, especially in hospitalized patients. Hospi­ generalizable multicenter trials like the Normoglycemia
talized patients often suffer from co-morbid conditions in Intensive Care Evaluation and Survival Using Glucose
like liver disease, renal failure and heart disease. They Algorithm Regulation (NICE- SUGAR) trial.46
also often undergo radiographic procedures with cont­
rast dye. These are all contraindications to the use of Critically ill Patients (ICU Patients)
metformin in the hospital. Thus, for all practical purposes, A single center trial (Leuven surgical trial) in surgical
metformin should not be used in hospitalized patients. ICU patients,44 most of them had undergone cardiac
However, short acting sulfonylureas, alpha-glucosidase surgery, provided the initial impetus to the notion that
inhibitors and a new class of medications called dipeptidyl controlling BG tightly can reduce mortality significantly.
peptidase-4 (DPP-4) inhibitors are oral agents which can There were two arms in this trial, intensive insulin
be used in the hospital and have a complementary effect therapy arm and conventional BG therapy arm. 1,548
in association with insulin. Glycemic control is more surgical ICU patients were randomized to either of the
evened out and smoother when select oral agents are two arms. The results showed that there was a good
combined with insulin. This may be attributed to their separation of BG values between the two treatment
effect in reducing insulin resistance. However, nothing arms. The mean BG in the intensive arm was 103 mg/dL
matches the versatility of insulin or substitutes for it. versus 153 mg/dL in the conventional arm. ICU mortality
Insulin is preferred over oral agents from a purely out­ was significantly lower in the intensive arm (4.6% vs
come-driven point of view (vide infra). 8%). Intensive insulin therapy reduced critical illness
neuropathy, acute renal failure, transfusion requirement
CLINICAL TRIAL EVIDENCE and bacteremia. This was hailed as a path breaking study,
the first real evidence from a prospective randomized
There is convincing evidence that glycemic control in the controlled clinical trial that controlling BG is important for
acute setting is associated with good clinical outcome. outcomes in ICU patients. The limitations of this study was
Multiple studies have demonstrated cardiac and neuro­ that it was a single center trial. Also as part of the protocol,
logical benefits of glucose-insulin-potassium (GIK) infu­ high glucose loads were given on the first and 2nd ICU
sions.39-42 GIK infusions are infusions of dextrose with days. Thus it is possible that a harmful intervention
insulin and potassium to counteract any possibility of (high glucose load) in the control group was reduced by
hypokalemia. This is because insulin drives glucose and aggressive insulin therapy in the intensive group. This
potassium into the cells. The effectiveness of GIK infusions was responsible for the observed high mortality in the
in producing these benefits even in normal people control group (8%) and a significant reduction of mortality
suggests that insulin therapy directly rather than through in the intervention group. Van den Berghe et al.47 sought
glycemic control is a key to the outcomes. Since BG control to replicate these results in a group of medical ICU
is conceivably not the goal of these GIK infusions, it is patients (Leuven medical trial). Again 1,200 medical ICU
likely that the effects of these infusions are due to a direct patients were randomized at a single center to receive
effect of insulin through glucose-independent pathways. intensive insulin therapy (target: 80–110 mg/dL) versus
Thus, small studies of individuals with or without diabetes conventional therapy (180–200 mg/dL). Intensive insulin
 Glycemic Management in Hospitalized Patients 615

therapy, in this case did not reduce overall hospital Acute Myocardial Infarction
mortality although it improved markers of mortality like
The literature about blood glucose targets and outcomes
ICU stay, hospital stay, acute renal failure and duration of
in MI patients is more sparse. More data is required in
mechanical ventilation.
this subpopulation of patients, as a typical myocardial
In order to reconcile these seemingly conflicting
results, a multicenter prospective randomized controlled infarction patient may not be as sick as a medical or
clinical trial was designed called the NICE-SUGAR trial.46 surgical critically ill ICU patient. The two or three trials that

chapter
The Leuven or Van den Berghe surgical and medical trials could sway our clinical decision making were not as big

40
had brought to center-stage the importance of glycemic or well designed as the ICU trials. Foremost among them
control in ICU or critically ill patients. The NICE-SUGAR was the DIGAMI trial.45 In the DIGAMI trial, 620 diabetic
trial was to conclusively show, one way or the other, patients with an MI were randomized to an insulin-
whether glycemic control in the ICU is impor­ tant. In glucose infusion followed by subcutaneous insulin for
this study, 6,104 medical and surgical ICU patients were more than or equal to 3 months or therapy with insulin,
randomized to intensive insulin therapy (target: BG 81– only if clinically indicated in the conventional arm.
108 mg/dL) or conventional glucose management (BG BG values were significantly lower (172.8 ± 59.4) in the
< 180 mg/dL). In the conventional arm, if the BG dropped intervention group at the end of 24 hours versus the control
below 144 mg/dL (8 mmol/L), then the insulin infusion group (210.6 ± 73.8 mg/dL). HbA1c was also lowered at
was discontinued. The average BG in the intensive insulin 3 months and 1 year follow-up. Mortality was significantly
arm was 115 mg/dL versus 144 mg/dL in the conventional reduced in the intensive arm at 1 year (19 vs 26%) and at
arm. The intensive insulin arm had a significantly higher 3.4 years (33 vs 44%). The greatest reduction in mortality
90 day mortality (27.5% vs 24.9%). Incidentally the inten­ was in low risk patients who were not getting insulin prior
sive insulin arm also had a significantly higher incidence to the MI.
of severe hypoglycemia (6.8 vs 0.5%). DIGAMI trial brings out the benefits of sustained and
There have been several other smaller trials, which are intensive glycemic control in MI patients. Here intensive
listed below, which showed either an increased mortality insulin therapy was conducted during hospitalization
in the intensive arm or no difference in mortality between and for at least more than or equal to 3 months post­
the intensive and conventional arms. discharge. However, it is difficult to attribute the advantage
• The COIITSS trial (Corticosteroids and Intensive accrued to the insulin glucose infusion alone, as intensive
Insulin Therapy for Septic Shock).48 Here 509 patients outpatient therapy with subcutaneous insulin was conti­
with septic shock receiving corticosteroids were rando­ nued for more than or equal to 3 months. What part of
mized to intensive insulin therapy versus conventional the advantage is attributable to the intensive in-hospital
glucose management. No difference in mortality was therapy and what part is due to the intensive outpatient
found. therapy is difficult to say, although the DIGAMI-2 trial was
• VISEP trial (Volume Substitution and Insulin Therapy designed to address the very same question.50 However, it
in Severe Sepsis) in a mixed population of ICU patients can be concluded that there is an advantage of intensive
(medical + surgical).49 The intensive arm was stopped insulin therapy in the MI setting specially in low cardiac
because intensive insulin therapy significantly incre­ risk patients. The patients with the least baseline disease
ased the rate of hypoglycemia and serious adverse (low cardiac risk) in DIGAMI study benefitted the most
events. from aggressive therapy. This is in tune with Action to
• Meta-analyses, too have concurred with the NICE- Control Cardiovascular Risk in Diabetes (ACCORD),
SUGAR trial and other subsequent trials, demonstrating Action in Diabetes and Vascular disease: PreterAx® and
no reduction in mortality in the intensive arm. DiamicronMR® Controlled Evaluation (ADVANCE) and
• To summarize, the NICE-SUGAR trial, the largest pros­ Veteran Affairs Diabetes Trial (VADT) studies which
pective multicenter randomized controlled clinical showed that glycemic control should be tight at the initial
trial of its class clearly demonstrated that in ICU diagnosis of type 2 diabetes and should be relaxed later or
patients, too tight glycemic control is actually dele­ when complications develop.
terious. Hence BG targets should be modified accor­ DIGAMI-250 was conceived to distinguish whether
dingly. inpatient or outpatient intensive insulin therapy was the
616 Management

important component responsible for the reduction in guidelines propose that BG levels be maintained between
mortality in DIGAMI-1. There were three treatment arms: 140 mg/dL and 180 mg/dL in ICU patients.
1. Arm 1: Inpatient insulin infusion and outpatient inten­ The data is sparser for cardiac patients and patients in
sive subcutaneous insulin therapy. general medical and surgical wards. By extrapolation, it
2. Arm 2: Inpatient insulin infusion and outpatient stan­ is recommended that BG should be maintained between
dard treatment. 140 mg/dL and 180 mg/dL in these patients as well.
3. Arm 3: Inpatient and outpatient routine glucose mana­
section

gement. STRATEGIES TO ACHIEVE BLOOD

8

Mortality rates in all three arms were similar, but the GLUCOSE TARGETS
study had several limitations. There was no separation of
Insulin remains the mainstay for the control of hypergly­
glycemic control between the three arms and power was
cemia in the hospital setting. Numerous contraindications
reduced due to small number of patients recruited.
exist to the use of several oral agents in the hospitalized
Thus to summarize, DIGAMI studies showed that
setting (as alluded to earlier).
aggressive glucose management in the setting of MI is
Insulin can be used intravenously or subcutaneously.
beneficial specially in patients with the least baseline
cardiac risk and in diabetics not on prior insulin therapy.
Intravenous Insulin Therapy
In patients who are at higher risk, one should be more
conservative as one runs the risk of increasing mortality Intravenous (IV) insulin therapy offers the greatest
(perhaps due to increasing severe hypoglycemia) with versatility in terms of controlling hyperglycemia in the
tight glycemic control. inpatient setting. Two methods of insulin delivery exist,
(1) a glucose plus insulin infusion where insulin is
General Wards added to a dextrose pint and thus insulin and glucose is
delivered together. The advantage of this rather simple
Data on glycemic control and targets for patients in general method of IV insulin therapy is that both glucose
wards is even more sparse. By extrapolation of data in and insulin are delivered together. Hence, if delivery
ICU patients and cardiac patients, it may be said that of glucose is stopped due to any reason, the delivery of
BG should be adequately controlled and hyperglycemia insulin also stops automatically. Hence, it may be argued
as well as hypoglycemia should be avoided. that this is a very safe method of IV insulin delivery.
The other method of IV insulin delivery is by (2) a
BLOOD GLUCOSE TARGETS IN syringe pump. Here the delivery of insulin is separated from
HOSPITALIZED PATIENTS the delivery of glucose which must occur simultaneously.
This is perhaps a more sophisticated approach, requiring
With regard to critically ill patients (ICU—medical and
the services of a device, the syringe pump. This may not
surgical patients)—the NICE-SUGAR trial has helped to be available in primary health care centers, but it could
define targets for ICU patients. A “U” shaped curve exists certainly be used in tertiary health care facilities. Since
between blood glucose and mortality. If BG is high or low, the delivery of insulin is divorced from the delivery of
mortality actually increases in the hospital. Hypoglycemia glucose, the risk of hypoglycemia is increased if glucose
is the trade off that you get when you intensively control delivery is stopped for any reason without stopping insulin
patients. Severe hypoglycemia can be fatal and can delivery. However, the advantages are tremendous.
cause brain damage and cardiac arrthymias. This might The rates of insulin delivery can be exquisitely controlled
be the primary reason for the increased mortality in and modifications can be made on an hourly basis.
the intensive arm of the NICE-SUGAR trial. Thus hypo­ We recommend IV insulin and glucose as the best
glycemic reactions should not be shrugged off as trivial option for patients who are nil by mouth or fasting
and dismissed. Hypoglycemia should be avoided as far in preparation for a surgical procedure or otherwise.
as possible. The NICE-SUGAR trial showed that it is best Starving diabetic patients require some glucose to be
to target a slightly higher BG than normal BG in ICU given to prevent starvation ketosis and a catabolic state.
patients and thus avoid the increased mortality and Along with glucose, insulin given intravenously either via
morbidity associated with both the low and high BG. Most a glucose-insulin infusion or a syringe pump is probably
 Glycemic Management in Hospitalized Patients 617

IV Insulin infusion (Prepared with IV Insulin infusion (Prepared with

50 units of regular insulin in 100 units of regular insulin in
50 cc of normal saline) 50 cc of normal saline)

Concentration: 1 unit/mL Concentration: 2 units/mL

Algorithm Same Algorithm
Blood Glucose (BG) mL/hr BG mL/hr

chapter
< 80 Off < 80 Off

40
80–120 0.2 80–120 0.2
If
121–160 0.5 121–160 0.5
uncontrolled
161–200 1 161–200 1
201–250 2 201–250 2
251–300 4 251–300 4
> 300 8 > 300 8

Fig. 40.1: Intravenous insulin infusion algorithms

the best method of glycemic control in patients who per cc of normal saline. This eliminates the use of multiple
are fasting for any extended period of time. This is a far algorithms and causes less confusion for the nursing staff.
better option than giving subcutaneous insulin on a 4 or Another advantage is that the infusate does not get over
6 hourly scheduled basis and treating blood glucose in a fast and you do not have to replace it or prepare new
post facto manner. solutions frequently (Fig. 40.1).
A number of various insulin infusion protocols now A few other practical points with respect to the
exist in the public domain. The Leuven protocol was the IV insulin infusion in use, at the Jaslok Hospital and
first protocol used in the Leuven studies. Markovitz et al. Research Center by our team deserve mention:
published one of the early protocols in which four insulin • The first 5–10 mL of the insulin infusate is flushed
algorithms were used.51 The first algorithm was for insulin through the tubing outside of the patient. This saturates
sensitive patients and the fourth algorithm was for the insulin adsorption sites on the plastic tubing of the
most insulin resistant patients. Most patients were IV. Hence, the insulin infusate, does not get adsorbed
started on algorithm one. Each algorithm defined a scale when it is connected to the patient and there is no
whereby a certain BG level was treated with a certain delay in its effect.
insulin infusion rate. If algorithm one and its scale did not • Further, to prevent delay in the effect of IV insulin
bring the BG down sufficiently, the patient was moved up infusion, a bolus of 6–10 units of regular insulin IV is
to algorithm two. The scale of algorithm two accounted given. This builds up levels fast to achieve an immediate
for a steeper, for example doubled insulin infusion rate effect before the infusion starts working.
for each corresponding BG level. If this did not control • Regular insulin is as good as insulin analogs like lispro,
BG, the patient was moved up to algorithm three and then aspart and glulisine when used intravenously. There is
algorithm four. no need to use insulin analogs in IV insulin infusions.
There are a number of different IV insulin protocols. This will unnecessarily increase costs.
Some are variations of the Leuven or Markovitz protocols. • Usually, capillary BG monitoring can be done on a
We tend to use a more practical approach. We initiate insulin 2 hourly basis for patients on IV insulin therapy.
infusions by using a fixed algorithm. Instead of moving the If the patient starts eating orally, capillary BG
patient up to an augmented algorithm (if uncontrolled monitoring should be linked with the meal. So when
on first algorithm), where the infusion rate is doubled, our patients start eating orally, while on IV insulin
we double the concentration of the insulin infusate. So infusion, capillary BG monitoring is done premeals,
if the original infusate has a concentration of 1 unit of 2 hours postmeals, midnight and 3 AM. This is to
regular insulin in 1 cc of normal saline, the new infusate prevent capillary BG monitoring from falling 30 min
will have a concentration of two units of regular insulin or an hour after a meal (if done 2 hourly) and thus
618 Management

prevent erroneous action. Also when the patient starts Basal insulin in the form of NPH, Glargine, Detemir
eating, boluses of subcutaneous (SC) insulin are given or Degludec provides the background insulin to cover
along with the IV insulin infusion. Here the insulin the basal needs of the patient. Prandial insulin is short
analogs have certain advantages over regular insulin. acting regular or ultrashort acting lispro, aspart or gluli­
This is because, with erratic and unpredictable food sine which is given with each meal. Correctional insulin
intake, the rapid acting insulin analogs can be injected is the additional insulin given for correction of the pre­
just after the meal. The dose can be titrated depending meal BG (if high) in addition to the prandial insulin.
section

on food intake and the premeal 30 min window of The correctional insulin is added to the prandial insulin
8

regular insulin is not required. and is given as a single shot before each meal. Hence, it
• From midnight to 4 AM, is the time of greatest insulin follows that the correctional insulin is either short acting
sensitivity. Hence, if IV insulin therapy is continued regular insulin or ultrashort acting lispro, aspart or
at the same rate, hypoglycemia often results. We have glulisine. This combination of basal, prandial and correc­
found that cutting the prevailing rate of insulin delivery tional insulin imitates the normal insulin physiology.
to half from midnight to 4 AM prevents hypoglycemia.
This mimics the physiological changes in insulin Oral Agents
sensitivity seen in normal individuals.
The problems with pioglitazone and metformin were
• In hospitalized type 1 diabetes, it is important to alluded to earlier. However, certain oral agents can be
provide uninterrupted insulin supply. Hence, insulin used in the hospital and offer certain advantages. Alpha-
infusion should not be completely stopped at low- glucosidase inhibitors like acarbose and voglibose,
normal BG values. A very low dose infusion must be although mild, have the benefit of working immediately
continued uninterruptedly. Alternatively, a small dose i.e. they block the carbohydrate in the next meal that
of Neutral Protamine Hagedorn (NPH) or other basal they are used with, hence producing an immediate effect.
insulin must be given once or twice a day. For the same Short acting sulfonylureas or meglitinides like repaglinide
reason, the premeal SC insulin dose must precede the or nateglinide also have a sharp onset and offset of
discontinuation of IV insulin infusion by half to 1 hour. action. They are not long acting like the conventional
sulfonylureas and hence can be used prior to each meal
Subcutaneous Insulin Therapy with a low rate of hypoglycemia. They help to reduce
insulin resistance, when used along with insulin. Thus
If IV insulin is the mode of choice for starving patients, insulin requirements come down and glycemic control
SC insulin in the form of basal, prandial and correctional is smoother. All insulins have an inherent coefficient of
doses are important modalities of the treatment of fed variation that is the bane of SC insulin therapy. Certain
patients. Use of sliding scale is wrong in principal, because oral tablets when combined with SC insulin will help to
it is post facto action. Using same sliding scale for all complement insulin in this regard. In the recovery phase
patients ignores the fact that insulin sensitivity varies of hospitalized patients where there is no cardiovascular or
between individuals. Not uncommonly, premeal insulin hepatorenal compromise, which often happens just prior
is omitted for a low-normal BG value like 80–100 mg/dL, to discharge from the hospital, it is possible to introduce
thus resulting in marked postmeal hyperglycemia. The an insulin sensitizer like metformin. This improves glyce­
high postmeal BG is treated with a large dose, thus mic control in most type 2 diabetics on a 3–4 dose insulin
resulting in normal or low BG after 2–3 hours. Thus, the regime.
sliding scale introduces iatrogenic lability of BG and must Another new and exciting class of oral tablets that we
be avoided. have found to be useful in hospitalized patients is DPP-4
A better strategy for using SC insulin would be to divide inhibitors. Although data on their use in hospitalized
it into three parts (Fig. 40.2): patients is sparse, we have found them a useful adjunct to
1. Basal subcutaneous insulin. They work through enhancing insu­
2. Prandial lin secretion, inhibiting glucagon secretion and slowing
3. Correctional gastric emptying. Thus, they help to even out glycemic
 Glycemic Management in Hospitalized Patients 619

Blood Glucose (BG) Monitoring: Before meals and at bedtime

______ hours after meals
2–3 AM
Goal premeal BG = ___________ (80–150 mg/dL for most patients)

Breakfast Lunch Dinner Bedtime

Prandial Orders Give __ units of: Give __ units of: Give __ units of: Give __ units of:

chapter
Lispro Lispro Lispro

40
Aspart Aspart Aspart
Glulisine Glulisine Glulisine
Regular Regular Regular

Basal Insulin Give __ units of: Give __ units of:

Orders Neutral Protamine Hagedorn (NPH) NPH
Detemir
Glargine
Degludec

Premeal “correction dose” algorithm for hyperglycemia: to be added to the prandial scheduled insulin dose to correct premeal hyperglycemia.

Lispro Aspart Glulisine Regular

Correctional Insulin Dose for low, Medium or High Dose Insulin requirements

Premeal BG Additional insulin based on patient’s daily dose

Low dose Medium dose High dose
(40 u of (40–80 u of (> 80 u of
Insulin/day) Insulin/day) Insulin/day)
150–199 1 1 2
200–249 2 3 4
250–299 3 5 7
300–349 4 7 10
> 349 5 8 12

Fig. 40.2: Subcutaneous insulin regimen52

control again with a lower rate of hypoglycemia than even FURTHER READING
meglitinides. The majority of them have now been appro­
ved for use along with insulin in the outpatient setting.53 1. Malmberg K. Prospective randomized study of intense
insulin treatment on long term survival after acute myo­
cardial infarction in patients with diabetes mellitus. BMJ.
SUMMARY 1997;314:1512-5.
2. Van den Berghe G, Wouters P, Weekers F, et al. Inten­
Good glycemic control in hospitalized patients is impor­
sive insulin therapy in critically ill patients. N Engl J Med.
tant for improving outcomes. However, it is not appro­ 2001;345:1359-67.
priate to attempt tight glycemic control, especially in 3. Clement S, Braithwaite SS, Magee MF, et al. Management
patients with chronic cardiovascular complications. Most of Diabetes and Hyperglycemia in Hospitals. Diabetes care.
guidelines suggest a target blood glucose level between 2004;27:553-91.
140 mg/dL and 180 mg/dL in the hospital. This can be 4. Van den Berghe G, Wilmer A, Hermans G, et al. Inten­
sive insulin therapy in the medical ICU. N Engl J Med.
achieved by using continuous intravenous insulin
2006;354:449-61.
therapy during the acute phase and subcutaneous insu­ 5. Finfer S, Chittock DR, Su SY, et al. Intensive versus conven­
lin therapy with select sensitizing oral agents during the tional glucose control in critically ill patients. N Engl J Med.
recovery phase. 2009;360:1283.
620 Management

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2. Bagdade JD, Stewart M, Walters E. Impaired granulocyte H2097-104.
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section

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3. Joshi N, Caputo G, Weitekamp M, et al. Infections in
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patients with diabetes mellitus. N Engl J Med. 1999; 341:

20. Marfella R, Nappo F, Angelis LD, et al. Hemodynamic
1906-12.
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4. Wheat LJ. Infection and diabetes mellitus. Diabetes Care.
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1980;3:187-97.
21. Pandolfi A, Giaccari A, Cilli C, et al. Acute hyperglycemia
5. Mowat A, Baum J. Chemotaxis of polymorphonuclear leu­
and acute hyperinsulinemia decrease plasma fibrinolytic
kocytes from patients with diabetes mellitus. N Engl J Med.
activity and increase plasminogen activator inhibitor type
1971;284:621-7.
1 in the rat. Acta Diabetologica. 2001;38:71-6.
6. Bagdade J, Root R, Bulger R. Impaired leukocyte func­
22. Williams S, Goldfine A, Timimi F, et al. Acute hyperglyce­
tion in patients with poorly controlled diabetes. Diabetes.
mia attenuates endothelium-dependent vasodilation in
1974;23:9-15.
humans in vivo. Circulation. 1998;97:1965-701.
7. Van Oss CJ, Border JR. Influence of intermittent hyper­
23. Kawano H, Motoyama T, Hirashima O, et al. Hyperglyce­
glycemic glucose levels on the phagocytosis of microor­
mia rapidly suppresses flow-mediated endothelium-de­
ganisms by human granulocytes in vitro. Immunol Com­
mun.1978;7:669-76. pendent vasodilation of brachial artery. J Am Coll Cardiol.
8. Davidson N, Sowden J, Fletcher J. Defective phagocyto­ 1999;34:146-54.
sis in insulin-controlled diabetics: evidence for a reaction 24. Shige H, Ishikawa T, Suzukawa M, et al. Endothelium-
between glucose and opsonizing proteins. J Clin Pathol. dependent flow-mediated vasodilation in the postpran­
1984;37:783-6. dial state in type 2 diabetes mellitus. Am J Cardiol. 1999;84:
9. Alexiewicz J, Kumar D, Smogorzewski M, et al. Polymor­ 1271-4, A9.
phonuclear leukocytes in non-insulin-dependent diabetes 25. Morohoshi M, Fujisawa K, Uchimara I, et al. Glucose-de­
mellitus: abnormalities in metabolism and function. Ann pendent interleukin 6 and tumor necrosis factor produc­
Intern Med. 1995;123:919-24. tion by peripheral human blood monocytes in vitro. Diabet
10. Leibovici L, Yehezkelli Y, Porter A, et al. Influence of Med. 1996;45:954-9.
diabetes mellitus and glycemic control on the characte­ 26. Coughlan MT, Olivia K, Georgiou HM, et al. Glucose-
ristics and outcome of common infections. Diabet Med. induced release of tumor necrosis factor-alpha from
1996;13:457-63. human placental and adipose tissues in gestational diabetes
11. Kwoun M, Ling P, Lydon E, et al. Immunologic effects of mellitus. Diabet Med. 2001;18:921-7.
acute hyperglycemia in non-diabetic rats. J Parenter Enteral 27. Lin Y, Rajala MW, Berger JP, et al. Hyperglycemia-induced
Nutr. 1997;21:91-5. production of acute phase reactants in adipose tissue. J Biol
12. McManus L, Bloodworth R, Prihoda T, et al. Agonist- Chem. 2001;276:42077-83.
dependent failure of neutrophil function in diabetes 28. Esposito K, Nappo F, Marfella R, et al. Inflammatory
correlates with extent of hyperglycemia. J Leukocyte Biol. cytokine concentrations are acutely increased by hyper­
2001;70:395-404. glycemia in humans: role of oxidative stress. Circulation.
13. Oldenborg P, Sehlin J. Hyperglycemia in vitro attenuates 2002;106:2067-72.
insulin-stimulated chemokinesis in normal human neu­ 29. Schiekofer NM, Andrassy M, Chen J, et al. Acute hypergly­
trophils: role of protein kinase C activation. J Leukoc Biol. cemia causes intracellular formation of CML and activa­
1999;65:635-40. tion of RAS, p42/44 MAPK and nuclear factor-kB in PBMCs.
14. Liu BF, Miyata S, Kojima H, et al. Low phagocytic Diabetes. 2003;52:621-33.
activity of resident peritoneal macrophages in diabetic mice: 30. Lin B, Ginsberg M, Busto R. Hyperglycemic exacerbation of
relevance to the formation of advanced glycation end prod­ neuronal damage following forebrain ischemia: microglial,
ucts. Diabetes. 1999;48:2074-82. astrocytic and endothelial alterations. Acta Neuropatho­
15. Sato N, Kashima K, Ohtani K, et al. Epalrestat, an aldose logica. 1998;96:610-20.
reductase inhibitor, improves an impaired generation of 31. Gisselsson L, Smith M, Siesjo B. Hyperglycemia and focal
oxygen-derived free radicals by neutrophils from poorly brain ischemia. J Cereb Blood Flow Metab. 1999;19:288-97.
controlled NIDDM patients. Diabetes Care. 1997;20:995-8. 32. Hoxworth JM, Xu K, Zhou Y, et al. Cerebral metabolic pro­
16. Bouter KP, Meyling FH, Hoekstra JB, et al. Influence of file, selective neuron loss, and survival of acute and chronic
blood glucose levels on peripheral lymphocytes in patients hyperglycemic rats following cardiac arrest and resuscita­
with diabetes mellitus. Diabetes Res. 1992;19:77-80. tion. Brain Res. 1999;821:467-79.
 Glycemic Management in Hospitalized Patients 621

33. Capes S, Hunt D, Malmberg K, et al. Stress hyperglyce­ 43. Lazar HL, Chipkin S, Phillippides G, et al. Glucose-insu­
mia and prognosis of stroke in non-diabetic and diabetic lin-potassium solutions improve outcomes in diabetics
patients: a systematic overview. Stroke. 2001;32:2426-32. who have coronary artery operations. Ann Thorac Surg.
34. Venables GS, Miller SA, Gibson G, et al. The effects of 2000;70:145-50.
hyperglycaemia on changes during reperfusion follow­ 44. Van den Berghe G, Wouters P, Weekers F, et al. Inten­
ing focal cerebral ischaemia in the cat. J Neurol Neurosurg sive insulin therapy in critically ill patients. N Engl J Med.
Psychiatry. 1985;48:663-9. 2001;345:1359-67.
45. Malmberg K. Prospective randomized study of intense
35. Anderson RE, Tan WK, Martin HS, et al. Effects of glucose

chapter
insulin treatment on long term survival after acute
and PaO2 modulation on cortical intracellular acidosis,
myocardial infarction in patients with diabetes mellitus.

40
NADH redox state, and infarction in the ischemic penum­
BMJ. 1997;314:1512-5.
bra. Stroke. 1999;30:160-70. 46. Finfer S, Chittock DR, Su SY, et al. Intensive versus conven­
36. Schurr A, Payne RS, Miller JJ, et al. Preischemic hypergly­ tional glucose control in critically ill patients. N Engl J Med.
cemia-aggravated damage: evidence that lactate utilization 2009;360:1283.
is beneficial and glucose-induced corticosterone release is 47. Van den Berghe G, Wilmer A, Hermans G, et al. Inten­
detrimental. J Neurosci Res. 2001;66:782-9. sive insulin therapy in the medical ICU. N Engl J Med.
37. Ishii H, Arai T, Segawa H, et al. Effects of propofol on lac­ 2006;354:449-61.
tate accumulation and oedema formation in focal cerebral 48. Annane D, Cariou A, Maxime V, et al. Corticosteroid treat­
ischaemia in hyperglycaemic rats. Br J Anaesth. 2002;88: ment and intensive insulin therapy for septic shock in
412-7. adults: a randomized controlled trial. COIITSS Study Inves­
38. Li P, Shuaib A, Miyashita H, et al. Hyperglycemia enhances tigators. JAMA. 2010;303:341-8.
extracellular glutamate accumulation in rats subjected to 49. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin
forebrain ischemia. Stroke. 2000;31:183-92. therapy and pentastarch resuscitation in severe sepsis. N
39. Machtey I, Syrkis I, Nissimov MR, et al. Potassium, glucose Engl J Med. 2008;358:125-39.
and insulin administration in acute myocardial infarction: 50. Malmberg K, Ryden L, Wedel H, et al. Intense metabolic
control by means of insulin in patients with diabetes melli­
a five-year study. J Am Geriatr Soc. 1976;24:534-7.
tus and acute myocardial infarction (DIGAMI 2): effects on
40. Rogers WJ, Stanley AW, Breinig JB, et al. Reduction of hos­
mortality and morbidity. Eur Heart J. 2005;26:650-61.
pital mortality rate of acute myocardial infarction with
51. Markovitz LJ, Wiechmann RJ, Harris N, et al. Description
glucose-insulin-potassium infusion. Am Heart J. 1976;92: and evaluation of a glycemic management protocol for
441-51. patients with diabetes undergoing surgery. Endocr Pract.
41. Scott JF, Robinson GM, French JM, et al. Glucose potassium 2002;8:10-8.
insulin infusions in the treatment of acute stroke patients 52. Trence D, Kelly J, Hirsch I. The rationale and manage­
with mild to moderate hyperglycemia: the glucose insulin ment of hyperglycaemia for inpatients with cardiovascular
in stroke trial (GIST). Stroke. 1999;30:793-9. disease: Time for change. J Clinical Endocrinol Metab.
42. Scott JF, Robinson GM, French JM, et al. Blood pressure 2003;88:2430-7.
response to glucose potassium insulin therapy in patients 53. Fonseca V, Schweizer A, Albrecht D, et al. Addition of
with acute stroke with mild to moderate hyperglycemia. vildagliptin to insulin improves glycemic control in type 2
J Neurol Neurosurg Psych. 2001;70:401-4. diabetes. Diabetologia. 2007;50:1148-55.
 Chapter 41
Short-Term Monitoring of
Glycemic Control
Suresh D Mehtalia, Premlata K Varthakavi

Monitoring Glycemic Control

Chapter Outline
♦♦ Evaluation at the Initial Hospital Visit ♦♦ Blood Glucose
♦♦ Monitoring Glycemic Control ♦♦ Barriers
♦♦ Urine Glucose ♦♦ New Monitoring Device Developments
♦♦ Ketones

INTRODUCTION complications trial (DCCT) had firmly established the

relationship between good glycemic control and the
The incidence of diabetes mellitus (DM) is increasing prevention of diabetic complications in persons with
worldwide. It currently affects 285 million people world­ type 1 DM.10
wide and is expected to affect 435 million by 2039.1 In the UKPDS, similar parameters were studied in
Recent surveys have established that India has the largest T2DM and the benefits accrued by good glycemic control
number of diabetics (61 million subjects) and by the year were similar to those obtained in type 1 diabetics.
2035 this is projected to increase by 195%, i.e. increase to The DCCT and the UKPDS have confirmed that inten­
about 101.2 million.2,3 This chronic progressive disease, a sive treatment (maintaining HbA1c to approximately 7% or
conglomerate of metabolic abnormalities, causes micro 1% above the upper limit of normal) was associated with
and promotes macrovascular complications and damages fewer long-term diabetic complications—provided early
multiple organs.4 Diabetes mellitus, in particular the intervention is undertaken to obtain good glycemic control
non-insulin dependent variety, may remain undiagnosed and modify risk factors.7,10 However, intensive control was
for long. Several recent population studies have demon­ found to increase the risk of severe hypoglycemia and
strated high prevalence rates of impaired glucose tole­ cause weight gain.
rance (IGT) and undiagnosed type 2 diabetes mellitus Diabetes complications account for 60% of the direct
(T2DM).5,6 Around 50% of type 2 diabetics already health care costs and almost 80–90% of the indirect health
have complications at diagnosis. A 37% had retinopathy care costs in developed nations.11 In our country diabetes
and an 18% had microalbuminuria (MAU) as reported in care spending tends to tilt towards treating the glycemia
the UK Prospective Diabetes Study (UKPDS).7 and the attendant complications and monitoring of
In dealing with a chronic disease like diabetes, glycemia is neglected.12 To prevent diabetes complications
manage­ment strategies should ideally aim at preventing it is crucial that proper monitoring is carried out: first
the long-term complications or at least intervening early to detect response to treatment (glycemic control) and
to prevent their progression.8,9 The diabetes control and second to detect any complications.
 Short-Term Monitoring of Glycemic Control 623

EVALUATION AT THE Urine testing cannot diagnose indirect low BG levels

INITIAL HOSPITAL VISIT13,14 and hence cannot diagnose hypoglycemia. Negative urine
glucose may indicate normoglycemia, hypoglycemia or
At the initial visit the physician should obtain a detailed even hyperglycemia in case of high renal threshold.
history and perform a complete examination and Children basically have a low renal threshold.18 However,
appropriate laboratory tests. This first assessment by the in a group of diabetic children, a negative urine test was
physician is aimed at classifying the patient, detecting the found with BG of 3–16 mmol/L (54–268 mg/dL).19

chapter
presence or absence of diabetes complications and other A positive test (2%) result was seen when the BG ranged

41
concomitant illnesses. In a known diabetic, the previous between 3 mmol/L and 20 mmol/L (54–360 mg/dL). Such
treatment and the past and present glycemic and other varying results confuse the patients and jeopardize comp­
risk factor control should be reviewed. Nutritional and liance.20 Therefore patients often keep the urine glucose
educational aspects and the exercise protocol should positive for fear of hypoglycemia.21
also be looked into. Laboratory tests should be performed Urinary glucose is fallacious in patients with autonomic
according to each patient’s clinical evaluation. The
dysfunction as they have some residual urine, which
management strategy should be to formulate a treatment
results in dilution of the urine sample. Urine testing is not
plan on the “whole person approach”.
always useful in pregnancy, which is associated with a
The management team should lay down the goals
lowering of renal threshold. Fluid intake and renal concen­
of patient management individualized for the patient.
tration influence the urine glucose.22 Drug intake also
It should include medical nutrition therapy, life style
affects the urine glucose levels. Ketone bodies, Vitamin C
modification and medication. A protocol for the contin­
uing care of the patient should be broadly outlined. They and salicylates may interfere even with enzymatic
should also educate the patient regarding the disease, its methods23 of urine glucose testing.
complications and its management. Urine glucose for the above reasons is not a sensitive
method to monitor glycemic control.24 It should never be
Monitoring Glycemic Control used to diagnose diabetes mellitus. However every indivi­
dual with glycosuria should be investigated for diabetes.
“Monitoring” is defined as a planned approach to diabetes Since most tests use color changes as end points, color
“wherein one needs to check” on the progress and thereby blindness is a source of interpretation error.25 Tests for
regulate or improve on previous performance.15 color blindness and renal threshold should ideally be
Monitoring glycemic control is extremely essential done before using glucose as a monitoring tool.16
to guide therapeutic interventions to achieve the best However, urine glucose tests are non-invasive, simple
possible blood glucose (BG) control. and cheap. Although tube tests for urine glucose may
be considered messy, reagent strips are easy to use and
Urine Glucose clean especially for children. Frequent testing is therefore
Urine glucose testing was the traditional method of possible during acute illnesses, change of treatment and
monitoring glycemic status since the discovery of insulin intensive insulin therapy. Younger patients may prefer
in 1922, until the advent of home glucose monitoring.16 daily urine testing and occasional blood testing to frequent
Rationale: Urine glucose reflects mean BG over the self-monitoring of blood glucose (SMBG).26 Studies done
time the urine was collected. The renal threshold for during the early days of SMBG regimens suggested that
glucose ranges between 54–279 mg/dL, with an average intensive management programs, which used urine glucose
of 180 mg/dL (<10 mmol/L). Beyond the renal threshold, testing, were as efficacious in maintaining euglycemia
urine glucose depends on BG concentrations and urine as SMBG programs.27 However, the introduction of
flow. The urine glucose is the average of the BG level over concomitant insulin adjustment algorithms with SMBG
the time of urine accumulation.17 programs has proven the superiority of SMBG.28
However, the renal threshold differs among people Targets for premeal BG are maintained at 110 mg/dL
and in the same person at different times. Hence, urine but intermediate testing may not always be possible.
glucose may not have a fixed relation with BG. Renal Especially when there are long gaps between meals, a
threshold is higher in long standing diabetics, in whom premeal urine glucose that would reflect the average BG
marked hyperglycemia may exist without glycosuria.16,17 concentration over time, may reflect the glycemic status
624 Management

of the individuals between meals. Thus, these tests are of Glucose Hexokinase
→ Glucose-6-phosphate + ADP
value in people who have limited goals for glucose control
Glucose-6-phosphate
and are unwilling or unable to perform BG tests as in Glucose-6-phosphate+ NADP dehydrogenase
→
T2DM.16,17
At present, it is recommended that all patients with 6-phosphogluconate + NADPH + H
diabetes, especially those who use insulin, should monitor NADPH is assayed by fluorescence or absorbance.
their blood, not urine, glucose levels. Notwithstanding Yet another method involves the use of glucose
section

its limitations, urine glucose monitoring is supported dehydrogenase

8

by the International Diabetes Federation (IDF) in those Glucose + NAD → Gluconolactome + NADH
situations in which BG monitoring is not accessible or NADH + MTT* → Formazan(Blue) + NAD
affordable, particularly in resource-poor settings.29
Sample collection: The first voided urine specimen *MTT, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra­
zolium bromide] is a color reagent.
reflects the average BG over the period of collection;
MTT is a pale yellow substrate that is cleaved to yield a
whereas the second void specimen reflects the instant­
dark blue formazan product.
aneous BG values. Both these collections have therefore
role to play in monitoring a diabetic patient. Older Methods for Glucose Analysis32
However, timed urine samples may be difficult to
obtain in the very young or in the elderly. The second Reduction of
voided urine sample does not offer an advantage over the • Cu +3 → Cu +2 by glucose in alkaline solution.
first voided sample.30 The use of a double voided specimen This test is non-specific; many non-glucose reducing
does not eliminate the limitations of urine testing in substances interfere with the assay.
patients with a high renal threshold, renal disease or • Fe(CN)6−3 → Fe(CN)6−2
bladder neuropathy.31
In a country like ours, urine glucose estimation can be Again a non-specific test.
used in people with a normal renal threshold to reduce Orthotoluidine test: Condensation of aromatic amines
costs. Done well, these tests are of greater value to the with the aldehyde group of glucose to glucosamine.
treating team than a poorly performed blood test!! This test has gone out of vogue, as o–toluidine is carci­
nogenic. Mannose and galactose specifically interfere
Methods for Glucose Analysis17,32 in this test.17,32

Tests for both urine and BG are today based on enzymatic Frequency of Testing
methods. The commonest enzymatic method is based on In a type 2 diabetic: At least two tests per day, at least three
glucose oxidase method. times per week.
Glucose+O2 Glucose
 oxidase
→ Gluconic Acid+H2 O2 In type 1 diabetic: Pre and postmeal and a bedtime
urine sugar (7- point profile).16,17
H2 O2 + ReducedDye → OxidizedDye + H2 O
Hydrogen peroxide can also be monitored ­electro­ Desirable Values by the Enzyme Methods
chemically at a positively charged electrode (+700 mV) as • Preprandial urine sugars negative.
shown in the following reaction: • Postmeal urine glucose negative or trace.
H2 O2 +
700 mV
→ O2 + 2H + + 2e − • Without the occurrence of frequent or severe hypogly­
cemia.
These are usually used in the laboratory glucose
analyzers and are being incorporated into some bedside Reagent Test Strips for Estimating
monitors now. Urine Glucose32-34
Oxygen consumption can also be measured as shown Reagent strips are quick, simple, qualitative color tests to
in the next equation: detect the presence of glucose in urine.
_
O2 + 4e + 4H+ → 2H2 O Composition: A strip of firm plastic, one end of which
Hexokinase and glucose-6-phosphate dehydrogenase has the pad having the reagent system comprising a
may also be used as the enzymes for glucose assays. buffered enzyme preparation and a chromogen system.
 Short-Term Monitoring of Glycemic Control 625

Table 41.1: Interference by other substances with urine glucose • The reactions should be read in the good light at the
estimation time stated by the manufacturer.
Substance GOD** Reduction (Cu) • Deterioration of the reagent strips results in brownish
Glucose Positive Positive discoloration of the test area. If this occurs the strips
Non-glucose sugars No effect Positive should not be used.
Ketones May depress color No effect • It is very essential to read the expiry date on a strip
Creatinine, uric acid No effect Positive before using it to perform a test.

chapter
Homogentisic acid No effect Positive

41
Sodium fluoride False negative No effect
To Prevent the Deterioration of the
L-dopa False negative No effect
Test Strips the Following are Important
Ascorbic acid May delay color Positive • Protect the strips from moisture, excessive heat (>30°C)
**Hexokinase and the glucose dehydrogenase methods are more and light.
specific for glucose. • Do not refrigerate.
• “A desiccant is supplied” either in the lid of the
The smallest concentration, which can be measured container or in the container as a sachet. Remove
by the test strips, varies from 0.6–5.5 mmol/L (10–99 strips only as required; after removing the strip replace
mg/dL) owing to variation in the urinary constituents and the container top immediately and tightly to prevent
pH in different specimens. Ascorbic acid may decrease moisture from harming the strips.
the sensitivity of the test and this fact should be borne in
mind in patients receiving therapeutic doses of Vitamin C Quality Control of Test Strips
or preparations like tetracycline where Vitamin C is used
as an antioxidant. A list of substances interfering with • Control reference solutions are available from the
glucose estimation is listed in Table 41.1. manufacturers of strips.
The reliability of the test strips depends on the correct • Checking regularly the strip reactions against those
storage, use and quality control. that are obtained by standard biochemical tests may
control the performance of most test strips.
Precautions to be Adopted when Using • Control urine samples of known negative and positive
reactions can also be prepared and tested with patient’s
Commercial Test Strips or Reagent Tablets
specimens.
• Accurate and reliable results are dependent upon • The manufacturers’ literature must always be consulted
strict observation of the manufacturer’s directions regarding the quality control of the strips and the
and careful following of recommended procedures for substances, which may interfere with the various
handling and testing. reactions.
• The specimen container should be clean and free from
contaminates, e.g. antiseptics and detergents. Selection of Urine Strips
• Fresh specimens should be tested whenever possible
When the patients are performing tests, reagent strips
because chemical changes take place on storage. catering to the assay of glucose and ketones would
• Test strips should be dipped into the urine specimen possibly suffice. However, the physician may use reagent
cleanly and quickly. Prolonged contact with the urine strips, which contain multiple test pads for albumin,
specimen may result in the reagent being dissolved ketones, bacteria, etc. so that additional information
into the urine. Excess urine should be removed from on the patients’ clinical status is available at the hospital
the strip by running the edge of the strip along the rim or clinic visit.
of the urine container. A wide variety of reagent test strips are available. They
• It is important to become familiar with the test areas are rapid, simple and often less expensive than performing
and the possible reactions before performing the test. the chemical tube tests. It costs more to use single
• The test area should not be contaminated by touching test strips to screen separately for each substance than
or by laying on a laboratory bench. The test should be to use a combined test strip with two or more test areas.
performed away from chemical fumes. Cutting strips in half lengthwise can significantly reduce
626 Management

the cost of using test strips. Strip splitters or a clean sharp Tests for Urine Ketone Determination16,34,35
pair of scissors may be used for the same.35
Acetoacetic Acid
Quantitative Analysis of Urine Glucose34,35 Gerhardt’s test: Ferric chloride reacts with acetoacetic acid
to give a characteristic red or purplish color. Phosphates
In the majority of cases sufficient information is obtainable
produce a precipitate of ferric phosphate, which should
from the qualitative tests for glucose. If an estimate of
be removed by filtering or centrifugation and the test
section

the amount of glucose lost daily is required, then, a

repeated with the clear supernatant. Salicylates give a
24 hour sample is collected and the glucose is estimated
8

similar color with ferric chloride, which persists on boiling.

accurately. To use these methods effectively, the urine
Boiling converts acetoacetic acid to acetone and the color
needs diluting in order to bring the concentration of glucose
disappears.
to within the range of the method adopted. When glucose
Rothera’s Nitroprusside test: Nitroprusside (sodium
oxidase methods are utilized the interfering substances
pentacyanonitrosyl ferrate) in alkaline solution reacts
need to be removed by using activated charcoal (0.5 g for
with a ketone group to form a purple color. It can detect
10 mL of urine or appropriate for dilution), centrifuging
and using an appropriate aliquot for glucose estimations. acetoacetic acid with greater sensitivity that the Gerhardt’s
Ninety-seven percent of normal, non-diabetic indivi­ test.
duals may have random urine glucose of 3–25 mg/dL and Method: Saturate 5 mL of urine with ammonium sulfate
3% have levels of more than 25 mg/dL (these individuals and add a small crystal of sodium nitroprusside. Mix well
have renal glucosuria or DM). The 24 hour urine glucose and then add 0.5 mL of concentrated ammonia. A purple
value is less than 3% of the carbohydrate intake or coloring indicates the presence of acetoacetic acid; and
10 g over 24 hours or about 20 mmol/L. These values are is maximal in 15 minutes. This test is less sensitive for the
proportional to the renal threshold and the urine flow. It detection of acetone than acetoacetic acid. When glycine
accurately estimates urine glucose losses. This is useful in is added to the reagent it can detect acetone. The rate of
color development is a better quantitative guide than the
checking the accuracy of premeal BG. It would be useful in
intensity of color.
a child who is not growing well due to the undernutrition
The “Tile test” is modification of the Rothera’s test
of uncontrolled DM or for someone with poor control,
using a powdered reagent. The reagent comprises fine
especially weight loss, but with negative urine sugars.
sodium nitroprusside (1 g) ammonium sulfate (20 g) and
Since the advent of glycated hemoglobin (HbA1c) this
anhydrous sodium carbonate (20 g). If kept dry it can
measure has fallen out of favor. HbA1c gives a good idea of
be preserved for at least 1 year. A small pinch of powder
overall glycemic control. Semiquantitative results may be
is kept on a tile, one drop of urine is added to it and the
obtained by test strips. However, this appears unreliable.
development of the violet color is noted.
False positives can occur with sulfhydryl drugs, e.g.
KETONES
Captopril, L-dopa, phenylketonuria and bromosulfo­
Urine Ketones phthalein dyes. Exposure to air can result in a negative
reaction. Urine, which has a high specific gravity and
Urine ketones are indicators of insulin deficiency and low pH, gives a trace positive reaction. False positives
warn against impending ketoacidosis or reflect established are also seen with the highly pigmented urine with
ketonemia. L-dopa metabolites. Phenylketonuria also gives an easily
There are three ketones bodies: (1) acetoacetic acid; (2) distinguishable orange red color with the nitroprusside
acetone; and (3) b-hydroxybutyric acid. It is important to test.
test for these substances as a part of routine evaluation of These reagents have also been incorporated into test
diabetic patients. Ketone bodies are normally present in strips and tablets.
urine but concentrations are below the limit of detectability “Acetest” is Rothera’s test in a tablet form. The tablet
with the routine detection methods. The excretion of even contains sodium nitroprusside, glycine, lactose and
a trace of these substances indicates ketonuria. disodium phosphate. The ketone group of acetone and
 Short-Term Monitoring of Glycemic Control 627

acetoacetic acid react with sodium nitroprusside at the the response to therapy. This is very useful in the intensive
optimal pH provided by the buffer system to give lavender care set up especially in situations of acidosis, and renal
or purple color. Lactose enhances this color. The reading insufficiency.16,17
is taken at 30 seconds. Sensitivity of this test to acetoacetic
Ketonuria should be sought–
acid is 0.012–1 mmol/L and to acetone is 4 mmol/L. • In a patient suffering from an acute illness.(hospi­
Testing of plasma or serum for ketones can also be talized patients, patients with acidosis, presurgical
performed using the above reagents. The test for both patients, pregnant women and persons with diabetes)

chapter
plasma and serum ketone estimation is read at the end when blood glucose levels exceed 240 mg/dL.

41
of 60 seconds. They can be performed in serial dilution as • In patients with symptomatic hyperglycemia.
well and are especially helpful in determining the severity • In a patient suffering from nocturnal hypoglycemia.
of ketosis in the treatment of diabetic ketoacidosis (DKA), • When patient has symptoms of DKA-nausea, vomiting,
provided the reagents are fresh.35 Tablets that appear abdominal pain.
moist and dark colored should not be used. • It should be part of the monitoring of
–– A pregnant female (pregestational diabetic or
β-hydroxy Butyric Acid gestational diabetic) to detect starvation ketosis.
–– A type 1 diabetic.
This ketone body, which is present in large concentra­
tions, is immeasurable by the conventional methods. Reference Values
Boiling the urine at an acidic pH to remove the acetone
and acetoacetic acid can allow estimation of this ketone Normal35
body. The b-hydroxybutyrate is converted to acetoacetic Urine ketones Negative (< 0.3 mg/dL or <0.05 mmol/L)
acid by hydrogen peroxide and can then be tested with Serum or plasma
Rothera’s reagent.35 Acetone: less than 2.0 mg/dL or less than 0.34 mmol/L
Acetoacetate: less than 1.0 mg/dL or less than 0.1 mmol/L
Commercial Test Strips  Beta hydroxyl butyric acid: 0.21–2.81 mg/dL or
These comprise a plastic strip, one end of which is impreg­ 20–270 pmol/L
“Testing for ketonuria should not be forgotten
nated with sodium nitroprusside and glycine. Precautions
especially in this era of blood glucose monitoring”.
in using these strips are the same as for glucose strips (vide
supra). Ketone test areas are also found in glucose test
BLOOD GLUCOSE
strips and on most of the multiple test strips.
Sensitivity: The test strips are sensitive to 0.5–1.0 Blood, plasma or serum glucose can be analyzed using
mmol/L of acetoacetic acid and 7–13 mmol/L of acetone. the same principle as described for urine glucose. Most
The reaction on the test strips can be interpreted semi­ standard laboratories now use the enzymatic methods
quantitatively, i.e. for the assay of BG.17 Ideal values for BG control are shown
Negative test = no ketonuria in Table 41.2.
+ (Small) = 0.5–4 mmol/L
++ (Moderate) = 4–10 mmol/L Reagent Strips34,35
+++ (Large) = >10 mmol/L Just as urine glucose can be estimated using test strips,
Stability: In urine samples, bacterial action will cause BG estimation can also be performed using test strips.
loss of acetoacetic acid in-vivo and in-vitro. Acetone is lost A drop of blood is obtained by a finger prick. The skin can
at room temperature but not if kept in a cold container be punctured by a needle or by various finger-pricking
or in a refrigerator. They should be ideally estimated in a devices comprising a lancet (which may be released by
fresh sample. a trigger). The procedure is quick and virtually painless.
Recently available is a test strip that measures Washing the hands in warm water, shaking the hands,
3-b hydroxybutyric acid. This test strip can also be read and avoiding spirit—which tends to harden the skin—
on a meter. This quantitative analysis is superior to urine could minimize pain. The finger is pricked on its lateral
ketone testing both for diagnosing ketosis and monitoring aspect, which has relatively fewer nerve endings so as to
628 Management

Table 41.2: Glycemic control for non-pregnant adults with diabetes capillary beds of the forearm and fingertip, regardless
ADA 2013 target modifications of how the glucose was assayed.38,39 The palm and the
• Preprandial capillary plasma glucose: 70–130 mg/dL
ball of the thumb do not show the same lag and hence
(3.9–7.2 mmol/L) may be better alternate sites than the fingertip.40
• Peak postprandial capillary plasma glucose: less than 180
mg/dL (< 10 mmol/L) Alternates to Lancing Devices
• HbA1c less than 7.0%
• Several companies make glucose testing devices that
section

Key concepts in setting glycemic goals only require a small drop of blood. The devices draw
8

• Postprandial values should be measured 1–2 hours after the blood from the upper arm or the thigh, areas that are
beginning of a meal and the highest value should be considered
less sensitive to pain as compared to the finger tips.
as the peak value.
• One device uses light suction to hold the skin firmly
• Goals should be individualized depending on the duration of
in place while an integrated lancet draws the blood.
diabetes, age or life expectancy, comorbid conditions, hypogly-
cemia unawareness and the presence of cardiovascular disease The drop is applied automatically to the test strip with
(CVD) or microvascular complications results in 20 seconds.
• Certain populations (children, pregnant women and elderly) • The Lasette draws a drop of blood from the finger—
require special consideration using a Laser. The Laser creates a small painless hole
• Less intensive goals may be indicated in patients with severe or in the skin producing only a mild tingling sensation.
frequent hypoglycemia. Lasers may penetrate less deeply and hence the sample
• More stringent glycemic goals (A1c < 6%) may reduce complica- is obtained from areas of lesser blood flow, which
tions at the cost of increased risk of hypoglycemia, particularly in again may result in glucose lags. The drop of blood so
those with type 1 diabetes obtained is transferred on to a test strip which has the
• Postprandial glucose may be targeted if A1c goals are not met reagent incorporated on to it.
despite correcting preprandial glucose goals.
• Also, efforts are being made to develop devices that
would replace fingerstick testing and lancets altoge­
minimize the pain. However, the pain and inconvenience ther. We shall discuss Non-invasive Blood Glucose
of the prick still acts as a deterrent to compliance with Monitoring in another section.
glucose monitoring.36 Efforts need to be made to modify Test strip techniques could be classified into:
technology to eliminate the pain altogether. 1. Those that use the “wipe technique” i.e. the drop of
blood is wiped (dry wipe) or washed (wet wash) off
Alternate Site Testing37 the strip after a stipulated reaction time—these strips
today are only of historic value.
Blood glucose readings obtained from the fingertip closely 2. Those that use the “no wipe technique” i.e. all that the
correlate with arterial BG levels. However, pain associated patient has to do is to add on a drop of blood to the rea­
with lancing is most severe at the fingertip and this is one gent strip which determines the BG after the given time
of the hindrances to SMBG. interval.41
Hence alternate sites for BG estimation were sought. The semiquantitative measurement of BG by a
The palm, volar forearm, upper arm, abdomen, anterior reagent strip method covers the range from 1 mmol/L to
thigh and pretibial region have also been evaluated as 44 mmol/L (20–800 mg/dL). There are two separate
sites for blood procurement. The inadequate sample test areas in each strip, which make it possible to assay
size and the variation in BG estimated at these sites are the BG in this range. These are suitable for use in an
major drawbacks to the use of these sites. The increment emergency situation by health centers and small hospital
of glucose after a meal and its reduction after insulin are laboratories unable to measure BG by a colorimetric
delayed by approximately 30 minutes in the forearm as technique. Test results are stable for several days. Foil
compared to the fingertip. This poses a major drawback packed strips are more expensive than strips stored in
in diagnosis of hypoglycemia. The mechanism for the containers. Cutting the strips in half, using sharp scissors
above appears to be related to the variations in blood can reduce costs. There appears to be no loss of accuracy
flow in these sites. Recent studies however have reported with half strips provided the strips are used within a day
no significant difference between glucose levels at the of cutting.35,41
 Short-Term Monitoring of Glycemic Control 629

Quality Control • Machines are also available which incorporate a voice

guide for the visually impaired.
Control glucose solutions are available for testing the
The accuracy of BG monitoring is instrument and user
accuracy of the strips. The strips can be stored at 30°C in a
dependent. Use of calibration and control solutions helps
tightly stoppered container protected from humidity and
ensure accuracy of results. Plasma glucose values are
bright light.35
10–15% higher than whole BG values. Instruments
Most strips use glucose oxidase methods. Full
however are not uniformly calibrated. Some manu­

chapter
instructions are supplied with the products and must be
facturers calibrate the instrument according to venous
followed exactly. Test strips that are read visually may be

41
plasma and others according to the capillary whole blood.
less accurate, giving an approximate rather than actual
The meter user has to know whether his instrument is
glucose level. However, the accuracy is good enough for
calibrated according to plasma or whole blood.
most and these methods can be performed at anytime,
There is reasonable correlation between the results
anywhere.42,43 Some of these strips may also be saved for as
obtained with the glucose meters and the laboratory
long as a week to be read by the physician (as a cross check
results, especially with systems using the no wipe system,
or to test the veracity of the patients reports).
but readings at hypo and hyperglycemic levels need
“Strip reading or reflectance meters”44 have been
scrutiny in a central laboratory.45,46
introduced and have improved the accuracy of BG levels
obtained by strips. Originally they were cumbersome,
Evaluating SMBG Systems
expensive and difficult to use. Newer models are smaller
(the size of a pocket calculator) easier to use and cheaper. Intensive glucose control invariably necessitates the
The meters work on two principles: accurate and frequent monitoring of BG levels and thus,
1. Reflectance photometry: They measure reflected light the SMBG results are, today, becoming increasingly
bouncing off the strip (containing the chromogen product important in the management of both type 1 and type
obtained by the reaction of glucose with glucose oxidase) 2 diabetes.47 Thus, the American Diabetes Association
and convert it into numerical values, which can be read off (ADA) today recommends at least 3–4 SMBGs a day
the meter. especially for patients with type 1 diabetes. The clinical
2. Amperometric electrochemistry: This system is consequence of the obtained SMBG value is a change in
one in which the electric current generated by glucose the therapeutic regimen that the patient is being treated
oxidation is measured by a sensor. The current generated with. Hence, the SMBG values need to be scrutinized
is proportional to the glucose concentration and can be closely. The method that is used to estimate error should
converted into a digital display. be such that it confirms the absolute value obtained by
The use of strips and reflectance meters is increasing the laboratory. The reference laboratory values and the
primarily when SMBG values therefore have to be as close as is possible.48
• Accuracy is desired. Statistical measures of deviation or correlation would
• Intensive insulin therapy is being used. not help a clinician manage instantaneous BG. These
• For visually impaired individuals. techniques would also not be useful to evaluate new
SMBG instruments.
Additional Features The ADA in 1987 recommended that the total error
(systems + user) should be less than 10% for all SMBG
• Machines now display the date and time of testing. systems for BG values between 30 mg/dL and 400 mg/dL.49
• In some meters, strips will draw blood from the These guidelines, however, have the limitation that all BG
puncture site, eliminating finger sticks and use less measurement errors of a given percentage may not have
painful sites. equal clinical significance.
• Instruments are also fitted with a computerized Hence, Clarke and his group of investigators intro­
memory and can be used with personal computers duced an error grid to evaluate SMBG values with respect
with a facility for extensive data management: to store, to laboratory gold standard readings.50,51
recall, analyze trends, calculate average readings and The “Error Grid analysis” is a method which assigns
display in a variety of formats the results of all the tests a specific level of risk to any possible SMBG error. Each
performed over a certain period. point on the grid is a plot of true BG versus the glucometer
630 Management

value. Each of the points on the grid is assigned a risk level one moves radially from the line of identity. This pattern
based on the clinical judgment of the investigators.52 contains no discontinuous risk category.
The assumptions underlying the assignment of risk The risk categories, in order of increasing severity, in
boundaries are: this paper were defined as follows:
• Target BG is 70–180 mg/dL and patients will only A. No effect on clinical action;
attempt to correct values outside that range. B. Altered clinical action or little or no effect on clinical
• Corrective treatment by the patient is inappropriate if it outcome;
section

results in BG levels outside the target range. C. Altered clinical action—likely to effect clinical outcome;
8

• Failure to treat BG less than 70 mg/dL and more than D. Altered clinical action—could have significant medical
240 mg/dL is inappropriate. risk; and
These assumptions formed the basis of the five risk E. Altered clinical action—could have dangerous conse­
levels, which are labeled and defined as follows; quences.
A. Self-monitoring of blood glucose less than 20% devia­ This survey (type 1 and 2 diabetes) was based on
tion from true BG or both SMBG and BG less than 70% specific descriptions. Thus, both these Error Grids have
mg/dL; some degree of arbitrariness.
B. Deviation from true BG more than 20% but leads to no These methods can and should be modified before
treatment or benign treatment; they can be used universally. Nevertheless, the principle
C. Over correction of acceptable BG levels; of Error Grid analysis has been applied by many scientists
D. Dangerous failure to detect and treat BG error; and to evaluate the patient data and also to evaluate the
E. Erroneous treatment (i.e. treatment contradictory to that performance of the newer glucose meters. Today this
actually required). principle has also been put to use to evaluate Continuous
The following True Blood glucose/:/SMBG readings Glucose Monitoring Systems (CGMS).
would be categorized as follows:
• 70 mg/dL/:/80 mg/dL; 300 mg/dL/:/310 mg/dL would Self-Monitoring of Blood Glucose
fall into risk category A In type 2 DM blood glucose levels are reasonably stable
• 70 mg/dL/:/100 mg/dL would fall into risk category B from day to day. The blood glucose fluctuates in a pattern
• 90 mg/dL/:/240 mg/dL or 70 mg/dL/:/200 mg/dL similar to non-diabetic subjects with higher plasma
would fall into risk category C fasting and post-prandial peaks.53,54 There exists a good
• 300 mg/dL/:/150 mg/dL or 50 mg/dL/:/100 mg/dL correlation between fasting plasma glucose, mean daily
would fall into category D plasma glucose and HbA1c levels in type 2 subjects.55
• 50 mg/dL/:/200 mg/dL would fall into risk category E. Therefore, a single random, preferably fasting BG gives a
This Error Grid could be criticized on the placement of good indication of control in these subjects.56
its boundaries, some of which skip risk categories. In type 1 patients, BG levels fluctuate widely throughout
Joan Parkes et al.48 therefore sought to produce an updated the day and are, in addition, unpredictable from day to
Error Grid based on the clinical judgment of a large day. Therefore fasting, prandial and random BG values are
number of clinicians: only applicable to the day of test. There is poor correlation
• They allowed the clinicians to determine risk based on between occasional BG testing and indicators of long-
their clinical expertize. term glycemic control viz. HbA1c.57 Best assessment of the
• Clinician responses were based on clinical descriptions variation in BG concentrations in the day is provided by
of hypothetical patients with type 1 and type 2 diabetes. serially timed measurement either at hospital or at home.
• To make a consensus Error Grid from the 100 responses In 1978, the first reports of SMBG appeared in
the five risk categories were assigned the values 1, 2, 3, literature.58,59 The concepts of involving the patient in the
4 and the weighted average obtained. diabetes care programs caught on in a big way thereafter.60
• To facilitate the use of the Grid, these average values The ADA held two consensus development programs
were converted mathematically to the glucose values on SMBG in 1986 and 1993 and since then this has become
in mg/dL and these values were used to draw the graph. an important component of diabetes management espe­
The risk zones in this Error Grid fan out from the 45° cially of intensive therapy aimed at meticulous glucose
line in a relatively simple pattern of increasing risk as control.61,62
 Short-Term Monitoring of Glycemic Control 631

Table 41.3: Situations where mandatory self-monitoring of blood is an excellent educational aid, increases patient
glucose (SMBG) is required participation, motivation and interest.
• Pregnant diabetics The patient is thus in control of his disease and has an
• Propensity to ketoacidosis improved quality of life; and thus has reduced hospital
• Acute illnesses admissions.
• Surgical emergencies However, a dampener to the routine use of SMBG is
• Intensive regimens: Basis for fine tuning insulin regimens and its considerable cost. Blood glucose strips are at least ten

chapter
warning against possible pump failure times as costly as the urine glucose strips based on the

41
• Recurrent hypoglycemia similar principle.
• Brittle diabetes
• Voluntary fasting
Training and Quality Control
• Hypoglycemia unawareness
• Acute and severe peripheral neuropathy Self-glucose monitoring has to be a part of an integrated
• Altered renal thresholds treatment program.28,41,65 The goals of treatment have to
• To achieve closer diabetes control be defined clearly, thus providing the reason to perform
SMBG. Patients should be capable of learning the proper
An educational program that helps the patient use of SMBG and should be motivated and willing to
understand the factors affecting the BG level and provides perform the tests accurately, and committed to modifying
appropriate options for correcting adjustments should the treatment plan [medical nutrition therapy (MNT),
accompany all home glucose monitoring programs.17,28 pharmacologic therapy and lifestyle] accordingly. Most
children and adolescents are eminently trainable and in
Indications one study 68% of tests done by strips (visual readings) did
not exceed 20% of the correct value.42 Such an individual
Normoglycemia, i.e. BG levels similar to non-diabetics
should also possess a stable personality psychologically.
is the ultimate goal of diabetes management. The ADA
The therapeutic benefits of SMBG accrue from using
guidelines recommend, based on the DCCT trial that most
the results to select appropriate insulin dosages and to
individuals with diabetes should attempt to achieve and
adjust diet.67 SMBG performed by type 2 diabetic patients
maintain BG levels as close to normal as safely possible.
on diet or oral hypoglycemic agents (OHAs) is useful to
This can be achieved by SMBG, which gives a quick
reinforce dietary principles and reveal benefits of diet
feedback on the glycemic status. It can be cross-checked
and exercise.68 The patient should not consider SMBG as
in the laboratory and requires a small amount of blood.
an annoying and unpleasant reminder to the presence of
Newer devices obtain blood as painlessly as possible, (vide
an incurable disease.
supra) and have increased compliance to the program.
As one can obtain real time glucose values63 with this Poorly performed tests can be misleading and are
method, therapeutic goals can be clearly defined and fraught with the danger of inappropriate therapeutic
diabetes control can be assessed and modified even as action. These could be due to “technical errors or instru­
the patient carries out his daily activities. The patient can ment errors” (Table 41.4).65
control his insulin dose on a day-to-day basis and the
Patient Technique
records can be verified and corrected by the physician. It
can signal possible emergency situations. Therefore it is • Insufficient blood sample; smearing of sample;
popular as the mainstay of monitoring diabetes control. incorrect blotting technique.
All treatment programs for type 1 diabetes and insulin • Manipulation: Incorrect timing; testing only when
treated type 2 diabetes should encourage SMBG and ill; recording only good readings; recording only at
itis especially mandatory in the following situations specific times; recording unperformed tests.
(Table 41.3).63-66 • Physiologic factors: Altered hematocrit; visual impair­
The advantages of SMBG are: Allows the management ment.
team to set goals for the patient to aspire to; defines the
level of glycemic control achieved in routine clinical asses­ Instrument Errors
sment and research; identifies hypoglycemia episodes • Standard of manufacturer of the test strips, out of date
especially in patients with hypoglycemia unawareness; and badly stored strips.
632 Management

Table 41.4: Situations and substances that interfere with the perfor- Table 41.5: Targets of glycemic control for young healthy type 1
mance of the glucometer diabetes mellitus (T1DM) on intensive insulin therapy [Capillary
The performance of the glucometers depends on the blood glucose (mg/dL)]
Time Ideal Acceptable
• Ambient temperature
Fasting or premeal 70–105 105–130
• Light and moisture
Postprandial
• Altitude
1 hour 100–160 160–180
• When the glucose level is above 300 mg/dL, an elevated hema- 2 hours 80–120 120–150
section

tocrit (> 55%) can lower (15%) the glucose results, likewise low
Bedtime 100–140 140–160
hematocrits (< 35) can increase the glucose results by as much
8

2.00 AM 70–105 105–130

as 10%
• Severe dehydration and excessive water loss can produce
falsely low readings • Coexisting medical illnesses where a motivated
• Sweat is acidic and hence touching the strips may affect the caretaker will have to be involved.71
values
Medications
Timing
Refer to the following document for cautionary statements in the Continuous blood glucose monitoring would give the most
use of the glucometers http://www.fda.gov/medicaldevices/dev- accurate picture of the 24-hour trends in BG (described
iceregulationandguidance/guidancedocuments/ucm094134.htm
below). However, a seven-point profile, before and 120
• Medications
minutes after each of the three main meals and at bedtime
• Endogenous substances
gives a reasonably detailed picture of the day’s trends. The
– Uric acid, glutathione, Vitamin C
frequency and timing of SMBG will depend on the clinical
• Exogenous substances
indication and the treatment program and the needs and
– Acetaminophen, Ascorbic acid, Dopamine, Ephedrine,
goals of the individual patient.
Gentistic acid, Ibuprofen, L-DOPA, Methyldopa, Salicylates,
Tetracycline, Tolazamide, Peritoneal dialysis solution that
contains icodextrin interfere with blood glucose monitoring Frequency of Blood Glucose Monitoring67
systems based on the glucose dehydrogenase-pyrroloquin-
olinequinone (GDH-PQQ) method. Self-monitoring of blood glucose should be performed
more frequently in labile type 1 diabetes for most patients
with type 1 diabetes, SMBG is recommended three or
• Calibration of the glucose meters.
four-times daily by the ADA (Table 41.5).
• Self-monitoring of blood glucose results may be
Patients on multiple-dose insulin (MDI) or insulin
fabricated to please physicians or caretakers and to
pump therapy should do SMBG at least prior to meals
avoid the unpleasantness that accrue from high blood
and snacks, occasionally postprandially, at bedtime, prior
sugars.69,70
to exercise, when they suspect low blood glucose, after
• It is therefore important that the medical team evaluates
treating low BG until they are normoglycemic, and prior to
each patient’s monitoring technique both initially and
critical tasks such as driving.
at regular intervals thereafter. Simultaneous laboratory
The optimal frequency of SMBG for patients on non-
testing should evaluate the accuracy of SMBG tests at
intensive regimens, such as those with type 2 diabetes on
least once in 3 months.
basal insulin, is not known, although a number of studies
have used fasting SMBG for patient or provider titration of
BARRIERS the basal insulin dose.72
• Cost of testing. The evidence base for SMBG for patients with type 2
• Discomforts of finger prick sampling. diabetes on non-insulin therapy is controversial. The cost
• Inconvenience pertaining to time and complexity and of routine SMBG in non-insulin-treated patients is
physical setting. exorbitant compared to the reported effect (HbA1c reduc­
• Inadequate understanding by patients of the benefits tion by 0.25% at 6 months). A Cochrane review concluded
and proper use of SMBG. that the overall effect of SMBG in such patients is
• Poor education and insufficient patient motivation by small up to 6 months after initiation and subsides after
the healthcare team! 12 months.66,73
 Short-Term Monitoring of Glycemic Control 633

Self-monitoring of blood glucose may be desirable hyperglycemia. Stringent round the clock control with
in patients treated with sulfonylureas or other insulin minimal adverse reactions could then be achieved. This,
secretagogues and in all patients not achieving glycemic however, may not be possible in all the patients for various
goals. The role of SMBG in stable patients treated with MNT reasons. Such testing is absolutely essential in pregnancy.
is not known. SMBG performed by type 2 diabetes patients The medical team should evaluate at regular intervals
on diet or OHAs is useful to reinforce dietary principles the patient’s ability to use SMBG data to guide treatment.
and reveal benefits of exercise and medication.67 Several glucometers are available that can store test

chapter
The tests should also be performed in relation to results and can be hooked up to computers to provide

41
meals, exercise, injections, and symptoms related sophisticated analyses to BG data. Nevertheless, a well
to the disease state.65 SMBG should be performed to maintained written logbook could serve this purpose as
establish hypoglycemia in subjects with angina pectoris, well (ADA 2004).
cerebrovascular disease and those on b-blockers.41 An
assay should be undertaken prior to performing critical Office Blood Glucose Measurement8,17,41
tasks like driving a motor vehicle.41 It should be performed
with increasing frequency in patients suspected of There is a need for performing the office blood glucose test
suffering from nocturnal hypoglycemia and in pregnant • For those not routinely performing SMBG, the office
patients.74 test is vital. It is the only method of monitoring in
Targets for ideal BG control on SMBG have been common use.
defined in (Table 41.2); they however should be indivi­ • When a patient is performing SMBG it helps to
dualized and should be wide enough to be acceptable. The determine the precision of the SMBG that the patient
dangers of hypoglycemia should be borne in mind while has reported. ADA recommends its use only for this
establishing targets especially for the elderly and those purpose. It also recommends the use of office testing in
with comorbid vascular disease. patients on oral medications for adjusting their dose.
Even in a developed country like USA only 40% of • In conjunction with urine glucose levels, it can help the
type 1 diabetics and 30% of type 2 diabetics perform physician to determine the renal threshold, as well as
routine SMBG.75 A study performed 8 years later reported provide a picture by which the current state of diabetes
that 24% of insulin-treated patients, 65% of those on oral control can be evaluated.
medications, and 80% of those treated by diet and exercise
alone either never performed SMBG or did so less than Indices of Blood Glucose Variation
once per month. Daily SMBG (at least one BG check
per day) was reported by only 39% of patients treated Serial BG values can be used to calculate several numerical
with insulin and just 5% of those treated with either oral indices, which can be used for research purposes.17
medications or diet and exercise.76 A large International study has established a strong

Efforts should be made to substantially increase the correlation between CGMS and HbA1c in Caucasian adults
use of SMBG.66 which led to a formula to derive estimated average glucose
Record keeping is an additional aspect of SMBG that is which has been recommended by the ADA in 2009.
integral to treatment.41
Non-invasive Blood Glucose Monitors
Good Records Technology developments in glucose monitoring have
• Help guide the physician during office visits. been targeted at reducing the pain and inconvenience of
• Allow the patient to notice subtle changes in his acquiring measurements so that glucose can be checked
condition. more often daily for better glycemic control. However,
• Help to understand the pattern of BG values and the glucose meters just discussed all use a blood sample
therefore offer an insight into the action and interaction and require user intervention to collect and measure
of insulin with other factors that control blood glucose that sample. Two new developmental approaches aim
levels. at making glucose measurement even easier and less
Knowledge of the temporal profile of BG would painful. Non-invasive measurement eliminates the need
help in anticipating hypoglycemia and help to prevent to violate the skin to acquire a usable sample. Continuous
634 Management

monitoring, where measurements are taken repeatedly The absorption can be spectroscopically determined by
and automatically over time, creates a long-range glycemic comparing measured and predicted amounts of thermal
profile from those frequent readings. energy at the skin surface and the difference can be
converted to a measure of BG concentration.
Interstitial Fluid Methods77 Radio wave impedance: When a radio wave passes
These minimally invasive techniques use various means through an aqueous solution that contains a non-ionic
of harvesting interstitial fluid from the skin. The rationale solute, such as glucose, the solute interacts with the beam
section

behind these tests is that interstitial fluid glucose is direc­ to attenuate the amplitude and shift its phase. Blood
8

tly proportionate to the blood glucose concentrations glucose is the non-ionic solute present in the highest
molar concentration. Using a conversion factor, the
The US Food and Drug Administration (FDA) has
glucose concentration in blood can be calculated from
approved the Glucowatch G2 Biographer78 manufactured
measuring the impedance of the radio wave as it passes
by Cygnus Inc.—a non-invasive blood glucose monitoring
through the fingertip.
system for use in adults, children and adolescents with
Polarized light: If a beam of polarized light is passed
diabetes. The device, which looks like a wristwatch is worn
through a fluid containing glucose, the polarization plane
on the forearm, pulls interstitial fluid from skin using
rotates in proportion to the concentration of glucose in
small electric currents. It has a lag time of about 5 minutes.
that fluid. A beam can be passed through a component
It can provide six measurements per hour for 13 hours.78
such as ocular aqueous humor and the amount of rotation
A transdermal patch called the TD glucose patch is
used to calculate the glucose concentration.
another method approved by FDA.77 This patch is placed
The devices being developed can be categorized as
on the skin for 5 minutes. It draws the interstitial fluid implantable, transdermal, and spectroscopic sensors.
using combination of skin enhancement medium and One device being developed features laser poration
reverse iontophoresis for transporting the glucose in the of the stratum corneum of the skin, followed by vacuum
interstitial fluid through the stratum corneum. Reverse extraction of interstitial fluid to an electrochemical sensor.
iontophoresis is the basis of transdermal glucose sampling Another similar device pretreats the skin with ultrasound
with the device under discussion. Because skin carries a net to optimize its permeability. An electrochemical sensor
negative electrical charge, positive sodium (Na+) ions can placed on the pretreated site measures the extracted
migrate more freely and carry most of the iontophoretic glucose. Both devices have undergone preliminary clinical
current. Migrating sodium ions create an electroosmotic trials.
fluid flow through the skin that carries neutral molecules Yet another technique assesses the viscosity of fluids
such as glucose out of the body. The amount of glucose under the finger tips in order to measure solutes.
collected by reverse iontophoresis correlates well with BG,
with an average lag time of 5 minutes.41 Continuous (Ambulatory)
Blood Glucose Monitoring
Other Methods of Non-invasive
A continuous glucose monitoring system is an FDA
Blood Glucose Monitoring79
approved device that records glucose levels throughout
Researchers are actively developing other methods of non- the day and night. The only approved device, Medtronics
invasive monitoring. The methods under study include:77 MiniMed device80 provides up to 288 glucose measure­
Near infrared radiation spectroscopy: It uses an ments every 24 hours. The system is used to measure BG
external light source whose wavelength is just above the for up to 3 days while the patient continues daily activities
visible spectrum. The light passes through or is reflected at home. The life of the sensor is now considered to be
by a body part and glucose and other blood constituents 7 days; hence it can be deployed for this period. It has a
absorb a small amount of light at each wavelength. The capacity to store data generated over 14 days.
reflected light is analyzed to determine the BG level. The MiniMed device comprises a tiny glucose-sensing
Mid-infrared radiation spectroscopy: It measures device called a “sensor” which is inserted under the skin of
natural thermal emissions or body heat. When radiation in the abdomen and held in place by a tape. The sensor has a
the mid-infrared, well outside the visual spectrum, passes platinum electrode, a glucose oxidase layer, a membrane
out of the body, glucose in the blood absorbs part of it. allowing conversion of glucose + O2 to glucuronic acid and
 Short-Term Monitoring of Glycemic Control 635

water generating electric current. The sensor measures glucose readings from the monitor and considers other
the level of glucose in the tissue every 10 seconds and information entered, e.g. target BG, insulin sensitivity,
sends the information via a wire to a device called a insulin to carbohydrate ratios, and calculates the amount
“monitor” attached to the belt or the waistline of the pants. of insulin bolus required. The dosing errors that would
The system records an average glucose value every occur if the calculations are done manually are therefore
5 minutes for up to 72 hours or more. eliminated.
Results of at least four finger stick BG readings taken

chapter
with a standard glucose meter and taken at different times Fructosamine and Glycated Albumin82

41
each day are entered into the monitor for calibration.
Insulin taken, exercise engaged in and meals and snacks Serum proteins, 70% of which is albumin, react with
consumed are all entered into a paper-based log and glucose to form an aldamine linkage, which undergoes an
recorded into the monitor. It is recommended that three Amadori rearrangement to form a ketamine. Fructosamine
calibrations are done with each sensor. It is important is the generic name for the protein ketamine product.84
not to calibrate when there will be large variation, such Quantitation of glycated protein can be used as a measure of
as postprandial period or for approximately one hour long-term glycemic control over appropriately the lifetime
following hypoglycemia or hyperglycemia. of albumin, i.e. 2–3 weeks (14–20 days).17,83 Fructosamine
After 3 days, the sensor is removed and the information correlates well with HbA1c in stable diabetics and less well
stored into the CGMS is downloaded into the computer, when control has altered over a week or so.83 It can be
wherein the information is analyzed and presented as assayed colorimetrically, or by affinity chromatography or
graphs or charts that can help reveal the pattern of BG by immunoassay.84
fluctuations. This device reveals only the trends of glycemic Colorimetry is interfered with by lipemia, serum
excursions. The CGMS does not provide information for bilirubin, ascorbate, hemolysis, uric acid and urea. This
individual tests and it is not intended for long-term self- assay has to be modified to avoid interference from the
care. Since the results are downloaded into a computer, above substances.85
this is not a real-time event analyzer. Hence, it must be
The affinity chromatography assay has good precision,
used in conjunction with and is not a replacement for
low cost and is easily automated. Hence, it is an alternative
standard blood glucose monitoring. It can be used in an
to HbA1c. It is especially useful in pregnancy as maternal
individual patient as often as the physician considers
fructosamine correlates better with fetal hyperinsulinemia
necessary. CGMS technologies are continuously impro­
than HbA1c.17,82 The half-time for fructosamine change is
ving.81 A real-time CGMS system is also available and can
be used with great advantage in critically ill diabetics. 12 days with the period of control being about 30 days.84
Advantages: CGMS can help to identify fluctuations However, it is not applicable in the event of a systemic
and trends that otherwise are unnoticed with intermittent illness due to the increased turnover of body proteins in
testing. The device could catch dangerously low night BG that condition or with liver disease where the synthesis of
levels; could give an idea of in-between meal glycemic albumin is affected.
trends, reveal the early morning peaks in BG levels and Glycated albumin assays are especially useful in
unravel how lifestyle could affect BG. situations where HbA1c cannot be measured or may not
Clinical applications: The CGMS device has been be useful (hemolytic anemias). This assay is useful to
tested and found useful in pediatric patients, gestational document short-term changes, e.g. pregnancy in a diabetic
diabetes and in continuous subcutaneous insulin infusion or major changes in therapy.
(CSII) initiation. Glycated fibrinogen reflects mean BG excursions over
2–3 days and can be measured by affinity chromatography.84
New Monitoring Device Developments
In July 2003, the FDA approved the first wireless combi­
Serum 1,5 Anhydroglucitol (AG)
nation system consisting of a glucose monitor and Anhydroglucitol 1-deoxyglucose is a naturally occurring
an intelligent insulin pump (Medtronic MiniMed analog of glucose, which is obtained from food. Its levels
and Becton Dickinson). In this system a BG monitor are approximately 90–200 mmol/L in healthy subjects.86
automatically sends BG readings taken in the monitor to There is competition between glucose and anhydroglucitol
a subcutaneous continuous insulin pump, which takes the for urinary excretion and hence a curvilinear relation
636 Management

exists between plasma AG and urinary glucose. Serum AG 6. Heine RJ, Mooy JM. Impaired glucose tolerance and uni­
levels will depend on the number of times plasma glucose dentified diabetes. Postgrad Med J. 1996;72:67-71.
crosses the renal threshold and may be an index for 7. Intensive blood sugar control with sulfonylureas or insulin
compared with conventional treatment and risk of com­
glucose excursions.87 The use of AG as a marker of diabetes plications in patients with type 2 diabetes (UKPDS 33).
control has been proposed by several authors but is still UK Prospective Diabetes Study (UKPDS) Group. Lancet.
not widely accepted in several countries.86,87 1998;352:837-53.
The ideal monitoring system should be simple, cheap 8. Cooppan R. General approach to the treatment of diabetes.
section

and reliable. It should be understood and useful to the In: Kahn CR, Weir GC (Eds). Joslin’s Diabetes Mellitus, 13th
edition. Philadelphia: Lea and Febiger; 1994. pp 397-403.
8

physician—be a tertiary care physician or a primary care

9. Krowlewski AS, Warram JH. Epidemiology of the late com­
physician—and to the patient. The patient should be at plications of Diabetes. In: Kahn CR, Weir GC (Eds). Joslin’s
least capable of adjusting the treatment on the basis of Diabetes Mellitus, 13th edition. Philadelphia: Lea and Fe­
glycemic excursions, solve his day-to-day problems and biger; 1994. pp. 605-19.
avoid hypoglycemia. Awareness that frequent monitoring 10. The Diabetes Control and Complications Trial Research
Groups. The effect of intensive treatment of diabetes melli­
will reduce the morbidity of diabetes and will be cost-
tus on the development and progression of long-term com­
effective in the long run is an important message that plications in insulin dependent diabetes mellitus NEJM.
should be driven home. In an era where there is discussion 1993;329:977-86.
about strategies to prevent diabetes and controversy over 11. Gruber W, Lander T, Lease B, et al (Eds). The economics of
whether IGT should be treated, India and many developing diabetes and diabetes care: a report of diabetes health eco­
nomics study group. Brussels: An IDF WHO Publication;
countries have a long way to go in the development of
1997.
efficiency and cost-effective health care program for 12. World Bank. World development report 1993: investing in
diabetics. health. World development indicators. Oxford University
Press; 1993; pp. 213-4.
FURTHER READING 13. ADA Diabetes Clinical Practice Recommendations, 1998.
Components of the initial and continuing care visits. Dia­
1. ADA 2013 Guidelines. Diabetes Care. 2013;36:S11-S66. betes Care. 1998;21:S23-S31.
2. Lane JE, Shivers JP, Zisser H. Continuous glucose monitors: 14. American Diabetes Association. Standards of Medical Care
current status and future developments. Curr Opin Endo­ in Diabetes, 2013 Diabetes Care. 2013:36:S11-S66.
crinol Diabetes Obes. 2013;20:106-11. 15. Guralnik DB. Webster’s New World Dictionary. Calcutta:
Amerind Publishing Company Co. (Pvt) Ltd.
16. Cohen M. Monitoring diabetes with urine tests. In: Albertis
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 Chapter 42
Continuous Glucose
Monitoring System
Jothydev Kesavadev

Continuous Glucose Monitoring

Chapter Outline
♦♦ What is Continuous Glucose Monitoring System? ♦♦ Continuous Glucose Monitoring: Studies from India
♦♦ Continuous Glucose Monitoring Technology ♦♦ Indications for Continuous Glucose Monitoring
♦♦ History of Continuous Glucose Monitoring ♦♦ Merits of Continuous Glucose Monitoring
♦♦ Clinical Utility of Continuous Glucose Monitoring ♦♦ Demerits of Continuous Glucose Monitoring
♦♦ Continuous Glucose Monitoring: Our Experience ♦♦ Limitations of Continuous Glucose Monitoring in India

INTRODUCTION use in patients with brittle diabetes and in those with

lack of correlation between blood sugar and hemo­
Self-monitoring of blood glucose (SMBG) and adjusting globin A1c (HbA1c), finally to prove as an invaluable tool
dosages of drugs and lifestyle accordingly, are proven for investigation in diabetes at any stage including
to be most effective in maintaining glycemic targets. prediabetes.
Although glucose monitors were invented in the 1970s,1
they became popular only during the last decade. The WHAT IS CONTINUOUS GLUCOSE
American Diabetes Association introduced SMBG as a MONITORING System?
vital component in diabetes care in 19872 and current
recommendations suggest regular SMBG in persons with A CGMS is a Food and Drug Administration (FDA)-
diabetes based on each patient’s needs.3 In India, home approved device that records blood glucose levels
blood glucose monitoring is still unpopular among the vast throughout the day and night. It can provide up to 288
majority of patients. However, the growth and acceptance blood glucose measurements every 24 hours. A tiny
of glucometers have been remarkable. glucose-sensing device called a sensor is inserted just
In the recent years, practice of medicine irrespective under the skin of the abdomen. The insertion is quick, and
of the specialty is depending more and more on techno­ is usually painless and a tape is used to hold it in place.
logical advancements. Continuous glucose monitoring The sensor measures the level of glucose in the tissue every
systems (CGMSs) have emerged as a poten­tially powerful 10 seconds and sends the information to a cell phone-
tool poised to redefine the concept of SMBG in diabetes sized device called a monitor. The system automatically
management. Continuous glucose monitoring (CGM) records an average glucose value every 5 minutes while the
emerged as a research tool initially, soon finding its patient continues his routine activities. Results of finger
640 Management

stick blood glucose readings taken with a standard glucose

meter and taken at different times each day are entered
into the monitor for calibration. Medications taken,
details on diet and exercise and any special activity are
also recorded. The sensor is removed and the information
stored is downloaded into a computer. Alternatively,
iPro2 is a stand-alone device (Medtronic) where the
section

patient is not required to interact with the device.

8

CONTINUOUS GLUCOSE
MONITORING TECHNOLOGY
There are two types of CGM devices; the most common
is the transmitter which transmits the CGM data to a
monitor and the patient may view the real-time data.
The second type is a recorder and is a blinded device
(the patient can view the data only when downloaded). A Fig. 42.1: Sensor needle in the interstitial fluid
typical CGM system consists of a glucose oxidase-based, Rebrin K, Steil GM, van Antwerp WP, et al. Subcutaneous glucose
electrochemical sensor inserted through the skin using predicts plasma glucose independent of insulin: implications for
continuous monitoring. Am. J. Physiol. 1999;277(3 Pt 1):E561-71.
a needle introducer, a transmitter that is fixed onto the
sensor and a receiver that picks up the interstitial fluid (IF)
signal. The oxidation of interstitial glucose by the sensor continuous accuracy of sensor data. Such calibrations
generates an electrical current. The electrical current transform the sensor signals into matching capillary
data are filtered and cleared from background noise by glucose levels and assumes that the plasma to IF glucose
the transmitter and sent to the receiver which provides gradient remains relatively constant.10 Recalibration
an approximation of the blood glucose level.4 iPro2 at fixed intervals is required to overcome signal drift
CGM systems include a glucose sensor and a small data issues.11 Calibration should take place when blood glucose
recorder, which automatically record glucose information. levels are relatively stable when the rate of change in
The glucose data can be obtained at every 5 minutes sensor glucose values is less than ± 0.5 mg/dL/minute.12,13
intervals (Fig. 42.1).
The sensor measures the IF glucose5 where a lag of HISTORY OF CONTINUOUS
average 15 minutes is associated with the sensor glucose GLUCOSE MONITORING
levels when compared to blood glucose levels. This Although CGM as a technology is more than 50 years
happens due to the physiologic delay in transferring old,14 CGM devices that measure IF glucose values
glucose between the blood and IF space (approximately continuously were first introduced approximately 10 years
2–8 minutes), the transit time of IF glucose through the ago. Evolution of CGM can be traced back to the mid-
sensor membrane (1–2 minutes) and signal filtering 1970s followed by the development of sensor technology
(3–12 minutes). Since the sensor insertion creates trauma and implantable glucose sensors in the early 1980s. The
to the tissues surrounding the sensor, a waiting period, first CGMS consisted of a holter-type monitor to store the
depending on the sensor type, is needed for the sensor continuous glucose data measured by a sensor. The first
signal to stabilize.6,7 Biocompatibility problems like bio- commercial CGM system by Minimed Medtronic known
fouling (obstruction of fluid exchange after non-specific as CGMS Gold (California, USA) came to market following
protein adsorption), passivation of electrodes (weakening the FDA approval in 1999. Although it did not provide
of signal by reduction in conductivity) and degeneration real-time glucose measurements, the recordings could be
can lead to changes in sensor function that contribute to downloaded into a computer for retrospective analysis.
drift in sensor signal over time.8,9 In 2004, Minimed Guardian system received FDA approval
The glucose sensor must be calibrated against and it came with the feature of alarm alerts to potentially
corresponding blood glucose meter levels to ensure the high and low glucose fluctuations. Minimed Medtronic’s
 Continuous Glucose Monitoring System 641

chapter
42
Fig. 42.2: iPro2 blinded continuous glucose monitoring system Fig. 42.3: Dexcom real-time continuous glucose monitoring system
(CGMS) (CGMS)

Guardian Real-Time system was FDA approved in 2005. Continuous glucose monitoring will help to detect
Later in 2006, Minimed Medtronic Paradigm Real- the chunk of data in between the finger pricks which will
Time System received FDA approval where CGM was enable the healthcare provider and the diabetes team
integrated in an insulin pump. iPro2 was launched in 2010 along with the patient to make therapeutic interventions.
following FDA approval (Fig. 42.2). In 2012, Dexcom G4 The advent of Real-Time CGM has revolutionized
Platinum Continuous Glucose Monitoring System was intensive diabetes management with its ability to provide
approved by FDA. a plethora of information like direction, magnitude, dura­
Food and Drug Administration approved the real-time tion, frequency and causes of fluctuation in glucose levels.
Short-Term Sensor (STS) glucose monitor from Dexcom, When integrated with an insulin pump, CGM helps to
Inc. (San Diego, California) in 2006 followed by the determine the prandial insulin requirements, correction
Dexcom Seven in 2007, with an improved sensor which doses for hyperglycemia, when adjusting the basal rate,
could be used for 7 days. In 2009, Dexcom Seven Plus was adjustments needed during and after exercise, when
approved by the FDA with its improved performance and taking a snack, changing the insulin-to-carbohydrate
accuracy (Fig. 42.3). ratio at meal time and changing the carbohydrate compo­
Continuous glucose monitoring has now emerged as sition of the diet.
an established tool in the treatment of diabetes, paving Continuous glucose monitoring helps fine tune, a
way to the development of a true closed-loop system with patient’s glycemic control by facilitating therapeutic
CGM, an insulin delivery system and a computer program decision-making like changing from a regular to a rapid
that adjusts the dosage of insulin according to the blood acting analogue at meal time, changing from an inter­
glucose levels (Artificial Pancreatic System). mediate to a long-acting analog once daily, increasing
or decreasing the basal or bolus dosage, decisions on
CLINICAL UTILITY OF CONTINUOUS treating intermittent, nocturnal hypoglycemia and
GLUCOSE MONITORING changing the night time regimen to avoid Dawn pheno­
menon. It is most useful in diagnosing and in preventing
With the realization of glycemic excursions in diabetes hypoglycemia and hypoglycemic unawareness.
and its effects on the endothelium and on quality of Continuous glucose monitoring is considered an
life, finger prick glucose measurements alone failed to inseparable part of clinical trials related to assessing the
provide the complete picture of glucose excursions. SMBG impact of lifestyle modifications on glycemic control,
with glucometers will provide only limited data and monitoring situations where tighter blood glucose control
requires frequent finger pricks. Blood glucose is one is sought as in pregnancy, prediabetes and in intensive
parameter, which gets altered by a multitude of factors. care unit (Fig. 42.4).
642 Management
section
8

Fig. 42.4: Continuous glucose monitoring (CGM) in a type 2 diabetes patient with fairly good glycemic control. As seen there are no significant
glycemic excursions

CONTINUOUS GLUCOSE MONITORING: real-time thereby providing more accurate data in nervous
OUR EXPERIENCE patients and in first time users.
Continuous glucose monitoring has hardly become
Although CGM was introduced in India way back in popular in India despite its profound investigational value
2005, it is still a new technology in its embryonic stages due to the cost, time and requirement of a multidisciplinary
of evolution. CGM with CGMS Gold though provided team to carry out the test and provide and interpret a
288 sugar values in 24 hours and gave opportunity for comprehensive report.
retrospectively analyzing the blood sugar trends, was not
free from teething problems of a novel technology. Sensor CONTINUOUS GLUCOSE MONITORING:
error, needle displacement and broken data used to be STUDIES FROM INDIA
common challenging problems when we started using
CGMS Gold. The inability of CGM to capture high glucose Used as a research tool initially, CGM soon emerged as
values and its inaccuracy with calibration timings were an investigation to modify treatment so as to normalize
soon realized. glycemic excursions. The utility of CGM as a therapeutic
The introduction of real-time sensors became a major tool in motivated subjects enabling them to restructure
turning point as the patients themselves could observe lifestyles based on glycemic pattern is well-documented.15
the trends in the glucose values. We started doing CGM The use of CGM in T2DM patients on insulin provides
with real-time devices in both type 1 diabetes mellitus massive information including trends missed in routine
(T1DM) and type 2 diabetes mellitus (T2DM) in 2007. SMBG, like nocturnal hypoglycemia, glycemic excursions
The clinical utility of CGM data in making therapeutic and Somogyi phenomenon. These observations may be
decisions over the past 4 years (2008–2011) provided us used for patient education, for changing number and type
sufficient evidence to decide on indications of this novel of insulin shots, duration and timing of exercise, timing
technology at our center. After introduction of iPro2, of snacks and diet composition.16 The role of CGM in
there was a clear difference in the way CGM was appre­ Therapeutic Decision Making in insulin requiring T2DM
ciated and analyzed by both patients and care-providers. patients were studied in a subset where the powerful
The graphs looked more natural and the trends were visual impact of CGM in making modifications in diet
matching more with the food and exercise data provided and lifestyle were impressive.17 In a cross-sectional survey
by the patient. This blinded device totally avoided conducted among patients and the nurse educators,
the stress of subjects visualizing their glucose excursions 97% of subjects opted to repeat CGM with 6 ± 1 days as
 Continuous Glucose Monitoring System 643

chapter
42
Fig. 42.5: Continuous glucose monitoring (CGM) in a type 1 diabetes patient demonstrating Dawn phenomenon and significant glycemic excursions

Fig. 42.6: Posthypoglycemic hyperglycemia (Somogyi phenomenon)

preferred duration. 84% of the nurse-educators were • A1c above the target despite frequent SMBG and
comfortable with CGM devices and the broken readings multiple daily injections.
were least with iPro2 (13%). • Patients on insulin/secretogogues to detect danger­
ously low sugars especially undetected hypoglycemia.
INDICATIONS FOR CONTINUOUS
GLUCOSE MONITORING • To look for Dawn phenomenon (Fig. 42.5), Somogyi
• An educated individual with diabetes or prediabetes phenomenon (Fig. 42.6) in individual diabetic patients.
willing to change his diet and lifestyle based on CGM • To decide on the number and type of basal profiles in a
patterns. patient on insulin pump therapy (IPT).
644 Management

• In diabetic patients with coronary artery disease of days monitored and the type of the report provided.
(CAD) and chronic kidney disease (CKD) to avoid Over the last 3 years, we have refined and focused on the
hypoglycemia. above mentioned indications and CGM is advised only
• In gestational diabetes on multiple insulin shot or IPT for those individuals where it is absolutely indicated and
• Real-time CGM is proven to be beneficial in adoles­ affordable. Since CGM needs to be supplemented by
cents with T1DM. SMBG, the combined expense may look less impressive
to the patients. In India, only Medtronic CGM systems are
section

MERITS OF CONTINUOUS available. However, by late 2013, Dexcom G4 Platinum,

GLUCOSE MONITORING
8

may hit the Indian Market. The introduction of novel

and accurate CGM devices will popularize this technology
• Unlike glucometer, CGM provides up to 288 readings/ with more and more eligible patients benefiting from it.
day continuously up to 3–6 days or even more depen­
ding on the technology used. CONCLUSION
• The data can be downloaded to the computer and
Continuous glucose monitoring is an invaluable tool in
detailed analysis can be carried out.
comprehensive diabetes care. There are real-time devices
• The data can be uploaded to official websites and
and blinded devices, each of them having its own merits
in-depth analysis is possible.
and demerits. Interpretation of a CGM is best carried out
• Continuous glucose monitoring provides data on
hypoglycemic and hyperglycemic excursions and by a trained multidisciplinary team. Like glucometers,
nocturnal glycemic events. CGM will also take decades to gain acceptability and
• The pattern of glycemic excursions during exercise, popularity. With the emergence of new generation sensor
stress, sleep and sexual activity can be studied and needles this technology will soon overtake glucometers
interpretations used for treatment modifications.15 but may never replace it.
These are not possible with SMBG.
FURTHER READING
DEMERITS OF CONTINUOUS 1. Riveline JP. Is continuous glucose monitoring (CGM) for
GLUCOSE MONITORING everyone? To whom should CGM be prescribed and how?
Diabetes Metab. 2011;37:S80-4.
• Time consuming. 2. Blevins T. Hemoglobin A1c values and CGM. Diabetes Tech-
• More expensive than SMBG. nol Ther. 2012;14:972.
• Infrastructure and expertize required. 3. Kim HS, Shin JA, Chang JS, et al. Continuous glucose
• Inconvenience of wearing the device. monitoring: current clinical use. Diabetes Metab Res Rev.
• Physiological lag between blood glucose levels and IF 2012;28:73-8.
4. Ramchandani N, Heptulla RA. New technologies for dia-
glucose levels.
betes: a review of the present and the future. Int J Pediatr
• Sensors are most inaccurate when there are huge Endocrinol. 2012;2012:28.
glycemic excursions. 5. Sartore G, Chilelli NC, Burlina S, et al. The importance of
• Although uncommon with new generation CGMS HbA1c and glucose variability in patients with type 1 and
devices, sensor needle displacement and other reasons type 2 diabetes: outcome of continuous glucose monitoring
for failure though uncommon can be scary for the (CGM). Acta Diabetol. 2012;49:153-60.
patient and the CGM technician. 6. Damiano ER, El-Khatib FH, Zheng H, et al. A comparative
effectiveness analysis of three continuous glucose moni-
tors. Diabetes Care. 2013;36:251-9.
LIMITATIONS OF CONTINUOUS 7. Mauras N, Fox L, Englert K, et al. Continuous glucose moni-
GLUCOSE MONITORING IN INDIA toring in type 1 diabetes. Endocrine. 2013;43:41-50.

Since its introduction in 2005, though the cost of sensor REFERENCES

needle has come down a little, the investigation is
1. Clarke SF, Foster JR. A history of blood glucose meters
still expensive. In our experience, Real-Time CGM in
and their role in self-monitoring of diabetes mellitus. Br J
combination with insulin pump in T1DM has never been Biomed Sci. 2012;69:83-93.
practiced continuously. The cost of performing CGM over 2. Consensus development conference on self-monitoring of
3–6 days may vary depending on the device used, number blood glucose. Diabetes Care. 1987;10:95-9.
 Continuous Glucose Monitoring System 645

3. American Diabetes Association. Standards of medical care 11. Koschinsky T, Heinemann L. Sensors for glucose monitor-
in diabetes—2012. Diabetes Care. 2012;35:S11-63. ing: technical and clinical aspects. Diabetes Metab Res Rev.
4. Cengiz E, Sherr JL, Weinzimer SA, et al. New-generation 2001;17:113-23.
diabetes management: glucose sensor-augmented insulin 12. Aye T, Block J, Buckingham B. Toward closing the loop: an
pump therapy. Expert Rev Med Devices. 2011;8:449-58. update on insulin pumps and continuous glucose moni-
5. Cengiz E, Tamborlane WV. A tale of two compartments: toring systems. Endocrinol Metab Clin North Am. 2010;39:
interstitial versus blood glucose monitoring. Diabetes 609-24.
Technol Ther. 2009;11:S11-6. 13. Wolpert HA. The nuts and bolts of achieving end points

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6. Gerritsen M, Jansen JA, Kros A, et al. Influence of inflam- with real-time continuous glucose monitoring. Diabetes

42
matory cells and serum on the performance of implantable Care. 2008;31:S146-9.
glucose sensors. J Biomed Mater Res. 2001;54:69-75.
14. Updike SJ, Hicks GP. The enzyme electrode. Nature.
7. Kyrolainen M, Rigsby P, Eddy S, et al. Bio-/haemocompat-
1967;214:986-8.
ibility: implications and outcomes for sensors? Acta Anaes-
15. Kesavadev J, Shamsudeen J, Badarudeen S, et al. Role of
thesiol Scand Suppl. 1995;104:55-60.
8. Boyne MS, Silver DM, Kaplan J, et al. Timing of changes continuous glucose monitoring in modifying diet and life-
in interstitial and venous blood glucose measured with styles in diabetes subjecs. Diabetes 2009; Abstracts 268-OR.
a continuous subcutaneous glucose sensor. Diabetes. 16. Kesavadev J, Pillai PBS, et al. Utility of CGM over con-
2003;52:2790-4. ventional SMBG in making treatment changes in insulin
9. Mang A, Pill J, Gretz N, et al. Biocompatibility of an elec- requiring T2DM patients. Diabetes. 2011;Abstract No. 912-P.
trochemical sensor for continuous glucose monitoring in 17. Kesavadev J, Pillai PBS, Remadevi GG, et al. CGM as a tool
subcutaneous tissue. Diabetes Technol Ther. 2005;7:163-73. for Therapeutic Decision Making (TDM) in type 2 diabetes
10. Rebrin K, Steil GM. Can interstitial glucose assessment mellitus. The 4th International Conference on Advanced
replace blood glucose measurements? Diabetes Technol Technologies & Treatments for Diabetes. Diabetes Tech­
Ther. 2000;2:461-72. nology & Therapeutics. 2011;13:173-293.
 Chapter 43
Monitoring Glycemic Control:
Long-Term Parameters
Hemraj B Chandalia

Glycated Hemoglobin

Chapter Outline
♦♦ Historical Aspects ♦♦ Clinical Relevance and Application of Glycated
♦♦ Process of Glycation of Hemoglobin Hemoglobin
♦♦ Methodology to Estimate Glycated Hemoglobin ♦♦ Glycated Albumin and Fructosamine
♦♦ Selection of Method and Quality Control

INTRODUCTION of GHb and chemical reactivity were developed rapidly

and utilized both for clinical and research purposes.
Glycated hemoglobin (GHb) is presently considered the Standardization of HbA1c has been undertaken on a wide
best laboratory parameter available to assess long-term scale in many advanced countries.6,7 Finally, HbA1c has
metabolic control in a diabetic. It is an extremely impor­ been employed in the diagnosis of diabetes.8,9
tant tool in research studies and has been used in all
important recently reported studies. In this chapter, a brief PROCESS OF GLYCATION OF HEMOGLOBIN
historical review, the methods available to estimate GHb
and the clinical relevance of GHb in monitoring control of Glycation of hemoglobin takes place by the interaction
diabetes and in diagnosis of diabetes are discussed. HbA1c of glucose with amino-terminal valine of one or both
is the usual parameter employed in clinical practice; beta chains of HbA (Fig. 43.1). This glycation site
hence, it will be used interchangeably with GHb. alters the mobility of hemoglobin in cation exchange
chromatography and many other systems. This is the
HISTORICAL ASPECTS major GHb and is called HbA1c. Glycation also occurs at
other sites of Hb molecule; for example, at the epsilon
Kunkel et al.1 observed in 1955 that adult Hb could amino groups of lysine residues and even alpha chains.
electrophoretically be shown to consist of fast and slow Although the glycation occurring at the latter site is
migrating components. Rahbar2 demonstrated that the extensive, it does not alter the ionic charge and hence
fast hemoglobin component was increased in persons cannot be separated from HbA0 by cation exchange
with uncontrolled diabetes. Clinical relevance of GHb chromatography. The chemical method described later
was established by Bunn,3 and Nathan4 and kinetics of in this chapter, measures total GHb, i.e. HbA1c plus
GHb were studied by Goldstein.5 Methods based upon glycated non-N-terminal sites, including amino group
ion exchange chromatography, structural characteristics of lysine residues. The initial process of glycation results
 Monitoring Glycemic Control: Long-Term Parameters 647

elutes faster from a cation exchange column than HbA0.

Preglycohemoglobin has similar mobility in this
system and hence, it should be removed before column
chromatography. Most of these systems cannot differen­
tiate between abnormal Hbs, but many advanced systems
possess such ability. Fetal hemoglobin co-elutes with
HbA1c and hence, produces falsely high values, while HbS

chapter
and HbC co-elute with HbA0 and thus produce falsely

43
low values. Carbamyl Hb interferes significantly in this
assay method. These methods are most commonly used
in clinical practice. By this method, HbA1c concentration
in normal subjects is 4.6–6%. Diabetes is considered to be
Fig. 43.1: Formation of glycated hemoglobin by combination of under good, fair or poor control at values of less than 7%,
glucose with amino-terminal valine of β-chain of hemoglobin, resulting 7–8%, and more than 8% respectively.
in a reversible aldimine (Schiff base). This further undergoes Amadori
rearrangement to form a stable ketamine
Hemoglobin A1c can be separated from HbA0 by
any electrophoretic method. The most commonly used
method is agar-gel electrophoresis where HbA1c migrates
in an unstable compound produced by the interaction to cathodic side of HbA0. Pre-GHb migrates with HbA1c
of amine group in hemoglobin with carbonyl group of in this system as well and hence has to be separated in
glucose. This produces the unstable Schiff base, which advance. Some hemoglobinopathies, like HbS or HbC trait
is proportional to current glycemia and hence can do not, but HbF does interfere with this method.
vitiate results of GHb assessment in cation exchange
chromatography where Schiff base (preglycohemoglobin) Methods Based on Structural
co-elutes with HbA1c. It is possible to remove Schiff base Characteristics of Glycated Hemoglobin
by a simple process of saline incubation. This fact has
One such method called boronic affinity method utilizes a
been used in many methods to separate pre-GHb from
column containing maminophenylboronic acid coupled
GHb. Schiff base can either dissociate or by Amadori
to agarose. GHb possesses more cis-diol groups, which
rearrangement convert into a stable ketamine10 (Fig. 43.1).
has stronger affinity to boronic acid and hence elutes
later than HbA0. This method is influenced to a lesser
METHODOLOGY TO ESTIMATE
extent by pH, temperature and storage conditions than
GLYCATED HEMOGLOBIN cation exchange chromatography. It is also unaffected by
Methods of GHb assays have primarily evolved around hemoglobinopathies. However, there is a batch-to-batch
four basic principles: variation in gel characteristics, which makes application
• Difference in ionic charge of this method difficult. Recently, immunoassays have
• Structural characteristics (e.g. immunoturbidimetric been developed by using an HbA1c specific monoclonal
and boronic affinity methods) antibody. An agglutinator is used in the system and
• Chemical reactivity inhibition of agglutination of HbA1c with its antibody by
• Enzyme method HbA1c in the sample is quantitated.11 This method is not
influenced by pre-GHb or hemoglobinopathies.
Methods Based on Differences in Ionic Charge
Methods Based on Chemical Reactivity
These methods are in extensive use at present. Cation
exchange chromatography can either be undertaken on Chemical method of GHb estimation is based on gene­
mini columns or in a sophisticated, automated system. ration of 5-hydroxymethylfurfural (5-HMF) from glyco­
The pH and temperature conditions affect the results amino groups on hemoglobin by heating the GHb in a
significantly; hence, the need for a sophisticated system weak acid.12 The chemical method measures total GHb,
where the conditions can be adequately controlled. i.e. HbA1c plus glycated non-N-terminal sites. The 5-HMF
HbA1c possesses lesser charge positivity and hence so generated is reacted with thiobarbituric acid and read
648 Management

colorimetrically. This method13 has been extensively used and enzyme method. While drugs that possess strong
in a modified form. It is laborious but least expensive. It is a ionic charges, like aspirin can alter GHb in ion-exchange
very sturdy method, least affected by storage, temperature chromatographic methods, this does not appear to be
and pH conditions. It is not influenced by pre-GHb, but clinically relevant, as the dosage of aspirin used is usually
it is advisable to remove free glucose from samples by small. Last of all, a shorter erythrocyte lifespan will alter
careful wash of erythrocytes before undertaking lysis. This GHb; usually producing lower values because of a larger
method is not affected by hemoglobinopathies. Instead population of younger erythrocytes. When anemia is
section

of a GHb standard, which is difficult to device, a fructose being treated, the rapid erythrocyte generation will also
8

standard can be used and results expressed as amount of produce similar alterations. GHb is significantly lower
5-HMF. As this method estimates HbA1c as well as HbA1a in hemolytic anemias; in fact, the degree of erythrocyte
and HbA1b, the values obtained are higher than those of lifespan reduction can be assessed by estimating GHb.15
anion exchange chromatography by 1–2%. By this method, However, stable anemias do not influence HbA1c.
good, fair and poor control is defined as GHb level of less The ambient blood glucose is low in pregnancy and
than 8%, 8–10% and more than 10% respectively. the erythrocyte generation is rapid; both these factors
will tend to reduce the GHb values. However, normal
Enzyme Methods HbA1c values for a non-diabetic pregnant female are
not yet fully established in all trimesters, which makes
In enzyme methods, hemoglobin is digested with a application of HbA1c values in this situation difficult.
protease to yield fructosyl amino acid, which on reaction However, assessment of metabolic control is so important
with fructosyl amino acid oxidase yields hydrogen in a pregnant diabetic that monthly HbA1c estimations are
peroxide which reacts with chromogens in the presence recommended and the targets set are usually 1–2% below
of peroxidase. Total hemoglobin is measured in the the usual values. Thus, the target HbA1c value, for good
same tube spectroscopically and a ratio of GHb to total control in pregnancy will be less than 6%. In renal failure,
hemoglobin is reported. carbamylated compounds abound, which also interferes
Direct enzymatic HbA1c assays have the advantages with HbA1c estimation. Altered rate of erythropoiesis in
of accuracy, specificity and applicability to all chemistry this situation further makes interpretation of GHb difficult.
analyzers.14 Separate measurement of hemoglobin is not Considering these facts, selection of a method
required; hence, single channel analyzers are sufficient. should depend upon the infrastructure of a laboratory,
Carbamyl hemoglobin, preglycohemoglobin and hemo­ workload, turn-around time desired and prevalence of
globinopathies like HbC and HbS do not interfere in this hemoglobinopathies in the population it desires to serve.
assay. The chemical method is the most inexpensive method,
requiring minimal infrastructure and most basic reagents.
Point-of-Care Methods However, the turn-around time for this method is about
Several points-of-care methods are available for use by 4 hours. The ion exchange chromatographic methods
non-laboratory clinical staff. These methods produce using mini-columns are notoriously inaccurate, as the
quick results. They are usually based on immuno­ pH and temperature conditions are difficult to control.
turbidimetric methods. The coefficient of variation (CV) The same method by sophisticated high performance
with these methods is higher (about 5%) than that by liquid chromatography (HPLC) is accurate and least time
standard laboratory techniques (about 2%). consuming but is a very expensive method.
In the chemical method, fructose can serve as a
SELECTION OF METHOD AND standard. In many other methods, a standard hemolysate
QUALITY CONTROL is now being used. Comparison of data from different
laboratories is difficult, but can be setup for study purposes.
Most GHb methods are beset with a number of metho­ Similarly, transfer of data obtained by one method to other
dological problems. In some of them, a GHb standard is by various formulae is not scientific, but is being practiced
not possible, but this has now been circumvented. Inter­ by many laboratories. Quality control of GHb method
ference by Schiff base or preglycohemoglobin occurs is problematical. However, it is important to determine
in many methods. Vitiation of results by hemoglobino­ inter-assay and intra-assay CV and as far as possible
pathies occurs in many methods, except the chemical run a high and low standard. An acceptable intra-assay
 Monitoring Glycemic Control: Long-Term Parameters 649

Table 43.1: Correlation of glycated hemoglobin with blood glucose21 likely to misconstrue the state of their metabolic control
HbA1c (%) Mean blood glucose (mg/dL) and looking at the lower reported values, relax on the
4 60
precautions required to sustain long-term good metabolic
control.20 It is possible to convert HbA1c obtained by any
5 90
method to mean blood glucose as per the following
6 120
equation:21
7 150
MBG (mmol/L) = 1.84*IFCC-HbA1c

chapter
8 180
MBG (mmol/L) = 1.98*NGSP-HbA1c—4.29

43
9 210
However, currently most patients with diabetes are not
10 240 fully aware of mean blood glucose (MBG) targets, while
11 270 they know that HbA1c of 7% is a desirable goal.
12 300 A genetic polymorphism has been described which
influences the rate of glycation22 but probably the
CV is 2–4% and interassay CV is 4–8%. More recently, prevalence of such polymorphisms is low. It is recomm­
a comparison has been made between the accuracy of ended that population-specific normative data must
a blood glucose assay and HbA1c assay. Preanalytical be generated for each ethnic group. Genetically deter­
errors, primarily due to ongoing glycolysis of glucose, mined differences in the erythrokinetics may alter the
even in a fluoride tube, has been found to influence the normative data more profoundly than the glycation-rate
accuracy of blood glucose methods, thus producing a CV polymorphism.22
of more than 5%, while CV of HbA1c has been recently
narrowed to about 1–2%.16,17 These facts are used to support
CLINICAL RELEVANCE AND APPLICATION
the superiority of HbA1c in the diagnosis of diabetes.
OF GLYCATED HEMOGLOBIN
Harmonization and standardization of HbA1c method
has been attempted by many organizations. The National Relationship to Mean Blood Glucose
Glycohemoglobin Standardization Program (NGSP) was
Clinical relevance of GHb was established by the initial
set up prior to the Diabetes Control and Complications
publications3,4 and has been re-examined extensively.
Trial (DCCT); the standards recommended by NGSP
In the first study reported from India, a group of subjects
have been used in DCCT; hence these methods are also
with type 2 diabetes was prospectively followed with
called DCCT traceable methods.18 More recently, the
repeated blood glucose estimations and the GHb values
International Federation of Clinical Chemistry (IFCC)
obtained after 2 months of follow-up were correlated
has estimated HbA1c in its purest form by an elaborate
with mean blood glucose values.13 A close correlation of
method of endoproteinase-Glu-C digestion of N-terminal
glycemic control with GHb was documented.
hexapeptides and separation of glycated and non-glycated In the DCCT, initial feasibility data measured HbA1c
fractions by mass spectroscopy or capillary electro­ and seven-point blood glucose profiles quarterly for a
phoresis. This method yields normal HbA1c values of 1-year period in 278 patients with type 1 diabetes, bringing
2.8–3.8%, in contrast to NGSP certified methods, which out a close linear relationship between glycemic control
yield normal values of 4–6%.19 Equations have been devi­ and HbA1c.23 In this study, each 1% increase in HbA1c
sed for inter conversion of test results by these methods corresponded to an increase of average blood glucose by
as under:20 30 mg/dL (Table 43.1). Clinical laboratories reporting the
NGSP–HbA1c = 0.915 (IFCC–HbA1c) + 2.15% correlation of mean blood glucose with HbA1c value often
International Federation of Clinical Chemistry has use this relationship. More recently, this relationship has
proposed that the results be expressed as mmol of HbA1c been confirmed.21
per mol of hemoglobin. If expressed in this fashion, HbA1c Glycated hemoglobin cannot be used as a measure of
of 7% by NGSP method would correspond to HbA1c of hypoglycemia, but in DCCT, the patients in the intensive
53 mmol/mol by IFCC method. Inspite of lengthy debates, group had a three-fold increase in hypoglycemic episodes
most clinicians agree that HbA1c should be reported by and as pointed out above, this group had a significantly
NGSP method. If expressed by IFCC methods, patients are lower HbA1c.24
650 Management

It is clinically relevant to know that stress hyper­

glycemia increases GHb levels.25 In a group of 29 patients
with acute vascular events and stress hyperglycemia as
determined by an initial and follow up glucose tolerance
test (GTT), a significant elevation of GHb was observed.
This lends support to the fact that such transitory hyper­
glycemia is important and merits treatment.25
section

Discrepancies between GHb and blood glucose values
8

reported by patients are expected, as self-monitoring of

blood glucose (SMBG) is not yet an accurate procedure
and falsification of data is possible by patients. GHb and
blood glucose values were measured in 4203 patients and
interpreted in a study as indicative of good, fair and poor
Fig. 43.2: Rate of fall of glycated hemoglobin over time15
control.15 The interpretation by these two parameters was
in agreement in 51.3%, one-step different (e.g. good by
one method, showing fair by other method) in 43% and the problem of moving 30–40% of the clinic population
two-step different (e.g. good by one method showing from a HbA1c of 8% towards 7%, strategies addressing the
poor by other method) in 5.7% of patients. In 63% of issue of prandial hyperglycemia are very important.
patients showing discrepant values, GHb showed poorer
control than post-prandial blood glucose (PPBG) values, Metabolic Control in the Past 2 to 3 Months
thus indicating that a large number of patients did a
In early period of GHb use, this parameter was presumed
little better on the day of testing to produce better blood
to reflect metabolic control over the past 120 days, this
glucose values. This brings out the importance of GHb as
period representing the life span of erythrocytes. A large
a non-manipulable and reliable parameter in assessing
number of kinetic studies have revealed that glycemia in
metabolic control as compared to SMBG or one-point
the recent past influences the GHb values more than the
blood glucose estimations. remote past.30 Thus, mean blood glucose of past 1 month,
2 months and 3 months contributes 50%, 40% and 10%
Glycemic Excursions and
respectively to the final result. By mathematical mode­
Relationship to FBG and PPBG ling the t1/2 of GHb is estimated to be 35.2 days.5 This
Although the relationship of MBG to HbA1c is firmly estab­ means that half of glycation seen during estimation
lished, it is important to understand that HbA1cdoes not has occurred in the previous 35.2 days. The rate of
reflect the glycemic excursions; a patient having marked dissipation of GHb was studied in a group of patients
glycemic excursions may exhibit same HbA1c values as with newly diagnosed type 2 diabetes in whom blood
one with acceptable glycemic excursions, because the glucose was lowered steadily using glipizide. It was found
peaks and troughs of glycemic excursions tend to cancel that lowering of GHb at 0–2, 2–4, 4–6, 6–8 and 8–10 weeks
each other.26,27 Hence, blood glucose monitoring by self of treatment was 1.0, 0.7, 0.5, 0.5 and 0.1% respectively
or continuous glucose monitoring continues to retain its (Fig. 43.2).15
role in the management of diabetes. This is further suppor­
ted by the fact that wide glycemic excursions have the Anemia and HbA1c
potential of worsening vascular complications.28 The commonest anemia seen is due to iron deficiency.

Relative contributions of fasting versus prandial Any stable anemic condition does not affect the estimation
hyperglycemia toward HbA1c values have been studied.29 directly when HPLC, boronic affinity or immunotur­
At very high fasting blood glucose (FBG), which is often bisdimetric or enzyme methods are used, as a certain
associated with prandial hyperglycemia, the HbA1c values amount of hemoglobin or lysate is used to carry out the
are in a very high range, such as 9–12%. With normali­ estimation. Although stable iron deficiency anemia does
zation of FBG, the values drop to about 8%. Hence, at not influence the assay, the dynamic phase of anemia,
lower level the major contributor to HbA1c is prandial associated with alterations in erythrokinetics, alters
BG. As currently most diabetes centers are grappling with the value, as during the recovery phase, more young
 Monitoring Glycemic Control: Long-Term Parameters 651

Table 43.2: Blood glucose targets in pregnancy based on

normative data31

Fasting blood glucose (mg/dL) < 90 mg/dL

2 hours post-prandial blood glucose < 120 mg/dL
(mg/dL)
HbA1c (%)
Non-pregnant 4.8–5.5%

chapter
Pregnant

43
Trimester 1 4.3–5.4%
Trimester 2 4.4–5.4%
Trimester 3 4.7–5.7%

relationship with blood glucose. The congenital anomalies

were 2% (CI 0.0–4.4), 3% (CI 0.4–6.1), 10% (CI 2.3–17.8)
Fig. 43.3: Glycated hemoglobin in hemolytic anemia, associated with for HbA1c with 0, 2 and 8 standard deviation (SD) above
reduced erythrocyte life-span15 normal mean value respectively.32 Hence, an effort should
be made to normalize HbA1c to the best possible extent
erythrocytes are included proportionally in the assay. This without producing hypoglycemia.
fact holds true of all anemias. In pregnancy, it is advisable to estimate HbA1c once
Hemolytic anemias will alter the result, because of every month, as the past one month period is a major
ongoing destruction of erythrocytes or rapid erythropoiesis contributor to HbA1c. It is crucial to achieve good control
during recovery. In a study of HbA1c in hemolytic throughout pregnancy as well as immediate pre-preg­
anemias, carried out by cobalt labeling and whole body nancy period in order to avoid fetal macrosomia33 and fetal
counting (Fig. 43.3), the reduced half-life of erythrocytes malformations. In practice, it is feasible to achieve HbA1c
correlated with lowering of HbA1c and degree of hemo­lysis values of less than 5.5% in gestational diabetes, less than
could be adjudged by the HbA1c value. 6.5% in pregestational type 2 diabetes and less than 7.0%
in type 1 diabetes with pregnancy.
Hemoglobinopathies that alter the ionic change of
the Hb molecule produce unreliable results of HbA1c by
methods that use ionic charge to separate HbA1c from
HbA1c in Renal Disease
HbA0. Such methods include column methods (not much Anemia due to micronutrient (iron, B12) and erythro­
used currently) and HPLC. However, with HPLC, the poietin deficiencies are common in renal failure. Further
abnormal hemoglobinopathy can be detected. more, erythrokinetics are altered in chronic renal failure.
Thus, the normative data are not available. Renal failure
HbA1c in Pregnancy also leads to accumulation of carbamylated compounds,
which have similar electrophoretic mobility as HbA1c
Monitoring and achieving metabolic control during
in assay systems based on electrophoresis. However,
pregnancy is an extremely important requirement. In
HbA1c estimation is considered an important parameter
non-diabetic pregnancy, the ambient blood glucose is
in this situation and almost similar targets as those in the
lower than in the non-pregnant state, thus HbA1c is lower
presence of normal renal function are used. It is obvious
by 1.5–2% during pregnancy (Table 43.2). This is mostly
that blood glucose monitoring should be preferentially
attributable to altered erythrokinetics in pregnancy.
used to assess metabolic control in renal disease, espe­
Concomitant iron deficiency is common in pregnancy,
cially, in the dynamic phases of anemia.
further changing the erythrokinetics.
The normative data for the HbA1c values in pregnancy
Relationship of HbA1c with
are available for the first trimester.31 However, there are
no clear data for the rest of the pregnancy period. The
Complications of Diabetes
threshold for the fetal malformation and for macrosomia Glycemic control bears a well-documented relationship
is not precisely known, but they bear a distinct dose-effect with vascular complications of diabetes. The relationship
652 Management

Table 43.3: Suggested targets of HbA1c based on ADA/EASD situations in diabetes (Table 43.3).40 In general, more
recommendations40 recent onset type 2 diabetes calls for a stricter target
Diabetes category Targets and long-standing type 2 diabetes calls for more relaxed
Type 2 DM targets. Fortunately, achieving stricter targets is feasible
• Newly discovered type 2 DM 6.0–6.5% in the first 5–10 years of type 2 diabetes. This also leads
• Most type 2 DM < 7%
to greater long-term benefits as shown in the follow up
• Long standing type 2 DM < 8%
• Long standing type 2 DM with < 8.5% studies of DCCT and UKPDS.34,36 In type 1 diabetes, the
section

complications targets are somewhat relaxed, because with the current

8

Type 1 DM standard insulin therapy, stricter targets are not achie­

• On multiple dose insulin < 7.5% vable without prod­ucing undue hypoglycemia.
• On insulin pump therapy < 7.0%
The current state of metabolic control, as reflected by
(ADA: American Diabetes Association; EASD: European Association HbA1c values is far from satisfactory. It is probably due to
for the Study of Diabetes; DM: Diabetes Mellitus).
imperfect treatment tools, behavioral problems on the
is stronger for microvascular disease than macrovascular part of the patients and imperfect application of therapy.
disease. In the DCCT, the intensive control group main­ In most clinics in India, only 25–40% of patients with
tained an average HbA1c at about 7% and conventional diabetes achieve an HbA1c of less than 7%. To sustain this
control groups at about 9%. The 2% lowering of HbA1c in degree of control over a long period of time seems to be
the intensive group resulted in significant reduction (about more difficult. Data from USA reveal an average HbA1c
30–80 %) of microvascular and neurological complications of 7.62 ± 0.11% in the years 1999–2002. This improved to
like retinopathy, nephropathy and peripheral neuro­ 7.15 ± 0.07% in the years 2003–2006.41 The percent of
pathy.24 Intensive control group continued to maintain patient achieving the target of HbA1c less than 7% were
benefits on 17 years of post-study follow up, as the risk 43.1 ± 2.7 and 57.1 ± 2.3 in the same two periods, respec­
of any cardiovascular disease was reduced by 42% as tively.41
compared to the standard treatment group.34
In the United Kingdom Prospective Diabetes Study Use of HbA1c in Diagnosis of Diabetes
(UKPDS), the mean HbA1c was about 1% lower in the
intensive control group as compared to the standard An effort was made to address this issue long ago.8 Most
control group.35 This resulted in 16% reduction in macro­ studies have brought out the fact that the GTT is a more
vascular disease and 25% reduction in microvascular sensitive diagnostic method and impaired GTT may be
disease. A 10-year follow up continued to reveal reduced associated with normal HbA1c. In one study,16 impaired
diabetes-related end-points (9%, p = 0.04), microvascular GTT was found to be associated with significantly elevated
disease (24%, p = 0.001) and myocardial infarction (15%, GHb and estimation of a single post-meal blood glucose
p = 0.01) in intensively treated group as compared to and GHb attained the same sensitivity in the diagnosis
standard treatment group.35,36 This firmly establishes of diabetes, as did a GTT. In hospitalized patients with
the importance of HbA1c as an important parameter in random hyperglycemia, HbA1c more than 6% reliably
long-term studies. However, rapid and marked lowering diagnosed diabetes and less than 5.2% reliably excluded
of HbA1c in the Action to Control Cardiovascular Risk in diabetes.42
Diabetes (ACCORD) and the Veterans Affairs Diabetes
More recently, this issue has been taken up earn­
Trial (VADT) studies could have been responsible for an estly.43,44 As reported in the earlier work,8,15 the sensitivity
increase in the cardiovascular disease.37,38 and specificity of using HbA1c in the diagnosis of diabetes
has been compared with the standard GTT. Using
HbA1c Targets and Current State of different cut-off points of HbA1c for the diagnosis, the
Target Achievement best balance of sensitivity and specificity was achieved
The HbA1c targets are derived on the basis of population by using less than 6.1% as normal, 6.1–6.5% as impaired
studies showing a threshold of 6.3–6.7% for a sudden glucose tolerance and more than 6.5% as diagnostic of
spurt in diabetic retinopathy.39 Various associations diabetes.33,34 An HbA1c value of 6.1% was 2 SD above mean
have recommended targets in general and in specific normal. Currently, HbA1c of < 5.7% is considered normal,
 Monitoring Glycemic Control: Long-Term Parameters 653

5.7–6.5% indicative of impaired glucose tolerance and Serum 1,5-Anhydroglucitol

> 6.5% as diagnostic of diabetes. When this was compared
Anhydroglucitol (1-deoxyglucose, AG) is an analog of
to diagnostic accuracy of elevated FBG, sensitivity of
glucose; normal blood levels being 50–200 µmol/L. This
63.2% and specificity of 97.4% was seen.45
level rises with the ingestion of meal and once it crosses

Using HbA1c instead of a blood glucose estimation
its renal threshold the compound is excreted in the urine
offers several advantages. Currently, the CV of HbA1c
through the same renal tubular mechanism as the urinary
assays has been brought down to about 2% while that of

chapter
glucose. Hence, with hyperglycemia, AG levels are low
blood glucose continues to be at about 5%.16,17 Samples for

43
and vice versa. AG estimation has been proposed as a
HbA1c are stable for more than a week while preanalytical measurement of glycemic control,48 and more so as a
glycolysis in blood glucose samples offers poor stability. measurement of glycemic excursions and post-prandial
HbA1c may be useful for epidemiological purposes but the glycemia.49-52 However, its values are affected by changing
cost of the test remains a drawback at present. renal threshold for glucose. This parameter has not yet
been fully utilized for clinical purposes.
GLYCATED ALBUMIN AND FRUCTOSAMINE
The process of glycation is ubiquitous and hence, SUMMARY
depending upon the half-life, an estimation of the percent Monitoring control of diabetes calls for assessment of
glycation of proteins can provide valuable information on both the short-term and long-term parameters. The short-
the glucose control in the past. Glucose reacts with serum term parameters are more useful in making day-to-day
albumin to form the aldimine link, which undergoes
adjustments in treatment of diabetes and diagnosis
the Amadori rearrangement to form the stable ketamine.
of hypoglycemia. The long-term parameters are more
Fructosamine includes measurement of all such keta­
relevant in correlating metabolic control with long-term
mines, the predominant being glycated albumin. The
complications of diabetes. Both types of parameters are
half-life of albumin being 2–3 weeks, fructosamine reflects
complementary to each other.
metabolic control for the same period.46
Amongst the long-term parameters, GHb is presently
Fructosamine can be assayed colorimetrically, by
considered the gold standard. It is the most extensively
affinity chromatography or by immunoassay. Lipids,
used parameter in long-term studies, like DCCT and
bilirubin, ascorbate, uric acid and urea interfere with
UKPDS. GHb is derived by non-enzymatic, irreversible,
colorimetric method and hence needs modification to
substrate-concentration-dependent attachment of glu­
avoid interference. The affinity chromatography assay
cose to amino acids in the hemoglobin molecule. GHb
has a good precision and can also be automated. In
non-diabetic subjects, fructosamine levels are 205–285 is estimated by a variety of methods; currently boronic
micromoles/liter. affinity, immunological and enzyme methods are in wide
The half-life of fructosamine is 12 days and it overall use. The chemical method has the great advantage of
reflects control of 7–21 days. This is very useful in assessing cost and non-interference by hemoglobinopathies and
metabolic control preoperatively because a 2-week period preglycohemoglobin but is a labor-intensive method and
of good control is considered adequate for a planned measures total GHb. Standardization and quality control
surgery. The control in the last 2 weeks of pregnancy is of methods of estimating HbA1c has been undertaken in
best assessed by fructosamine estimation, which is closely many countries.
correlated with fetal hyperinsulinemia and neonatal Clinical relevance of GHb has been critically examined.
hypoglycemia. HbA1c primarily reflects control over the past 2 months.
Alterations in serum proteins will spuriously alter the It is a time-averaged value and does not reflect the
fructosamine values.47 Hence, in all critically ill patients excursions in the blood glucose. HbA1c value is non-
with rapid changes in albumin synthesis and turnover manipulable by patients as compared to self-monitored
the test is not valid. Overall, the test has not gained great blood glucose values. HbA1c targets in type 1 diabetes
popularity as it is now proven that HbA1c also primarily and type 2 diabetes are different; so also are the targets in
reflects the metabolic control of the past 1–2 months.30 newly discovered uncomplicated type 2 DM as compared
The methods to estimate fructosamine have not been to long-standing type 2 diabetes with complications.
adequately standardized. Globally, the HbA1c target of less than 7% is being
654 Management

achieved only in 25–50% of patients with diabetes. In 5. Goldstein DE, Oermann CM, Madsen RW, et al. Glycated
pregnancy, HbA1c targets are as low as possible, without hemoglobin kinetics: predicted and actual rates of change.
Diabetes. 1989;38:459.
producing hypoglycemia and starting from the pre-
6. Goodall I. HbA1c standardization destination—global IFCC
pregnancy period. As in non-diabetic pregnancy, the Standardisation. How, why, where and when—a tortuous
HbA1c is 4.8–5.5%, every effort should be made to achieve pathway from kit manufacturers, via inter-laboratory
similar values, especially in gestational diabetes. HbA1c lyophilized and whole blood comparisons to designated
coupled with PPBG value can be utilized for the diagnosis national comparison schemes. Clin Biochem Rev. 2005; 26:
section

5-19.
of diabetes. The sensitivity of HbA1c as compared to a
7. Chandalia HB. Standardization of hemoglobin A1c. Int J
8

GTT is about 65% and specificity is more than 90%. HbA1c Diab Dev Ctries. 2010;30:109-10.
is increased in impaired glucose tolerance and stress 8. Chandalia HB, Khera S, Bhargav A. Use of glycosylated hemo­
hyperglycemia. Use of HbA1c offers many advantages over globin in diagnosis of diabetes. In: Baba S (Ed). Diabetes
the GTT in the diagnosis of diabetes. Research and Clinical Practice. Amsterdam: Elsevier; 1985.
9. The International Expert Committee report on the role of
Glycated albumin and fructosamine reflect the meta­
the A1c assay in the diagnosis of diabetes. Diabetes Care.
bolic control over the past 2–3 weeks. Serum 1,5-AG is 2009;32:1327-34.
another interesting parameter, inversely related to the 10. Bookchin RM, Gallop PM. Structure of hemoglobin A1c:
degree of hyperglycemia. These parameters have not been nature of the N-terminal beta chain blocking group.
used extensively in clinical practice. Biochem Biophys Res Commun. 1968;32:86-93.
11. Knowles WJ, Haig WB, Michand GC, et al. A monoclonal
antibody based immunoassay for glycosylated A1c. Diabetes.
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1. Chandalia HB, Gokani AH. Stress hyperglycemia. Lancet. 12. Flückiger R, Winterhalter KH. In vitro synthesis of hemo-
1984;2:811. globin A1c. FEBS Lett. 1976;71:356-60.
2. Chandalia HB, Krishnaswamy PR. Glycated hemoglobin. 13. Chandalia HB, Sadikot S, Bhargava DK, et al. Estimation of
Current Science. 2002;83:1522-32. glycosylated hemoglobin by a simple chemical method and
3. Monnier L, Lapinski H, Colette C. Contributions of fast- its use in monitoring control of diabetes mellitus. J Assoc
ing and postprandial plasma glucose increments to the Physicians India. 1980;28:285.
14. Sakurabayashi I, Watano T, Yonehara, et al. New enzymatic
overall diurnal hyperglycemia of type 2 diabetic patients:
assay for glycohemoglobin. Clin Chem. 2003;49:269-74.
variations with increasing levels of HbA1c. Diabetes Care.
15. Chandalia HB, Krishnaswamy PR. Glycated hemoglobin.
2003;26:881-5.
Current Science. 2002;83:1522-32.
4. Nathan DM, Kuenen J, Borg R, et al. Translating the A1c
16. Miller WG, Myers GL, Ashwood ER, et al. State of the art
assay into estimated average glucose values. Diabetes Care.
in trueness and interlaboratory harmonization for 10 ana-
2008;31:1473-8.
lytes in general clinical chemistry. Arch Pathol Lab Med.
5. The International Expert Committee report on the role of
2008;132:838-46.
the A1c assay in the diagnosis of diabetes. Diabetes Care.
17. Petersen PH, Jørgensen LG, Brandslund I, et al. Conse-
2009;32:1327-34.
quences of bias and imprecision in measurements of glu-
6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management
cose and HbA1c for the diagnosis and prognosis of diabetes
of hyperglycemia in type 2 diabetes: a patient-centered
mellitus. Scand J Clin Lab Invest Suppl. 2005;240:51-60.
approach: position statement of the American Diabetes 18. Little RR, Rohlfing CL, Wiedmeyer HM, et al. The national
Association (ADA) and the European Association for the glycohemoglobin standardization program: a five-year pro-
Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-79 gress report. Clin Chem. 2001;47:1985-92.
19. Consensus Committee. Consensus statement on the world-
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2008;359:1577-89. Diabet Med. 2008;25:200-5.
 Chapter 44
Monitoring Beyond
Glycemic Control
Ashok Kumar Das, Stalin Viswanathan

Monitoring Beyond Glycemic Control

Chapter Outline
♦♦ Anthropological and Physical Parameters ♦♦ Other Complications
♦♦ Laboratory Monitoring ♦♦ Monitoring in High Risk Population
♦♦ Organ Complications: Microvascular ♦♦ Monitoring and Assessment of Common
♦♦ Organ Complications: Macrovascular Comorbid Conditions

INTRODUCTION Table 44.1: Medical history (Comprehensive diabetes evaluation)1

• Symptoms, lab reports related to diagnosis of diabetes including A1c
Diabetes is a disease of its complications as well as its com­ • Frequency, severity of acute complications like ketoacidosis,
orbidities. Diabetes is a metabolic disease that concerns hypoglycemia
not just control or treatment of high blood sugars, but • Prior and current infections
– Skin
one which requires lifelong medical care in terms of
– Foot
management by both self and the medical community at – Dental
large to control hyperglycemia, prevent and treat acute – Genitourinary
and chronic micro and macrovascular complications, treat • Symptoms of complications
– Microvascular
comorbid illnesses like hypertension, dyslipidemia, their
– Macrovascular
debilitating complications and, educating patients so that • Atherosclerotic risk factors like
people at risk be screened for diabetes and its subsequent – Smoking
consequences as early as possible and all efforts be made – Hypertension
in delaying and preventing such untoward effects. Care – Dyslipidemia
• Other endocrine and eating disorders
of a diabetic is multifaceted that requires many aspects
• Eating patterns, nutritional status and weight history
of the illness to be addressed by a team of professionals • Family history of diabetes and other endocrine disorders
(and preferably physician co-ordinated) so that a decrease • Lifestyle, psychosocial, economic factors affecting diabetes
in morbidity and mortality may ensue. Diabetes care has management
moved from glucose and lipids centered management • Contraceptive and reproductive health history
• Exercise history
model to a multicentric approach. All diabetics should, if • Addictions, substance use
possible, undergo a comprehensive diabetes evaluation, • Medications affecting blood glucose levels
at initial presentation, the components of which are • Details of previous and current treatment regimen including
listed in Tables 44.1 to 44.3.1 health beliefs
 Monitoring Beyond Glycemic Control 657

Table 44.2: Physical examination (Comprehensive diabetes Table 44.3: Laboratory evaluation (Comprehensive diabetes
evaluation)1 evaluation)1
• Height and weight measurement (and comparison to norms in • A1C
children and adolescents) • Fasting lipid profile, including
• Sexual maturation staging (during pubertal period) – Total cholesterol
• Evaluation of pulses by palpation and with auscultation – High-density lipoprotein (HDL) cholesterol
• Blood pressure determination, including orthostatic measure- – Triglycerides,
ments when indicated, and comparison to age-related norms – Low-density lipoprotein (LDL) cholesterol

chapter
• Hand/finger examination • Test for microalbuminuria

44
• Foot examination – In type 1 diabetic patients who have had diabetes for at
• Skin examination (for acanthosis nigricans and insulin-injection least 5 years
sites) – In all patients with type 2 diabetes
• Funduscopic examination • Serum creatinine in adults (in children if proteinuria is present)
• Oral examination • Thyroid-stimulating hormone
• Thyroid palpation – In all type 1 diabetic patients
• Cardiac examination abdominal and neurological examination – In type 2 if clinically indicated
• Electrocardiogram in adults, if clinically indicated
• Urinalysis for
ANTHROPOLOGICAL AND – Ketones
PHYSICAL PARAMETERS – Protein
– Sediment
Waist Circumference, Waist/Height Ratio
Waist circumference correlates strongly with both visceral
and central abdominal fat in diabetic as well as non-
diabetic individuals and such increased fat accumulation
may be one of the contributors toward increased risk
of diabetes in these individuals. Body mass index
(BMI) which is related to central abdominal fat, but not
associated with visceral fat in the diabetic population is
predicted poorly when compared to waist circumference,
because even in young individuals visceral obesity is the
one which probably predisposes to diabetes. NCEP-ATP
III criteria underestimate the risk of metabolic syndrome
in Asians, while a reduced circumference cutoff caused
the prevalence to be comparable to western populations Fig. 44.1: Sagittal abdominal diameter
as shown in studies. Hence a waist circumference of
greater than 80 and greater than 90 cm in women and
men respectively, more appropriately defined central Height and Body Mass Index
obesity in the Asian population.2,3 This must be done at
Annual measurement of height is recommended in type
the time of initial comprehensive diabetes evaluation and
1 diabetic children along with medical nutrition therapy.6
regularly thereafter. Also the waist/height ratios for males
This will permit monitoring of linear growth. The WHO
and females were 0.88 and 0.81 respectively.4
has endorsed a cut-off of 23 kg/m2 which has been taken
Sagittal Abdominal Diameter as the definition of overweight in Asians Indian adults.7
This should also be documented at the time of initial
The sagittal abdominal diameter (SAD) is an inexpensive
evaluation and subsequent visits especially when dietary,
means to non-invasively predict insulin resistance, and
lifestyle changes are being made to reduce weight and
thereby glucose intolerance, cardiovascular morbidity
improve fitness.
and mortality. Figure 44.1 shows the method to measure
the “abdominal height” from the iliac crest at the
Pulses
L4–L5 level, while the knees remain flexed with a SAD of
greater than 25 cm correlating with a waist circumference Even though palpation of all peripheral pulses suffers
of about 100 cm or greater.5 from being insensitive indicators in the diagnosis of
658 Management

Table 44.4: Goals in dyslipidemia10 for testing are twice a year in patients who have stable
Risk Goals glycemic control and quarterly in patients who are other­
High risk individuals LDL < 70 mg/dL
wise poorly controlled. The best conclusion of adequate
glycemic control can be made only after a combination of
Otherwise LDL <100 mg/dL or reduction by 30–40%
SMBG reports and current A1c levels.
TG < 150 mg/dL
HDL > 40 (males) and > 50 (females)
Lipids
section

(HDL: High-density lipoprotein; LDL: Low-density lipoprotein;

TG: Triglycerides). The lipids measured include total cholesterol, low-density
8

lipoprotein (LDL), high-density lipoprotein (HDL) chole­

peripheral arterial disease (PAD), they must be looked for sterol and triglycerides. It is preferable to have a direct
at the time of initial comprehensive evaluation and at least LDL-cholesterol estimation, because elevated triglycer­
annually. ides often vitiate calculated LDL-cholesterol values. About
97% of diabetics have evidence of lipid abnormalities.2
Blood Pressure (Casual and Ambulatory) Starting from levels of 70 mg/dL, every 10 mg/dL increase
in LDL increases risk of CVD by about 12%.1,10,11
Diagnosis is made when blood pressure (BP) levels exceed
In adults, screening is recommended annually. Levels
above 130/80 mm Hg at least on two separate occasions,
of total cholesterol, HDL-c, LDL-c and triglycerides should
one week apart [JNC-7 (Joint National Committee on
be measured at the time of initial diagnosis. Testing
Prevention, Detection, Evaluation, and Treatment of
may be done every two years if patients have low-risk
High Blood Pressure)]. Blood pressure must be checked
values (LDL-c < 100 mg/dL, HDL-c > 50 mg/dL, and
at every scheduled visit. Ambulatory BP monitoring
triglycerides < 150 mg/dL).1 Goals in dyslipidemia are
in controlled studies, have shown to predict microalbu­
given in Table 44.4.
minuria excretion rates even before the development of
Oxidation of LDL in the arterial extracellular matrix
nephropathy and also cardiovascular morbidity and
is a key event in the development of atherosclerosis
mortality.8,9 Nocturnal non-dippers develop microalbu­
and autoantibodies against oxidized LDL antigens
minuria and autonomic dysfunction and is a marker of
reflect disease severity and the risk of developing acute
incipient hypertension.
cardiovascular events. Low-density lipoprotein oxidation
is involved in the pathogenesis of diabetic retinopathy
LABORATORY MONITORING and autoantibodies against apolipoprotein B peptides
Blood Glucose may act as biomarkers for both micro- and macrovascular
complications in diabetes.12
For type 1 diabetics and pregnant women, self-monitoring
of blood glucose (SMBG) is recommended more than or
Renal Function Tests
equal to three times daily, while the frequency or timing
is not exactly known in type 2 diabetics on oral hypo­ Presence of proteinuria of more than or equal to
glycemic agents. The exact frequency is usually dictated 0.5 gm/dL is classically defined as diabetic nephropathy,
by each patient’s goals or needs. Health professionals which has a prevalence of 15–40% in type 1 diabetes and
must guide patients regarding usage of data obtained in about 5–20% in type 2 diabetes. This stage is also called
adjusting their food intake, drugs or exercise.1 overt nephropathy or macroalbuminuria.13

HbA1c Screening
A patient’s glycemic control over the preceding Screening for microalbuminuria must be done annually
2–3 months can be measured by regular measurement for all type 2 diabetics starting from the time of initial
of HbA1c whose frequency depends on the clinician’s diagnosis, and in type 1 diabetics with duration of illness
discretion, and also dependent on the treatment regimen. more than 5 years; in type 1 diabetics especially with poor
A target level of less than 7% is desirable, with levels of glycemic control, about 18% can have microalbuminuria
less than 6% is recommended in pregnant women and and hence, in such patients, screening is recommended
patients with high risk of CVD1 (The recommendations of 1 year after initial diagnosis. Screening using albumin/
AAEC is to maintain the A1c < 6.5 %). Recommendations creatinine ratio is given in Table 44.5.
 Monitoring Beyond Glycemic Control 659

Table 44.5: Albumin/creatinine ratio13 Table 44.6: Stages of diabetic nephropathy13

Category Spot collection (µg/mg creatinine) Stages Albuminuria Cut-off values
Normal < 30 Microalbuminuria 20–199 µg/minute
Microalbuminuria 30–299 30–299 mg/24-hour
Macro (clinical)-albuminuria > 300
30–299 mg/g
Macroalbuminuria 200 µg/minute

chapter
300 mg/24-hour

44
> 300 mg/g

Table 44.7: Strategies and goals in diabetic nephropathy13

Goal
Intervention Microalbuminuric Macroalbuminuric
ACE inhibitor and/or Reduction of albuminuria or reversion to Proteinuria as low as possible or
ARB normoalbuminuria < 0.5 g/24-hour and
Low-protein diet 0.6–0.8 g/kg wt./day GFR stabilization GFR decline <2 mL / min/year
Antihypertensive agents BP < 130/80 mm Hg
Strict glycemic control HbA1c ≤ 7
Statins LDL < 100 mg/dL
Acetyl salicylic acid Thrombosis prevention

(ACE: Angiotensin-converting-enzyme; ARB: Angiotensin receptor blocker; BP: Blood pressure; GFR: Glomerular filtration rate; LDL:
Low-density lipoprotein).

Such patients must be monitored by measuring • Timed collection, few hours or overnight.
glomerular filtration rate (GFR- Cockgroft-Gault formula) • Stages of diabetic nephropathy based on albumin
which is the best parameter for renal function. In type 1 excretion values are given in Table 44.6.
diabetic patients with nephropathy, the GFR decreases
at the rate of 1.2 mL/minute/month if no therapeutic Evaluation
interventions are made. In type 2 diabetes, the GFR
In diabetes of more than 10 years duration in type 1
is relatively stable but studies have shown that they decr­
diabetes, diagnosis is easily established, especially in the
ease at the rate of 0.5 mL/minute/month. Patients should
presence of retinopathy. In type 2 diabetes, because of
be referred to the nephrologists once the GFR reaches
30 mL/minute/1.73m². uncertainty of onset and absence of retinopathy (in 28%)
diagnosis may be difficult in some patients. After initial
ORGAN COMPLICATIONS: MICROVASCULAR diagnosis of microalbuminuria, patients must undergo
a complete evaluation including that for associated
Nephropathy comorbidities which can worsen nephropathy and
Definition increase risk of CVD like hypertension, dyslipidemia,
smoking along with hyperglycemia and dietary protein
Microalbuminuria is the earliest stage of nephropathy
intake. Monitoring for the goals in diabetic nephropathy
in type 1 diabetes and is a marker for development of
is given in Table 44.7 and management of CKD in diabetes
nephropathy in type 2 diabetes.
has been summarised in Table 44.8.
• At least two of the following tests should be elevated
over a period of 6 months:13
Retinopathy
• Albumin-creatinine ratio in a random spot urine
sample; this test is recommended strongly with values It is the most common microvascular complication of
greater than 30 μg/mg being suggestive of microal­ diabetes, developing at least 7 years before diagnosis of
buminuria. diabetes clinically.14 This is a highly specific complication
• Twenty-four-hour timed collection, which allows in both types of diabetes and is strongly related to the
simultaneous measurement of creatinine. duration of diabetes. After 20 years of diabetes, nearly
660 Management

Table 44.8: Management of CKD in diabetes

eGFR Recommended
All patients • Yearly measurement of creatinine, UAE, potassium
45–60 • Referral to nephrology if possibility for non-diabetic kidney disease exists (duration type 1 diabetes
< 10 years, heavy proteinuria, abnormal findings or renal ultrasound, resistant hypertension, rapid fall
in GFR, or active urinary sediment on ultrasound)
• Consider need for dose adjustment of medications
section

• Monitor eGFR every 6 months

• Monitor electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, parathyroid hormone at least
8

yearly
• Assure vitamin D sufficiency
• Consider bone density testing
• Referral for dietary counseling
30–44 • Monitor eGFR every 3 months
• Monitor electrolytes, bicarbonate, calcium, phosphorus, parathyroid hormone, hemoglobin, albumin,
weight every 3–6 months
• Consider need for dose adjustment of medications
< 30 • Referral to nephrologists

Source: Adapted from National Kidney Foundation guidelines (available at http://www.kidney.org/professionals/KDOQI/guideline_diabetes/)

all patients with type 1 diabetes and more than 60% of retinopathy. One of the studies done in this field stated that
patients with type 2 diabetes have some degree of retino­ in addition to VEGF, almost all platelet-derived growth
pathy. It is the leading cause of blindness in the western factor (PDGF) isoforms (AA, AB and BB) in the vitreous
world. Diabetic retinopathy consists of micro aneurysms, are also correlated with non-proliferative diabetic retino­
hemorrhages, exudates, and retinal edema, as well as pathy (NPDR). The clinical utility of these markers will be
proliferation of newly formed vessels in some cases. more defined in the coming years.
Vascular endothelial growth factor is universally
Screening accepted as a primary factor in the regulation of vessel
patency in vascular networks throughout the body and
Similar to screening for diabetic nephropathy, a detailed
including the retina. There is considerable evidence
eye examination after dilatation must be done in
that the VEGF system is disturbed early in diabetes and
type 2 diabetics at the time of initial diagnosis, while in
interacts with other pathways and vasoactive factors to
persons with type 1 diabetes, an examination should be
stimulate breakdown of the blood retinal barrier (BRB) and
done 5 years after diagnosis. Thereafter, annual exami­
nations must be done by an ophthalmologist.1 Women eventually promote angiogenesis, the hallmark feature of
with diabetes, becoming pregnant, should be examined proliferative diabetic retinopathy (PDR).15
in the first trimester and be followed up every 2 weeks
Evaluation
till 1 year postpartum. Women developing gestational
diabetes are not at a higher risk of developing retinopathy, Gradation of stereoscopic color fundus photographs in
when compared to women with diabetes. Though it was seven standard fields (SSFs), though being the recognized
suggested that fewer screening intervals might be of standard for the detection of diabetic retinopathy, due
benefit, there are a host of other benefits accrued due to to its accuracy and reproducibility, is expensive and
detection of presbyopia, cataracts, age-related macular cumbersome. Single-field photography with its usefulness
degeneration that may be detected by annual screening; demonstrated by cost, convenience and ease of use can
also the feeling that longer intervals between visits may serve as initial evaluation by identifying patients that
give an impression that visual loss is less likely and they require further ophthalmic management (Fig. 44.2). Even
may be lost to contact.14 The severity scale for diabetic so, ophthalmoscopy is the most frequently used procedure
retinopathy is given in Table 44.9. to monitor for diabetic retinopathy. However, when done
Newer studies show that vascular endothelial growth by non-eye care providers, it has poor sensitivity since it is
factor (VEGF) can be used as a biomarker of diabetic usually done on undilated eyes—direct ophthalmoscopy
 Monitoring Beyond Glycemic Control 661

Table 44.9: International clinical diabetic retinopathy disease Table 44.10: Neuropathy disability scoring18
severity scale14
Neuropathy disability score (NDS) Right Left
Proposed disease Findings observable upon dilated
Vibration perception threshold; Normal = 0
severity level ophthalmoscopy
128Hz tuning fork; apex of Abnormal = 1
No apparent retinopathy No apparent retinopathy big toe
Mild NPDR Micro aneurysms only Temperature perception on
Moderate NPDR More than just micro aneurysms, but dorsum of foot; Use tuning

chapter
less than severe NPDR fork with beaker of ice/ warm

44
water
Severe NPDR Any of the following:
Pin prick; apply pin proximal
> 20 intraretinal hemorrhages in each of
to nail just enough to deform
4 quadrants
the skin;
Definite venous beading in 2+ quad- Trial pair = sharp, blunt
rants Normal = Can distinguish
Prominent intraretinal microvascular sharp/ not sharp
abnormalities in 1+ quadrant Achilles reflex Present = 0
And no signs of proliferative retinopathy With reinforce-
PDR One or more of the following: ment = 1
Absent = 2
Neovascularization
NDS total out
Vitreous/preretinal hemorrhage
of 10
(NPDR: Non-proliferative diabetic retinopathy; PDR: Proliferative
diabetic retinopathy).

Neuropathy
Ten to twenty percent of patients with chronic DPN have
bothersome complaints requiring therapy, while about
50% can remain asymptomatic.

Evaluation
All patients should be screened for distal symmetric
polyneuropathy (DPN) starting at diagnosis of type 2
diabetes mellitus (DM) and 5 years after diagnosis of
type 1 DM and at least annually thereafter. Electrophysi­
ological testing is rarely needed, except in situations
where the clinical features are atypical. Identification of
neuropathic symptoms alone is not useful for diagnosis
Fig. 44.2: Color fundus photography or screening. Assessment of clinical signs has shown in
Source: www.uihealthcare.com/ news/currents/volume 3, issue3 studies to be a very good predictor of risk. A neuropathy
disability score (NDS) of 6 or above predicts the risk of
by non-ophthalmologists has a sensitivity of only 50% for foot ulceration (Table 44.10).
the detection of proliferative retinopathy.14 Figures 44.3 Annual screening for diabetic neuropathy should
and 44.4 show NPDR and PDR. be conducted using superficial pain sensation testing,
Fluorescein angiography, is a process where rapid Semmes-Weinstein Monofilament Examination, or vibra­
sequence photography of the retina is done following tion testing by the on-off method.
intravenous administration of the dye. It detects macular The reported operating characteristics for each sensory
ischemia and subtle diabetic macular edema (DME). It modality can be applied to positive findings on the
detects aneurysms with a sensitivity of 82% and hence physical examination of individual patients to predict the
used for treatment planning before photocoagulation.16 likelihood of neuropathy.17
662 Management
section
8

Fig. 44.3: Non-proliferative diabetic retinopathy (NPDR) Fig. 44.4: Proliferative diabetic retinopathy (PDR)
Source: www.ohiovalleyeye.com/ eyeinfo_dsgdia.html Source: www.hubnet.buffalo.edu/eye_disorders.html

Fig. 44.5: Biothesiometer Fig. 44.6: Monofilament

Source: www.topaz47.freeserve.co.uk/ footsensexam.html

Table 44.11: Staging severity of diabetic peripheral neuropathy Quantitative Sensory Testing
(DPN)19
Semmes-Weinstein monofilament also called the 5.07
N0: No objective evidence of DN monofilament, the Rydel-Seiffer tuning fork, and tactile
N1: Asymptomatic polyneuropathy circumferential discriminator, biothesiometer, heat-
N1a: No symptoms or signs but neuropathic test abnormalities cold sensitometer are various hand-held devices used
N1b: Test abnormalities plus neuropathy impairment on neurolo­ to quantify polyneuropathy (Figs 44.5 and 44.6). But
gical examination quantitative sensory testing (QST) alone is not useful for
N2: Symptomatic neuropathy the diagnosis as the sole criteria of diabetic neuropathy
N2a: Symptoms, signs, and test abnormality
because it is a semiobjective test which depends on the
subject’s co-operation, attention and anthropometric
N2b: N2a plus significant ankle dorsiflexor weakness
variables of the subject being tested.18 Staging of severity
N3: Disabling polyneuropathy
of DPN is given in Table 44.11.
 Monitoring Beyond Glycemic Control 663

Table 44.12: Diagnostic tests of cardiac autonomic neuropathy (which carries a bad prognosis and which is constantly
• Beat-to-beat heart rate variability (HRV)
neglected in daily practice). Silent myocardial ischemia
• Heart rate response to standing is seen in about 20% of diabetics (DIAD study).22
• Heart rate response to the Valsalva maneuver Candidates for a diagnostic cardiac stress test include
• Systolic blood pressure response to standing an abnormal resting electrocardiogram (ECG) with or
• Diastolic blood pressure response to isometric exercise
without typical or atypical cardiac symptoms. In diabetes
• ECG QT/QTc intervals The QTc should be < 440 ms.
• Spectral analysis the stress test has a sensitivity of 50–60% and specificity

chapter
of 75–80% compared to 68% and 77% respectively in

44
average individuals.23
Nerve conduction studies are sensitive, but non-
specific and are useful in monitoring the progression of Screening
neuropathy, and ruling out other causes of neuropathy.
Patients with diabetes require at least an annual evalua­
NCVs may change with glycemic control and improve with
tion of cardiovascular risk factors and these risk factors
therapy.19
should be treated as discussed below. Traditionally scree­
ning had been recommended (cardiac stress test) in
Diabetic Autonomic Neuropathy
patients with PAD or carotid occlusion disease, those over
Though many systems are affected, cardiovascular system 35 years of age embarking on a vigorous exercise program,
is most commonly affected by autonomic neuropathy or had two or more of CVD risk factors (hypertension,
(about 20%) and hence cardiovascular autonomic neuro­ smoking, dyslipidemia, microalbuminuria, family history
pathy is the most well-studied of all autonomic neuro­ of premature CVD). Though the traditional risk factors
pathies. The common manifestations include orthostatic are not predictive of CVD, until results of outcomes of
hypotension, resting tachycardia, exercise intolerance and screening asymptomatic diabetic individuals are avail­
silent myocardial ischemia. Most important investigations able, screening and intensive management of risk factors
include heart rate variability (HRV with deep breathing, enable reduction in mortality and morbidity.
standing, Valsalva maneuver), and BP variation on The new risk factors (inflammatory and coagulation
standing and sustained hand grip testing (Table 44.12). related) like fibrinogen, high sensitivity c-reactive protein
Reduced autonomic function is associated with silent (hs-CRP), interleukin 2 (IL-2), tumor necrosis factor α are
myocardial ischemia and increased mortality. HRV tes­ under evaluation.
ting at initial diagnosis in type 2 diabetics and 5 years after
diagnosis of type 1 diabetes serves as reliable baseline Hypertension
for comparison. Presence of autonomic dysfunction
stipulates treatment with angiotensin converting enzyme The evaluation of hypertension is given in Table 44.13.
(ACE) inhibitors and β-blockers and glycemic control This is 1.5 times more common in diabetics than
which can retard the progression of symptoms.20,21 in the normal population and affects about 40–60% of
the diabetics—30% of type 1 diabetics (mostly due to
ORGAN COMPLICATIONS: MACROVASCULAR nephropathy) and 20–60% of type 2 diabetics. An increase
of 5 mm Hg in diastolic/systolic blood pressure increases
Cardiovascular Disease CVD by nearly 20–30%.23
Indications for treatment and goals of treating
Type 2 diabetes is an independent risk factor for
hypertension are given in Table 44.14.
macrovascular complications and CVD is the most
important and major cause of mortality in type 2 diabetes.1
Diabetics are at 2–4 times risk of CVD than non-diabetic
Dyslipidemia
individuals and CVD is the cause of about 75% of About 97% of diabetics have evidence of lipid abnorma­
diabetes-related mortality. Reduction of risk of CVD lities and the profile is usually one of elevated trigly­
includes the screening and treatment of its risk factors ceride levels, increased triglyceride-rich very-low-density
namely, hypertension, dyslipidemia, microalbuminuria/ lipoprotein (VLDL) fraction and low HDL which is termed
nephro­pathy, smoking and autonomic neuropathy diabetic dyslipidemia.10 This kind of dyslipidemia bestows
664 Management

Table 44.13: Evaluation of hypertension Table 44.14: Indications for initial treatment and goals
Physical examination • Height/weight/body mass index (BMI) Blood pressure
• BP both supine and standing Systolic Diastolic
• Two or more determinations in each Goal < 130 < 80
position Behavioral therapy(maximum 3 months, 130–139 80–89
• Appropriate sized cuff (encircles 80% then add drugs)
of arm) Behavioral and drug therapy ≥ 140 ≥ 90
section

• Fundus
• Arterial circulation development of microvascular complications. Hence,
8

Investigations • Blood urea, creatinine,

avoidance of all tobacco products is essential.
serum electrolytes
• Urine albumin
Peripheral Arterial Disease
• Fasting lipids
• HbA1c About 20% of diabetics have PAD, which may be an
• ECG underestimation (peripheral neuropathy may blunt pain
• Chest X-ray response), since more often than not, patients with PAD
are asymptomatic (more than half). About a third of pati­
Table 44.15: Goals in dyslipidemia10
ents have claudication as the most common complaint,
while the rest have severe manifestations which are
Risk Goals
grouped under the umbrella term “critical limb ischemia”
High risk individuals LDL < 70 mg/dL
and includes rest pain, gangrene or tissue loss.
Otherwise LDL <100 mg/dL or reduction by 30–40%
Prevalence is underestimated by the common tests
TG < 150 mg/dL being used, namely presence of claudication and absence
HDL > 40 (males) and > 50 (females) of pulses which suffer from being insensitive indica­
(HDL: High-density lipoprotein; LDL: Low-density lipoprotein; TG: tors. Risk factors include diabetes and smoking (which
Triglyceride). have the highest risk), age (proportional), hypertension
and dyslipidemia. Other probable risk factors include
risk of CVD that is equal to or higher than that arising increased levels of CRP, fibrinogen, homo­cysteine, apoli­
from LDL levels of 150–220 mg/dL. As compared to non- poprotein B, plasma viscosity, alcohol consumption
diabetics, LDL levels do not differ much significantly in (inversely proportional).24
diabetics. LDL-cholesterol is an independent predictor
of CVD as are HDL-cholesterol, diabetes, albuminuria, Screening
fibrinogen (Strong Heart Study). Starting from levels of
It should be done in any diabetic with symptoms of PAD,
70 mg/dL, every 10 mg/dL increase in LDL increases risk
or in diabetics under 50 years of age with other risk factors
of CVD by about 12%.1,10,11
for PAD like hypertension, dyslipidemia, smoking, or
Screening and Evaluation duration of diabetes more than 10 years. If initially normal,
a repeat test should be done after 5 years. Ankle brachial
In adults, screening is recommended annually. Levels of index (ABI) using a hand-held Doppler probe is a simple
total cholesterol, HDL, LDL and triglycerides should be non-invasive test which is nearly 95% sensitive and 100%
measured at the time of initial diagnosis. Testing may be
specific for PAD; it is more accurate than an exhaustive
done every 2 years if patients have low-risk values (LDL
medical history or assessment of peripheral pulses and has
< 100 mg/dL, HDL > 50 mg/dL, and triglycerides < 150
been corroborated angiographically, the only limitation
mg/dL).1 Goals for treatment of dyslipidemia are given in
being calcified, poorly compressible vessels which may
Table 44.15.
artificially elevate values (Table 44.16)24
Smoking
Diagnosis and Evaluation
In smokers, there is increased risk of morbidity and
premature death arising from macrovascular compli­ The evaluation of PAD in diabetes is given in Table 44.17.
cations. Also there is an association in the premature Since symptoms of PAD in diabetics are mostly subclinical,
 Monitoring Beyond Glycemic Control 665

Table 44.16: Peripheral arterial disease—investigations24 Table 44.17: Peripheral arterial disease clinical evaluation21
Ankle–brachial index (5–10 MHz Doppler) History Claudication/Rest pain/Ulcers/Gangrene
• Patient in supine position for 5 minutes Physical examination • F
 oot inspection: dependent rubor/pallor
• Blood pressure of both arms—higher value: denominator on elevation/ dystrophic toe nails
• SBP of DP and PT- higher value: numerator
• Absence of hair growth/cool dry fissured
• Normal, if 0.91–1.30 skin/
• Mild obstruction, if 0.70–0.90 • Palpation of peripheral pulses.

chapter
• Moderate obstruction, if 0.40–0.69

44
• Severe obstruction if < 0.40 early diagnosis would enable institution of preventive/
• Poorly compressible if > 1.30 (poorly compressible arteries) correctable measures. More important is to identify
Anatomical studies (if revascularization being considered) those with CVD and stroke risk, and treat symptoms of
• Duplex sonography PAD to prevent functional disability and limb loss.
• Magnetic resonance angiogram
• Contrast angiography
Graded treadmill
OTHER COMPLICATIONS
• Patients with atypical symptoms
Foot Examination
• Typical symptoms with normal ABI
• If claudication present- drop in ankle BP by 20 mm Hg Foot ulcers and amputation are the most common con­
Segmental pressure/volume recordings sequences of diabetic neuropathy which are major causes
(ABI: Ankle-brachial Index; SBP: Systolic blood pressure; DP: Dossalis of morbidity and disability and is commonly seen in
pedis; TP: Posterior tibial arteries). patients with poor glycemic control and in males, with
long duration of diabetes and the presence of either
Table 44.18: Tools for assessing neuropathy, circulation and foot
deformity macro- or microvascular complications. Apart from
• Neuropathy neuropathy, local changes, peripheral vascular disease,
– 10 g monofilament sensitivity altered biomechanics, nail and joint deformities, callus
– Vibration perception (tuning fork or biothesiometer)
and previous amputation increase risk of foot ulceration1.
– Neuropathy disability score–ankle (Achilles) reflexes
and the sensory modalities of pinprick, vibration and Table 44.18 provides an overview of the tools for assessing
temperature perception neuropathy, circulation and foot deformity.
• Circulation Calluses occur more often and build up faster on the
– Palpation of peripheral pulses feet of people with diabetes. This is because there are high-
– Ankle-brachial pressure index (ABPI)
pressure areas under the foot. Calluses, if not trimmed, get
– Toe-brachial pressure index
• Foot deformity score very thick, break down, and turn into ulcers.
6 point scale (1 point for each characteristic) People with diabetes are far more likely to have a foot
– small muscle wasting or leg amputated than other people. Many people with
– charcot foot deformity
diabetes have PAD, which reduces blood flow to the feet.
– bony prominence
– prominent metatarsal heads
Also, many people with diabetes have neuropathy, which
– hammer or claw toes reduces sensation. Together, these problems make it easy
– limited joint mobility to get ulcers and infections that may lead to amputation.
Score of 3 or above indicates foot deformity Most amputations are preventable with regular care and
Defining risk of foot complications and amputation
proper footwear.
EBR 3 Stratify foot risk in the following manner:
• “low risk”—people with on risk factors and no
An annual foot examination should be done in all
previous history of foot ulcer/amputation individuals with diabetes so that pre-emptive measures
• “intermediate risk”—people with one risk factor may be instituted. Examination includes evaluation of
(neuropathy, peripheral arterial disease or foot protective sensation, foot biomechanics (deformities,
deformity) and no previous history of foot ulcer/
mobility, and gait), skin integrity and vascular status
amputation
• “high risk”—people with two or more risk factors (Table 44.19). Assessment of protective sensation includes
(neuropathy, peripheral arterial disease or foot quantitative sensory examination using a monofilament,
deformity) and/or a previous history of foot ulcer/ and visual inspection by a health professional at every
amputation1 visit. Skin integrity should be carefully looked for, espe­
666 Management

Table 44.19: Foot care cause of diabetes-related hospital bed-days. The major
Protective sensation QST Biothesiometry risk factor is foot ulcer which in turn is predisposed by a
Monofilament testing host of other conditions.27 The risk factors for diabetic foot
Plantar pressure monitoring infection are given in Table 44.20.
Foot structure/ Bony deformities Hammertoes The classification of diabetic foot ulcers has been
biomechanics Bunions given by the International Consensus on the Diabetic
Charcot’s
Foot [International Working Group on the Diabetic Foot
section

Joint mobility limitation

Gait problems
(IWGDF)] for research purposes which are given below,
8

the main essentials given by the acronym PEDIS— per­

Vascular status Pulses
Skin integrity Temperature fusion, extent, depth/tissue loss, infection and sensation.
ABI/ vascular Doppler The classification of diabetic foot is given in Table 44.21.
Between toes and metatarsals
Erythema and warmth
Callus formation
Osteoporosis
Osteoporotic fractures are more common in diabetics
cially between the toes and under the metatarsal heads (type 1 > type 2), especially of the hip and foot. Foot frac­
for erythema, warmth and calluses. Screening for PAD tures are related to the focal osteopenia (arising from
should be done if there is a history of claudication and severe peripheral neuropathy) and in part to obesity.
pedal pulses are weak or are absent.25 Studies have shown decreased BMD in diabetic adole­
There were no studies providing evidence for the scents as compared to non-diabetic controls in the range
optimal frequency of foot assessment in people with of 20–50% and that microvascular complications corre­
and without foot ulceration. Expert opinion suggests lated inversely with the BMD of normally menstruating
the following frequencies. In people stratified as having females.28
low-risk feet (where no risk factors or previous foot
complications have been identified), foot examination Screening
should occur annually. In people stratified as having
Screening is generally recommended for all women over
intermediate-risk or high-risk feet (without current
65 years, women between 60 and 64 years with increased
foot ulceration), foot examination should occur at least
risk, and in diabetics, not meeting the above criteria
every 3–6 months. The main aim of the more frequent
(type 1 patients, female or male with complications, thin
assessment of those at intermediate or high risk is to
women with extensive diabetic complications).
reassess for new risk factors and for other more rapidly
developing problems, such as tinea, gangrene, ulcers and
MONITORING IN HIGH RISK POPULATION
Charcot’s neuro arthropathy, which may need immediate
intervention. Prediabetes
Infections Projections reveal rising trends of incidence and preva­
lence of diabetes due to the increase in obesity and aging
The pathophysiology is incompletely understood and is population. Studies done showed that various strategies
probably related to defects in chemotaxis and possibly could delay or prevent diabetes state in patients of
complement function. Common infections include that of very high risk. Prediabetes was diagnosed if the patient
the urinary tract and the respiratory system (complicated had a fasting plasma glucose (FPG) = between 100 and
UTIs, pneumonias), soft tissue infections of the lower 125 mg/dL (IFG) or a 2-h value in the oral glucose tolerance
extremity and also emphysematous cholecystitis, malig­ test (OGTT) = between 140 and 199 mg/dL impaired glu­
nant otitis externa and mucormycosis. There is increased cose tolerance (IGT).
risk of carriage rates of Staphylococcus aureus and higher Studies such as the diabetes prevention program
risk of tuberculin reaction (PPD positivity) and developing (DPP), STOP- NIDDM trial showed that lifestyle modifica­
tuberculosis.26 Diabetic foot infections are the most com­ tions including exercise, low-fat diet and intensive dietary
mon non-traumatic cause of lower limb amputations and counseling, oral hypoglycemic drugs like metformin,
 Monitoring Beyond Glycemic Control 667

Table 44.20: Risk factors for diabetic foot infection

• Peripheral motor neuropathy • Abnormal anatomy and foot biomechanics
• Peripheral sensory neuropathy • Minor injuries, unnoticed, unattended
• Peripheral autonomic neuropathy • Dry, cracking skin (decreased sweating)
• Neuro-osteoarthropathic deformities • Abnormal anatomy and biomechanics
• Vascular (arterial) insufficiency • Impaired wound healing

chapter
• Hyperglycemia/other derangements • Impaired neutrophil function/healing

44
• Patient disabilities • ↓vision, ↓mobility, previous amputation(s)
• Maladaptive patient behaviors • Inadequate preventive/precautionary measures
• Health care system failures • Inadequate glycemic control/ patient education

Source: Modified from Infectious Diseases Society of America guidelines27

Table 44.21: Diabetic foot ulcer classification

PEDIS grade Infection severity Clinical manifestations
1 Uninfected No purulence or any manifestations of inflammation
2 Mild ≥ 2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration
cellulitis/erythema extends ≤ 2 cm around the ulcer,
infection limited to skin or superficial subcutaneous tissues
3 Moderate Patient is systemically well and metabolically stable +
≥ 1 of the following characteristics:
• Cellulitis extending > 2 cm,
• Lymphangitic streaking,
• Spread beneath the superficial fascia,
• Deep-tissue abscess,
• Gangrene,
• Involvement of muscle, tendon, joint or bone
4 Severe Patient has systemic toxicity or metabolic instability
Fever Tachycardia, hypotension
Chills Azotemia, hyperglycemia
Vomiting Leukocytosis
Confusion Acidosis

Source: Infectious Diseases Society of America guidelines (modified) 25

acarbose, and weight reduction delayed or prevented normal middle aged subjects, testing at 3-year intervals
diabetes state in high risk individuals (45 years or older if initial levels were normoglycemic is recommended
with BMI > 25 kg/m2).1,2 Prevalence of IFG or IGT was due to the age-related incidence rate of diabetes and the
seen in greater numbers during the 5th decade and increased rate of evolution to diabetes.29
peaked between ages 60 and 75 years. Hence, evidence
suggests that screening for diabetes should be also MONITORING AND ASSESSMENT OF
considered in people under 45 years with risk factors COMMON COMORBID CONDITIONS
along with the screening that is recommended for people
45 years or older with a BMI of more than or equal to In addition to the commonly appreciated comorbidities
25 kg/m using either the FPG or the IGT, albeit the former of obesity, hypertension, and dyslipidemia, diabetes is
is preferred. Screening not only detects prediabetics, but also associated with other diseases or conditions at rates
also undiagnosed cases of diabetes and once identified, higher than those of age-matched people without diabetes.
prediabetics should be evaluated for cardiovascular risk A few of the more common comorbidities are described
factors like their diabetic counterparts. In otherwise here, and listed in Table 44.22.
668 Management

Table 44.22: Common comorbidities for which increased risk is the Look AHEAD trial exceeded 80%. Treatment of sleep
associated with diabetes apnea significantly improves quality of life and blood
• Hearing impairment pressure control. The evidence for a treatment effect on
• Obstructive sleep apnea glycemic control is mixed.
• Fatty liver disease Cardiovascular autonomic neuropathy (AN) in diabetic
• Low testosterone in men patients is associated with increased mortality, and there
• Periodontal disease has been some speculation that impaired neural control
section

• Certain cancers of breathing in diabetics with AN might lead to sleep-

8

• Fractures disordered breathing and, thus, contribute to the poor

• Cognitive impairment prognosis. In addition, there is epidemiological evidence
that diabetes is a risk factor for mortality in patients with
sleep apnea syndrome. These epidemiological findings
Hearing Impairment tend to support the hypothesis that AN might be associated
Hearing impairment, both high frequency and low/mid with sleep-disordered breathing in some patients.31
frequency, is more common in people with diabetes,
perhaps due to neuropathy and/or vascular disease. In Fatty Liver Disease
an NHANES (National Health and Nutrition Examination
Unexplained elevation of hepatic transaminase concen­
Survey) analysis, hearing impairment was about twice
trations are significantly associated with higher BMI,
as great in people with diabetes than in those without
waist circumference, triglycerides, fasting insulin and with
diabetes, after adjusting for age and other risk factors for
hearing impairment. High-frequency loss in those with lower HDL cholesterol. Type 2 diabetes and hypertension
diabetes was significantly associated with history of CHD are independently associated with transaminase eleva­
and with peripheral neuropathy, while low/infrequency tions in women. In a prospective analysis, diabetes was
loss was associated with low HDL cholesterol and with significantly associated with incident non-alcoholic
poor reported health status. chronic liver disease and with hepatocellular carcinoma.
Sensorineural hearing loss (SNHL) is more common in Interventions that improve metabolic abnormalities in
patients with diabetes than in non-diabetic patients, and patients with diabetes (weight loss, glycemic control,
severity of hearing loss correlate with the progression of treatment with specific drugs for hyperglycemia or dyslipi­
disease. This can be due to microangiopathic disease in demia) are also beneficial for fatty liver disease.
the inner ear. Non-alcoholic fatty liver disease (NAFLD) is reported
The link between diabetes and SNHL makes intuitive commonly in patients with type 2 diabetes mellitus, which
sense, given the documented neuropathic and micro­ has been suggested as a risk factor for the progressive form
vascular complications of diabetes and the complex of NAFLD, or non-alcoholic steatohepatitis.
blood supply of the inner ear. Most audiometric studies of Patients with NAFLD and DM are at risk for the
hearing in patients with diabetes show a mild to moderate development of an aggressive outcome, such as cirrhosis
high-frequency SNHL. of liver. Insulin resistance plays an important role in the
The effects of different variables such as duration of development of poor clinical outcomes in patients with
diabetes, blood sugar control, and presence of end-organ NAFLD.32
damage on hearing loss have not yet been clarified, despite
several studies on this topic.30 Low Testosterone in Men
Mean levels of testosterone are lower in men with diabetes
Obstructive Sleep Apnea
compared with age-matched men without diabetes, but
Age-adjusted rates of obstructive sleep apnea, a risk factor obesity is a major confounder. The issue of treatment in
for CVD, are significantly higher (4- to 10-fold) with obesity, asymptomatic men is controversial. The evidence for
especially with central obesity, in men and women. The effects of testosterone replacement on outcomes is
prevalence in general populations with type 2 diabetes mixed, and recent guidelines suggest that screening and
may be up to 23% and in obese participants enrolled in treatment of men without symptoms is not recommended.
 Monitoring Beyond Glycemic Control 669

The key response to the aging, overweight man with recommended age and sex appro­priate cancer screenings
type 2 diabetes and subnormal testosterone levels should and to reduce their modifiable cancer risk factors (obesity,
be implementation of lifestyle measures such as weight smoking, physical inactivity).
loss and exercise, which, if successful, raise testosterone Evidence from population-based studies and clinical
and provide multiple health benefits. Although approved trials indicate that diabetic patients experience higher
therapy for diabetes should be used, testosterone therapy mortality and recurrence rates after diagnosis with, and
should not be given to such men until benefits and risks treatment for, cancer. The association between diabetes

chapter
are clarified by adequately powered clinical trials.33 and cancer is complex and warrants further study as the

44
general population ages and the magnitude of both health
Periodontal Disease problems continues to grow.35

Periodontal disease is more severe, but not necessarily Fractures

more prevalent, in patients with diabetes than those
Age-matched hip fracture risk is significantly increased
without diabetes. Numerous studies have suggested asso­ in both type 1 and type 2 diabetes in both sexes. Type 1
ciations with poor glycemic control, nephropathy, and diabetes is associated with osteoporosis, but in type 2
CVD, but most studies are highly confounded. A compre­ diabetes an increased risk of hip fracture is seen despite
hensive assessment, and treatment of identified disease, higher bone mineral density (BMD). One study showed
is indicated in patients with diabetes, but the evidence that prevalent vertebral fractures were significantly more
that periodontal disease treatment improves glycemic common in men than in women with type 2 diabetes,
control is mixed. but were not associated with decreased BMD. In three
Infection-mediated upregulation cycle of cytokine large observational studies of older adults, femoral neck
synthesis and secretion by chronic stimulus from lipopoly­ BMD T-score and the WHO fracture risk algorithm (FRAX)
saccharide (LPS) and products of periodonto­ pathic score were associated with hip and non-spine fracture,
organisms may amplify the magnitude of the advanced although fracture risk was higher in diabetic participants
glycation end product (AGE)-mediated cytokine response compared with participants without diabetes for a given
operative in DM. T-score and age or for a given FRAX score risk. It is
Infection and AGE-mediated cytokine upregulation, appropriate to assess fracture history and risk factors in
helps to explain the increase in tissue destruction seen in older patients with diabetes and to recommend BMD
diabetic periodontitis. Periodontal infection complicates testing if appropriate for the patient’s age and sex. For
the severity of diabetes and the degree of metabolic at-risk patients, it is reasonable to consider standard
control. primary or secondary prevention strategies (reduce risk
Control of chronic periodontal infection is essential factors for falls, ensure adequate calcium and vitamin D
for achieving long-term control of DM. Elimination intake, and avoid use of medications that lower BMD,
of periodontal infection by using systemic antibiotics such as glucocorticoids) and to consider pharmacotherapy
improves metabolic control of diabetes, defined by for high-risk patients. For patients with type 2 diabetes
reduction in glycated hemoglobin or reduction in insulin with fracture risk factors, avoidance of TZDs is warranted.
requirements.34 Diabetes mellitus adversely affects the skeleton and
is associated with an increased risk of osteoporosis and
Cancer fragility fractures. The mechanisms underlying low bone
strength are not fully understood but could include
Diabetes (possibly only type 2 diabetes) is associated with impaired accrual of peak bone mass and diabetic compli­
increased risk of cancers of the liver, pancreas, endome­ cations, such as nephropathy. T1DM affects the skeleton
trium, colon, rectum, breast and bladder. The association more severely than T2DM, probably because of the lack of
may result from shared risk factors between type 2 dia­ the bone anabolic actions of insulin and other pancreatic
betes and cancer (obesity, age, and physical inactivity) but hormones. Bone mass can remain high in patients with
may also be due to hyperinsulinemia or hyperglycemia. T2DM, but it does not protect against fractures, as bone
Patients with diabetes should be encouraged to undergo quality is impaired.
670 Management

A physically active, healthy lifestyle and prevention diabetes, hypertension, dyslipidemia, small vessel diseases
of diabetic complications, along with calcium and of brain, defect in cerebral insulin receptors signaling
vitamin D repletion, represent the mainstay of therapy for and role of IGF-I and insulin degrading enzymes (IGF-I)
osteoporosis in patients with T1DM or T2DM.36 have been postulated as possible mechanism for the
cognitive decline in diabetes. Studies have shown that
Cognitive Impairment insulin is required for learning and memory. Insulin affects
Diabetes is associated with significantly increased risk the metabolism of Aβ (Amyloid beta) and tau proteins,
section

of cognitive decline, a greater rate of cognitive decline, the building blocks for amyloid plaques and neuro fibri­
8

and increased risk of dementia. In a 15-year prospective llary tangles in the brain, the major pathological findings
study of a community-dwelling people over the age of 60 of Alzheimer’s disease.37
years, the presence of diabetes at baseline significantly
increased the age and sex-adjusted incidence of all cause SUMMARY
dementia, Alzheimer disease, and vascular dementia
compared with rates in those with normal glucose tole­ The essentials of adequate diabetic care, frequency of
rance. In a sub-study of the ACCORD study, there were testing (for complications, comorbid illnesses), and goals
no differences in cognitive outcomes between intensive for each clinical standards have been difficult to remember
and standard glycemic control, although there was by both the patient as well as the care-giver themselves.
significantly less of a decrement in total brain volume Because of the enormity of the tasks involved, a succinct
by MRI in participants in the intensive arm). The effects message about the all-inclusive components of diabetic
of hyperglycemia and insulin on the brain are areas of care has been difficult to develop and put into practice.
intense research interest. Hence, the elements have been summarized in an easy-to-
Usually diabetic patients are not routinely assessed remember format (the ABCs of diabetes), which is given
for cognitive function. In addition to the duration of in Table 44.23.24,38

Table 44.23: Parameters to be monitored in diabetes mellitus37

Parameter Goal Frequency
A Aspirin Primary prevention ≥ 30 years of age with CVD risk Evaluate every visit—regarding aspirin indications
Albuminuria ARB (HTN/nephropathy/ T1DM—annually (start at diagnosis); T2DM
Macroalbuminuria/renal insufficiency); (start 5 years after diagnosis)
ACE-I (> 55 years, CVD risk +/- HTN)
Arteries-PAD To prevent / treat critical limb ischemia Q 5 years, if initially normal
Alcohol Moderation < 20 g/day Evaluate—every visit
B Blood pressure < 130/80 mm Hg At every scheduled visit
< 125/75 if albuminuria > 1 g or creatinine > 1 mg/dL
C Cholesterol LDL < 100 mg/dL Annually; q 2 years if less than goal.
TG < 150 mg/dL
HDL > 40 mg/dL
Cigarette Cessation of smoking Evaluate every visit
D Diabetes education Understanding, participation in diabetes health care; Annual visit to diabetes educator
Self-management education
E Eye examination Preserve vision by early treatment T1DM—annually starting 3–5 years after diagnosis;
T2DM—annually; Pregnancy—1st trimester, observe
until one year postpartum
F Foot care Reduction amputation rates—45–80% Daily by patient
At every visit by physician
Annually—foot care specialist
Fitness Obese and fit better than lean and unfit 150 minute/week moderate exercise;
90 min/week of vigorous exercise
Contd...
 Monitoring Beyond Glycemic Control 671

Contd...
Parameter Goal Frequency
G Glucose monitoring Self-monitoring of blood glucose(SMBG)—use data T1DM and pregnant women on insulin: > 3 times/day
to adjust food intake, exercise, drug therapy
Glycated Hb < 7% Q 6 months (stable)
HbA1c Q 3 months (poor glycemic control)
H Health maintenance Prevention of morbidity and mortality Pneumococcal—at least once

chapter
Influenza—all diabetics 6 months or older; health

44
education
I Indication - Referral for diabetic foot/cardiac evaluation/nephropathy/retinopathy
specialty care

further reading 9. Voros P, Lengyel Z, Nagy V, et al. Diurnal blood pressure

variation and albuminuria in normotensive patients with
1. Bloomgarden ZT.. Approaches to cardiovascular disease insulin-dependent diabetes mellitus. Nephrol Dial Trans­
and its treatment. Diabetes Care. 2003;26:3342-8. plant. 1998;13:2257-60.
2. Anjana M, Sandeep S, Deepa R, et al. Visceral and central 10. Henry RR. Preventing cardiovascular complications of Type
abdominal fat and anthropometry in relation to diabetes in 2 diabetes: focus on lipid management. Clinical Diabetes.
asian Indians. Diabetes Care. 2004;27:2948-53. 2001;19:113-20.
3. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropa­ 11. Buse J. Statin treatment in diabetes mellitus. Clinical Diabe­
thies: a statement by the American Diabetes Association. tes. 2003;21:168-72.
Diabetes Care. 2005;28:956-62. 12. Fredrikson GN, Anand DV, Hopkins D, et al. Associations
4. American Diabetes Association–Standards of Medical Care between autoantibodies against apolipoprotein B-100 pep­
in Diabetes. Diabetes Care. 2005;28:S4-36S. tides and vascular complications in patients with type 2
diabetes. Diabetologia. 2009;52:1426-33.
REFERENCES 13. Gross JL, de Azevedo MJ, Silveiro SP, et al. Diabetic
nephropathy: diagnosis, prevention and treatment. Diabe­
1. American Diabetes Association–Standards of Medical Care tes Care. 2005;28:164-7.
in Diabetes. Diabetes Care. 2005;28:S4-36S. 14. Fong DS, Aiello LP, Ferris FL, et al. Diabetic retinopathy.
2. Tan CE, Ma S, Wai D, et al. Can we apply the national cho­ Diabetes Care. 2004;27:2540-53.
lesterol education program adult treatment panel defini­ 15. Wilkinson-Berka JL. Vasoactive factors and diabetic retin­
tion of the metabolic syndrome to Asians? Diabetes Care. opathy: vascular endothelial growth factor, cyclooxyge­
2004;27:1182-6. nase-2 and nitric oxide. Curr Pharm Des. 2004;10:3331-48.
3. Snehalatha C, Viswanathan V, Ramachandran A. Cutoff 16. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and
values for normal anthropometric variables in asian Indian diabetic macular edema: pathophysiology, screening, and
adults . Diabetes Care. 2003;26:1380-4. novel therapies. Diabetes Care. 2003;26:2653-64.
4. The IDF consensus worldwide definition of the metabolic 17. Perkins BA, Olaleye D, Zinman B, et al. Simple screen­
syndrome. [online] available from the website. www.idf.org. ing tests for peripheral neuropathy in the diabetes clinic.
[Accessed September, 2013]. Diabetes Care. 2001;24:250-6.
5. Risérus U, Ärnlöv J, Brismar K, et al. Sagittal abdominal 18. Andrew JM. Boulton AJ. Management of diabetic peripheral
diameter is a strong anthropometric marker of insulin re­ neuropathy. Clinical Diabetes. 2005;23:9-15.
sistance and hyperproinsulinemia in obese men. Diabetes 19. Boulton AJ, Malik RA, Arezzo JC, et al. Diabetic somatic
Care. 2004;27:2041-6. neuropathies. Diabetes Care. 2004;27:1458-86.
6. Silverstein J, Klingensmith G, Copeland K, et al. Care of 20. Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic
children and adolescents with Type 1 diabetes: a state­ neuropathy. Diabetes Care. 2003;26:1553-79.
ment of the American Diabetes Association. Diabetes Care. 21. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropa­
2005;28:186-212. thies: a statement by the American Diabetes Association.
7. Anjana M, Sandeep S, Deepa R, et al. Visceral and central Diabetes Care. 2005;28:956-62.
abdominal fat and anthropometry in relation to diabetes in 22. Wackers FJ, Young LH, Inzucchi SE, et al. The detection of
asian Indians. Diabetes Care. 2004;27:2948-53. ischemia in asymptomatic diabetes (DIAD) investigators:
8. Nakano S, Konishi K, Furuya K, et al. A prognostic role of detection of silent myocardial ischemia in asymptomatic
mean 24-h pulse pressure level for cardiovascular events diabetic subjects. Diabetes Care. 2004;27:1954-61.
in type 2 diabetic subjects under 60 years of age. Diabetes 23. Bloomgarden ZT.. Approaches to cardiovascular disease
Care. 2005;28:95-100. and its treatment. Diabetes Care. 2003;26:3342-8.
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24. Hoyt RE. Peripheral arterial disease in people with diabe­ 30. Kakarlapudi V, Sawyer R, Staecker H. The Effect of Diab­etes
tes: response to consensus statement. Clinical Diabetes. on Sensorineural Hearing Loss. Otol Neurotol. 2003;24:382-6.
2004;22:181-9. 31. Ficker JH, Dertinger SH, Siegfried W, et al. Obstructive
25. International Working Group on the Diabetic Foot sleep apnoea and diabetes mellitus: the role of cardiovas­
(IWGDF) –International consensus on the diabetic foot. cular autonomic neuropathy. Eur Respir J. 1998;11:14-9.
32. Younossi ZM, Gramlich T, Matteoni CA, et al. Non-alco­
[online] Available from www.diabetic-foot-consensus.com.
holic fatty liver disease in patients with type 2 diabetes.
[Accessed September, 2013] Clin Gastroenterol Hepatol. 2004;2:262-5.
26. Schaberg DS, Norwood JM. Case study: infections in diabe­ 33. Grossmann M. Low testosterone in men with type 2 diabe­
section

tes mellitus. Diabetes Spectr. 2002;15:37-40. tes: significance and treatment. J Clin Endocrinol Metab.
8

27. Lipsky BA, Berendt AR, Deery HG, et al. ISDA guidelines 2011;96:2341-53.
diagnosis and treatment of diabetic foot infections. [online] 34. Grossi S, Genco RJ. Periodontal disease and Diabetes mel­
Available from www.idsociety.org. [accessed September, litus: A two-way relationship. Ann Periodontal 1998;3:51-61
2013]. 35. Richardson LC, Pollack LA. Therapy insight: influence
28. Brown SA, Sharpless JL. Osteoporosis: An under-appreciated of type 2 diabetes on the development, treatment and
outcomes of cancer. Nat Clin Pract Oncol. 2005;2:48-53.
complication of diabetes. Clinical Diabetes. 2004;22:10-20.
36. Hamann C, Kirschner S, Günther KP, et al. Bone, sweet
29. Eyre H, Kahn R, Robertson RM. On behalf of the ACS/
bone—osteoporotic fractures in diabetes mellitus. Nat Rev
ADA/AHA collaborating writing committee for preventing Endocrinol. 2012;8:297-305.
cancer, cardiovascular disease, and diabetes: A common 37. Dash SK. Cognitive impairment and diabetes. Recent Pat
agenda for the American Cancer Society, the American Endocr Metab Immune Drug Discov. 2008;2:218-23.
Diabetes Association, and the American Heart Association. 38. Abate SL. Expanded ABCs of diabetes. Clinical Diabetes.
Diabetes Care. 2004;27:1812-24. 2003;21:128-33.
 Chapter 45
Current Status of Indigenous Drugs
and Alternative Medicine in the
Management of Diabetes Mellitus
Ashok DB Vaidya, Nutan Sham Nabar, Rama Ashok Vaidya

“I would never have undertaken the isolation of insulin had I known how much had previously been published in this field.”1
Sir Frederick Banting (1891–1941)

Indigenous Drugs

Chapter Outline
♦♦ Indigenous Drugs and Medicinal Plants ♦♦ Complementary and Alternative Medicine
♦♦ Pharmacology and Clinical Studies of Antidiabetic ♦♦ Ayurvedic Prevention and Management
Medicinal Plants ♦♦ Dietary and Exercise Management of Diabetes
♦♦ Marketed Ayurvedic Formulations ♦♦ Indian Homeopathic Remedies
♦♦ CSIR-NMITLI Diabetes Project

INTRODUCTION AND BACKGROUND products and their medical claims deserves a close
scrutiny by reverse pharmacology path.
In view of the global epidemic of obesity and diabetes—
diabesity, there is an active and widespread resurgence of Historical Continuity of the
research interest in the medicinal plants and alternative
Knowledge Capital
remedies, claimed to be useful in diabetes mellitus.2
There are many studies in the experimental models of Diabetes mellitus was well known to the founders of
diabetes. However, valid clinical trials are limited. The Ayurveda, as judged from the detailed descriptions of the
evidence from the basic in-vitro and in-vivo studies have disease in the classic texts like Charaka Samhita, Sushruta
to be reviewed critically, as relevant to their current status Samhita and Bhrigu Samhita, etc.4 The terms Prameha,
and scope in the prevention and management of diabetes Madhumeha and Ikshumeha are prevalent and retain a
mellitus.3 We need to learn openness to Ayurveda. Carl clinical continuity for thousands of years in India both for
Sagan has said, “At the heart of science is an essential the diagnosis and management of diabetes. Ayurveda has
balance between two contradictory attitudes—openness a sound base of philosophical (lifestyle related) and logical
to new ideas, no matter how bizarre or counterintuitive principles.5,6 The different nature of the epistemology and
they may be, and the most ruthless skeptical scrutiny evidence in Ayurveda has to be grasped so as to benefit
of all ideas, old and new. This is how deep truths are from these live traditions and the widespread use of
winnowed from deep non-sense”. The field of natural ayurvedic drugs.7
674 Management

Table 45.1: Previous reviews on antidiabetic plants and formula­tions relief of complications. A major multicentric-networked
Author Theme Remarks research and development program was carried out
Satyavati et al.8 Experimental and clinical References under the Council of Scientific and Industrial Research-
cited—188 New Millennium Indian Technology Leadership Initia­
Aiman9 Research around 1970 A critical overview tive (CSIR-NMITLI) for herb-based novel drugs with
Chaudhury and Pharmacology models Leads suggested insulin-sensitizing activity.24 The approach of reverse
Vohra10 pharmacology was selected for this programme.25 Inter­
section

Mukherjee11 CDRI—selected plants Drug development esting findings have emerged and also have new drug
8

plants discovery potential. This too shall be briefly reviewed.

Ajgaonkar12 Clinical Ayurveda Experiential leads
Ivorra et al.13 Wider choice of plants Comparative leads INDIGENOUS DRUGS AND
Handa et al.14 Experimental activity Priority leads MEDICINAL PLANTS
Bever15 West African plants Folklore claims
Bailey and Day 16
A general review Careful use Though the total number of herbal remedies claimed to
Mishra and Adra 17
Scientific basis Reference have a therapeutic effects in diabetes is quite large, the
cited—198 effective remedies adopted are few.
Yeh et al.18 Systematic review Trials 108/36 herbs In India, the traditional systems—Ayurveda, Unani and
Agarwal et al. 19
Shilajit—a review Widely used Siddha did not continue to grow and adopt the emerging
Patel et al.20 Insulin mimetic Bioactive drugs basic sciences. The advances of insulin, oral hypoglycemic
and References agents (OHA), monitoring of glycemic control and the
cited—53 mechanisms of complications, however, have been appre­
Khan et al.21 Parts of the plants used References ciated and utilized by ayurvedic practitioners. There is
cited—289 a relatively lesser reciprocal effort to understand and
Kavishankar et al.22 Plants covered 76 References adopt the basics of ayurvedic management of diabetes by
cited—177
biomedical scientists.

Classic Remedies in Ayurveda

Previous Reviews on Indigenous
In Ayurveda, three types of Pramehas—Kaphaja, Pittaja
Drugs for Diabetes Mellitus and Vataja have been described in detail. The herbs
The subject of antidiabetic medicinal plants and formula­ or plants selected are based on their dravyagunas, i.e.
tions has been of interest to many. Table 45.1 lists some ayurvedic properties of rasa (taste), guna (properties),
of the reviews on this subject.8-22 Several recent reviews veerya (cold/hot), vipaka (metabolite) and prabhava
cover the new therapeutic targets such as aldose reductase, (specific effects).17
DNA damage and islet β cells. Charaka Samhita has described several decoctions
Self-medication with herbal drugs is a common as per the dominant dosha.26 But a common and safe
practice among diabetic patients.23 Hence, it is desirable to decoction for several Pramehas is Phalatrikadi Kwath,
learn more information on such widely and concomitantly recommended by Sharangdhara and widely used in
used herbal drugs—their safety, efficacy and interactions. India.27 The ingredients are Triphala (Terminalia chebula,
Terminalia bellirica and Phyllanthus emblica), Musta
(Cyperus rotundus), Daruharidra (Berberis aristata),
Scope of the Present Review
Indrayan (Citrullus colocynthis) and Haridra (Curcuma
As the targeted readership of the present textbook will longa). All these plants individually, have a significant
be wide and varied in the field of diabetes, an attempt pharmacodynamic and anti-inflammatory activity profile
is made to provide a broad view. A pragmatic review of that would provide a rationale for their use in mild to
the use of remedies will be for the practice-oriented moderate diabetes.28-34 This formulation enhances the liver
personnel, and the data on some interesting leads will intermediary metabolism in diabetes mellitus, reducing
be useful to the postgraduates and research workers. fatty liver change. Triphala preparations are also used
Novel paths for anti-diabetic drugs have been identified for the weight control in obesity (Medoroga).35 Diabetic
as to new therapeutic targets and for prevention or and obese patients can be prescribed two tablets or a
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 675

teaspoonful of Triphala every night. Gogte28 has rightly be taken in a dose of 15 mL after meals with equal amount
stated, “In all ayurvedic texts, in the form of Triphala, of water twice in a day for 1–3 weeks. It has potent anti-
Terminalia chebula is used very often. There is no remedy inflammatory effects and can reduce the high specific
like that—with many beneficial effects and the diverse C-reactive protein (CRP) and inflammatory cytokines.
manner in which its formulation and combinations Some of the other plants often used in India, for
are made. It has a supreme place in therapeutics and diabetes mellitus are: Azadirachta indica (nimba), Aegle
for health”. A major active ingredient of Triphala viz. marmelos (bilva), Eugenia jambolana (jambu), Momordica

chapter
gallic acid has been shown to protect pancreatic islet charantia (karvellaka), Coccinia indica (bimbi), Aloe vera

45
β cells, reduce DNA damage and enhance superoxide (kumari), Allium cepa (palandu), Allium sativum (rasoon),
dismutase mRNA levels.36 Other two common household Embelia ribes (vidanga), Murraya koenigii (girinimba),
remedies, which can be used safely in diabetes mellitus, Achyranthes aspera (apamarga), Ficus benghalensis
are Chandraprabhavati and Sudarshan ghanvati. (vata), Gymnema sylvestre (madhunashini), Pterocarpus
Chandraprabha Gutika is widely used all over India by marsupium (vijaysar), Tinospora cordifolia (guduchi),
many diabetic subjects. It is administered per os in a Hibiscus rosa-sinensis (japa), Trigonella foenum-graecum
(methica), Withania somnifera (ashwagandha), Feronia
dose of 1–2 pills twice in a day with milk or turmeric and
limonia (kata bel), Acacia catechu (khadir), Cassia tora
Amala Choorna. Har Swaroop Sharma37 a very eminent
(chakramarda), Tribulus terrestris (gokshur) and Stephania
vaidya, described, “It is most up-to-date and efficacious a
japonica (agaru).17 All these plants have both experiential
remedy for all sorts of Prameha, Hastimeha, Madhumeha,
and exploratory data of varying levels of evidence. Some
Crystalluria, etc”.
of these, studied well, will be reviewed later. It is likely
Sudarshana choorna and ghanavati are very popular
that instead of potent antihyperglycemic activity, several
household remedies in India to enhance immunity and
of these plants may be of benefit by other mechanisms,
prevent or mitigate minor infections and fever. The major e.g. antioxidant activity, cytoprotective actions and
(50%) constituent of Sudarshana choorana is Swertia endothelial function enhancement or improvement in
chirata, an active antimicrobial, antipyretic, hepato­ pancreatic β-cell function.
protective and immunity-enhancing plant.38 The dose
of Sudarshan ghanvati is 1–2 tablets twice or thrice in a PHARMACOLOGY AND CLINICAL STUDIES
day with water for 5–7 days, or till the minor infections
OF ANTIDIABETIC MEDICINAL PLANTS
subside. The powder is given in a dose of 2–4 g with water.
In Japan, an herbal tea of the powder is quite popular Mishra and Adra17 have reviewed the experimental data
for health-maintenance and as an anti-obesity tea (late on the following plants: (1) Gymnema sylvestre (madhu­
Parikh KM, personal communication). Swertia chirata nashini), (2) Momordica charantia (karvellaka), (3)
along with a proper dose of the rhizome powder of Trigonella foenum-graecum (methi), (4) Coccinia indica
Picrorhiza kurroa is widely used in India by many diabetic (bimbi), (5) Pterocarpus marsupium (vijaysar) and (6)
subjects as a self-medication (Sheela Dave, personal Ficus benghalensis (vata).
communication). Swertiamarin, an active ingredient of Table 45.2 summarizes some of the pharmacological
S. chirata, has clinically shown a marked reduction in data on these six plants.40-51 Streptozotocin-induced
hypertriglyceridemia in animals and patients.39 diabetes mellitus (STZ-DM), alloxan-induced diabetes
According to Sharma,37 the following formulations mellitus (AX-DM), special diabetic strains, in vivo models
are indicated for diabetes mellitus: Vasant Kusumakara for complications have been utilized for screening the
Rasa, Brihat Bangeswar Rasa, Malla Sindur and Swarna activity of selected plants. The results often vary due to
Rajbangeshwar Rasa. However, these are metal bhasmas experimental conditions, methods, strains of animals,
and have to be prepared with great care and specifications diverse extracts of plants from undisclosed sources, and
for quality and purification, so as to drastically reduce drug doses. Hence, some of the factors make extrapolation
metal toxicity. Hence, only reliable, well-prepared to humans difficult.
and well-tried bhasmas can be used by experts and
experienced vaidya, and only on their advice. However, Momordica Charantia Linn.
Dashamoolarishta and Balarishta, also recommended by Bitter vegetables have been used extensively in Ayurveda
Sharma can be used in diabetes. Dashamoolarishta has to in the management of diabetes mellitus. Nanal52 in his
676 Management

Table 45.2: Pharmacological data of plants

Plant Activity Model Reference
Gymnema sylvestre Hypoglycemic (secretion or release of In vitro, Shanmugasundaram et al.40
(madhunashini) insulin) In vivo (STZ rats) Shanmugasundaram et al.41
Hypoglycemic Clinical Balasubramanium et al.42
Momordica charantia Linn. Hypoglycemic (decrease in IR), STZ-DM rat Leatherdale et al.43
(karvellaka) Hypoglycemic in GTT Mice
section

Miura et al.44
Clinical Srivastava et al.45
8

Trigonella foenum-graecum Antidiabetic Animal Ribes et al.46

(methika) Hypoglycemic Clinical Sharma et al.47
Coccinia indica (bimbi) Hypoglycemic Animal Khan et al.48
Improvement in GTT Clinical Khan et al.49
Pterocarpus marsupium Hypoglycemic Animal Shah et al.50
(vijaysar) Hypoglycemic Clinical ICMR study51

(GTT: Glucose tolerance test; STZ-DM: Streptozotocin-induced diabetes mellitus)

Table 45.3: Pharmacological activities of Momordica charantia Linn. For example, Senanayake et al.,90 found potent
Activity Models References triglyceride reducing effect of Koimodori variety
Anti-hyperglycemic and AL-DM, STZ-DM, 44,53–70 unlike Reishi or Hyakumari. So there is an urgent
hypoglycemic GLI-HG need to re-evaluate the standardized extracts (high-
Anti-hyperglycemic with kk-Ay mice 71 performance liquid chromatography/high-performance
exercise thin-layer chromatography extractive values) of different
Insulin modulation High Fat diet, kk-Ay 71–73 varieties in multiple animal models: STZ-DM, AL-DM,
Hypolipidemic STZ-DM, Adipocytes 74–76 db/db, ob/ob, kk-Ay strains, etc.
Anti-inflammatory, in-vitro, in-vivo 77–79 The plant has been analyzed and studied for active
analgesic ingredients: momordicin, cucurbitacin B, momordin,
Anti-oxidant, hepatopro- Hepatocytes, in-vitro 80–82 charantin, charantosides, momordicoside and other
tective terpenoid compounds. Momorcharin and momordin are
PPAR agonist Hepatoma cells 83 cytotoxic proteins.91,92 Recently, two molecular varieties
Cytoprotective Pancreatic islet β-cells 84 of Momordica charantia have been characterized.93 Such
STZ-DM diversity may influence the variation in clinical response.
Glucose homeostasis Absorption, gluconeo- 85–88
genesis and utilization Clinical Studies with Momordica Charantia Linn.
(AL-DM: Alloxan-induced diabetes; STZ-DM: Streptozotocin-induced There have been several open-labeled clinical studies
diabetes; GLI-HG: Dlucose-induced hyperglycemia; PPAR-γ: Peroxi- with the juice of the fruits of Momordica charantia. But
some proliferation activated receptor)
there have been few controlled comparative trials
book on dietary management of diseases has mentioned with OHA.94 Table 45.4 summarizes some of the trials
bitter gourd (karela) amongst the other items of food. conducted with M charantia.43,95-98 It is obvious that
Table 45.3 lists the diverse and important activities of several investigators have shown hypoglycemic and
Momordica charantia besides the hypoglycemic and anti- antihyperglycemic activity. A Cochrane database99
hyperglycemic activity.53-88 Most of the studies, despite analysis concluded that there is insufficient evidence
variations in the source of the plant, did show a positive to recommend M charantia in type 2 diabetes but
anti-diabetic activity in diverse models. However, there suggested the need of further trials. Recently, Gadang
are some negative results reported too, as to some of the et al.100 have shown that dietary bitter seeds increases
claimed activities.68,89 M charantia has several varieties, peroxisome proliferator-activated receptor-γ (PPAR-γ)
and hence the activity may vary accordingly. gene expression in adipocytes and down regulates nuclear
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 677

Table 45.4: Clinical trials of Momordica charantia Linn. in non-insulin- showed STZ-DM increase in insulin secretion.107 The study
dependent diabetes mellitus (NIDDM) of hypoglycemic activity in animals is summarized in
Product Used Clinical Response Reference Table 45.5.108-113 The anti-inflammatory effects have been
Aqueous extract 50 Significant on GTT (50 g) Leatherdale further confirmed in acute and chronic animal models of
mL + OHA et al.43 inflammation.114 Chronic inflammation is emerging as a
Decoction of fruit HbA1c 8.37–6.95% Welihindia major factor for diabetes, this aspect needs to be pursued
100 mL et al.95 clinically with cytokine assay.

chapter
Dry powder of fruit Significant hypoglycemia p Akhtar96

45
50 mL/kg < 0.001 Clinical Studies with Eugenia jambolana Linn.
Fruit pulp suspen- FBS and PPBS reduced in Ahmed
The use of alternative therapies to treat diabetes including
sion 5 g 86% (n = 100) et al.97
tea, prepared with different vegetables is widespread in
Aqueous Extract Significant hypoglycemia Srivastava
India. The tea prepared from leaves of “jambu” has been
(100 mL) et al.45
reported to be used frequently by diabetic patients. To
Dried powder tablet No significant change/place- John et al.98
evaluate the validity, a randomized placebo controlled
bo FBS, PPBS, fructosamine
trial was carried out in 30 non-diabetic young volunteers
(OHA: Oral hypoglycemic agents; HbA1c: Glycosylated hemoglobin;
for 2 weeks. The trial did not show any hypoglycemic effect
FBS: Fasting blood sugar; PPBS: Postprandial blood sugar)
on glucose tolerance tests. A longer term (3–6 months)
trial with E jambolana showed a significant decrease in
factor-κB (NF-κB) expression while relieving features
fasting glucose, a rise in high density lipoprotein and
of metabolic syndrome. A recent study, from Brazil, has
suggested enhanced insulin sensitivity.115
shown significant antibacterial activity in fresh and dried
leaves of M charantia.101
The side effects of M. charantia consumed in diverse Pterocarpus Marsupium Roxb.
manners have been briefly reviewed and include Pterocarpus marsupium Roxb. is known as bijak, vijaysar
gastrointestinal upset, hypoglycemic interactions and in Sanskrit and kino tree in English. The wood is used to
the contraindication of glucose-6-phosphate dehydro­ treat diabetes.116 Water is filled in its wood cup and drank
genase.102 for diabetes. A MadhuvijayTM tumbler is marketed for
such a use.
Eugenia Jambolana Linn. Many experiments have been done to evaluate
various activities besides hypoglycemic activity. Vijaysar
Commonly known as “jambu” or blackberry, it is widely
was evaluated mainly for hypoglycemic activity.
consumed as a seasonal fruit. Ayurvedic classics, such
Table 45.6 summarizes all the activities of the plant.50,117-124
as Charaka Samhita, Ashtangahridaya and Bhaishajya
A comprehensive review on Pterocarpus marsupium
Ratnawali, have recommended the use of this fruit in
Roxb. has covered the photochemistry, pharmacology
the dietary management of “Prameha” (prediabetic
and usage.125
condition).103 Rajnighantu and Nighantu Ratnakar104
Brahmashankar Misra126 has described its use in
have explained its properties. The kernel of seed of jambu
Prameha. The bark is used as an astringent for gums. It
is recommended specially in Madhumeha as it causes
contains epicatechin, protocatechic acid and a reddish
a reduction in the urine output. Impairment of liver
brown coloring matter.127 Active constituents epicatechin
function has been associated with diabetes is improved
was reported to show the hypoglycemic activity in alloxan-
by seed powder.105 Whereas other workers have shown
induced diabetic rats.128 In vitro study of active ingredient
hepatoprotective effects of the seeds against carbon
epicatechin in isolated islets of Langerhans of rats showed
tetrachloride (CCl4) liver damage.106 Many marketed
effect on insulin secretion.129
antidiabetic ayurvedic formulations contain jambu as a
main ingredient. Jambwasava, “jambu beej churna” are
Clinical Studies with Pterocarpus Marsupium Roxb.
widely used for Madhumeha by ayurvedic physicians.
Self-medication of jambu beej churna is very common. The Indian Council of Medical Research collaborating
Extensive research has been done in animal and centers evaluated the activity of the plant in 97 diabetic
clinical studies. In vitro study of fruit pulp extract in rats patients, for 12 weeks. Ninety-three patients completed
678 Management

Table 45.5: Experimental Studies with Eugenia jambolana Lam.

Part of Plant Activity Model References
Seed Hypoglycemic Alloxan DM rat Prince et al.108
Seed Antioxidant Alloxan DM rat Prince et al.108
Seed Reduction in tissue damage in brain Diabetic rats Mainzen et al.109
Seed Hypolipidemic Diabetic rats Mainzen et al.109
section

Seed Antidiabetic and antihypolipidemic ↑hemo- Diabetic rats Prince et al.110

globin
8

Seed Hypolipidemic improves glucose tolerance Normal and alloxan DM rats Pandey and Khan111
Seed Hypoglycemic and hypolipidemic Alloxan DM rabbits Sharma et al.112
Seed ↓Activity of HMG-CoA reductase Alloxan-induced DM rabbits Sharma et al.112
Pulp of fruit Hypolipidemic Streptozotocin-induced DM rats Achrekar et al.113

(DM: Diabetes mellitus; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A)

Table 45.6: Experimental studies with Pterocarpus marsupium Linn.

Parts Used Activity Model Reference
Wood Antihyperglycemic Alloxan-induced DM rat Vats et al.117
Heart wood Hypoglycemic Preliminary study Shah50
Wood Hypoglycemic Ahmed et al.118
Active ingredients from wood Antihyperglycemic Streptozotocin-induced DM rats Manickam et al.119
Wood Hypoglycemic Different rat models Nagaraju et al.120
Wood Antihyperglycemic Rat Jahromi and Ray121
Bark Not hypoglycemic in normal rat but Normal and diabetic rats Kameswara et al.122
antihyperglycemic in diabetic rat
Wood active ingredient Reverse hyperglycemia Alloxan-induced DM rats Sheehan123
Epicatechin Regeneration of islets of Langerhans Alloxan-induced diabetic rats Chakravarthy et al.124

the study. Fasting and postprandial blood glucose level Experiments to evaluate its hypoglycemic activity have
fell significantly from initial mean 151–216 mg/dL to been carried out in animals. The medicinal properties
119–171 mg/dL respectively. No significant hypolipidemic have been reviewed recently, with the phytoconstituents,
change was observed.130 In a further comparative trial the safety studies, etc.146 Hepato­protective effects have been
plant had a glycemic control equal to tolbutamide.131 The shown.147 Improvement in diabetic neuropathy in rats was
formulation, being from the wood had environmental shown to be a protective effect mediated via α2 adrenergic
restrictions. receptors.148

Aegle Marmelos Corr. Clinical Studies with Aegle Marmelos Corr.

Aegle marmelos is known as “bilva” in Sanskrit, and Limited clinical trials are carried out with the plant. The
Bengal quince in English. The trees are seen mainly near clinical studies are mainly limited to bronchial asthma,
the temples as leaves are offered in worship to Shiva. intestinal parasites, dysentery and diarrhea.
Root, root bark, leaves, fruits (both, ripe and unripe) In an uncontrolled clinical trial, the leaves of the plant
are used in medicine.132 It is used as an edible fruit and were macerated and given orally along with powdered
fruit drink also. There is fairly large use of the leaves black pepper on empty stomach to eight patients with
by diabetic patients. There have been other pharmaco­ diabetes mellitus for 15 days. A significant diminution in
dynamic activities referred (Table 45.7).133-144 Antimi­ the blood cholesterol levels with slight lowering of blood
crobial144 and antiprotozoal145 activities have been shown glucose levels in all patients was reported. All the patients
against bacteria and fungus and protozoa respectively. also had a sense of well-being during treatment.146-149
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 679

Table 45.7: Experimental studies with Aegle marmelos Corr.

Part Used Activity Model Reference
Root bark Inhibit spontaneous beating of myocardial Myocardial cell of mouse Kakiuchi et al.133
cells, calcium antagonist action
Whole plant Antiproliferative effect Human tumor cell line Lampronti et al.134
Whole plant Antiproliferative Human breast cancer cell line Lambertini et al.135
Leaf Regeneration of pancreas Streptozotocin (STZ) induced diabetic rat Das et al.136

chapter
pancreas

45
Fruit Hypoglycemic STZ rats Kamalakkannan and
Prince137
Fruit Hypoglycemic, ↓HbA1c, ↑insulin, ↓Liver Wistar rat STZ-induced diabetic Kamalakkannan et al.138
glycogen
Leaf Hypoglycemic, Hypocholesteremic Alloxan-induced rats Ponnachan et al.139
Leaf Hypoglycemic STZ, diabetic rats Seema et al.140
Leaf Hypoglycemic Glucose-induced Hyperglycemic rats Sachadeva et al.141
Plant Hypoglycemic Alloxan diabetic Albino rats Kar et al.142
Leaf Antioxidant and chemopreventive Mice Singh et al.143
Root Anti-inflammatory Carrageenan induced inflammation rats Pitre and Srivastava144

Azadirachta Indica Linn. (worms). Antimicrobial, wound healing, anti-ulcer, anti-

inflammatory, antifungal, and antioxidant activities
Considered as a village pharmacy, the neem tree has are well investigated. Antidiabetic use as stated in the
been used in India from ancient times to treat various ayurvedic classics is evaluated in animal models exten­
ailments. Practically all parts of the tree, from root to sively, however clinical studies reported are very
shoot, are used for medicinal purposes. Renewed interest few159,169,170 (Table 45.9). Biswas et al.167 have reported
on the medicinal property of this tree has led to extensive anti-diabetic activity in both in humans and animals.
investigation in animal models and in clinical settings. A Though we get anti-diabetic reference as early as 1973,
number of reviews, in recent years, have highlighted these Vaidya et al.94 has studied the plant in diabetic patients
developments.14,150,151 We have focused to identify the at Podar Ayurvedic Hospital, Mumbai in early seventies
antihyperglycemic and hypoglycemic properties of neem with placebo-controlled studies in diabetic patients
tree along with its effect on lipids and hepatoprotective showing marginal activity.
activities.152,153 Recently, Waheed et al.171 investigated hypoglycemic
Publications on animal models, in vitro models as effect of seeds of neem in type 2 diabetic patients. The
well as information on clinical trials have been referred activity was evaluated by two doses (0.5 g TID and 2 g
to understand the latest status in these areas of interest as TID) in drug-naive diabetic patients, diabetic patients
summarized in Table 45.8.154-166 with OHA and control subjects. Significant hypo­
glycemic activity at high dose was reported. Melziq172 in
In-Vitro Effects of Azadirachta Indica Linn. his review stated that herbal alpha amylase inhibitors
Reports on the in vitro models are mainly for testing the have the ability to lower postprandial blood glucose;
antimicrobial properties167 of neem. However, Chatto­ mainly polyphenolic compounds have this ability. Neem
padhyay168 used this model to show the possible mech­ does have polyphenolic compounds.
anism of anti-hyperglycemic effect of the leaf extract of
A indica. The extracts blocked significantly the inhibitory Trigonella Foenum-graecum Linn.
effect of serotonin on insulin secretion.
Trigonella foenum-graecum known as methika in Sanskrit
and methi in Hind, Gujarati and Marathi is widely used
Clinical Trials with Azadirachta Indica Linn. as a vegetable and household spice in India. Ayurvedic
As per the ayurvedic classics, neem is recommended classics, such as Bhavaprakasha Nighantu and Dhanv­
mainly for wounds, skin disorders, fever and infections antari Nighantu, describe various medicinal properties
680 Management

Table 45.8: Experimental studies with Azadirachta indica Linn

Parts Used Activity Model Reference
Leaf Hypoglycemic Dogs Murty et al.154
Leaf Hypoglycemic Diabetic animals Anonymous155
Hypoglycemic Diabetic animals Sharma et al.156
Leaf Hypoglycemic STZ-induced rats Chakraborty et al.157
section

Neem oil Hypoglycemic Hyperglycemic rats Dixit et al.158

8

Neem Synergistic agent to antidiabetic drugs Dogs Bhargava159

Leaf Hypoglycemic Rats Chattopadhyay et al.168
Neem oil Hypoglycemic Normal and alloxan-induced Dixit et al.161
diabetic rats
Leaf Hypoglycemic Glucose fed rats Chattopadhyay et al.162
Leaves Hypoglycemic and non-toxic (1 g/kg) Mice Chattopadhyay et al.162
Nimbidin from oil Hypoglycemic Glucose fed rabbits Siddiqui et al.163
Leaves Hypoglycemic on oral glucose tolerance Fasting albino rats Kar at al.164
Leaf Hypoglycemic Rats Chattopadhyay165
50% ethanolic extract of flower Hypoglycemic Rabbits Purohit and Daradka166

Table 45.9: Clinical studies with Azadirachta indica on diabetic Table 45.10: Experimental studies with Trigonella foenum-graecum
patients Linn
Parts Activity Reference Activity Model Reference
Used Hypolipidemic Alloxan-induced dia- Yadav et al.173
Leaf Reduced insulin doses without signifi- Shukla et al.
169
betes in female albino
cant effect in blood glucose level Wistar rats
Neem oil Antihyperglycemic helped to gradually Bhargava159 Antihyperglycemic Alloxan-induced dia- Yadav et al.173
reduce the intake of conventional drugs of seed powder betes in female albino
Neem oil Antihyperglycemic Jha170 Wistar rats
Antihyperglycemic Streptozotocin-induced Devi at al.174
of the plant. Ayurveda describes its use as antidiabetic of leaves diabetes in rats

and antiobesity. Sizable research has been done in Antioxidant aque- In vivo rat model of Thirunavukkarasu
ous extracts of ethanol toxicity in vitro et al.175
recent times for its hypoglycemic, antihyperglycemic and
fenugreek seeds iron-induced lipid per-
hypolipidemic activities in both experimental animal oxidation
models (Table 45.10)173-177 and clinical studies.
Immunomodulatory Male Swiss albino mice Bin-Hafeez et al.176
effect of aqueous
Experimental Studies with Trigonella extract
foenum-graecum Linn. Anti-inflammatory Formation-induced Ahmadiani et al.177
analgesic and edema model
In experimental rat models of diabetes, several investi­ antipyretic
gators have demonstrated antihyperglycemic effects of
seed powder of T foenum-graecum alone or particularly
in combination with sodium orthovanadate (SOV). The on glycemia, insulinemia, dyslipidemia and platelet
combinations have been shown to be more effective in its aggregation in diabetic rats were also observed.180
hypoglycemic as well as hypolipidemic effects in diabetic Puri et al.181 in alloxan-induced subdiabetic and diabetic
rat model. The combination also restored and normalized rabbit model found insulin secretagogue and hypogly­cemic
glyoxalase-1 activity and creatine kinase activity in effect of water extract of tim seeds of T foenum-graecum.
diabetic rat liver and other tissues respectively.177-179 The Extra-pancreatic model of action was also suspected
effect of soluble dietary fiber fraction of T foenum-graecum as hypoglycemic effects that occurred independent of
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 681

Table 45.11: Clinical studies with Trigonella foenum-graecum Linn ingestion. This study showed hypoglycemic effect of the
Activity Design Reference hypoglycemic, anti-hyperglycemic, hypo-lipidemic, insu­
Antihyperglycemic Double-blind, Placebo Sharma182
lin sensitizing effects of the plant.
and insulin sensi- controlled type 2 dia-
tizing betes MARKETED AYURVEDIC FORMULATIONS
Hypolipidemic Type 2 diabetes Sharma et al. 183

Innumerable classic and proprietary formulations

No change in Healthy volunteers Bordia et al.184

chapter
blood glucose
(n > 200), claimed to be useful in diabetes mellitus, are

45
currently being marketed in India and some even abroad.
Antihyperglycemic Placebo-controlled Bordia et al.184
and Hypolipidemic in type 2 diabetes Several of these may add certain therapeutic value. How
with coronary artery many have doubtful efficacy and whether some are
disease even formulated irrationally, needs a careful scrutiny.
Antihyperglycemic, Open labeled in type Sharma et al.47 Personal long-term experience with reputed formulations
Hypolipidemic 1 diabetes
as to their safety and activity profile is desirable. The
Hypoglycemia Volunteer studies Abdel-Barry et al.185 detailing by ayurvedic companies or the tall claims in the
safety and activity
advertisements. bespeak often of more commercialism
rather than robust evidence.
Brand names are made interesting and attractive,
insulin-modulation. The plant extract showed a significant
suggestive of not only antidiabetic activity but also
increase in phagocytic capacity of macrophages.
explaining target sites of action. Any claim regarding
Clinical Studies with Trigonella the use of formulations, in insulin-dependent diabetes
Foenum-graecum Linn. mellitus (IDDM) patients, should be discouraged. There
are around 8,500 manufacturing units for Ayurveda drugs.
Several clinical observational and some placebo-
Majority of these have hardly any quality control, even
controlled randomized clinical trials show that fenugreek
as to the microbial contamination or shelf life except for
seeds improve glycemic control and decrease insulin
some major reputed companies. There is a paucity of
resistance in patients with mild type-2 diabetes mellitus
information regarding ingredients and use of the medicine
(Table 45.11).47,182-185 In a double-blind placebo-controlled
study of hydroalcoholic extracts (1 g/day × 2 months) of as per ayurvedic management of the disease on labels and
fenugreek seeds, the plant showed hypoglycemic and even in package inserts of the marketed formulations.
insulin sensitizing effect in 12 patients of type 2 diabetes There is a need in general for an ethical code of marketing
mellitus. Hypolipidemic effects were also recorded in the for ayurvedic marketed drugs, uniform implementation
study. In another study, significant lowering of fasting of regulatory requirements by the industries and
blood glucose, improvement in glucose tolerance test, clinician’s support. Table 45.12 lists some of the marketed
decline in low-density lipoprotein, very-low-density formulations for diabetes with main ingredients and some
lipoprotein, plant in healthy volunteers. of classical formulations that are commonly consumed by
The cited clinical studies (Table 45.11)182-185 have diabetic patients. A few of these have undergone adequate
shown a reduction in cholesterol and serum triglycerides clinical trials. More studies are desirable.
when defatted fenugreek seed powder (100 g) divided in The following formulations have undergone clinical
two equal doses was incorporated with food during lunch studies, besides some studies on the formulations cited in
and dinner for 10 days to patients with type 1 diabetes. Table 45.12.
The safety as well as hypoglycemic activity was • Ayush-82 (a mixture of the seeds of Mangifera indica,
assessed in 20 young healthy male volunteers, where half Syzygium cuminum, Momordica charantia and the
of them were randomly assigned to 40 mg/kg aqueous leaves of Gymnema sylvestre) with shuddha shilajit.
extract powder of T foenum-graecum in 10 mL of distilled The study (n=100) was non-comparative, and despite
water and the rest were given 10 mL distilled water with a reduction in fasting blood sugar (FBS) and postpran­
coffee simulating the extract. The extract also significantly dial blood sugar (PPBS), the glycemic control was
lowered blood glucose levels by 13.4% four hours after inadequate.186
682 Management

Table 45.12: List of marketed formulations of ayurvedic drugs for type 2 diabetes
Sl. No. Name Company Main Ingredients
1 Hyponidd Charak Pharma, Mumbai Haridra, avartaki, jambu, amlaki, mamejava, meshashringi, amruta,
vijaysar
2 Jambrulin Unjha Pharmacy, Gujarat Jambu, shilajit, meshashringi, trivanga bhasma, karvellaka,
mamejava, nimba, bilva
3 Madhumehari Dane Shree Baidyanath Ayurved Meshashringi, jambu, guduchi, karvellaka, haridra, amlaki, vijaysar,
section

Bhawan Ltd., Nagpur methika, nimba, bilva

4 Lokmanya Churna Koral Pharma, Nashik Karvellaka, mamejava, meshashringi, methika, haritaki, katuka,
8

shilajit, vanga bhasma

5 Amree Plus Aimil Pharmaceuticals, Karvellaka, bilva, vijaysar, meshashringi, jambu, methika, amlaki,
New Delhi bimbi, yashad bhasma, shilajit
6 D.B.T. Sharangdhar, Pune Jambu, madhunashini, saptachakra, haridra, katuka, guggulu, jasad
bhasma, naga bhasma, vanga bhasma
7 Diabecon Himalaya Health Care, Guggulu, shilajit, meshashringi, saptarangi, jambu, amruta,
Bangalore shatavari, punarnava, karvellaka surasa, haridra, yashad bhasma
8 Mamejava Ghanavti Shree Naranarayan Ayurvedic Mamejava
Pharmacy, Ahmedabad
9 Tribangasheela Zandu Pharmaceuticals, Vapi, Meshashringi, nimba, jambu, mamejava, shilajit, yashad bhasma,
Gujarat vanga bhasma
10 Yasaka Syrup Simandhar Herbal Pvt. Ltd. Saptarangi, guduchi, haridra, karela, kutki, jambu, gudmar, neem
11 Incudil Powder Simandhar Herbal Pvt. Ltd. Jamun, amlaki, gulvel, chirata, mamejava, jira, saptarangi
Classical Formulations Manufactured By Various Industries
12 Jambvasava Bajaj Consumer Care Ltd., Jambupatra, jambutwak, jambubeeja, lodhra
Andhra Pradesh
13 Vasant Kusumakar Rasa Shree Dhootapapeshwar Ltd., Suvarna bhasma, roupya bhasma, nag bhasma, vanga bhasma,
Mumbai abhrak bhasma, praval bhasma, vasa, malati pushpa, shwet chan-
dan, ushir, haridra
14 Arogyavardhini Ayurveda Rasashala, Pune Kutki
15 Chandraprabha Vati Ayurved Seva Sangh, Nashik Vacha, musta, haridra, daruharidra, shilajit, guggulu, suvarna mak-
shik
16 Trivanga Bhasma Shree Dhootapapeshwar Ltd., Naga bhasma, vanga bhasma, jasad bhasma
Mumbai
17 Devdarvyarishta Sandu Bros Pvt. Ltd., Mumbai Devdaru, vasa, manjishtha, haridra, daruharidra, vidanga, musta,
shirish, khadir, arjun
18 Gokshuradi Gugglu Shree Dhootapapeshwar Ltd., Gokshur, guggulu
Mumbai
19 Phalatrikadi Kashaya Shree Baidyanath Ayurved Triphala, haridra, vishala, daruharidra, musta
Bhawan Ltd., Nagpur
20 Shilajitwadi Bati Shree Baidyanath Ayurved Shilajit, guggulu, suvarna bhasma, loha bhasma, abhrak bhasma
Bhawan Ltd., Nagpur

• D-400 (a mixture of Eugenia jambolana, Pterocarpus non-insulin-dependent diabetes mellitus (NIDDM)

marsupium, Ficus glomerata, Gymnema sylvestre, (n = 30). A positive and safe response has been
Momordica charantia, Ocimum sanctum and shilajit). reported.188
The study (n = 38) had three arms and showed a • Sandana (a mixture of Tinospora cordifolia starch,
reduction in blood sugar and cholesterol.187 Further Santalum album, Andropogon citratus, Vetiveria ziza-
studies are indicated in a larger group. nioides, Syzygium aromaticum, Anacyclus pyrethrum
• M-93 (a mixture of Aegle marmelos, Azadirachta indica, and shuddha shilajit) was studied—300 mg BD in
Ocimum sanctum and Piper longum) was studied in NIDDM (n = 20) patients for 45 days. The FBS and
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 683

PPBS were reduced along with a symptomatic relief.189 CSIR-NMITLI DIABETES PROJECT
The dose-finding for efficacy needs to be pursued fur-
ther. Under the funding of CSIR, Delhi, a nationwide project
• MA-471 (a mixture of Enicostemma littorale, Phyllan­ on diabetes was undertaken, under the direction of the
thus amarus, Eugenia jambolana, Azadirachta indica, steering committee of experts (Chairman, Dr AB Vaidya).
Terminalia arjuna, Aegle marmelos and shilajit) was The emphasis was on insulin sensitization. The project
studied in NIDDM patients (n = 69), with three arms. was based on an earlier decade’s research on ayurvedic

chapter
The dosage was 500 mg BD for nine months. Symptoms antidiabetic plants. Six medicinal plants were short-

45
were ameliorated better in conjunction with OHA.190 listed for studies under Reverse Pharmacology path in
The ingredients need to be rationalized as to their type 2 diabetic patients. The plants were Curcuma longa,
concentrations for further definitive studies. Phyllanthus emblica, Enicostemma littorale, C absus,
• ARL 367-Pankare (a mixture of Pterocarpus marsupium, Gymnema sylvestre and Coccinia indica. The plants were
Coccinia indica, Salacia reticulata, Tribulus terrestris, identified, standardized and investigated for the essential
data. Phase I to III were conducted with paraclinical
Azadirachta indica and Boerhavia diffusa) was
studies targeting various models at different hospitals
studied for 30 days in NIDDM patients (n = 30) as
and laboratories in India. Two formulations from the
an add-on therapy to OHA and existing diet.191 The
plants were studied in depth. One from Curcuma longa
investigators have reported mean drop in PPBS of
and Phyllanthus emblica (DM-FN01) was found to have
39.7 mg%. But the entire study is suspect because the
insulin sensitization activity whereas the formulation
Table cited shows FBS and PPBS values as zero in
from Enicostemma littorale (DM-FN02) was found to
patients’ number 27 and 10, respectively. Such non-
have antihyperglycemic, antidyslipidemic, antioxidant
peer reviewed papers are often used for advertisements
activity. Drug interactions of DM-01 2 formulations with
and propaganda. There is an urgent need to institute
metformin were studied in healthy volunteers. It was
vigorous peer-review process for research publications
noticed that plasma metformin levels were decreased
on ayurvedic drugs.
with simultaneous administration of the first form­
• Diabrid (a mixture of Gymnema sylvestre, Momordica
ulation DM-FN01 (powder) and not with of second
charantia, Eugenia jambolana and Trigonella foenum-
formulation (tablet).194 Tablets (DM-FN 01A), developed
graecum) was studied in 60 patients for 6 months. Four
from the powder DM-FN 01 formulation, were evaluated
groups (10 patients per group) received Diabrid alone
in one common volunteer to both studies. This volunteer
in increasing dose (1–6 caps per day) and other two
showed reduction in Cmax of metformin by 60% when
groups received either as add-on to sulfonylurea or only
co-administered with powder form however no
OHA and existing diet. The investigators have reported
significant difference in Cmax or AUC of metformin was
that the drug has tolerated well and dose dependent
noted when co-administered with the tablet form of
and gradual hypoglycemic activity was seen caps per
DM-FN 01.195 DNA protective activity also observed in
day) and other two groups received either as add-on
second formulation.196
to sulfonylurea or only OHA and existing diet. The
investigators have reported that the drug has tolerated
COMPLEMENTARY AND
well and dose dependent and gradual hypoglycemic
activity was seen.192
ALTERNATIVE MEDICINE
• Polyherbal cream (a cream prepared from a mixture Several “authorities” of complementary and alternative
of Glycyrrhiza glabra, Curcuma longa, Aloe vera, medicine (CAM) do not like the lumping of all traditional
Musa paradisiaca) was studied in NIDDM patients systems under the generic title complementary and
(n = 40) having diabetic foot ulcer, as local application. alternative. There is even an endeavor that certain types
The results were compared with standard silver of CAM too can be mainstream systems of medicine, and
sulfadiazine cream. There was significant reduction in sometimes the conventional medicine (allopathy) may
size and shape of the wound in both the groups. Many serve as CAM to it.197 These debates would go on until
polyherbal formulations have undergone preclinical large comparative studies of the diverse systems for their
testing.193 efficacy; quality, safety and health-care economy are
684 Management

Table 45.13: Types of diabetes mellitus in Ayurveda196 Apathya nimittaja or aberrant lifestyle as well as
Etiological Constitutional Dosha-Guna obesity are managed by correcting the lifestyle (diet,
Sahaja—Hereditary Sthula—Obese Kaphaja—10 exercise, rest), samshodhana (panchkarma procedures)
types and samshamana (medications, etc.). Singh has recently
Kulaja—Familial Samanya—Normal Pittaja—6 rightly emphasized the principle of samanya (homology)
weight types and vishesha (heterology) in the management of diabetes
Apathyaja—Faulty Krisha—Lean Vataja—4 mellitus.196 The emphasis is on dietary substrates that
section

lifestyle types lead to synthesis of similar or derivatives or polymers in

8

the body.
undertaken. The vested interests of systems and industry
would not permit or fund such important studies. Hence, DIETARY AND EXERCISE
it is desirable to pragmatically integrate only the best of MANAGEMENT OF DIABETES
the multiple systems, in the overall interest of the
There are several books, reviews and monographs on
patient. For diabetes, the current management cannot be
ayurvedic dietetics.198-201 Nanal has very well described
abandoned. It can only be complemented and enhanced
his long clinical experience and expertise as to role of the
with judicious use of CAM.
diet and exercise in management of diabetes mellitus.202
The following summary would be useful to clinicians:
AYURVEDIC PREVENTION AND
chapattis prepared from equal fresh wheat flour plus
MANAGEMENT flour of roasted barley and other cereals, fresh vegetables,
It is amazing to note that ayurvedic classics description chutney of sesame, bitter gourd or garlic are advised.
of drug and non-drug management of diabetes mellitus The salads are made of carrots, cabbage, onions and
strikingly resembles the latest modern knowledge on green methi (sprouted). Dal is prepared of masur, chana,
the subject.197 The emphasis, in Ayurveda, to reverse the kulittha. The fruits to be taken are jambu, unripe bananas
etiopathogenesis of type 2 diabetes mellitus, through step- and dates. He advises omission of polished rice. But Nanal
wise management, is quite a rational approach. Ayurveda further states that roasted unpolished rice can be cooked
has provided a unique concept of prevention as well and taken once at noon. For pickles, the advice is to
as reversal of pathogenesis of the disease. The reversal consume one made of fresh turmeric, ginger and amala.
in the pathogenesis helps in the delay or mitigation Every morning, the juice of amala with paste of turmeric
of complications. The emphasis on healthy lifestyle in together serves both as a medicine and as a dietary
Ayurveda is illustrated by daily regimen (swasthavritta), supplement. In case, these are not available, the powders
seasonal care (ritucharya) and appropriate individualized of both the plants can also be taken. Everyday at least,
diet (pathya ahara). For diabetics, these have been there has to be a walk for 1–2 miles.
elaborated well, besides drugs, plants and complex Daily Suryanamaskaras can be done once for 24 times.
formulations. The causes, symptoms, complications of These Suryanamaskaras are quite helpful in diabetes, as a
diabetes according to the classification are well described holistic exercise. Other asanas found useful are Halasana,
in the classics of Ayurveda. The management of diabetes Naukasana, Chakrasana, Tadasana, Vakrasana and
in Ayurveda is based on the classification of the disease. Shavasana.203 After meals, betel leaf, betel nut, best quality
Table 45.13 describes the types of diabetes. catechu, cloves and a bit of nutmeg have to be taken twice
Sahaja or beeja dosha type of diabetes was said to be in a day.
quite recalcitrant (Asadhya), probably implying type 1 The habit of siesta has to be given up. Nanal has also
diabetes mellitus. Until insulin became available, there advised dietary articles for symptoms, e.g. cabbage for
was little hope for type 1 diabetes mellitus patients. urinary burning and pruritus, cucumber for burning of
Currently, the leaders of Ayurveda do understand this hands and feet and juice of zendu leaves for fatigue.
need of insulin for juvenile diabetics and do not advocate Mehra204 has described several properties of dietary
its discontinuation. The obese and lean diabetics were articles and herbs, which are useful for diabetes mellitus.
managed by langhana, fasting (calorie restriction) and Table 45.14 describes certain of these selected items.
brinhana (santarpana)—additional nutrition (calorie Singh has emphasized the need to address the
supplementation and nutrients). problems of ojas and bala in diabetes mellitus.191 He has
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 685

emphasized the health-promotive and disease-preventive locally for minor skin infections. Cephalandra [Coccinia
principles of such a management: indica (bimba)] was given 1 × 4 times, for months, to reduce
• Avoidance of the etiological factors: Excessive intake fatigue and urinary sugar and to enhance the weight-gain
of sweet, salty, fatty, heavy and cold items in the in diabetics. Ficus benghalensis, tincture of aerial roots
diet, lack of exercise/walking, sleeping during days, and pods, has been used when urinary burning is
very infrequent sexual intercourse, severe stress and common in diabetics. Govind Ram Sharma carried out
anxiety, no stress at all, obesity. studies, for 5 years, described it “as a sovereign remedy

chapter
• To encourage and continue pungent, bitter, astringent, for diabetes”. There have been experimental and clinical

45
dry and hot items in the diet. Lifestyle intervention to studies too.
counteract the factors cited above as to diet, exercise. Syzygium jambolanum or Eugenia jambolana was
• Use of rasayanas to promote ojas and bala. stated to be “a most powerful remedy in diabetes mellitus”,
• Samshodhana karma through langhana (fasting), particularly where the inflammatory component is
pachana (digestive modalities), vamana (induced
dominant. Dried seeds on the tincture of jambu were
vomiting), virechana (laxative), basti (enema) to
used. Boericke had included Syzygium jambolana,
correct the function of srotas.
besides other remedies for diabetes.204 A homeopath (Jyoti
• Samshamana therapy through (1) katu-tiktakashaya,
Mody, personal communication) provided the list of the
ruksha, ushna drugs (2) specific pramehghna remedies.
following plant remedies for diabetes mellitus to be used
• Use of specific madhumeha-hara drugs such as haridra
as based on the syndromic indications: (1) Bryonia—
(Curcuma longa), amrita (Tinospora cordifolia),
useful in the symptoms of hepatic dysfunction, bitter
nimba (Azadirachta indica), bilva (Aegle marmelos),
taste in month, loss of strength and dryness of lips;
vijaysar (Pterocarpus marsupium) jambu (Eugenia
(2) Syzygium jambolanum in all stages of diabetes, for
jambolana), shilajit.
reducing polyuria and urinary sugar; (3) Cocoa for diabetes
• Stress management through medhya rasayanas, yoga
and meditation. with impotence, socializing inability, peppery sensation
• Prevention and management of diabetic complications in the mouth, flatulence, reduced appetite for sweets;
of heart, kidneys, eyes and autonomic nervous system. (4) Hellebore for muscle weakness, melancholy, halitosis,
In a trial, in NIDDM patients, the symptoms of low vitality; (5) Rhus aromatica for renal and urinary
oja-kshaya were quite significantly improved, with complaints, atony of bladder, polyuria and (6) Croton
moderate changes in blood sugar and glycosylated tiglium for foamy urine of dark orange color and turbid
hemoglobin. The ayurvedic formulation used was amrita- on standing with fatty particles on the surface, eruptions
pippali-nimba-yoga, in a dose of 5–10 g twice in a day on the face.
for12 weeks. The score of ojas-kshaya dropped from Besides the plants, organic and mineral-derived
10.07 ± 8.45 to 6.07 ± 6.09 (p < 0.01 with students paired remedies are also used frequently in homeopathy. These
“t” test).198 are phosphoric acid, arsenic, phosphorus, lactic acid,
argentum metallism, natrium sulfate, uranium nitricum,
INDIAN HOMEOPATHIC REMEDIES acetic acid, silica, etc. Homeopaths nowadays, understand
well importance of diet, exercise, insulin and OHA. The
Sarat Chandra Ghose,199 a leading homeopath of India, patients are most often given the homeopathic remedies
wrote a remarkable book “Drugs of Hindoosthan: with as complementary to these modalities.
their homeopathic uses, provings and clinical verifi­
cations”. The first edition was in 1944, followed by
SUMMARY
nine more editions. He has also considered Ayurvedic
and Unani properties and uses of the plants studied. Current global epidemic of diabesity (obesity + diabetes)
The allopathic uses too have been mentioned. Some of and an active resurgence of public interest in medicinal
the plants studied are mentioned below. plants and indigenous drugs compelled this critical
Abroma augusta (ulatkambal) was used in a tincture review of the scope and status of alternative medicine in
form (from leaves) by Ray for ten years in his practice for prevention and management of diabetes mellitus. The
diabetes mellitus with positive results.204 Polyuria at night living tradition of Ayurveda has provided an opportunity
is considered a specific indication. Azadirachta indica was to multidisciplinary scientists, in India and abroad, for
used homeopathically for burning of hands and feet and widening the existing experiential base. This has led to
686 Management

Table 45.14: Dietary articles and herbs useful in diabetes mellitus antioxidant activity, anti-inflammatory activity, hypolipi­
Common name Botanical name Properties and Uses
demic activity or positive effects on β cell function and its
regeneration. It would be interesting to carry out long-
Pippali Piper longum Anti-nauseant and
prokinetic term studies with precise molecular and biochemical
Kadali, Banana Musa sapientum Stem-juice for
markers as well as good clinical end points or surrogate
polyuria markers. The recent literature has highlighted the
Cucumber Cucumis sativus Cucumber juice for mechanisms of various diabetic complications, and it is
section

seborrheic skin likely that indigenous drug supplements could have some
8

Bitter gourd, karela Momordica charantia Karela (3–4) juice— properties to arrest or prevent the complication, acting at
hypoglycemic some intermediate stage in metabolic pathway.
Horse gram, kulthi Dolichos biflorus Soup for obesity and The dietary and other lifestyle management as
hepatic dysfunction advocated by ayurvedic experts are very apt and reflect
Kumari Aloe vera Bowel hypotony and the depth of thinking of ancient scholars. Some of the
poor digestion suggestions mentioned here are highly recommended
Jambu Eugenia jambolana Bark (inner) ash for to diabetologists to advise their patients and observe
urinary frequency
and document the results. Commonly used medicinal
Tulsi Ocimum sanctum Seeds for fatigue; plants along with their properties are presented for the
leaves for antistress
benefit of practicing physicians (Table 45.14).
Neem Azadirachta indica Leaves and bark for
A brief mention has also been made on the limited role
skin infection
of Indian homeopathic remedies in the management of
Onion Allium cepa Onion soup for
diabetes.
urinary burning
Bilva Aegle marmelos Bilva-asava for
energy
ACKNOWLEDGMENT
Radish Raphanus sativus Fresh juice for We thank the Indian Council of Medical Research for the
throat—irritation
support of the Advanced Centre of Reverse Pharmacology
Garlic Allium sativum garlic for dyslipi- at our institute. We thank Sri Dhirubai S Mehta, President,
daemia
Kasturba Health Society for his support.
Haritaki, Harda Terminalia chebula Fruit—powder for
memory, cognition,
etc.
Further Reading
1. Chaudhury RR, Vohra SB. Plants with possible hypogly-
exploratory and experimental studies in vitro and in vivo cemic activity. In: Udupa KN, Chaturvedi GV, Tripathi SN,
(Eds). Advances in Research in Indian Medicine. Varanasi:
and well designed clinical trials. The present chapter
Banaras Hindu University; 1970. pp 57-62.
briefly reviews ayurvedic pathogenetic mechanisms of 2. Indian Council for Medical Research (ICMR), collaborating
diabetes (Madhumeha) that forms the basis of selection centres, New Delhi. Flexible dose open trial of Vijaysar in
of non-drug measures and specific medicinal plant(s) cases of newly diagnosed non-insulin dependent diabetes
and commonly used classical ayurvedic remedies in the mellitus. Indian J Med Res. 1998;108:24.
management of diabetes. 3. Chopra A, Doiphode VV. Ayurvedic medicine. Core
concepts, therapeutic principles, and current relevance.
All the physicians who are treating diabetics have
Med Clin North Am. 2002;86:75-89.
experienced the faith with which ayurvedic medications 4. Poongothai S, Karkuzhali K, Sharadha J, et al. Evaluation of
are consumed by patients either alone or in combination safety and efficacy of Hyponidd—an Ayurvedic compound:
with modern therapy. Though there are tall claims regar­ A double blind, placebo-controlled study in type 2 diabetic
ding potent hypoglycemic effects of various formulations, patients with secondary failure to oral drugs. Int. J Diab Dev
the available evidence suggests the limited hypogly­ Countries. 2002;22:19-27.
5. Vaidya AB. Reverse pharmacological correlates of ayur­
cemic property of single plant products or multidrug
vedic drug actions. Indian J Pharmacol. 2006;37:311-5.
ayurvedic formulations. There is limited data on the long- 6. Khan V, Najmi AK, Aktar M, et al. A pharmacological
term beneficial effects of these herbal-based products. appraisal of medicinal plants with anti-diabetic potential.
However, the other desirable, potentially useful effects are J Pharm Biol Sci. 2012;4:27-42.
 Current Status of Indigenous Drugs and Alternative Medicine in the Management of Diabetes Mellitus 687

7. Patel DK, Prasad SK, Kumar R, et al. An overview on 21. Khan V, Najmi AK, Aktar M, et al. A pharmacological
antidiabetic medicinal plants having insulin mimetic appraisal of medicinal plants with anti-diabetic potential.
property. Asian Pacific J Trop Biomed. 2012;320-330. J Pharm Biol Sci. 2012;4:27-42.
22. Kavishankar GB, Laxmidevi M, Murthy SM, et al. diabetes
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163. Siddiqui S. A note on the isolation of three new biter princi- status of type 2 diabetic model rats. J Ethnopharmacol.
ples from neem oil. Current Sci. 1942;11:278-9. 2003;88:73-7.
692 Management

181. Puri D, Prabha KM, Murthy PS. Mechanism of action of a 192. Qadri NM, Rehman Z, Shireen K. Evaluation of antidiabetic
hypoglycemic principle isolated from fenugreek seeds. activity of diabrid, a herbal formulation, in type-II diabetic
Indian J Physiology Pharmacol. 2002;46:457-62. patients. J Chem Soc Pak. 2006;28:281-3.
182. Sharma RD. Effect of fenugreek seeds and leaves on blood 193. Viswanathan V, Kesavan R, Kavitha KV, et al. A pilot study
glucose and serum insulin responses in human subjects. on the effects of a polyherbal formulation cream on diabet-
Nutr Res. 1986;6:1353-64. ic foot ulcers. Indian J Med Res. 2011;134:168-73.
183. Sharma RD, Sarkar A, Hazra DK, et al. Hypolipidemic
194. Puranik AS, Nabar NS, Joshi JV, et al. Single dose Metformin
effect of fenugreek seeds. A study in non-insulin dependent kinetics after co-administration of Nisha-Amalaki powder
section

diabetic patients. Phytother Res. 1996;10:332-4. or Mamejwa ghanavati, Ayurvedic antidiabetic formula-
184. Bordia A, Verma SK, Srivastava KC. Effect of ginger
tions: a randomized crossover study in healthy volunteers.
8

(Zingiber officinale Rosc) and fenugreek (Trigonella Submitted to e CAM. Special issue on Drug Interaction 2014.
foenum-graceum) Linn on blood lipids, blood sugar and 195. Sheth JJ, Shah UJ, Sheth FJ, et al. Genoprotective Effect of
platelet aggregation in patients with coronary artery disease. Indian gentian in type 2 diabetes mellitus (T2DM): comet
Prostaglandins Leukot Essent Fatty Acids. 1997:56:379-84. assay, sister chromatid exchange and protein oxidation
185. Abdel-Barry JA, Abdel Hassan IA, Jawad AM et al. Hypo- studies. Int J Hum Genet. 2011;11:83-8.
glycaemic effect of aqueous extract of the leaves of Trigo- 196. Gangadharan GD. Ayurvedic industries at crossroads: the
nella foenum-graecum in healthy volunteers. East Mediterr potential and problems from scientific political, cultural
Health J. 2000:6:83-8. and industrial angles. In Proceedings of First National
186. Chowdhary DP, Dua M. Hypoglycemic effect of a coded for- Symposiurn on Ayurvedic Industry: Today & Tomorrow.
mulation: Ayush-82. J Res Ayurveda Sidda. 1998;19:107. Delhi: ADMA; 1998.
187. Maji D, Singh AK. Clinical trial of D-400; a herbomineral 197. Singh RH. Diabetes Mellitus: A Novel Approach. 7th

preparation in diabetes mellitus. J Diabetic Association edition. Bangalore: Ayurvedline. 2003; pp. 209-13.
India. 1995;35:1-4. 198. Singh RH. The Holistic Principles of Ayurvedic Medicine.
188. Kumar N, Kumar A. A clinical trial of M-93 compound in Mumbai: Vedic Life Sciences; 1998.
the management of Madhumeha Diabetes mellitus. J Res 199. Mehra U. Diabetes Ka Upachar, Delhi: Qualis Books; 2004.
Ayurveda Siddha. 1995:16:102-7. 200. Bhagwan Dash. Fundamentals of Ayurvedic Medicine, 7th
189. Shankar R, Singhal RK. Clinical assessment of the effects edition. Mumbai: Vedic Life Sciences; 1992.
of sandana (sandal) Podi-a in the treatment of diabetes 201. Paranjpe A. Pathyapathya Vinishchaya. (Marathi). Parijat
mellitus (neerazhiv). J Res Ayurveda Siddha. 1994:15:89-97. Publication 1998.
190. Sircar AR, Ahuja RC, Natu SM, et al. Hypoglycemic,
202. Nanal R. Ahar Rahasya. vol 1–5, Madhavi Prakasban. Pune;
hypolipidemic and general beneficial effects of an herbal 1988.
mixture MA-471. Altern Ther Clin Pract. 1996;3:26-31. 203. Dewan AP. Back to Nature for Healthy Living. New Delhi:
191. Ramdas Rajshekhar K Pankhare. A new antidiabetic herbal AC Specialist Publisher Pvt Ltd., 1990; 91-103.
drug for NIDDM, 7th edition. Bangalore: Ayurvedline; 204. Mehra U. Bhojan Dwara Chikitsa, Delhi: Qualis Books;
401-405. 2003.
 Chapter 46
Transplantation in the
Management of Diabetes Mellitus
Timothy O’Connor, John Thomas O’Brian, Romesh Kumar Khardori

Pancreas Transplant in Diabetes

Chapter Outline
♦♦ Justification ♦♦ Effects of Transplant on Complications of Diabetes
♦♦ Indications and Patient Selection ♦♦ Pregnancy and Pancreatic Transplant
♦♦ Transplant Options ♦♦ Transplantation Associated Risks
♦♦ Procedure ♦♦ Hyperglycemia After Pancreas Transplant
♦♦ Nutrition after Transplant ♦♦ Islet Cell Transplant
♦♦ Patient and Graft Survival ♦♦ Clinical Xenotransplantation

INTRODUCTION kidney-pancreas transplant (SKPT) in a diabetic patient

with end-stage renal disease (ESRD) is also a cost effective
Diabetes mellitus affects 25.8 million1 people in the strategy.3
United States of America (USA), out of which as many as In 1967, the first SKPT was reported in T1DM.4 After
3 million have type 1 diabetes mellitus (T1DM). Diabetes this, several attempts were made, but maintenance of insu­
and its long-term complications cause a financial burden. lin independence in less than 10% discouraged pancreas
Since discovery of insulin, life expectancy of patients with transplant.
diabetes has vastly improved compared to the pre-insulin In 25 years of pancreas transplantation, patient and
era. The benefits of strict glycemic control with intensive graft survival have improved, including reduced technical
insulin regimen have been realized, as evidenced by the graft loss rates and immunological graft loss rates.5 The
diabetes control and complications trial (DCCT) in 1993.2 factors that have influenced these results are (1) technical
However, these benefits were at the expense of significant improvements;6 (2) better immunosuppressive drugs; (3)
hypoglycemic episodes. The requirement for multiple feasibility of biopsy to diagnose early graft rejection; and
daily injections (MDI), frequent self-monitoring of blood (4) availability of more efficient antimicrobial agents for
glucose (SMBG), dietary restrictions and other disabling prophylaxis and treatment. Improvements in protocols
long-term complications significantly affect the quality have yielded better survival for SKPT.7 In case of live
of life (QOL) and longevity in patients with diabetes. organ donors for living donor simultaneous pancreas-
In view of the above, pancreatic transplant, with its kidney transplant (LDSPK), donor morbidity (15%)
associated freedom from MDI, SMBG, dietary restric­ can be reduced further by simultaneous laparoscopic
tions and prevention and/or regression of the long-term nephrectomy and distal pancreatectomy as suggested by
complications, seems a logical choice. Simultaneous Zielenski et al.8 Furthermore, pancreatic transplants are
694 Management

documented to be functional even after 10–18 years with recipients suggest that when pancreatic graft is successful,
restoration of euglycemia, and normalization of endo­ the re-occurrence of diabetic nephropathy is prevented,
genous insulin secretion and insulin secretory reserve.9 but this needs to be confirmed with further studies.20

JUSTIFICATION INDICATIONS AND PATIENT SELECTION

Publication of the DCCT in 1993 settled the arguments Successful pancreas transplantation has demonstrated
about the need for intensive glycemic control.2 This study
section

significantly improved QOL,13-15 along with prevention

unambiguously demonstrated a clear benefit of intensive and/or reduction in the acute metabolic and chronic
8

insulin regimen compared to the conventional regimen complications. However, there is no evidence available
in the development and progression of the long-term to support the benefits of early pancreatic transplant on
diabetic complications in T1DM. After an average 7-year chronic complications of diabetes. Risks of surgery and
follow-up, the intensive insulin arm showed a decrease in immunosuppression, and possibility of graft loss outweigh
the risk for the development of retinopathy by 76%, slowed benefits of transplant early after diagnosis of T1DM, when
progression of existing retinopathy by 54%, reduced chronic complications have not developed. Therefore,
occurrence of clinical neuropathy by 60%, albuminuria pancreatic transplant is usually considered after about
by 54% and microalbuminuria by 39%. Intensive insulin
20 years of diabetes with overt diabetic complications and
regimen was associated with increased incidence of
poor QOL due to extreme swings in glycemic control.
hypoglycemic episodes, but there was no added risk of
Pancreas or islet cell transplant should be performed
mortality. Intensive insulin regimen is projected to add an
in a tertiary or quaternary care hospital that has an active
average of 5.1 years to the lifespan.10
kidney transplant program and is equipped to adequately
After several years of diabetes, the glucagon and epine­
handle the complex medical and psychosocial needs of
phrine responses to hypoglycemia are blunted rendering
the transplant patients over the long-term.21 The trans­
these patients vulnerable to defense against hypoglycemia
plant centers have their own patient selection criteria,
including blunting of awareness.11,12 However, avoidance
although general criteria are as follows:
of hypoglycemia can restore hypoglycemic awareness
• Type 1 diabetes mellitus—however, during the past
at the expense of loosened glycemic control. Pancreatic
decade, an increasing number of non-obese type 2 dia­
transplant seems beneficial as it would avoid the wide
betic patients are being considered for the pancreatic
fluctuations in the blood sugar levels with a significant
transplant. In 2010, approximately 8% of SPKT, 5% of
improvement in general and diabetes related QOL.13-15
At present, there are 93,817 patients awaiting kidney pancreas-after-kidney transplant (PAKT) and 1% of PTA
transplant, 1,229 awaiting pancreas transplants and 2,141 were performed on type 2 diabetics.5 Usually, a patient
awaiting kidney/pancreas transplant.1 Diabetic patients with type 2 diabetes mellitus (T2DM) is not a candidate
with ESRD on hemodialysis (HD) have significantly for pancreatic transplant unless strict acceptance
increased mortality of any group of patients with ESRD, criteria are met. A retrospective review of single center
dominated by life-threatening coronary atherosclerotic experience found that patients with T2DM fared worse
events.16 Even in the absence of other cardiac function with regards to overall graft and patient survival rates
abnormalities, diastolic dysfunction predisposes diabetic than patients with T1DM and non-diabetic patients
patients to cardiac events. Short-term normoglycemia over 50 years of age despite similar immunologic
(6 months) after pancreas transplant alone (PTA) has been graft failure rate.22 These differences were primarily
shown to positively affect diabetic heart by improving due to high patient death rate among those with
diastolic function parameters, in particular end-diastolic T2DM. Yet, in another study, the type of diabetes did
volume (EDV).17 not affect the outcome of the SPK transplant.23 The
Since diabetic renal disease accounts for the majority subjects in this study were mostly African-American.
of ESRD patients on dialysis, and considering the best The successful outcome also challenged the time-
survival and financial benefits, simultaneous pancreas- honored notion that insulin resistance in patients
kidney transplantation (SPKT) is more cost-effective for with T2DM might be a cause for concern. Thus, those
diabetic ESRD than kidney transplantation alone (KTA) with T2DM might deserve consideration, if following
and dialysis.18,19 Recent studies in pancreas transplant requirements are met: (1) insulin requiring for at
 Transplantation in the Management of Diabetes Mellitus 695

least 5 years with complicated diabetes; (2) body mass donor provides a kidney and pancreas from a single donor,
index (BMI) of less than 30 (30–35: marginal, more in one operation, and with the best pancreas transplant
than 30 Kg/m2 are excluded); and (3) age under success rate. In many regions, those awaiting SKPT are
55 years (55–65: marginal, more than 65 are excluded). given preference in allocation and thus waiting time for
• Age between 18 years and 65 years. SKPT is often less than for KTA.
• Able to withstand the surgery and immunosupp­ In other areas, those awaiting SKPT are not given
ression, i.e. absence of uncorrectable peripheral vas­ special preference, and only if the patient is near the “top”

chapter
cular disease (PVD) or coronary artery disease (CAD). of the waiting list for a kidney, then both organs would

46
Cardiac function is evaluated by non-invasive assess­ be allocated. KTA from a willing living donor should also
ment of cardiac risk by two-dimension echocardio­ be considered. PAK could subsequently be undertaken,
graphy and dipyridamole-thallium scanning, and but benefits of PAK compared to SKPT are not as clearly
routine use of cardiac catheterization is not necessary delineated, particularly in life expectancy, and thus
unless indicated.24 SKPT candidates waiting longer PAK should be undertaken selectively, and cannot be
than 2 years should undergo repeat cardiac assessment; considered a standard of care at this time.
firm practice guidelines are lacking for this, but it seems A few transplant centers offer simultaneous live donor
reasonable for ESRD diabetic patients with multiple
kidney transplant/deceased donor pancreas transplant,
cardiac risk factors. In addition to screening for
but this approach is fraught with the logistics of keeping
hepatitis B, C and HIV, age appropriate cancer scree­
a living donor on standby. Combined donor nephrectomy
ning should be conducted (Pap smear, mammogram,
plus distal pancreatectomy from a single live donor has
prostate-specific antigen and colonoscopy). Some
been performed by both open operation and laparoscopic
centers do accept patients with uncorrectable coro­
techniques, but only infrequently.
nary disease or diffuse small vessel disease, if the
cardiologist determines that the remaining ventricular
function is likely to support the patient through a trans­ Types of Transplant Options
plant procedure. Patients, who have undergone lower • Pancreas-alone transplant or islet cell transplant:
extremity amputations because of microvascular flow Native renal function, measured as glomerular filtration
to support the allograft, should not be viewed as a strict rate (GFR), declines in patients undergoing pancreas-
contraindication to the transplant.25 A lower extremity alone transplant, regardless of initial GFR.26 This may
vascular Doppler study is advisable whenever in doubt be in part due to use of calcineurin inhibitors, which
about the PVD. routinely cause renal arteriolar vasoconstriction and
• Absence of active infection, malignancy or chemical sometimes renal tubular injury. Immunosuppressive
dependency. regimens that avoid calcineurin inhibitors have not
• Presence of complications of diabetes especially renal yet been widely studied. Thus, it is reasonable to
disease. limit pancreas-alone transplant to patients with GFR
• Psychosocial stability, social support, compliance, more than 40 mL/min. A cyclosporine or tacrolimus
commit­ment and understanding of long-term bene­ challenge may be given in the evaluation stage, with
fits and risks associated with transplantation and
measurement of GFR to predict whether these agents
immuno­suppression.
will too adversely affect renal function.27,28
• Absence of obesity, i.e. BMI less than 30 kg/m2.
• Simultaneous kidney-pancreas transplant
• Pancreas-after-kidney transplant (PAKT) or islet cell
TRANSPLANT OPTIONS transplant-after-kidney transplant.
With ongoing advances in immunosuppression and • Retransplant.
operative techniques, multiple combinations of trans­ Choices may have to be made between cadaveric
plants are available to the diabetic patient. Preemptive organs versus organ from a living donor.
transplant, when the patient had uremic symptoms but
has not yet initiated dialysis, is ideal since long-term Living Donor Selection Criteria
renal allograft success is superior. However, in reality this • Age under 60 years
occurs infrequently. SKPT from a deceased brain dead • Ideal BMI (< 27 Kg/m2)
696 Management

• In excellent physical condition, i.e. no history of gesta­ superior mesenteric vein). Portal drainage is more physo-
tional diabetes mellitus, other illnesses—hypertension, logic as insulin is drained via hepatic circulation allowing
CAD, pancreatitis for first pass metabolism whereby about 50% is extracted.
• Absence of anti-insulin and anti-islet antibodies Therefore, portal drainage prevents hyperinsulinemia
• No T2DM in first-degree relatives found with systemic drain­age. Hyperinsulinemia asso­
• No T1DM in other first-degree relative other than ciated acceleration of atherosclerosis and increased lower
recipient. extremity PVD in pancreas recipients have been repor­
section

By the first year, about 25% of live donors have oral ted.35 However, neither portal nor systemic venous drain-
age has shown advantages in human transplantation.36,37
8

glucose tolerance results diagnostic of diabetes29 and

long-term follow up indicates that fasting hyperglycemia Systemic drainage after SKPT is associated with dimi­
is more likely to develop in live donors who become nished early (6 months) insulin sensitivity. With sustained
obese.30 Therefore; these individuals should be monitored euglycemia, improved renal function and reduction
aggressively for early detection of glucose intolerance. in prednisolone dose, insulin sensitivity improves by
Patients with complicated diabetes who are consi­ 12 months and normalizes by 24–48 months after trans­
dering a solitary pancreas transplant must weigh the plant. There is a time-dependent decrease in the post-
potential benefits of insulin independence against an stimulatory insulin response, which is thought to be a
apparent increase in the mortality for at least the first 4 response to normalization of insulin sensitivity and not
years post-transplantation.31 due to a gradual b-cell function decline. This observation
Simultaneous kidney-pancreas transplant offers a suggests that portal rather than systemic drainage of
variety of benefits including improved QOL,13,15 improved endocrine pancreas may not be necessary for achievement
patient survival32,33 and improved renal graft survival.30 of normal glucose homeostasis.38 However, pancreas-
Therefore, diabetic patients with ESRD in need for a kidney transplant patients with systemic allograft drainage
kidney should be offered SKPT rather than kidney have a persisting profile of hyperinsulinemia, high lipo­
transplant alone.31,34 protein lipase and cholesterol ester transferase that
resemble T1DM patients treated with continuous sub­
PROCEDURE cutaneous insulin infusion (CSII), although with unclear
clinical implications.39
The pancreaticoduodenal allograft is retrieved from the Management of the exocrine secretions of the pan­
deceased heart-beating brain-dead donor by mobili­ creatic allograft remains challenging. Exocrine secretions
zation of its attachments and intra-aortic flush of preser­ may be treated by either enteric or bladder drainage.
vation solution. Either University of Wisconsin solution Bladder drainage developed in Nebraska, USA, by
or histidine-tryptophan-ketoglutarate solutions are satis­ Carry and Sallinger remains the most frequent surgical
factory. Proximal and distal duodenum is stapled and choice. It allows early detection of the allograft rejection
divided, root of the mesentery is ligated and divided, by measu­ ring the pancreatic enzyme amylase in the
and superior mesenteric artery (SMA), splenic artery urine in addition to allograft biopsy for early lymphocytic
and portal vein divided. The pancreas may be stored in infiltration within exocrine tissue. The complications
solution for up to 24–30 hours with good outcome. Prior associated with bladder drainage include bicarbonate-
to transplantation, the spleen is detached after ligation of wasting leading to metabolic acidosis requiring massive
vessels at the tail of the pancreas. A Y-shaped conduit of oral replacement, leakage at the anastomotic site,
donor iliac artery bifurcation is anastomosed to splenic hyperkalemia, dehydration and allograft pancreatitis.40-42
artery and SMA, so that only one arterial anastomosis Enteric drainage consists of anastomosis of donor
to recipient is needed. Implantation of the organ varies duodenum to small bowel; we find an end-to-side anasto­
depending on the choice of endocrine and exocrine mosis of third part of donor duodenum to mid-small
secretions drainage. bowel to be satisfactory. Anastomotic leakage, though
The drainage of the endocrine and exocrine pancreas infrequent, can cause severe septic complications in the
is performed in different ways, each with certain pros immunosuppressed recipient. Now increasingly popular,
and cons. Drainage of pancreatic venous flow, containing enteric drainage was introduced by Groth in 1970s,
secreted insulin, may be via a systemic vein (iliac) or by which appears to show a trend toward improved graft
portal drainage (by end-to-side anastomosis to recipient survival.41 However, the rate of graft loss was higher than
 Transplantation in the Management of Diabetes Mellitus 697

chapter
46
Fig. 46.1: Annual number of US pancreas transplantations reported to Fig. 46.2: Annual number of US pancreas transplantations for the
UNOS/IPTR, 1966–20105 major recipient categories, 1988–20105

the bladder drained complications group.43 A bladder the effects of immunosuppressive agents. Weight gain
drainage can be converted to enteric drainage if threatened is commonly seen following transplantation due to
by complications. The monitoring of enteric drained corticosteroid-induced increased appetite, changes in
pancreatic allograft in SKPT is usually accomplished by deposition of adipose tissue and fewer dietary restrictions.
measurement of serum creatinine levels. Serum lipase Adequate energy intake should be encouraged for weight
appears to be a useful marker for acute rejection, which maintenance.45
may be useful as a non-invasive indicator of rejection in
solitary pancreas transplantation where creatinine cannot PATIENT AND GRAFT SURVIVAL
be used.44
Data pertaining to United States (US) pancreas trans­
plantation as reported to United Network for Organ
NUTRITION AFTER TRANSPLANT
Sharing/International Pancreas Transplant Registry
Pancreas transplant allows for more freedom in the (UNOS/IPTR) are graphically depicted in Figures 46.1
dietary regimen. However, medical nutrition remains to 46.5.5
an important component of care to promote short-term Patient survival rates after pancreas transplant have
wound healing and counteract long-term nutritional progressively improved, with 3-year patient survival
complications of immunosuppressive medication. rate exceeding 90% in all three categories for 2006–2010
For approximately one month after surgery, caloric transplantations. Earlier one year patient survival rates
and protein needs are elevated as wounds heal and of 95% were reported in simultaneous cadaver pancreas
recovery begins. If the surgery used bladder anastomosis, living-donor kidney transplantation.46 The 3-year pan­
fluid needs increase to 50–60 mL/kg/day with additional creas graft survival rate reached almost 80% in SPKT. In
sodium and bicarbonate needs during this time. After the all three categories, cardio/cerebrovascular problems
short-term recovery period, most nutrients are needed and infections were leading causes of both early and
similar to general population to encourage overall health late death.5 Hemoglobin A1c (HbA1c) more than 6.5%
with a few exceptions. Specifically, carbohydrate is not and systolic blood pressure more than 140 mm Hg were
modified as long as fasting glucose remains within a associated with an increased rate of renal graft failure.47,48
normal range. With bladder anastomosis, fluids needs may The only variable associated with an increased overall
be as high as 4 liters per day with dietary sodium intake mortality risk was a higher discharge serum creatinine
at least 4,000 mg per day. Higher intake of magnesium, value following the incidental transplant hospitalization
phosphorous and calcium are also needed to counteract (RR 1.16 for each 0.1 mg/dL rise in serum creatinine
698 Management
section
8

Fig. 46.3: Annual rates of US pancreas transplantations in patients with type 2 diabetes, 1994–20105

A B

C D
Figs 46.4A to D: Primary deceased donor graft function over 10 years for (A) simultaneous pancreas-kidney (SPK) pancreas graft; (B) SPK
kidney graft; (C) pancreas-after-kidney pancreas graft; and (D) pancreas transplant alone pancreas graft5
 Transplantation in the Management of Diabetes Mellitus 699

chapter
46
A B

C D
Figs 46.5A to D: Primary deceased donor graft function for recipients who reached the 1-year mark with a functioning graft over 5 yeras for
(A) simultaneous pancreas-kidney (SPK) pancreas graft; (B) SPK kidney graft; (C) pancreas-after-kidney (PAK) pancreas graft and (C) pancreas
transplant alone pancreas graft5

from 1.0 mg/dL).47 The race or type of diabetes has no as evident by about half the magnitude of AIRgluc, AIRarg
effect on the outcome of SKPT.23,49 and AIRargmax in the segmental pancreas transplant
The long-term success of pancreatic or islet cell recipients.50 Successful pancreatic transplant recipients
transplant is evaluated by assessing the reciprocal who maintained euglycemia without exogenous insulin
relationship between the magnitude of the acute insulin did experience time dependent decline in b-cell respon­
response to glucose (AIRgluc) and the fasting glucose sivity as reflected by AIRgluc. However, clinically, the most
levels. This, normal physiological relationship is main­ important indicator of successful pancreatic transplant
tained in successful recipients of pancreatic transplant. is their ability to maintain stable levels of fasting blood
The measurements of AIRgluc and acute insulin response glucose, intravenous glucose tolerance and HbA1c.50
to arginine (AIRarg) can be used reliably to estimate
insulin secretory reserve in pancreatic transplant and EFFECTS OF TRANSPLANT ON
presumably islet cell transplant recipients.50 The recipients COMPLICATIONS OF DIABETES
of whole pancreata from cadaveric donors have twice the
amount of insulin secretory reserve as that found in the The foremost and most impressive benefit of both
recipients of segmental grafts from living, related donor pancreas transplant is insulin and kidney independence
700 Management
section
8

Fig. 46.6: Pancreas graft survival rates at 1 year from 1996 to May Fig. 46.7: Glucagon level is during hyperinsulinemic hypoglycemic
15, 2003 for non-US SPK primary cadaveric pancreas transplants was clamps in pancreas transplant recipients (■, n = 8), subjects with type
85% (IPTR data) 1 diabetes (▲, n = 9), and normal control subjects (■, n = 10). In pan-
creas recipients and control subjects, as opposed to diabetic subjects,
increase in glucagons secretion were seen during the hypoglycemia
normoglycemia and significantly improved QOL.13-15 At period58
thesame time a functioning pancreatic graft offers better
patient survival,32,51 allowing diabetic recipients to live
more of their predicted lifespan.33,47,52 A functioning pan­ patient develop less light microscopic and electron
creatic graft appears to provide a survival advantage for an morpho­metric changes in their kidney graft.62 Also, kidney
SKPT recipient compared to the recipients of a cadaveric graft survival is better with SKPT in comparison to renal
kidney graft and SKPT recipients whose pancreatic transplant patients who are continued on exogenous
graft failed.51 The annual mortality rate was 1.5% for the insulin.33 Normoglycemia of 10 years after a functional
recipients of SKPT, 6.3% for cadaveric kidney recipients PTA improved nephropathy that was evident at baseline.
and 3.7% for living donor kidney recipients.51 It showed reversibility of glomerular lesions characteristic
Despite some increase in insulin resistance by gluco­ of diabetes, including Kimmelstiel-Wilson bodies as well
corticoids and direct inhibitory action on insulin secre­ as tubular lesions as confirmed by renal biopsy at base­
tion by corticosteroids, cyclosporine and tacrolimus,53-56 line, 5 years and 10 years from PTA.63 However, five years
improvement in HbA1c is better than the inten­sive insulin of normoglycemia did not reverse established diabetic
arm of DCCT (Figs 46.6 and 46.7). glomerular lesions in patients with T1DM, suggesting a
Patients with long-standing diabetes have defective long latency between restoration of euglycemia and the
counter-regulatory hormonal responses. Poor response reversal of morphological lesions of diabetic nephropathy.
of glucagon and epinephrine to hypoglycemia improves Solitary pancreas transplant has shown improvement in
significantly 20–78 months after successful pancreatic the urinary albumin excretion,20,63 at the same time no
transplant, restoring hypoglycemic awareness (Figs 46.7 significant difference was noted in GFR or renal blood
and 46.8A and B).57,58 flow, 10 years after SKPT or KTA.64 Short of renal biopsy, it
About 30% of the renal failure patients in the USA is difficult to identify patients who would benefit from
have T1DM.59 The benefits of tighter glycemic control on pancreatic transplant. Patients with uncontrolled diabetes
the progression of microalbuminuria are evident with despite treatment (HbA1c > 9%), urinary albumin excre­
improved metabolic control with the use of CSII.60 tion more than 100 mg per 24 hours and GFR between
SKPT is a valuable therapeutic modality for end-stage 60 mL and 100 mL per minute can be considered good
diabetic nephropathy and should be considered before candidates for a pancreatic transplant.65 Still, benefits of
uremia commences.61 In comparison to live donor kidney pancreatic transplant must outweigh the risks of surgery
trans­plant, which is associated with less exposure to and immunosuppression. Thorough critical appraisal of
immunosuppression and fewer rejection episodes, T1DM reversal of diabetic nephropathy following pancreatic
 Transplantation in the Management of Diabetes Mellitus 701

chapter
46
A B
Figs 46.8A and B: Epinephrine response to hypoglycemia in pancreas transplant recipients (PX TX) and type 1 patients with (IDDM + KID TX,
n = 5) and without (IDDM, n = 12) prior renal transplant. Both groups of type 1 diabetic subjects had similar impairment of epinephrine response
and both were less than those observed after pancreas transplantation. *p < 0.5.57

transplantation would suggest that human kidney has the one year) and one of these suggested that these differenc-
potential to repair itself and achieve substantial architec­ es could be correlated with prednisolone dose and serum
tural remodeling of glomerular and tubular structures.20 creatinine.71
Simultaneous kidney-pancreas transplant impacts The beneficial effects of a functional pancreatic graft
CAD and PVD in a positive way. There is a trend for lower on the progression of PVD are lacking.73,74 Despite a better
prevalence of CAD and PVD in SKPT recipients versus patient survival rate with SKPT, CAD remains the predo­
KTA13 due to the reduction in the risk for the development minant cause of death; thus, exercise stress testing can be
of microangiopathy, but fails to halt the progression of justified when clinically indicated or at least every three
macrovascular disease.66 Hyperglycemia is believed to years after the transplant.48
contribute to atherosclerotic plaque formation in a num­ Simultaneous kidney-pancreas transplant improves
ber of ways, including glycation of collagen, alteration of hypertension in hypertensive, uremic, T1DM patients by
addressing the hyperglycemia and hyperinsulinemia.
endothelial cell function, glycoxidation of low-density
Hyper­glycemia stimulates proximal tubular glucose Na+-K+
lipoprotein cholesterol and increased platelet reactivity.67
ATPase co-transporter with resultant glomerular hyperfil-
A functioning pancreatic graft probably improves auto­
tration. This can increase the total exchangeable sodium,
nomic neuropathy thereby decreasing high mortality due
inducing sodium retention.75
to abnormal cardiopulmonary reflexes causing sudden
Chronic hyperglycemia increases the number of highly
cardiac death. Regression of coronary athero­ sclerosis
cross-linked proteins to AGEs (advanced glycated end-
occurred in 38% of patients with a functioning pancreatic
products), resulting in vascular hypertrophy and remode­
graft compared with none of the patients in whom the lling.67 It is linked to enhanced production of extracellular
pancreas graft failed after SKPT.16 The beneficial effects matrix and proliferation of vascular smooth muscle
of a functioning pancreatic graft on progression of coro­ cells. Prolonged hyperglycemia is also associated with
nary atherosclerosis are comparable to statin therapy.68 decreased elasticity of vascular arterial wall connective
Other benefits with a functioning pancreatic graft incl­ tissue and elevated pulse pressure which is also related
ude decreased progression of coronary atherosclerosis,16 in part to AGEs.76 Insulin on the other hand may interfere
decreased cardiovascular deaths69 and a favorable effect with the normal activity of Na+-K+ ATPase and Na+-H+
on the lipid profile.70 There are some conflicting reports co-transporter, thus changing the distribution of ions
concerning PTA and PAKT, and the benefits on the lipo- at the vascular smooth muscle level which may enhance
proteins.71,72 There were short-term follow-ups (about peripheral vascular resistance or predispose to volume
702 Management

overload by increasing the absorption of sodium or other • Presence and persistence of secondary hyperpara­
cations by renal tubular cells. Therefore, hyperinsulinemia thyroidism after SKPT, due to persistent parathyroid
in view of insulin resistance can worsen hypertension. hyperplasia, causes cortical bone loss.
This could argue against systemic vascular drainage of the • Tendency for metabolic acidosis in patients with
pancreatic graft. The improvement in insulin resistance is bladder drained SKPT due to obligatory urinary bicar­
greater after SKPT than diabetic patients receiving KTA.77 bonate loss, which if not adequately corrected, could
Diabetic retinopathy (DR) is present in a high percen­ further contribute to hyperparathyroidism.
section

• Low vitamin D levels may also contribute to hyper­

tage of cases prior to SKPT depending on duration of
parathyroidism, especially when vitamin D supplement
8

unstable T1DM and ESRD. The progression of the DR

is inadequate.
post-transplant was most pronounced in the first post-
transplant year, therefore, close ophthalmologic follow-up
PREGNANCY AND PANCREATIC
is very important.78 Following the first 12 months, DR
appears to remain stable in most cases. In patients with
TRANSPLANT
laser treated proliferative DR prior to undergoing PA Pregnancy is uncommon in uremic patients due to increa­
transplant, 86% experienced disease stabilization of sed anovulatory cycles and reduced sexual activity.
retinal disease after transplant (compared to 43% in those Simultaneous kidney-pancreas transplant may permit
that did not receive transplant) and 14% experienced pro­ a successful conception in diabetic women with ESRD.84
gression (compared to 57% in those that did not receive Many successful pregnancies and delivery of healthy
transplant).79 Several factors including reduction in children have been documented.84-86 They should be
hyperglycemia induced enhanced retinal vascular blood managed in a high-risk pregnancy unit in a tertiary care
flow, and changes in circulating growth hormone have facility with neonatal intensive care unit (Tables 46.1
been implicated. and 46.2).
Diabetic polyneuropathy affects about 80% of patients Before attempting conception, patient should have a
with T1DM and renal failure. Apart from vascular changes, stable serum creatinine level of less than 2.0 mg/dL and
hyperglycemia has deleterious effects on nerves. Long- achieve a maintenance immunosuppressive regimen for
term follow ups, up to 7 years after SKPT, have documented approximately two years.85,87 Pregnancy could increase
improved nerve conduction velocity (NCV).80,81 Action the risk of long-term reduction in renal function and graft
potential amplitude is a measure of the nerve fibers survival. Patient should also consider future parenting
capable of conducting the impulse and is useful for the issues due to limited lifespan after transplant causing
assessment of axonal loss and conduction block. It is the emotional, physical and financial stress.
most significant electrodiagnostic indicator of diabetic
neuropathy than NCV, which signifies demyelination.82 Table 46.1: Maternal/fetal complications and drug side effects
After SKPT, conduction velocity shows rapid initial Maternal complications:
recovery while action potential recovers in a slow mono­ • Proteinuria
phasic pattern over a long observation period.82 • Hypertension

Diabetic osteodystrophy is characterized by low bone • Deterioration of pancreatic or renal graft function
formation rates and a generalized decrease in the bone Fetal complications:
turnover. Low bone mass is prevalent after SKPT and is • Prematurity, IUGR, cataracts, congenital anomalies
associated with high incidence of fractures. Low bone • Monitor for any signs/symptoms of graft failure/rejection
mass can be observed about one year after successful Adverse effects of immunosuppressive therapy:
SKPT in up to 50% of the recipients. This bone loss is • Prednisolone crosses placenta—may cause adrenal insuffici­
ency in the newborn. It may aggravate hypertension, hypergly-
predo­minantly cortical. The following reasons are sug­
cemia and premature rupture of the membranes and infection
gested for this bone loss:83
• Azathioprine can cause thymic atrophy, chromosome aberration
• More frequent rejection episodes during first few in lymphocytes, thrombocytopenia and liver toxicity in neonates
months after SKPT versus KTA, requires more frequent • Cyclosporin is nephrotoxic and is associated with hypertension,
pulse doses of corticosteroids. IUGR and prematurity. It is secreted in breast milk, therefore
• Long-standing T1DM is a risk factor for cortical breastfeeding is contraindicated
osteoporosis. (IUGR: Intrauterine growth restriction).
 Transplantation in the Management of Diabetes Mellitus 703

Table 46.2: Pregnancy care in a simultaneous kidney-pancreas Also, pancreatic transplant is associated with longer
transplant patient hospital stay, more readmissions, increased acute rejec-
Visits and hospitalization: tion episodes, more reoperations and more infections.89-91
• Prenatal visit with perinatologist and transplant team Increasing experience with SKPT in the recent years
• Prenatal visit every 2 weeks until 24 weeks, then weekly has resulted in reduced but still considerable number of
• Monitor blood levels of cyclosporine every 2 weeks complications. Independent of the draining techniques,
• If on steroids, obtain glucose tolerance test at 24, 28 and the most common causes of technical failure are graft

chapter
34 weeks gestation thrombosis, infection, anastomotic leak and bleeding.

46
• Continue prepregnancy regimen of immunosuppressive agents Patients requiring re-laparotomy have increased morbi­
• Hospitalize if evidence of renal or pancreas function deteriora- dity, mortality and decreased graft survival.92 The live donor
tion and consider delivery if failure to reverse pancreatic graft is associated with increased vulnerability
• Superimposed pregnancy induced hypertension maybe difficult to pancreatic graft thrombosis due to anato­mic difficulty
to control
with the blood supply.93 The immunosuppressive regi-
• Counsel about contraindication to breastfeeding men can cause insulin resistance with the corticosteroid
Antepartum fetal surveillance: use, also, there is suggestion of decreased pancreatic
• Ultrasound for congenital anomalies and serial ultrasound every b-cell function associated with cyclosporine and tacro­
3–4 weeks for growth and amniotic fluid volume
limus use.53,55,94
• Non-stress test at 28 weeks gestation and then weekly
One year after transplantation, daily mean glucose
Laboratory studies at first prenatal visit and then every 4 to 6 weeks
concentration more than 125 mg/dL has 93% specificity
• Complete blood count
and 100% sensitivity for predicting individuals at higher
• Platelets
risk for returning to diabetic state within 4 years.95 Such
• Hemoglobin A1c
individuals require intense monitoring for any signs of
• Serum electrolytes, creatinine and blood urea nitrogen (BUN)
decreasing graft function.
• Liver function tests
Diabetic muscle infarction has been reported about
• Serum uric acid
1–8 months after a successful SKPT.96 Diabetic muscle
• Serum calcium and phosphorus
infarction in long-term diabetic patients after SKPT is felt
• Cyclosporine levels as above
to result from:
• Serum and urinary amylase
• Peripheral microvascular disease
• 24-hour urine for creatinine clearance and protein
• Hypercoagulability, although there is no proven role of
• Urine analysis and culture
anticoagulation therapy
Delivery:
• Impaired arterial neuropathic response to local
• Continuous fetal monitoring during labor
hyperemia
• Administer prophylactic antibiotics and steroids during and after
• Other risk factors include hypertension, steroids and
delivery
calcineurin inhibitors (cyclosporine and tacrolimus)
Postpartum visit:
• Obtain same laboratory studies as above
HYPERGLYCEMIA AFTER
PANCREAS TRANSPLANT
TRANSPLANTATION ASSOCIATED RISKS Hyperglycemia may ensue after a pancreas transplant. It
The risks associated with transplant include those related can have different etiologies with an incidence varying
to surgery, immunosuppression and function of the from 4% to 50% across different studies (Table 46.3).
graft. Procedure related complications include leakage Post-pancreatic transplant hyperglycemia is often
at the anastomotic site, intra-abdominal infections and defined as the random daytime plasma glucose exceeding
abscesses. These may require re-laparotomy in up to 200 mg/dL requiring insulin treatment. Daytime glucose
20–30% of the recipients. In the first three admissions elevations may result from initial high doses of cortico­
per patient, more hospital days per patients and more steroids. Fasting blood glucose of greater than 110 mg/dL
intensive care unit days per patient13 and at one year, had is often a cause for concern.
higher morbidity and complications compared to the KTA Pancreatic b-cells begin processing insulin imme­
in T1DM patients.88 diately after reperfusion. C-peptide is detectable early
704 Management

Table 46.3: Early and delayed causes111 sinusoids. The potential complications of liver infusion
Early causes Delayed causes include bleeding, portal venous thrombosis and portal
• Technical complications • Acute/chronic rejection
hypertension.
The recent successes in graft survival are claimed to
• Vascular thrombosis • Drug toxicity
be due to steroid free, low-dose immunosuppression.98
• Ischemia • Chronic pancreatitis
The immunosuppression regimen used in Edmonton pro­
• Primary non-function • Recurrence of autoimmunity
tocol is diabetogenic, possibly due to direct inhibitory
section

• Actue rejection action on insulin secretion by cyclosporine and tacro­

• Drug toxicity limus.53-55 A variety of growth factors have been used to
8

improve and prolong the function of β-cells.

Recently, ex vivo adenoviral vector induced hepatic
at 30 minutes after pancreas transplantation. The appe­ growth factor (HGF) expression into murine pancreatic
arance of graft at the time of transplantation is often a β-cells, which after transplantation into diabetic rats
good indicator of its function. In some cases, the graft remained functional longer with a lower transfused islet
recovery is delayed. Unlike renal transplant, there is no equivalent (IE) volume.100
good definition for delayed endocrine graft function. In Islet transplant usually needs two separate infusions
simultaneous kidney-pancreas transplantation, delayed and with the initial loss of transfused islets, the demand
graft function in one organ does not have implications for the available pancreata is unmatched. There are not
for the graft function of other transplanted organ. The enough pancreata to meet even the need of T1DM patients
incidence of delayed graft function varies from 31% to who have poor hypoglycemic awareness and frequent
36%. In one study delayed graft function was defined hypoglycemic episodes.99 Apart from the adverse effects
as insulin requirement of more than 30 units between of the procedure, other complications include transiently
day 5 and day 10 post-transplantation, and/or more than elevated liver enzymes, hypercholesterolemia, further
15 units between day 11 and day 15 irrespective of insulin increase in serum creatinine levels in patients with pre-
dose administered during the first 5 days post-trans­ existing renal disease, increased proteinuria in patients
plantation.97 with pre-existing proteinuria, need for increase in the doses
of antihypertensive drugs and the need for retinal laser
ISLET CELL TRANSPLANT photocoagulation.99 With the impressive clinical outcomes
from pancreatic transplantation, islet transplantation is
The islets of Langerhans constitute about 2–3% of the total still considered an experimental procedure.21
pancreatic volume and a normal pancreas has about one An excellent review on islet cell replacement
million islets. The islets comprise of alpha, beta, delta and therapy has been published for those particularly inte­
PP cells that secrete glucagon, insulin, somatostatin and rested in this topic.101 The National Institute of Diabetes
pancreatic polypeptide respectively. and Digestive and Kidney Disease (NIDDK) established
The islets for transplantation are procured from a the Collaborative Islet transplant Registry (CITR) in
healthy pancreas and then purified using various separa- September 2001.
tion and configuration techniques. There is some contro- As of April 2008, CITR registry comprised 325 adult
versy about this process as purification yields a smaller recipients of 649 islets infusion derived from 712 donors.
mass with loss of substantial number of islets, and it At 3 years post-first infusion, 23% of islet-alone recipients
removes pancreatic duct stem cells that might give rise to were insulin independent more than and equal to 2 weeks,
new islets after transplantation. 29% were insulin dependent with detectable C-peptide,
The rewarding results with islet transplant are evident 26% had lost function, and 22% had missing data. Seventy
only recently despite multiple efforts in the past.98 With percent achieved insulin independence at least once,
the initial graft survival approaching 80%, islet cell trans­ of whom 71% were still insulin independent 1 year later
plant offers a viable option to much invasive and expensive and 52% at 2 years.102
pancreatic transplant.99 Another study investigating the role of induction
The procedure permits infusion of procured islet cells chemotherapy in insulin independence after islet trans­
via cannulation of portal vein percutaneously, avoiding plant alone reported 5-year insulin independence rates
major surgery and other expenses. Once infused into comparable to outcomes in PTA. Induction immun­
the portal circulation, islets get lodged in the hepatic osuppression was significantly associated with 5-year
 Transplantation in the Management of Diabetes Mellitus 705

insulin independence, regardless of maintenance this to be an acceptable procedure in the right candidate.
immunosuppression or other factors.103 However, it is still not an acceptable treatment option in

A critical perspective on islet transplantation high­ the vast majority of the uncomplicated diabetic patients
lights drawbacks of current practices, and offers insight due to associated morbidity and mortality.31 Note that all
into reasons for dwindling interest and possible solutions the benefits of pancreatic transplantation are documented
including search for use of β-cell surrogates (stem in a highly selective patient population, therefore, these
cells or modified cell lines) and non-hepatic sites for variables must be taken into account when choosing or

chapter
transplantation.104 There is a critical need to transition recommending these procedures to the hopeful diabetic

46
from requirement from two to four donors down to one patients. PTA and PAKT are currently recommended
donor per recipient that would expand islet graft pool to T1DM patients debilitated with disabling metabolic
to accommodate the growing patient base with type 1 problem and autonomic neuropathy, which can cause
diabetes. Furthermore, this would avoid the exposure of postural hypotension, gastroparesis and shortened life
recipients to multiple different human leukocyte asso­ span.108-110 The beneficial effects of a functional pancreatic
ciated (HLA) antigens.105 Islet transplantation has been graft on the native63 as well as transplanted kidneys along
hindered by immune assault on engrafted tissue resulting with the survival benefit,31 SKPT should be offered to
in rejection. Recently, it has been recognized that CXCR1/2 T1DM patients with ESRD.
chemokine receptors and their ligands are crucial negative The rates of successful pancreatic islet cell graft are
determinants for islet survival after transplantation. improving, but as per the American Diabetes Association,
In human, the CXCR1/2 allosteric inhibitor-reparixin it is still considered an experimental procedure.21
improved outcome in a phase 2 randomized, open label
pilot study using single infusion of allogeneic islets.106 Acknowledgment
CLINICAL XENOTRANSPLANTATION The authors acknowledge and appreciate the contribu­
tions of Ketan Goswami and Shilpa Swami in preparation
Shortage of human tissues/organs has prompted a of this article.
close scrutiny of transplantation across species. Porcine
pancreatic cells have been studied as a source of β-cell FURTHER READING
replacement in humans.107 The porcine tissue would
require to be humanized (stripped of alpha-galactosyl 1. Halban PA, German MS, Kahn S, et al. Current status of
antigen) in order to resist rejection, since humans contain islet cell replacement and regeneration therapy. J Clin En-
docrinol Metab. 2010;95:1034-3.
natural antibodies directed against alpha-galactosyl
2. Arifin DR, Bultej WM. Imaging of pancreatic islet cells. Dia-
antigens. Baboon and Chimpanzees cells leak this antigen, betes Metab Res Rev. 2011;27:761-6.
which diminishes immune barrier. However, concern 3. Floretto P, Maurere M. Reversal of diabetic nephropa-
about transmission of infections has dominated the thy: lessons from pancreas transplantation. J Nephrol.
debate. There is fear of zoonotic infections in recipients 2012;25:13-8.
(prions, endogenous retroviruses). 4. Johnson PR, Jones KE. Pancreatic islet transplantation.
Semin Pediatr Surg. 2012;21:272-80.
5. Ollinger R, Margreiter C, Bosmuller C, et al. Evolution of
SUMMARY pancreas transplantation. Annals Surg. 2012;256:780-7.
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section

tion. 1995;91:2528-40. transplantation. Med J Austr. 1999;170:368-70.

69. Tyden G, Bolinder J, Solders G, et al. Improved survival 85. Van Winter J, OgburnJr P, Ramin K, et al. Pregnancy after
8

in patients with insulin-dependent diabetes mellitus and pancreatic renal transplantation because of diabetes: case
end-stage diabetic nephropathy 10 years after combined report. Mayo Clinic Proc. 1997;72:1044-7.
86. Skannal D, Miodovnik M, Dungy-Poythress L, et al. Suc-
pancreas and kidney transplantation. Transplantation.
cessful pregnancy after combined renal-pancreas trans-
1999;67:645-8.
plantation: a case report and literature review. Am J Perina-
70. Larson J, Larson C, hirst K, et al. Lipid status after combined
tol. 1996;13:383-7.
pancreas-kidney transplantation and kidney transplanta-
87. Pahl M, Vaziri N, Kaufman D, et al. Childbirth after renal
tion alone in type 1 diabetes mellitus. Transplantation.
transplantation. Transplant Proc. 1993;25:2727-31.
1992;54:992-6. 88. Navarro M, Perez R, del Castillo D, et al. SPKT compared
71. Henley S, Akhter J, Stratta R, et al. Lipids increase after with kidney transplant in type 1 diabetic patients with
solitary pancreas transplantation. Diabetes Care. 1999;22: ESRD. Transplant Proc. 2002;34:204-5.
320-7. 89. Cheung A, Sutherland D, Gillingham K, et al. SPKT versus
72. Hughes TA, Gaber AO, Amiri HS, et al. Lipoprotein compo- KAT in diabetic patients. Kidney International. 1992;41:
sition in insulin-dependent diabetes mellitus with chronic 924-9.
renal failure: effect of kidney-pancreas transplantation. 90. Lee C, Scandling J, Krieger N, et al. Outcomes in diabetic
Transplant Proc. 1994;26:500. patients after SPKT versus KAT. Transplantation. 1997;64:
73. Knight R, Schazner H, Guy S, et al. Impact of kidney-pan- 1288-94.
creas transplantation on the progression of peripheral vas- 91. Douzdjian V, Rice J, Gugliuzza K, et al. Renal allograft and
cular disease in diabetic patients with ESRD. Transplant patient outcome after transplantation: pancreas-kidney
Proc. 1998;30:1947-9. versus kidney alone transplants in type 1 diabetic patients
74. Morrissey P, Schaffer D, Madras P, et al. Progression of versus kidney alone transplant in non-diabetic patients.
peripheral vascular disease after combined kidney-pancre- Am J Kidney Dis. 1996;27:106-16.
as transplantation in diabetic patients with end-stage renal 92. Michalak G, Czerwinski J, Kwiatkowski A, et al. Surgical
failure. Transplant Proc. 1997;29:662-3. complications observed in SPKT: thirteen years of experi-
75. Sowers J, Epstein M. Diabetes mellitus and associated ence of one center. Transplant Proc. 2002;34:661-2.
hypertension, vascular disease and nephropathy: an up- 93. Sharara A, Dandan I, Khalifeh M. Living related donor
date. Hypertension. 1995;26:869-79. transplantation other than kidney. Transplant Proc. 2001;
76. Cerami A, Vlassara H, Brownlee M. Protein glycosylation 33:2745-6.
and the pathogenesis of atherosclerosis. Metabolism. 1985; 94. Teuscher A, Seaquist E, Robertson R. Diminished insulin
34:37-44. secretory reserve in diabetic pancreas transplant and non-
77. Rocca E, Gobbi C, Ciurlino D, et al. Improvement of glu- diabetic kidney transplant recipients. Diabetes. 1994;43:
cose/insulin metabolism reduces hypertension in insulin- 593-8.
dependent diabetes mellitus recipients of kidney-pancreas 95. Battezzati A, Benedini S, Caldara R, et al. Prediction of the
transplantation. Transplantation. 1998;64:390-3. long-term metabolic success of the pancreatic graft func-
78. Pearce I, Ilango B, Sells R, et al. Stabilization of diabetic tion. Transplantation. 2001;71:1560-5.
retinopathy following simultaneous pancreas and kidney 96. Delis S, Ciancio G, Casillas J, et al. Diabetic muscle infarc-
transplant. Br J Ophthalmol. 2000;84:736-40. tion after SKPT. Clin Transplant. 2002;16:295-300.
79. Giannarelli R, Coppeli A, Sartini MS, et al. Pancreas trans- 97. Troppmann C, Gruessner A, Papalois BE, et al. Delayed
plant alone has beneficial effects on retinopathy in type 1 endocrine pancreas graft function simultaneous pancreas
diabetic patients. Diabetologia. 2006;49:2977-82. kidney transplantation. Transplantation. 1996;61:1323-30.
80. Recasens M, Ricart M, Valls-Sole J, et al. Long-term 98. Shapiro A, Lakey J, Ryan E, et al. Islet transplantation in sev-
follow up of diabetic polyneuropathy after SKPT in type 1 en patients with type 1 diabetes mellitus using a glucocor-
diabetic patient. Transplant Proc. 2002;34:200-3. ticoid-free immunosuppressive regimen. NEJM. 2000;343:
81. Caldara R, Sanseverino R, Lefrancois N, et al. Pancreas 230-8.
transplantation: long term results. Clin Transplant. 1991;5: 99. Robertson R. Islet transplantation as a treatment for
260-4. diabetes–a work in progress. NEJM. 2003;350:230.
 Transplantation in the Management of Diabetes Mellitus 709

100. Lopez-Talavera J, Garcia-Ocana A, Sipula I, et al. Hepato- 106. Citro A, Cantarelli E, Maffi P, et al. CXCR1/2 inhibition enha­
cyte growth factor gene therapy for pancreatic islets in dia- nces pancreatic islet survival after transplantation. J Clin
betes: reducing the minimal islet transplant mass required Invest. 2012;122:3647-51.
in glucocorticoid-free rat model of allogeneic portal vein 107. Groth C, Korsgren O, Tibell A, et al. Transplantation of por-
islet transplantation. Endocrinology. 2004;145:467-74. cine fetal pancreas to diabetic patients. Lancet. 1994;344:
101. Nath DS, Hering BJ. Islet cells replacement therapy. Clin 1402-4.
Lab Med. 2005;25:541-56. 108. Robertson R. Pancreatic and islet transplantation for diabe-
102. Alejandro R, Barton FB, Hering BJ, et al. 2008 Update from
tes. NEJM. 1992;327:1861-9.

chapter
the collaborative Islet Transplant Registry. Transplanta-
109. Navarro X, Kennedy W, Aeppli D, et al. Neuropathy and
tion. 2008; 86:1783-88.

46
mortality in diabetes: influence of pancreas transplanta-
103. Bellin MD, Barton FB, Heitman A, et al. Potent induction
immunotherapy promotes long-term insulin independ- tion. Muscle and Nerve. 1996;19:1009-16.
ence after islet transplantation in type 1 diabetes. Am J 110. Navarro X, Kennedy W, Loewenson R, et al. Influence of
Transplantation. 2012;12:1576-83. pancreas transplantation on cardiorespiratory reflexes,
104. Robertson PR. Islet transplantation a decade later and strat- nerve conduction and mortality in diabetes mellitus.
egies for filling a half full glass. Diabetes. 2010;59:1285-91. Diabetes. 1990;39:802-6.
105. Shapiro JAM. Strategies toward single-donor islets of
111. Modified from Egidi FM. Management of hyperglycaemia
Langerhans transplantation. Curr Opin Organ Transplant. after pancreas transplantation: are new immunosuppres-
2011;16:627-31. sants the answer? Drugs. 2005;65:153-66.
 Chapter 47
Stem Cell Therapy in
Diabetes Mellitus
Anil Bhansali

Stem Cells in Diabetes

Chapter Outline

♦♦ Animal Studies ♦♦ Mechanism of Action

♦♦ Human Studies

INTRODUCTION autopsy series showed a loss of β-cell-mass by 40% in sub-

jects with impaired glucose tolerance (IGT) and by 60%
The prevalence of diabetes is rapidly increasing all over at the time of diagnosis of T2DM.7 Defects in the entero-
the globe possibly due to population growth, aging incretin-insulin axis entail another facet in the patho-
(increased life expectancy) and increasing prevalence genesis of T2DM, where therapeutic interventions can be
of obesity and sedentary lifestyle. As per an estimate by targeted.8 Although there are effective options available to
the International Diabetes Federation at least 382 million target insulin resistance and incretin defects,7,8 effective
people are affected by diabetes and this number is likely therapeutic modalities targeting β-cell dysfunctions are
to grow to 592 million by the year 2035.1 India houses lacking. Early intensive insulin therapy,9 rosiglitazone10
62.4 million people with diabetes and an almost equal and possibly dipeptidyl peptidase IV (DPP-IV) inhibitors
number with prediabetes contributing almost one-fifth of and glucagon-like peptide-1 (GLP-1) analogs11 have been
the world diabetic population.2 demonstrated to have some beneficial effects on β-cell
Type 2 diabetes mellitus (T2DM) is characterized by function.
two defects: (1) insulin resistance; and (2) insulin defi­ Irrespective of the type of diabetes, the current focus
ciency. However, insulin resistance alone cannot produce is to target β-cell dysfunction and/or mass to achieve
T2DM unless β-cells fail to compensate.3 Moreover, insulin the cure of diabetes. Islet cell transplantation is a viable
resistance remains fairly constant after evolution of diabe- option and has been successfully performed with insulin
tes in a given individual, while β-cell mass and function independence in initial years in majority of diabetic
progressively declines with advancing duration of disease patients.12 However, limited availability of donors, progres­
as evidenced by United Kingdom Prospective Diabetes sive decline in insulin independence and graft rejection
Study (UKPDS).4 The functional defects resulting from are major limitations of this therapy.13 Stem cells, which
dual glucotoxicity and lipotoxicity are reversible upon cor- have the ability to differentiate into insulin producing cells
rection of respective metabolic abnormalities. However, either in-vitro14 or in-vivo,15 would provide a potentially
islet abnormalities that are observed with advancing dura- unli­mited source of islet cells for the treatment and
tion of T2DM including pseudohypertrophy of islets with alleviation of the major limitations of availability and
reversal of β/α-cell ratio and progressive interstitial fibro- rejection of allogeneic pancreatic islets.16 Therefore, there
sis as a result of amylin deposition are irreversible.5,6 An is a growing interest in cell-based therapies.
 Stem Cell Therapy in Diabetes Mellitus 711

Bone marrow is an important source of adult stem HUMAN STUDIES

cells enriched with hematopoietic stem cells (HSCs) and
mesenchymal stem cells (MSCs). Although HSCs are in Voltarelli et al.27 studied the effect of HSCs in non-
abundance in bone marrow, they have limited proliferative myeloablative state in patients with Type 1 diabetes
and restricted capacity. MSCs are multipotent and can mellitus (T1DM) who had duration of disease less than
differentiate into bone, cartilage, fat and connective tissue 6 weeks and without ketosis. Sixteen out of seventeen
and also have anti-inflammatory and immunomodulatory patients became insulin independent with significant

chapter
properties.17 The endoderm germ layer is responsible for increase in C-peptide. Another study from China, showed

47
pancreatic endocrine regeneration and differentiation,18-21 the beneficial effect of umbilical cord derived MSCs in
hence the MSCs may enrich islet b-cell mass. Moreover, T1DM. However, there are very limited number of studies
the MSCs are hypoimmunogenic as compared to HSCs, in T1DM, with limited number of patients and short
which decreases the probability of allogeneic rejection, duration of follow-up. Very few studies have examined the
thereby providing an opportunity to administer these cells utility of bone marrow derived stem cell transplantation
even without prior irradiation. Other sources of stem cell for the treatment of T2DM in humans. A previous study
are umbilical cord and embryonic stem cells. Although by Estrada et al. showed that the combined use of auto­
cells of their origin are pluripotent, highly proliferative and logous bone marrow derived stem cell infusion into the
capable of unrestricted lineage, they also have potential for dorsal pancreatic artery and hyperbaric oxygen (HBO)
malignant transformation. Moreover, certain ethical and therapy resulted in a significant reduction in fasting pla­
ethnic issue dampens their usefulness in clinical practice. sma glucose and insulin doses and increase in C-peptide
levels at the end of 1 year.28 The authors hypothesized
ANIMAL STUDIES that the infused stem cells led to the differentiation of
the local progenitor cells and decreased inflammation
Studies both with HSCs and MSCs have shown encoura­ in the pancreas which was augmented by HBO therapy.
ging results in animals. These studies showed that there However in this study, there was no placebo arm and the
was an improvement in the glucose profile and develop­ recruited patients had varying degree of glycemic control
ment of new islets on histology.22,23 Banerjee et al.24 used and were receiving different antidiabetic medications.
HSCs in streptozotocin (STZ) induced diabetic wistar rats Moreover, the follow-up data was available for only one-
and demonstrated that there was a significant reduction third of the patients at the end of 1 year. Another study
in blood glucose level and islet neogenesis. Azab et al.25 by Wang et al.6 used combined ability for basic move­
used the HSCs and MSCs derived from human bone ment scale for children type T (ABMSCT) and HBO in 31
marrow and injected separately in alloxan induced dia­ patients of T2DM and showed a decrease in hemoglobin
betic rats. They demonstrated that there was a significant A1c (HbA1c) of more than 1.5% as quickly as 1 month after
alleviation of blood glucose level and transdifferentiation therapy which was maintained over the study period of 1
of few MSCs into insulin producing cells. As expected, year.29 The C-peptide increased significantly at 3 months
the MSCs are likely to have a better outcome than HSCs but declined to baseline at 1 year. The author concluded
because of their multipotency, higher proliferative that the combined ABMSCT and HBO therapy led to
capacity and less restricted lineage. However, the overall improvement in glucose control, decrease in requirement
outcome was more favorable in the HSCs group than in of insulin and oral hypoglycemic agents and a transient
the MSCs in the study, possibly because of various growth improvement in β-cell function.29 In a recent study,
factors along with the fact that HSCs may incite residual Hu et al. demonstrated the long-term efficacy and safety
β-cells. Our study showed significant reduction in blood of autologous bone marrow mononuclear cells (ABMNC)
glucose level after administration of allogeneic MSCs into in comparison to intensive insulin therapy in patients
the diabetic rat model. However, a rising trend in blood with T2DM.30 One-hundred and eighteen patients
glucose level was observed after 3 weeks of stem cell were followed up for a period of 33 months and showed
transplantation, as has also been shown by others.25 This ABMNC group could achieve significantly lower HbA1c
can be attributed to glucotoxicity, as high glucose milieu with reduction in oral hypoglycemic drugs and insulin
may have an inhibitory effect on stem cell proliferation doses as compared to the control group on intensive
and function and possibly graft rejection.26 insulin therapy. However, the study was not appropriately
712 Management

designed as patients were open to choose their mode of or targeted needs to be determined. If targeted, which
treatment and it was not oriented with intention-to-target artery would be most favorable for use : dorsal pancreatic,
HbA1c less than 7%. Moreover, the control group was not superior pancreaticoduodenal or splenic artery? Lastly, the
appropriately matched for the operative procedure.30 In mechanism of action of the HSCs and their fate following
our previous study, (n = 10) we showed more than or equal administration needs to be studied further.
to 50% reduction in the insulin requirement from the
baseline in three-fourth of the patients with a reduction ACKNOWLEDGMENT
section

in HbA1c from 8.4 ± 0.6% to 7.3 ± 0.8% and a significant

I am thankful to Shobhit Bhansali, Ph. D fellow, for his
increase in stimulated C-peptide after ABMSCT. This
8

contribution to this chapter particularly regarding animal

reduction in insulin requirement and the change in HbA1c
experiments with cultured MSCs.
persisted for at least 15 months in almost two-third of the
patients (unpublished observation). However, in this study
there was no placebo group, the patients had uncontrolled
Further reading
diabetes with a mean HbA1c of 8.4% at baseline and had 1. Banerjee M, Kumar A, Bhonde RR. Reversal of experi­
significant weight loss after the ABMSCT.14 Therefore, the mental diabetes by multiple bone marrow transplantation.
improvement in β-cell function was due to improvement Biochem Biophys Res Commun. 2005;328:318-25.
2. Voltarelli JC, Couri CE, Stracieri AB, et al. Autologous
in glucotoxicity and/or due to weight loss after the stem
non-myeloablative hematopoietic stem cell transplan­
cell therapy was debatable. Another study by our group tation in newly diagnosed type 1 diabetes mellitus. JAMA.
overcame the above deficits and showed that targeted 2007;297:1568-76.
administration of HSCs resulted in insulin doses reduction 3. Estrada EJ, Valacchi F, Nicora E, et al. Combined treatment
with sustained HbA1c less than 7% in 82% of patients with of intrapancreatic autologous bone marrow stem cells
significant improvement in C-peptide levels. and hyperbaric oxygen in type 2 diabetes mellitus. Cell
Transplant. 2008;17:1295-304.
4. Bhansali A, Upreti V, Khandelwal N, et al. Efficacy of
MECHANISM OF ACTION
autologous bone marrow-derived stem cell transplantation
The mechanism of action of stem cell therapy remains in patients with type 2 diabetes mellitus. Stem Cells Dev.
elusive, the possible proposed mechanisms for improve­ 2009;18:1407-16.
5. Azab NI, Al Kholy AF, Salem RF, et al. Comparison bet­ween
ment in β-cell mass or function include: (1) Secretion of
bone marrow derived mesenchymal stem cells and hema­
various growth factors which may promote angiogenesis topoietic stem cells in: B-Islet Transdifferen­tiation. Stem
and stimulate resident stem cells in the pancreatic duct Cell. 2011;2:1-10.
to differentiate into islets; (2) Transdifferentiation into 6. Wang L, Zhao S, Mao H, et al. Autologous bone marrow
β-cells; and (3) Pancreatic and duodenal homeobox 1 stem cell transplantation for the treatment of type 2
(PDX-1) upregulation, thereby enhancing islet diffe­ diabetes mellitus. Chin Med J (Engl). 2011;124:3622-8.
7. Hu J, Li C, Wang L, et al. Long-term effects of the implan­
rentiation.31-33 Recently, Si et al. demonstrated that MSC’s
tation of autologous bone marrow mononuclear cells for
infusion in STZ induced type 2 diabetic rat not only type 2 diabetes mellitus. Endocr J. 2012;59:1031-9.
promoted β-cell function but also ameliorated insulin 8. Si Y, Zhao Y, Hao H, et al. Infusion of mesenchymal
resistance by enhancing the glucose transporter type 4 stem cells ameliorates hyperglycemia in type 2 diabetic
(GLUT-4) expressions and increasing insulin receptor rats: identification of a novel role in improving insulin
substrate-1 (IRS-1) and protein kinase B expression in sensitivity. Diabetes. 2012;61:1616-25.
insulin target tissues.
ReferenceS
CONCLUSION
1. International Diabetes Federation's Diabetes Atlas (2013).
Stem cell therapy holds great promise for the treatment Sixth Edition. Brussels: International Diabetes Federa-
of diabetes. It is a novel approach targeting b-cell tion. Available from http://www.idf.org/sites/default/files/
dysfunction and/or mass. Although the available data EN_6E_Atlas_Full_0.pdf. Accessed on 29.04.2014
2. Holman RR. Assessing the potential for alpha-glucosidase
is very encouraging, several important issues remain
inhibitors in prediabetic states. Diabetes Res Clin Pract
unresolved. Firstly, the number of HSCs required to have 1998;40:S21-25
a sustained effect needs to be ascertained. Secondly, the 3. Diagnosis and classification of diabetes mellitus. Diabetes
appropriate route of administration, whether peripheral Care. 2012;35:S64-71.
 Stem Cell Therapy in Diabetes Mellitus 713

4. Reaven GM. HOMA-beta in the UKPDS and ADOPT. Is the marrow without evidence of cell fusion. J Clin Invest.
natural history of type 2 diabetes characterised by a pro- 2003;111:843-50.
gressive and inexorable loss of insulin secretory function? 20. Yin D, Tao J, Lee DD, et al. Recovery of islet beta-cell func-
Maybe? Maybe not? Diab Vasc Dis Res. 2009;6:133-8. tion in streptozotocin-induced diabetic mice: an indirect
5. Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and role for the spleen. Diabetes. 2006;55:3256-63.
alpha-cell expansion in patients with type 2 diabetes mel- 21. Oh SH, Muzzonigro TM, Bae SH, et al. Adult bone marrow-
litus in Korea. J Clin Endocrinol Metab. 2003;88:2300-8. derived cells trans-differentiating into insulin-produc-
6. Janson J, Ashley RH, Harrison D, et al. The mechanism of ing cells for the treatment of type I diabetes. Lab Invest.

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islet amyloid polypeptide toxicity is membrane disruption 2004;84:607-17.

47
by intermediate-sized toxic amyloid particles. Diabetes. 22. Gao X, Song L, Shen K, et al. Transplantation of bone mar-
1999;48:491-8. row derived cells promotes pancreatic islet repair in diabet-
7. Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit ic mice. Biochem Biophys Res Commun. 2008;371:132-37.
and increased beta-cell apoptosis in humans with type 2 23. Si Y, Zhao Y, Hao H, et al. Infusion of mesenchymal stem
diabetes. Diabetes. 2003;52:102-10. cells ameliorates hyperglycemia in type 2 diabetic rats:
8. Drucker DJ. The biology of incretin hormones. Cell Metab. identification of a novel role in improving insulin sensi­
2006;3:153-65. tivity. Diabetes. 2012;61:1616-25.
9. Li Y, Xu W, Liao Z, et al. Induction of long-term glycemic 24. Banerjee M, Kumar A, Bhonde RR. Reversal of experimen-
control in newly diagnosed type 2 diabetic patients is as- tal diabetes by multiple bone marrow transplantation. Bio-
sociated with improvement of beta-cell function. Diabetes chem Biophys Res Commun. 2005;328:318-25.
Care. 2004;27:2597-602. 25. Azab NI, Al Kholy AF, Salem RF, et al. Comparison Bet­
10. Kahn SE, Haffner SM, Heise MA, et al. Glycemic dura­bility ween Bone Marrow Derived Mesenchymal Stem Cells and
of rosiglitazone, metformin, or glyburide monotherapy. Hematopoietic Stem Cells in B-Islet Transdifferentiation.
N Engl J Med. 2006; 355:2427-43. Stem Cell. 2011;2:1-10.
11. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipepti- 26. Eizirik DL, Korbutt GS, Hellerstrom C. Prolonged expo-
dyl peptidase-4 with a sitagliptin analog preserves pancre- sure of human pancreatic islets to high glucose concentra-
atic beta-cell mass and function in a rodent model of type 2 tions in vitro impairs the beta-cell function. J Clin Invest.
diabetes. Diabetes. 2006;55:1695-704. 1992;90:1263-68.
12. Shapiro AM, Ricordi C, Hering BJ, et al. International trial 27. Voltarelli JC, Couri CE, Stracieri AB, et al. Autologous non-
of the Edmonton protocol for islet transplantation. N Engl J myeloablative hematopoietic stem cell transplantation
Med 2006;355:1318-30. in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;
13. Halban PA, German MS, Kahn SE, et al. Current status of 297:1568-76.
islet cell replacement and regeneration therapy. J Clin En- 28. Estrada EJ, Valacchi F, Nicora E, et al. Combined treatment
docrinol Metab. 2010;95:1034-43. of intrapancreatic autologous bone marrow stem cells and
14. Bhansali A, Upreti V, Khandelwal N, et al. Efficacy of au- hyperbaric oxygen in type 2 diabetes mellitus. Cell Trans-
tologous bone marrow-derived stem cell transplantation plant. 2008;17:1295-304.
in patients with type 2 diabetes mellitus. Stem Cells Dev 29. Wang L, Zhao S, Mao H, et al. Autologous bone marrow
2009;18:1407-16. stem cell transplantation for the treatment of type 2 diabe-
15. Shi Q, Luo S, Jin H, et al. Insulin-producing cells from hu- tes mellitus. Chin Med J (Engl). 2011;124:3622-8.
man adipose tissue-derived mesenchymal stem cells de- 30. Hu J, Li C, Wang L, et al. Long term effects of the implan-
tected by atomic force microscope. Appl Microbiol Biotech- tation of autologous bone marrow mononuclear cells for
nol. 2012;94:479-86. type 2 diabetes mellitus. Endocr J. 2012;59:1031-9.
16. Zhu D, Chen L, Hong T. Position Statement of the Chinese 31. Bell GI, Meschino MT, Hughes-Large JM, et al. Combinato-
Diabetes Society regarding stem cell therapy for diabetes. rial human progenitor cell transplantation optimizes islet
J Diabetes 2012;4:18-21. regeneration through secretion of paracrine factors. Stem
17. Ryan JM, Barry FP, Murphy JM, et al. Mesenchymal stem Cells Dev. 2012;21:1863-76.
cells avoid allogeneic rejection. J Inflamm (Lond) 2005;2:8. 32. Cheng H, Zhang YC, Wolfe S, et al. Combinatorial treatment
18. Tang DQ, Cao LZ, Burkhardt BR, et al. In vivo and in vitro of bone marrow stem cells and stromal cell-derived factor 1
characterization of insulin-producing cells obtained from improves glycemia and insulin production in diabetic mice.
murine bone marrow. Diabetes 2004;53:1721-32. Mol Cell Endocrinol. 2011;345:88-96.
19. Ianus A, Holz GG, Theise ND, et al. In vivo derivation of 33. Deans RJ, Moseley AB. Mesenchymal stem cells: biology
glucose-competent pancreatic endocrine cells from bone and potential clinical uses. Exp Hematol. 2000;28:875-84.
Section 9

COMORBID CONDITIONS
Section Editor: Hemraj B Chandalia
 Chapter 48
Comorbid Conditions in
Diabetes Mellitus
Hemraj B Chandalia

Comorbid Conditions

Chapter Outline
♦♦ Definition and Significance of Comorbid Conditions ♦♦ Hyperuricemia
♦♦ Tobacco Abuse ♦♦ Hyperhomocysteinemia
♦♦ Obesity

DEFINITION AND SIGNIFICANCE OF association with coronary heart disease (CHD), but the
COMORBID CONDITIONS intervention data are limited.1 Con­trol of diabetes was
often considered class II intervention earlier, but evide­
Over a period of time, diabetes takes a serious toll on nces of benefits from glycemic control are now well
microvasculature and macrovasculature. Hence, those documented.2,3 Considering these facts, recognition and
risk factors that are known to have an on the vascular management of comorbid conditions becomes a very
system are extremely important to be recognized and important strategy. Hypertension and high LDL-chole­
addressed. There are a series of markers of vascular sterol are two risk factors, where the poor clinical outcome
disease being studied aggressively at present. A study of
is so obvious in the absence of intervention. In a situation
these markers has a predictive value in the emergence
like diabetic nephropathy, the preeminence of the con­
of vascular disease. Hence, these are also viewed as com­
trol of hypertension over that of control of diabetes is
orbid conditions. In essence, study of these comorbid
well documented.4
conditions lends addi­ tional depth to patient’s clinical
Diabetes mellitus has been considered a multisystem
evaluation, making it truly comprehensive.
disease. In earlier times, syphilis, and later, hepatitis B
The importance of some comorbid conditions even
supersedes the importance of metabolic control of and acquired immunodeficiency syndrome (AIDS) have
diabetes. For example, looking from the viewpoint of held similar status. Hence, evaluation of a patient with
coronary artery disease, management of hypertension, diabetes without good attention to all organ systems is
increased levels of low-density lipoprotein (LDL) considered a poor strategy. In-depth study and control of
cholesterol and tobacco abuse are considered class I comorbid conditions is an important strategy for a success­
interventions because the benefits of such interventions ful long-term outcome in diabetes.
have been adequately documented. Control of high- This chapter discusses tobacco abuse, obesity, hyper­
density lipoprotein (HDL) cholesterol, triglycerides, uricemia and hyperhomocysteinemia as comorbid condi­
physical inactivity and obesity are considered class II tions. Other important comorbid conditions; hyper­tension
interventions because they appear to have strong causal and dyslipidemia are discussed elsewhere.
718 Comorbid Conditions

TOBACCO ABUSE Table 48.1: Health hazards of tobacco abuse14

It is a very important risk factor, which is often dutifully Premature death Deaths in the year 2000

recorded in the patient history. However, a planned Total number 4.8 million
action to combat this menace is seldom initiated. In • Deaths due to cardiovascular disease 1.7 million
India, besides tobacco smoking, chewing tobacco and • COPD 1.0 million
use of tobacco snuff and paste is rampant. In this form, • Lung cancer 0.9 million
the addiction also affects lot of females. Prevalence of Risk as compared to non-smokers
section

tobacco use has been reported in a few large studies. The • Fatal heart disease 2 times
9

National Sample Survey Organization, presently known • Lung cancer 10 times

as National Sample Survey Office, (NSSO) reported in • Strokes 2–3 times
1993–1994 that 51.3% males and 10.3% females were regu­ • Acid peptic ulcer 2–3 times
lar tobacco users. Smoking was the common modality of • Cancer of mouth, esophagus, throat
tobacco consumption in males while smokeless tobacco peripheral vascular disease 2 times
(zarda) use was common amongst females.5 The National • Breast cancer, osteoporosis Increased
Family Health Survey (NFHS) reported a prevalence of (COPD: Chronic obstructive pulmonary disease).
tobacco use in 46.5% of males and 13.8% of females in
1998–1999.6 A good diabetes center must also incorporate
a good tobacco cessation program. Cigarette smoking At each follow-up visit, status of tobacco habit should
has been shown to increase the prevalence of diabetes. be reviewed. Those patients who succeed in quitting
Men smoking more than or equal to two packs per day should be congratulated. Those who fail in their attempts
had 45% increase and women 74% increase in diabetes as should be encouraged to learn the cause of failure and try
compared to those who never smoked.7 Quitting smoking again with a different strategy. Another tobacco user in the
restored the prevalence to that of non-smokers after family reduces the chances of success, so also the alcohol
5 years in women and 10 years in men. Another meta- habit, which is often associated with tobacco abuse. Use of
analysis showed a dose response relationship of smoking inadequate dosage of nicotine replacement therapy is also
and prevalence of type 2 diabetes, with a relative risk associated with failure.15,16 Benefits of cessation, even at an
(RR) of 1.61 in heavy smokers (≥ 20 cigarettes/day) and advanced age have been well documented and can serve
1.23 in lighter smokers.8 The Nurses’ Health Study also as a motivational force.17 Those having low consumption
showed similar dose-response relationship.9 Smoking of tobacco or those suffering from acute vascular problem,
aggravates insulin resistance and thus causes clustering such as acute coronary syndrome or peripheral vascular
of cardiovascular risk factors.10 Adiposity and smoking occlusion, may decide to discontinue tobacco use abruptly
increased mortality 5–6 times in a concerted manner.11 without any assistance. This method is called “cold turkey”
Smoking increases the ischemic heart disease risk in and is quite successful, at least temporarily. It needs to
women with type 2 diabetes.12 In China, the leading causes be reinforced in order to prevent relapse. Patients also
of death attributable to smoking were cancer (268,200), need supportive treatment for combating constipation,
cardiovascular disease (146,200) and respiratory disease nervousness or insomnia.
(66,800).13 It is important to appreciate the morbidity Nicotine replacement in de-escalating dosage is often
and mortality associated with tobacco abuse, as this may the key to success and its use should be encouraged in all
need to be emphasized during the motivational phase of tobacco users except those with very low consumption.
a cessation program. A few hazards of tobacco abuse are Contraindications to nicotine replacement are pregnancy,
presented in Table 48.1.14 ischemic heart disease and peripheral vascular disease.
Nicotine patches can be used in low tobacco consumers
Tobacco Cessation Strategies while chewing gum or nasal spray should be used in heavy
In order to help patients quit tobacco abuse, all tobacco tobacco consumers. Patches are used in dosage of about 1
users should be systematically identified at each visit and mg/hr initially and reduced every 1–2 weeks, over a period
strongly urged to quit tobacco use. Those willing to quit of 8 weeks to a dose of 5–8 mg/16 hr (waking hours). At
should then be identified and systematic help should be this stage, total cessation is easy. Local skin reactions are
offered to them. Literature related to cessation strategies common but can be minimized by rotating application
should be available in the clinic. sites or using a steroid cream locally. Nicotine gum is
 Comorbid Conditions in Diabetes Mellitus 719

available as 2 or 4 mg per piece preparation. Initially, a The prevalence of obesity in Indian adults has been
2 or 4 mg piece per 2 hours may be required. This should reported by the Second National Family Health Survey
be reduced over the next eight weeks. The gum should be (NFHS-2).24 The prevalence varied in different states of
chewed till a “peppery” taste is experienced; thereafter, it India from as low as 4–6% in Bihar and Orissa to as high
should be parked in the buccal cavity for about 30 minutes. as 30–35% in Punjab and Delhi. Higher prevalence of
Side effects like local soreness and dyspepsia can occur. obesity was associated with greater prosperity.
Another useful drug is an antidepressant, bupropion. A series of studies from the years 1994–2004 from

chapter
It is used as a slow release preparation of 150–300 mg/day Rajas­than, India, over a decade have demonstrated the

48
orally. It raises the intracerebral levels of dopamine and rise in the prevalence of obesity and rural-urban differ­
noradrenaline, much like the action of nicotine. Usually ences.13-16 The prevalence in urban areas was high and
the drug is administered for 1–6 months, with a decision to over the course of a decade, BMI in young adults (20–29
quit tobacco after 2–4 weeks. This drug is contraindicated year age) increased from 21.1 ± 3.9 to 25.68 ± 11.1 and
in those with a history of seizures. Combining nicotine in older people (50–59 year age) from 23.2 ± 5.7 to 27.8
patch and sustained-release bupropion can achieve 1-year ± 4.5 kg/m2. At the age of 50–59, 29.4% were overweight
quit-rate of 35%.18 (BMI > 25 kg/m2) and 7.6% obese (BMI > 30 kg/m2) in 1995
Weight gain is a common side effect of tobacco cessa­ while 82.3% were overweight and 32.4% were obese in the
year 2004.
tion. Combined use of nicotine and bupropion minimizes
A school-based study of adolescent children from Delhi
weight gain. This is an important side effect in patients
revealed an increasing secular trend of overweight and
with type 2 diabetes where obesity is a common comorbid
obese children from Delhi. The prevalence of overweight
condition. Hence, a simultaneous intensification of diet
increased over a period of 3 years (2006–2009) from 24.2%
and exercise program is important component of a tob­
to 25.2% (P = 0.280, P = NS) and obesity increased from
acco cessation program.
9.8% to 11.7% (P < 0.001) in the same period.25

OBESITY Definition and Diagnosis

Epidemiology Obesity is defined as an excess of adiposity. As it is
difficult to determine the amount of body fat or body fat
Obesity is a highly prevalent disorder, commonly asso­
percent by simple clinical methods, various surrogate
ciated with type 2 diabetes. The prevalence of obesity is on
parameters have been utilized. BMI has been the most
the increase, mainly in the past two decades. Data from
widely used parameter (Table 48.2). However, it does
the National Health and Nutrition Examination Surveys
not reflect accurately the degree of adiposity, because
(NHANES) reveal an increase in obesity [body mass index
body weight can be constituted by excess adipose tissue
(BMI) > 30 kg/m2] from 14.5% to 30.5% over a period of
or muscle mass. To overcome this drawback, a simple
about 2 decades from 1980 to the year 2000.19,20 Prevalence
waist measurement or waist-to-hip ratio is used clinically.
of overweight (BMI > 25 kg/m2) was very high in the year Normal values are presented in Table 48.3. It is obvious
1999–2000, as 64% of adults in USA were overweight.20 that if there is an increase in both the waist and hip
Commensurate with the rapid rise of obesity, a dramatic circumferences, the waist-to-hip ratio may not be altered.
30–40% increase in the prevalence of type 2 diabetes was Hence, an absolute waist circumference measurement or
observed between the years 1990 and 2000. Furthermore, a sagittal diameter of waist (vertical distance between bed
a distressing rise in the prevalence of obesity has been and top of abdomen in supine position) should be used.
reported in childhood, together with the advent of type 2 Abdominal fat, either intra-abdominal or extra-abdominal
diabetes in childhood. In USA, more than 50% of children produces more insulin resistance and predisposes to
are either overweight or obese.21 In the USA, prevalence of cardiovascular disease as compared to the fat in the lower
obesity in children 6–11 years of age doubled between the (gluteofemoral) part of the body. It has been demonstrated
two NHANES studies in about two decades. In Japan, the that Asian Indians have greater amount of body fat than
situation is not as grim, but obesity doubled from 5% to Caucasians for a given BMI; thus, the body fat percentage
10% between 1974 and 1993.22 In India, obesity has been in Caucasians with BMI of 25 kg/m2 has been found to be
described in 18.3% of school children especially from equal to the percent body fat in Asian Indians with a BMI
affluent communities23 and emergence of type 2 diabetes of 23 kg/m2.26 Hence, the BMI of 23 kg/m2 is used as a
in childhood is expected to occur rapidly in India. cut-off point in the Asian Indians.
720 Comorbid Conditions

Table 48.2: Body mass index [weight (kg)/height (m2)] Table 48.3: Assessment of truncal obesity
Caucasians Asian Indians Males Females
Underweight < 20 < 18 Waist
Normal 20–24.9 18–22.9 • Caucasians ≥ 102 cm ≥ 88 cm
• Indians ≥ 90 cm ≥ 80 cm
Overweight ≥ 25 ≥ 23
Waist-to-hip ratio ≥1 ≥ 0.8
Obese ≥ 30 ≥ 25
Sagittal diameter
section

• Caucasians ≥ 32 cm ≥ 28 cm
• Indians ≥ 29 cm ≥ 25 cm
9

The most accurate measurement of body fat is made

by studying body composition by classic methods. For
example, body water can be determined by underwater environmental influences. The environmental factors are
weighing and lean and fat body compartments estimated well described and continue to escalate inspite of being
by using deuterium or tritiated water. The next accurate countered constantly in media headlines. These are high
method to measure body fat is that by skin-fold measure­ caloric intake mainly as fats, use of refined carbohydrates
ments at suitable sites both on the body trunk and on and low fiber foods, physical inactivity and mental stress.
limbs. Determination of percent body fat by bioimpe­ Genetic factors are very obvious in rare cases of mono­
dance method is not very reliable, but used clinically genic diseases due to gene mutations, such as mutations
because of the ease of its use. Body composition can be of leptin or leptin receptor gene, prohormone convertase
studied by using dual-energy X-ray absorptiometry gene 1 (PC-1), pro-opiomelanocortin gene and melano­
(DEXA), which gives estimates of body fat percent more cortin-4 receptor gene.
accurately than bioimpedance method.
The measurements of truncal fat have been further Environmental Factors
partitioned into intra-abdominal and extra-abdominal
Nutritional
compartments. These measurements are carried out by
a single or multiple CT or MRI images of the truncal area, Overnutrition is part of an environmental problem leading
and either a calculation of adipose tissue surface area by to obesity. During certain phases of life, where nutrition
planimetry or a calculation of fat volume by a three-dimen­ is enhanced and physical activity declines, onset of
sional reconstruction of multiple images is undertaken. obesity is precipitated. This can occur in children at the
Some additional clinical parameters have been pro­ time of examinations and women during pregnancy. The
posed to bring out the presence of truncal obesity. Total convalescent phase of any major illness can be associated
body weight divided by the abdominal girth is one such with obesity, because physical activity may not commence
parameter. A summed value of skin-fold thickness over the while increased caloric intake occurs. Post-enteric fever
trunk area (subscapular, suprailiac) gives some estimate and post-hepatitis obesity is still seen in the developing
of truncal obesity. The ratio of truncal skinfold thickness world. Physical inactivity increases with acculturation and
to limb skinfold (triceps, biceps, thigh) thickness gives urbanization. Although the calories expended in physical
further insight into the distribution of body fat. activity are not very large, the small energy imbalance so
caused can result in slow weight gain.
Etiology
Energy Balance in Health and Disease
The basic causes of obesity are genetic, environmental
The basic equation of thermodynamics dictates that in a
and hormonal.
person in energy balance, the intake and expenditure are
equal. Although this equation is inviolable, unknown and
Genetic Factors
known alterations in metabolism can result in weight gain
The basic etiology of the common form of obesity is a on a comparatively normal or moderately low calorie diet.
complex interaction of multiple genes and environment. This has always been enigmatic, but several possibilities
There are multiple susceptibility genes, which either are being explored to explain this phenomenon. It is
express directly through various hormones and enzymes possible that the intake is under-reported by obese
to produce obesity or their expression is enhanced by the subjects on a dietary recall.27 The energy expenditure has
 Comorbid Conditions in Diabetes Mellitus 721

a small component, called thermic effect of meal, which A large number of psychotropic drugs especially
is described to be low in obese subjects.28 Exercise also antidepressants produce weight gain. This includes
produces a thermic effect, which could be impaired in olanzapine, clozapine and venlafaxine.
obese subjects.29 In the metabolic pathways, there are
certain wasteful pathways, which may be hypoactive in Hormonal Factors
obesity, thus allowing them to accumulate energy. The
These are often invoked by the clinicians and patients alike
coupling and decoupling of oxidative phosphorylation

chapter
in the causation of obesity but are rarely responsible for
is governed by certain enzymes. Polymorphisms and
moderate-to-severe obesity. Hypothyroidism is a common

48
impaired activity of uncoupling proteins have been shown
disease. It causes marginal weight gain, rarely exceeding
in obese subjects.
5 kg. Subclinical hypothyroidism can also cause weight
A potential role of gut microbiome has been recognized
gain and hence, forms an indication for treating subclinical
recently.30 The obesogenic microbes are able to harvest
disease. Hypercortisolism induced by exogenous cortico­
additional energy from the fermentation of unutilized
steroids or endogenous secretion (Cushing’s syndrome)
polysaccharides in the bowel, generating monosa­
also causes borderline weight gain of 2–5 kg due to excess
ccharides and short chain fatty acids. These microbes
adipose tissue and edema. Biochemical abnormalities in
may also regulate host genes in a manner that promotes
steroidal pathways, like an excess of 11β-hydroxysteroid
deposition of fat in the host adipose tissue.31 Obese
dehydrogenase type 1 (11βHSD-1) has recently been
subjects have enriched flora of Lactobacillus reuteri and
described as an important anomaly in obesity. It
are depleted in the flora of Bifidobacterium animalis and
amplifies the glucocorticoid concentration in liver and
Methanobrevibacter smithii.32
adipose tissue by converting 11-keto steroids into active

The caloric equivalent of weight gain is 7,000 kcal for
glucocorticoids.37
each kilogram. Thus, a positive balance of 50 kcal/day
The most important endocrine obesity is seen
will result in a slow and imperceptible weight gain of
in-patients of insulinoma. The weight gain can be grossly
more than two kilograms in each year. Similarly, a small
excessive in this situation. However, insulinomas or
negative balance can result in substantial weight loss over
similar disorders, like nesidioblastosis, are extremely rare
the years.
causes of obesity.
Medications
Pathophysiology
A variety of drugs can induce obesity. Corticosteroids
uniformly cause weight gain, while oral contraceptives do
Insulin Resistance
so in some women. The treatment related weight gain in Excess of adipose tissue confers a state of insulin resis­
patients with diabetes has been seriously discussed in the tance in obesity. There has always been a debate whether
literature.3,33-35 However, the weight gain connected with insulin resistance or obesity, which of the two, is the
insulin, and sulfonylurea therapy is related to the weight primary event. In a group of 12 obese subjects, weight loss
loss occurring in the pre-treatment period.36 It occurs was induced by a hypocaloric diet. Serum insulin levels
because the body weight moves towards its set point. The dropped on weight reduction, but when the subjects were
only drugs that can disturb the set point in diabetes and refed for three days before post-weight-loss testing, the
result in inordinate weight gain are thiazolidinediones. It insulin levels were similar to the pretreatment levels.38
is possible that this is determined genetically, as genetic The same phenomenon was observed in a group of eight
polymorphism has been shown in animals exhibiting obese, impaired glucose tolerance subjects. This proves
excessive weight gain with thiazolidinediones. However, the point that insulin resistance is a primary abnormality.
most treated patients exhibit weight gain with these com­ Recently, the relationship of obesity and insulin resistance
pounds, which is a major drawback of these drugs. The was further dissected by studying insulin resistance in
weight gain with thiazolidinediones has been ascribed to non-obese, non-diabetic individuals. Asian Indians were
an accelerated recruitment of preadipocytes to adipocytes, shown to have insulin resistance even when non-obese.39
a process likely to result in improved insulin sensitivity. This resistance is associated with polymorphism of
The fat deposition is also described to be in the limbs and ENPP1 (also known as PC-1) gene.40 These seminal obser­
not truncal, but these facts need wider documentation. vations prove that insulin resistance is the primary event.
722 Comorbid Conditions

In clinical practice, obesity and insulin resistance appear On administration of hypocaloric diets, the weight
to coexist in most of the patients. loss usually occurs in a step-ladder pattern, the plateaus
It is not only the quantity of adipose tissue but also are usually due to water retention. At times, a plateau
the dysfunction of adipose tissue that causes insulin persists for a long time because with weight loss, the caloric
resistance and cardiovascular disease.41 Adipose tissue expenditure is lowered. In these situations, a further
is an active endocrine organ. It gets inflamed in certain intensification of diet and exercise therapy is required.
situations to produce more cytokines like interleukin-6 or Very rapid weight loss can occur with starvation diets or
section

tumor-necrosis factor. This process is also associated with very low calorie diets. Without dietary re-education, there
9

a raised high sensitivity C-reactive protein (hsCRP) level, is usually a relapse and weight gain. Such rapid changes in
a marker now described to be associated with obesity, weight disrupt the metabolic processes by causing rapid
diabetes and cardiovascular disease. Leptin and resistin mobilization or accretion of fat and should be avoided.
are increased, and adiponectin is reduced in this situation. It must be added that the advent of bariatric surgery has
Increased leptin is probably caused by a state of leptin drastically altered the course of obesity.
resistance while resistin is the main hormone responsible
for insulin resistance. Adiponectin normally ameliorates Complications
insulin resistance.
Irisin, a recently characterized peptide, is encoded Obesity, without any other cardiovascular risk factors,
by FNDC 5 gene and is expressed in adipose tissue and like hypertension or high LDL-cholesterol or tobacco
skeletal muscle. The concentration in muscle is almost abuse may not be responsible for any grave cardiovascular
200-fold than that in the adipose tissue. Irisin significantly consequences. However, it is difficult to study obesity in its
expresses the uncoupling protein (UCP-1) in the muscle pure form. Extreme obesity obviously produces mechanical
and induces conversion of white adipose tissue into problems of weight-bearing joints, social unacceptability
brown adipose tissue. The presence of brown adipose and psychological problems. Most frequently, obesity is
tissue has been questioned in the adult humans in the accompanied by other risk factors (metabolic syndrome),
past but is now recognized that it is present in neck and and hence a large number of complications are associated
thorax. Brown adipose tissue contributes to non-shivering with obesity.
thermic energy expenditure due to the increased expres­ A small proportion, probably around 30% of obese
sion of UCP-1 and increased mitochondrial mass. Exercise subjects exhibit normal metabolic parameters like blood
releases irisin from the cell membrane of the skeletal glucose, lipids and blood pressure. This is labeled as
muscle which reaches adipose tissue to exert its effect.42,43 normometabolic obesity (NMO). It is not clear what
determines this state of metabolic normality, but probably
intra-abdominal fat content, physical activity level44 and
Natural History and Clinical Course
ectopic fat deposition in muscle and liver45 are different
Natural history of obesity gives an insight into the inter­ from the dysmetabolic syndrome. The genetic background
ventional strategies and treatment targets. Most obese of metabolically normal obesity may also be different
subjects go through a familiar pattern of weight trend from that of dysmetabolic obesity, as fat deposition in
throughout their lives. They are usually obese in child­ the visceral area is determined genetically.46-48 Metabolic
hood and young adult life. Their body weight is distinctly normal obesity needs longitudinal follow-up to clearly
above the ideal body weight. This weight is called desir­ establish its uncomplicated course.
able body weight for these individuals, as they maintain
it at its set-point for most part of their lives. With repeated Cardiovascular Complications
pregnancies in females or a prolonged illness in both
sexes, at times the weight settles down to a new set point In the Framingham Heart Study,49 the incidence of
higher than the desirable body weight. This is called the ischemic heart disease (IHD) increased by a factor of
settling point weight. Most obese subjects, when treated 2.4 in obese women and by a factor of 2 in obese men.
optimally, will reduce weight down to the settling point In the Nurses’ Health Study, the increased risk of IHD as
or rarely down to the desirable body weight, but almost related to obesity was found to be present (RR 3.4) but
never down to the ideal body weight. was low when adjusted for other risk factors (RR 1.9).50
 Comorbid Conditions in Diabetes Mellitus 723

Obesity is associated with left ventricular hypertrophy transporters are decreased in muscle and adipose
and increased incidence of congestive heart failure and tissue.60 On the basis of insulin clamp studies, both the
arrhythmia. Several types of lipoprotein abnormalities oxidative and non-oxidative glucose disposal have been
have been described in obesity. High triglyceride levels shown to be impaired, the latter more than the former.61
were emphasized by Albrink.51 Additionally, dense LDL Impairment of glycogen synthase activity is one of the
phenotype with low HDL-cholesterol is associated with early abnormalities.62
obesity.52

chapter

Obesity is associated with an increased prevalence of Other Complications of Obesity

48
hypertension. With the use of standard blood pressure Cholelithiasis is found more commonly in the obese sub­
cuffs, a spuriously high value is obtained. The distensible jects. The risk of gallstones is two times more in women
bladder in the cuff must cover the circumference of the with a BMI over 30 kg/m2 and seven times in those with
arm as well as 75% of the length of the arm. Increase in BMI over 45 kg/m2.63 This is probably caused by a combina­
blood pressure has been described in the obese population tion of cholesterol hypersecretion in the bile, and reduced
in massive life insurance data. The Framingham study gallbladder motility. Rapid weight loss further renders
showed twice the prevalence of hypertension in obese as the bile more lithogenic. The incidence of gallstones is
compared to non-obese subjects.49 Obesity was described markedly increased following bariatric surgery. Bile acid
as the cause of hypertension in 30% of the individuals.53 (ursodeoxycholic acid, UDCA) supplementation may be
Weight gain is associated with raised blood pressure and indicated in these situations.
weight loss has a salutary effect on the lowering of blood Obesity affects pulmonary function adversely. The
pressure. The mechanism of production of hypertension lung compliance is lowered and work of breathing incre­
in obesity is probably via insulin resistance, which is ased in obesity. There is alveolar hypoventilation with
associated with sodium retention, stimulation of the hypercarbia due to alterations in the respiratory drive.
renin-angiotensin-aldosterone system and increased Obese subjects frequently suffer from sleep-disordered
sympathetic activity. breath­ing or obstructive sleep apnea. Obstructive sleep
apnea further aggravates insulin resistance due to incre­
Obesity and Diabetes ased sympathetic activity.64 Medically as well as surgically
induced weight loss improves a large number of respira­
Obesity and diabetes are closely interrelated, as both of
tory abnormalities.65
them originate from a common pathogenetic mechanism;
that is, insulin resistance. High insulin levels and
Obesity and Cancer
insulin resistance in obesity as well as early diabetes is
well described.38,54 In fact, the triad of obesity, insulin Obesity is associated with a higher prevalence of cancer,
resistance and glucose intolerance or diabetes coexists in most notably, cancer of colon, esophagus, breast (in
the metabolic syndrome (See Chapter 49). postmenopausal women), endometrium, liver, pancreas,
In the Nurses’ Health Study, where 114,824 women gallbladder, prostate and kidney.66,67 Various mechanisms
were followed for 14 years, it was demonstrated that risk have been postulated: carcinogens released from adipose
of type 2 diabetes increases pari passu with an increase in tissue, ingestion of carcinogens together with hypercaloric
BMI.55 Distribution of body fat has independent influence diet and reduced physical activity. Dietary factors may
on the development of diabetes.56 Fasting blood glucose include increased fat content and ingestion of toxins and
increased with increasing waist-to-hip ratio.57 In USA, food additives, whose derivatives, toluene and nitrites
association of truncal obesity with diabetes has been have been shown to cause large bowel cancer.68 Increased
particularly observed in Mexican Americans. Either oxidative stress and cytokine levels may be responsible for
measured as higher subscapular to triceps skinfolds or carcinogenesis.
increased waist-to-hip ratio, upper body obesity was Obesity increases osteoarthritis of knees and hip
associated with diabetes.58 The mechanism of glucose joints. The mechanism of production of osteoarthritis is
intolerance in obesity is insulin resistance. This is induced direct weight-bearing trauma. Additionally, some syste­
mostly at the post-receptor levels; but at times at the mic mechanisms like raised cholesterol, blood glucose
receptor level, as the receptor-kinase activity is decreased or uric acid may be operative through some unknown
in obesity and diabetes.59 In these situations, the glucose mechanism.
724 Comorbid Conditions

Obesity has been associated with hyperuricemia or shown a preferential fatty acid oxidation with slow and
gout in many studies. A cross-sectional study of 73,532 prolonged exercise as compared to brisk exercises, but
women aged 30–49 showed a significant association of these data have not been uniformly reproducible.80,81
obesity with gout.69 In a Dutch study, serum uric acid
In clinical practice, a combination of aerobic and
levels were positively associated with bodyweight in men resistance exercises should be prescribed. The precautions
but not women.70 In Fiji, both the Melanesian and Asian are same as in the case of persons with diabetes under­
population showed a significant association of BMI with taking exercise. The exercises should be brought to the
section

plasma uric acid levels in both diabetic and non-diabetic target level gradually over 2–4 weeks of time. In those,
9

men and women.71 More importantly, uric acid levels rise who have never exercised before or in all subjects beyond
when obese subjects are on severely hypocaloric diets, 50 years age, a cardiovascular check-up is essential before
and this may, at times, precipitate an attack of gout. instituting a full-scale exercise program. Many obese
Obesity also affects endocrine function of several subjects suffer from osteoarthritis of knees and hip joints,
endocrine glands. Adrenocorticoid synthesis as well as so that non-weight-bearing exercises may need to be
degradation is increased, the cortisol levels and their prescribed. In urban centers in India, patients must have
diurnal variation remaining normal.72 The total growth access to at least two types of exercise options, one indoor
hormone secretion is lowered in obese subjects, with and other outdoor. In addition to a planned exercise pro­
blunting of periodic growth hormone spurts.73 The gram, incorporation of extra activities in the daily schedule
insulin-like growth factor 1 (IGF-1) levels are, however, would give better results. For example, one can use stairs
normal, probably because of its stimulation by the instead of an elevator, or walk up to a colleague instead
hyperinsulinemic state.73 Hyperinsulinemia and insulin of using an intercom.
resistance is present in obesity and has been described
above. Behavioral Therapy
Behavioral approach is a powerful tool in the management
Management of Obesity
of obesity. Eating pattern and exercise habits are learned
Nutrition Therapy behaviors, and hence can be modified. A large number
(See Chapter 31) of studies from 1970 to 1990 brought out the effect of
behavioral therapy. In most of these studies, a weight
Exercise Therapy loss of 3.8–8.5 kg occurred over 8–20 weeks of behavioral
An inverse relationship between physical activity and treatment.82 A large number of subsequent studies have
body weight has been noted as early as in 1965 in the further established the role of behavioral therapy.83-85
population of West Bengal.74 More importantly, exercise The most important components of behavioral therapy
therapy prevents relapse; subjects with reportedly low include self-monitoring, goal setting and stimulus or cue
physical activity have a three times possibility of relapse control. When applied to nutrition and exercise program,
over a 10-year year follow-up period as compared to those behavioral approaches improve the results substantially.
reportedly physically active.75 Television viewing and Self-monitoring is an important component, so also is
lately, computer use has fostered physical inactivity.76,77 setting up of a realistic goal. Patient is guided to identify the
Prolonged hours of television viewing can increase obe­ cue or stimulus that is leading to excessive nutrient intake
sity 2–4 times in adults as well as adolescents.53,54 The and strategies to eliminate the stimulus are undertaken.
most evident mechanism of weight loss on exercise is Some simple behavioral strategies are:
quantitatively increased caloric expenditure. As the • Slow intake of food to allow time for experiencing
magnitude of this effect is not great, other explanations satiation
need to be invoked. These include thermic effect of exercise, • Fixing up time, place or crockery to be used for the
increased cycling of substrates and elevated resting meal to eliminate between meal intake
metabolic rate. Certain behavioral changes may occur • Putting down fork and knife after each morsel
with exercise, like decreased preference for fatty foods • Avoid eating while watching television.
and psychological facilitation.78 The resting metabolic rate Besides such non-specific methods, specific strategies
increased by 10% in aerobic trained individuals and 5% can be evolved after studying the eating behavior of the
in resistance-trained individuals.79 Several studies have individual.
 Comorbid Conditions in Diabetes Mellitus 725

Pharmacotherapy (10 ± 1.6%) and reduced triglycerides (13 ± 3.5%).

Rimonabant also increased adiponectin levels. The side
Although lifestyle interventions are useful in weight
effects of this drug include nausea, anxiety and depression.
reduction, there are frequent failures and relapses. Hence,
The last side effect led to the withdrawal of this drug in the
search for medications has always been intensive in this
year 2009.92
area.
Lipase inhibitor: Tetrahydrolipstatin (Orlistat, Xenical)
Noradrenergic serotonergic drugs: All of these com­
is an inhibitor of pancreatic lipase. It prevents hydrolysis

chapter
pounds are in disuse at present except fluoxetine. The
of dietary triglycerides and promotes its excretion through

48
typical noradrenergic compounds were amphetamine,
the fecal route.65,66 More recently, in a study called
benzphetamine and diethylpropion. They have an abuse
XENDOS, orlistat has been used together with lifestyle
potential and are no longer used. The serotonergic drugs
changes in the prevention of type 2 diabetes.93
used earlier were fenfluramine and dexfenfluramine. On
Orlistat is used in dosage of 120 mg thrice a day with
prolonged use, they were also shown to cause pulmonary
meals. The only unpleasant side effect is fecal soiling of
hypertension and hence, their use has now been aban­
clothes. The diet should not exceed 30% fat, as high fat
doned. Fluoxetine, a serotonergic compound has the
aggravates this side effect. On hypocaloric diets, it may be
least side effects and may be used currently but does not
possible to use the drug in dosage of 60–120 mg once daily
produce consistent weight loss. Sibutramine is an inhibitor
with the principal meal. This strategy avoids fecal soiling of
of reuptake of both serotonin and norepinephrine. In
clothes. In full dosage, the drug can cause malabsorption
dosage of 5–20 mg/day, it produced significantly greater
of fat-soluble vitamins. It should be given 2 hours before or
weight loss than placebo.86 It is best used together with
dietary re-education for the initial period of 2–3 months. after the ingestion of multivitamin or lipophilic drugs.
Additionally, long-term (up to 1 year) use of sibutramine Pseudonutrients (see Chapter 31): These are extensively
has been reported with beneficial effects.87 The side marketed by the food industry. Artificial sweeteners take
effects of sibutramine include headache, constipation, dry place of sugar and many fat substitutes, which are either
mouth, insomnia and a minimal rise in blood pressure and low caloric or calorie-free, take place of fat in the diet.
pulse rate.88 The drug was contraindicated in patients with The most eminent example of calorie-free fat substitute is
coronary artery disease, stroke and heart failure, although olestra.
no causal relationship of the drug to the cardiovascular
complications was proven. In the Sibutramine Cardio­
Surgical Approach to Obesity
vascular Outcomes (SCOUT) study, obese subjects with Bariatric surgery is a highly effective modality of treat­
cardiovascular disease were treated with sibutramine. ment in obesity. Bariatric surgery involves two different
An increased risk for non-fatal myocardial infarction types of surgical procedures, restrictive and malabsorp­
and non-fatal stroke was demonstrated, although there tive. Restrictive procedures include intragastric balloon,
was no increase in mortality.89 This led to banning of the gastric banding and sleeve gastrectomy. Malabsorptive
drug in 2010. procedures include Roux-en-Y-gastric bypass and bilio­
Endocannabinoid receptor antagonists: This is a novel pancreatic diversion.
class of drugs, which antagonizes the cannabinoid type 1 Bariatric surgery is clearly indicated in morbid obe­
receptor. Rimonabant is one such well-studied com­ sity (BMI > 40 Kg/m2) or at a lower BMI of 35 kg/m2, if
pound, which was used in clinical practice a decade ago. co-morbid conditions like hypertension or diabetes
In the Rio-Europe study, the drug was used in dosage coexist. It is indicated at a lower BMI in Asian Indians,
of 5 or 20 mg/day in obese subjects with BMI more who are known to have greater degree of adiposity at a
than 30 kg/m2. It produced significant weight loss and lower BMI than Caucasians.26 Bariatric surgery has been
improved HDL-cholesterol, triglyceride levels and insulin compared with intensive medical therapy for obesity
resistance.90 In the Rio-lipid study, rimonabant was used and diabetes.94 The primary end-point was proportion of
in obese subjects with dyslipidemia.91 In comparison to patients achie­ving a HbA1c of less than or equal to 6.0%
placebo, rimonabant, a dose of 20 mg, produced signifi­ at 12 months. The primary end-point was attained in
cantly greater weight loss (6.7 ± 0.5 kg), reduced waist 12% of medical therapy group as compared to 42%
circumference (5.8 ± 0.5 cm), increased HDL-cholesterol in the gastric bypass group. Mean HbA1c was 7.5 ± 1.8% in
726 Comorbid Conditions

medical therapy group and 6.4 ± 0.9% in the gastric bypass

group. Weight loss was – 29.4 ± 9.0 kg, –25.1 ± 8.5 kg and
– 5.4 ± 8.0 kg in gastric bypass, sleeve gastrectomy and
medical therapy groups respectively. The major adverse
events in the surgery group were: gastrointestinal leak and
wound infection, in the immediate postoperative period
and cholelithiasis, anemia, hypoglycemia and hernia in
section

the follow-up period.

9

In another study,95 bariatric surgery has been

compared with conventional therapy for type 2 diabetes.
The remission rate for diabetes at 2 years was nil in the
medical therapy group, but 75% in the gastric bypass
group and 95% in the biliopancreatic diversion group.
Liposuction is only indicated for localized obesity
unresolved by a good general weight loss program.
Fig. 48.1: Role of vitamin B12 in homocysteine metabolism. Vitamin
B12 deficiency leads to inhibition of both, methionine synthase and
HYPERURICEMIA methyl malonyl CoA-mutase leading to hyperhomocysteinemia and
methyl malonyl acidemia
Hyperuricemia is a common biochemical anomaly in the
population at large. It is seen in 2–13% of non-hospitalized
adults and 25% of hospitalized adults. treatment consists of colchicine orally for 1–2 weeks in
tapering dosage or indomethacin or other non-steroidal
Etiology anti-inflammatory drugs. This should be followed by long-
term allopurinol with an overlap therapy with colchicine
Hyperuricemia can result either from decreased excretion
and allopurinol for 1–2 weeks.
(90% of the patients) or from increased synthesis of uric
Febuxostat, a newer agent was introduced in clinical
acid. Decreased excretion is usually idiopathic or due
use in the year 2009. It inhibits xanthine oxidase, an
to renal insufficiency or metabolic acidosis. Diabetic
enzyme that breaks down hypoxanthine (a purine base)
nephropathy may be accompanied by hyperuricemia.
to xanthine, and later, to uric acid. The drug can be used
Hyperuricemia can be a component of metabolic syn­
both during the acute and chronic phase of gouty arthritis
drome. More significantly, a weight reduction or starvation
in dosage of 40–80 mg daily.97 No adjustment in dosage
diet can lead to hyperuricemia, both due to increased pro­
is required in mild to moderate hepatic-renal disease.
duction and decreased excretion of uric acid. A few com­
Common side effects include liver function abnormalities,
monly used drugs like thiazide or other diuretics, alcohol,
nausea, rash and joint pain.
pyrazinamide, nicotinic acid and cyclosporine cause
hyperuricemia due to decreased excretion. Overproduc­
tion of uric acid is rare but should be considered in hemo­
HYPERHOMOCYSTEINEMIA
lytic states, alcohol abuse, obesity and myeloproliferative Hyperhomocysteinemia has received increased attention
or lymphoproliferative disorders. as a cardiovascular risk factor in the past two decades.
Metabolism of homocysteine to methionine requires the
Management presence of methionine synthase and vitamin B12, which
Asymptomatic hyperuricemia does not require treatment. in turn needs the presence of folic acid and methylenete­
It does not contribute to cardiovascular disease.96 Hyperu­ trahydrofolate reductase (MTHFR) (Fig. 48.1). Homo­
ricemia needs to be treated when symptomatic, producing cysteine can alternatively be converted to cysteine in the
either nephrolithiasis or uric acid nephropathy or gouty presence of enzyme cystathionine beta-synthase, which
arthritis. Allopurinol, 100 mg TID is the key drug. Urine is dependent upon the supply of pyridoxine (vitamin B6).
should be alkalinized in case of urolithiasis or uric acid Thus, normal homocysteine metabolism requires the
nephropathy. In case of gouty arthritis, the immediate presence of vitamin B12, folic acid and pyridoxine.
 Comorbid Conditions in Diabetes Mellitus 727

Hyperhomocysteinemia in Asian Indians CI 95%: 1.31–2.89) in the Chinese population.110 Raised

homocysteine levels produced increased reactive oxygen
The prevalence of hyperhomocysteinemia is high in
species and platelet hyperactivity in type 2 diabetes
India.98-100 It has been ascribed to poor intake of vitamin
mellitus.111 A distinct effect of vitamin supplementation
B12 in vegetarians and destruction of folic acid because
on the stroke mortality was observed in US and Canada.112
of prolonged cooking. Additionally, almost one-third of
After 1998, folate supplement was introduced in cereals,
the Asian Indians have a polymorphism of the enzyme
which showed a fall in stroke mortality rate from 2.9% to
MTHFR.101,102 Hyperhomocysteinemia has been described

chapter
0.3% per year.
in obese insulin resistant children.103 This has also been

48
demonstrated in type 1 diabetes.104 On the other hand,
Management
there are data to show that hyperhomocysteinemia
and the common C677T variant of MTHFR gene are not As hyperhomocysteinemia is highly prevalent in India in
associated with metabolic syndrome in subjects with type individuals both with and without diabetes,98 one could
2 diabetes.105 consider universal vitamin supplementation, especially
if the link with vascular disease is unequivocally
Drug Induced Hyperhomocysteinemia proven. If homocysteine levels are above 12 µmol/L, it
is recommended that a vitamin supplement containing
A number of drugs commonly used to treat diabetes
methylcobalamin 500 µg, folic acid 5 mg and pyridoxine
and hypertension induce hyperhomocysteinemia.106
10 mg is given. As two commonly used drugs in diabetes—
Use of fibric acid derivatives can raise homocysteine
metformin and fenofibrate raise homocysteine levels,
levels by 20–50%. This increase is reduced partly by
vitamin supplementation may be considered in subjects
concomitant supplementation with vitamin B12, B6 and
receiving these drugs.
folic acid. Statins and angiotensin converting enzyme
(ACE) inhibitors do not elevate homocysteine levels and
SUMMARY
the effect of nicotinic acid and N-3 fatty acids is not very
clear. Hydrochlorothiazide increases homocysteine levels. Tobacco abuse, hypertension, hyperlipidemia and obesity
In a study of patients with type 2 diabetes and peripheral are important comorbidities in diabetes. This chapter has
neuropathy, metformin caused elevated homocysteine focused on tobacco abuse and obesity, as hypertension
levels associated with increased severity of peripheral and hyperlipidemia are discussed elsewhere in this book.
neuropathy.107 The mechanism responsible for drug- This chapter also discusses two other comorbidities:
induced hyperhomocysteinemia is not reported but could hyperuricemia and hyperhomocysteinemia.
be altered metabolism of vitamin B6, B12 or folate. Tobacco abuse is a potent cardiovascular risk factor.
As diabetes leads to multiple cardiovascular complica­
Significance of Hyperhomocysteinemia tions, it is important to address other cardiovascular risk
Currently, a large number of studies have attempted to factors. Tobacco cessation strategy should form an impor­
elucidate relationship of vascular complications with tant part of management strategies in diabetes mellitus.
hyperhomocysteinemia in individuals with and without In the modern world obesity has become rampant.
diabetes. The Hoorn study108 failed to demonstrate any Almost two-third of subjects with type 2 diabetes are
association between homocysteine levels and cardio­ obese or overweight. Besides this fact, obesity is asso­
vascular autonomic function in either diabetic or non- ciated with multiple comorbidities like hypertension
diabetic subjects. In HOPE-2 study, supplements of and hyperlipidemia, thus amplifying the cardiovascular
vitamins, folic acid, B6 and B12 did not reduce the complications of diabetes. Significance of hyperuricemia
incidence of major cardiovascular events.109 The homo­ and hyperhomocysteinemia as comorbidities is not yet
cysteine levels decreased by 2.4 µmol/L in the active clear. Obesity is also associated with an increased inci­
treatment group, while they rose by 0.8 µmol/L in the dence of a number of cancers.
placebo group. However, these data are vitiated by the Management of obesity primarily rests on lifestyle
fact that the placebo group also received folic acid from modifications. The pharmacotherapy area of obesity has
the fortified cereals. On the other hand, MTHFR gene witnessed introduction of a large number of compounds,
polymorphism was associated with raised homocysteine which were eventually banned. Bariatric surgery is a good
levels and increased macroangiopathy (odds ratio 1.94, option for morbid obesity.
728 Comorbid Conditions

further reading 8. Willi C, Bodenmann P, Ghali WA, et al. Active smoking and
the risk of type 2 diabetes: A systemic review and meta-
1. Boshell BR, Chandalia HB, Kreisberg RA, et al. Serum analysis. JAMA. 2007;298:2654-64.
insulin in obesity and diabetes mellitus. Am J Clin Nutr. 9. Al-Delaimy WK, Willett WC, Manson JE, et al. Smoking and
1968;21:1419-28. mortality among women with type 2 diabetes. The Nurses’
2. Banerji MA, Faridi N, Atluri R, et al. Body composition, Health Study cohort. Diabetes Care. 2001;24:2043-8.
visceral fat, leptin and insulin resistance in Asian Indian 10. Chiolerol A, Faehl D, Paccaudl F, et al. Consequences of
men. J Clin Endocrinol Metab. 1999;84:137-43. smoking for body weight, body fat distribution, and insulin
section

3. Chandalia HB, Lamba PS, Chandalia SH. Weight gain resistance. Am J Clin Nutr. 2008;87:801-9.
in type 2 diabetics with different treatment modalities. 11. Koster A, Leitzmann MF, Schatzkin A, et al. The combined
9

Metabc Syndr Rel Disord. 2005;3:130-6. relations of adiposity and smoking on mortality. Am J Clin
4. Chandalia M, Abate N. Metabolic Complications of obesity: Nutr. 2008;88:1206-12.
inflated or inflamed? J Diabetes Compl. 2006;21:128-36. 12. Al-Delaimy WK, Manson JE, Solomon CG, et al. Smoking
5. Sun J, Xu Y, Zhu Y, et al. Methylenetetrahydrofolate reduc­ and risk of coronary heart disease among women with type
tase gene polymorphism, homocysteine and risk of macro­ 2 diabetes mellitus. Arch Intern Med. 2002;162: 273-9.
angiopathy in type 2 diabetes mellitus. J Endocrinol Invest. 13. Dongfeng GU, Kelly TN, Wu X, et al. Mortality attributable
2006;29:814-20. to smoking in china. N Engl J Med. 2009;360:150-9.
6. Koster A, Leitzmann MF, Schatzkin A, et al. The combined 14. Parmet S, Lynm C, Glass RM. JAMA Patients page: Smoking
relations of adiposity and smoking on mortality. Am J Clin and the heart. JAMA. 2003;290:146.
Nutr. 2008;88:1206-12. 15. Murphy-Hoefer R, Griffith R, Peterson LL, et al. A review of
7. Wile DJ, Toth C. Association of metformin, elevated interventions to reduce tobacco use in colleges and univer­
homocysteine, and methylmalonic acid levels and clini­ sities. Am J Prev Med. 2005;28:188-200.
cally worsened diabetic peripheral neuropathy. Diabetes 16. Schroeder SA. What to do with a patient who smokes?
Care. 2010;33:156-61. JAMA.2005;294:482-7.
17. Critchley JA, Capewell S. Mortality risk reduction associat­
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ostat compared with allopurinol in patients with hyper­ 106. Dierkes J, Luley C, Westphal S. Effect of lipid-lowering and

chapter
uricemia and gout. N Engl J Med. 2005;353:2450-61. anti-hypertensive drugs on plasma homocysteine levels.

48
98. Refsum H, Yajnik CS, Gadkari M, et al. Hyperhomocyst­ Vasc Health Risk Manag. 2007;3:99-108.
einemia and elevated methylmalonic acid indicate a high 107. Wile DJ, Toth C. Association of metformin, elevated

prevalence of cobalamin deficiency in Asian Indians. Am J homocysteine, and methylmalonic acid levels and clini­
Clin Nutr. 2001;74:233-41. cally worsened diabetic peripheral neuropathy. Diabetes
99. Misra A, Vikram NK, Pandey RM, et al. Hyperhomocyst­ Care. 2010;33:156-61.
einemia and low intakes of folic acid and vitamin B in urban 108. Spoelstra-De Man AM, Smulders YM, Dekker JM, et al.
North India. Eur J Nutr. 2002;41:68-77. Homocysteine levels are not associated with cardiovas­
100. Yajnik C, Deshpande SS, Lubree HG, et al. Vitamin B12 cular autonomic function in elderly Caucasian subjects
deficiency and hyperhomocysteinemia in rural and urban without or with type 2diabetes mellitus: the Hoorn Study.
Indians. J Assoc Physicians India. 2006;54:775-82. J Intern Med. 2005;258:536-43.
101. Mukherjee M, Joshi S, Bagadi S, et al. A low prevalence 109. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering
of the C677T mutation in the methylenetetrahydrofolate with folic acid and B vitamins in vascular disease. New Engl
reductase gene in Asian Indians. Clin Genet. 2002;61:155-9. J Med. 2006;354:1567-77.
102. Kalita J, Srivastava R, Bansal V, et al. Methylenetetrahy­ 110. Sun J, Xu Y, Zhu Y, et al. Methylenetetrahydrofolate reduc­
drofolate reductase gene polymorphism in Indian stroke tase gene polymorphism, homocysteine and risk of macro­
patients. Neurol India. 2006;54:260-3. angiopathy in type 2 diabetes mellitus. J Endocrinol Invest.
103. Martos R, Valle M, Morales R, et al. Hyperhomocysteinemia 2006;29:814-20.
correlates with insulin resistance and low-grade systemic 111. Signorello MG, Viviani GL, Armani U, et al. Homocysteine,
inflammation in obese prepubertal children. Metabolism. reactive oxygen species and nitric oxide in type 2 diabetes
2006;55:72-7. mellitus. Thromb Res. 2007:120:607-13.
104. Dinleyici EC, Kirel B, Alatas O, et al. Plasma total homocyst­ 112. Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke
eine levels in children with type 1 diabetes: relationship mortality in Canada and United States, 1990 to 2002. Circu­
with vitamin status, methylenetetrahydrofolate reductase lation. 2006;113:1335-43.
 Chapter 49
Metabolic Syndrome
Anoop Misra, Suchitra Behl

Metabolic Syndrome

Chapter Outline
♦♦ Historical Perspective and Definition ♦♦ Prevention and Control of the Metabolic Syndrome in
♦♦ Prevalence South Asians
♦♦ Risk Factors for the Development of the Metabolic
Syndrome

INTRODUCTION Definitions were put forth by the World Health Organiza­

tion (WHO), National Cholesterol Educ­ation Program’s
Type 2 diabetes mellitus (T2DM) and cardiovascular dis­ (NCEP) panel on Detection, Evaluation and Treatment of
ease (CVD) are rapidly escalating in prevalence in recent High Blood Cholesterol in Adults [Adult Treatment Panel
decades in developing countries such as India and have III (ATP III)], International Diabetes Federation (IDF),
emerged as leading causes of mortality.1,2 The term “meta­ and American Association of Clinical Endocrinologists
bolic syndrome” refers to a group of meta­bolic abnormali­ (AACE) in efforts to standardize diagnosis universally. We
ties which often occur together in pati­ents with T2DM and shall discuss the definitions of the NCEP ATP III and the
CVD and whose identification and management can play IDF in detail in the Asian Indian context (Table 49.1).
a key role in managing and minimizing the incidence and The guidelines developed in 2001 by the NCEP ATP III
progression of these major health problems. were updated in 2005 by the American Heart Association
(AHA)/National Heart, Lung and Blood Institute (NHLBI).
HISTORICAL PERSPECTIVE AND DEFINITION A joint scientific statement was released in 2009 by IDF,
Historically, it was observed that a group of medical traits AHA, NHLBI and other bodies. The current definition of
often occurred together and increased risk of develop­ metabolic syndrome includes the presence of three of
ing CVD and diabetes. The term “Syndrome X” was used the following in Caucasian population.4
in 1988 by Gerald Reaven to describe a constellation of 1. Abdominal obesity: defined as waist circumference
abnormalities including insulin resistance, high triglyce­ higher than or equal to 102 cm (40 in) in males and higher
rides plus low high density lipoprotein cholesterol than or equal to 88 cm (35 in) in females; if Asian Indian
(HDL-C) and hypertension.3 Since then these groups of higher than or equal to 90 cm (35 in) in men or higher
medical traits have been additionally referred to as “meta­ than or equal to 80 cm (32 in) in women.
bolic syndrome”, “insulin resistance syndrome”, “obesity 2. Serum triglycerides higher than or equal to 150 mg/dL
dyslipi­demia syndrome” and “dysmetabolic syndrome”. or drug treatment for elevated triglycerides.
 Metabolic Syndrome 733

Table 49.1: Definitions of the metabolic syndrome for Asian Indians

Criteria Consensus definition IDF NCEP/ATP III
(Any 3 out of 5 criteria) (Abdominal obesity plus any 2 of (Any 3 out of 5 criteria)
the other criteria)
Abdominal obesity (in cm) Males ≥ 90 Males ≥ 90 Males ≥ 102
Females ≥ 80 Females ≥ 80 Females ≥ 88

chapter
Fasting blood glucose (mg/dL) ≥100 ≥100 ≥100

49
Blood pressure ≥130/≥85 ≥130/≥85 ≥130/≥85
Serum triglycerides (mg/dL) ≥ 150 ≥ 150 mg/dL ≥ 150 mg/dL
Serum HDL-C (mg/dL) Males < 40 Males < 40 Males < 40
Females < 50 Females < 50 Females < 50

3. Serum HDL less than 40 mg/dL in males and less than lifestyle patterns and socio-economic-cultural factors.10
50 mg/dL in females or on treatment for low HDL-C. Review of Indian studies show that about one-third of the
4. Blood pressure higher than or equal to 130/85 or drug urban population in major cities in India has metabolic
treatment for elevated blood pressure. syndrome and this prevalence is rapidly increasing.10-14
5. Fasting plasma glucose higher than or equal to The prevalence of metabolic syndrome in Asian Indians
100 mg/dL or drug treatment for elevated blood glucose. shows a gender difference with prevalence in women
The IDF definition has ethnicity specific cut-offs for reported as 1.5–2 times higher as compared to men.15 For
abdominal obesity, which is an obligatory component example, in urban north India (New Delhi), prevalence
for the diagnosis of the metabolic syndrome. For Asian of the metabolic syndrome overall was 45.3% (32.7% in
Indians, the waist circumference cut off for males is higher males and 56.6% in females) with criteria of NCEP ATP III
than or equal to 90 cm and higher than or equal to 80 cm being used.16 Further, age related increase in prevalence of
for females. In the IDF criteria, if the body mass index metabolic syndrome has been shown.17
(BMI) is higher than or equal to 30 kg/m2 then abdominal The rising prevalence of metabolic syndrome has
obesity can be assumed and waist circumference does been documented in rural India in both obese and non-
not need to be measured. In 2009, a consensus statement obese Asian Indians.18 A study in rural east India showed
for the diagnosis of obesity, abdominal obesity and the prevalence of the metabolic syndrome as 26.9% in men and
metabolic syndrome in Asian Indians endorsed the same 18.4% in women [according to (NCEP, ATP III criteria)],
cut-offs of waist circumference for the diagnosis of the which further increased to 32.5% and 23.9%, in men and
metabolic syndrome, while retaining the non-obligatory women, respectively when modified Asian criteria were
criterion status of abdominal obesity.5 used.19,20 Studies in other parts of the countries have
Elevated levels of inflammatory and prothrombotic demonstrated prevalence of 57.8% in urban women and
markers like C-reactive protein (CRP), interleukin-6 (IL-6), 34.8% in rural women (West Bengal),21 29% in women and
and plasminogen activator inhibitor-1 (PAI), which are 23% in men in Jaipur.22
associated with an increased risk for subsequent CVD The prevalence of childhood obesity or overweight
and T2DM are also seen in patients with the metabolic has a role in the increased prevalence of the metabolic
syndrome.6-8 However, etiological relationship between syndrome. Prevalence of childhood obesity has been
elevated CRP and the metabolic syndrome has not been steadily increasing from 16% in 2002, 24% in 2006–2007
proven9 and measurement of these is not a component of and up to 29 % in another study published in 2008.23
the metabolic syndrome. This increased prevalence would imply an increase in
the prevalence of metabolic syndrome which has been
PREVALENCE
previously reported as up to 4.2% in adolescents and
The prevalence of the metabolic syndrome in Asian 6.5% in children in age group of 6–18 years who were in the
Indians varies according to region, extent of urbanization, high income group.23,24
734 Comorbid Conditions

RISK FACTORS FOR THE DEVELOPMENT OF be implicated in the increased incidence of metabolic
THE METABOLIC SYNDROME diseases and further research on metabolic impact of
dietary modifications is required.
Ethnicity
Asian Indians are predisposed to develop the meta­
Physical Activity
bolic syndrome which is partly attributed to their body Physical activity levels are lower in South Asians compared
composition. The “Asian Indian phenotype” is chara­ to other ethnic groups.13,43-46 Increased mechanization at
section

cterized by higher body fat with comparatively low BMI, work, decreased household work, decreased outdoor
9

greater abdominal obesity, truncal subcutaneous fat, and lei­sure activities, increased indoor entertainment (tele­
intra-abdominal fat and lower lean body mass (LBM) than vision and computer games) contribute to decreasing
other ethnicities. It is associated with increased clustering physical activity.36 In the Asian Indian context, girls and
of risk factors constituting the “metabolic syndrome”.25-28 women are more sedentary than men.13,47 In a recent study
Skeletal muscle is a major constituent of LBM and recent done in South India, 79% of the industrial population
studies on myostatin gene have shown association of were demonstrated to follow a sedentary lifestyle.48
polymorphisms of myostatin gene with increased adiposity
and low LBM.29 Studies have shown that compared to Migration
white Caucasians, Asian Indians have higher prevalence,
earlier onset and increased complications of T2DM and The effect of migration on adiposity and diabetes has been
coronary heart disease (CHD) at lower BMIs.30 discussed in a published review.49 Migration (both intra-
as well as inter-country) leads to significant stress due to
Overweight, Obesity and Abdominal Obesity new environment, social, economic, language disparities,
job challenges and lack of social support, which may lead
Increase in body weight is associated with increased to metabolic derangements and diabetes. An adverse
prevalence and risk of development of the metabolic coronary risk profile was reported among rural-to-urban
syndrome.31,32 Increased waist circumference (a marker migrant populations living in urban slums in India.50 Work
of abdominal obesity) is a predictive factor for the future
and society related factors contributory to stress were
development of metabolic syndrome.33
higher in migrant South Asian men in United Kingdom
(UK) compared with the white Europeans which possibly
Diet is contributory to their increased abdominal obesity and
There have been changes in food consumption patterns vulnerability to CHD.51
with declining intake of traditional foods. Traditional
foods contained lower amounts of saturated fat and Genetic versus Environmental Factors
simple sugars and higher amounts of fiber. These foods
are now partly replaced by energy-dense foods, which A role of genetic predisposition in the development of the
are high in calories, carbohydrates, saturated fats and obesity, metabolic syndrome, dyslipidemia and T2DM in
low in fiber.13,34,35 Consumption of animal fats, dairy pro­ Asian Indians has been reported.52-57 Adverse intrauterine
ducts, carbohydrates and hydrogenated oils (Vanaspati) environment has been reported to contribute to insulin
containing high amount of trans-fatty acid (TFA) has resistance and the metabolic syndrome. Both fetal over­
increased.34-38 High intake of fat, dairy products and nutrition and undernutrition (leading to low birth weight)
sugars in various regions in India has been shown to increases the risk of future diabetes and adiposity in
correlate with increased cardiovascular mortality.39 children in later life. Low birth weight is associated with
Higher carbohydrate intake is linked to hyperinsulinemia, higher systolic blood pressure, fasting and postprandial
post-prandial hyperglycemia, hypertriglyceridemia, while hyperinsulinemia, subscapular/triceps skin fold ratio,
low HDL-C levels associated with insulin resistance.40-42 plasma low density lipoprotein (LDL), along with insulin
South Asians also have significantly lower intake of w-3 resistance.58 In one study, small and thin Indian newborns
polyunsaturated fatty acids (PUFAs), monounsaturated (weight 2.7 kg) were shown to have poor muscle mass but
fatty acids (MUFAs), and higher intake of w-6 PUFAs.37-40 higher adiposity for a given weight compared with white
These changes in patterns of dietary consumption may Caucasian babies.59 Further, “catch up” obesity seen in
 Metabolic Syndrome 735

low birth weight (LBW) offspring seems to be important in the BMI had worsening of their metabolic syndrome
for adult-onset insulin resistance and associated cardio­ components compared to those who maintained their
vascular risk factors.60 BMI.66 Diets should be balanced and include carbohydrate
(55–65% of calories with emphasis on complex carbo­
Psychological Stress hydrates), restricted total fats and saturated fat (7–10% of
Stressful life events and perceived stress has been the total calories), adequate MUFAs, w-3 PUFAs and fiber.
associated with increased risk of the metabolic syndrome.61 Trans fatty acid (TFA) containing oils and diets should

chapter
Stress has been postulated to activate sympathetic nervous be strictly avoided.5 The Mediterranean diet, the Dietary

49
system leading to hormonal fluctuations. A recent study Approaches to Stop Hypertension (DASH) diet and use
in adolescent Asian Indians demonstrated stress levels of food with low glycemic index have been evaluated to
similar to that in United States (US) adolescents.62 Further, have benefits in losing weight, lowering blood pressure
it was associated with hypertension, a component of the and improving lipid parameters.67-69 Patients with obesity
metabolic syndrome.62 However, more data are required should be advised dietary modifications under nutritionist
for defining relationship of psychological stress and the supervision aimed at losing weight.
metabolic syndrome. In general, a total of 60 minutes of physical activity
including aerobic activity, work-related activity and mus­
Other Factors
cle strengthening activity is recommended every day for
Other factors associated with the metabolic syndrome in Asian Indians with obesity or the metabolic syndrome in
the National Health and Nutrition Examination Survey recent guidelines.5 Patients with obesity, hypertension,
(NHANES III) include postmenopausal status, smoking pre-diabetes or diabetes mellitus and dyslipidemia should
and low socioeconomic status.31 be appropriately treated.70 Pharmacotherapy for obesity
should be started at a BMI above 27 kg/m2 in patients
PREVENTION AND CONTROL OF THE without co-morbidities and at a BMI above 25 kg/m2 with
METABOLIC SYNDROME IN SOUTH ASIANS co-morbidities. Orlistat has been used for treatment of
obesity and recently approved drugs include lorcaserin71
It is clear from the preceding discussion that South Asians
and phentermine-topiramate72 combination drug. Dyslipi­
have higher cardiovascular risk due to wide prevalence of
the metabolic syndrome and diabetes. Prevention of these demia should be treated with statins aiming at a LDL goal
conditions requires early and aggressive management of less than 70 mg/dL in patients with CVD and less than
based on the following key principles. 100 mg/dL in patients without CVD. Treatment of blood
Prevention of the metabolic syndrome starts with incre­ pressure should aim at lowering of blood pressure to lower
ased public awareness as Asian Indians are at high risk than 130/80 and drugs like beta-blockers and thiazide
for development of T2DM and CHD. General awareness diuretics which raise glucose levels should not be used as
level should be increased regarding the family history first-line antihypertensives.
of T2DM or premature CHD being adverse risk factors. Three out of five criteria need to be met for diagnosis
Growth velocity and weight monitoring in childhood of metabolic syndrome. Criteria include previously
will increase early recognition of childhood obesity. Out­ diagnosed patients with hypertension, high triglycerides,
door physical activity of 60 minutes/day is recommended low HDL-C, impaired fasting glucose, impaired glucose
for children.5 tolerance or T2DM, and those on treatment for the above
Detection of one component of the metabolic synd­ disorders. If BMI is higher than or equal to 30 then waist
rome should lead to search for the other components. circumference does not need to be measured. (Adapted
Monitoring of weight and waist circumference should from reference number 5).
be accompanied by advice to maintain BMI between
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States. J Am Diet Assoc. 1996;96:257-61. 60. Sachdev HS, Fall CH, Osmond C, et al. Anthropometric
43. Kanjilal S, Rao VS, Mukherjee M, et al. Application of cardi­ indicators of body composition in young adults: relation to
ovascular disease risk prediction models and the relevance size at birth and serial measurements of body mass index
of novel biomarkers to risk stratification in Asian Indians. in childhood in the New Delhi birth cohort. Am J Clin Nutr.
Vasc Health Risk Manag. 2008;4:199-211. 2005;82:456-66.
738 Comorbid Conditions

61. Raikkonen K, Matthews KA, Kuller LH. Depressive symp­ 66. Lloyd-Jones DM, Liu K, Colangelo LA, et al. Consistently
toms and stressful life events predict metabolic syndrome stable or decreased body mass index in young adulthood
among middle-aged women: a comparison of World and longitudinal changes in metabolic syndrome compo­
Health Organization, Adult Treatment Panel III, and Inter­ nents: the Coronary Artery Risk Development in Young
national Diabetes Foundation definitions. Diabetes Care. Adults Study. Circulation. 2007;115:1004-11.
2007;30:872-7. 67. Esposito K, Marfella R, Ciotola M, et al. Effect of a mediter­
62. Suchday S, Kapur S, Ewart CK, et al. Urban stress and ranean-style diet on endothelial dysfunction and markers
health in developing countries: development and valida­ of vascular inflammation in the metabolic syndrome: a ran­
section

domized trial. JAMA. 2004;292:1440-6.

tion of a neighborhood stress index for India. Behav Med.
68. Azadbakht L, Mirmiran P, Esmaillzadeh A, et al. Beneficial
9

2006;32:77-86.
effects of a Dietary Approaches to Stop Hypertension eating
63. World Health Organization 2000. The Asia-Pacific Perspec­
plan on features of the metabolic syndrome. Diabetes Care.
tive. Redefining Obesity and its Treatment. International 2005;28:2823-31.
Diabetes Institute. Health Communications Australia 69. Brand-Miller J, Hayne S, Petocz P, et al. Low-glycemic
Pvt. Ltd, available at http://www.obesityasiapacific.com/ index diets in the management of diabetes: a meta-analysis
default.htm (accessed Dec, 2008). of randomized controlled trials. Diabetes Care. 2003;26:
64. Misra A, Wasir JS, Vikram NK. Waist circumference criteria 2261-7.
for the diagnosis of abdominal obesity are not applicable 70. Grundy SM. Pre-diabetes, metabolic syndrome, and cario­
uniformly to all populations and ethnic groups. Nutrition. vascular risk. J Am Coll Cardiol. 2012;59:635-43.
2005;21:969-76. 71. Taylor JR, Dietrich E, Powell J. Lorcaserin for weight man­
65. Misra A, Vikram NK, Gupta R, et al. Waist circumference agement. Diabetes Metab Syndr Obes. 2013;6:209-16.
cutoff points and action levels for Asian Indians for iden­ 72. Smith SM, Meyer M, Trinkley KE. Phentermine/Topira­
tification of abdominal obesity. Int J Obes (Lond). 2006;30: mate for the treatment of obesity. Ann Pharmacother.
106-11. 2013;47:340-9
 Chapter 50
Diabetes and
Hypertension
Sudeep K, Nihal Thomas

Diabetes and Hypertension

Chapter Outline
♦♦ Diabetes and Hypertension ♦♦ Pathophysiology
♦♦ Defining Hypertension ♦♦ Management of Hypertension

INTRODUCTION adult population of developed countries it is expected

to increase by 60% in the next 20 years.4 More than
Diabetes mellitus is a chronic metabolic disease where two-thirds of adults with diabetes have a blood pressure
both microvascular and macrovascular complications (BP) above 130/80 mm Hg or are on antihypertensives.1
contribute to morbidity and mortality. Cardiovascular dis­ While diastolic BP rises till age 50 years and plateaus,
eases are the most common macrovascular complications systolic BP progresses with advancing age and contributes
of diabetes and the leading cause of death. Hypertension to hypertension in the elderly population. The Seventh
itself is an independent risk factor for vascular diseases, Report of the Joint National Committee on Prevention,
and perhaps the leading cause of mortality. When hyper­ Detection, Evaluation, and Treatment of High Blood
tension occurs in diabetes, it becomes an additional major Pressure (JNC 7 report) has given emphasis to the role of
comorbidity, and the mortality increases by more than systolic hypertension in causing cardiovascular morbidity,
seven-fold.1 mortality, stroke and heart failure and hence calls for a
In type 1 diabetes, hypertension occurs at the onset tighter systolic BP control.5
of nephropathy, while in type 2 diabetes more than 50% In children, the incidence of type 2 diabetes is progre­
have hypertension at the time of diagnosis of diabetes.2 ssively increasing with increase in the incidence of obesity.
Both diabetes and hypertension affect the same target Many of these obese children have features of metabolic
organs and the clinical effects are a result of a synergetic syndrome. Essential hypertension, which was considered
damage to the vascular tree. There is acceleration of uncommon in children, is now the commonest cause of
retinal and renal damage, and progression of cerebral and hypertension in adolescents. In type 1 diabetes, the pre­
cardiovascular diseases. valence of essential hypertension is not different from the
general population while increased prevalence of hyper­
DIABETES AND HYPERTENSION tension has been documented in those with incipient or
established nephropathy.6
The Burden
The prevalence of type 2 diabetes is currently highest
DEFINING HYPERTENSION
among the adults.3 With the process of aging, there is an Accurate measurement of BP is vital for the diagnosis and
increase in the prevalence of hypertension and in the monitoring of hypertension. BP readings are considered
740 Comorbid Conditions

Table 50.1: Stages of hypertension decrease in coronary oxygen supply leads to the accen­
Blood Pressure Systolic BP (mm Hg) Diastolic BP (mm Hg) tuation of ischemia and heart failure. Cardiac failure
(BP) category may commence as diastolic dysfunction and eventually
Normal ≤ 120 ≤ 80 progress to overt systolic failure.
Prehypertension 120–139 or 80–89 Strokes result from thrombosis, thromboembolism or
Stage 1 140–159 or 90–99
intracranial hemorrhage. There is progressive glomerular
Stage 2 ≥ 160 or ≥ 100
injury to the kidneys with progressive albuminuria and
section

subsequent glomerulosclerosis.
accurate when an average of two or more proper BP
9

measurements on each of two or more office visits is Pathophysiology

taken. BP should be measured on both arms supported
at the level of the heart, when the subjects are seated The risk of hypertensive subjects developing diabetes is
comfortably after a 5 minutes rest with their feet flat on 2.5 times higher than in the general population. Simi­
the ground. They should have been stress-free and should larly, diabetes is a risk factor for subsequent hyper­
have refrained from smoking, exercise, alcohol or taking tension.8 This explains the basis for the theory that a
caffeine at least 30 minutes prior to the measurement. common pathophysiological mechanism contributes to
The BP measurement devices should have been properly both occurrences as well as exacerbation of these two
maintained and validated. Supine and standing BP conditions. Clustering of risk factors like central obesity,
measurement should be performed to look for autonomic insulin resistance, dyslipidemia, hypercoagulation, pro­
neuropathy. inflammation and ventricular hypertrophy is seen to
According to JNC report, the term “Prehypertension” occur when hypertension coexists with diabetes. Thus
in subjects without diabetes mellitus refer to the high- in type 2 diabetes, hypertension is part of the metabolic
risk group which does not require drug therapy but are syndrome. The underlying insulin resistance and the
at the risk for future hypertension.5 In the presence of resultant hyperinsulinemia affect the nitric oxide pathway,
coexisting diabetes or chronic kidney disease (CKD), sympathetic drive, smooth muscles cells and sodium
those with prehypertension also require drug therapy if fluid retention, all contributing to the pathogenesis of
lifestyle modification fails to bring the BP to less than hypertension. Hyperglycemia also has a direct effect on
or equal to 130/80 mm Hg. The American Diabetes the renin-angiotensin-aldosterone system (RAAS).
Association also recommends a BP of less than or equal
to 130/80 mm Hg for patients with diabetes (Table 50.1).7 Insulin and Sympathetic
Nervous System Activity
Hypertension: A Vascular Risk Factor An increase in the sympathetic activity has been observed
Hypertension plays a significant role in the development in people with insulin resistance and obesity. Increased
of arteriosclerosis and atherosclerosis. There is reduction circulating norepinephrine has been observed in these
in the elasticity of blood vessels and endothelial damage. individuals and a reduction in plasma norepinephrine
This allows lipids to deposit in the form of atheromas, levels and BP were observed during weight loss.9
which in turn leads to thrombus and emboli formation. High serum leptin levels resulting from the increased
This impedes blood flow and leads to ischemic vascular fat mass or secondary to leptin receptor resistance are
diseases. Hypertension is one of the most important further potentiated by hyperinsulinemia. The hyperle­
independent risk factors for macrovascular complications ptinemia has been shown to be directly related to BP,
in diabetes, and it results in the acceleration of atherogenic heart rate and inversely related to insulin sensitivity in
process and premature atherosclerosis. obese hypertensive subjects. Leptin may increase sympa­
In the heart, concentric left ventricular hypertrophy is thetic drive via central and peripheral mechanisms;10 thus
caused by pressure overload, which results in increased contributing to increased BP and heart rate. Adiponectin,
muscle mass and wall thickness. As a result, the diastolic an adipocyte-derived peptide has anti-inflammatory,
function, i.e. relaxation and filling is compromised. Left insulin-sensitizing and endothelium-protective proper­
ventricular hypertrophy is an independent risk factor ties. Adiponectin levels are lower in obese subjects and
for sudden death. When there is chronic hypertension, are inversely related to systolic and diastolic pressure in
pressure related increase in oxygen demand and a human subjects.11
 Diabetes and Hypertension 741
Flow chart 50.1: Angiotensin II mediated effects. Cardiac and renal RAAS activation also leads to uninhibited production
effects occur through the PLC and PKC pathway. Mitotic activity is
of aldosterone, which in turn induces salt retention,
activated through the MAPK pathway after transactivation occurs
through the EGF-1 receptor enhanced sympathetic and decreased parasympathetic
activity and increased extracellular matrix deposition.
In the advanced stages of diabetic nephropathy,
hyporeninemic hypoaldosteronism with elevated arterial
pressure and hyperkalemia is most often seen. Micro­

chapter
angiopathy and autonomic neuropathy result in low renin

50
and aldosterone levels. However an increase in the activity
of the local tissue renin-angiotensin system (especially
vascular renin with local generation of angiotensin II) and
enhanced arterial sensitivity to angiotensin II is a possible
explanation for the progression of nephropathy inspite of
the systemic hyporeninemia and hypoaldosteronism.13
Increased plasma angiotensin-converting enzyme (ACE)
has been reported in type 1 diabetic subjects with nephro­
pathy. The ACE D isoform is associated with an increase in
the circulating ACE activity and has recently been shown
to be a significant predictor of weight gain and abdominal
(RAS: Renin angiotensin system; EGF: Epidermal growth factor;
adiposity in men.14
PLC: phospholipase C; DAG: Diacylglycerol; PKC: Protein kinase C;
MAPK: Mitogen activated protein kinase). Sodium-Lithium Counter Transport and
Proximal Tubule Handling of Sodium
Erythrocyte sodium-lithium counter transport, which
Sodium and Water Retention
represents sodium reabsorption in the proximal tubule,
An increase in the total exchangeable sodium has been has been found to be overactive in those with diabetes
observed in diabetic subjects.12 This is attributed to the and hypertension. In patients with type 1 diabetes who
ability of insulin to promote renal tubular reabsorption develop nephropathy, nearly 30–40% have a family
of sodium via the direct stimulation of the Na/H antiport history of hypertension. First-degree relatives of patients
system or the Na/K-ATPase in the renal tubule. This theory with diabetic nephropathy also display increased activity
is strengthened by the antihypertensive response seen to of Na/Li counter transport. Hence, there is a familial
thiazide diuretics in diabetic subjects. association between abnormal renal sodium handling,
hypertension, and the propensity for nephropathy in
The Renin-Angiotensin-Aldosterone System genetically susceptible patients with type 1 diabetes.15
In early uncomplicated diabetes although normal to
suppressed aldosterone and renin levels are seen, it may
Insulin Resistance
still represent an inappropriate elevation for the increased Insulin resistance is the primary defect in type 2 diabetes
exchangeable sodium and intravascular volume in dia­ mellitus and is seen in more than 90% of the patients.16
betes. Rat studies have shown that hyperglycemia can acti­ As mentioned earlier, hypertension is an established
vate angiotensinogen gene expression in adipose tissue risk factor for future diabetes mellitus in which situation
and liver. Insulin, which suppresses angiotensinogen insulin resistance and hyperinsulinemia are the common
expression, is less effective in the presence of insulin linking factors. This view is further strengthened by the
resistance. Activation of the RAAS results in unregulated reported increase in prevalence of glucose intolerance in
angiotensinogen II activity through its angio­ tensin-1 the offsprings of hypertensive parents.17
receptor leading to the formation of reactive oxygen Insulin resistance can be defined as an impaired
species (ROS). Insulin action through the PI3 kinase/Akt response of the body cells to the physiological effects
signal pathway is inhibited (Flow chart 50.1) by the ROS. of insulin including those on glucose, lipid and protein
742 Comorbid Conditions

Flow chart 50.2: Insulin resistance. Through PI3 kinase-Akt2 path- cortisol, have been associated with central obesity and
way; the metabolic effects of insulin cannot proceed in the presence of
hypertension. Enhanced activity of enzyme 11β-hydro­
insulin resistance. Mitotic activity however is unhindered through
Grb2 signaling and MAPK pathway xysteroid dehydrogenase type 1 leading to increased
fat tissue-specific cortisol production, and reduced
inactivation of cortisol by altered 11β-hydroxysteroid
dehydrogenase type 2 in fat cells has been demonstrated
in insulin resistant obese subjects.19
section

Effect of Insulin on the Blood Vessel Cells

9

Insulin stimulates the proliferation of VSMCs by increa­

sing insulin-like growth factor 1 (IGF-1) expression.
It can also stimulate endogenous angiotensinogen and
angiotensin II expression and upregulation of angio­
tensin-1 receptors. There is potentiation of mitogenesis
through epidermal growth factor/platelet-derived growth
factor receptor (EGF/PDGF). This contributes to smooth
muscle cell migration and proliferation.
The expression of endothelin-1, a potent mitogen for
VSMCs is increased by hyperinsulinemia, while resistance
to insulin action prevents both the stimulatory effect of
insulin on nitric oxide synthase and the inhibitory effect
(IGF-1: Insulin-like growth factor 1; IRS: Insulin receptor substrate; of insulin on intercellular adhesion molecule-1 (ICAM-1).
PI3 kinase: Phosphoinositide 3-kinase; Grb2: Growth factor receptor- Insulin resistance prevents intracellular magnesium
bound protein 2; SOS: Son of sevenless). transport into VSMCs and diminishes Na/K-ATPase acti­
vity resulting in elevated cytosolic calcium and increased
metabolism and vascular endothelium. Insulin resistance
vascular tone.
prevents the favorable effects of insulin on the vascular
Sodium retention, increased intracellular calcium,
and fat cells, while the unfavorable effects of insulin are
incre­ased sympathetic nervous system activity and
unhindered (Flow chart 50.2). Thus insulin’s impact on
reduced distensibility due to reduced nitric oxide medi­
glucose utilization, lipid metabolism, and endothelial-
ated relaxation increases the vascular sensitivity to pres­
dependent vasodilatation are defective. On the other hand,
sor factors.
sodium retention, activation of the sympathetic nervous
system, increase in vascular smooth muscle cell (VSMC)
cyto­solic calcium, induction of endothelin secretion, and
Hyperglycemia
enhance­ ment of vascular lipid deposition all progress Worsening hyperglycemia has been positively associated
under the influence of hyperinsulinemia. with hypertension.20 High glucose concentrations have
Genetic factors possibly play a significant role in the mitogenic and antiapoptotic effects on VSMCs. Glucose
pathogenesis of diabetes and hypertension. Polymor­ activates the nuclear transcription factor (NFκB) through
phisms of genes involved in the regulation of fat cells have a protein kinase C (PKC) dependent pathway and upregu­
been demonstrated in subjects with insulin resistance. lates plasminogen activator inhibitor (PAI-1) expression
A missense mutation of the β3-adrenergic receptor gene and angiotensin II mediated action. In addition, vasodi­
(ADRB3) is associated with low resting metabolic rate, latory capacity itself is reduced due to the direct suppres­
weight gain, early onset of type 2 diabetes and hyper­ sive effect of acute hyperglycemia on nitric oxide release.
tension.18 Elevated fatty acid concentration underthe Increased oxidative stress and reduced pro­stacyclin syn­
influence of adrenergic overstimulation increases vascular thase activity compromises vasodilatation. Increased
reactivity and impairs nitric oxide synthase activity, thus circulating and vascular wall advanced glycation end-
reducing endothelium-dependent vaso­relaxation. products (AGEs) in diabetic patients are associated with
Polymorphisms of the glucocorticoid receptor gene, impaired endothelial-dependent vasodilatation and
particularly those which alter the receptor’s sensitivity to increased vascular wall stiffness.
 Diabetes and Hypertension 743

Table 50.2: Causes of secondary hypertension

Clinical situations Etiology to be considered
Headache, flushing, sweating Pheochromocytoma
Central obesity, uncontrolled hypertension and hyperglycemia, proximal myopathy and skin Cushing’s syndrome
changes
Weight gain, edema, goiter, lethargy, diastolic hypertension, bradycardia Hypothyroidism

chapter
Weight loss, goiter, hyperactivity, eye signs, systolic hypertension, tachycardia Hyperthyroidism

50
Brachial to femoral systolic blood pressure difference of ≥ 20 mm Hg Coarctation of aorta
Renal bruit, worsening creatinine on angiotensin-converting enzyme inhibitors or angiotensin recep- Renal artery stenosis
tor blockers
Apneic spells Obstructive sleep apnea
Spontaneous or diuretic induced hypokalemia, alkalosis Hyperaldosteronism
Multiple drug intake (including over the counter drugs) Drug induced hypertension

Diabetic Nephropathy and Hypertension Drug induced hypertension is likely to be missed

while other causes are being evaluated for. Medications
Hypertension in type 1 diabetes begins with the onset
such as nasal decongestants, glucocorticoids, tricyclic
of nephropathy and is prevalent in more than 70% of
antidepressants, antiobesity drugs like sibutramine
subjects with type 1 diabetes when they are in the microal­
(appetite suppressant), amphetamine, cocaine and oral
buminuric stage. A history of hypertension in the parents
contraceptives can increase the BP.21
and increased erythrocyte sodium-lithium counter trans­
The common endocrine causes with hypertension
port are markers of genetic susceptibility to hyper­tension
include hyperthyroidism, hypothyroidism, Cushing’s
and nephropathy in type 1 diabetes. The DD iso­form of the syndrome, acromegaly, pheochromocytoma and hyper­
ACE gene, which is linked to increased ACE generation, aldosteronism. These conditions can have associated
has been proposed as a probable marker of risk and hyperglycemia.
progression of diabetic nephropathy. In the general population, fibromuscular dysplasia in
In type 2 diabetes, about 50% already have obesity and young adults is the most common cause of renal artery
age related essential hypertension. A large proportion of stenosis. In diabetics, diffuse atherosclerosis of the renal
the hypertensive population has systolic hypertension arteries can result in stenosis and secondary hypertension.
predominantly with normal renal function. The data on Renal artery stenosis should be suspected in those who
the prevalence of nephropathy is inconsistent because of have worsening creatinine after starting ACE inhibitors
the racial differences in the population. Hypertension is or angiotensin receptor blockers (ARBs), and those
present in more than 90% of diabetics with impaired renal presenting with acute pulmonary edema, resistant or
function. malignant hypertension.

Secondary Hypertension Management of Hypertension

About 5–10% of patients have secondary hypertension The initial laboratory assessment includes renal function
where there is a potentially correctable underlying etio­ tests, hemogram, serum electrolytes, urine albumin excre­
logy. In certain situations, where there are prominent tion, urine microscopic examination, electrocardiography
clinical findings or laboratory abnormalities (Table 50.2), and lipid profile. Based on the investigation reports and
evaluation for secondary hypertension is indicated. Even clinical features, additional investigations to assess end-
where there are no signs or symptoms, preadolescent organ damage and tests to rule out secondary hypertension
onset hypertension, resistant hypertension, hypertension should be ordered.
in type 1 diabetics without nephropathy, late or rapid A target BP of less than or equal to 130/80 mm Hg is
onset hypertension all require evaluation for a secondary recommended by JNC 7 to prevent morbidity and mortality
cause. in subjects with diabetes.5 Even at the pre-hypertensive
744 Comorbid Conditions

Table 50.3: Lifestyle modification Table 50.4: Blood pressure cut-off values for initiation of lifestyle
modifications and drug therapy
Lifestyle Component Modification Advised
Blood Pressure Goal Lifestyle Lifestyle
Physical activity Moderate-intensity activity 30–45 min a
Modifications Modifications
day, at least 5 days a week
Therapy Alone Therapy + Drugs
Smoking Complete abstinence
Systolic < 130 130–139 ≥ 140
Alcohol Two drinks per day for men and one drink
Diastolic < 80 80–89 ≥ 90
per day for women
section

Sodium Less than 2.4 gram per day

9

DASH diet 6–8 servings of whole grains; 4–5 servings complications. The UKPDS also showed that the benefits
of fruits and vegetables; saturated fat 6% of reaped from intensive hypertension control (diastolic BP,
total calories; total cholesterol intake to less 87 mm Hg vs 82 mm Hg) were much better than those
than 150 mg/day. Adequate potassium and
of intensive glucose control (mean HbA1c level, 7.9% vs
magnesium in diet.
7.0%), with a two-fold to five-fold absolute risk reduction
Weight loss To maintain body mass index less than
and much lower numbers needed to treat. A diastolic BP
25 kg/m2
of less than 80 mm Hg was associated with 50% lesser
morbidity than those who had a higher diastolic BP in the
stage initiation of lifestyle modifications is paramount in hypertension optimum trial (HOT) study.25 Hence a BP
the management of hypertension. value less than or equal to 130/80 mm Hg is recommended
Lifestyle modifications include modification of the as a reasonable target. There is no defined lower target and
quality and quantity of diet (including salt and cholesterol the risk reduces as the BP decreases into the normal range.
restriction) and substitution with healthier foodstuffs. However, reducing the diastolic BP to less than 60 mm Hg
The dietary approach to stop hypertension (DASH) has an adverse impact on the cardiovascular outcome.
diet plan with low sodium, low calorie, high potassium Hence, reduction of diastolic BP to less than 60 mm Hg is
and high fiber diet have been proven to be beneficial not recommended.5 Thus, lowering the BP beyond a limit
(Table 50.3).22 A decrease in the daily total salt intake may increase the cost of therapy and increases the risk
from 4.5 g to 2.3 g has been shown to reduce systolic BP of adverse drug effects. However, it has to be noted that
by 5 mm Hg and diastolic BP by 3 mm Hg. Cessation of even in well-designed studies with intensive volunteer
smoking and moderation of alcohol consumption are very follow-up as in the HOT trial, only about 50% of these
important for a successful hypertension management. subjects could achieve the target BP.
Simple physical activities like walking (30–45 minutes In individuals who have diabetes, certain groups of
for at least 5 days a week), jogging, cycling and swimming drugs have additional benefits over the others. Majority of
help in reducing body weight, sympathetic pressor tone, the studies have used ACE inhibitors, ARBs and diuretics
insulin resistance, lipid levels and induce physical and as the first line of therapy. Majority of patients require
social well-being. Weight reduction has been shown to more than two drugs and a substantial number in the
lower the need for medications and to be beneficial in latter group end up with three or more drugs to achieve
BP reduction (1 kg weight loss accounts to 1 mm Hg fall satisfactory BP control. Once a patient requires more than
in BP). If lifestyle modification fails to control BP within one drug, a second drug with an alternative mechanism
the target range, pharmacotherapy has to be initiated23 of action has to be utilized (Flow chart 50.3). Fixed dose
(Table 50.4). combinations can be used if it suits the individual.
The UKPDS 38 (the United Kingdom Prospective Adverse effects like dyslipidemia, worsening hyper­
Diabetes Study) had shown a significant reduction in glycemia, dyselectrolytemia, worsening renal function,
stroke, cardiovascular morbidity and diabetes-related edema, cardiac failure, peripheral vasoconstriction and
mortality after achieving tight BP control.24 Each bronchoconstriction are a matter of concern with some
10 mm Hg of BP reduction was associated with a 12% antihypertensive drugs. Studies on hypertension control
reduction in any complication related to diabetes, 15% in diabetes have shown that the control of BP in itself
reduction in the deaths due to diabetes, 11% reduction in leads to substantial reduction in the risk of cardiovascular
myocardial infarction and 13% reduction in microvascular events and death. Hence, in situations where an adverse
 Diabetes and Hypertension 745

Flow chart 50.3: Treatment approach to a patient with diabetes and should be ACE inhibitors in type 1 or type 2 diabetes
hypertension
and ARBs in type 2 diabetes.
• Diuretics and beta-blockers have enough evidence to
show effectiveness in diabetes. They are particularly
effective in heart failure and coronary artery disease.
• Non-dihydropyridine calcium channel blockers
(DCCB)can be used as second line agents.

chapter
• Since albuminuria is associated with significant cardi­

50
ovascular morbidity and mortality, proteinuria reduc­
tion has to be undertaken aggressively as it may reduce
morbidity. The maximal reduction in proteinuria has
been shown with the RAAS blockers or Non-DCCB.
• When a preferred group of antihypertensive drug is not
tolerated or is contraindicated, an alternative agent to
control hypertension to achieve the target BP should
be initiated.
• In case of postural fall in BP, liberal intake of salt
and fluids should be carried out and medications
should be titrated carefully.

Antihypertensive Drugs in
Diabetes (Table 50.6)
Diuretics
Thiazide diuretics are the most commonly used antihy­
pertensive diuretics, which are effective when the
glomerular filtration rate (GFR) is at least or more than
50 mL/min/m2. They are associated with lower risk of
*In case of established coronary artery disease, beta-blocker should heart failure, stroke, combined cardiovascular events,
be preferred. all-cause mortality and have been found to be as effective
†
In situations where hypertension control alone (particularly elderly as ACE inhibitors (lisinopril) in reducing all-cause
with systolic hypertension) or if albuminuria reduction is the primary
goal non-DCCBs are preferred. mortality. Worsening of hyperglycemia, hypercalcemia,
‡
If GFR ≤ 50 mL/min, Loop diuretics should be used. hypokalemia, hyperuricemia and dyslipidemia is a matter
§
Combination of both is initiated if the BP is more than 20 mm Hg of concern only with higher doses of thiazide diuretics.
above the target.

Angiotensin-Converting Enzyme Inhibitors

effect to a particular first line drug is a concern, lowering They are the preferred first-line antihypertensive agents in
of BP with a suitable alternative/second line agent so as to patients with type 1 diabetes and microalbuminuria and
achieve the target BP should be the immediate objective. considered to be effective than other drugs in retarding
Principles in management of hypertension (Table 50.5):26 the progression of renal failure. Treatment at maximum
• It is acceptable to start ACE inhibitors in type 1 and tolerable dose has shown a reduction in all-cause morta­
type 2 patients with diabetes who have mild hyper­ lity.26 The heart outcome and prevention evaluation
tension. Those who do not tolerate ACE inhibitors can (HOPE) study showed that diabetics in the ramipril
be started on ARBs. group had lower risks of cardiovascular morbidity, total
• In those with microalbuminuria and nephropathy, mortality and rate of microvascular complications and the
unless there is a contraindication, the first-line therapy significance persisted after adjusting for BP.27
746 Comorbid Conditions

Table 50.5: Evidence-based general principles for antihypertensive therapy in diabetes

Level of evidence
Level A 1. The target blood pressure in patients with diabetes is less than 130/80 mm Hg.
2. Those chosen for lifestyle modification should be given a period of 3 months before considering drug therapy.
Medications are initiated if blood pressure ≥ 140/90 mm Hg
3. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are preferred agents
in the management of patients with hypertension and diabetes with or without microalbuminuria. ACE inhibitors in
section

type 1 diabetes and ACE inhibitors/ARBs in type 2 diabetes are used. Also in situations where ACE inhibitors are not
tolerated, ARBs can be used.
9

4. In the presence of microalbuminuria without hypertension with any degree of albuminuria, ACE inhibitors retard
progression of nephropathy.
5. Beta-blockers should be used as part of the initial antihypertensive regimen in patients with diabetes and a history of
myocardial infarction, heart failure, coronary artery disease, or stable angina.
6. Dihydropyridine calcium channel blockers should be reserved for patients with diabetes who cannot tolerate
preferred antihypertensive agents or those who need additional agents to achieve target blood pressure.
7. In situations where creatinine is elevated and serum potassium cannot be monitored, ACE inhibitors or ARBs should
be avoided.
Level B 1. Patients with diabetes should be treated to achieve a target systolic blood pressure of ≤130 mm Hg.
2. If target blood pressure is not achieved with an ACE inhibitor or ARB, addition of a thiazide diuretic is the preferred
second-line therapy for most patients with diabetes.
Level C 1. Most subjects with diabetes require a combination of antihypertensive drugs to achieve target blood pressure.
2. A non-dihydropyridine calcium channel blockers (DCCB) or beta-blocker should be considered in those patients with
nephropathy but not tolerating ACE inhibitors or ARBs.

Expert consensus:
1. Monitoring of potassium and renal function is essential while patients are on ACE inhibitors or ARBs.
2. In elderly patients, blood pressure should be brought down slowly.
3. Those with significant renal disease or those who are not achieving satisfactory blood pressure control inspite of three drugs (including a
diuretic) need an expert’s opinion.

Table 50.6: Antihypertensive class of drugs

Class Type Side effects Practical considerations
Diuretics
Reduce plasma volume, 1. Thiazides Hypokalemia, hypomagnesemia, Cheaper, effective in elderly,
cardiac output and 2. Loop (used when the erectile dysfunction volume overload states and in
peripheral resistance. GFR ≤ 50 mL/min/m2 and Thiazides: Hypercalcemia, hyperurice- systolic hypertension; have
resistant blood pressure) mia, hyperglycemia morbidity and mortality reduction
3. Potassium sparing Potassium-sparing diuretic: benefit
Hyperkalemia
Angiotensin Converting
Enzyme (ACE) Inhibitors
Reduce aldosterone Class I: Captopril Cough, postural hypotension, skin Reduce all-cause and CVS
levels; increase levels of Class II: (prodrug): Ramipril, rashes, angioedema, renal failure, mortality; Renal protection;
vasodilatory bradykinin and enalapril, perindopril hyperkalemia, teratogenicity; Favorable metabolic profile
prostacyclin Class III: Lisinopril (water Contraindicated in bilateral renal
soluble) artery stenosis
Aldosterone Receptor
Blockers (ARB)
Block aldosterone I and Losartan, irbesartan, valsar- Similar to ACE inhibitors, but no cough First alternative to ACE inhibitor
aldosterone II receptors tan, telmisartan, olmesartan intolerance; Renal protection
proven; Studied more in type 2
diabetes mellitus; costlier
Contd....
 Diabetes and Hypertension 747

Contd....
Class Type Side effects Practical considerations
Beta-Blockers
Decrease in cardiac output Cardioselective: Atenolol, Should not be discontinued abruptly; Cardioprotective; Reduced cardio-
and decreased peripheral metoprolol, bisoprolol Bronchoconstriction, bradycardia, vascular mortality; Mainly in
resistance Combined alpha and beta vasospasm, erectile dysfunction, subjects with diabetes and coronary
blockers: Labetalol, carvedilol dyslipidemia artery disease and supraventricular

chapter
tachycardia
Calcium Channel Blockers

50
Vasodilators; increase renal Dihydropyridine calcium chan- Flushing, headache, pedal edema No metabolic or sexual
blood flow nel blockers (DCCB): Nifedi- disturbances;
pine, amlodipine, nicardipine, Heart failure, heart block Antianginal; useful in elderly
cilnidipine and Raynaud’s phenomenon
Non-DCCB: Verapamil,
diltiazem
Alpha-1 Adrenergic Prazosin, doxazosin Postural hypertension, tachycardia, Improve insulin sensitivity, lipid
Receptor Blockers edema neutral; Also useful in prostatic
hypertrophy
Central Sympatholytics Methyldopa Sedation, hepatotoxicity, hemolytic Methyldopa can be used in
anemia pregnancy; increases renal
blood flow
Central Alpha-2 Agonists Clonidine Dry mouth, sedation, bradycardia, Clonidine can bring down blood
erectile dysfunction; rebound hyper- pressure rapidly
tension after abrupt withdrawal
Peripherally Acting Reserpine Depression, lethargy, weight loss, Neutral metabolic effect; cheaper
Adrenergic Antagonists peptic ulcer, diarrhea, erectile
dysfunction
Imidazoline Receptor
Agonists
Reduce sympathetic Moxonidine, rilmenidine Supraphysiological doses produced Improve insulin sensitivity, lipid
activity by acting at the heart failure; Contraindicated in angi- neutral; can promote sodium
brain stem level oedema excretion

Angiotensin Receptor Blockers If the serum creatinine rises by more than 30% or if there
is hyperkalemia, then ACE inhibitors or ARBs should be
Like ACE inhibitors, they have been proven to delay
reduced or stopped.
the onset of end-stage renal disease in type 2 diabetes,
There are no long-term trials that effectively compare
hypertension and microalbuminuria. However, they have
ACE inhibitors and ARBs, while the existing data show
not been shown to be effective in the reduction of all-cause
that both these agents have comparable effect on BP and
mortality although they are superior to beta-blockers in
renal effects. ARBs are costlier but are better tolerated.
reducing cardiovascular events and mortality.28 Owing to
They can be combined together to have a probable syne­
this reason and the cost factor, ARBs are recommended
rgetic effect but at the risk of worsening of renal function.
when ACE inhibitors are not tolerated.
Angiotensin-converting enzyme inhibitors, angio­
tensin receptor blockers and diuretics are considered the Beta-Blockers
first-line antihypertensive agents. Renoprotection of ACE These agents are particularly important in patients with
inhibitors or ARBs are independent of BP reduction.29 diabetes who have coronary artery disease and unstable
Following the initiation of ACE inhibitors, an elevation in angina. They have been shown to reduce post-myocardial
serum creatinine occurs temporarily along with a transient infarction mortality. There were no significant differences
fall in GFR both of which may improve subsequently. in the treatment outcomes between beta-blockers and
748 Comorbid Conditions

ACE inhibitors in the UKPDS-Hypertension in diabetes require more than two drugs, and the objective is to
study. However, the subjects who were on beta-blockers achieve and maintain the target BP as close as possible to
had greater weight gain and a higher discontinuation rate. have a favorable macrovascular outcome.
They are superior to DCCBs in reducing cardiac failure and
myocardial infarction. The concern about their masking Further Reading
of hypoglycemic attacks is less with cardioselective beta-
1. Tight blood pressure control and risk of macrovascular and
blockers and atenolol, when compared to captopril microvascular complications in type 2 diabetes: UKPDS 38.
section

which did not show a higher incidence of hypoglycemia.30 UK Prospective Diabetes Study Group. The JNC 7 report.
9

Worsening of insulin resistance or hyperglycemia has not BMJ. 1998;317:703-13 [BMJ. 1999;318:29].
been of major concern in most of the studies. 2. Chobanian AV, Bakris GL, Black HR, et al. The seventh
report of the joint national committee on the prevention,
detection, evaluation and treatment of high blood pres­
Calcium Channel Blockers sure: The JNC 7 report. JAMA. 2003;289:2560-72 [JAMA.
Dihydropyridine calcium channel blockers have been 2003;290:197].
3. Bakris GL. The importance of blood pressure control in the
shown to be associated with an excessive number of
patient with diabetes. Am J Med. 2004:116:30S-38S.
cardiac adverse events in some studies when compared 4. American Diabetes Association. Standard of medical care:
to ACE inhibitors. Beta-blockers and ACE inhibitors are 2008. Diabetes Care. 2008;31:S12-54.
superior to DCCBs in preventing myocardial infarction 5. Whalen KL, Stewart RD. Pharmacologic management of
and cardiac failure. However, when combined with ACE hypertension in patients with diabetes. Am Fam Physician.
inhibitors, diuretics and beta-blockers, they were not 2008;78:1277-82.
associated with increased cardiovascular morbidity.25
Non-DCCB like diltiazem and verapamil reduce albumin REFERENCES
excretion and coronary events. 1. KDOQI. KDOQI clinical practice guidelines and clinical
practice recommendations for diabetes and chronic kidney
Other Drugs disease. Am J Kidney Dis. 2007;49:S12-154.
2. Bakris GL. The importance of blood pressure control in the
There is very little information on the benefits of other patient with diabetes. Am J Med. 2004:116:30S-38S.
group of antihypertensive drugs (alpha-blockers, loop 3. Pavkov ME, Hanson RL, Knowler WC, et al. Changing
diuretics and central agents) in diabetic population. An patterns of type 2 diabetes incidence among Pima Indians.
Diabetes Care. 2007;30:1758-63.
increased incidence of new onset heart failure was seen in
4. Kearney PM, Whelton M, Reynolds K, et al. Global
the ALLHAT (antihypertensive and lipid-lowering treat­ Burden of hypertension: analysis of worldwide data. Lan­
ment to prevent heart attack trial) study when they were cet. 2005;365:217-23.
on alpha-blockers.31 Hence, they can be best used as an 5. Chobanian AV, Bakris GL, Black HR, et al. The seventh
alternative when other agents are not tolerated or if there report of the joint national committee on the prevention,
are coexisting problems like benign prostatic hyperplasia. detection, evaluation and treatment of high blood pressure:
The JNC 7 report. JAMA. 2003;289:2560-72 [JAMA. 2003;
290:197].
SUMMARY 6. Norgaard K, Feldt-Rasmussen B, Borch-Johnsen K, et al.
Prevalence of hypertension in type 1 (insulin-dependent)
Diabetes mellitus and hypertension are frequently
diabetes mellitus. Diabetologia. 1990;33:407-10.
coexisting morbid illnesses that synergistically inflict 7. American Diabetes Association. Standard of medical care:
vascular damage. Although optimal management of 2008. Diabetes Care. 2008;31:S12-54.
hyperglycemia is essential for the reduction of micro­ 8. National High Blood Pressure Education Program working
vascular complications, control of hypertension with equal group report on hypertension in diabetes. Hypertension.
aggression may result in the reduction of macrovascular 1994;23:145-58.
complications. The superiority of antihypertensive drugs 9. Tuck ML. Obesity, the sympathetic nervous system and
essential hypertension. Hypertension. 1992;19:1-67.
over placebo in risk reduction has been proven beyond
10. Shek EW, Brands MW, Hall JE. Chronic leptin infusion
doubt. Certain groups of antihypertensive drugs have increases arterial pressure. Hypertension. 1998;31:409-14.
added advantage over others in terms of cardiovascular, 11. Adamczak M, Wiecek A, Funahashi T, et al. Decreased
renal and mortality benefits. However, a significant plasma adiponectin concentration in patients with essential
number of individuals with diabetes and hypertension hypertension. Am J Hypertens. 2003;16:72-5.
 Diabetes and Hypertension 749

12. Florkowsky CM, Kendall MJ. Pathophysiology of hyperten­ 24. Tight blood pressure control and risk of macrovascular and
sion in diabetes mellitus—implications for management. microvascular complications in type 2 diabetes: UKPDS 38.
J Clin Pharma Ther. 1991;16:153-60. UK Prospective Diabetes Study Group. The JNC 7 report.
13. Hsueh WA. Effect of renin angiotensin system in the vas­ BMJ. 1998;317:703-13 [BMJ. 1999;318:29].
cular disease of type 2 diabetes mellitus. Am J Med. 25. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of
1992;92:13S-19S. intensive blood pressure lowering and low dose aspi­
14. Fujisawa T, Ikegami H, Kawaguchi Y, et al. Meta-analysis of rin in patients with hypertension: principal results of the
association of insertion/deletion polymorphism of angio­ Hypertension Optimum Trial (HOT) randomized trial.

chapter
tensin I-converting enzyme gene with diabetic nephropa­
HOT Study Group. Lancet. 1998;351:1755-62.

50
thy and retinopathy. Diabetologia. 1998;41:47-53.
26. Whalen KL, Stewart RD. Pharmacologic management of
15. Mead PA, Wilkinson R, Thomas TH. Na/Li counter trans­
hypertension in patients with diabetes. Am Fam Physician.
port abnormalities in type 1 diabetes with and without
nephropathy are familial. Diabetes Care. 2001;24:527-32. 2008;78:1277-82.
16. Sechi LA, Melis A, Tedde R. Insulin Hypersecretion: a 27. Effect of ramipril on cardiovascular and microvascu­
distinctive feature between primary and secondary hyper­ lar outcome in people with diabetes mellitus: results of
tension. Metabolism. 1992;41:1261-6. the HOPE study and the MICROHOPE substudy. Heart
17. Lindstom J, Tuomilehto J. The diabetes risk score: a prac­ Outcome Prevention Evaluation Study Investigators. Lan­
tical tool to predict type 2 diabetes risk. Diabetes Care. cet 2000;355:225-59 [Lancet. 2000;356:860].
2003;26:725-31. 28. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular mor­
18. Ringel J, Kreutz R, Distler A, et al. The Trp64Arg polymor­ bidity and mortality in patients with diabetes in the Losar­
phism of the beta3-adrenergic receptor gene is associated tan Intervention for endpoint reduction in hypertension
with hypertension in men with type 2 diabetes mellitus. Am study (LIFE): a randomised trial against atenolol. Lancet.
J Hypertens. 2000;13:1027-31. 2002;359:1004-10.
19. Rask E, Olsson T, Soderberg S, et al. Tissue-specific 29. Strippoli GF, Bonifati C, Craig M, et al. Angiotensin convert­
dysregulation of cortisol metabolism in human obesity. ing enzyme inhibitors and angiotensin receptor antago­
J Clin Endocrinol Metab. 2001;86:1418-21. nists for the prevention of progression in diabetic kidney
20. Major SG. Blood pressure in diabetes mellitus: a statistical
disease. Cochrane Database Syst Rev. 2006; 006257.
study. Arch Intern Med. 1989;44:797-812.
30. Efficacy of atenolol and captopril in reducing risk of macro­
21. Viera AJ, Hinderliter AL. Evaluation and management of
vascular and microvascular complications in type 2 diabe­
the patient with difficult-to-control or resistant hyperten­
sion. Am Fam Physician. 2009;79:863-9. tes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ.
22. Sacks FM, Svetky LP, Vollmer WM, et al. Effects on blood 1998;317:713-20.
pressure of reduced dietary sodium and the dietary 31. Whelton PK, Barzilay J, Cushman WC, et al. Clinical out­
approach to stop hypertension (DASH) diet. N Eng J Med. comes in antihypertensive treatment of type 2 diabetes,
2004;344:3-10. impaired fasting glucose concentration, and normogly­
23. Arauz-Pacheco C, Parrot MA, Raskin P. The treatment of cemia: Antihypertensive and Lipid-Lowering Treatment
hypertension in adult patients with diabetes. Diabetes to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med.
Care. 2002;25:134-47. 2005;165:1401-9.
 Chapter 51
Dyslipidemia in
Diabetes
Subhankar Chowdhury, Kaushik Pandit

“I believe the chief cause for premature development of arteriosclerosis in diabetes, save for advancing age, is excessive fat; an excess of fat in body,
obesity; an excess of fat in diet; and an excess of fat in blood. With an excess of fat diabetes begins and from an excess of fat diabetics die; formerly of
coma, recently of arteriosclerosis.”
Elliott P Joslin. Arteriosclerosis and diabetes. Ann Clin Med. 1927;5:1061.

Dyslipidemia in Diabetes

Chapter Outline
♦♦ Lipoprotein Physiology ♦♦ Fibrates
♦♦ Lipoproteins and Atherosclerosis ♦♦ Ezetimibe
♦♦ Lipid Disorders in Diabetes ♦♦ Miscellaneous
♦♦ Screening for Dyslipidemia in Diabetes ♦♦ Novel Vistas in Lipid Modification
♦♦ Treatment of Dyslipidemia in Diabetes ♦♦ Rational Choice of Drugs
♦♦ Statins

INTRODUCTION has been found to be much higher for diabetic than

non-diabetic people in the large multiple risk factor
Lipid disorders are not uncommon in diabetes. They may intervention trial, irrespective of the presence of other risk
arise from a lack (in type 1 diabetes) or a defect in the factors.2 However, apart from dyslipidemia, other factors
action (in type 2 diabetes) of insulin; in type 2 diabetes part also contribute towards the increased risk of coronary
of the problem may be a causally independent component heart disease (CHD) in diabetes, e.g. hypertension, obe­
of the “metabolic/dysmetabolic syndrome”. Besides, an sity, hyperglycemia, oxidative stress and smoking.2-4
individual with diabetes may also have some form of
familial or genetic dyslipidemia. LIPOPROTEIN PHYSIOLOGY
Whatever the mechanism, they contribute importantly All the major lipids in our body, namely cholesterol,
to the considerable increase in the risk of atherosclerosis triglycerides and phospholipids have important physio­
and consequent mortality in diabetes. In the Framingham logical functions as follows:
study, it was documented that the incidence of cardio­ Cholesterol:
vascular disease in diabetic men was twice that among • Structural constituent of cell membranes
non-diabetic men, and in diabetic women, it was about • Precursor of steroid hormones
three times.1 The absolute risk of cardiovascular death • Precursor of bile acids.
 Dyslipidemia in Diabetes 751

Triglycerides: circulation without the need for packaging into chylo­

• Major energy store of the body. microns. Apolipoprotein B48 is necessary for secretion
Phospholipids: of chylomicron from the intestinal cell. In the circulation,
• Structural constituent of cell membranes. chylomicrons acquire further apoproteins, C and E, from
circulating HDL. Of these, apoprotein CII (apo C-II)
Lipoprotein Structure activates an enzyme, lipoprotein lipase (LPL) located
Lipoproteins are macromolecular complexes carrying on the endothelium of capillaries in skeletal muscle and

chapter
hydrophobic lipids like triglycerides and cholesterol esters adipose tissue, while apo C-III inhibits it. The net effect

51
in plasma; these latter comprise the core of the lipopro­ is hydrolysis of triglyceride component of chylomicrons
teins and are enveloped by the amphipathic (i.e. both in muscle and fat to yield fatty acids and glycerol; both
may be used as fuel, while the fatty acids may also be re-
hydrophobic and hydrophilic) monolayer of phospho­
esterified to triglyceride and stored in adipose tissue. In
lipids, free cholesterol and proteins which solubilize the
the process of catabolism of chylomicrons, triglycerides
lipids for transport in plasma. The proteins, called apopro­
get depleted from the core while surface apo C-II, apo
teins (or apolipoproteins), not only play a mechanical
C-III, free cholesterol and phospholipids are transferred
role in lipid transport but also regulate lipoprotein
to HDL cholesterol. The chylomicron remnant (now
metabolism.
with a cholesterol-ester-rich core) is then taken up by
Several major subclasses of lipoproteins have been
the hepatocytes with the help of apoE binding to hepatic
defined by their physical-chemical characteristics, namely,
LDL receptors. In effect, chylomicrons deliver dietary
chylomicrons, very-low-density lipoproteins (VLDL),
triglycerides to muscle and adipose tissue, while dietary
intermediate-density lipoproteins (IDL), low-density lipo­
cholesterol goes to the liver.
proteins (LDL) and high-density lipoproteins (HDL). The
size of the particles decreases (while density increases),
continuously from the chylomicrons (diameter 75–1,200
Endogenous Lipids
nm) to the HDL (diameter 5–12 nm). Roughly, there is Endogenous lipid synthesis occurs primarily in the
a reciprocal relationship between the triglyceride and liver. Triglycerides are made from fatty acids that may
cholesterol contents of the lipoproteins, with chylomicrons be synthesized locally or derived from the circulation.
and VLDL being high in triglycerides (80–90% and 50– Cholesterol is synthesized in the liver [with hydroxy­
80% respectively of triglycerides and 2–7% and 5–15% methylglutaryl coenzyme A reductase (HMG-CoA
respectively of cholesterol) and LDL cholesterol and HDL reductase) as the rate-limiting step], but some of the
cholesterol being relatively high in cholesterol (40–50% and cholesterol transported out of the liver may actually be
15–25% respectively of cholesterol and 5–15% and 5–10% derived from the circulation, e.g. from chylomicron rem­
respectively of triglycerides); the phospholipid content nants. These lipids are secreted from the liver as VLDL
shows a gradual increase from 5–10% in chylomicrons to with apoB100 being the major apoprotein; once in
20–30% in HDL cholesterol. circulation VLDL acquires apoC and apoE from HDL. In
the plasma VLDL, like chylomicrons, loses triglyceride by
Lipoprotein Metabolism the action of LPL in muscle and adipose tissue and gets
For the sake of easy understanding, this may be discussed converted to smaller and denser VLDL remnants. These
under two broad groups: the handling of dietary (exoge­ remnants can have two fates: the larger (triglyceride rich)
nous) and that of endogenous lipids. ones are likely to be taken up by the liver directly, with
the help of apoE binding to LDL receptors; the smaller
ones undergo progressive triglyceride (and redundant
Dietary (Exogenous) Lipids
surface component) depletion to get converted to
Dietary fats are absorbed into the intestinal mucosa as LDL through IDL; apoE and hepatic triglyceride lipase
fatty acids, monoglycerides, glycerol and cholesterol; here (HTGL) are actively involved in this process. Apo B100
they are re-esterified to triglyceride and cholesterol ester, is the only protein remaining on the surface of the LDL
which are incorporated in the lipid core of chylomicrons and cholesterol the predominant lipid in the core. Thus,
and enter the circulation via the thoracic duct. Medium- the cholesterol-rich LDL particles are actually derived
chain triglycerides can be absorbed directly into the portal from VLDL.
752 Comorbid Conditions

Low-density lipoprotein particles are further sub- A common, heritable phenotype characterized by
classified in terms of decreasing size from LDL1–3. The the predominance of small, dense LDL3 particles (LDL
small dense LDL3 is catabolized more slowly5 and is more subclass B) is associated with increased concentration of
susceptible to oxidation.6 About 60% of the LDL is taken plasma triglyceride, reduced levels of HDL cholesterol and
up by the liver (with the help of apoB100 recognition site increased risk of CHD in comparison with subjects with
on the LDL receptor), where cholesterol can be utilized larger LDL (LDL subclass A).
for bile acid synthesis, while the remainder is delivered Modified LDL, e.g. by oxidation, is avidly taken up by
section

to peripheral tissues, including the adrenal cortex and “scavenger” receptors on macrophages and endothelial
gonads, where cholesterol is used for steroid hormone cells in the arterial wall leading to the formation of
9

synthesis. The cholesterol content of the hepatocyte feeds cholesterol-laden foam cells; this sows the seed for
back negatively on both de novo cholesterol synthesis and atherosclerosis. These scavenger receptors differ from
hepatic LDL receptor number. classical LDL receptors in that they are not downregulated
by increasing amounts of cholesterol inside the cell.
Reverse Cholesterol Transport Oxidized LDL may also stimulate secretion of cytokines and
High-density lipoprotein provides the means for reverse growth factors by endothelial cells, smooth muscle cells
cholesterol transport from the peripheral cells to the liver. and macrophages. This results in complex changes in the
Nascent HDL particles containing the crucial apoA-1 and arterial wall involving further attraction of macrophages,
phospholipids are produced by the liver and intestine. proliferation of smooth muscle cells and laying down of
These particles accept free cholesterol from peripheral extracellular matrix, altogether completing the process of
cells or other lipoproteins; this cholesterol is esterified by atherosclerosis.
the enzyme lecithin-cholesterol acyltransferase (LCAT) to
cholesterol ester, which moves to the hydrophobic core
High-Density Lipoprotein Cholesterol
of HDL. LCAT is present in the HDL particle itself and is High-density lipoprotein cholesterol has a strong negative
activated by apoA-I . Nascent HDL, by acquiring more and correlation with CHD risk.8 High-HDL cholesterol may
more cholesterol (and also by receiving redundant surface protect against atherosclerosis by several hypothetical
components from other lipoproteins), is converted to mechanisms:
larger and less dense HDL2. HDL2 can be taken up directly • Most attractively by reverse cholesterol transport from
by the liver; more commonly cholesterol esters from HDL2 foam cells in the arterial wall to the liver or by protec­
are exchanged with triglycerides from triglyceride-rich ting LDL from oxidation.
apoB lipoproteins (chylomicrons and VLDL) with the • Indirectly, because of the commonly associated lowe­
help of cholesterol ester transport protein (CETP). The ring of apoB containing lipoproteins, which deliver
reverse cholesterol transport is complete when these apoB cholesterol to the endothelium.
lipoproteins are removed by the liver.
Thus there are four important enzymes that control Triglyceride and Very-Low-Density
lipoprotein metabolism: LPL, HTGL, LCAT and CETP; Lipoprotein
defects in any of these enzymes can cause disturbances in
plasma lipids, all of which are rare clinical entities. The relationship between plasma triglyceride level and
CHD risk is still not settled beyond doubt. Many studies
LIPOPROTEINS AND ATHEROSCLEROSIS have found a significant positive correlation between
plasma triglyceride level and CHD risk on univariate
Cholesterol and Low-Density Lipoprotein analyses; however, quite often, this is lost on multivariate
Plasma cholesterol is a well-recognized risk factor for analyses where other factors like HDL cholesterol are also
atherosclerosis-related diseases, in particular CHD. This is included. The apparent risk of hypertriglyceridemia may
well illustrated in the multiple risk factor intervention trial be secondary to other associated disorders like:
(MRFIT) where CHD death was positively correlated to • Low HDL cholesterol
plasma cholesterol level independent of hypertension and • Preponderance of small dense LDL3 subfraction (which
smoking.2 It is believed that 80% of the worldwide variation is more atherogenic because of greater propensity to
in CHD incidence can be explained by differences in oxidation and slower catabolism)
plasma cholesterol.7 It is the cholesterol carried in LDL • Higher level of the coagulation factor VII (now
that is primarily implicated in atherosclerosis. recognized as an independent risk factor for CHD)
 Dyslipidemia in Diabetes 753

• Higher level of plasminogen activator inhibitor-1 these changes are the type of diabetes and the degree of
(PAI-1) (which can promote CHD by inhibiting glycemic control.
fibrinolysis).
While it is true that atherosclerotic plaques do not con­ Dyslipidemia in Type 2 Diabetes
tain triglyceride, we are to remember that triglyceride-rich
Dyslipidemia is more frequent in type 2 diabetes and is
lipoprotein particles like VLDL (more specifically VLDL
a major contributor to the high risk of CHD seen in this
remnants) also contain significant amounts of cholesterol

chapter
condition.
ester and hence may be atherogenic.

51
Moreover, in a recently published meta-analysis invol­
Quantitative Changes
ving seventeen population-based prospective studies,
triglyceride was found to be an independent risk factor The most frequent form of quantitative dyslipidemia is
for CHD even after adjustment for HDL cholesterol.9,10 increased triglyceride.14-16 The United Kingdom Prospec­
tive Diabetes Study (UKPDS) has shown that the hyper­
Lipoprotein(a) triglyceridemia of type 2 diabetes is already present at the
This is an LDL particle, which has an additional apoprotein, time of diagnosis.17 In fact, this has been noted in the pre­
designated apo(a), attached covalently to the apoB100. diabetic phase as well.18 This is also influenced by the pres­
Apo(a) has striking structural similarity to plasminogen. ence of other factors unrelated to hypergly­cemia or insulin
The physiological role of lipoprotein(a) [Lp(a)] is not resistance, e.g. presence or absence of nephropathy, obe­
well understood. However, its plasma level is positively sity, hypothyroidism, the frequent occurrence of geneti­
associated with CHD in non-diabetics.11 cally determined lipoprotein disorders (familial combined
hyperlipidemia or familial hypertriglyceridemia), alcohol
Risk Factors Versus Markers and estrogen usage, etc.
The other quantitative dyslipidemia associated with
A variable can be a predictor for CHD in an observational type 2 diabetes is low HDL cholesterol concentration.
study but not in clinical trials if the variable is a marker In the multivariate analysis, the male diabetic had lower
(i.e. closely associated with other risk factors) rather than HDL cholesterol levels than corresponding non-diabetic
a true risk factor. Modification of a marker may or may not subjects after adjusting for other variables.19 UKPDS con­
change the actual risk of CHD. firmed this and found the abnormality more commonly in
Low-density lipoprotein cholesterol is a recognized diabetic females.20 The Prospective Cardiovascular Munster
risk factor for CHD, and its lowering has been unequivo­
(PROCAM) study in the German population also noted
cally beneficial in clinical trials. It is possible that elevated
the prevalence of low HDL cholesterol in diabetics.21 The
triglyceride may be a better marker of CHD than elevated
same feature was once again noted in a Finnish popula­
LDL cholesterol in type 2 diabetics in an observational
tion study. The future risk for CHD death in the study was
study, because triglyceride levels are more correlated with
found to be twofold to fourfold higher in diabetics with
other components of the insulin resistance syndrome
low HDL cholesterol than in diabetics without it.22 Other
than is LDL cholesterol. However, triglyceride lowering
studies noted that it is the HDL2 subfraction which is
may not be that effective. Since clinical trials provide stron­
specifically depressed in the high-risk population with
ger data than observational studies, primary emphasis
CHD in diabetics.23,24 The low HDL cholesterol usually
should be placed on LDL lowering, but interventions to
persists despite achievement of glycemic control.
lower the triglyceride levels and raise HDL cholesterol
Total and LDL-cholesterol concentrations approach
levels may also be useful.12,13
those in non-diabetics, especially on achievement of good
metabolic control.
LIPID DISORDERS IN DIABETES
The similarity of plasma total cholesterol levels in type
The lipid abnormalities associated with diabetes are 2 diabetics and in those without diabetes should not lead
better termed as “dyslipoproteinemia” or “dyslipidemia”, one to conclude that cholesterol has no coronary risk effect
rather than “hyperlipoproteinemia” or “hyperlipidemia”, in diabetics. The multiple risk factor intervention trial has
because there may be changes in both, the quantity and shown that the incidence of coronary mortality increases
quality of the lipoproteins. The two main determinants of in a curvilinear manner with increasing concentrations of
754 Comorbid Conditions

serum cholesterol both in those with and without diabetes. Lipoprotein(a) is of special interest in type 2 diabetics
The two curves were similar in shape but differed, with because of its known association with CHD. Studies have
the curve for those with diabetes being higher than the shown higher levels,32 no difference11 and even lower
curve for those without. At any given serum cholesterol levels33 in type 2 diabetic subjects. However, most of
concentration, those with diabetes had a risk of CHD the studies on Lp(a) and type 2 diabetes are small and
mortality between two and four times greater than those except for a few do not account for the apo(a) phenotype,
without diabetes.2 There may be several reasons for this. which is a major determinant of Lp(a) concentration. The
section

First, the level of cholesterol in serum reflects the level consensus appears to be that the diabetic state does not
9

of all lipoproteins, not just LDL. Thus an elevation of have any impact on Lp(a) concentration,34 though diabetic
serum cholesterol may, in part, indicate an increase in the patients with CHD have been found to have higher Lp(a)
triglyceride-rich lipoproteins. Second, there may be many concentration than diabetic patients without CHD.35 A
non-lipoprotein atherogenic factors, e.g. advanced glyca­ recent study from South India echoes the same conclusion
tion end-products that might increase the risk in diabetes. that in diabetic population Lp(a) is an independent risk
Third, LDL may be modified in a way that would make factor for CHD, though the level is not increased.36
any given amount more atherogenic such as glycation, Diabetic subjects have been found to have greater
oxidation. Another aspect also needs mention. The LDL glycation of LDL particles, which are more susceptible to
cholesterol concentration is usually calculated by Friede­ oxidation.37 Increased oxidized LDL has also been found
wald formula [LDL cholesterol = total cholesterol – (HDL in diabetic subjects.38
cholesterol + triglyceride/5) (all concentrations in mg/
dL)]. However in diabetes the calculated LDL cholesterol Mechanism of Dyslipidemia in Type 2 Diabetes
correlates poorly with that actually determined by Insulin resistance, which is important in the genesis of
ultracentrifugation, probably because of changes in chole­ type 2 diabetes itself, can also cause hypertriglyceridemia
sterol-to-triglyceride ratio in VLDL.25 and the preponderance of small dense LDL particles may
be explained in terms of hypertriglyceridemia.
Qualitative Changes Insulin normally inhibits hormone-sensitive lipase in
Low-density lipoprotein distribution is tilted towards adipose tissue; insulin resistance, therefore, causes unre­
smaller and denser LDL3 particles (LDL B phenotype) strained lipolysis leading to increased flux of fatty acids
which have greater atherogenic potential.26 Feingold to the liver, which ends in higher hepatic triglyceride
et al. found that normolipidemic men with diabetes have synthesis. On the other hand, activity of the endothelial
two-fold increase in the percentage of individuals with the insulin-dependent LPL will be less, resulting in dimi­
LDL B phenotype compared with normolipidemic men nished triglyceride clearance from triglyceride-rich lipo­
without diabetes.27 In the Kaiser-Permanente Women proteins. The direct effect of insulin on hepatic VLDL
Twins Study, prevalence of LDL phenotype B has been triglyceride synthesis appears to depend on the duration
found to be an integral feature of insulin resistance synd­ of exposure. Short-term exposure inhibits,39 while chronic
rome.28 Conversely, subjects with predominance of hyperinsulinemia increases VLDL triglyceride secretion
small LDL had a greater than two-fold increased risk from the liver.40 In type 2 diabetes hyperinsulinemia does
of developing type 2 diabetes mellitus over a follow-up occur secondary to insulin resistance, but whether the
period of 3.5 years.29 liver remains sensitive to the VLDL secretory effects of
High-density lipoprotein particles show enrichment chronic exposure to insulin is not clear. It may well be
in triglyceride, increased cholesterol-to-protein ratio and that in type 2 diabetes both deficient (on adipose tissue
a selective reduction of apoAI. There is also increased lipase and endothelial LPL) and excessive (on hepatic
glycosylation of apoAI and apoAII, which appears to VLDL secretion) insulin action may underlie the raised
accelerate HDL catabolism so that there is rapid clearance triglyceride. As a consequence of triglyceride enrichment
before they have circulated long enough to acquire suffi­ of VLDL, there is increased transfer of triglyceride to LDL
cient cholesterol to become HDL2.30 Glycosylation of HDL with the help of CETP; these triglyceride-rich LDL particles
probably also impairs its ability to promote cholesterol are substrates for hepatic lipase activity leading to the
efflux from cells in vitro.31 formation of small dense LDL.
 Dyslipidemia in Diabetes 755

Hyperinsulinemia, Dyslipidemia and mellitus compared to controls. However, type 1 diabetic

Coronary Heart Disease subjects have an increased cholesterol-to-triglyceride
ratio in VLDL particles, which may not resolve with inten­
It is common knowledge that insulin resistance and the
sive insulin therapy.47 A lower lecithin (a phospholipid)
compensatory hyperinsulinemia (if pancreatic β-cells are
content of VLDL and IDL has also been reported in type 1
competent) are associated with an atherogenic plasma
diabetic patients.48
lipid profile, comprising elevated triglyceride and depres­
Lipoprotein (a) levels have been variously reported as

chapter
sed HDL cholesterol levels. A number of prospective
high or normal in type 1 diabetes.
studies, albeit in non-diabetic subjects, have also found

51
Presence of nephropathy (even at the stage of micro­
plasma insulin to be an independent and statistically
albuminuria) adversely affects practically all aspects of
significant correlate of CHD. This naturally raises the
lipid profile leading to elevation of LDL cholesterol, VLDL
important issue of the long-term safety of the use of insulin
triglyceride and reduction of HDL cholesterol, particularly
in type 2 diabetes, where hyperinsulinemia is already
HDL2.49
believed to exist. However, administration of insulin to
both insulin-dependent (i.e. insulinopenic) and non- Dyslipidemia in “Malnutrition-Related
insulin-dependent (i.e. hyperinsulinemic) diabetics (to Diabetes”
control hyperglycemia) or indeed to non-diabetic subjects
produces a decrease in serum triglyceride levels.41 Also, World Health Organization (WHO) recognized malnutri­
insulinoma is associated with low plasma concentrations tion related diabetes mellitus as a separate type of diabetes
of triglycerides.42 Hence direct role of hyperinsulinemia in in 1985. These patients tend to have rather low levels of
the genesis of hypertriglyceridemia has been questioned. cholesterol and triglyceride, which may partly explain
their low rates of macrovascular disease. However, current
Moreover, in the UKPDS the intensive glycemic control
view tends to be against identifying this as a separate class
group, many of whom were treated with insulin, far from
of diabetes.
showing increased CHD mortality actually showed a non-
significant 16% decrease.14 Diabetic Dyslipidemia and Ethnicity
Dyslipidemia in Type 1 Diabetes In an analysis in UKPDS cohort followed up for 9 years,
it was noted that the Asian Indian population cohort had
It differs from that in type 2 diabetes in two important
lower total cholesterol, LDL cholesterol and HDL chole­
respects: sterol, but higher triglyceride compared to the White
1. It is closely related to the degree of glycemic control. Caucasian and Afro-Caribbean cohort. This probably signi­
2. Low-HDL cholesterol is not a feature (in the absence of fies that the Asian Indians are more insulin resistant, a fact
renal involvement). that has been proved in many other studies comprising
In poorly controlled type 1 diabetics, the characteristic multi-ethnic population.50
lipid abnormality is increased triglycerides. This can be well During the follow-up period of 9 years, the Asian
explained by absolute deficiency of insulin. As expected, Indians showed a similar decrease of total and LDL chole­
the level normalizes with adequate insulinization. sterol as well as of triglyceride level compared to the white
In the Wisconsin Epidemiological Study on Diabetic Caucasian and Afro-Caribbean peer cohorts, but there
Retinopathy (WESDR) the mean levels of total and HDL was no significant change in HDL cholesterol level, which
cholesterol were similar in type 1 diabetic subjects and age showed an upward trudge in the other groups. This was
matched control population.43 In the DCCT population seen despite a less significant increase in body weight
(n = 1,569) lipids and lipoproteins were similar to non- and marginal worsening of blood pressure and glycemic
diabetic subjects participating in the Lipid Research parameters amongst the cohorts. The lipid changes were
Clinics Program.44 not related to the lipid lowering therapy because less than
In fact, type 1 diabetic subjects who are in good control 2% of the population was receiving it.51
tend to have normal (and sometimes even better than
normal) levels of lipoproteins (lower levels of triglyceride Risk Calculation of CHD and Stroke in Diabetes
and cholesterol and higher levels of HDL cholesterol).45,46 and Primary and Secondary Prevention
Regarding qualitative changes in plasma lipids, it may The Framingham study first provided the means
be noted that LDL size is not different in type 1 diabetes of calculating the risk estimation for CHD (10-year
756 Comorbid Conditions

probability of CHD by Framingham point score, based Tests

on age, smoking, treatment of blood pressure, systolic
Total cholesterol, HDL cholesterol and triglyceride should
blood pressure and total cholesterol and HDL cholesterol)
be checked on fasting state (only triglyceride levels are
and which is adopted by National Cholesterol Education
significantly affected by meals within previous 12 hours).
Program-Adult Treatment Panel III (NCEP-ATP III). But
Unless there is urgency, lipid profile should be checked
the validity of the equation was not tested in diabetic
only after achieving good glycemic control; this can
subpopulation, who seem to have a higher risk compared
obviate some needless lipid lowering prescriptions.
section

to the non-diabetic population. Recently, UKPDS have Most clinical laboratories cannot measure LDL
9

provided a risk estimating method for CHD in diabetics cholesterol directly but give a calculated value based on
incorporating the glycemic parameters as well.52 The risk Friedewald formula; however, as we have already seen,
calculation is needed probably to rationalize aggressive this is liable to be fallacious in diabetics. On the other
intervention to prevent CHD in a high-risk subject. hand, many standard recommendations (e.g. the NCEP in
Whether the same formula is justifiable in type 2 diabetics the USA) on interventions in lipid control depend heavily
is open to question, as there was no evidence in the litera­ on the LDL cholesterol level.54 As a rough substitute
ture to suggest such an approach. This was because the intervention may be initiated at a total cholesterol level
evidence of primary prevention of CHD with statins that is one-and-a-half times the recommended LDL
in diabetes was sparse in the literature, and the proponents cholesterol value.
of the aggressive lipid interventions in diabetes extra­ In diabetics, it may be instructive to know the LDL and
polated the evidence from secondary prevention trial HDL subfractions (especially as the harmful small dense
data. The recently published heart protection study (HPS) LDL may be elevated despite a normal total LDL) as well.
has provided a strong evidence that primary prevention If fasting lipids are normal, there is a scope for studying
of CHD in diabetes with statins is indeed very effective. postprandial lipemia because of known defect in clearing
HPS is the first study involving a large number of patients, chylomicrons in diabetics and which probably has
which has addressed the specific query of benefit of usage influence on atherogenesis.
of statins in people with diabetes with no evident CHD and
having lower than average cholesterol level.53 The evidence TREATMENT OF DYSLIPIDEMIA IN DIABETES
is so robust that based on this single evidence; American Goals
Diabetes Association (ADA) has recently changed its
The ADA recommendation (based on the NCEP-ATP
position statement and recommended that all diabetics
III guidelines) states that the first goal is to lower LDL
older than 40 years and having serum LDL cholesterol
cholesterol followed by HDL cholesterol elevation and
of more than 135 mg/dL with no evident CHD be put
triglyceride lowering.54,55
on statin therapy. Another large study, which involved
The current recommendations of primary goal of
19,342 hypertensive patients (24% of whom were diabetic)
therapy for LDL cholesterol is to lower it to below
without any evident CHD and who had less than average
100 mg/dL. In people with diabetes over the age of
cholesterol showed only marginal benefit of lowering
40 years with a total cholesterol of more than or equal to
cholesterol by statin in the diabetic subgroup.
135 mg/dL, statin therapy is recommended to achieve an
LDL cholesterol reduction of 30% irrespective of baseline
SCREENING FOR DYSLIPIDEMIA IN LDL cholesterol level.
DIABETES Since the publication of ATP III, major clinical trials
of statin therapy with clinical end points have been
Frequency published. These trials addressed issues that were not
This should be done on an annual basis, especially in type examined in previous clinical trials of cholesterol-lowering
2 diabetics because of their higher risk of atherosclerosis- therapy. This necessitated a relook at the problem and
related diseases. Once an abnormality is detected, testing issue new guideline. The recently published updated
may need to be more frequent, e.g. to titrate the dose of recommendation of NCEP-ATP III, it was proposed that
lipid lowering agent. patients with diabetes and manifest cardiovascular disease
 Dyslipidemia in Diabetes 757

it is reasonable to target a goal of less than 70 mg/dL; and Table 51.1: Two-step approach to treatment of hypercholestero­
in people with diabetes without manifest cardiovascular lemia
disease, a target of less than 100 mg/dL (which is equal Nutrient Step I diet Step II diet
to target of non-diabetic with cardiovascular disease) is Total calories To achieve and To achieve and
recommended.56 maintain desirable maintain desirable
Raising HDL cholesterol levels appears desirable, but body weight body weight
pharmacologically difficult in type 2 diabetes. In the recent Total fat < 30% of total < 30% of total

chapter
ADA recommendation, the goal for HDL cholesterol calories calories

51
has been set at more than 40 mg/dL. In women, an HDL Fatty acid
cholesterol goal 10 mg/dL higher may be appropriate. Saturated < 10% of total < 7% of total
Though triglyceride lowering has been recommended, calories calories

there are no widely-accepted targets. However, the Monounsaturated 10–15% of total 10–15% of total
calories calories
recent ADA recommendation suggests pharmacological
Polyunsaturated 10–15% of total ≤ 10% of total
intervention at triglyceride levels more than 400 mg/dL,
calories calories
with a target of 150 mg/dL even in the absence of other risk
Cholesterol < 300 mg/day < 200 mg/day
factors. In the case of severe hypertriglyceridemia (>1,000
Carbohydrate 50–60% of total 50–60% of total
mg/dL), severe dietary fat restriction (<10% of calories),
calories calories
in addition to pharmacological therapy is necessary to
Protein 10–20% of total 10–20% of total
reduce the risk of pancreatitis. Improved glycemic control
calories calories
is also very effective for reducing triglyceride levels and
should be aggressively followed before the introduction of
fibrates.55 sertraline, isotretinoin, cyclosporine, and human immu­
nodeficiency virus protease inhibitors). Correction of the
Treatment Modalities underlying abnormality may cure the dyslipidemia.

The options are lifestyle measures, glycemic control and Lifestyle Measures
specific lipid-modifying drugs. As a general principle,
pharmacological therapy should be initiated only after Diet
behavioral interventions are used. However, in patients Dietary treatment is a necessary foundation of drug
with clinical CHD or very high LDL cholesterol levels (>200 treatment. The NCEP of USA recommends a step I diet
mg/dL), pharmacological therapy should be initiated for practically all Americans, with a step II diet for
along with behavioral therapy. Studies conducted by the greater cholesterol lowering (Table 51.1). In long-term
American Heart Association have found that medical studies, the step II diet decreased serum LDL cholesterol
nutrition therapy can reduce LDL cholesterol only by up concentration 8–15%. A diet more restricted in fat than
to 15–25 mg/dL; hence, if the LDL cholesterol exceeds the in step II diet results in little additional reduction in LDL
goal by 25 mg/dL, the physician may decide to institute cholesterol, rather it raises triglyceride and lowers HDL
pharmacological therapy at the same time as behavioral cholesterol concentrations.58
therapy for high risk patients (e.g. diabetic patients with The benefits of restriction of saturated fat with replace­
a prior myocardial infarction and/or other CHD risk ment by mono and polyunsaturated fats are believed to act
factors).57 in the following manner:
However, before implementing any therapy for • Upregulation of LDL receptors in the liver, allowing
dyslipidemia we must exclude other secondary causes greater hepatic uptake of LDL cholesterol.
like hypothyroidism (even if subclinical), renal disease • Increased conversion of cholesterol to bile acids and
(nephrotic syndrome and chronic renal failure causing increased bile acid secretion from the liver.
separate types of dyslipidemia), alcoholism, liver disease • Secretion of bigger VLDL particles with diminished
(chronic obstructive liver disease as well as acute cholesterol content from the liver.
hepatitis) and drugs (non-specific β-blockers, thiazides, Diets low in fat are invariably rich in carbohydrates,
glucocorticoids, anabolic steroids, estrogen, progestogen, and carbohydrates tend to decrease not only LDL
758 Comorbid Conditions

cholesterol but also HDL cholesterol; the beneficial effect has hypercholesterolemia (remembering, of course,
may thereby be minimized or negated. It has been reco­ that the cutoff levels are more stringent in presence of
gnized that partial replacement of dietary carbo­hydrates diabetes). The diet should also maintain an optimum ratio
by monounsaturated fats not only helps improve glycemic (<10:1) between n-6 and n-3 polyunsaturated fats.
control, but also favorably impacts on the dyslipidemia
in type 2 diabetes (by increase of HDL cholesterol and Exercise
decrease of triglyceride, with no difference of LDL chole­
It can be successfully incorporated in a weight-reducing
section

sterol).58 A recent report suggests that not all carbohydrates

program, and thereby improve (1) insulin sensitivity
lower HDL cholesterol; carbohydrates with a low glycemic
9

and (2) glycemic control. The effects on lipid profile

index may actually raise it.59 While the concept of “good”
are beneficial, with lowering of triglyceride and LDL
and “bad” carbohydrates is interesting, further studies are
cholesterol and elevation of HDL cholesterol.63
needed to confirm it.
While it is well established that the benefits of lifestyle
Special mention may be made of the consumption of
modification in a diabetic extend beyond improvement of
margarines and fish oils.
dyslipidemia, the stark reality is that long-term compliance
Margarine: This is derived by partial hydrogenation of is poor. Hence, pharmacological intervention is required
vegetable oils and is therefore devoid of cholesterol. quite frequently.
However, during this manufacturing process trans-isomers
of polyunsaturated fatty acids are formed, which can raise Glycemic Control
LDL cholesterol and Lp(a) and lower HDL cholesterol.60 At
Both in type 1 and type 2 diabetes, plasma triglyceride falls
present trans-fatty acids may be considered as equivalent
almost parallel with blood glucose, whatever may be the
to saturated fatty acids. So margarine may not be a modality of improving glycemic control. While tightening
safer alternative to butter; in fact, unrestricted intake of of glycemic control in type 1 diabetics causes lipid profile
margarine, in the mistaken belief of its safety, based on to become normal (or, even super-normal!), LDL and HDL
“zero cholesterol” advertisements, may be more harmful. cholesterol usually do not show impressive changes in
Fish oil: In non-diabetics marine fish oils, rich in ω-3 type 2 diabetes.
(n-3) polyunsaturated fatty acids, have multiple salutary As mentioned earlier, there should be no hesitation
effects: (1) reduction of triglyceride; (2) reduction of in using insulin for achieving glycemic control, as this
platelet aggregation; and (3) reduction of blood pressure. does not cause any worsening, in fact can only improve
However, concern has been raised that in type 2 diabetes dyslipidemia. Among the oral hypoglycemic agents,
large doses (> 7 g/day) may be harmful by causing (1) biguanides and thiazolidinediones seem to have an edge
increase in LDL cholesterol and (2) worsening of glycemic over sulfonylureas because of insulin sensitizing property.
control.61 A meta-analysis of 26 published trials on Among thiazolidinediones, pioglitazone appears to be
diabetics has shown that fish oils decrease triglyceride to more lipid-friendly than rosiglitazone.
a significant extent in type 2 diabetic subjects and do not Finally, because of the influence of glycemic control
increase glycated hemoglobin.62 Hence, fish intake may be on lipid levels, it will be cost-effective in most situations
encouraged in the diet, even if fish oil supplementation is (especially relevant in a developing country like ours)
to defer estimation of plasma lipids till reasonable
not indicated routinely in type 2 diabetes.
glycemic control is achieved. About two-thirds of the lipid
In addition to reducing hypercholesterolemia, diet can
abnormalities resolve with glycemic control.64
also help to: (1) achieve weight loss (relevant for the obese)
and thereby reduce hypertriglyceridemia; (2) improve
insulin resistance; and (3) reduce blood pressure.
Specific Lipid-Modifying Drugs
However, it has to be remembered that up to 50% The major classes of lipid-modifying drugs are:
of Indian diabetics (including type 2) may be non- • Statins (HMG-CoA reductase inhibitors)
obese (some are actually underweight) and thus calorie • Fibrates (fibric acid derivatives)
restriction should not be indiscriminately advocated in • Cholesterol absorption inhibitors (bile acid seques­
the Indian context. Moreover, blanket restriction of foods trants and azetidinones)
rich in saturated fats and cholesterol (e.g. butter, ghee, egg, • Nicotinic acid
mutton) will serve no useful purpose unless the individual • Miscellaneous
 Dyslipidemia in Diabetes 759

Table 51.2: Lipid-modifying drugs

Type Mechanism Effect on lipid profile Dose
HMG-CoA reductase ↓Cholesterol synthesis; ↓LDL cholesterol 25–40%; Lovastatin 10–80 mg/d
inhibitor (statin) ↑LDL receptor ↓Triglyceride 10–30% Simvastatin 5–80 mg/d
Atorvastatin 10–80 mg/d
Pravastatin 10–40 mg/d
Fluvastatin 10–40 mg/d
Rosuvastatin 5–20 mg/d

chapter
Pitavastatin 1–4 mg/d

51
Fibrate ↑Fatty acid oxidation→ ↓Triglyceride 25–40% Gemfibrozil 600 mg BD
↓Hepatic triglyceride synthesis ↑HDL cholesterol Bezafibrate 200 mg TD (400 mg OD)
↑LPL ↑or ↓LDL cholesterol Fenofibrate 67–200 mg, or 54–160 mg in
↑Triglyceride hydrolysis micronized form.
Ciprofibrate 100 mg OD
Bile acid sequestrant ↓Reabsorption of bile acids in ↓LDL cholesterol 20–30% Cholestyramine 8–12 g BD or TD
intestine ↑HDL cholesterol Colestipol 10–15 g BD or TD
↑Synthesis of new bile acids and ↑Triglyceride
↑LDL receptor
Ezetimibe ↓Absorption of cholesterol from ↓LDL cholesterol by 15% Ezetimibe 10 mg OD usually along with statin
intestinal micelles
Nicotinic acid ↓Hepatic triglyceride synthesis; ↓LDL cholesterol 15–25% 50–100 mg TD; gradually increased to
↓Secretion of apoB100 contain- ↑VLDL cholesterol 25–35% 1,000–2,500 mg TD
ing lipoprotein; ↑Lp(a) 30%
↓VLDL→LDL conversion HDL cholesterol 25%
↓Triglyceride 25–85%

HMG-CoA: Hydroxymethylglutaryl coenzyme A; LPL: Lipoprotein lipase Lp(a), lipoprotein(a)

Of these, the first three are first-line therapy against achieved with different statins ranging from 25% to 60%;
hypercholesterolemia, while fibrates are most effective for rosuvastatin, atorvastatin and simvastatin are the most
lowering of triglycerides (Table 51.2). efficacious. These drugs also lower triglyceride levels,
The most commonly used groups are the statins and though by a lesser extent of 10–30%, again with atorvastatin
the fibrates, which have been discussed in detail. and simvastatin (along with pravastatin) being more
efficacious than lovastatin, fluvastatin or cerivastatin.
STATINS There can be slight elevation of HDL cholesterol by 5–10%.
Rosuvastatin has been found to have the highest potency
Mechanism of Action to reduce LDL cholesterol amongst the available statins.
These drugs are structurally similar to HMG-CoA, a Pitavastatin is the new statin with a novel effect of apoA1
precursor of cholesterol, and are competitive inhibitors of production in hepatocyte cells thereby increasing the
the rate-limiting enzyme in cholesterol biosynthesis, potential to increase HDL. It is also minimally metabolized
namely HMG-CoA reductase; these agents also upregulate by cytochrome P450 (CYP) enzymes thereby making it free
hepatic LDL receptor activity. Because endogenous of interference from other important drugs employing the
cholesterol synthesis is maximal at night, the statins are cytochrome P450 pathway. The effects of atorvastatin and
best administered in the evening. simvastatin on HDL levels remained constant over the long
Additionally, some statins may activate endothelial term, but the pitavastatin-treated patients experienced
nitric oxide synthase65 and diminish uptake of LDL by vas­ progressive and maintained elevations in HDL over a long
cular smooth muscle cells,66 thus may reduce CHD beyond period.67,68
that achieved by cholesterol lowering. The utility of the statins for both primary prevention
(i.e. prevention in subjects who have not yet suffered
from myocardial infarction) and secondary prevention
Efficacy
(i.e. prevention of progression of CHD in those who have
Statins are the most effective agents for lowering already sustained a myocardial infarction) of heart disease
cholesterol, the maximal LDL cholesterol reduction is now established beyond doubt in the general population;
760 Comorbid Conditions

these drugs cause reduction of coronary artery disease by out to be the most efficacious of the three statins, both for
25–60% and reduce the risk of death from any cause by lowering LDL cholesterol and for reaching the target level
about 30%.69,70 of less than 70 mg/dL for LDL. It was also more effective
There are few studies solely on diabetics. But, the than atorvastatin at raising HDL cholesterol in the dia­
conclusions from diabetic subgroup analyses of the many betes population.75
big trials are that diabetics benefit equally, if not more,
compared to non-diabetics from the use of statins. Adverse Effects
section

Considering secondary prevention trials, we can refer The most common are gastrointestinal upset, muscle
to the diabetic subgroup analysis71 of the Scandinavian
9

aches (not frank myopathy) and hepatitis. Rarer are

Simvastatin Survival Study (4S Study) (5% of the 4,444 myopathy, peripheral neuropathy and central nervous
subjects were diabetic) where LDL cholesterol levels were system (CNS) side effects like insomnia, bad dreams
rather high to start with, or the cholesterol and recurrent and difficulty concentrating. Atorvastatin or pravastatin,
events (CARE) study (11% of the study subjects were which do not penetrate the CNS, may be tried when CNS
diabetic, absolute number of diabetics being 586)72 where side effects are prominent. The risk of myopathy is
mean LDL cholesterol of 139 mg/dL was only modest. In increased in the elderly in presence of renal impairment
the former the reduction of risk of CHD among diabetics and when coprescribed with fibrates, nicotinic acid, eryth­
was 55% (significantly higher than 32% observed in non- romycin or cyclosporine. Cerivastatin has been withdrawn
diabetics), while in the latter the risk reduction was less by its original manufacturer because of reports of fatal
(around 25%) and similar in diabetics and non-diabetics. rhabdomyolysis.
It appears that the benefit is greater, higher the initial LDL Trials of statin therapy have had conflicting findings
cholesterol level. on the risk of development of diabetes mellitus in patients
Primary prevention trials on diabetic subjects with given statins. Meta-analysis of many studies had shown
statins are scarce. In a recently conducted large clinical that statin therapy is associated with a slightly increased
trial in Britain HPS with 40 mg of simvastatin (and risk of development of diabetes, but the risk is low both in
antioxidants) in the age group of 40–75 years to assess absolute terms and when compared with the reduction
the efficacy of primary prevention of CHD in diabetic and in coronary events.76 The risk has also been found to
non-diabetic persons. The results of the study showed be dose dependent, with intensive-dose statin therapy
that with the usage of statin the rate of first major vascular associated with an increased risk of new-onset diabetes
events are reduced by about a quarter.54 compared with moderate-dose statin therapy.77 But the
In the recently published similar primary prevention cardiovascular benefits of statin therapy clearly outweigh
study in 2,838 patients with type 2 diabetes with the risk of developing diabetes.78 Similar benefits were
atorvastatin—collaborative atorvastatin diabetes study observed in the recent analysis of the JUPITER primary
(CARDS) has shown use of atorvastatin in patients with prevention trial, where cardiovascular and mortality
type 2 diabetes causes significant reduction in mortality benefits of statin therapy exceed the diabetes hazard,
by 27%, acute coronary events by 36% and stroke by 48%.73 including in participants at high risk of developing
Rosuvastatin significantly reduced the incidence of diabetes.79
major cardiovascular events in non-diabetic healthy The exact pathophysiology of development of diabetes
persons without hyperlipidemia but with elevated high- with usage of statins as yet are not quite clear. However,
sensitivity C-reactive protein levels (an independent some studies suggest atorvastatin decreases adipocyte
cardiac risk factor). The JUPITER (Justification for the maturation and results in decline in the expression of
Use of Statins in Primary Prevention: An Intervention glucose transporter 4 (GLUT4) in cultured preadipocytes
Trial Evaluating Rosuvastatin) study focused attention on in mice, resulting in decreased insulin sensitivity and
ostensibly healthy individuals with “normal” lipid profiles glucose intolerance.80 It is also possible that the statin
and high C-reactive protein values who benefited from induced insulin resistance may result from inhibition
statin therapy.74 In the VOYAGER (an individual patient of isoprenoid biosynthesis, an intermediary product in
data-meta-analysis of statin therapy in at risk groups: cholesterol biosynthesis.81 Statins may also affect insulin
Effects of rosuvastatin, atorvastatin, and simvastatin) secretion by inhibiting glucose stimulated increase in
study a head to head analysis with the other two statins free cytoplasmic calcium by blocking the L-type calcium
namely atorvastatin and simvastatin, rosuvastatin turned channels.82
 Dyslipidemia in Diabetes 761

FIBRATES Amongst the primary prevention trials, the best known

is the Helsinki heart study; it showed that gemfibrozil
Mechanism of Action caused a significant reduction of CHD events, especially in
These partly resemble short chain fatty acids and increase those with elevated triglyceride and lower HDL cholesterol
the oxidation of fatty acids, which causes diminished levels.89 There was no effect on mortality. The diabetic
triglyceride synthesis and VLDL secretion from the liver; subgroup comprised 135 subjects. In these subjects,
these also increase LPL activity in muscle and adipose gemfibrozil reduced the risk of CHD by 60%, although the

chapter
tissue causing increased triglyceride clearance. result was not statistically significant.

51
Some fibrates may also reduce fibrinogen levels. The SENDCAP (St. Mary’s, Ealing, Northwick Park
diabetes cardiovascular disease prevention) study
Efficacy suggests that improving dyslipidemia in type 2 diabetic
subjects with bezafibrate might result in a reduction in
Fibrates are the most effective triglyceride-lowering the incidence of CHD, despite no effect on the progress
agents, reducing plasma levels by 25–60%; this is of ultrasonically measured arterial disease (in the carotid
accompanied by a beneficial increase in HDL cholesterol and femoral arteries).90
concentration by 10–20%. Depending on initial LDL The FIELD (Fenofibrate Intervention and Event
cholesterol level, they can cause increase (if initial level is Lowering in Diabetes) study has shown that the absolute
low) or decrease (if initial level is high) of LDL cholesterol. benefits of fenofibrate are likely to be greater when
Fenofibrate appears to be the most effective in lowering metabolic syndrome parameters are present. The highest
LDL cholesterol. Fibrates also tend to increase the risk and greatest benefits of fenofibrate are seen among
proportion of favorable large and buoyant LDL particles.83 those with marked hypertriglyceridemia.91 In addition,
To determine the clinical benefit derived from the the effect of fenofibrate was found to be slightly better
apparently favorable influence of fibrates on lipid profile in in patients who did compared to who did not have prior
diabetics, we should examine the results of clinical trials. cardiovascular disease.92
However, these are generally much smaller compared to Another important CVD outcome study on the diabetic
many of the trials on statins. subjects, the ACCORD (Action to control cardiovascular
For secondary prevention, gemfibrozil and bezafibrate risk in diabetes) lipid trial, there were no significant
have been used most often. In the recently reported differences between patients with type 2 diabetes and
bezafibrate coronary angiographic intervention trial a high risk of CVD events who received fenofibrate
(BECAIT), bezafibrate reduced coronary events in 92 plus simvastatin and those who received placebo plus
men over a 5-year period.84 The diabetes atherosclerosis simvastatin for any of the primary or secondary cardio­
intervention study (DAIS) was a multi-centre, double- vascular outcomes. However, fenofibrate plus simvastatin
blind, randomized, placebo-controlled trial in colla­ was of benefit in patients who had markedly high
boration with the WHO, which studied micronized triglyceride levels and markedly low HDL cholesterol
fenofibrate versus placebo in 418 patients with type 2 levels at baseline.93
diabetes for at least 3 years.85 Half of the patients had a There are now robust and consistent clinical data
clinical history of CHD; it was thus a mixture of a primary to which may recommend fenofibrate as an adjunctive
and secondary intervention trial. It showed significantly treatment for early diabetic retinopathy in patients with
less angiographic progression of coronary artery disease type 2 diabetes.94
in the fenofibrate group.86 Another large secondary
prevention trial, the bezafibrate infarction prevention Adverse Effects
trial, is underway in Israel on 3,000 diabetics.87 Most common are gastrointestinal upsets (more with
In a study from Finland, comparing the efficacy of gemfibrozil) and gallstones. Others include erectile
simvastatin and gemfibrozil in diabetic patients, it was dysfunction in men and myositis.
found that simvastatin was useful in both mixed and In one placebo-controlled study clofibrate use was
isolated hypercholesterolemia, whereas gemfibrozil was associated with higher mortality as a result of diseases
useful in patients with high triglyceride and low or normal of the biliary tract and cancer, though this has not been
LDL cholesterol levels.88 reproduced in other studies, or with other fibrates.
762 Comorbid Conditions

Fenofibrate causes an initial but reversible rise in induced by ezetimibe, were associated with an increase
plasma creatinine, which is not long lasting, and it reduced in the carotid intima-media thickness led to premature
albuminuria and slowed the estimated glomerular filtra­ termination of the trial.100
tion rate loss over 5 years.95,96 Nicotinic acid or niacin is a very useful agent in the
treatment of dyslipidemia. It decreases LDL cholesterol
EZETIMIBE and triglycerides, increases HDL cholesterol to a
significant extent and is the only agent known to reliably
Ezetimibe belongs to a group of selective and very effective
section

decrease Lp(a); the major adverse effect being flushing

2-azetidinone cholesterol absorption inhibitors, which act
9

of skin and rarely hepatitis. It was believed to have the

on the level of cholesterol entry into enterocytes. Recent
tendency to worsen glycemic control in patients with
data indicated that the drug prevents the formation of a
diabetes. But recent data from clinical trials on patients
heterocomplex consisting of annexin-2 and caveolin-l
with diabetes have put to rest such unfounded fears, and
and leads to specific inhibition of an NPCILI-dependent
niacin can be safely used in patients with diabetes, and
cholesterol uptake pathway required for uptake of
niacin therapy may be considered as an alternative to
micellar cholesterol into enterocytes.97 Ezetimibe does not
statin drugs or fibrates for patients with diabetes in whom
inhibit cholesterol synthesis in the liver, or increase bile
acid excretion. Instead, ezetimibe localizes and appears to these agents are not tolerated or fail to sufficiently correct
act at the brush border of the small intestine and inhibits hypertriglyceridemia or low HDL levels.101 As noted earlier,
the absorption of cholesterol, leading to a decrease in the the ARBITER6-HALTS study, noted clear superiority of
delivery of intestinal cholesterol to the liver. This causes niacin over ezetimibe, provide support for the concept
a reduction of hepatic cholesterol stores and an increase that the use of statins to reduce LDL cholesterol to target
in clearance of cholesterol from the blood; this distinct levels with the subsequent addition of a drug to raise HDL
mechanism is complementary to that of HMG-CoA cholesterol levels (niacin), rather than a drug to lower LDL
reductase inhibitors.97 cholesterol levels (ezetimibe), is a more effective treatment
Ezetimibe is not recommended as a monotherapy for patients at high cardiovascular risk. However, it fails
option till date. But in a clinical trial setting it has to answer whether this result is due to the effect of niacin
significantly reduced LDL cholesterol by a mean of 16.9%, on HDL cholesterol, LDL cholesterol, remnants, Lp(a)
compared with an increase of 0.4% with placebo in patients lipoprotein, high-sensitivity C-reactive protein, or any
with primary hypercholesterolemia.98 combination of these factors.100,102
In a double-blind, placebo-controlled study in patients However, in a recently concluded study (AIM-HIGH)
with primary hypercholesterolemia, ezetimibe when patients with atherosclerotic cardiovascular disease
co-administered with statin significantly lowered total-C, and LDL cholesterol levels of less than 70 mg/dL, no
LDL and triglyceride, and increased HDL cholesterol incremental clinical benefit could be attained from the
compared to placebo (coadministration therapy with addition of niacin to statin therapy.103
statin caused additional reduction of LDL cholesterol In a recently concluded large trial whose results are
by 34–41%, triglyceride by 21–23%, and increased HDL yet to be published, the HPS2-THRIVE Study on 25,673
cholesterol by 7.8–8.4%, depending on the dose of statin.99 patients and followed up for nearly 4 years, which focused
In a recently concluded study ARBITER6-HALTS on the people with established vascular insults (myocardial
(arterial biology for the investigation of the treatment infarction, stroke or peripheral vascular disease) to assess
effects of reducing cholesterol 6-HDL and LDL treatment whether by increasing the HDL by addition of niacin and
strategies in atherosclerosis) trial, designed to address laropiprant to statin further reduces the risk of myocardial
the question of whether the addition of ezetimibe (to infarction, stroke or peripheral vascular revascularizations.
further reduce LDL cholesterol levels) or the addition of Niacin by binding to the dermal Langerhans cell receptor
niacin (to improve levels of multiple lipoproteins) is more increases the production and release of prostaglandin D2,
effective in decreasing the progression of carotid intima- a vasodilator. Laropiprant was added to niacin to reduce
media thickness (a surrogate measure of atherosclerosis) the flushing, as laropiprant blocks the prostaglandin D2
in patients receiving statin therapy, showed a clear receptors in the dermal vascular channels. The study
superiority of niacin over ezetimibe. The unexpected showed that the addition of niacin with laropiprant to
finding that large reductions in the LDL cholesterol level, increase HDL fails to lower the vascular risk.104
 Dyslipidemia in Diabetes 763

Bile acid sequestrants, like colesevelam, are now A meta-analysis of 41 trials showed that intake of
used only as adjuncts to statins for further lowering of 2 g/day of stanols or sterols reduced LDL by 10%. Effects
cholesterol. In addition to lowering total cholesterol in are additive with diet or drug interventions: eating foods
patients with diabetes, it causes modest improvement in low in saturated fat and cholesterol and high in stanols or
the glycemic control. An important limitation is their sterols can reduce LDL by 20%; adding sterols or stanols
tendency to raise triglyceride levels. Prominent gastro­ to statin medication is more effective than doubling the
intestinal side effects often affect patient compliance.105 statin dose.111

chapter
Cholesteryl ester transfer protein (CETP) is a plasma In a randomized prospective trial with plant stanol

51
protein that mediates the exchange of cholesteryl ester esters on children with the aim of atherosclerosis
in HDL for triglyceride in VLDL. This process decreases prevention in childhood (STRIP study). The results
the level of anti-atherogenic HDL cholesterol and incre­ showed that plant stanol esters reduce serum cholesterol
ases pro-atherogenic VLDL and LDL cholesterol, so concentration in healthy children irrespective of their
CETP is believed to be potentially atherogenic. A CETP gender or apoE4 phenotype.112
inhibitor thereby may increase the HDL concentration. A
synthetic CETP inhibitor known as torcetrapib has been MISCELLANEOUS
used in a randomized controlled trial in humans to note
Orlistat, a pancreatic lipase inhibitor, was noted to cause
the efficacy of elevating HDL cholesterol. The results
significant reductions in total cholesterol, LDL cholesterol,
of the trial suggest that torcetrapib increases HDL to a
triglycerides and apoB concentration in obese type 2
significant extent as monotherapy (46–106%), whereas in
diabetics.113
association with atorvastatin, there is further elevation of
Similar results have been reported with pramlintide, a
HDL.106 However, the research on torcetrapib was halted
synthetic amylin analogue.114
in 2006 when phase III studies showed excessive all-cause
Acipimox is a nicotinic acid congener, and does not
mortality in the treatment group receiving a combination
worsen glycemic control in diabetes. It causes significant
of atorvastatin and torcetrapib.107 Anacetrapib, another
triglyceride lowering along with decreasing total
CETP inhibitor which increases HDL by 44–133%108 is
cholesterol and apoB. But, it has no significant effect in
undergoing development and proved its efficacy and
safety in a study.109 Dalcetrapib is another CETP inhibitor elevating HDL cholesterol or apoA1 level.115
which is also under investigation for its efficacy as a Fish oils containing eicosapentaenoic acid and
lipid modifier especially increasing the HDL to the tune docosahexaenoic acid (n-3 polyunsaturated fatty acids)
of 33%.110 are known to decrease triglycerides. However, as already
Plant sterols and stanols, which are structurally related discussed, large doses increase LDL cholesterol and may
to cholesterol, decrease the incorporation of dietary and worsen glycemic control.
biliary cholesterol into micelles. This lowers cholesterol Dietary “soluble” fibers, like guar gum and pectin,
absorption. Furthermore, these components increase cause mild lowering of cholesterol.
ATP-binding cassette (ABC)-transporter expression, Oral estrogen in post-menopausal women can lower
which may also contribute to the decreased cholesterol LDL cholesterol by 10% and raise HDL cholesterol by 15%.
absorption. Consequently, cholesterol synthesis and Finally, severe hypercholesterolemia can be treated by
LDL receptor activity increase, which ultimately leads to apheresis.
decreased serum LDL cholesterol concentrations.
Plant sterols and stanols also lower plasma lipid-
NOVEL VISTAS IN LIPID MODIFICATION
standardized concentrations of the hydrocarbon carote­ Many other modalities are still at an experimental stage.
noids but not those of the oxygenated carotenoids and Squalene synthase is the enzyme that converts farnesyl
tocopherols. Also, vitamin A and D concentrations are pyrophosphate to squalene in the cholesterol biosyn­
not affected. Although absorption of plant sterols and thesis pathway, and inhibitors of squalene synthase
stanols (0.02–3.5%) is low compared to cholesterol enzyme, namely TAK-475 and 1,1-bisphosphonates inhi­
(35–70%), small amounts are found in the circulation and bit hepatic cholesterol biosynthesis. They have shown
may influence other physiological functions. significant lowering of LDL cholesterol and triglyceride
764 Comorbid Conditions

in animal studies but does not cause an elevation of compound, which effectively lowers LDL cholesterol.
HDL cholesterol.116,117 Microsomal triglyceride transfer Lifibrol causes a competitive inhibition of HMG-CoA
protein (MTP) inhibitors are agents, which block the synthase, an important enzyme in the cholesterol
hepatic secretion of VLDL and the intestinal secretion of synthesis pathway. It however does not have the property
chylomicrons. Hence, they are powerful agents to cause of inhibiting the HMG-CoA reductase. A potential
reduction of postprandial lipemia, but suffer from the advantage of lifibrol is that therapeutic concentrations do
drawback of potential adverse effects due to blockage of not interfere with the production of mevalonate, which
section

intestinal fat absorption and hepatic lipid secretion.118 is required not only to synthesize sterols but also as a
9

Implitapide, a new MTP inhibitor, reduces plasma precursor of electron transport moieties, glycoproteins
cholesterol and triglyceride levels by 70% and 45%, and farnesylated proteins.126 Peroxisome proliferator
and VLDL secretion rate by liver by 80%.119 Naringenin, activated receptor-alpha (PPAR-α) plays a significant role
the principal flavonoid in grapefruit, reduces plasma in lipid metabolism in addition to its activity in the glucose
lipids in vivo as well as inhibits apoB secretion and metabolism. Activation of PPAR-α leads to an elevation
cholesterol esterification. The possible mechanism of of HDL cholesterol and reduction of triglycerides. A novel
action is by inhibition of hepatic MTP activity.120 The acyl- compound PD-72953 is found to have PPAR-α stimulating
CoA:cholesterol acyltransferase (ACAT) is an important property. Animal studies have shown that PD-72953
enzyme in the cholesterol transport pathway. Inhibitors causes an elevation of HDL cholesterol and reduction of
of this enzyme namely avasimibe, KY-455 and MCC-147 triglycerides.127
have shown significant reduction of serum esterified and
free LDL cholesterol levels. ACAT inhibitors increase RATIONAL CHOICE OF DRUGS
reversible binding of apoA-I to the cells and enhance
This is guided primarily by the type of dyslipidemia;
apoA-I-mediated release of cellular cholesterol and
comorbid conditions also need to be considered.
phospholipid but did not influence non-specific cellular
For isolated moderate hypercholesterolemia due to
cholesterol efflux to lipid microemulsion. It was therefore
elevated LDL cholesterol, the first choice is a statin.
concluded that the ACAT inhibitor increased the release
While there is really not much of a difference between
of cholesterol from the cholesterol-loaded macrophages
the different statins, for coexistent mild to moderate
by increasing the expression of ABCA1, putatively through
hypertriglyceridemia atorvastatin scores over the other
shifting cholesterol distribution from the esterified to the
agents; for individuals developing CNS side effects with
free compartments.121,122 SC-435, a competitive inhibitor
simvastatin, atorvastatin or pravastatin may be tried.
of ileal apical sodium-dependent bile acid cotransporter
For severe hypercholesterolemia, a statin may be
(ASBT) inhibits ileal bile acid absorption, and the hepatic
combined with ezetimibe.
nuclear receptor FXR (farnesoid X receptor), which
For moderate hypertriglyceridemia with low HDL
regulates cholesterol 7 alpha-hydroxylase. To keep the
cholesterol and normal LDL cholesterol, treatment is best
biliary bile acid output intact liver increases bile acid
initiated with a fibrate.
production from hepatic cholesterol. This leads to lowering
For severe hypertriglyceridemia, fish oils may be added
of plasma cholesterol. This agent has shown promise in
to fibrates.
animal studies.123 Upregulation of LDL receptor (LDLr) is a
For moderate mixed dyslipidemia, a statin or a fibrate
key mechanism to control elevated plasma LDL cholesterol
may be tried first; it may be necessary to combine the two,
levels. A new class of compounds has been detected that
of course, with greater safety monitoring.
directly binds to the sterol regulatory element-binding
In presence of renal failure, statins are safer than
protein (SREBP) cleavage-activating protein (SCAP). SCAP
fibrates because of predominant biliary excretion.
ligands reduced both LDL cholesterol and triglyceride
levels by up to 80%.124 Gemcabene, a new lipid-altering CONCLUSION
agent has undergone an efficacy and tolerability study
in a double-blind, randomized controlled trial and has Cardiovascular complications in type 2 diabetics is
shown its efficacy in reducing LDL cholesterol but lacks pretty common, which has been documented in various
the property of elevating HDL cholesterol or reducing large prospective trials. This is not decreased by strict
triglycerides.125 Lifibrol is a new hypocholesterolemic glycemic control alone. Dyslipidemia in the form of
 Dyslipidemia in Diabetes 765

increased triglyceride and decreased HDL cholesterol 4. Bierman EL. Atherogenesis in diabetes (review). Arterio­
has been noted to be a common occurrence in type 2 scler Thromb. 1992;12:647-56.
diabetics. Increased LDL cholesterol has been implicated 5. Caslake MJ, Packard CJ, Series JJ, et al. Plasma triglyceride
and low density lipoprotein metabolism. Eur J Clin Invest.
as the etiological agent in the causation of atherosclerotic
1992;22:96-104.
vascular disease. In diabetics, apart from the genetic 6. De Graaf J, Hak-Lemmers HLM, Hectors MPC, et al.
dyslipidemic phenotype, qualitative change in LDL Enhanced susceptibility to in vitro oxidation of the dense
cholesterol (LDL B phenotype and oxidized LDL) has also low density lipoprotein subfraction in healthy subjects.

chapter
been implicated as the cause of increased incidence of Arterioscler Thromb. 1991;11:298-306.

51
cardiovascular complications. The decreased HDL choles­ 7. Law MR, Wald NJ, Wu T, et al. Systematic underestimation
of association between serum cholesterol concentration
terol concentration also contributes to the increased
and ischaemic heart disease in observational studies: data
incidence of cardiovascular disease. Insulin resistance from the BUPA study. BMJ. 1994;308:893-6.
and/or hyperinsulinemia has been implicated as the 8. Gordon DJ, Probstfield JL, Garrison RJ, et al. High density
etiological phenomenon behind the increased triglyceride lipoprotein cholesterol and cardiovascular disease: four
and decreased HDL cholesterol concentration. In type 1 prospective American studies. Circulation. 1989;79:8-15.
diabetics, HDL cholesterol does not decrease and lipid 9. Hokanson JE, Austin MA. Plasma triglyceride level is a risk
disorder is closely related to degree of hyperglycemia. factor for cardiovascular disease independent of high-den­
sity lipoprotein cholesterol level: a meta-analysis of popu­
All type 2 diabetics should undergo annual lipid check
lation-based prospective studies. J Cardiovasc Risk. 1996;3:
up for cholesterol, triglyceride and HDL cholesterol. 213-9.
The treatment goals for diabetic with or without CHD 10. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceri­
is stricter compared to people without diabetes. The demia as a cardiovascular risk factor. Am J Cardiol. 1998;81:
ADA recommendation for treatment of dyslipidemia in 7B-12B.
diabetics harps on LDL lowering. Statins are the most 11. Haffner SM, Morales PA, Stern MP, et al. Lp(a) concentra­
tions in NIDDM. Diabetes. 1992;41:1267-72.
common drugs used followed by fibrates.
12. Haffner SM. Management of dyslipidemia in adults with
diabetes (Technical Review). Diabetes Care. 1998;21:160-78.
FURTHER READING 13. American Diabetes Association. Management of dyslipi­
demia in adults with diabetes (position statement). Diabe­
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tes Care. 1998;21:179-82.
lipid disorders in diabetes. In: Kahn CR, Weir GC, King GL,
14. Wilson PW, Kannel WB, Anderson KM. Lipids, glucose
Moses AC, Smith RJ, Jacobson AM, (Eds). Joslin’s Diabetes
tolerance and vascular disease: the Framingham Study.
Mellitus, 14th edition. Philadelphia: Lippincott Williams &
Wilkins; 2005. pp. 563-84. Monogr Atheroscler. 1985;13:1-11.
2. Viljoen A, Wierzbicki AS. Dyslipidemia: Diabetes Lipid 15. Harris MI. Hypercholesterolemia in diabetes and glu­
Therapies. In: Holt RIG, Cockram C, Flyvbjerg A, Goldstein cose intolerance in the U.S. population. Diabetes Care.
BJ. Textbook of Diabetes, 4th edition. West Sussex, UK: 1991;14:366-74.
Wiley-Blackwell; 2011. pp 672-83. 16. Steiner G. The dyslipoproteinemias of diabetes. Atheroscle­
3. Laker MF, Neely RDG. Monitoring of Lipids in Diabetes. rosis. 1994;110:S27-S33.
In: Ferrannini E, DeFronzo RA, Keen H. International Text­ 17. UKPDS Group. U.K. prospective diabetes study 27: plasma
book of Diabetes Mellitus, 3rd edition. 2004. West Sussex, lipids and lipoproteins at diagnosis of NIDDM by age and
UK: Wiley-Blackwell; 2013. pp 1713-27. sex. Diabetes Care. 1997;20:1683-7.
18. Haffner SM, Stern MP, Hazuda HP, et al. Cardiovascular
risk factors in confirmed prediabetic individuals. Does the
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82. Yada T, Nakata M, Shiraishi T, et al. Inhibition by simvas­ 94. Wong TY, Simó R, Mitchell P. Fenofibrate-a potential
tatin, but not pravastatin, of glucose-induced cytosolic systemic treatment for diabetic retinopathy? Am J Ophthal­
Ca2+ signalling and insulin secretion due to blockade of mol. 2012;154:6-12.
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1999;126:1205-13. renal function in patients with type 2 diabetes mellitus: the
83. De Graaf J, Hendriks JC, Demacker PN, et al. Identifica­ fenofibrate intervention and event lowering in diabetes
tion of multiple dense LDL sub-fractions with enhanced (FIELD) study. Diabetologia. 2011;54:280-90.
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section

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85. Steiner G. The diabetes atherosclerosis intervention study 2004;320:1337-41.
(DAIS): a study conducted in co-operation with the World 98. Dujovne CA, Ettinger MP, McNeer JF, et al. Ezetimibe
Health Organization; The DAIS Project Group. Diabeto­ study group. Efficacy and safety of a potent new selective
logia. 1996;39:1655-61. cholesterol absorption inhibitor, ezetimibe, in patients
86. Goldbourt U, Behar S, Reicher-Reiss H, et al. Rationale and with primary hypercholesterolemia. Am J Cardiol. 2002;90:
design of a secondary prevention trial of increasing serum 1092-7.
high-density lipoprotein cholesterol and reducing triglyc­ 99. Melani L, Mills R, Hassman D, et al. Ezetimibe study group.
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simvastatin and gemfibrozil with NIDDM. A multicenter niacin or ezetimibe and carotid intima–media thickness.
study. Diabetes Care. 1998;21:477-81.
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88. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of
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serum triglyceride and LDL cholesterol and HDL choles­
niacin on lipid and lipoprotein levels and glycemic control
terol concentrations on coronary heart disease risk in the
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the ADMIT study: A randomized trial. Arterial disease
tion. 1992;85:37-45.
multiple intervention trial. JAMA. 2000;284:1263-70.
89. Koskinen P, Mänttäri M, Manninen V, et al. Coronary heart
102. Kastelein JJP, Bots ML. Statin therapy with ezetimibe or
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90. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular
103. The AIM-HIGH investigators. Niacin in patients with low
outcomes in type 2 diabetes. A double-blind placebo-con­
HDL cholesterol levels receiving intensive statin therapy.
trolled study of Bezafibrate: the St. Mary’s, Ealing, North­
N Engl J Med. 2011;365:2255-67.
wick Park diabetes cardiovascular disease prevention
(SENDCAP) study. Diabetes Care. 1998;21:641-48. 104. Armitage J, Baigent C, Chen Z, et al. A randomized trial
91. Scott R, O’Brien R, Fulcher G. Effects of fenofibrate treat­ of the long-term clinical effects of raising HDL choles­
ment on cardiovascular disease risk in 9,795 individu­ terol with extended release niacin/laropiprant. Avail­
als with type 2 diabetes and various components of the able at: http://clinicaltrials.gov/ct2/show/NCT00461630,
metabolic syndrome: the Fenofibrate Intervention and http://www.ctsu.ox.ac.uk/hps2-thrive/ [Accessed January
Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2013].
2009;32:493-8. 105. Younk LM, Davis SN. Evaluation of colesevelam hydro­
92. Tonkin A, Hunt D, Voysey M, et al. Effects of fenofibrate on chloride for the treatment of type 2 diabetes. Expert Opin
cardiovascular events in patients with diabetes, with and Drug Metab Toxicol. 2012;8:515-25.
without prior cardiovascular disease: The fenofibrate inter­ 106. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an
vention and event lowering in diabetes (FIELD) study. Am inhibitor of cholesteryl ester transfer protein on HDL
Heart J. 2012;163:508-14. cholesterol. N Engl J Med. 2004;350:1505-15.
93. Keating GM. Fenofibrate: a review of its lipid-modifying 107. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torce­
effects in dyslipidemia and its vascular effects in type 2 trapib in patients at high risk for coronary events. N Engl
diabetes mellitus. Am J Cardiovasc Drugs. 2011;11:227-47. J Med. 2007;357:2109-22.
 Dyslipidemia in Diabetes 769

108. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and 118. Chang G, Ruggeri RB, Harwood HJ Jr. Microsomal triglyc­
safety of the cholesteryl ester transfer protein inhibitor eride transfer protein (MTP) inhibitors: discovery of clini­
anacetrapib as monotherapy and coadministered with cally active inhibitors using high-throughput screening and
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352-60.e2. 2002;5:562-70.
109. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib 119. Shiomi M, Ito T. MTP inhibitor decreases plasma choles­
in patients with or at high risk for coronary heart disease. terol levels in LDL receptor-deficient WHHL rabbits by
N Engl J Med. 2010;363:2406-15. lowering the VLDL secretion. Eur J Pharmacol. 2001;431:

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110. Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of 127-31.
120. Borradaile NM, de Dreu LE, Barrett PH, et al. Hepatocyte

51
dalcetrapib (RO4607381/JTT-705): results from a 48-week
apoB-containing lipoprotein secretion is decreased by
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the grapefruit flavonoid, naringenin, via inhibition of
111. Miettinen TA, Gylling H. Plant stanol and sterol esters in
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112. Tammi A, Ronnemaa T, Miettinen TA, et al. Effects of
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gender, apolipoprotein E phenotype and cholesterol-low­ of ATP-binding cassette transporter A1 and thereby
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Special Turku Coronary Risk Factor Intervention Project. macrophages. Biochim Biophys Acta. 2004;1636:69-76.
Acta Paediatr. 2002;91:1155-62. 122. Raal FJ, Marais AD, Klepack E, et al. Avasimibe, an ACAT
113. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat inhibitor, enhances the lipid lowering effect of atorvas­
in the treatment of obese patients with type 2 diabetes. tatin in subjects with homozygous familial hypercholes­
A 1-year randomized double-blind study. Diabetes Care. terolemia. Atherosclerosis. 2003;171:273-9.
1998;21:1288-94. 123. Li H, Xu G, Shang Q, et al. Inhibition of ileal bile acid
114. Thompson RG, Pearson L, Schoenfeld SL, et al. Pramlintide, transport lowers plasma cholesterol levels by inactivating
a synthetic analogue of human amylin, improves the meta­ hepatic farnesoid X receptor and stimulating cholesterol
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The pramlintide in type 2 diabetes group. Diabetes Care. 124. Grand-Perret T, Bouillot A, Perrot A, et al. SCAP ligands are
1998;21:987-93. potent new lipid-lowering drugs. Nat Med. 2001;7:1332-8.
125. Bays HE, McKenney JM, Dujovne CA, et al. Effectiveness
115. Fulcher GR, Catalano C, Walker M, et al. A double blind
and tolerability of a new lipid-altering agent, gemcabene,
study of the effect of acipimox on serum lipids, blood
in patients with low levels of high-density lipoprotein
glucose control and insulin action in non-obese patients
cholesterol. Am J Cardiol. 2003;92:538-43.
with type 2 diabetes mellitus. Diabet Med. 1992;9:908-14. 126. Scharnagl H, Schliack M, Loser R, et al. The effects of lifibrol
116. Nishimoto T, Amano Y, Tozawa R, et al. Lipid-lowering (K12.148) on the cholesterol metabolism of cultured cells:
properties of TAK-475, a squalene synthase inhibitor, in evidence for sterol independent stimulation of the LDL
vivo and in vitro. Br J Pharmacol. 2003;139:911-18. receptor pathway. Atherosclerosis. 2000;153:69-80.
117. Ciosek CP Jr, Magnin DR, Harrity TW, et al. Lipophilic 127. Bisgaier CL, Essenburg AD, Barnett BC, et al. A novel

1,1-bisphosphonates are potent squalene synthase inhibi­ compound that elevates high density lipoprotein and
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Biol Chem. 1993;268:24832-37. J Lipid Res. 1998;39:17-30.
Section 10

COMPLICATIONS
Section Editor: Gumpeny Ramachandra Sridhar
 Chapter 52
Diabetes Complications:
Overview
SV Madhu

Diabetes Complications

Chapter Outline
♦♦ Diabetes Exposure and Risk of Complications ♦♦ Cellular and Molecular Mechanisms of
♦♦ Importance of Glycemic Control in Development Hyperglycemia-Induced Cellular Damage
of Chronic Complications ♦♦ Role of Oxidative Stress in Development of
♦♦ Mechanisms of Diabetic Tissue Damage Diabetic Complications

INTRODUCTION Table 52.1: United Kingdom prospective diabetes study: summary

of results2
The disease burden of diabetes mellitus (DM) is prima­ Endpoint risk reduction of
rily due to its many complications. Diabetes exposure, complications:
which results from the level as well as duration of hyper­ Any diabetes related endpoint 12%
glycemia favors the development of several long‑term Microvascular endpoints 25%
complications of the eye, kidney and heart. Several
Myocardial infarction 16%
carefully conducted, prospective, randomized clinical
Cataract extraction 24%
studies like Diabetes Complications and Control Trial
Retinopathy at 12 years 21%
(DCCT),1 United Kingdom Prospective Diabetes Study
Albuminuria at 12 years 33%
(UKPDS)2 (Table 52.1) and the Kumamoto study3 have
clearly shown that strict control of glycemia prevents or
postpones complications in both type 1 diabetes melli­ Table 52.2. The late vascular complications may be micro­
tus (T1DM) and type 2 diabetes mellitus (T2DM). Also, vascular or macrovascular.
there has been substantial progress in the past 2–3
decades in our understanding of the pathways that lead DIABETES EXPOSURE AND
to the development of chronic complications in DM. RISK OF COMPLICATIONS
Oxidative stress, protein kinases C (PKC) and advanced
glycation end products (AGE) pathways among others Retinopathy, particularly non-proliferative retinopathy is
have been elucidated. This has not only contributed to seen in DM but is very rare in those without diabetes
our understanding of pathogenesis of diabetic complica­ suggesting that it is diabetes exposure that drives its
tions but has also opened up novel areas of therapeutic development.4
potential. Diabetes Complications and Control Trial for the first
A wide spectrum of complications may develop in case time established the dose-response relationship between
of diabetes. These include the acute metabolic complica­ hyperglycemia and the development and progression
tions, the late complications and others as shown in of diabetic retinopathy. A non-linear threshold value
 774 Complications

Table 52.2: Complications of diabetes mellitus ocular factors also increase the risk of retinopathy in the
Acute metabolic complications diabetic patient.4
•• Diabetic ketoacidosis (DKA)
The natural history of diabetic kidney disease, progres­
ses from normoalbuminuria to microalbuminuria and
•• Hyperosmolar hyperglycemic non-ketotic state (HHNS)
overt proteinuria and from there to end stage renal
•• Lactic acidosis
diseases (ESRD).5 Many studies have demonstrated that
Chronic complications
the level of diabetes exposure is the strongest risk factor
section

•• Microvascular for progression from normoalbuminuria to microalbu­

10

–– Retinopathy minuria6,7 with the threshold value for HbA1c being 8.1%.8
–– Nephropathy However, the effect of hyperglycemia on the progression
–– Neuropathy of microalbuminuria to overt proteinuria and then to
•• Macrovascular ESRD is not so clear. A number of factors other than hyper­
–– Hypertension glycemia increase the risk of predisposition to diabetic
–– Coronary heart disease (CHD) kidney disease. These include hypertension, cigarette
–– Cerebrovascular disease (CVD) smoking, high serum low-density lipoprotein (LDL) and
–– Peripheral vascular disease (PVD)
cholesterol levels. Genetic predisposition to diabetic
kidney disease may also promote development of overt
Others
proteinuria.4 While all these risk factors have been clearly
•• Cardiac
demonstrated in T1DM, data in patients with T2DM is
–– Diabetic cardiomyopathy
less well documented. Available data suggest a similar
•• Infection
relationship by and large. Studies in Asians, where T1DM
–– Bacterial, fungal, mycobacterial is rare and T2DM occurs at a younger age, have shown that
•• Ocular there is a higher risk of diabetic nephropathy. This may be
–– Infections due to poorer glycemic control or due to a higher genetic
–– Cataract or other environmental susceptibility among Asians.8
–– Glaucoma Diabetes is frequently associated with the development
•• Dermatological of premature atherosclerotic vascular disease.9 This incre­
–– Necrobiosis lipoidica diabeticorum ased risk has been attributed to the high prevalence of
–– Granuloma annulare multiple atherosclerotic risk factors.9,10 However, the
–– Diabetic bullae
excess of coronary artery disease (CAD) in type 2 diabetics
cannot be accounted for only by the four major risk factors
–– Diabetic sclerederma
identified for CAD viz. hypertension, smoking, serum
•• Connective tissue
cholesterol and age suggesting a role for other factors.9,10
–– Osteopenia, osteoarthritis
Diabetes specific exposure including hyperglycemia, dia­
–– Scleroderma diabetic corum
betic dyslipidemia, treatment with insulin and diabetic
–– Carpal tunnel syndrome nephropathy are all believed to contribute to this increase
–– Dupuytren’s disease in risk4 but still cannot explain the entire risk. Thus, there
–– Flexor tenosynovitis has been a search for non-conventional increase in risk
–– Adhesive capsulitis of shoulder factors like Lp(a), homocysteine and postprandial (PP)
–– Limited joint mobility (LJM) lipemia.
•• Oral Lipid abnormalities in the post-prandial state parti­
–– Periodontal disease cularly hypertriglyceridemia may contribute significantly
–– Caries, xerostomia and candidiasis to the development of macrovascular complications.11,12
Postprandial hypertriglyceridemia is associated with
carotid intimal medial thickness13 and with postprandial
of 8.5% HbA1c above which there is a steep rise in inci­ oxidative stress and endothelial dysfunction.14 These sug­
dence of retinopathy has been demonstrated.1 Several gest that postprandial lipemia particularly postprandial
other allied factors such as, hypertension, neuropathy; hypertriglyceridemia plays an important role in diabetes
cardiac autonomic neuropathy; dyslipidemia and local related atherosclerotic vascular disease (Fig. 52.1).
 Diabetes Complications: Overview 775

chapter
52
Fig. 52.1: Post-prandial lipid abnormalities in type 2 diabetes mellitus Fig. 52.2: Diabetes complications and control trial: relationship of
glycosylated hemoglobin and diabetes complications

The risk of CAD in diabetes is seen much before the Wisconsin epidemiological study of diabetic retino­
diagnoses of diabetes well into the prediabetes categories pathy demonstrated a strong and consistent relationship
particularly impaired glucose tolerance (IGT). There is a between glycemia (baseline glycated hemoglobin) and
wide variation in the prevalence of CAD among different incidence and progression of microvascular (diabetic
diabetic populations. This has been attributed to the fact retinopathy, vision loss and nephropathy) and macro­
that prediabetic (insulin resistance and hyperinsulinemia) vascular (lower extremity amputation and cardi­ovascular
and diabetic exposure may affect the progression but disease mortality) complications in patients with either
not the frequency of atherosclerotic lesions so that pop­ type of DM.
ulations with infrequent initial atherosclerosis like Pima Several prospective intervention trials were conducted
Indians, Tokyo-Japanese and Hongkong Chinese, may in the 70s and 80s particularly in T1DM. The Steno, Oslo
remain unaffected by diabetes exposure.4 and Kroc studies using continuous subcutaneous insulin
infusion (CSII), the Stockholm Diabetes Intervention
IMPORTANCE OF GLYCEMIC Study (SDIS) using multiple dose insulin injections (MDI),
and the Dallas Diabetes Prospective Trial (DDPT) were
CONTROL IN DEVELOPMENT OF
the most important. All the studies reported in varying
CHRONIC COMPLICATIONS degree a positive impact of glycemic control on develop­
Several studies in the 1950s, 60s and 70s suggested a posi­ ment of various diabetic complications. However, they
tive relationship between hyperglycemia and develop­ were small and of short duration. Besides, intervention
ment of the late complications of diabetes. However, all did not start early enough in the course of diabetes to have
these studies had limitations in methodology. Early obser­ had a major impact.4
vational studies in the late 70s, 80s and 90s that showed a
robust relationship between glycemia and diabetic comp­ Diabetes Control and
lications included the Brussels study15 and the Wisconsin Complications Trial1 (Fig. 52.2)
study.16 In the former, Pirart15 observed over 4,000 patients Diabetes Control and Complications Trial was the land­
in Brussels for up to 25 years and concluded that a longer mark study that unequivocally demonstrated that strict
duration of diabetes and cumulative glycemic control control of glycemia reduces the risk of several long-
correlated significantly with the frequency and severity term complications in T1DM. This was a randomized,
of diabetic microvascular complications. The Wisconsin multicentric controlled clinical trial conducted in 1,441
epidemiological study of diabetic retinopathy (WESDR) subjects across 29 centers in USA. 726 of these (“Primary
was a carefully conducted prospective epidemiological prevention” cohort) had no incidence of diabetic compli­
study in a large population cohort of diabetic subjects cations and had duration of diabetes of less than 5 years.
who were followed up for 10 years.16 The remaining 715 (“Secondary prevention” cohort) had
 776 Complications

Table 52.3: Diabetes complications and control trial: impact of inten- events (including non-fatal MI, stroke, or death from car­
sive therapy on reduction of long‑term complications1 diovascular disease).18
Endpoint risk reduction:
First appearance of retinopathy 27% Studies in Type 2 Diabetes Mellitus
Progress of retinopathy 60%
The Kumamoto study3 in Japan was a small study of 110
New nephropathy 34%
patients with Type 2 diabetes carried out over 6 years. The
Progress of nephropathy 43%
patients were randomized to receive intensive insulin
section

New neuropathy 69%

therapy (MDI) or conventional insulin therapy. At the
10

Progress of neuropathy 57%

end of the study, glycemic control in the two groups
Macrovascular disease 44%
was similar to that observed in DCCT; HbA1c was 7.1%
(mean blood glucose 157 mg/dL) in the intensively treated
mild to moderate background diabetic retinopathy and group versus 9.4% (mean blood glucose 221 mg/dL)
macro or microalbuminuria with disease duration of in the group assigned to conventional treatment. A signi­
under 15 years. Subjects were randomly assigned to ficant reduction in microvascular complications, such
either intensive therapy (CSII/MDI) aimed at near normal as diabetic retinopathy was noted in the intensively
glycemia or conventional therapy and followed up for a treated group (7.7% vs 32%, p = 0.039). Similarly, reduced
mean duration of 6.5 years. The intensively treated groups progression of diabetic nephropathy (7.7% vs 28%,
achieved a median GHb throughout the study of 7.2% p = 0.032) and neuropathy was seen in the intensively
versus 9.1% in the conventional group and mean blood treated group. A further 8-year prospective study demon­
glucose of 155 mg/dL, versus 231 mg/dL. The results of strated that intensive glycemic control is instrumental
the study are given in Table 52.3. The most important in delaying the onset and progression of early stages of
adverse events in the intensive therapy group were a diabetic microvascular complications.19
three times higher incidence of severe hypoglycemia and The 10-year follow-up data from the UKPDS study
weight gain. The relationship of glycemic exposure and revealed that relative risk reduction in microvascular
the risk for progression of diabetic complications was a endpoints persisted despite early loss of difference in
curvilinear one with a steep relationship at higher levels glycated hemoglobin between the intensive and conven­
of HbA1c. This continuous relationship would suggest that tional therapy groups. Further, in the intensively treated
any improvement in glycemic control is beneficial. Thus, group, significant risk reductions for myocardial infarction
DCCT showed unequivocally that intensive therapy that (15%, p = 0.01) and death from any cause (13%, p = 0.007)
achieves near normoglycemia is associated with a signi­ emerged as a benefit of intensive blood glucose lowering
ficant delay in the onset and progression of diabetic therapy, despite lack of significant reduction during the
retinopathy, nephropathy and neuropathy in T1DM. intervention phase.20 Comparatively, 10-year follow-up
The Epidemiology of Diabetes Interventions and Com­ data from the blood pressure intervention cohort demon­
plications (EDIC) study is a follow-up study of the DCCT strated that benefits seen in patients assigned to the
cohort and it has spanned a period of more than 20 years. intensive regime were not maintained once the difference
The goal of this study was to examine the longer-term in blood pressure seen during original trial were lost.
effects of the original DCCT interventions on diabetes- The lower blood pressure levels attained in the early
related microvascular and macrovascular complications. stages of diabetes did not appear to confer a subsequent
Four years post-DCCT, the difference in median HbA1c “legacy effect” as was seen with glycemic control.21
values between the conventional treatment and inten­
sive therapy groups during the DCCT study (9.1% vs 7.2%, MECHANISMS OF DIABETIC
respectively) narrowed to 8.2% vs 7.9% (p < 0.001), respec­ TISSUE DAMAGE4,22-24
tively. However, the proportion of intensively treated pati­
ents with worsening microvascular complications such as The major cause of tissue damage in diabetes is vascular
retinopathy remained significantly lower (72% vs 87%, disease affecting the micro- and macrocirculation. There
p < 0.001).17 Nine years post-DCCT, a 42% (p = 0.02) is progressive narrowing and occlusion of lumen of the
reduction in cardiovascular events was reported in addi­ vessels leading to decreased perfusion, ischemia and
tion to a 57% (p = 0.02) decrease in risk of severe clinical tissue damage. Also, there is increased permeability to
 Diabetes Complications: Overview 777

Flow chart 52.1: The polyol pathway—non-diabetic states Flow chart 52.2: Polyol pathway in diabetes mellitus

chapter
52
plasma proteins that may get deposited in the vessel
wall. In addition to expansion of the extracellular matrix
around perivascular cells such as the pericytes in the
retina and the mesangial cells in the glomeruli leading to
thickening of the basement membrane. In large vessels
there is increased deposition of collagen and lipids in
atheroslcerotic plaques. Endothelial, mesangial and arte­
rial smooth muscle hyperplasia and hypertrophy also
(AGEs: Advanced glycation end products; PKC: Protein kinase
results in vascular wall thickening. These processes, C; NADPH: Nicotinamide adenine dinucleotide phosphate; NAD:
together with an increased coagulability in the vessel leads Nicotinamide adenine dinucleotide)
to vascular occlusion and tissue damage. Diabetic tissues
damage occurs in those tissues which fail to down regulate of blood levels. Thus, it is these tissues that are the primary
their glucose uptake in the face of hyperglycemia with targets of diabetic tissue damage resulting in neuropathy,
resultant intracellular hyperglycemia. retinopathy, cataract, nephropathy and vasculopathy.
Activation of the polyol pathway causes tissue dam­
CELLULAR AND MOLECULAR age by several mechanisms—osmotic damage secondary
MECHANISMS OF HYPERGLYCEMIA- to sorbitol accumulation, increased oxidative stress secon­
INDUCED CELLULAR DAMAGE dary to decreased NADPH levels, PKC activation from
increase NADH/NAD+ ratio, and increased AGE forma­
There are four major pathways that are thought to be tion secondary to methylglyoxal and acetol and to raised
activated in the causation of diabetic complications.4 NADH/NAD+ ratio.
1. Activation of polyol or (aldose reductase) pathway In a study of serum AGE levels in controls and type 2
2. Increased formation of intracellular advanced glycation diabetic patients with and without microvascular com­
end products (AGEs) plications34 we showed that serum AGEs were raised in
3. Activation of protein kinase C (PKC) isoforms T2DM as compared to controls. There was a progressive
4. Overactivity of the hexosamine pathway. and significant increase in the levels of AGEs from healthy
controls to diabetic patients without microvascular com­
Increased Activation of the Polyol Pathway22-27 plications to those with microvascular complications. The
study shows the importance of AGEs in the development
Polyol pathway is inactive in the non-diabetic state (Flow
of microvascular complications in diabetes.
chart 52.1); as most of the glucose is metabolized through
Aminoguanidine, an inhibitor of AGE, has been shown
the glycolytic pathway. In diabetes mellitus, hyperglycemia
to prevent the pathological changes of experimental dia­
and the resultant increase in intracellular glucose and
betic retinopathy35 and nephropathy.36 AGE induced tissue
other glucose-derived substrates for aldose reductase like
damage results from both extracellular and intracellular
methylglyoxal lead to activation of the polyol pathway
effects.
and increased glucose flux through this pathway (Flow
chart 52.2).
Formation of Advanced Glycation
Aldose reductase is located in nerves, retina, lens,
glomeruli and walls. Also in these tissues, glucose uptake
End Products (AGEs)4,22-24,28,29
is insulin independent, and hence, there is rise in intra­ Glucose and the other glycating compounds such as
cellular glucose in direct proportion to blood glucose levels decarbonyl-3 deoxy glucosone, methylglyoxal and glyoxal
 778 Complications

Flow chart 52.3: Advanced glycation end products and vascular compli­ complications (Flow chart 52.3). AGE accumulation has
cations
been demonstrated in glomerular tissues of rats as well
as humans4,24,30 and retinal tissues31,32 of diabetic animals.
AGE infusion in animals resulted in pathological changes
similar to those induced by hyperglycemia.33 We studied
the serum AGE levels in controls and type 2 diabetic pati­
ents with and without microvascular complications.34
section

Serum AGEs were significantly raised in type 2 DM as

10

compared to controls. There was a progressive and

significant increase in the levels of AGEs from healthy
controls to diabetic patients without microvascular com­
plications to those with microvascular complications. The
study reinforces the importance of AGEs in the develop­
ment of microvascular complications in diabetes. Amino­
guanidine, an inhibitor of AGE, has been shown to
prevent the pathological changes of experimental diabetic
retinopathy35 and nephropathy.36 AGE induced tissue
damage results from both extracellular and intracellular
effects.

Extracellular Effects of
Advanced Glycation End Products
(AGEs: Advanced glycation end products; PKC, Protein kinase C; Advanced glycation end products modify extracellular
TGF-β1, Transforming growth factor beta 1; CTGF, Connective tis-
sue growth factor; VEGF, Vascular endothelium-derived growth factor;
structure proteins including type 1 and type 2 collagen
NFκB, Nuclear factor kappa B; P38 MAPK, P38 mitogen activated and laminin2,37 by forming intermolecular covalent cross
protein kinase) linking bonds. These alter the function of blood vessels
and the glomerular basement membrane by reducing
react with proteins and nucleic acids to form glycation vascular wall elasticity and increasing glomerular perme­
products. These reactions are reversible to start with but ability to albumin.30 Adhesion, proliferation and migration
later on they become less reversible to yield early glycation of endothelial cells are also impaired by AGEs. Binding of
products and finally with the development of glucose- AGE to its receptors on endothelial cells (RAGE) affects
derived cross-links between protein molecules these expression of several genes including thrombomodulin,
become completely irreversible and lead to the formation tissue factor and VCAM-1 resulting in increased coagu­
of AGEs. The advanced glycation alters the structural and lability.38-42 Vascular permeability is also increased. RAGE
functional characteristics of these proteins and renders
mediates generation of reactive oxygen species (ROS) and
them non-functional in most cases. Hyperglycemia in
NF-κB activation, a pathway that leads to oxidative stress
diabetes mellitus induces irreversible glycation of both
induced tissue damage.
intracellular and extracellular proteins. It is believed that
Advanced glycation end products can also bind to spe­
increased intracellular glucose is the primary factor that
cific receptors on monocytes and macrophages leading
drives both intracellular and extracellular AGE formation.
to increased production of cytokines like interleukin-1,
The high intracellular glucose leads to increased formation
tumor necrosis factors-α (TNF-α), transforming growth
of intracellular glucose derived decarbonyl precursors
factor-beta (TGF-β), macrophage colony-stimulating factor
which readily react with the amino groups of intra- and
(MCSF) and granulocyte colony stimulating factor (GCSF)
extracellular proteins. These decarbonyl precursors of
which mediate tissue damage and inflammation.38-40
methyl glyoxal and glyoxal generate AGEs at a much faster
rate than glucose itself and are detoxified by the glyoxalase
Intracellular Effects of AGEs43
system.
Several animal and human studies support an Glycation of intracellular proteins causes altered intra­
important role for AGEs in the pathogenesis of diabetes cellular signaling and cell dysfunction. Altered extra­
 Diabetes Complications: Overview 779
Flow chart 52.4: Activation of protein kinase C in diabetic vascular Flow chart 52.5: Role of hexosamine pathway in diabetic complica-
compli­cations tions

chapter
52
(AGE: Advanced glycation end products; RAGE: Receptor for adva­ (PAI–1: Plasminogen activator inhibitor–1; TGF-β‑1: Transforming
nced glycation end products; NADPH: Nicotinamide adenine dinucleo- growth factor-beta1; GFAT: Glutamine fructose-6-phosphate amino­
tide phosphate; NAD: Nicotinamide adenine dinucleotide) transferase; UDP-Glc NAC: UDP-N-acetyl glucosamine)

cellular matrix secondary to advanced glycation results in intra­

cellular adhesion molecule (ICAM). Furthermore,
abnormal binding with matrix receptors on cell surfaces PKC activation is associated with increased expression of
causing cellular dysfunction. Also, binding of glycated plasminogen activator inhibitor-1(PAI-1) that promotes
plasma proteins on macrophage receptors increases ROS hypercoagulopathy. It thus appears that PKC activation
production and activation of transcription factor NF-κB has a central role to play in the development of diabetic
causing tissue damage via pathological expression of genes. vascular complications.

Increased Activation of Protein Kinase C22-24,44-50 Increased Flux through the

Inappropriate activation of the diacylglycerol-protein Hexosamine Pathway 51-56
kinase C (DAG-PKC) also causes hyperglycemia induced Shunting of glucose into the hexosamine pathway is an
diabetic tissue damage. PKC activation can result from important mechanism for hyperglycemia induced tissue
several mechanisms (Flow chart 52.4). Hyperglycemia damage (Flow chart 52.5). Fructose-6-phosphate is diver­
mainly activates PKC β and PKC δ isoforms as shown from ted from the glycolytic pathway to increase production
animal studies in retina, glomeruli and vascular tissues. of glucosamine-6-phosphate, a substrate utilized to form
PKC activation particularly the β isoform causes abnorma­ UDP-N-acetyl glucosamine. This causes glycation of trans­
lities of retinal blood flow, increased permeability of cription factors for many genes in the nucleus particularly
vessels, pathological angiogenesis especially in the retina TGF-α, TGF-β and PAI-1. This altered gene expression
through vascular endothelial growth factor (VEGF). as well as altered protein function together mediates the
Some of the structural and hemodynamic effects of development of diabetes complications.
PKC activation are secondary to inhibition of nitric oxide Long-term complications of DM are a major health
(NO) production and altered gene expression for vasoac­ problem in addition to acute metabolic complications
tive and growth factors such as endothelin-1 (ET-1), VEGF, and infections. The atherosclerotic macrovascular compli­
TGF-β1 and connective tissue growth factor (CTGF). cations such as coronary artery disease, stroke and peri­
PKC also induces expression of adhesion molecules pheral vascular disease are common causes of disease
platelet/endothelial cell adhesion molecule (PECAM) and and death. Diabetic tissue damage occurs primarily in
 780 Complications

tissues where glucose uptake is insulin independent. and reduced GSH67 have been recorded in some patients.
Therefore, the lack of insulin, whether absolute or relative, However, normal SOD and GSH60,68 have also been
leads to unregulated and excessive influx of glucose into reported.
the cells in the face of hyperglycemia. Target organ damage Antioxidant status, lipid peroxidation and NO end
in diabetes occurs mainly in the eyes, kidneys, nerves, products were estimated in patients of T2DM with and
heart and blood vessels. Overall the vascular wall appears without nephropathy, taking care to avoid confounders.
to be the primary target in diabetes related complications Serum MDA was higher in T2DM patients compared to
section

regardless of the organs. Since little can be done after the controls and higher in T2DM with nephropathy compared
10

development of overt complications, the emphasis has to controls. Erythrocyte SOD, CAT activities were lower
always been on preventing or delaying complications. in T2DM and CAT activity and GSH levels in erythrocytes
were lower in diabetes with nephropathy when compared
ROLE OF OXIDATIVE STRESS IN with controls. The study showed that oxidative stress is
DEVELOPMENT OF DIABETIC increased and antioxidant defenses are compromised in
diabetic patients with nephropathy.69
COMPLICATIONS
We assessed oxidative stress in type 2 diabetic pati­
Oxidative stress is defined as a condition where the overall ents with and without macroangiopathy.70 There was a
generation of free radicals exceeds the total antioxidant progressive increase in oxidative stress (MDH levels) and
levels in the body. It can result from overproduction of ROS a progressive decrease of antioxidant defense systems
and/or decreased efficiency of inhibitory and scaveging (GSH, SOD and CAT) from control subjects, diabetic
antioxidant systems. Targets of ROS can be direct such as patients without macroangiopathy and diabetic patients
peroxidation of the lipids of cell membranes, oxidation, with macroangiopathy suggesting that enhanced oxidative
crosslinking and fragmentation of protein enzymes amino stress in diabetes with reduced antioxidative defense
acids (enzymes) and single strand breaks and crosslinking mechanism may play an important role in pathogenesis
of DNA or indirect such as activation of stress sensitive of macroangiopathy (Figs 52.3A to D). When parameters
signaling pathways that regulate gene expression resulting of oxidative stress were measured in the fasting state as
in tissue damage. Antioxidant defense systems help well as 2, 4, 6 and 8 hours after a standardized high fat, low
reduce the oxidative stress and keep oxidative damage cholesterol meal challenge in diabetic subjects with and
without macroangiopathy there was a significant increase
in check by scavenging oxidative radicals. These include
in thiobarbituric acid reactive substances (TBARS), a
antioxidant enzymes like superoxide (ROS) dismutase
measure of oxidative stress following a high fat meal
(SOD), catalase (CAT) and glutathione peroxidase (GSH-
challenge which peaked at 4–6 hours and declined at
Px), chain breaking antioxidants like vitamin E, β carotene,
8 hours in non-diabetics as well as both diabetic study
GSH, vitamin C protein bound thiol groups and transition
groups (Fig. 52.4). Clearly, there was a significantly higher
metal binding proteins like ferritin, transferrin, lactoferin
PP oxidative stress and a deficient antioxidant defense
and ceruloplasmin.57,58
system observed in T2DM patients particularly those with
Oxidative stress plays a crucial role in the development
macroangiopathy in addition to fasting abnormalities
of the late complications of DM. We demonstrated that suggesting a specific role for postprandial oxidative stress
there is enhanced oxidative stress in T2DM, early in the in the development of diabetic macroangiopathy. The
course of the disease. It increases with increasing duration magnitude of PP hypertriglyceridemia was a major deter­
of DM and is present even without evidence of significant minant of PP oxidative stress in this group (Fig. 52.5).
micro- or macrovascular complications. It correlated best It would appear71,72 that the increased risk of macro­
with PP glucose levels.59 vascular disease in diabetic subjects conferred by
Increased generation of ROS in DM reported from PP hypertriglyceridemia and PP hyperglycemia is media­
other studies includes increased lipid peroxidation,60-62 ted by an increase in PP oxidative stress and thereby
decreased NO end products along with increased malon­ through activation of stress sensitive gene expression.73
dialdehyde (MDA) levels63 and elevated diene conjugates Thus, oxidative stress resulting from increased produ­
in T2DM with microvascular complications but not in ction of ROS or their inadequate removal plays a key
those without.64 On the other hand, lowered antioxidative role in the pathogenesis of late diabetic complications.
defenses such as decrease in leucocyte vitamin C,60 Hyperglycemia induced oxidative stress leads to tissue
erythrocyte SOD activity,65 total radical trapping capacity66 damage.
 Diabetes Complications: Overview 781

chapter
52
A B

C D
Figs 52.3A to D: Assessment of oxidative stress in type 2 patients with and without macroangiopathy Group I: Non-diabetic; Group II: Diabetic
without macroangiopathy; Group III: Diabetics with macroangiopathy.(MDA: Malondialdehyde; GSH: Reduced glutathione; SOD: Superoxide
dismutase)70

Fig. 52.5: Correlation of postprandial triglyceride levels and PP

MDA levels in type 2 diabetes mellitus with macroangiopathy (MDA:
Fig. 52.4: Postprandial malondialdehyde levels in patients of type 2 Malondi­aldehyde; TG: Triglyceride; PPTG: Postprandial triglyceride;
diabetes mellitus with and without macroangiopathy PP MDA: Postprandial malondialdehyde)
 782 Complications

Flow chart 52.6: Elevated free fatty acids and hyperglycemia in Hyperglycemia induced increase in mitochondrial ROS
the pathophysiology of diabetes complications via the generation of
can also induce mitochondrial DNA mutations. It is
reactive oxygen species
hypothesized that this could sustain the elevated ROS
production long after euglycemia is restored and thereby
result in continued activation of all major pathways that
cause diabetic complications.
section

Glycemic Memory-Epigenetic Mechanism and

10

Vascular Complications82-84
Epigenetic mechanisms such as post-translational modi­
fication of histones and DNA methylation play a central
role in regulation of gene by affecting the chromatin
structure and function. Long standing hyperglycemia
leads to activation of NF-κB signaling pathway, production
of AGEs and other inflammatory mediators which can lead
to impaired regulation of epigenetic mechanism which
may ultimately affect gene function. This leads to changes
in epigenome of the cell which is responsible for the
“glycemic memory” that results in chronic inflammation
and vascular dysfunction that progresses in severity even
after patient achieving glycemic control.
(AGE: Advanced glycation end products; RAGE: Receptor for advan­
ced glycation end products; DAG: Di acyl glycerol; PKC: Protein SUMMARY
kinase C; ROS: Reactive oxygen species; NFκB, Nuclear factor
kappa B; MAPK: Mitogen activated protein kinase; JNK: Janus kinase; Long-term complications of diabetes mellitus constitute
SAPK: Serine activated protein kinase) a major health problem in addition to acute metabolic
complications and infections. The atherosclerotic macro­
Hyperglycemia induced late diabetic complications vascular complications like coronary artery disease,
result from a cycle of self-perpetuating oxidative stress stroke and peripheral vascular disease are assuming high
mediated cellular damage that is brought about by proportions. Diabetic tissue damage occurs primarily in
hyperglycemia dependent NF-κB activation in patients tissues where glucose uptake is insulin independent and
with DM. The importance of NF-κB in this regard has been therefore, the influx of glucose into the cells is unregulated
well documented. In patients with DM, NF-κB activa­ and greatly increased in the face of hyperglycemia. Target
tion correlates positively with HbA1c and significantly organ damage in diabetes occurs mainly in the eyes,
with severity of albuminiuria in those with nephropathy. kidneys, nerves, heart and blood vessels although no organ
Also, antioxidant lipoic acid treatment significantly of the body is spared. Overall the vascular wall appears to
supresses NF-κB activation. Activation of NF-κB which is be the primary target in diabetes related complications
a transcription factor, triggers gene expression of a variety regardless of the organs. Since little can be done after the
of genes that result in tissue damage (Flow chart 52.6).73-78 development of overt complications, the emphasis has
always been on preventing or delaying complications.
The Unifying Hypothesis for The role of hyperglycemia in the development of dia­
betic complications and the beneficial effects of strict
Diabetic Complications79-81
glycemic control have now been well established by well
Recent studies suggest that overproduction of ROS in designed controlled clinical trials. There are four major
mitochondria secondary to excessive glucose metabolism pathways that are believed to mediate the development of
is the common underlying initiating event that drives complications:
all other pathways including the polyol pathway, AGEs 1. The polyol pathway
production, PKC activation and hexosamine pathway 2. The advanced glycation end product pathway
activation.73 This is believed to be due to oxidative stress 3. The protein kinase pathway and
related pathways that are known to be operating in DM. 4. The hexosamine pathway.
 Diabetes Complications: Overview 783

Hyperglycemia is the initial trigger for most steps of these 2. UKPDS Research Group. UK Prospective diabetes study 16,
pathways, which through a cascade of events specific to Overview of 6 years’ therapy of type II diabetes: a progres­
sive disease. Diabetes. 1995;44:1249-58.
each pathway result in diabetic tissue damage. The role
3. Okhubo Y, Kishikawa H, Araki E, et al. Intensive insulin
of oxidative stress is critical in this process and several therapy prevents the progression of diabetic microvascu­
studies including studies done at our institution support lar complications in Japanese patients with non-insulin
a very important role for ROS in oxidative stress. Major dependent diabetes mellitus: A randomized prospective
links in the oxidative stress pathway particularly the 6-year study. Diabetes Res Clin Pract. 1995;28:103-17.

chapter
4. Andrzej S, Krolewsk, James H, et al. Epidemiology of late
stress sensitive gene expression mechanisms and the

52
diabetic complications: a basis for the development and
events leading to NF-κB activation have now been fully evaluation of preventive programs. Endocr Metab Clin
elucidated, thereby greatly enhancing our understanding North Am. 1996;25:217-42.
of the basis of diabetic complications. Recently, a unifying 5. Mogensen CE, Christensen CK, Vittinghus E. The stages in
concept for the development of diabetic complications has diabetic renal disease with emphasis on the stage of incipi­
ent diabetic nephropathy. Diabetes. 1983;32:64-78.
been proposed that links all the major pathways through a
6. Chase PH, Jackson WE, Hoops SL, et al. Glucose control
common trigger, oxidative stress. Recent understanding and the renal and retinal complications of insulin-depend­
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diabetic complications has opened up novel areas of 7. Krolewski AS, Laffel LMB, Krolewski M, et al. Glycated he­
potential therapeutic benefit in this regard. moglobin and risk of microalbuminuria in patients with
insulin dependent diabetes mellitus. N Engl J Med. 1995;
332:1251-55.
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genetics of diabetes mellitus In: Kahn CR, Weir GC (Eds).
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Joslin’s Diabetes Mellitus. Phaladephia: Lea and Febiger;
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1994. pp. 201-15.
ween 1947 and 1973. Diabetes Metab. 1977;3:97-107, 173-82,
9. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from cor­
245-56.
onary heart disease in subjects with type 2 diabetes and in
2. Mogensen CE, Christensen CK, Vittinghus E. The stages in
non-diabetic subjects. N Engl J Med. 1998;339:229-34.
diabetic renal disease with emphasis on the stage of incipi­
10. Fontbonne A. Relationship between diabetic dyslipopro­
ent diabetic nephropathy. Diabetes. 1983;32:64-78.
teinemia and coronary heart disease risk in non-insulin
3. Diabetes Control and Complications Trial Research dependent diabetes mellitus. Diabetes Metab Rev. 1991;7:
Group. The effect of intensive treatment of diabetes on the 179-89.
development and progression of long-term complications 11. Lewis GF, O’Meara NM, Soltys PA, et al. Fasting Hypertri­
in insulin-dependent diabetes mellitus. N Engl J Med. glyceridemia in non-insulin dependent diabetes mellitus
1993;329:683-89. is an important predictor of postprandial lipid and lipo­
4. UKPDS Research Group. UK Prospective diabetes study 16, protein abnormalities. J Clin Endocrinol Metab. 1991:72:
Overview of 6 years’ therapy of type II diabetes: a progres­ 934-44.
sive disease. Diabetes. 1995;44:1249-58. 12. Madhu SV, Mittal V, Krishna Ram B, et al. Postprandial lipid
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onary heart disease in subjects with type 2 diabetes and in cians India. 2005;53:1043-6.
non-diabetic subjects. N Engl J Med. 1998;339:229-34. 13. Shinichi Teno, Uto Y, Nagashima H, et al. Association of
6. Diabetes Control and Complications Trial/Epidemiology postprandial hypertriglyceridemia and carotid intima-
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sity lipoprotein and oxidative stress in people with type 2 cells. Am J Physiol Renal Physiol. 2000;278:F676-83.
diabetes without complications. Diabetes Res Clin Pract. 82. Reddy M A, Natrajan R. Epigenetic mechanisams in diabetic
2001;54:33-9. vascular complications. Cardiovasc Res. 2011;90:421-9.
64. Jennings PE, Jones AF, Florkoski CM, et al. Increased diene 83. Bell CG, Teschendorff AE, Rakyan VK, et al. Genomewide
conjugates in diabetic subjects with microangiopathy. Dia­ NA methylation analysis for diabetic nephropathy in type 1
bet Med. 1987;4:452-6. diabetes mellitus. BMC Med Genomics. 2010;3:33-42.
65. Skrha J, Hodinar A, Kvasnicka J, et al. Relationship of oxida­ 84. Brennan EP, Ehrich M, O’Donovan H, et al. DNA methyla­
tive stress and fibrinolysis in diabetes mellitus. Diabet Med. tion profiling in cell models of diabetic nephropathy. Epige­
1996;13:800-5. netic. 2010;5:396-401.
 Chapter 53
Acute Metabolic
Complications
Hemraj B Chandalia

Acute Metabolic Complications

Chapter Outline
♦♦ Diabetic Ketoacidosis ♦♦ Lactic Acidosis
♦♦ Hyperglycemic Hyperosmolar Non-ketotic State

INTRODUCTION Table 53.1: Etiology, clinical antecedents and prevention of diabetic

ketoacidosis (DKA)
Acute metabolic emergencies in diabetes are mostly Etiology Insulinopenia
preventable and treatable. A good knowledge of their Clinical antecedents Omission of insulin dose
pathogenesis and management strategies is likely to
Undiagnosed type 1 diabetes mellitus (DM)
produce a successful outcome. The emergencies to be
Stress situations with resultant increase in
considered in this chapter are diabetic ketoacidosis (DKA), contrainsulin hormones
hyperglycemic hyperosmolar non-ketotic state (HHNKS) Prevention or early Educate type 1 diabetics regarding sick-day
and lactic acidosis (LA). Hypoglycemia in diabetic patients diagnosis routine
is an important iatrogenic emergency and is discussed Suspect type 1 DM in sick children with
elsewhere. polyuria, polydipsia and weight loss

DIABETIC KETOACIDOSIS are important to identify because it is possible to apply

Definition a preventive approach at this level (Table 53.1). In most
patients, it occurs due to omission or reduction of insulin
Three essential components of DKA are hyperglycemia,
dosage and is most commonly seen in Type 1 diabetics.
ketosis and resultant metabolic acidosis. A firm diagnosis
Often DKA is the presenting feature of type 1 diabetes:
of DKA requires these three criteria to be fulfilled.
it is estimated that 20% of DKA is accounted for by undia­
Usually, the blood glucose is more than 250 mg/dL, pH
gnosed type 1 diabetics at times even from the elderly
less than 7.3, urine ketones moderately positive, serum
group. In type 1 diabetics on pump therapy, failure of
ketones positive in 1:4 dilution and bicarbonate less than
pump can result in rapid advent of DKA. This is because
15 mEq/L.
the pump delivers regular insulin on minute-to-minute
basis and its failure results in total non-availability of
Etiology and Precipitating Factors insulin in a short period. At times, infection or an acute
The basic etiology is total or subtotal insulinopenia. cardiovascular event places increased insulin demands
How this leads to genesis of DKA is discussed in patho­ on the patient. This is probably brought about by an
genesis. However, the immediate clinical antecedents increased secretion of contrainsulin hormones like
 Acute Metabolic Complications 787

catecholamines, cortisol, glucagon and growth hormone. occurred amongst 750 type 1 diabetics; two episodes in
Theoretically, in this situation, a type 2 diabetic, especially a patient on insulin pump because of pump failure and
one with subtotal insulinopenia can develop DKA. In one in a type 1 diabetic in a prison because of omission of
practice, however, most type 2 diabetics under such insulin dose.
stressful situations with increased insulin demands Factors delaying the initial diagnosis of DKA are:
develop a hyperglycemic, hyperosmolar non-ketotic state younger age, diagnostic error, ethnic minority, lack of
(HHNKS). They are usually non-ketotic but at times have health insurance, lower body mass index (BMI) and

chapter
mild-to-moderate acetonuria and are often mistakenly infection. The delay was prevented in those with family

53
diagnosed as having DKA (see HHNKS). Their blood pH is history of diabetes, highly educated parents and where
usually normal. overall type 1 diabetes was highly prevalent in the
In some situations, clinical type 2 diabetic patients community.11 In another study, 25% of the type 1 diabetics
can develop a full-blown DKA. It is possible that these presented with DKA.12 This occurred mainly in younger
patients are truly type 1 diabetics having slow immune and poorer patients. DKA is getting rarer in pregnancy;
destruction of their β-cells (late onset autoimmune currently it occurs in 1–2% of pregnant diabetics.13
diabetes of adults) or suffer from other forms of type 1 Mortality in DKA is falling rapidly over the last six
diabetes. Thirty-nine percent of type 2 diabetics in India decades because of insulin therapy, better understanding
may have islet cell antibody 512 (ICA 512) positivity.1 These of fluid, electrolytes and acid-base disturbances and
patients are true type 1 diabetics, masquerading as type 2 finally, patient education and empowerment. Near 100%
diabetics. To confound this issue further, it is known that mortality of preinsulin era was brought down to 30% with
one-third of metabolic decompensations seen in diabetes the advent of insulin. Advent of antibiotic therapy and an
are of mixed type, e.g. DKA coupled with a hyperosmolar improved understanding of fluid and electrolyte therapy
state or starvation ketosis or alcoholic ketosis or lactic brought down the mortality to about 10% in most centers
acidosis. around the world. Mortality is closely related to the severity
More recently, a number of psychotropic drugs of DKA at the time of presentation. It is also closely related
(clozapine, olanzapine),2,3 “ecstasy” (3,4-methylenedi- to osmolarity and state of consciousness of the patient. In
oxymethamphetamine) ingestion4 and treatment of established diabetes centers, DKA as a primary disease
kidney transplant patients with FK506/tacrolimus5 have has been associated with as a low mortality as 2.7%.14
been shown to aggravate diabetes or precipitate an acute When coupled with acute vascular events and infections
episode of DKA.5 An isolated example of DKA caused by as primary diseases, mortality can still be high. In our
growth hormone treatment in a patient of Prader-Willi patients with primary diagnosis of DKA, we have had no
syndrome has also been reported.6 Severe hyperglycemia mortality in the past 10 years.
may occur in the treatment of human immunodeficiency
virus-acquired immunodeficiency syndrome (HIV-AIDS) Pathogenesis
patients.7 Pentimidine used for pneumocystis carinii
Metabolic changes of DKA arise from absolute insuli­
infection can cause DKA probably by producing pancr­
nopenia or subtotal insulinopenia with increased levels
eatitis.8 The antiretroviral drugs like indinavir, lamivudine
of counter-regulatory hormones like catecholamines, glu­
or stavudine may suppress the activity of prohormone
cagon, cortisol and growth hormone.15 These hormonal
convertase enzymes, thus inhibiting the proinsulin to
changes result in increased glucose concentration because
insulin conversion and resulting in hyperglycemia. Use of
of (1) inadequate glucose utilization by insulin sensitive
antileukemia oncolytic agents like L-asparaginase may be
tissues like muscles, adipose tissue and liver; (2) increased
associated with acute onset of diabetes with DKA, which
glycogenolysis and most important; (3) increased glucose
is reversible.9
production by the liver from amino acids (Flow chart 53.1).
Such hormonal milieu also leads to lipolysis, resulting
Prevalence and Mortality in increased free fatty acid (FFA) and glycerol. The FFA
Prevalence of DKA is difficult to establish. Faich10 reported undergoing β-oxidation to generate ketone bodies
a prevalence of 1.6% in Rhode Island. DKA continues to be are also converted in the liver to very low-density lipo­
rare in our clinic population of type 1 diabetics. At Diabetes proteins (VLDL). Ketone bodies generated are acetone,
Endocrine Nutrition Management and Research Centre, acetoacetic acid and β-hydroxybutyric acid. The latter
in the year 2011, three episodes requiring hospitalization acid is derived from acetoacetic acid by a process of
 788 Complications

Flow chart 53.1: Pathophysiology of diabetic ketoacidosis (DKA)

Table 53.2: Average deficits of water and electrolytes per kg of body
weight in diabetic ketoacidosis
Water 100 mL
Na +
7–10 mEq
Cl –
3–5 mEq
K+ 3–5 mEq
section

Mg2+ 1–2 mEq

10

PO43– 1–2 mEq

is 5% of body water in mild and 10% or more of body

water in well-developed DKA. Thus, the loss of water is
50–100 mL, sodium 7–10 mEq, potassium 3–5 mEq, chlo­
ride 5–7 mEq/kg of body weight. Hyperglycemia causes
shift of water from intracellular to extracellular and intra­
vascular compartment. This water is further lost by osmotic
diuresis through kidneys. Serum sodium is modified by
hyperglycemia and hyperlipidemia. For every 100 mg
of blood glucose rise above the baseline serum sodium
drops by 1.6 mEq.19 Hyperlipidemia can be very severe at
(FFA: Free fatty acid). times; triglycerides of over 1,000 mg/dL are not unusual.
This can be easily seen in the fundus in the form of lipemia
reduction. In most patients of DKA, β-hydroxybutyrate retinalis or at the bedside by looking at the serum, which
to acetoacetate ratio is 4:1.16 Furthermore, when reducing is lipemic. The lipids reduce the aqueous compartment of
ions or substances like ascorbic acid are present in the blood in which serum Na+ is present and hence, cause
abundance, β-hydroxy butyrate may form the sole spurious lowering of serum sodium. The net result of these
ketoanion. As the usual methods for testing ketone bodies various opposing events (water loss raising serum Na+;
(ketostix, nitroprusside test) detect only acetone and hyperglycemia and hyperlipidemia decreasing serum Na+)
acetoacetic acid, these tests can be falsely-negative when is such that serum Na+ is almost normal or slightly low at
the redox state is predominantly toward a more reduced the time of presentation. Total body potassium is negative
state. by 3–5 mEq/kg of body weight, but the initial serum
The amount of ketones is moderate to large in the potassium could either be normal, high or low, depending
urine (45–90 mg/dL, 3 to 4 + on ketostix) as compared to upon the following factors:
starvation ketosis where the amount of ketones is small • Osmotic loss through kidneys decreasing serum K+.
(< 30 mg/dL, 1 to 2 + on ketostix). Plasma ketones are • Vomiting or acute gastric dilatation causes loss of
positive in the undiluted state and 1:2 dilutions, a finding potassium and decreases serum K+.
not seen in starvation ketosis or HHNKS. Recently, a direct • Decreased intravascular volume and diminished
measurement of β-hydroxybutyrate has been introduced.17 glomerular filtration rate (GFR) decreases K+ excretion
A method to estimate β-hydroxybutyrate by a glucometer and raises serum K+.
and special strip is also available. • Metabolic acidosis causes migration of intracellular
Overall, the metabolism in DKA simulates that in potassium into extracellular compartment and thus
starvation,18 but the intensity of lipolysis, gluconeogenesis raises serum potassium. As acidosis is reversed by
and ketogenesis is very high in DKA, resulting in profound bicarbonate and insulin therapy, there is migration of
acid-base and electrolyte disturbances (Table 53.2). potassium into the intracellular compartment resulting
Osmotic diuresis results in loss of large amounts of water, in severe and at times life-threatening hypokalemia.20
sodium, potassium, magnesium and phosphate. Overall, Metabolic acidosis is an important feature of DKA.
water loss is more than the loss of electrolytes and hence, The ketone bodies, except acetone which can be elimi­
the loss is not iso-osmolar. The amount of water lost nated through lungs are fixed anions. They encroach on
 Acute Metabolic Complications 789

Table 53.3: Protocol for the management of diabetic ketoacidosis (DKA) (moderately severe)
On Admission: Initial treatment
Obtain complete blood count (CBC), blood glucose (BG), electrolytes, creatinine, urine glucose and ketone, plasma ketone, blood gases
Secure two intravenous (IV) lines:
Line 1: Give 10–20 units human regular insulin IV bolus
100 mL normal saline + 100 units regular human insulin: Infuse at the rate of 5–10 units/hour. Flush out first 10 mL fluid rapidly.
Line 2: Normal saline 1 L over 1 hour; simultaneously infuse (through piggyback or bivalve) sodium bicarbonate 50–100 mEq in 250–500 mL

chapter
of normal saline over 1 hour (optional)

53
0–4 hours: Monitor BG and K+ hourly
Line 1: Continue insulin infusion
Line 2: May infuse 500–1,000 mL of half normal saline
Change to 5% dextrose when BG drops to about 200 mg/dL
Start potassium chloride (KCl) 40 mEq/L of IV fluids if serum K+ less than 4.0 mEq/L or if urine output is good and BG is dropping
4–24 hours: Monitor BG and K+ 2 hourly.
Line 1: Reduce insulin infusion rate to 2–5 units/hours IV when BG drops to 200 mg/dL
Line 2: Five percent dextrose solution IV to correct half of calculated fluid requirement: KCl 40 mEq/L of IV fluids
24–48 hours: Repeat CBC, electrolytes, and creatinine once a day
Line 1: Intravenous insulin infusion at 1–5 units/hour; Give 10–20 U subcutaneous (SC) human regular insulin 2 hours before discontinuation
of insulin infusion. Use basal (infusion) + bolus (IV 4–8 U regular insulin) regime when patient is on IV fluids + oral feeds
Line 2: Five percent dextrose infusion. Reduce IV fluids infused when able to retain fluids per os (PO)
After 48 hours: Shift to oral feeds
Start multiple dose insulin regime SC
Start KCl PO

the alkali reserve and as acidosis progresses, result in of skin, lungs or urinary tract. Clinical examination and
low blood pH. In mild DKA, pH is about 7.3 but in severe simple investigations will also reveal any vascular problem
acidosis it can be as low as 7.0 or 6.8. Metabolic acidosis is like a myocardial infarct, stroke or peripheral vascular
accompanied by respiratory alkalosis as a compensatory occlusion. The treatment should preferably be initiated
mechanism; this causes further lowering of peripheral in emergency room, continued in intensive care for
bicarbonate, which cannot be used as an accurate guide to 1–3 days and thereafter be undertaken in the general
judge the degree of acidosis. This acidosis is reversible and ward. Table 53.3 summarizes the treatment. In a study
hence with treatment, the ketone body generation stops, from India,25 children with DKA were treated without any
ketone utilization and excretion continue and bicarbonate morbidity and mortality by using standard protocol and
is regenerated. avoiding the use of sodium bicarbonate.

Management of Diabetic Ketoacidosis Fluid and Electrolyte Therapy

General Guidelines21-24 Fluid and electrolyte therapy is aimed at the replacement
A patient with DKA needs urgent hospitalization. General of previous losses, concurrent losses and daily require­
nursing care and supportive measures are instituted ments. As a general rule, the pace of replacement, espe­
immediately, depending upon the severity of DKA and cially of previous losses should be commensurate with
state of consciousness. It is important to ask for laboratory the speed with which DKA has developed. As it takes
investigations initially and periodically thereafter as about 48–72 hours to develop DKA, full replacement of
indicated in Table 53.3. At the same time, two intravenous previous losses and correction of acid-base disturbance is
(IV) lines are secured, one for fluid, electrolyte and best undertaken with the same speed. This is true of any
acid-base correction and the other for insulin therapy. A severe fluid and electrolyte problem as rapid correction
search is made for the possibility of an infection, notably is fraught with further disequilibrium, especially across
 790 Complications

Table 53.4: Potassium therapy in diabetic ketoacidosis Table 53.5: Bicarbonate therapy in diabetic ketoacidosis
• Do serum K initially, every 1-hour for 6 hours, every 2 hours for
+
• Give bicarbonate only if pH is less than 7.2. Attempt correction
next 6 hours and 12 hourly thereafter only up to pH 7.2
• Initial serum K+: Low, normal or high • Give half of the calculated dose. Do not repeat the dose
• If initial serum K+ is low, give 40 mEq KCl/L of fluids to start with. • Give sodium bicarbonate diluted in normal saline or 5% dextrose
Make sure urine output is adequate (> 50 mL/hour) in ratio of 1:4 (bicarbonate 1 part, saline 4 parts) over 1 hour
• Potassium will drop precipitously after 2–4 hours of treatment
section

and successful lowering of blood glucose. Continue 40 mEq

10

KCl/L of intravenous (IV) fluids administered Potassium Therapy20

• On institution of oral feed, 15–20 mEq KCl is recommended
thrice a day po As outlined in pathophysiology, initial serum potassium
can be often normal, low or high. When very low initially,
the blood-brain barrier. Excessive and too rapid rate potassium infusion is started right away. In most cases,
of fluid administration also increases the possibility of potassium drops after 4–6 hours of hydration and insulin
development of an adult respiratory distress syndrome therapy and at times drops to dangerously low levels.
(ARDS). Thus, one-fourth previous losses can be replaced As glucose utilization occurs intracellularly, potassium
in first 4–6 hours, another one-fourth by 24 hours and the migrates from extracellular fluid (ECF) to intracellular
last one-half in 24–48 hours. Concurrent losses continue compartment. In case alkali is being administered,
unabated till hyperglycemia is controlled. the potassium drop is aggravated, because alkalosis
causes migration of potassium to intracellular sites. It
Replacement of Water and Salt is recommended that 20–30 mEq of potassium chloride
This is the most important and urgent aspect of fluid (KCl) be added to each liter of saline or other IV fluids.
therapy. As the water loss is in excess of salt loss, ideal Theoretically, one-third of potassium replaced can be in
repair fluid will be a half normal saline. However, in the form of potassium phosphate (KPO4), but in practice,
the initial period, half-normal saline is likely to cause a the need of phosphate replacement in patients of DKA is
further contraction of blood volume and cellular edema rare (vide infra). IV KCl should be continued to maintain
with the migration of water from the vascular bed to the the serum K+ at 4–5 mEq/L. Potassium infusion should not
intracellular compartment. ordinarily exceed 40 mEq/hour. It may be necessary to
Hence, normal saline is considered an ideal initial administer about 150–300 mEq of KCl in the first 24 hours.
replacement fluid. About a liter of normal saline must be Monitoring of serum K+ is required at 1–2 hour intervals
infused in the first 1–2 hours of treatment; subsequently, during this critical period (Table 53.4).
the infusion pace is slowed as per general guidelines
provided above. However, excess of saline infusion is Bicarbonate Therapy
fraught with danger: (1) because the previous losses
are not iso-osmotic, water loss being in excess of NaCl This has been the most controversial aspect of therapy in
loss; and (2) the chloride in normal saline is in excess DKA (Table 53.5).26-28 Theoretically, a metabolic acidosis
of physiological requirement, so that large amount of can be best corrected by alkali therapy. However, the follo­
saline produces a state of hyperchloremic acidosis. For wing features of metabolic acidosis in DKA call for a great
these reasons, saline infusion should be replaced by 5% caution in the use of alkali (Flow chat 53.2):
dextrose infusion after 4–6 hours of initial treatment. At • Acidosis in DKA usually develops slowly over 2–3 days
this point, usually the blood glucose has started a steady, and hence needs correction at the same pace. As
linear decline and as such, supply of nutrients in the form fluid and insulin therapy reverses the acidosis, a good
of dextrose is called for. In practice, usually these events amount of self-correction is possible.
coincide, in exceptional cases half-normal saline can be • Rapid correction of peripheral acidosis can, for a
used if blood glucose is still high and adequate saline has period, aggravate intracerebral acidosis.
already been infused in the first 4–6 hours. Infusion of • Lastly, oxygen dissociation and hence oxygen deli­
dextrose at the right time obviates several difficulties: very to the tissues, is better in the acidotic state as
• It provides the calories and prevents hypoglycemia, compared to alkalotic state. Hence, sudden correction
• It provides free water once glucose is metabolized and can jeopardize brain oxygenation and result is cerebral
it forestalls possibility of excessive Na+ and Cl– load. edema.
 Acute Metabolic Complications 791
Flow chart 53.2: Mechanism of the deleterious effects of bicarbonate Table 53.6: Insulin therapy in diabetic ketoacidosis
therapy
• Intravenous (IV) insulin bolus 10–20 units
• Intravenous 5–10 units/hours till blood glucose is about
250–300 mg/dL
• Intravenous 2–5 units/hours till blood glucose is about 200 mg/dL
• Intravenous 1–2 units/hours plus 6–12 units IV bolus TDS,
premeal, when on oral feed and IV fluids are being continued

chapter
(basal-bolus plan)
• Subcutaneous (SC) 6–12 units STAT 1 hour before stopping

53
IV insulin infusion
• Subcutaneous multiple dose (usually three doses) regime when
IV fluids are being discontinued
Note: Link all insulin doses to patient’s previous insulin requirements.
Always use human regular insulin. Switch patient to multiple subcuta-
neous (SC) dose regimes when patient is on oral feed.

• Elimination of ketone bodies through the kidneys is Magnesium and Phosphate Therapy31-33
also better in the acidotic environment.
Deficit of magnesium can be quite high. Profound, unexpl­
• Alkali therapy also aggravates hypokalemia.
ained weakness, should suggest hypomagnesemia and if
• Use of sodium bicarbonate also generates CO2 resulting
confirmed, treated.
in aggravation of intracellular acidosis for some time.
It is important to understand the interaction of
Against all these arguments is the fact that a severe
magnesium, parathormone, potassium and calcium ions.
metabolic acidosis, especially when pH is less than 7.0, is
In hypomagnesemia, parathormone secretion is inhibited
likely to produce multiple organ dysfunctions and must
and concomitant hypocalcemia is resistant to correction.
be corrected. Use of newer type of alkalinizing drugs, like
When required, a couple of doses of magnesium sulfate,
carbicarb [a combination of sodium carbonate (Na2CO3)
2 mL of 50% solution, intramuscular (IM) or the same
and sodium bicarbonate] and tris-hydroxymethyl-amino­
infused IV diluted in 100 mL saline is sufficient to produce
methane (THAM) may be advantageous in this regard.
At present, the guidelines for alkali therapy have been initial correction. In most patients, early institution of oral
fairly well-established. Alkali therapy may be considered feeds takes care of magnesium deficit.
if pH is less than 7.2. If pH is less than 7.0, alkali therapy Phosphate therapy is also theoretically desirable.
is considered essential. In any case, the dose of sodium The erythrocyte concentration of 2,3-diphosphoglycerate
bicarbonate required is 50% of that calculated by the (2,3-DPG) is depleted in DKA. A normal concentration
routine formula: of 2,3-DPG is required for optimum oxygen delivery to
Sodium bicarbonate (mEq) tissues. However, use of phosphate containing fluids
= (bicarb deficit) × (1/3 body water) is associated with hypocalcemic tetany and hence is
Recently, non-invasive monitoring of end-tidal carbon not routinely recommended. Again, early institution of
dioxide (CO2) or transcutaneous CO2 (TC-CO2) has been oral feeds, especially with milk replenishes phosphate
shown to be a reliable guide to the bicarbonate concen­ quite rapidly. Severe hypophosphatemia (serum level
tration and hence acid-base status of the patient.29,30 < 1.5 mg/dL) is associated with skeletal muscle weakness,
Usually, a single dose of sodium bicarbonate in slow respiratory depression and hemolysis. In such situations,
infusion over half to 1 hour is considered adequate. The phosphate can be replaced conveniently by undertaking
dose often works out to be 50–150 mEq and is hardly ever one-third of potassium replacement in the form of pota­
required to be repeated because the whole metabolic ssium phosphate.
acidosis starts reversing in 4–6 hours of effective fluid and
insulin therapy. The 7.5% sodium bicarbonate solution Insulin Therapy in Diabetic Ketoacidosis34-36 (Table 53.6)
(supplying 0.9 mEq/mL) should be diluted 1:4 by dextrose Insulin therapy is obviously an important aspect of
or saline solution, as concentrated sodium bicarbonate therapy in DKA. However, the blood glucose is known to
is known to have caused severe thrombophlebitis of drop considerably with hydration alone, if undertaken
peripheral veins or even extensive tissue necrosis. prior to insulin therapy. As DKA is a grave metabolic
 792 Complications

emergency and the initiating event is insulin deficiency, it We routinely employ the method of flushing out
will be unwise to withhold insulin either in the initial or 10–20 mL of insulin containing fluid in our patients of DKA
subsequent part of its management. or any emergency in diabetic patients calling for insulin
The type of insulin to be used is regular human infusion.
insulin. At present, these insulins are in extensive use. The If fluid overload is the problem, as in DKA with left
immunological insulin resistance observed with conven­ ventricular failure or renal failure, larger amount of insulin
tional insulin is almost never seen with the use of human can be used IV, alternatively insulin can be given IM in
section

insulin. Keeping in mind such a possibility, it is advisable doses of 5–10 units every hour.38 We do not recommend
10

to use only human insulin in this emergency. The preferred SC insulin till all metabolic parameters are stabilized. At
route of administration of insulin is by continuous IV that point, and about an hour before the discontinuation
infusion. Although it is possible to administer insulin in of IV insulin infusion, a SC dose of 6–12 units of regular
mild DKA by subcutaneous (SC) or IM route, in moderately insulin is given. Thereafter, a multiple dose insulin regime
severe DKA with volume depletion and variable SC insulin is instituted.
absorption, it is better to resort to IV insulin. More recently,
however, insulin aspart has been used subcutaneously at General Management and Supportive Measures
1–2 hour intervals successfully.37 As insulin half-life is less Leukocytosis can occur in DKA and is not necessarily
than 8 minutes, repeated IV boluses are ineffective. On the indicative of an infection. However, with a positive diag­
other hand, if an IV infusion is set-up without a bolus, the nosis of infection, appropriate antibiotics are required.
desired concentration of plasma insulin (about 100 μU/ In India, gastrointestinal infections, especially food pois­
mL) is achieved only after a lapse of 30 minutes to 2 hours. oning of all varieties are common precipitating factors and
Considering these facts, the recommended method is to would require treatment with appropriate antibiotics like
give a small bolus of 10–20 units human regular insulin IV ciprofloxacin or norfloxacin combined with tinidazole. In
and start an infusion of insulin at the rate of 5–10 units/ patients with vascular episodes or in gravely ill, elderly
hour. Some authors have suggested a loading dose of patients, heparinization has been considered but is not
0.3–0.4 U/kg, whereas investi­gations have shown that a routinely recommended unless the complicating disease
loading dose is not required. The present author uses a itself is a clear indication for heparinization (e.g. throm­
loading dose and links it with the patients’ previous insulin boembolism). Patients often have an acute gastric dilata­
requirement, as this is a measure of patient’s insulin tion; this may be treated by continuous aspiration,
sensitivity. About 20% of total daily requirement should
augmenting amount of fluids and electrolytes admini­
be used as a loading dose. We usually link the continuous
stered (water, Na+, K+) and probably using prokinetic
infusion rate to patient’s previous requirements;
drugs. Unconscious patients will require general nursing
5 U/hour is initiated in those needing small insulin doses
care. Urinary catheterization is often required in drowsy or
(< 40 units/d) while higher infusion rate is used for those
unconscious patients with retention or in order to assess
needing larger doses. This appears to be the most rational
the hourly urinary output.
approach. Several studies have compared low dose insulin
regimes with high dose regimes. Low dose regimes reduce Metabolic Complications of
the risk of hypokalemia and hypoglycemia, but in the event Diabetic Ketoacidosis
of poor response, can be risky. The doses recommended
here are somewhere in between and employed by most Several complications are likely to develop in the course
clinicians. When using insulin by continuous infusion of treatment of DKA. A knowledge of the pathophysiology
through a simple drip (with some flow regulator like dial- of these complications is essential so that they can be
flo) or a syringe-pump (preferable mode), the problem of forestalled.
insulin adsorption to stars and plastic ware is real. There
are several methods to obviate this problem: Hypokalemia
• Use larger doses (about 30–50% more) than required If blood glucose is lowered too rapidly and if sodium
• To flush about 10–20 mL of insulin containing fluid bicarbonate is used in large dose, lowering of serum
rapidly before connecting to patient potassium becomes precipitous and life-threatening. In
• Add human albumin or 5 mL of patient’s blood or 2 mL situations where a timely and accurate potassium reading
of patient’s serum to the IV fluid before adding insulin. is not available, which may happen in remote areas of our
 Acute Metabolic Complications 793

country, it is good to note that whenever blood glucose starts fundi or by a computed tomography (CT) scan. In such
dropping clearly, potassium supplement is called for. If urine a situation, the pace of metabolic corrections should
output is good at this point, there is no contraindication be slowed down. It may be necessary to use mannitol
to instituting a KCl infusion in normal saline or 5% or corticosteroids as anti-edema measures. Recently,
dextrose solution. In a good intensive care unit (ICU) hyper­tonic saline has been used.42
setting, potassium should be estimated initially and there­ With the systemic evidence of infection and neck
after 2 hourly for the first 12 hours and less frequently stiffness, possibility of meningitis must be considered

chapter
thereafter. as a differential diagnosis. The cerebrospinal fluid (CSF)

53
glucose concentration in meningitis in this situation may
Hypoglycemia not be low because of high peripheral blood glucose.43

This was a known complication until the insulin therapy Adult Respiratory Distress Syndrome44,45
was rationalized. If large doses of insulin are used as
Use of excessive fluids, especially crystalloids can result
IV boluses, IM or subcutaneously, there is a possibility
in ARDS. At the time of presentation, a patient of DKA
of hypoglycemia. At times, extra doses of insulin are
usually has an increased colloid osmotic pressure (COP)
recommended for continuing acetonuria. Fortunately,
because of gross deficits of water and sodium. During the
such approaches have been abandoned at the present
course of treatment the COP falls and creates a tendency
time. IV infusion of insulin is the preferred mode of
toward edema formation. This results in pulmonary
treatment. When the response starts, the drop of blood
edema and a gradual decrease in PO2, which can easily be
glucose is linear and predictable. Once the blood glucose
monitored by pulse oximetry. It is advisable to recognize
is lowered to 200 mg%, it is advisable to institute a 5%
this complication early on as a reduction in the volume
dextrose infusion.
of crystalloids infused and use of a colloid solution like
albumin for infusion can forestall the development of
Cerebral Edema
ARDS.
This complication can arise after 4–6 hours of successful
therapy. The precipitating factors appear to include:39-41 Relapse of Diabetic Ketoacidosis
1. A rapid lowering of blood glucose: In well-developed
As IV insulin infusions are usually employed in the
DKA, the brain generates some osmolar substances, so
treatment of DKA at present, a relapse is possible with the
called idiogenic osmoles to hold intracellular water in
cessation of insulin infusion. It is, therefore, considered
place in the face of grave extracellular hyperosmolar-
important to inject insulin SC or IM almost 1–2 hours
ity. With rapid lowering of blood glucose, extracellular
prior to the time at which IV infusion is proposed to be
osmolarity is reduced and water migrates intracellularly
discontinued. It is important to bear in mind that DKA
in the brain.
is indicative of total endogenous insulinopenia; hence,
2. Rapid alkalinization reduces oxygen delivery to the
assured delivery of insulin is essential at all phases of
tissues including brain or aggravates intracerebral
treatment.
acidosis transiently (vide supra, sodium bicarbonate
therapy). This results in cerebral edema. In order
Non-metabolic Complications of
to prevent cerebral edema, sodium bicarbonate should
Diabetic Ketoacidosis
be used judiciously and blood glucose should be low-
ered slowly. To reiterate a basic principle of metabolic Infections and vascular events dominate the scene in most
corrections, the time taken to correct an anomaly should elderly patients of DKA. Infections are often located in
be about the same as that taken to develop the anomaly. skin, lungs and urinary tract; e.g. carbuncle, pneumonia,
As DKA usually develops over 24–72 hour time (except urinary tract or foot infection and can be serious and
in case of pump withdrawal), euglycemia should only lead to life-threatening septicemia. Mucormycosis is an
be aimed at within 24–72 hours-time. If a patient is interesting but rare type of infection in DKA and should
doing well initially regarding the state of consciousness, be considered if clinical presentation indicates sinusitis,
but starts deteriorating after 4–6 hours of treatment, rhinitis or disturbance of external ocular movement or
cerebral edema should be suspected. It can be con- proptosis. Foot problems are often a combination of
firmed by venous congestion or mild papilledema in the vascular occlusion and infection. Patient may present
 794 Complications

with a major vascular event like myocardial or cerebral Flow chart 53.3: Clinical spectrum of diabetic ketoacidosis (DKA) and
hyperglycemic hyperosmolar non-ketotic state
infar­ction. The outcome is often dependent upon the
severity of these non-metabolic complications. Occasio­
nally, a vascular event is precipitated during DKA, probably
induced by hypotension, severe dehydration and profound
hemobiological changes like sludging, hyperosmolarity,
increased platelet aggregation and hyperviscosity.
section
10

Prevention and Early Intervention

The prognosis in DKA is strongly related to the severity is invariably evidence of gross ketoacidosis. At the other
of metabolic disturbance at the time of presentation. extreme end of the spectrum, HHNKS typically occurs
State of consciousness and degree of hyperosmolarity at with lesser degree of insulin deficiency, usually in type 2
presentation are important factors. Hence, early detection diabetes, patients tend to be older, onset is more gradual
and intervention is important which can be most effec­ and there is either no ketoacidosis or mild insignificant
tively done by patient education empowerment and ketonemia but there is severe hyperosmolarity.54 The most
training of primary care physicians. common clinical situation in a hospitalized patient is that
Type 1 diabetic patients must know a sick-day of a type 2 diabetic who is ill with some concurrent illness
routine and should have rapid access to a knowledgeable like a stroke, myocardial infarction or acute infection and is
physician. They should report to hospital early if they are found to have severe hyperglycemia. Upon closer scrutiny,
unsuccessful in combating DKA with a few supplemental the patients are found to have only a mild ketonemia and
doses of insulin or especially if presence of vomiting near normal blood pH and are indeed suffering from
precludes adequate fluid replacement orally. In the past HHNKS and not DKA. Not so commonly recognized is the
20 years, our center has not experienced a single death due fact that the patient with DKA who has come in a comatose
to DKA mainly due to these precautions. In this period, state to the emergency room is inevitably suffering from
all of our patients have been hospitalized in a conscious a hyperosmolar state.55 The estimated prevalence of
or drowsy state and have been either ambulatory or the intermediate state characterized by both, hyperos­
transported in a wheel-chair at the time of admission. molarity and metabolic acidosis is about 33%.56 It is
imperative to recognize that the comatose patient must
HYPERGLYCEMIC HYPEROSMOLAR be treated for the hyperosmolar state and failure to do so
NON-KETOTIC STATE is the major cause of mortality in the hyperosmolar-DKA
syndrome.54 Although rare, young patients with type 1
Hyperglycemic hyperosmolar non-ketotic state along with
diabetes may present with HHNKS55 (Flow chart 53.3).
DKA is increasingly being recognized as one of the most
serious complications of diabetes mellitus (DM) and if
misdiagnosed, untreated or undertreated, it carries a high
Definition
mortality.46-53 Whereas DKA is associated predominantly The essential components of HHNKS are:54
with type 1 diabetes, HHNKS is associated with type 2 1. Blood glucose more than 700 mg/dL.
diabetes. But, it is important to realize that any of these 2. Serum osmolarity more than 320 mOsm/L or more than
metabolic emergencies can occur in any types of DM, 340 mOsm/L (when patient is comatose).
irrespective of the age or gender of the patient. 3. Serum bicarbonate more than 15 mEq/L.
It is important for the physician to realize that HHNKS 4. Serum pH more than 7.3.
and DKA represent a continuum with DKA at one end 5. Urinary ketones negative or weakly positive.
of the spectrum and HHNKS at the other (Flow chart 53.3). 6. Serum ketones negative in 1:4 dilution.
As DKA with significant hyperosmolarity typically indi­ The major criteria is a very high blood glucose
cates a total absence of insulin (type 1 diabetes), the onset associated with markedly elevated serum osmolarity
tends to be acute, it is accompanied by modest degrees of (> 340 mOsm/L, if the patient is comatose) with minimal
hyperglycemia, usually less or around 300 mg/dL and there or no ketoacidosis.
 Acute Metabolic Complications 795
Flow chart 53.4: Pathophysiology of hyperglycemic hyperosmolar Flow chart 53.5: Osmotic effects of hyperglycemia
non-ketotic state and diabetic ketoacidosis syndrome

chapter
53
Pathogenesis the hyperosmolarity of the ECF. The increased glucose
concentration in the ECF in turn causes an osmotic shift of
Partial or complete absence of insulin, initiates the
water out of the cells into the smaller extracellular space.
hyperglycemia, which leads to the development of the
The result is a modest loss of ECF volume. The movement
hyperosmolar state. Insulin deficiency greatly enhances
of fluid from the intracellular to the extracellular vascular
hepatic gluconeogenesis. The resulting excess of glucose is
space serves the important function of providing an
released into the extracellular space, where in the absence
“autotransfusion” that is by compensating for the
of adequate amounts of insulin, glucose can neither be
water lost by osmotic diuresis, it initially preserves the
normally transported into the cell nor can the glucose
vascular volume, thereby preventing hypovolemia and
that enters the cell be normally metabolized. The excess
its serious consequences. These phenomena will be
glucose is thereby restricted to the extracellular space.
later discussed in the section detailing the treatment of
The combined hepatic overproduction and inadequate
HHNKS, since inappropriate therapy can cause reversal
peripheral utilization of glucose therefore results in
of autotransfusion into the vascular space, resulting in
progressively increasing hyperglycemia. The amount
of insulin needed to prevent lipolysis from the adipose severe hypovolemia and death. With increasing hyper­
tissue and ketogenesis in the liver is less than that needed glycemia, the renal threshold for glucose is exceeded
to promote glucose utilization in all the insulin sensitive leading to massive osmotic diuresis with increasing loss
tissues. of water and potassium in urine. As a result, both intra­
As shown in Flow chart 53.4, in HHNKS, there is cellular and extracellular dehydration occurs (Fig. 53.1).
enough insulin available, which prevents the activation of At this last stage of HHNKS, transfer of water from the
hormone sensitive lipase and thus prevents lipolysis in the intracellular to the extracellular space is no longer adeq­
adipose tissue. Similarly in the liver, excess ketogenesis uate to maintain the vascular volume. This results in
is prevented as enough insulin is available to counteract cellular dehydration including brain dehy­ dration and
the effects of counter-regulatory hormones especially coma. An increasing loss of volume from the extracellular
glucagon.57-60 space leads to hypovolemic shock or vascular collapse.
Most critical to the understanding of the pathogenesis Either or both of these consequences may be responsible
of HHNKS is the role of hyperglycemia, which on the one for a fatal outcome.
hand causes osmotic shifts within the body, and on the The important point emphasized so far is that the
other hand, causes severe osmotic diuresis with loss of free coma in HHNKS or for that matter in DKA is the result
water and electrolytes from the body.61,62 These changes of hyperglycemia and the consequent hyperosmolarity
are responsible for the hyperosmolar and hypovolemic and is not linked to acidosis.57,63,64 Fulop et al.56 and
state and death in the HHNKS.57,63,64 others54,63,64 have demonstrated that there is no correlation
As shown in Flow charts 53.4 and 53.5, early in the between serum pH and either mental status or mortality
course of the development of hyperosmolar state, hyper­ in patients with HHNKS-DKA syndrome. By contrast,
glycemia is responsible for the osmotic diuresis and for there is a very good correlation between depression of the
 796 Complications

Table 53.8: Precipitating factors in hyperglycemic hyperosmolar

non-ketotic state-diabetic ketoacidosis (HHNKS-DKA) syndrome
• Too little insulin
• Infection (even minor)
• Severe stress (physical or emotional)
• Hypokalemia (usually diuretic induced)
• Renal failure
section

Inadequate fluid intake:

10

– Old age (reduced sensitivity to thirst)

– Infancy (poor access to water)
Fig. 53.1: Compartmentalization of osmotically active molecules in
insulin deficient states – Incapacitation occurring at any age (poor access to water)

back and forth between the extracellular and intracellular

Table 53.7: Calculation of serum osmolarity
spaces. Thus, these molecules are not osmotically active
2 (Na + K) (mOsm/L) +
and are thus clinically irrelevant. The “calculated” osmo­
Glucose(mg/dL)
= “Effective” Osmolarity (mOsm/L) larity includes only the osmotically effective molecules
20
(glucose, sodium and perhaps potassium), but the “meas­
ured” osmolarity includes many molecules that do not
sensorium and serum glucose levels. More significantly, play a role in producing cellular dehydration.54
plasma osmolarity is very closely related with degree
Thus, a patient of type 2 DM, aged 50 years who presents
of obtundation. In fact, various studies54,57,63 demonstrate with fever and a measured osmolarity of 345 mOsm/L but
that coma does not occur until the plasma osmolarity a calculated osmolarity of 310 mOsm/L, is not comatose
exceeds approximately 340 mOsm/L. This means that if a due to HHNKS, but is more likely to have meningitis or
patient with DKA presents in a coma and has a calculated another similar complication leading to coma.
serum osmolarity of 310 mOsm/L, the coma is not due to
DKA or HHNKS and another cause, e.g. stroke or mening­ Precipitating Factors
itis, must be sought. As already mentioned, inadequate insulin therapy, infec­
Osmolarity is readily calculated at the bedside by tion and an acute cardiovascular event can precipitate
the formula shown in Table 53.7. Note that a value of either DKA or HHNKS (Table 53.8). Special mention
20 rather than the actual molecular weight of glucose however must be made of certain precipitating factors,
(180/10) is used to convert glucose from milligrams per which are more likely to precipitate HHNKS.65 Stress,
deciliter to milliequivalents per liter. In addition to making usually physical, but occasionally emotional, can preci­
it easier to calculate, the value 20 more accurately reflects pitate HHNKS by causing an increase in catecholamines
the osmotic activity of the glucose molecule. and cortisol. Hypokalemia is an important cause. It
In clinical situations, one should use the bedside aggravates the hyperglycemic state by reducing insulin
calculation of effective osmolarity rather than the free­ secretion as well as by decreasing insulin sensitivity.44
zing point depression method to obtain the estimate of More often than not, hypokalemia is a consequence of
osmolarity.61 Figure 53.1 shows how that in a decom­ osmotic diuresis and diuretic abuse.
pensated diabetic state, the lack of insulin aggravated by A major and probably essential factor in producing
severe insulin resistance, prevents glucose from entering HHNKS is the inability of the patient to sense the need for
the intracellular space, and the glucose is confined to or have access to water. The patient may either suppress or
the smaller extracellular space, resulting in more severe not recognize thirst or the patient may be unable to obtain
hyperglycemia. Sodium, even under normal conditions, water because of a physical disability (e.g. in the very
does not enter the intracellular space to a significant young or the very old). There is evidence that the thirst
extent. By contrast, urea, alcohol and a number of center may become less sensitive with age.54 Additionally,
other compounds that are measured by freezing point once established, the hyperosmolar state may suppress
depression method of determining osmolarity, pass freely the sensitivity to insulin, there by initiating a vicious cycle.
 Acute Metabolic Complications 797

Table 53.9: Drugs than can precipitate hyperglycemic hyperosmolar Table 53.10: Major signs and symptoms of hyperglycemic hyper-
non-ketotic state (HHNKS) osmolar non-ketotic state-diabetic ketoacidosis (HHNKS-DKA)
Drugs Effect syndrome

Cortisone Decreased insulin secretion, • In 50–60% of hyperglycemic hyperosmolar non-ketotic state

Increased insulin resistance (HHNKS), hyperosmolar coma is the first sign of diabetes

Thiazides Decreased insulin secretion • Dehydration can be manifested by thirst, decreased turgor, soft
eyeballs and orthostasis (HHNKS)
Furosemide Increased water loss

chapter
• Temperature is usually normal or low, but if elevated, infection is
Dilantin sodium Decreased insulin secretion
usually present

53
• Stupor, coma and convulsions are more common in HHNKS,
Beta-blockers Decreased insulin secretion
than in diabetic ketoacidosis (DKA)
Calcium channel blockers Decreased insulin secretion
• Kussmaul breathing indicating pH < 7.2 (DKA)
Alcohol Subclinical pancreatitis
• Abdominal pain is present in at least 30% patients (DKA-
HHNKS)
Antidiuretic hormone secretion reaches a maximum at • Vomiting is seen in 50–60% of patients (DKA). Causes further
an osmolarity of about 295 mOsm/L, thereafter thirst and dehydration. May precipitate hyperosmolar state

increased water intake, normally serve as the only prote­

ction against more severe hyperosmolarity. It is difficult,
a case report of HHNKS being precipitated by lithium-
if not impossible, to produce hyperosmolar coma in
induced diabetes insipidus.67 HHNKS has also been
the patient who can obtain and drink adequate amounts
reported in central diabetes insipidus.68
of water.59
In hospitalized, mentally obtunded patients or tube-
Mortality
fed patients, inadequate supply of water can occur, unless
there are clear instructions to provide appropriate amo­ Mortality rate in HHNKS approaches 20–40% as compared
unts of free water in the tube-feeding plan. This factor to 3–9% in DKA.69,70 In recent times, mortality in DKA
coupled with use of drugs listed in Table 53.9 form the has been lowered to about 2–3% and HHNKS to about
two most common precipitating causes of HHNKS. 10%.23 High mortality in HHNKS is explained by severe
A large number of commonly used drugs can preci­ concomitant complications and older age. Inappropriate
pitate HHNKS (Table 53.9). Thiazide diuretic induces therapy (inadequate fluid replacement) and associated
hypokalemia, which in turn causes hyperglycemia by vascular complications (myocardial infarction, strokes
reducing insulin secretion and inducing hormone resis­ and thrombosis in lower extremities) contribute to both
tance. Propranolol and other β-blockers decrease insulin morbidity and mortality.
secretion, as does dilantin sodium. Calcium channel bloc­
kers also reduce insulin secretion. Alcohol may act by Clinical Features
producing subclinical pancreatitis. On the other hand, The major signs and symptoms of HHNKS are shown in
given the large number of patients who simul­taneously Table 53.10. As mentioned, patients frequently present
receive a thiazide diuretic, calcium channel blocker and with both hyperosmolar coma and ketoacidosis; hence,
β-blockers HHNKS or DKA is rare. However, these drugs the symptoms of the two are combined, but depending
can induce this condition, singly or in combination. on their frequency of occurrence, the specific condition is
Corticosteroid use is probably the most common mentioned in parenthesis.
iatrogenic cause of HHNKS. Cortisol induces a marked It is important to emphasize that 50–60% of patients
peripheral resistance to insulin. Deaths have been with HHNKS at presentation have not been diagnosed
reported due to HHNKS in patients not known to be to have DM earlier. It is not unusual, therefore, for the
diabetic at the time they receive corticosteroids.66 In diagnosis of hyperosmolar coma to be seriously delayed
addition to inducing peripheral resistance, cortisol may until the elevated plasma glucose suggests the correct
also be instrumental in the production of ketone bodies diagnosis.68-73
by the liver and it is unlikely that significant DKA-HHNKS The signs and symptoms of HHNKS linked to hyperos­
occurs in hypoadrenal states (e.g. Schmidt’s syndrome), molarity induced dehydration are thirst, decreased turgor,
wherein both insulin and cortisol are deficient. There is soft eyeballs, hypotension and orthostasis (Table 53.10).
 798 Complications

Table 53.11: Laboratory abnormalities in hyperglycemic hyperos­

molar non-ketotic state (HHNKS)
Plasma glucose > 700 mg/dL
Hyperosmolarity 340 mOsm/L
(> 320 mOsm/L-significant
280–295 mOsm/L-normal)
Sodium Low, normal or high, but total
body sodium always low
section

Potassium Normal or high

10

Urine ketones Nil or mild+

pH > 7.3
Bicarbonate > 15 mEq/L
Temperature Normal or low
Leukocytosis 15,000–40,000 cells/mm3 in
diabetic ketoacidosis (DKA) even
without infection.
Normal in pure hyperglycemic
hyperosmolar non-ketotic state
(HHNKS)

It is worth emphasizing that hyperosmolar state or ketoa­ Fig. 53.2: Fluid balance in hyperglycemic hyperosmolar state. (A)
cidosis do not cause an elevation of body temperature. Normal glycemia and hydration; (B) Early: Extracellular fluid (ECF) is
Presence of fever in a comatose or acidotic diabetic hyperosmolar, causing H2O to shift from intracellular fluid (ICF) to ECF—
an autotransfusion; and (C) Late: Continued osmotic diuresis cause
patient is an indication of infection, which usually is the
dehydration, volume loss and hyperosmolarity in both ECF and ICF
precipitating factor.
Obtundation, stupor, coma and generalized or partial
seizures are characteristic of severe HHNKS and are rarely, Management of Hyperglycemic
if ever, observed in pure DKA.64,71 Kussmaul respiration, Hyperosmolar Non-ketotic State
abdominal pain and vomiting are more often linked to
DKA.
Fluid Replacement
The laboratory data observed in HHNKS is shown The principle of treatment is to correct the hyperosmolar
in Table 53.11. Marked hyperglycemia, usually greater state and dehydration that is primarily responsible for
than 800 mg/dL, is typical of hyperosmolar coma, and a coma and death in this syndrome. Hyperosmolarity is
total osmolarity above 340 mOsm/L is required for coma simply treated by rapidly correcting the water deficit.
to be present. For all practical purposes, coma is never The electrolytes are replaced with saline containing
seen till this level of hyperosmolarity is attained. For the potassium. The hyperglycemia is corrected primarily by
hyperosmolar state, a serum osmolarity of 320 mOsm/L is fluid replacement,72,73 as well as with insulin. Ketones and
sufficient and this warrants a prompt therapeutic response acidosis, if at all associated, are simultaneously corrected
to prevent onset of coma. by the same measures.
Serum sodium may be low, normal or high; however, The importance of adequate fluid replacement during
total body sodium is always low. Potassium maybe normal insulin therapy cannot be over emphasized.47,51,70-75 If
or high, but again there is total body potassium deficit. insulin is administered to the hyperosmolar patient
Serum ketones, if measured, are below 7 mmol/L and without simultaneously correcting the fluid deficit, glucose
serum bicarbonate more that 15 mEq/L and pH is usually and water move from the vascular space into the cells and
more or equal to 7.3. Contrary findings suggest an acidotic the “autotransfusion” described earlier is reversed. The
state, either DKA or the intermediate syndrome. As noted result is an acute loss of vascular volume, worsening of
temperature is normal, unless an infection is present. Pure hypernatremia, shock and increased mortality (Fig. 53.2).
HHNKS does not affect the leukocyte count, however, DKA Adequate fluid replacement is defined as replacing
or acidosis can cause severe leukocytosis (15,000–40,000/ one-half of the water deficit in the first 5 hours. The average
cells/mm3 with a marked shift to the left). Leukocytosis, water deficit in the patient with hyperosmolar coma, with
therefore, per se, does not indicate infection. or without acidosis, is about 10% of the total body weight.
 Acute Metabolic Complications 799

Table 53.12: Fluid replacement in hyperglycemic hyperosmolar secondly the fear of causing cerebral edema. Literature
state (HHNKS) does not support the concept that fluid replacement
• Estimated H2O deficit 10% of body weight in the severely dehydrated patient causes congestive
• Replace 50% of deficit in the first 5 hours cardiac failure.50,54,72 The one exception to this may be in
– Normal saline if: the severely acidotic patient, since, it is well-established
 Hypotensive that acidosis from any cause leads to segregation of fluid
 Na < 140 mEq/L in the pulmonary bed. However, acidosis is usually never

chapter

– One-half normal saline if: severe in HHNKS. Additionally, a large number of studies,

53
 Na > 145 mEq/L
reviewed by Rosenbloom73 have documented that cerebral
edema in HHNKS-DKA syndrome is unrelated to either
 Patient normotensive
the rate of fluid replacement or the rate of correction of
Rate Hours Volume
hypernatremia or hyperglycemia. Finally, cerebral edema
½–1 1L
is not related to the tonicity of the hydrating solution.
2 1L
Assessment of the patient’s hydration status during therapy
3 500 mL-1 L
is made by clinical evaluation. One has to judge hydration
4 500 mL-1 L
by evaluating turgor, blood pressure, degree of orthostasis,
5 500 mL-1 L
monitoring of central venous pressure and urinary output
Total 1st 5 hours 3.5–5 L
as well as reckoning of the fluid balance with meticulous
6th to 12th hour 250–500 mL/hour
care. Serum glucose and sodium, corrected or uncorrected
are of much less value in determining the patient’s state of
A 70 kg patient with total body water of about 40 L would hydration.
therefore have a deficit of about 4 L and should receive a
net intake of about 2 L of water during the first 5 hours. A
Insulin
recommended protocol for fluid replacement in HHNKS While insulin therapy is less critical in the HHNKS, yet
is shown in Table 53.12. it should be instituted immediately after establishing
The choice between normal saline or one-half normal the diagnosis. The principles and the dosage followed are
saline as the vehicle for fluid replacement is controversial. the same as that for DKA and are shown in Table 53.6.
It is reasonable to employ normal saline if the serum When serum glucose levels decrease to about 250–300
sodium is decreased or the patient is hypotensive. If mg/dL, 5% glucose in saline is to be infused at the rate of
serum sodium is elevated, initial fluid replacement should 250–500 mL/hour. Insulin drip must however continue
consist of one-half normal saline, followed by normal at the rate of 1–2 U/hour to maintain blood glucose of
saline when the sodium returns to normal; or preferably approximately 200 mg/dL. The same weaning of regimen
dextrose solution when blood glucose is controlled or from IV to SC should be followed as advised for DKA.
alternatively free water orally or through nasogastric tube. The replacement of potassium is as for DKA. Acidosis is
As vast majority of patients are conscious or in mentally never prominent in HHNKS; hence, bicarbonate therapy
obtunded patients where nasogastric tube is in place, it has no role to play. Phosphates and magnesium are
is possible to give water orally. This simplifies the fluid rarely required except when phosphate level is less than
therapy considerably. 1.5 mEq/L, one can either give potassium phosphate (one-
The rate of fluid replacement, as noted, is critical. There third of potassium replacement) or potassium hydrogen
is almost unanimity in the literature that at least 1–2 L of phosphate. There is, however, justifiable concern that
fluid should be administered in the first hour.51,53,54,72 This IV phosphate will lower both serum calcium and cause
is irrespective of age or associated disease. If physicians metastatic calcium phosphate deposits in soft tissues.
persist in correcting at the rate of 150–250 mL hour, the Early oral replacement of phosphate (in the form of milk)
result is that 24 hours later, the serum osmolarity, far from is preferred.
being corrected, actually increases and the patient remains
comatose. There are two major reasons why physicians are
Complications
reluctant to infuse fluids rapidly in-patients with HHNKS; There are a number of complications that may accompany
firstly, the fear of causing congestive heart failure and or follow the successful treatment of HHNKS. The
 800 Complications

Table 53.13: Complications of hyperglycemic hyperosmolar state Table 53.14: Laboratory findings typically associated with lactic
(HHNKS) acidosis
• Infections: Urinary tract, pneumonia (aspiration and linked to • Blood Lactic acid rise (> 5 mmol/L)
dehydration), pancreatitis • Metabolic acidosis
• Disseminated intravascular coagulopathy • Elevated anion gap
• Venous and arterial thrombosis: (e.g. femoral arterial occlusion) • Hyperuricemia
• Myocardial infarction • Hyperphosphatemia
section

• Cerebrovascular accident • Leukocytosis

10

• Hypoglycemia • Normokalemia
• Hypokalemia
• Cerebral edema

metabolic complications are similar to those in DKA, acidosis has the poorest prognosis amongst all of the acute
except that in the absence of severe acidosis, pulmonary metabolic complications of DM. Thus, it is extremely
complications such as collection of fluid in the pulmonary important to prevent this condition and to detect it early,
vascular bed and ARDS are less common. However, few so that remediable measures can be instituted prior to the
other complications tend to predominate (Table 53.13). onset of irreversible damage.
The extent of the complications is probably directly Definition: For the sake of convenience, lactic acidosis
related to the duration of symptoms and inversely related is defined as a metabolic acidosis in which the arterial
to the rate at which the hyperosmolar state is reversed.54,73 blood lactate equals or exceeds 5 mmol/L (45 mg/dL) and
Urinary tract infections may occur due to poor flow and the arterial pH is below 7.35. Regardless of the specific
pneumonia may be due to dehydration or aspiration, the biochemical criteria, it should be emphasized that
result of the obtunded state or hyperosmolar state induced lactic acidosis may not necessarily produce “acidemia”,
convulsions. Obviously, infection can be a precipitating depending upon (1) the magnitude of hyperlactatemia;
factor or a complication of the HHNKS. (2) the buffering capacity of the body; and (3) the coexi­
Pancreatitis can likewise both precipitate and comp­ stence of other conditions (e.g. liver disease, sepsis) that
licate the hyperosmolar state. There may be a marked predispose to tachypnea and alkalosis. Thus hyperla­
hypertriglyceridemia. Hyperosmolarity per se, perhaps ctatemia is synonymous with lactic acidosis and may be
due to impairment of blood flow to the pancreas may associated with acidemia, a normal pH, or alkalemia. The
cause pancreatitis, and this may be obvious a day or two typical laboratory findings associated with lactic acidosis
after the patient has regained consciousness. are shown in Table 53.14.76,77
Disseminated intravascular coagulopathy has been
reported following an episode of HHNKS. Arterial throm­ Pathogenesis
bosis, myocardial infarction, stroke and femoral arterial The lactate ion arises from the reduction of pyruvate.
thrombosis have been noted, following an episode of Lactate dehydrogenase (LDH) catalyzes the reversible
HHNKS. Cerebral edema is occasionally observed, but is formation and removal of lactate in all cells.
not linked to the rate or amount of fluid administered.
Pyruvate + NADH + H+ ↔ Lactate + NAD–
There is good data demonstrating that the prompt
In the healthy, rested, overnight-fasted adults, the
recognition of the HHNKS and institution of adequate
basal lactate concentration usually ranges between
therapy has consistently reduced the mortality and comp­
0.75 mmol/L to 1 mmol/L (6.8−9.0 mg/dL). It has been
lications of this potentially disastrous complication of
estimated that under basal conditions, whole body lactate
DM.47,54
production by healthy adults averages 0.8 mmol/kg body
weight per hour, or about 1,400 mmol/70 kg per human
LACTIC ACIDOSIS
per 24 hours.74 Major sources of lactate production include
Explosive in onset and often unyielding to therapy, lactic skin, erythrocytes, brain, skeletal muscles and intestinal
acidosis usually reflects the presence of an underlying mucosa.75,78 Pyruvate, the basic metabolite for lactate
disorder that, if left untreated, leads to death. Lactic production is derived mainly from oxidation of lactate via
 Acute Metabolic Complications 801

LDH, from proteolysis by a variety of dehydrogenation During fasting, neoglucogenesis assumes the major
and transamination reactions and from glycolysis by the route of lactate use (at least in the liver), and the glucose
Embden-Meyerhof pathway. Six amino acids (alanine, released into the circulation becomes available for uptake
cysteine, glycine, serine, threonine and tryptophan) and catabolism by peripheral tissues. Lactate released
provide the protein derived carbon backbones for pyruvate by these tissues then serves as a substrate for hepatic
formation. In the basal state, proteolysis contributes and renal glucose synthesis. This process of carbon
about 15% of the lactate generated intracellularly.74,78 The shuttling between sites of a glucose synthesis and

chapter
largest and quantitatively, the most important pathway anaerobic glycolysis is called Cori’s cycle. Lactate uptake

53
for pyruvate genesis is from glycolysis. Glycolysis occurs by liver and kidney is concentration-dependent and is
in the cytoplasm at a rate largely determined by three saturable and both organs can respond to hyperlactatemia
unidirectional reactions catalyzed by hexokinase (HK), by increasing lactate extraction by several folds above the
6-phosphofructokinase (PFK) and pyruvate kinase (PK). basal rates. When the renal threshold for lactate is reached,
Of these, PFK is the most important. Glycolysis per se excretion becomes another mechanism for lactate
does not produce lactic acid, but provides its conjugate removal. The operation of the Cori’s cycle also involves
base, lactate, adenosine triphosphate (ATP) and water. the continual production (via glycolysis) and removal (via
Hydrolysis of ATP in turn generates protons in an amount oxidative phosphorylation) of hydrogen ions and thus is
stoichiometrically equivalent to that of lactate. The major crucial for maintaining the acid-base equilibrium. Protons
source of lactate generation is anaerobic glycolysis when liberated in the cytoplasm by the hydrolysis of ATP during
one mole of glucose generates two moles of ATP and two glycolysis are used by the mitochondrial respiratory
moles of lactate.79 chain for synthesis of new ATP, available to drive such
Approximately, 1,400 mmol of lactic acid is produced undergoing processes such as gluconeogenesis. Thus,
endogenously and consumed daily by a typical human hepatic and renal functional adequacy is of paramount
being. Diffusion of 1,400 mmol of acid into the ECF dest­ importance in lactate homeostasis. Failure of these two
roys 1,400 mmol of sodium bicarbonate (NaHCO3), con­ organs either singly or jointly associated with anaerobic
verting the alkali to sodium lactate. Hepatic oxidation of conditions (hypoxia, septicemia, etc.) will definitely lead
extracted sodium lactate regenerates lost bicarbonate in to life-threatening lactic acidosis.79
this cyclical process. In the healthy state, lactate production In summary, hyperlactatemia or lactic acidosis will
is balanced by lactate removal. When there is plentiful result when its production exceeds its use or disposal.
supply of oxygen to tissues, the metabolism of pyruvate is From the above discussion it is obvious that:
primarily oxidative rather than reductive. Pyruvate in the • Mitochondrial oxygen supply determines the efficiency
presence of pyruvate dehydrogenase (PDH) is converted by which substrate fuels are oxidized and energy is
to acetyl coenzyme A in the mitochondria. This is then generated.
further incorporated into the tricarboxylic acid (TCA) cycle • The liver plays a pivotal role in both the production and
and leads to generation of 38 moles of ATP, compared to use of lactate and hydrogen ions and in maintaining
two moles of ATP when only anaerobic glycolysis occurs whole body acid-base balance.
and lactate is the end-product. Consumption of lactate by • Lactic acidosis results from a fundamental disorder
oxidative reactions occurs in all cells except erythrocytes, of pyruvate metabolism, of which hyperlactatemia
which lack mitochondria. The other major routes for lactate is an indicator, and from an imbalance between ATP
removal are via biosynthetic mechanisms, involving either hydrolysis and ATP production.
the decarboxylation of pyruvate to acetyl coenzyme A Considerable hyperuricemia is often associated with
(acetyl-CoA) or via net synthesis of glucose from pyruvate. lactic acidosis because lactate competes with urate for
Quantitatively the most important non-oxidative secretion by the renal tubules, thereby competitively
process of lactate removal is by gluconeogenesis by the reducing urate excretion.80 Hyperphosphatemia results
liver and to a lesser extent, the kidney cortex. Here, it is from widespread cellular efflux due to persistent, unre­
either reduced to glucose or oxidized to CO2 and water. plenished ATP hydrolysis and tissue hypoxia.80,81 Acidemia-
The liver accounts for approximately 50% and the kidneys induced catecholamine release prompts demargination
for about 30% of the whole body lactate uptake in the of white blood corpuscles, causing leukocytosis.82 Lactic
resting state.78 acidosis typically does not cause hyperkalemia. Unlike
 802 Complications

Table 53.15: Classification of acquired lactic acidosis mineral acidic ions (e.g. HCl), the lactate ion more readily
Type A: Due to tissue hypoxia permeates the cell membranes. This cellular entry prevents
1. Tissue hypoperfusion the development of electrical gradients resulting from
• Abnormal vascular tone or permeability isolated H+ entry into the cells, which would favor extrusion
• Left ventricular failure of cationic K+ down the electrochemical gradient.83
• Decreased cardiac output Blood samples for lactate assays should be collected
• Massive catecholamine excess in tubes containing 10 mg of sodium fluoride and 2 mg of
section

2. Reduced arterial oxygen content potassium oxalate, or rapidly precipitated with perchloric
10

• Asphyxia acid, to avoid in vitro lactate synthesis by red blood cells.

• Hypoxia (PaO2 < 35 mm Hg) Samples should be kept on ice until plasma is separated
• Carbon monoxide poisoning from unprecipitated specimen. This should be done within
• Life-threatening anemia 15 minutes of collection.84
Type B: Not due to tissue hypoxia
Most cases of lactic acidosis are considered to be
1. Common disorders
acquired (Table 53.15). This is in contrast to congenital
• Sepsis
lactic acidosis which is caused by a wide array of inborn
• Hepatic failure
errors of metabolism that are due to genetic defects in
• Renal failure
gluconeogenesis, PDH, TCA cycle or the respiratory
• Diabetes mellitus
chain.84
• Cancer
• Malaria
Acquired lactic acidosis has been conventionally
• Cholera
classified into type A (due to tissue hypoxia) and type B
2. Drugs or toxins in which factors other than tissue hypoxia are the primary
• Biguanides cause.78,85 However, in a clinical setting, patients with lactic
• Ethanol acidosis can rarely be classified as purely hypoxic (type A)
• Salicylates or non-hypoxic (type B), as by the time lactic acidosis is
• Methanol diagnosed, multiple precipitating or exacerbating causes
• Ethylene glycol can be identified and these are inexorably linked. As a
• Cyanide result, most cases of lactic acidosis, on diagnosis, are best
• Nitroprusside classified as mixtures of type A and type B and reflect
• Niacin problems in both the production and removal of lactate
• Catecholamines and protons.79
• Diethylether
• Papavarine Adverse Consequences of Lactic-acidemia
• Paracetamol
Severe acidosis is defined as pH less than 7.2. The adverse
• Nalidixic acid
• Isoniazid
consequences of severe acidosis are listed in Table 53.16.
• Streptozotocin
These consequences are not linked to the cause of acidosis
• Sorbitol, xylitol, fructose and can occur in metabolic, respiratory or mixed forms
• Parenteral nutrition of acidosis. The effects on the cardiovascular system are
• Lactulose especially life-threatening and include hypotension,
• Theophylline decreased cardiac output, centralization or pooling of
• Cocaine blood volume and reduced hepatic and renal blood flow.
• Vitamin deficiency Of special note is the increased likelihood of re-entrant
• Paraldehyde arrhythmias and a reduced threshold for ventricular
3. Other conditions fibrillation, while the defibrillation threshold remains
• Strenuous muscular exercise unaltered. Acidosis triggers a sympathetic discharge but
• Grand mal seizures also progressively attenuates the effects of catecholamines
• D-lactic acidosis on the heart and vasculature. Thus, at pH less than 7.2, the
• Hypoglycemia direct effects of acidemia predominate.86
 Acute Metabolic Complications 803

Table 53.16: Major adverse consequences of severe acidemia Table 53.17: Normal anion gap
1. Cardiovascular Na+ – (Cl– + HCO3–) = 8–16
• Impairment of cardiac contractility Or
• Arteriolar dilatation, venoconstriction and centralization of (Na++ K+) – (Cl + HCO3) = 12–20
blood volume
• Increased pulmonary vascular resistance of acutely ill-diabetic patients have blood lactate levels
• Reduction in cardiac output, arterial blood pressure, hepatic greater than 5 mmol/L and the diabetic predisposition

chapter
and renal blood flow to lactic acidosis seems particularly more heightened

53
Sensitization to re-entrant arrhythmias and reduction in
•  during ketoacidotic episodes. This may be attributed to
threshold of ventricular fibrillation
an inhibitory effect of ketones on hepatic lactate uptake.77
• Attenuation of cardiovascular responses to catecholamines Increase in nicotinamide adenine dinucleotide (NAD
2. Respiratory or NADH+) ratio, hypoperfusion and an increase in H+
• Hyperventilation concentration accompanying the volume depletion and
• Reduced strength of respiratory muscles and muscle fatigue the acidemia of DKA, all lead to lactate accumulation.
• Dyspnea Thus, it is not surprising that lactic acidosis can be observed
3. Metabolic in any acute metabolic emergency linked with any type of
• Increased metabolic demands DM. In DKA (more often in type 1 diabetes), the presence
• Insulin resistance of a high anion gap (Table 53.17) in the absence of signi­
• Inhibition of anaerobic glycolysis ficant ketonemia should make one suspect an associated
• Reduction of adenosine triphosphate (ATP) synthesis
lactic acidosis. Ideally, this should be confirmed by an
arterial plasma lactate level, and active remedial measures
• Hyperkalemia
must be taken.
• Increased protein degradation
Diabetic ketoacidosis is often linked with hypoxia
4. Cerebral
(either as a complication of uncontrolled or prolonged
• Inhibition of metabolism and cell volume regulation
ketoacidosis or as a precipitating cause such as fulminant
• Obtundation and coma
pneumonia). Further acidosis per se induces insulin
resistance, inhibits PFK activity, inhibits anaerobic
Although metabolic demands may be augmented by
glycolysis and leads to depressed cardiac output, central
the associated sympathetic surge, acidemia decreases
blood pooling, reduced hepatic plus renal blood flow and
the uptake of glucose in tissues by inducing insulin resis­
hypotension, all of which contribute to causation of lactic
tance and inhibits anaerobic glycolysis by depressing
acidosis. In this situation, the hepatic extraction of lactate
PFK activity. This has grave consequences on survival, as
is markedly inhibited; rather the liver itself becomes a
anaerobic glycolysis is the main source of energy during
net lactate producer. Further, reduced renal blood flow
hypoxia. The uptake of lactate by the liver is curtailed and
impairs the excretion of lactate.
the liver can be converted from the premier consumer of
In HHNKS, acidosis is usually not marked. If present,
lactate to a net producer. Acidemia promotes potassium
lactic acidosis needs exclusion. Often HHNKS is
egress from the cells leading to hyperkalemia. Brain meta­
precipitated by myocardial infarction and renal failure,
bolism and the regulation of its volume are impaired,
both conditions tending to favor lactic acidosis. Further,
resulting to progressive obtundation and coma.
severe volume loss and hypotension also contribute to
hyperlactatemia. Patients with type 2 diabetes frequently
Diabetes Mellitus and Lactic Acidosis
have very mild hyperlactatemia under basal conditions,87 a
Diabetes mellitus sets the stage for lactate accumulation condition which has been attributed to a defect in pyruvate
in several ways.87 Insulin normally activates PDH, the oxidation. Hyperlactatemia during ketoacidosis may be
rate-limiting enzyme for the oxidation of pyruvate. due, in part, to an inhibitory effect of ketones on hepatic
Insulinopenia causes a build-up of pyruvate, which in turn lactate uptake.88 Biguanides, especially phenformin has
is converted to lactate. Insulin deficiency also provokes been linked with membrane dysfunction of renal and
muscle catabolism, providing more alanine to serve as hepatic mitochondria, which can lead to lactic acidosis.
additional substrate for pyruvate synthesis. About 10−15% This is discussed further below.
 804 Complications

Biguanides and Lactic Acidosis Lactate Adaptation

Biguanides are guanidine derivatives of which three Although phenformin induced lactic acidosis was widely
compounds, phenformin, buformin and metformin have reported from the West, reports from the Indian subcon­
glucose lowering activity. Of these, phenformin and tinent reflected otherwise.101 Hardly any or only a few
metformin have found maximal clinical application. cases were reported, while the drug was very widely
used. This low incidence has been attributed to a high
Phenformin and Lactic Acidosis
section

carbohydrate intake, suboptimal doses of phenformin

and lesser prevalence of concurrent alcohol intake in the
10

Phenformin (phenethyl biguanide) was widely used

Indian population.100 To elucidate these phenomena, a
in most countries till about four decades ago. It has
series of patients were studied on phenformin therapy.
been clearly linked with lactic acidosis. Phenformin
Lactate levels were estimated prior to and after four
was withdrawn from several countries in the seventies
weeks of treatment with phenformin. In another group,
because of the high-risk of lactic acidosis associated with
lactate levels were estimated in patients who had been on
it.89,90 The frequently fatal side effect was a consequence
phenformin for more than 6 months.102,103 It was observed
of its capacity to bind to mitochondrial membranes and
that a significant proportion of patients demonstrated
uncouple oxidative phosphorylation.91 Metformin binds
hyperlactatemia on initiation of therapy. However, after
poorly to mitochondrial membranes and is therefore
6 months of therapy, the blood lactate levels came back to
associated with a 10-fold reduced risk of lactic acidosis.92
normal. This implies that on prolonged therapy, the blood
The blood glucose lowering potential of phenformin
lactate levels drop because of a process of adaptation. The
appears to be related, in part, to its ability to enhance the
exact mechanism of this adaptive process is not known,
rate of glucose utilization in the peripheral tissues and
but may be linked to altered drug pharmacokinetics.
increase the conversion of glucose to lactate. Phenformin
It is possible that under adverse circumstances like
may also inhibit pyruvate oxidation to acetyl-CoA.93,94
increasing the dose of phenformin, hypoxic insult, renal,
Experimental models of phenformin induced lactic
cardiac or hepatic failure, this adaptation in a previ­
acidosis have demonstrated that extrahepatic splanchnic
ously compensated patient breaks down leading to
lactate production was increased and hepatic uptake was
lactic acidosis. Genetically conferred defect in hepatic
reduced, due to a fall in the portal vein blood flow.85,95
hydroxylation impedes the metabolism of phenformin.102
Although phenformin may increase blood lactate
This subset of patients develop brisk hyperlactatemia
modestly in the basal state, most cases of phenformin-
following phenformin and are especially prone to lactic
induced lactic acidosis were attributed to either high drug
acidosis. It is possible that such patients who have a brisk
levels (due to overdose or failure of renal excretion) or the
hyperlactatemia on initiation of phenformin therapy, may
consequences of serious illnesses (renal failure, shock)
have adverse clinical reactions and may thus discontinue
that themselves predispose to acidosis.96,97
the medication. Therefore, these patients may have been
Raised pyruvate levels may be related to defective
inadvertently excluded from the study.
utilization of pyruvate caused by the partial inhibition of
the TCA cycle. This in turn may be linked to phenformin-
Metformin and Lactic Acidosis
induced inhibition of certain essential enzymes such as
succinic dehydrogenase and the cytochrome oxidases.98,99 Metformin (N-1,6-dimethyl biguanide) is a bisubstituted
In order to maintain supply of ATP, enhanced glycolytic guanidine with two polar methyl groups.104,105 Phosph­
conversion of glucose to pyruvate occur. Diminished olipids are considered to be the primary and unspecific
gluconeogenesis may also contribute to the fall in binding site for the non-polar side chain of metformin
blood glucose levels, since intermediates of TCA cycle and the drug may exert a variety of metabolic effects via
are needed for gluconeogenesis. An alternate theory alteration of biological membrane functions.91,105 The bio­
explains the elevation of blood pyruvate and lactate as a availability of ingested metformin is only 50−60% and peak
consequence of enhanced activity of the hexose mono­ plasma concentration of about 10 mmol/L are reached in
phosphate shunt. It has been further hypothesized that the about 2 hours of ingestion of 500−1000 mg of the drug.106,107
liver is unable to utilize the excess lactate due to changes Very high concentrations of the drug accumulate in the
in its pH. The fall in the hepatic pH is probably brought intestinal wall.108,109 Metformin does not bind to plasma
about by the direct effect of the drug.100 proteins and is excreted unmetabolized in the urine and
 Acute Metabolic Complications 805

Table 53.18: Phenformin and metformin: potential for causation of Table 53.19: Metformin: contraindications
lactic acidosis
• Impaired renal function
Phenformin Metformin
• Impaired hepatic function
Pharmacokinetics Hydroxylation in liver Excreted in urine and
(30%); Genetic poly- feces unchanged • Cardiac failure
morphism + Excreted • Hypoxia of any origin, poor tissue perfusion, respiratory failure
in urine • Proposed intravenous (IV) radiological contrast studies

chapter
Mitochondrial Binds avidly Binds poorly • Acutely ill-patients with dehydration, hypotension, perioperative
membrane period

53
Prevalence of • Type 1 diabetes mellitus (without insulin)
Lactic acidosis:
• Diabetes with complications, lean diabetic
Ratio 10−20 times that of metformin

partially in the feces. The average elimination half-life in serum creatinine (80−120 μmol/L). They found that
plasma is 2–5 hours.109,110 As mentioned, metformin binds plasma lactate levels are higher in diabetic subjects taking
poorly to mitochondrial membranes in contrast to phen­ metformin compared to normal volunteers, but within the
formin. Consequently, it improves insulin stimulated diabetic groups, the small elevation in serum creatinine
non-oxidative glucose metabolism, whereas glucose was not associated with a higher lactate level.
oxidation remains more or less unaffected.111-113 Phen­ Yet caution has to be exercised in the use of metformin.
formin, on the other hand, has a clear inhibitory effect on Common contraindications to metformin use are enlisted
glucose oxidation.91 Table 53.18 enlists the predominant in Table 53.19. It must be avoided in the elderly, during
differences between phenformin and metformin regarding any acute illness, perioperatively, and during IV contrast
their potential to cause lactic acidosis. This is linked with studies, in any condition linked to hypoxia or impaired
marked reduction in the incidence of hyperlactatemia with renal, hepatic or cardiac function.91,106,119 The role of met­
metformin, which is 10-fold lower than with phenformin.92 formin has been more critically evaluated recently.120-122
The prevalence of metformin-induced lactic acidosis is Lactic acidosis developed with similar frequency in
estimated to be about 0.24 cases per 10,000 patient-years114 patients using metformin (70,490 patients-years), as com­
in contrast to phenformin, with which a rate of 1.5 cases pared to those not on the drug (55,451 patients-years).120
per 10,000 patient-years was reported. In a recent study, In another study, there was no difference in the metformin
Brown et al.115 found only 10 cases amongst 41,000 person- users and non-user; lactic acidosis occurred more in the
year usage; of these, four were confirmed, three were setting of acute renal failure, cardiorespiratory disease
possible and three were borderline cases of lactic acidosis. and sepsis.122,123 It is recommended that metformin can
All of them had at least one medical condition that could be used safely at the reduced level of GFR (up to 45 mL/
have caused lactic acidosis on its own. Berger116 estimated minute) in reduced doses, as is done for all renally
the prevalence at 0.01−0.067 per 1,000 person-years and excreted drugs.124 However, lactic acidosis can develop
a mortality of 33%. with metformin use even in the absence of predisposing
Can lactic acidosis occur with normal renal function? factors stated above in patients with mild creatinine rise.
Extensive review of literature reveals an odd-isolated Hence, caution regarding its use in renal failure should
case report, but most studies have shown that lactic continue to be observed.125
acidosis with metformin is inevitably linked with renal In conclusion, it must be stated that biguanide-induced
compromise. Lalau et al.117 studied 14 cases of met­ lactic acidosis should be considered in the differential
formin associated lactic acidosis and found clinical diagnosis of metabolic acidosis with an increased anion
evidence of shock or hypoxia in 13 patients and the gap. Metformin should be used very carefully in any
14th had non-steroid anti-inflammatory agent-induced diabetic with renal or hepatic impairment, congestive
anuria. Amongst these patients, significant metformin heart failure, alcohol abuse, proposed IV radiological
accumulation was documented only in 10 patients. In contrast studies, poor tissue perfusion and hypoxia.
another study, Connolly et al.118 studied metformin levels
in diabetics with moderately raised serum creatinine
Clinical Presentation
levels (120−160 μmol/L) and compared them with normal As obvious from the preceding discussion, lactic acidosis
volunteers taking metformin and diabetics with normal arises most often in the presence of a life-threatening
 806 Complications

concomitant disease. In the diabetic, it usually presents Table 53.20: Management of lactic acidosis
as a result of severe sepsis, ketoacidosis, HHNKS, myo­ • Hydration
cardial infarction, renal or hepatic failure, major trauma • Sodium bicarbonate, dichloroacetate, carbicarb
or surgery. Alcoholic binges, severe exercise in poorly
• Forced diuresis or hemodialysis
controlled type 1 diabetes or poisoning (salicylates,
• Insulin and thiamine
ethylene glycol, methanol, cyanide, nitroprusside and
theophylline) should be excluded.
section

Unexplained tachypnea associated with hypotension, decrease portal vein flow, lower intracellular pH in muscle
10

and deteriorating mental status without significant and liver, raise circulating lactate levels, lower arterial
ketonemia in a diabetic should point towards lactic pH and worsen cardiac output.84
acidosis.75,86,94 Although an elevated anion gap and a low Sodium bicarbonate is usually given diluted in normal
serum bicarbonate (in absence of significant ketonemia) saline in a dose of 1–2 mmol/kg (44 mmol = 50 mL in 500
point toward lactic acidosis, both these criteria may not be mL normal saline) over a period of few hours. It should
fulfilled in many cases with significant lactic acidosis. In never be given as a bolus and used mainly as a temporary
conditions such as associated hepatic failure and sepsis, measure while controlling the major precipitating
which induce metabolic alkalosis, these findings may condition. It should only be given when arterial pH is less
be masked. Hyperventilation increases the likelihood than 7.2.
of respiratory alkalosis. Hence, in any critical condition Dichloracetate (DCA) has recently been proposed as a
where lactic acidosis is a possibility, measurement of potential therapy in lactic acidosis. Theoretically, it has the
arterial or central venous blood lactate is essential to following advantages:
confirm the diagnosis. Various studies have demonstrated 1. It is the most potent known pharmacologic stimulus of
that lactate levels more than 10 mmol/L are associated PDH, the rate-limiting enzyme for the aerobic oxidation
with a very poor prognosis.78,79,86 Significant hyperlac­ of glucose, pyruvate and lactate. PDH activation occurs
tatemia should be considered at lactate levels more than within minutes and in virtually all tissues following
5 mmol/L and treatment initiated at that stage.84,86 Contro­ parenteral DCA administration.
versy still prevails as to whether levels between 3 mmol/L 2. Under certain experimental conditions, DCA may inhibit
and 5 mmol/L need energetic management in absence of glycolysis and thereby lactate production.
significantly lower pH values.79,84,126 3. Dichloracetate exerts a positive inotropic effect that has
been attributed to improvement in myocardial glucose
Management use and ATP production. This effect has been linked to
The cornerstone of therapy for lactic acidosis is to treat the increased cardiac output, and increased blood pressure
precipitating cause. Stoppage of biguanides, alcohol or in patients with heart failure or hypotension or both.79,127
other offending toxin is a prerequisite. In DKA or HHNKS, However, the theoretical potential of DCA has not
fluid replacement and insulin therapy must be given been proven in a controlled clinical trial.128 Although
adequately. If there is an associated condition such as various reports indicated that it was well-tolerated and
sepsis, hepatic, renal or myocardial compromise, it should associated with increased pH and reduced lactate levels,
be treated promptly. Patients may require ventilatory the magnitude of change was small and it did not alter
assistance. Cardiovascular collapse should be managed hemodynamics or survival.
by fluid replacement (preferably normal or diluted saline Carbicarb: A buffering agent, which is an equimolar
preparations). Drugs that specifically increase myocardial mixture of NaHCO3 and Na2CO3. Carbicarb has a buffering
contractility or reduce afterload are preferable. Vasocon­ capacity similar to NaHCO3, but does not generate CO2.
strictive agents must not be used as they further aggravate Reports of controlled studies with carbicarb in patients
the lactic acidosis (Table 53.20). with metabolic acidosis are still awaited.129-131
Severe lactic acidosis (pH < 7.2) is an indication for Thiamine and Insulin have been used jointly in lactic
alkali therapy. The use of alkali in moderate and mild acidosis. Thiamine is a cofactor for PDH. For a patient with
acidosis has been and still is a subject of controversy. lactic acidosis who is vitamin deficient (e.g. alcoholism),
Potential ill effects of alkali administration are shown in thiamine is a safe and useful medication. It is also of
Flow chart 53.2.74 IV alkali administration may increase benefit in beriberi induced lactic acidosis and congenital
lactate production, particularly in the splanchnic bed, deficiency of either PDH or pyruvate carboxylase. Insulin
 Acute Metabolic Complications 807

stimulates the activity of PDH. Further its anabolic effect Duffy TP, et al. (Eds). Debates in Medicine. Chicago: Year
reduces the generation of alanine from the skeletal muscle, Book Medical Publishers; 1990. pp. 200-33.
2. Chandalia HB, Rangnath M. Biguanide induced lactic
thus reducing the substrate for lactic acid formation. In
acidosis. J Assoc Physic Ind. 1990;38:520-2.
most diabetic emergencies, insulin therapy as such is 3. Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr.
mandatory and achieving glycemic control must be an 2006;26:1-22.
early target.132 4. Kitabchi AE, Umpierrez GE, Fisher JN, et al. Thirty years
Forced diuresis and hemodialysis has been advocated of personal experience in hyperglycemic crises: diabetic

chapter
especially in the presence of fluid overload. Hemodialysis ketoacidosis and hyperglycemic hyperosmolar state. J Clin

53
Endocrinol Metab. 2008;93:1541-52.
is the preferred modality in the presence of significant
5. Usher-Smith JA, Thompson MJ, Sharp SJ, et al. Factors
renal compromise. However, it is important to remember associated with the presence of diabetic ketoacidosis at
that the majority of diabetic emergencies are associated diagnosis of diabetes in children and young adults: a sys-
with hypovolemia. temic review. BMJ. 2011;343:d4092.
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section

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 Chapter 54
Hypoglycemia

Siddharth N Shah, Shashank R Joshi

Hypoglycemia

Chapter Outline
♦♦ Definitions ♦♦ Differential Diagnosis
♦♦ Etiology ♦♦ Course and Prognosis
♦♦ Pathogenesis ♦♦ Complications
♦♦ Clinical Features ♦♦ Management
♦♦ Investigations

INTRODUCTION DEFINITIONS
Hypoglycemia is a barrier to reach safe and desired Hypoglycemia or low blood glucose in adults is a clinical
glycemic goals in patients with diabetes mellitus (DM). state associated with low (less than 50 mg/dL) or relatively
It is very difficult to achieve an optimal target in diabetes low plasma glucose concentration usually associated
treatment with insulin or insulin secretagogues without a with signs and symptoms of autonomic hyperactivity and
single attack of hypoglycemia, major or minor in nature. neuroglycopenia.1
Development of hypoglycemia hampers not only the An event is considered hypoglycemia if seizure,
biochemical control but also the mental makeup of the coma, confusion, irrational or other symptoms consistent
patient by creating anxiety and fear. This prevents the with hypoglycemia, e.g. sweating, palpitation, hunger or
patient from achieving tight glycemic control. blurred vision occur in conjunction, with:
The overall benefit of excellent glycemic control is • A laboratory-determined or finger stick blood glucose
beneficial in reducing cardiovascular risk, if implemented less than 50 mg/dL
early in the course of both type 1 and type 2 diabetes. • Amelioration by treatment that raises blood glucose
But attaining the goal is not always eventless, and • Prodromal symptoms of hypoglycemia (e.g. sweating,
intensive glycemic control commonly is complicated palpitations, hunger or blurred vision) remembered by
by a three-fold increased risk of severe hypoglycemia, the subject as occurring shortly before the event
often without warning symptoms and potentially with • Severe hypoglycemia, coma or seizure or a reaction
severe consequences, especially to the heart and brain. requiring hospitalization or intravenous glucose or
Hypoglycemia occurs not uncommonly in patients on glucagon.
sulfonylureas (especially elderly patients on long acting There is no absolute consensus regarding threshold
drugs, like glibenclamide) and insulin. values for diagnosis or treatment.
 Hypoglycemia 813

Table 54.1: Causes of fasting hypoglycemia Table 54.2: Fed state (reactive) hypoglycemia
Underproduction Overutilization Early (Alimentary) within Late (occult diabetic)
• Hormone deficiencies • Hyperinsulinism 2–3 hours after meals 3–5 hours after meals
– Hypopituitarism – Insulinoma • Alimentary • Delayed insulin release due to
– Adrenal insufficiency – Exogenous insulin hyperinsulinism β-cells dysfunction
overdose • Postgastrectomy • Counter-regulatory deficiency
– Catecholamine deficiency – Sulfonylurea overdose (dumping syndrome) of growth hormone, glucagon,

chapter
– Glucagon deficiency – Insulin autoimmunity cortisone, autonomic response,

54
epinephrine
• Enzyme defects • Appropriate insulin level
• Functional fructose
– Glucose-6-phosphatase – Extrapancreatic tumors
intolerance
– Liver phosphorylase – Cachexia with fat
depletion, e.g. advanced • Hereditary fructose
cancer intolerance

– Pyruvate carboxylase • Galactosemia

• Substrate deficiency • Leucine sensitivity
– Ketotic hypoglycemia of
infancy
– Severe malnutrition;
muscle wasting Relative Hypoglycemia
– Late pregnancy
This is a condition where a person with diabetes reports
• Acquired liver disease
any of the typical symptoms of hypoglycemia, and
– Hepatic congestion
interprets those as indicative of hypoglycemia, but with
– Cirrhosis
a measured plasma glucose concentration more than
– Severe hepatitis
70 mg/dL (3.9 mmol/L). This group reflects the fact that
• Drugs
patients with chronically poor glycemic control can
– Alcohol
experience symptoms of hypoglycemia at plasma glucose
– Propranolol levels more than 70 mg/dL (3.9 mmol/L) as plasma glucose
– Salicylates concentrations decline rapidly. This condition though
causes distress and interferes with the patient’s sense
ETIOLOGY of well-being, and potentially limits the achievement of
optimal glycemic control, probably poses no direct harm
The most common cause of hypoglycemia is iatrogenic, and therefore may not be a suitable outcome measure for
i.e. drug induced.2 Hypoglycemia secondary to alcohol, clinical studies that are aimed at evaluating therapy, but
insulinoma, liver disease and that associated with endo- they should be reported.
crine dysfunction, renal failure and neonatal hypoglyce-
mia are among the other causes of hypo­glycemia.3-5 Cause Pseudohypoglycemia
of fasting hypoglycemia are enumerated in Table 54.1.
Pseudohypoglycemia occurs in certain chronic leukemias
Fed State Hypoglycemia when the leukocyte counts are markedly elevated. This
artifactual low blood glucose reflects utilization of glucose
Non-specific reactive functional hypoglycemia is the by leukocytes after the blood sample has been drawn. Such
most frequent cause of hypoglycemia in the normal a hypoglycemic finding is not associated with symptoms.
population and is associated with anxiety.6 These patients
Plasma glucose is about 15% higher than corresponding
tolerate physical exercise and prolonged fasting very well
whole-blood glucose values.
(Table 54.2).
In early diabetes, hypoglycemia is seen to occur
Glucose Counter-Regulation
3–5 hours after a carbohydrate rich meal. It is resolved
when pancreatic exhaustion occurs. There is a strong Energy requirements are met from substrates derived
family history of diabetes. Fasting blood glucose is normal from food and substrates stores as fat, protein, and
or elevated and prolonged fast is well tolerated. glycogen. Insulin is the primary hormone mediating the
 814 Complications

Table 54.3: Glycemic threshold for physiologic and patho­physiologic Table 54.4: Signs and symptoms of hypoglycemia
responses Autonomic hyperactivity Neuroglycopenia
Glycemic threshold (mg/dL) • Adrenergic • Headache
• Decreased insulin secretion 83 ± 3 – Palpitation – Fatigue
• Increased counter- – Sweating – Mental dullness
regulatory hormones action: – Anxiety – Dizziness
– Epinephrine 69 ± 2 – Tremors – Blurring or clouding of
section

vision
– Glucagon 68 ± 2
10

– Tachycardia – Confusion
– Growth hormone 66 ± 2
• Parasympathetic • Abnormal behavior
– Cortisol 58 ± 2 – Hyperactivity – Amnesia
– Symptoms of hypoglycemia 53 ± 2 – Nausea – Seizure
– Cognitive dysfunction 49 ± 2 – Hunger – Unconsciousness

anabolic phase of metabolism while the counter regula­ • Alcohol induces slowing of the Krebs’ cycle with
tory hormone levels are suppressed.7 The metabolic impairment of gluconeogenesis, giving rise to reduced
adjustment during the catabolic phase includes the glucose output and hypoglycemia
activation of glycogenolysis and gluconeogenesis in the • Fasting hypoglycemia in an otherwise healthy adult
liver, use of free fatty acid derived from triglyceride stored is most commonly due to an adenoma of the islet of
in adipose tissue. The first defense against falling plasma Langerhans.9 In leucine sensitivity, leucine stimulates
glucose concentration is decreased insulin secretion and the release of insulin from the b-cells like a sulfony­
activation of glucose by counter-regulatory hormones.8 lurea compound. In hereditary fructose intolerance,
The symptoms of hypoglycemia are seen on average accumulation of fructose-1-phosphate by unknown
at blood glucose of 54 mg/dL and those of cognitive mechanisms gives rise to hypoglycemia
dysfunction at 49 mg/dL. The glycemic threshold of various • Drugs, like salicylates, mono amino oxidase inhibitors,
counter-regulatory hormones is elaborated in Table 54.3.8 phenylbutazone, methotrexate, probenecid, clofibrate
and dicoumarine, potentiate the action of oral hypo­
PATHOGENESIS glycemic drugs and hence care must be taken during
their administration. Non-selective b-blockers mask
Hypoglycemia is most commonly encountered due
the adrenergic symptoms of hypoglycemia and also
to overdosage of insulin or oral hypoglycemic drugs.2
delay recovery. Whole blood glucose values may be
This may be caused by any one or a combination of the
spuriously low in polycythemia vera, leukemia and
following factors:
hemolytic crisis.
• If more than the required dose of insulin or oral drug is
administered
• If a meal is skipped, or is inadequate in amount or is
CLINICAL FEATURES
unduly delayed after insulin injection or oral drugs The signs and symptoms of hypoglycemia can be divided
• Unusual physical exertion, such as swimming, cycling, into those due to autonomic hyperactivity and those
running and weight lifting, is undertaken especially resulting from neuroglycopenia (Table 54.4).1
after taking insulin Patients may present with weakness, palpitations,
• Rapid gastric emptying in postgastrectomy patients nervousness, sweating and mental confusion progressing
with brisk absorption of glucose results in excessive to unconsciousness.
insulin release, leading to fall of glucose concentration Whipple’s triad consisting of symptoms of hypo­
and hypoglycemic symptoms glycemia with low blood glucose values and imme­diate
• When the liver function is severely impaired, relief after ingestion of glucose is characteristic of b-cell
hypoglycemia occurs because glycogen storage and tumor. Occasionally, the tumor is associated with severe
insulin are deficient in hepatic disease diarrhea, muscle wasting and/or carcinoid syndrome.
 Hypoglycemia 815

Patients who have undergone gastrectomy complain Table 54.5: Differential diagnosis of hypoglycemic and hyper­gly­
of nausea, abdominal discomfort, diarrhea, sweating, cemic coma
palpitation and giddiness (dumping syndrome). Symptoms, signs and Hypoglycemic coma Hyperglycemic
laboratory findings coma
INVESTIGATIONS • Physical findings
– Pulse rate Increased Increased
Diagnosis of Postprandial Hypoglycemia – Pulse volume Full Weak

chapter
Unequivocal diagnostic test is the demonstration of – Temperature May be decreased May be decreased

54
low plasma glucose concentration (< 50 mg/dL) during – Respiration Shallow or normal Rapid and deep
(air hunger)
spontaneously developed symptoms.1 A 5-hour oral
– Blood pressure Normal May be increased
glucose tolerance examination showing a plasma glucose
– Skin Clammy, sweating Dry
value of 50 mg/mL or less is suggestive.
– Tongue Moist Dry
– Tissue turgor Normal Decreased
Diagnosis of β-cell Adenomas (Insulinoma)
– Eyeball Normal Reduced
• Serum insulin level of 20 μU/mL or more in the pres- tension
ence of blood glucose values below 40 mg/dL. – Breath No acetone Acetone present,
• Elevated circulating proinsulin level; this is chara­ fruity odor
cteristic and does not occur in fictitious hyper­ – Reflexes Brisk reflexes Diminished reflexes
insulinism. • Laboratory tests
• Increasing ratio of insulin to glucose. – Urine glucose Negative to positive Positive
depending on timing
• Non-suppression of C-peptides during hypoglycemia
of last voiding
induced by the infusion of 0.1 unit of insulin per kg
– Plasma glu- Low Raised; 300 mg/dL
body weight per hour. A normal person would suppress cose or over
the peptide level to 50% or more during hypoglycemia. – Plasma Negative Usually raised
• Computerized tomography scan may or may not acetone
pick-up the tumor. – Bicarbonate Normal Low less than
• Pancreatic arteriography can locate tumor preoper­ 20 mEq/L
atively. – Blood pH Normal Diminished (< 7.3)
In normal persons, the insulin/glucose ratio is always
less than 0.4; in insulinomas, the ratio is greater than
0.4 and often above 1.0. Multiple sampling is required for neurological illness. A suspected patient of reactive
confirmation. hypoglycemia has to undergo 5-hour oral glucose tole­
In islet cell tumors, provocative tests with tolbutamide, rance test with plasma sampling every half hour and at the
glycogen or leucine may be of help. In factitious hypo­ time the symptoms occur. A good history will clinch the
glycemia,9 the triad of low blood sugar, high immuno­ diagnosis of iatrogenic hypoglycemia.10
reactive insulin and suppressed plasma C-peptide
immunoreactivity is pathognomonic of exogenous insulin
COURSE AND PROGNOSIS
administration. If detected early, hypoglycemia is reversible and can be
prevented. Surgical removal of b-cell tumor alleviates all
DIFFERENTIAL DIAGNOSIS symptoms.11 If hypoglycemia occur only at night and is not
detected, it might lead to loss of memory and cognitive
Hypoglycemia should be differentiated mainly from
impairment.
hyperglycemia especially when a patient is in coma.1
Differentiating features of hyperglycemia and hypogly­
cemia are mentioned in Table 54.5. Hypoglycemia may
COMPLICATIONS
also present as transient ischemic attack, giddiness, mental Hypoglycemia may be misdiagnosed as hyperglycemia
confusion, convulsion or coma and may be mistaken for a and if not treated promptly may lead to death. Chronic
 816 Complications

hypoglycemia may lead to loss of memory, clouding of Beta-Cell Tumors

vision, blunted mental activity, confusion, abnormal
Surgical removal, chemotherapy and irradiation help in
behavior, convulsions and coma.12
eradication of the tumor.9
Somogyi Effect Neonatal Hypoglycemia
Insulin treated diabetic patients may show a rapid swing Hypoglycemia in the immediate postpartum period needs
to hyperglycemia after episodes of hypoglycemia. The
section

recognition, as the phenomenon is transient.5 It occurs

rebound hyperglycemia or Somogyi effect is thought to
10

frequently in newborn of diabetic mothers, especially if

be caused by actions of hormonal antagonists or insulin glycemic control is poor in the third trimester.
secreted in response to hypoglycemia.
Autoimmune Hypoglycemia
Hypoglycemia Unawareness
This may be associated with insulin antibodies or insulin
Some elderly, long-standing diabetic subjects on sulfo­ receptor antibodies.16 The age of onset varies from a few
nylurea do not get adrenergic symptoms and present with days to an advanced age. Hypoglycemia occurs at any time
severe neuroglycopenic symptoms such as confusion, and is often self limited.
convulsions or coma during the hypoglycemic episodes.
It is characterized by low sympathetic response with Hypoglycemia Due to Non-β-cell Tumor
insignificant increase in circulating epinephrine and
• Mesenchymal tumors constitute 45–64% of reported
glucagons. Since the hypoglycemia-induced glucagon
cases of tumors with hypoglycemia.
response is invariably reduced in patients with diabetes
• Hepatomas (22% of cases), large adrenal tumors,
after 5 years, the main factor responsible for unawareness
carcinoma lung. These large tumors metabolize large
of hypoglycemia is inadequate response of epinephrine.
amount of glucose. They may also secrete insulin-like
It is postulated that hypothalamus has specialized
polypeptides.
area, which detects hypoglycemia and triggers autonomic
response. Exposure of this area to hypoglycemia might Tight Glycemic Control and Hypoglycemia
reset the trigger threshold at a lower level resulting in
diminished counter-regulation. Before the results of three studies of glycemic control and
diabetes complications, like ACCORD (Action to Control
MANAGEMENT Cardiovascular Risk in Diabetes),17 ADVANCE (Action
in Diabetes to Prevent Vascular Disease),18 and VADT
Hypoglycemia associated with unconsciousness or stupor (Veterans Administration Diabetes Trial)19 it was known
should be treated on an emergency basis. The treatment that severe hypoglycemia is not that common with tight
of choice is to give 25–50 mL of 50% glucose solution glycemic control in type 2 in comparison with type 1 DM.
intravenously over a period of 2–3 minutes. One milligram The DCCT (Diabetes Control and Complications Trial) a
of glucagon injected intravenously is preferable in an study of type 1 DM, showed that in the intensive control
emergency, the patient regaining consciousness within group the severe insulin reactions are several fold more than
15 minutes to permit ingestion of sugar.13,14 History of 60 per 100 patient-years and have a threefold increased
the precipitating cause of hypoglycemia must be ascer­ risk compared to control groups with less intensive glucose
tained and the future course of action chalked out to control. Majority of the studies of type 2 diabetes, by
prevent further episodes. The treatment of reactive hypo­ contrast, have documented a risk of severe hypoglycemia
glycemia of fed state is alteration in dietary habits.15 with tight glycemic control substantially less but some
Frequent small feeds are advised in non-specific reactive studies have shown that some type 2 DM20-27 patients have
hypoglycemia; the diet should contain some slowly absor­ a risk comparable with that seen with intensive control in
bable carbohydrates and more protein. Alcohol-induced type 1 DM.28-33
hypoglycemia is prevented by reducing the intake of A target of hemoglobin A1c of less than 7% is recom­
alcohol and increasing the ingestion of food.3 mended by the American Diabetes Association.34
 Hypoglycemia 817

However, one should be cautious in targeting tight REFERENCES

glycemic control for those with long diabetes duration,
1. Field JB. Hypoglycemia. Definitions, clinical presentation,
older population in the presence of advanced complica­
classification, and laboratory tests. Endocrinol Metab Clin
tions or multiple comorbidities. North Am. 1989;18:27-44.
Excellent control can be achieved with low hypo­ 2. Cryer PE. Iatrogenic hypoglycemia in IDDM: consequenc-
glycemia risk with newer insulins and strategies, such es, risk factors and prevention. In: Marshall SM, Home PD,
as insulin pumps and continuous glucose monitoring in Alberti KGMM, Kralt LP (Eds). Diabetes Annual. Amster-

chapter
dam: Elsevier; 1993. pp. 317-31.
type 1 DM, and use of newer oral hypoglycemic agents

54
3. Arky RA. Hypoglycemia associated with liver disease
combined with insulin in type 2 DM, with lower risk of and ethanol. Endocrinol Metab Clin North Am. 1989;18:
hypoglycemia. 75-90.
4. Peitzman SJ, Agarwal BN. Spontaneous hypoglycemia in
CONCLUSION end-stage renal failure. Nephron. 1977;19:131-39.
5. Sunehag AL, Haymond MW. Glucose extremes in newborn
The commonest type of hypoglycemia seen in clinical infants. Clin Perinatol. 2002;29:245-60.
practice is iatrogenic. Treatment with sulfonylurea com­ 6. Bolli G, De Feo P, Perrielto G, et al. Reactive hypoglycemia
in humans. J Clin Invest. 1985;75:1023-31.
pounds and insulin is more likely to produce hypoglycemia
7. Cryer PE. Glucose counterregulation: prevention and
than other therapeutic modalities. correction of hypoglycemia in humans. Am J Physiol.
Symptoms of hypoglycemia can be subtle or alarming, 1993;264:E149-55.
but tend to be same in a given individual. Hypoglycemia 8. Davis MR, Shanoon H. Counterregulatory adaptation
unawareness occurs in diabetics with very tight glyce­ to recurrent hypoglycemia in normal humans. J Clin
Endocrinol Metab. 1991;73:995-1001.
mic control. It needs to be recognized and treated. A
9. Fajans SS, Vinik AL. Insulin-producing islet cell tumors.
2–3 week period of relaxed metabolic control usually Endocrinol Metab Clin North Am. 1989;18:45-74.
restores hypoglycemia awareness. 10. Seltzer HS. Drug-induced hypoglycemia. A review of 1418
Hypoglycemia can be frightening and when severe cases. Endocrinol Metab Clin North Am. 1989;18:163-83.
produce cognitive impairment and occasionally cardiac 11. Service FJ, Mcmahon MM, O’Brien PC, et al. Functioning
arrhythmia and acute autonomic failure. When occurring insulinoma—incidence, recurrence, and long-term sur-
vival of patients: a 60-year study. Mayo Clin Proc. 1991;66:
with high frequency in a patient, the glycemic targets must 711-9.
be relaxed. 12. Gold AE, Deary IJ, Frier BM. Recurrent severe hypogly-
Other common type of hypoglycemia is reactive cemia and cognitive function in type 1 diabetes. Diabetic
hypo­glycemia which usually resolves with divided, low Med. 1993;10:503-8.
carbohydrate, high protein meals. Occasionally, a carbo- 13. Glucagon. In: Mosby (Ed). Mosby’s Drug Consult; 2005,
15th edition. Mosby; 2004.
hydrate blocker like acarbose or voglibose can be used.
14. Elrick H, Witten TA, Arai Y. Glucagon treatment of insulin
reactions. N Eng J Med. 1958;258:476-80.
Further Reading 15. Horeldt F. Reactive hypoglycemia. Metabolism. 1956;24:
1195.
1. Bolli G, De Feo P, Perrielto G, et al. Reactive hypoglycemia 16. Archambeaud-Mouveroux F, Huc MC, Nadalon S, et al.
in humans. J Clin Invest. 1985;75:1023-31. Autoimmune-insulin syndrome. Biomed Pharmacother.
2. Davis MR, Shanoon H. Counterregulatory adaptation to re- 1989;43:581-6.
current hypoglycemia in normal humans. J Clin Endocrinol 17. Action to Control Cardiovascular Risk in Diabetes Study
Metab. 1991;73:995-1001. Group, Gerstein HC, Miller ME, et al. Effects of inten-
3. Cryer PE. Glucose counterregulation: prevention and sive glucose lowering in type 2 diabetes. N Engl J Med.
correction of hypoglycemia in humans. Am J Physiol. 2008;358:2545-59.
18. The ADVANCE Collaborative Group, Patel A, MacMahon
1993;264:E149-55.
S, et al. Intensive blood glucose control and vascular out-
4. Glucagon. In: Mosby (Ed). Mosby’s Drug Consult; 2005,
comes in patients with type 2 diabetes. N Engl J Med. 2008;
15th edition. Mosby; 2004. 358:2560-72.
5. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in 19. Duckworth W, Abraira C, Moritz T, et al. Glucose control
types 1 and 2 diabetes:effects of treatment modalities and and vascular complications in veterans with type 2 diabetes.
their duration. Diabetologia. 2007;50:1140-7. N Engl J Med. 2009;360:129-39.
 818 Complications

20. Akram K, Pedersen-Bjergaard U, Carstensen B, et al. complications in Japanese patients with non-insulin-
Frequency and risk factors of severe hypoglycaemia in dependent diabetes mellitus: a randomized prospective
insulin treated type 2 diabetes: a cross-sectional survey. 6-year study. Diabetes Res Clin Pract. 1995;28:103-17.
Diabet Med. 2006;23:750-6. 28. Wright AD, Cull CA, Macleod KM, et al. Hypoglycemia in
21. Henderson JN, Allen KV, Deary IJ, et al. Hypoglycaemia in Type 2 diabetic patients randomized to and maintained on
insulin-treated type 2 diabetes: frequency, symptoms and monotherapy with diet, sulfonylurea, metformin, or insulin
impaired awareness. Diabet Med. 2003;20:1016-21. for 6 years from diagnosis: UKPDS73. J Diabetes Complica-
22. Murata GH, Duckworth WC, Shah JH, et al. Hypoglycemia tions. 2006;20:395-401.
section

in stable, insulin treated veterans with type 2 diabetes: a 29. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in
types 1 and 2 diabetes:effects of treatment modalities and
10

prospective study of 1662 episodes. J Diabetes Complica-

tions. 2005;19:10-7. their duration. Diabetologia. 2007;50:1140-7.
23. Saudek CD, Duckworth WC, Giobbie-Hurder A, et al. 30. MacLeod KM, Hepburn DA, Frier BM. Frequency and mor-
Implantable insulin pump vs multiple-dose insulin for bidity of severe hypoglycaemia in insulin-treated diabetic
non-insulin-dependent diabetes mellitus: a randomized patients. Diabet Med. 1993;10:238-45.
clinical trial. Department of Veterans Affairs Implantable 31. Donnelly LA, Morris AD, Frier BM, et al. Frequency and
Insulin Pump Study Group. JAMA. 1996;276:1322-7. predictors of hypoglycaemia in Type 1 and insulin-treated
24. Gürlek A, Erbas T, Gedik O. Frequency of severe hypogly- Type 2 diabetes: a population-based study. Diabet Med.
caemia in type 1 and type 2 diabetes during conventional 2005;22:749-55.
insulin therapy. Exp Clin Endocrinol Diabetes. 1999;107: 32. Reichard P, Pihl M. Mortality and treatment side-effects
220-4. during long-term intensified conventional insulin treat-
25. Abraira C, Colwell JA, Nuttall FQ, et al. Veterans Affairs ment in the Stockholm Diabetes Intervention Study. Dia­
Cooperative Study on glycemic control and complications betes. 1994;43:313-7.
in type II diabetes (VA CSDM). Results of the feasibility 33. Diabetes Control and Complications Trial Research
trial. Veterans Affairs Co-operative Study in Type II Dia­ Group. The effect of intensive treatment of diabetes on the
betes. Diabetes Care. 1995;18:1113-23. development and progression of long-term complications
26. Yki-Järvinen H, Ryysy L, Nikkilä K, et al. Comparison of in insulin-dependent diabetes mellitus. N Engl J Med.
bedtime insulin regimens in patients with type 2 diabetes 1993;329:977-86.
mellitus. A randomized, controlled trial. Ann Intern Med. 34. Hepburn DA, MacLeod KM, Pell AC, et al. Frequency
1999;130:389-96. and symptoms of hypoglycaemia experienced by patients
27. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin with type 2 diabetes treated with insulin. Diabet Med.
therapy prevents the progression of diabetic microvascular 1993;10:231-7.
 Chapter 55
Acute Infections in
Diabetes Mellitus
Sanjay Kumar Bhadada

Acute Infections in DM

Chapter Outline
♦♦ Host Defense ♦♦ Common Infections in Diabetes Mellitus
♦♦ Common Microorganisms Associated with Infections in
Patients of Diabetes Mellitus

INTRODUCTION Table 55.1: Factors predisposes for infection in diabetes

Primary factors Secondary factors
Diabetes mellitus is the most common chronic metabolic
• Altered innate immunity: • Peripheral vascular disease
disorder. It is associated with high mortality and morbi­
PMNLs, monocyte/mac- • Peripheral neuropathy
dity. Increased morbidity and mortality in diabetes is often rophage dysfunction • Gastroparesis
caused by chronic complications, like coronary artery • Defective complement-medi- • Chronic renal failure and
disease, peripheral vascular disease (diabetic foot), renal ated function dialysis
failure and retinopathy. In contrast to this, in India infec­ • Cytokine mediated (TNF-α • Ketoacidosis
and IL-1) • Urinary catheters and intra-
tion continues to be the most common cause of mortality.
vascular lines
It is commonly believed that patients with diabetes are
(PMNLs: Polymorphonuclear leukocytes; TNF-α: Tumor necrosis
more susceptible to infection. However, there are reports factor alpha; IL: Interleukin).
which suggest lack of strong evidence for this association.1
However, many observations allude to the fact that infec­ by hyporesponsiveness to phytohemagglutinin but nor­
tions are commonly seen in patients of diabetes. Some of mal response to Candida antigen.6 Humoral immune
the infections occur with increased frequency and severity system is unaffected with B-lymphocytes showing normal
while others are exclusively associated with diabetes. antibody production when challenged by vaccines.
Recent findings support a causal relationship between There is evidence suggesting that good glycemic control
high blood glucose and infection as evidenced by a corrects some of the immunological defects.7 Therefore, it
decrease in morbidity with improved glycemic control2,3 is imperative that blood glucose levels should be closely
and worsening of diabetes during infection. monitored in diabetic subjects with infection. Other
Several factors contribute to increased predilection predisposing factors, which increase susceptibility to
for infection which includes, most importantly, an altered infection are: ketoacidosis, peripheral vascular disease,
immunity. The innate immune system is predominantly peripheral neuropathy, frequent catheterization and dia­
affected manifesting as dysfunction of polymorphonu­ lysis in patients of chronic renal failure (Table 55.1).
clear cells,4 as well as, monocytes and macrophages.5 Urinary tract, respiratory tract and deep soft tissue
There is limited T-lymphocyte dysfunction as evidenced infections occur with increased frequency and some
 820 Complications

Table 55.2: Common infections in diabetes mellitus level, persistent activation of PMNLs5,8 characterized by
Infections-associated with Infections predominantly associ- spontaneous oxidative burst and release of enzymes,
increased incidence ated with diabetes like myeloperoxidase, elastase and neutrophil granule
• Genitourinary tract infections: • Malignant otitis externa components. The end result is an exhausted PMNL
– Cystitis • Rhino-orbital-cerebral incapable of adequate response to a challenge by an
– Pyelonephritis mucormycosis infectious pathogen.8 Tolerance, as a result of sponta­
– Renal and perinephric • Emphysematous neous hyper excitement, has also been reported in peri­
section

abscess cholecystitis
pheral blood mononuclear cells in diabetic subjects.4
– Balanoposthitis and • Emphysematous
10

vulvovaginitis pyelonephritis Besides, the activity of antibacterial proteins, like lyso­

• Respiratory tract infections: • Emphysematous cystitis zyme and lactoferrin gets affected after binding to AGE-
– Staphylococcus aureus • Necrotizing fasciitis modified proteins. The enzymatic and bactericidal
pneumonia • Fournier’s gangrene function of lysozyme is inhibited along with bacterial
– Gram-negative
agglutinating and killing activity of lactoferrin.9 There is
pneumonia
– Tuberculosis
significant reduction in the number of phagocytic cells.10
– Lung abscess Abnormalities in monocyte/macrophage chemotaxis
• Skin and soft tissue and phagocytic function have also been reported.
infections: Studies have demonstrated improved function of these
– Surgical wound infection cells with regard to phagocytic activity on controlling
– Pyomyositis
blood glucose.11 Proinflammatory cytokines, like tumor
– Foot infection
• Abdominal infections: necrosis factor alpha (TNF-α), interleukin (IL) 1 and IL-8
– Salmonella enteritidis are increased in diabetic patients in basal state, but
– Campylobacter jejuni significantly less IL-2 and IL-6 are produced on stimula­tion
of cells from these subjects.8 IL-1 and TNF-α are known
of them can lead to complications and high mortality.8 to increase glucose flux and oxidation.12 Stress related to
Some infections are exclusively associated with diabetes, hyperglycemia causes release of these cytokines. The
namely, Rhino-Orbital-Cerebral Mucormycosis (ROCM) complements are an important arm of the innate
and invasive malignant otitis externa, emphysematous immune system, which are affected in the hyperglycemic
cholecystitis, emphysematous cystitis (EC), emphy­sema­ state. There is an abnormality of the opsonic binding
tous pyelonephritis (EPN), emphysematous myositis site of C3 which increases susceptibility to Candida
(Table 55.2). infection.13 Humoral immunity in diabetic subjects is
unaffected as evidenced by normal levels of circulating
HOST DEFENSE immunoglobulins as compared to healthy controls and
good antibody response to vaccination challenge.8 Cell-
Innate cellular immunity is more affected than adaptive mediated adaptive immunity is affected as evidenced by
immunity. Abnormalities in functions of polymorpho­ poor lymphoproliferative response to phytohemagglutinin
nuclear leukocytes (PMNLs), monocytes and lymphocytes and Staphylococcus aureus. However, a dichotomy is
have been widely reported. PMNLs have abnormalities revealed in some studies showing normal response to
of chemotaxis, adherence, phagocytosis, oxidative bursts C albicans.6 There are several studies which indicate that
and intracellular killing.4 good glycemic control rectifies immune deficiencies
Despite increased expression of adhesion molecules resulting in reduced risk of infection.2,3,14
and free radical activation, significantly lower neutrophilic
chemotaxis has been observed in diabetic subjects.4 Leu­ Common Microorganisms
kocyte dysfunction has been attributed to poor glycemic Associated with Infections in
control.7 There is a negative correlation between glycated
Patients of Diabetes Mellitus
hemoglobin and bactericidal activity of neutrophils.
Although several mechanisms have been postulated, Organisms that cause pulmonary infections are similar to
it is currently believed that advanced glycation end- those found in individuals without diabetes. An increase
products (AGEs) have a role in immune dysfunction. in incidence of S aureus infection has been reported
Hyperglycemia or presence of AGEs correlate with low but a recent study failed to corroborate that evidence.15
 Acute Infections in Diabetes Mellitus 821

chapter
55
Fig. 55.1: Computed tomography pelvis showing air-fluid level (arrow) Fig. 55.2: Contrast-enhanced computed tomography (abdomen)
in the lumen of urinary bladder suggestive of emphysematous cystitis showing emphysematous pyelonephritis

Mortality is also unaffected in diabetic patients with Diabetes predisposes patients to severe infections of
S aureus bacteremia.16 A high incidence of group B Strep­ upper urinary tract. Acute pyelonephritis is several times
tococcal bacteremia,17 Klebsiella related infections,18,19 more common in diabetic subjects, commonly with
certain enteric pathogens, like Salmonella enteritidis20 bilateral involvement.28 Pyelonephritis in diabetics is accom­
and Campylobacter,21 Hepatitis C22 and Candida infection23 panied by an increased risk of complications, like renal
are commonly observed with increased frequency in papillary necrosis, renal or perinephric abscess, and rarely,
patients with diabetes. EPN.8 EC is another extremely rare complication that
occurs predominantly in patients with diabetes.
Common Infections in Escherichia coli is the most common pathogen
Diabetes Mellitus isolated in UTI and complications associated with it.
Other organisms isolated are Klebsiella and Proteus spe­
Urinary Tract Infections
cies. Presence of Pseudomonas and Candida in the isolate
Urinary tract infection (UTI) is the most common infection indicates a possibility of use of catheters and instrumen­
seen in diabetes, it is a common cause of hospital admis­ tation of the urinary tract. Besides being a saprophytic
sion as well. Symptomatic as well as asymptomatic UTI is colonizer, Candida sometimes causes invasive infection
commonly encountered in diabetic subjects24 with higher of lower as well as upper urinary tract in diabetes.23
incidence of bacteriuria seen as compared to controls.25 Clinical presentations of UTI in diabetic subjects do not
This observation is less well documented in men with differ from non-diabetics. The general management also
diabetes. In an Indian series, symptomatic infection remains the same except when complications develop,
was reported to be 14% in mostly menopausal diabetic which should be suspected when high temperature
women.26 In another study, the prevalence of UTI in persists into fourth or fifth day despite adequate antimi­
diabetes mellitus was found to be 9%. crobial therapy.
Several factors have been implicated for increase in Investigations, like radiography, demonstrate air in
the incidence of UTI, like catheterization, presence of the bladder wall or lumen (Fig. 55.1) in case of EC,29 or
autonomic neuropathy, diabetic cystopathy with resultant gas in kidney in EPN (Fig. 55.2). At times, it can involve
increased residual urine and vesicoureteral reflux.1,27 Other two intra-abdominal organs viz. kidney and gallbladder
concomitant causes, like vaginitis, cystocele and rectocele (Fig. 55.3). Ultrasonography (USG), computed tomography
also contribute to a higher incidence.8 Interestingly, imaging (CT) or Magnetic resonance imaging (MRI) scans
diabetic women with bacteriuria do not have higher for renal or perinephric abscess, and retrograde pyelo­
glycosylated hemoglobin compared to non-bacteriuric graphy for renal papillary necrosis, assist in diagnosing
diabetic women.8 complications.8 Air production in these emphysematous
 822 Complications

community acquired pneumonia is not higher in patients

with diabetes.34 However, individuals with diabetes when
hospitalized with pneumonia have a higher mortality than
those without diabetes.35 The incidence of bacteremia,
delayed resolution of pneumonia, and recurrence of infec­
tion may also be higher in these patients.
Certain organisms, like S aureus, Gram-negative
section

infections and Mycobacterium tuberculosis infect patients

10

with diabetes more often, while some microorganisms,

like Streptococcus pneumoniae, Legionella and influenza
virus cause increase in morbidity and mortality in patients
with diabetes.33 In the Indian series, 11.6% of diabetic
patients presented with pneumonia, and Klebsiella was
the commonest organism isolated.26
There is increased colonization of upper airway by
Fig. 55.3: Computed tomography of the abdomen with oral contrast
at presentation showing air within the right kidney (k) and the gall
S aureus35 and Gram-negative bacteria in diabetic pati­
bladder (g) ents, which may be responsible for increased incidence
of bacterial pneumonias.8 Colonization by S aureus make
disorders is usually by Gram-negative organisms, because patients susceptible to lower respiratory tract infection
these behave as facultative anaerobes (in absence oxygen) following an attack by influenza virus, which affects mucosal
and produce air by anaerobic fermentation of glucose and ciliary activity.8 Increased incidence of bacterial pneumonia,
albumin. The air is a combination of various gases, like ketoacidosis and mortality has also been reported among
hydrogen, carbon dioxide and methane. individuals with diabetes during epidemics of influenza
Treatment consists of good glycemic control and pneumonia.32 Mortality due to bronchopneumonia in
(by insulin because of obvious reasons), appropriate anti­ diabetes was 17.4% in an Indian study.30 Fungal infections,
biotics and surgical intervention according to disease like aspergillosis and Cryptococcus neoformans can also
severity. Antibiotics are usually required for 6–8 weeks. cause primary pneumonia.
Appropriate antimicrobial therapy is supported by surgi­ It is recommended that diabetic patients receive pneu­
cal intervention in case of abscess, and EPN, at times mococcal and influenza vaccine annually36 to reduce
patient also requires unilateral nephrectomy. Mortality in morbidity and mortality. This is a cost-effective preventive
these emphysematous disorders is 60–80% with medical strategy.
therapy alone.30 In a study from North India, mortality
related to UTI in diabetic patients was 2.4%.31 Gastrointestinal Infections
In case of fungal infection, resolution occurs in most
cases without treatment, or on removal of urinary catheter. There is increased susceptibility to certain enteric patho­
Antifungal, like oral fluconazole, is preferred in invasive gens in diabetes because of gastrointestinal dysmotility
cases.32 Rarely, mucormycosis can invade urinary tract syndrome.8 Normal motility is an important host defense
and present with renal failure and anuria. mechanism against infection. Salmonella enteritidis20 and
Asymptomatic bacteriuria is not an indication for Campylobacter infections21 are reported with increased
antimicrobial therapy. Since prevalence of upper tract frequency. Diabetes is also a risk factor for infection with
involvement in diabetic women with bacteriuria is high, Listeria monocytogenes, in whom mortality is higher than
management of asymptomatic bacteriuria in diabetic in healthy individuals.37
patients has remained debatable. Emphysematous cholecystitis is a rare complication
of acute cholecystitis.38,39 Air is found in lumen and wall
Respiratory Tract Infections of gallbladder (Fig. 55.3). It results from ischemia of the
gallbladder wall and infection with gas producing orga­
The issue regarding increased susceptibility of diabetic nisms. Emphysematous cholecystitis afflicts males more
patients to respiratory tract infection compared to non- commonly (75%) and gall stones are present in half of
diabetics has not been resolved.33 The overall incidence of patients. Perforation (30 times) and gangrene (5–10 times)
 Acute Infections in Diabetes Mellitus 823

chapter
55
Fig. 55.4: Microphotograph showing aseptate long, broad, slender Fig. 55.5: Clinical photograph showing facial necrosis
right angled branching hyphae of Mucor spp (arrow) with tissue debris
in background (Grocott’s stain)

are many fold higher compared to non-emphysematous debridement along with broad-spectrum anti­ biotics.
cholecystitis. Interestingly, mortality is higher in younger Despite appropriate therapy mortality is nearly 60%.1
population. Emphysematous cholecystitis can be diagno­ Fournier’s gangrene is a form of necrotizing fasciitis
sed with plain radio graph, USG and computed tomo­ with predilection for the scrotum, penis and perineum.
graphy (CT) scan (Fig. 55.4). Air if found in hypochon­ An estimated 40–60% of patients with this condition are
drium, suggests perforation. Common organisms are associated with diabetes.42 Predisposing genitourinary
E coli and Clostridium perfringens.38-40 It needs prolonged pathologies are found in most cases.43 Infection is poly­
antibiotics and at times cholecystectomy.39 microbial which includes Clostridium, Gram-negative
bacilli, bacteroides and anaerobic streptococci. Mortality
Skin and Soft Tissue Infections ranges between 20% and 35% despite adequate therapy.44
There are no controlled studies to prove a higher associa­
Rhino-Orbital-Cerebral Mucormycosis
tion of skin and soft tissue infections like folliculitis,
furunculosis and subcutaneous abscess in patients with Rhino-orbital-cerebral mucormycosis is a rare but acute,
diabetes.1 However, diabetic patients are more predis­ fungal infection, associated with high morbidity and
posed to postsurgical wound infection14 in case of poor mortality. Diabetes is the most common predisposing
glycemic control. Both cutaneous fungal infections and factor.38 This is caused by Rhizopus and Mucor species of
pyomyositis caused by S. aureus occur with increased fungi. Mucor is ferrophilic, acidophilic and angioinvasive
frequency.39 fungus characterized by aseptate hyphae with right
Several skin and soft tissue infections, like diabetic angle branching (Fig. 55.4). Its angioinvasive nature is
foot, necrotizing fasciitis and Fournier’s gangrene occur responsible for tissue necrosis (Fig. 55.5). In view of its
exclusively in these patients. Seventy-five percent of ferrophilic nature, it rapidly multiplies in the presence
patients with necrotizing fasciitis have diabetes.1 Infection of acidosis (diabetic ketoacidosis) because acidosis
spreads along facial planes and subsequently affects provides free iron which is an important nutrient for
muscle and skin. The infection is usually polymicrobial Mucor.45,46 In addition to this, lack of serum inhibitory
and categorized as type I, if caused by an anaerobe in activity,47 and defective pulmonary macrophage function
combination with facultative anaerobes, like streptococci due to hyperglycemic state48 also predisposes for ROCM.
or enterobacteriaceae, and type II, if caused by group A It is an invasive disease and it can enter into brain
β-hemolytic streptococci alone or in combination with (Figs 55.6A and B) through nasal cavity and sphenoid
staphylococci.41 Common sites affected include nape of sinus. Combined medical and surgical treatment imp­
neck, back, abdominal wall, extremities and perineum. The roves treatment outcome in ROCM patients.45 Predictors
infection is life-threatening and needs immediate surgical of poor outcome in ROCM are delay in diagnosis, poor
 824 Complications
section
10

A B
Figs 55.6A and B: (A) Contrast-enhanced computed tomography (coronal section) of paranasal sinuses showing opacity involving bilateral
ethmoidal cells, left maxillary and frontal sinuses; (B) Contrast-enhanced computed tomography (axial section) of orbit, showing extraconal soft
tissue mass with destruction of lamina papyracea and extension into the ipsilateral ethmoidal air cells

drug delivery due to vascular occlusion, limited surgery malignant external otitis. The diagnosis of malignant
due to anatomy of rhino-orbital region and low index of external otitis is based upon a constellation of clinical,
suspicion.46 Early diagnosis and aggressive treatment is laboratory and radiographic findings. Elevated erythro­
mandatory. Medical treatment consists of amphotericin B cyte sedimentation rate is consistent feature of mali­gnant
(2–2.5 g) in divided doses. Surgical treatment consists of external otitis. Early diagnosis depends on demonstration
local debridement, sinus drainage and orbital exenteration. of Pseudomonas by Gram-stain and culture. Tissue biopsy
Recently, lipid complex formulations of amphotericin B is mandatory to exclude non-invasive otitis. MRI with
has allowed higher doses of the drug with lower systemic gadolinium is the radiological examination of choice for
toxicity.49 If untreated, the disease is universally fatal. its ability to delineate soft tissue and bone involvement.38
Technetium and gallium scans are superior to CT or
Malignant Externa Otitis MRI in demonstrating early temporal bone osteomyelitis.
Malignant (necrotizing) external otitis (also termed malig­ Management includes surgical debridement of necrotic
nant otitis externa) is an invasive infection of the external tissue and appropriate antipseudomonal therapy. Cipro­
auditory canal and skull base, which typically occurs in floxacin is treatment of choice (750 mg bd or intrave­
elderly patients with diabetes mellitus.50 Patients with nous ciprofloxacin for initial few days). Total duration of
malignant external otitis present with exquisite otalgia and therapy is 6–8 weeks like in case of osteomyelitis. Mortal­
otorrhea, which are not responsive to topical measures ity is close to 30% in patients with extensive intracranial
used to treat simple external otitis. The pain is generally involvement.53,54
more severe than that found in simple external otitis, and
can be life-threatening due to its intracranial extension. Foot Infections
Predisposing factors, like poor glycemic control, use of
hearing aids, swimming in contaminated pools, and In patients with diabetes, foot infection is an extremely
use of non-sterile water for ear irrigation6 contribute to common problem.55 Clinically, manifest neuropathy is
the development of this infection. Majority of cases are present in 25% of cases and close to 40% of patients with
caused by Pseudomonas51 and sometimes, secondary a foot ulcer will require amputation within three years.
to colonization by Aspergillus of the external auditory Several factors contribute to increased susceptibility to
canal.52 Spread of infection leads to cranial osteomyelitis, foot infection.55 Presence of neuropathy, vasculopathy,
facial nerve palsy,6 lower cranial nerve palsies as well as minor trauma, skin breakdown caused by dermatophytes
involvement of sigmoid sinus and the meninges.51 and paronychia results in entrance of pathogens which
Increased pH in diabetic cerumen and microangio­ progresses leading to life-threatening infection if not
pathy of ear canal are important predisposing factors for treated early.
 Acute Infections in Diabetes Mellitus 825

Foot infection may be mild or severe. Mild infection can be helpful for identification of the extent of infection
is superficial when there is no evidence of ischemia, sys­ with greater subtlety than other modalities, if needed.
temic toxicity or bone involvement. Severe infection is Early stage of pyomyositis can be treated with antibiotics
associated with manifestations mentioned above.8 Mild alone; however advance stage requires both antibiotic
infection can be controlled with appropriate antibiotic and definitive management. However, broad spectrum
therapy while moderate to severe infection will require antibiotic coverage for Gram-positive, Gram-negative and
debridement, evaluation of osteomyelitis and necessary anaerobic organisms is required. In such circumstances,

chapter
surgical inter­vention. Empiric coverage with antibiotics vancomycin may be combined with a broad spectrum

55
should include agents active against S aureus, Pseudo­ regimen that has activity against Gram-negatives and anae­
monas, enterococci and anaerobes.8 Details regarding robes. The duration of antimicrobial therapy should be
foot infection in diabetes is covered elsewhere in this text­ tailored to clinical and radiographic improvement. Three
book (Chapter 62). to four weeks of parenteral therapy is usually sufficient.
Acute infections in diabetes are still important cause
Pyomyositis of morbidity and mortality. Many specific infections and
some exclusive ones are commonly seen in patients with
Pyomyositis is a purulent infection of skeletal muscle that diabetes. Some of the infections (ROCM, EPN and EC) are
arises from hematogenous spread. It is usually associated associated with dangerous complications which needs
with abscess formation. Diabetes is an important risk high index of suspicion for early recognition and timely
factor other than immunodeficiency, trauma, concurrent intervention. Defective innate immunity contributes to
infection and malnutrition. S. aureus is the most common increased susceptibility to infection, and mostly immune
organism responsible for pyomyositis. Group A streptococci deficiencies are linked to glycemic control. Blood glucose
is the second most common pathogen. Less common levels should be meticulously controlled in the presence
causes include non-group A streptococci, pneumococci of infection and appropriate antimicrobial therapy started
and Gram-negative enteric bacilli. Pyomyositis in diabetes early to reduce morbidity and mortality.
is often polymicrobial.55
Pyomyositis usually presents with fever and pain with ACKNOWLEDGMENT
cramping localized to a single muscle group. The disease
I would like to thank Vandana Dhiman for assistance in
occurs most often in the lower extremity (sites include the
preparing the manuscript. As most of the information in
thigh, calf and gluteal muscles), but any muscle group can
this chapter has been generously drawn upon from the
be involved, including the iliopsoas, pelvic, trunk, para­
same chapter which appeared in 2nd edition of RSSDI
spinal and upper extremity muscles. Multifocal infection
textbook by BK Das and PK Das, I acknowledge their
with involvement of more than one muscle group may
contributions to the present chapter.
be observed in up to 20–30% of cases. The course of
pyomyositis is variable; although most patients present
with stage 2 or 3 disease, some experience a more indolent
Further Reading
course; a delay in diagnosis in such cases may result in 1. Bhansali A, Chattopadhyay A, Dash RJ. Mortality in diabe­
tes: a retrospective analysis from a tertiary care hospital in
involvement of multiple muscle groups, requiring pro­
North India. Diabetes Res and Clin Pract. 2003;60:119-24.
longed therapy. Recurrent infection is uncommon but can 2. Bhadada S, Reddy KS, Bhansali A, et al. Co-occurrence of
cause mortality. emphysematous cystitis and emphysematous myositis in
Pyomyositis may be confused with muscle strain, type 2 diabetes. J Assoc Physicians India. 2005;53:821-3.
contusion, hematoma, cellulitis, deep vein thrombosis, 3. Bhadada S, Bhansali A, Reddy KS, et al. Rhino-orbital-
cerebral mucormycosis in type 1 diabetes mellitus. Indian
osteomyelitis, septic arthritis, or neoplasm. It must also be
J Pediatr. 2005;72:671-4.
distinguished from clostridial myonecrosis, necrotizing 4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guide­
fasciitis, spontaneous gangrenous myositis, diabetic mus­ lines for the diagnosis and management of skin and
cle infarction, septic arthritis, and other forms of myositis. soft-tissue infections. Clin Infect Dis. 2005;41:1373-406.
Tools for diagnosis of pyomyositis include radiography, 5. Diabetes and Sepsis: Preclinical Findings and Clinical
Relevance Diabetes Care. 2011;34:771-8.
cultures and laboratory data. 6. Tuberculosis and non-communicable diseases: Neglected
Although CT is preferable if available, USG is also a links and missed opportunities. Eur Respir J. 2011.37:
potentially useful diagnostic and therapeutic tool. MRI 1269-82.
 826 Complications

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2. Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control mellitus—a newly described risk factor for infection from
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patients with diabetes mellitus (DM). FEMS Immunol Med Dis Clin North Am. 1995;9:97-116.
Microbiol. 1999;26:259-65. 24. Sobel JD. Pathogenesis of urinary tract infection. Role of
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clinicians. Infectious Disease Reports. 1995;1:1. 25. Vejlsgaard R. Studies on urinary tract infection in diabetes.
7. Gallacher S, Thomson G, Fraser WD, et al. Neutrophil I. Bacteriuria in patients with diabetes mellitus and in
bactericidal function in diabetic mellitus: evidence for control subjects. Acta Med Scand. 1964;179:173-82.
association of blood glucose control. Diabet Med. 1995; 26. Sridhar CB, Anjana S, Thomas Mathew J. Acute infections.
12:916-20. In: Tripathy BB, Das AK, Rao PV, Madhu SV, Mohan V (Eds).
8. Calvet HM, Yoshikawa TT. Infections in diabetes. Infect Dis RSSDI Textbook of Diabetes Mellitus, 1st edition. JAYPEE
Clin North Am. 2001;15:407-21. publishers; 2002. pp. 471-7.
9. Li YM, Tan AX, Vlassara H. Antibacterial activity of lysozyme 27. Geerlings SE, Stolk RP, Camps MJ, et al. Asymptomatic
and lactoferrin is inhibited by binding of advanced bacteriuria may be considered a complication in women in
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1995;1:1057-61. riuria Utrecht Study Group. Diabetes Care. 2000;23:744-9.
10. Katz S, Klien B, Elian I, et al. Phagocytotic activity of 28. Ellenbogen PH, Talner LB. Uroradiology of diabetes
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6:479-82. 29. Bhadada S, Reddy KS, Bhansali A, et al. Co-occurrence of
emphysematous cystitis and emphysematous myositis in
11. MacRury SM, Gemmel CG, Paterson KR, et al. Changes
type 2 diabetes. J Assoc Physicians India. 2005;53:821-3.
in phagocytic function with glycaemic control in diabetic
30. Patterson JE, Andriole VT. Bacterial urinary tract infections
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in diabetes. Infect Dis Clin North Am. 1997;11:735-50.
12. Ling PR, Bistrian BR, Mendez B, et al. Effects of systemic
31. Bhansali A, Chattopadhyay A, Dash RJ. Mortality in dia­
infusion of endotoxin, tumor necrosis factor, and inter­
betes: a retrospective analysis from a tertiary care hos­
leukin-1 on glucose metabolism in the rat: relationship
pital in North India. Diabetes Res and Clin Pract. 2003;60:
to endogenous glucose metabolism and peripheral tissue
119-24.
glucose uptake. Metabolism. 1994;43:279-84. 32. Leu HS, Huang CT. Clearance of funguria with short-course
13. Hostetter MK. Handicaps to host defenses. Effects of antifungal regimens: a prospective randomized, controlled
hyperglycemia on C3 and Candida albicans. Diabetes. study. Clin Infect Dis. 1995;20:1152-7.
1990;39:271-5. 33. Koziel H, Koziel MJ. Pulmonary complications of diabetes
14. Pomposelli JJ, Baxter J 3rd, Babineau T, et al. Early postop­ mellitus. Pneumonia. Infect Dis Clin North Am. 1995;9:
erative glucose control predicts nosocomial infection rate 65-96.
in diabetic patients. JPEN J Parenter Enteral Nutr. 1998; 34. Woodhead MA, Macfarlane JT, McCracken JS, et al. Pro­
22:77-81. spective study of the aetiology and outcome of pneumonia
15. Breen JD, Karchmen AW. Staphylococcus aureus infec­ in the community. Lancet. 1987;1:671-4.
tions in diabetic patients. Infect Dis Clin North Am. 1995;9: 35. Fine M, Smith MA, Carson C, et al. Prognosis and outcome
11-24. of patients with community acquired pneumonia. A meta-
16. Cooper G, Platt R. Staphylococcus aureus bacteremia in analysis. JAMA. 1996;275:134-41.
diabetic patients. Endocarditis and mortality. Am J Med. 36. ACP Task Force on Adult Immunization: immunization for
1982;73:658-62. immunocompromised adults. Guide for Adult Immuni­
17. Farley MM, Harvey RC, Stull T, et al. A population-based zation. Philadelphia, Pennsylvania: American College of
assessment of invasive disease due to Group B Strepto­ Physicians; 1994. p. 49.
coccus in non-pregnant adults. N Eng J Med. 1993;328: 37. Skogberg K, Syrjänen J, Jahkola M, et al. Clinical pres­
1807-11. entation and outcome of listeriosis in patients with and
18. Leibovici L, Samra Z, Konisberger H, et al. Bacteremia in without immunosuppressive therapy. Clin Infect Dis. 1992;
adult diabetic patients. Diabetes Care. 1991;14:89-94. 14:815-21.
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38. Bhadada S, Bhansali A, Reddy KS, et al. Rhino-orbital- 47. Meyer BR, Wormser G, Hirschman SZ, et al. Rhinocerebral
cerebral mucormycosis in type 1 diabetes mellitus. Indian mucormycosis: premortem diagnosis and therapy. Arch
J Pediatr. 2005;72:671-4. Intern Med. 1979;139:557-60.
39. Bhansali A, Bhadada SK, Shridhar C, et al. Concurrent 48. Gale GR, Welch AM. Studies of opportunistic fungi. I.
emphysematous pyelonephritis and emphysematous chol­ Inhibition of Rhizopus oryzae by human serum. Am J Med
ecystitis in type 2 diabetes. Australas Radiol. 2004;48:411-3. Sci. 1961;241:604-12.
40. Nirmal J, Mahajan M. Infection and diabetes. In: John C 49. Waldorf AR, Ruderman N, Diamond RD. Specific suscepti­
Pickup, G Williams (Eds). Textbook of Diabetes, 3rd edition. bility to mucormycosis in murine diabetes and bronchoal­

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1984;74:150-60.

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41. Mentzer RM Jr, Golden GT, Chandler JG, et al. A compara­
tive appraisal of emphysematous cholecystitis. Am J Surg. 50. Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B
lipid complex for invasive fungal infections: analysis of
1975;129:10-5.
safety and efficacy in 556 cases. Clin Infect Dis. 1998;
42. Giuliano A, Lewis F Jr, Hadley K, et al. Bacteriology of
26:1383-96.
necrotizing fasciitis. Am J Surg. 1977;134:52-7.
51. Sapico F, Bessman A. Infections in the diabetic patient.
43. Dutta P, Bhansali A, Singh SK, et al. Presentation and Infect Dis Clin Pract. 1995;1:339.
outcome of emphysematous renal tract disease in patients 52. Tierney MR, Baker AS. Infections of the head and neck in
with diabetes mellitus. Urol Int. 2007;78:13-22. diabetes mellitus. Infect Dis Clin North Am. 1995;9:195-216.
44. Sentochnik DE. Deep soft-tissue infections in diabetes 53. Phillips P, Bryce G, Shepherd J, et al. Invasive external otitis
patients. Infect Dis Clin North Am. 1995;9:53-64. caused by Aspergillus. Rev Infect Dis. 1990;12:277-81.
45. Bhansali A, Bhadada S, Sharma A, et al. Presentation and 54. Rubin J, Yu VL. Malignant external otitis: insights into
outcome of rhino-orbital-cerebral mucormycosis in pati­ pathogenesis, clinical manifestations, diagnosis, and ther­
ents with diabetes. Postgrad Med J. 2004;80:670-4. apy. Am J Med. 1988;85:391-8.
46. Artis WM, Fountain JA, Delcher HK, et al. A mechanism of 55. Stevens DL, Bisno AL, Chambers HF, et al. Practice guide­
susceptibility to mucormycosis in diabetic ketoacidosis: lines for the diagnosis and management of skin and
transferrin and iron availability. Diabetes. 1982;31:1109-14. soft-tissue infections. Clin Infect Dis. 2005;41:1373-406.
 Chapter 56
Chronic Infections and
Diabetes Mellitus
Samar Banerjee

Chronic Infections in DM

Chapter Outline
♦♦ Immune Alterations in Diabetes ♦♦ HIV Infection and Diabetes
♦♦ Secondary Factors ♦♦ Rhinocerebral Mucormycosis
♦♦ Chronic Infections ♦♦ Cholecystitis
♦♦ Hepatitis C and Diabetes ♦♦ Chronic Pyelonephritis and Cystitis
♦♦ Diabetes Mellitus and Tuberculosis ♦♦ Chronic Foot Infections
♦♦ Periodontal Disease and DM ♦♦ Fungal Infections in Diabetes

INTRODUCTION IMMUNE ALTERATIONS IN DIABETES

Infection in diabetes is one of the common and important The following changes in immune alteration occur in
terminal events. This complication by hampering gly­ diabetes.
cemic control worsens the prognosis of a diabetic person. Chemotaxis: By this process, polymorphonuclear cells
Diabetes mellitus (DM) predisposes a person to infection migrate to the site of infection as a response to chemotactic
which in turn affects metabolic control. Effective control substances secreted by microorganisms. In diabetes,
of one affects the other favorably. Dia­betes is considered diminished chemotaxis has been noted and is well corre­
a secondary immune deficiency disorder by World Health lated to metabolic control.2
Organization (WHO)1 as the disease is characterized by Phagocytosis: Adhesion and ingestion of foreign particles
the fact that: are the stages of phagocytosis and is triggered by serial
• Elimination of underlying cause leads to resolution mechanisms involving actin, myosin, immuno­ globulin
• Frequent, severe, prolonged and recurrent infections (Ig) and complement system. Phagocytosis is impaired
are seen in long-standing uncontrolled diabetes, together with
• Alteration of at least one of the immune response intrinsic defect of polymorphs from increase in sialidase
mecha­nisms (e.g. polymorphonuclear leucocytes or enzyme secretion and reduction of cell membrane sialic
lymphocyte response) is seen. acid. High level of blood glucose saturates lectin receptors
Chronic hyperglycemia impairs host defense and some which fail to start phagocytosis.3
infections occur more in diabetics whereas some other Killing activity: This activity is produced by lysosomal
infections occurs both in diabetics and non-diabetics. enzymes from polymorphs after phagosome and lysosome
 Chronic Infections and Diabetes Mellitus 829

fusion and is dependent upon both oxidative and non- • Inappropriate antibiotic usage
oxidative metabolism. Decrease in this activity with high • Peripheral vascular diseases
blood glucose and restoration by insulin therapy of this • Neuropathy
activity within 48 hours has been noted in diabetes.4 • Gastroporesis, reflux and pulmonary aspiration
Production of sorbitol also hampers the oxidative killing • Indwelling catheterization
process. • Frequent minor or major surgery
Lymphocyte function: In Type 1 DM, reduction of total • Chronic renal failure requiring dialysis, blood trans­

chapter
number of lymphocytes, especially of CD4 (helper cells) fusion.

56
has been noted and this may be due to insulin deficiency
or inefficacy.5 Normalization of glycemic control reverses
CHRONIC INFECTIONS
this effect. Because of this CD4 deficiency probably poor Infections occurring commonly in diabetes are mostly
antibody response against hepatitis B vaccine is also bacterial or fungal. Nowadays viral diseases like hepatitis
observed reflecting poor cellular and humoral response.6 particularly hepatitis C and human immunodeficiency
Immunoglobulins: Lower level of immunoglobulins both virus (HIV) infection are also noted.
IgG and IgA is reported in diabetic persons.7 Infections commonly seen in diabetics are as follows:
Complement: In diabetic patients often low C4 levels asso­
Bacterial
ciated with C4A null gene has been seen in 25% of cases
of Type 1 DM.8 Deficiency of C1q and C3 complement has • Tuberculosis (TB)
also been observed. • Malignant otitis externa
Beyond these immune factors, local factors also pre­ • Pyelonephritis
dispose to infections as follows: • Necrotizing fasciitis
• Hyperglycemia predisposes to bacterial and fungal • Staphylococcal infections
infection by altering the endothelial function and • Erythrasma
oxidative stress. • Perinephric abscess
• Angiopathy both micro and macrovascular produces • Non-clostridial gas gangrene
anoxia and results in microbial proliferation, impaired • Cholecystitis
oxygen dependent polymorphonuclear function and • Periodontal infection.
improper drug perfusion of antibiotics.
Fungal
• Sensory motor neuropathy produces pressure sores,
ulcers, abnormal pressure points in the foot due to • Candidiasis
small joint arthropathy and small muscle myopathy • Rhinocerebral mucormycosis.
of foot and microangiopathy predisposing to diabetic
foot. Autonomic neuropathy is a predisposing cause of Viral
chronic urinary tract infection because of retention of • Viral hepatitis particularly hepatitis C
bladder. It also impairs the microvascular circulation • Human immunodeficiency virus infections
and causes peripheral gangrene. Microvascular Out of all these chronic infections the most important,
impairment leads to decreased renal blood flow and are diabetic foot, cholecystitis, pyelonephritis, candidiasis,
frequent renal infection resulting in papillary necrosis. rhinocerebral mucormycosis, hepatitis C and HIV.

SECONDARY FACTORS HEPATITIS C AND DIABETES

As a part of disease management and diseases process, Hepatitis C virus (HCV) infection and diabetes are
the factors which make a diabetic more vulnerable to becoming an epidemic worldwide. Both are slowly and
infection, are as follows: silently developing, diagnosed very late and often with
• Frequent hospitalizations complications at diagnosis. Patients with chronic HCV
• Diabetic ketoacidosis infection can present with non-hepatic features like cryo­
• Intravenous or intramuscular drugs, fluids or blood globulinemia, glomerulonephritis, sialadenitis and por­-
administrations phyria cutaneous tarda.
 830 Complications

Table 56.1: Aetiology of chronic liver disease in India10

NASH with cirrhosis NASH Cryptogenic cirrhosis HBV HCV
Diabetic group 11.3% 18.9% 22.6% 17% 13.2%
Non-diabetic group 1.7% 13.0% 7.8% 30.43% 29.6%

(HBV: Hepatitis B virus; HCV: Hepatitis C virus; NASH: Non-alcoholic steatohepatitis).

section

Table 56.2: Incidence of DM in cirrhosis and after hepatic transplant17

10

Before transplant 1st year of transplant 5th year of transplant

HCV related cases 29% 37% 41%
HBV related cases 6% 10%
Cholestatic liver disease 4% 10%

(DM: Diabetes mellitus; HBV: Hepatitis B virus; HCV: Hepatitis C virus).

Epidemiology infection, alcoholic liver disease and biliary cirrhosis.15

Petit JM et al. (2001) observed that older age, obesity,
Allison et al. first reported a link in the incidence between
severe liver fibrosis and family history of DM are related to
HCV and DM in 1994.9 In a study of 100 patients, with
potential risk of developing DM in HCV infected patients.16
cirrhosis, 50% of cases related to hepatitis had diabetes
In patients with cirrhosis planned for hepatic trans­
whereas hepatitis C negative cirrhosis group had diabetes
plantation development of Type 2 DM is five times higher
in 9% of cases with an odds ratio of HCV by DM status
who are HCV origin17 (Table 56.2).
of 10.0 (95% confidence interval, 3.4–29.3). Subsequent
This study has also shown that HCV-related liver
studies have also supported this association. Similarly
fail­
ure, pretransplantation diabetes and male sex are
higher incidence of HCV infection is noted amongst
independent predictors of developing DM, a year after
diabetics than non-diabetics.
transplantation.
Amarapurkar et al. (2002) from India10 compared the
Though majority of studies showed increased pre­
etiology of chronic liver diseases with and without DM,
valence of DM amongst HCV chronic infection cases,
and found higher evidence of HCV than HBV in diabetics
Mangia A et al. reported negative correlation between
than non DM (Table 56.1).
Wang CS et al. (2003) studied 2,327 consecutive these two.18 They reported high rate of DM in patients
subjects in the community and found anti HCV positivity suffering from cirrhosis irrespective of etiology.
to be strongly associated with Type 2 DM in subjects aged A prospective study of 9 years has shown that among
35–49 years (odds ratio 3.3). Sonographic evidence of fatty those at high risk for developing diabetes, persons with
liver and chronic liver disease in HCV-positive cases were HCV infection were 11 times more likely to develop dia­-
also moderately associated with Type 2 DM. No correlation betes in comparison to those without HCV infection.19
­
with hepatitis B infection and alcohol consumption were Genotype 1a and 1b infection constitutes 70% of HCV
noted.11 DM may also be significantly associated with infection but whether particular genotype involves dia­betic
hepatocarcinogenesis in chronic HCV patients as studied persons is not settled. Though some workers claim geno-
in 311 liver biopsies of HCV patients by Tajawa J et al.12 type 2a is seen more in diabetes in HCV infection, others
Third National Health and Nutrition Examination claim DM in HCV does not have any special pre­dilection
Survey (NHANES III) published in 2000 proved unique for genotype.20,21 Moreover, alcohol does not exert any
association between HCV infection and DM,13 where additive effect over HCV infection in developing DM.
presence of HCV infection amongst persons over 40 years The long-term outcome in patients with chronic hepa­
are statistically higher for the development of DM than titis C and Type 2 DM treated with interferon and ribavirin
HCV-negative persons (odds ratio 3.77). However, is not clear. Giordanino et al. compared incidence of
hepatitis B infection does not increase the risk of deve­ liver-related events and mortality rates between HCV-
loping DM.14 Incidence of DM amongst HCV chronic positive patients with or without DM, and the incidence of
infection are much higher than those with chronic HBV diabetes-related events between diabetic patients with and
 Chronic Infections and Diabetes Mellitus 831

without hepatitis C.22 Sixteen percent of chronic hepatitis Table 56.3: Pathogenesis of DM in HCV infection31
C patients had DM. Diabetics showed a higher number of • Hyper insulinemia, insulin resistance
diabetes and liver-related events than non-diabetics (10% • Insulin deficiency or poor insulin secretion
vs 1.5%, p = 0.006; 18% vs 5.7%, p = 0.007, respectively) • Pancreatic infection by HCV
with a mortality of 14% versus 1.5% (p = 0.0003). Baseline • Autoimmune b-cell damage
cirrhosis (p = 0.002) and non-sustained virological • Non-alcoholic fatty liver disease
response (p = 0.01) were independent risk factors for

chapter
• Increased iron stores
liver events. DM (p = 0.01) and hypertension (p = 0.0017)

56
(DM: Diabetes mellitus; HCV: Hepatitis C virus).
were independent factors for diabetes-related events. The
conclusion of the study was that in patients with chronic
age over 57 years, family history of DM, body mass index
hepatitis C, comorbidity with DM was associated with > 25 kg/m2, and previous interferon treatment were all
a higher mortality rate and incidence of liver or diabetes- independent factors for the development of Type 2 DM in
related events. Independent risk factors for liver-related patients with chronic hepatitis C.28
events were non-response to antiviral therapy and cirr­ Interferon has been shown to induce insulin resis­
hosis at baseline. tance in the splanchnic and peripheral tissues of
The glucose homeostasis is maintained by a dynamic patients with HCV.29 Zein et al, studied the prevalence of
equilibrium between endogenous glucose production diabetes mellitus and impaired fasting glucose among
and glucose use, regulated mainly by insulin and gluca­ interferon-naive patients with HCV. They found a higher
gon. However, liver also plays a crucial role in both prevalence of DM and IFG among HCV-infected patients
endogenous glucose production and glucose use. Glucose with advanced histological disease compared to those
intolerance in cirrhotic patients is because of insulin with early changes only. Additionally, family history was
resistance caused by a postreceptor defect, decreased noted to be an independent prediction of DM and IFG
in this cohort. Therefore, genetic predisposition and
binding of insulin to target tissue and inadequate response
advanced histological disease are strong predictors for
of the β-cells of the pancreas to appropriately secrete
the development of DM and IFG among HCV-infected
insulin to overcome the defect in insulin action.23
individuals.30
Simo et al.24 showed a significantly higher prevalence
rate of positive serum anti-HCV (11.5%) in 176 diabetic
Mode of Transmission of Hepatitis C Virus
patients when compared with 2.5% in 6,172 blood donors.
Chen et al. evaluated serum anti-HCV and hepatitis B Conventionally raised alanine aminotransferase (ALT) in
surface antigen (HBsAg) among 820 Type 2 DM patients diabetes indicates fatty liver, but this is also seen frequently
and 905 non-DM healthy check-up subjects. They reported due to coexistent HCV infection as documented in UKPDS
a higher seroprevalence of HCV infection among patients (UK Prospective Diabetes Study) trial. Though finger prick
with Type 2 DM (6.8%) than in the control group (2.6%), for blood sugar examination and insulin injection is a
but no difference in positive HBsAg between the groups mode of transmission, different studies have ruled out the
(13.5% vs. 12.4%). They found a 2.8 times higher risk of possibility.31
hepatitis C in Chinese patients with Type 2 DM.25 The
Pathogenesis of Diabetes in HCV Infection
results of Chen et al. are consistent with previous reports
indicating the possible association between Type 2 DM Multiple pathomechanisms have been suggested but none
and chronic hepatitis C. is clearly confirmed. They are as follows (Table 56.3).31
A higher prevalence of DM has been reported in
HCV-infected patients compared with those with other Insulin Resistance
liver diseases such as chronic hepatitis B, primary biliary This is observed in all cases of cirrhosis regardless of
cirrhosis and primary sclerosing cholangitis.26 etiology and is considered a key factor in the development
The post-liver transplant setting also shows a relation­ of hepatogenous DM. HCV infection is reported to induce
ship between HCV and DM. The prevalence of DM is insulin resistance as observed in 250 cases of HCV-
higher in HCV-positive than in HCV-negative liver infected patients.32 This may be possibly due to liberation
transplant recipients.27 In a previous study by Chen et al. of different cytokines like tumor necrosis factor a (TNF-a),
 832 Complications

which inhibits tyrosine kinase phosphorylase pathway. of HCV proteins on insulin signaling pathways. Aytug et
Insulin resistance is also an independent predictor of al. (2003) showed that hepatitis C leads to a postreceptor
hepatic fibrosis and is irrespective of degree of hepatic defect in insulin receptor substrate (IRS)-1 association
failure and the lowest with gentotype 3 HCV. with the insulin receptor; insulin signaling defects in
The tumor necrosis factor a probably is important in hepatic IRS-1 tyrosine phosphorylation and phosphatidyl
the pathogenesis of DM in chronic hepatitis C patients.33 inositol 3-kinase association/activation may contribute to
TNF-a has been shown to inhibit insulin-stimulated insulin resistance.38 This can lead to the development of
section

tyrosine phosphorylation of insulin receptor and insu­ Type 2 DM.

10

lin receptor substrate 1 in adipocytes, stimulate lipolysis Using a transgenic animal model, Shintani et al.
and increase serum-free fatty acids, leading to insulin (2004) suggested that the HCV core gene may be directly
resistance in muscle and liver, mediate hepatic insulin involved in the development of insulin resistance.39
resistance to increase hepatic glucose production, and The investigators demonstrated that HCV-transgenic
down-regulate genes in adipocytes encoding proteins such mice developed hepatic insulin resistance by means of
as insulin receptor substrate 1, glucose transporter-4, per­ suppression of the inhibitory effect of insulin on hepatic
oxisome proliferator-activated receptors and adiponectin. glucose production at an early age without weight gain or
Moreover, TNF-a may reduce β-cell function by direct affecting glucose utilization by muscle.
toxic effects, further contributing to the development of
DM. Recent studies have documented significantly higher Autoimmune b-cell Damage due to HCV
levels of soluble TNF-a receptors in diabetic HCV patients
than in non-diabetic HCV patients and controls.34 Though the genome of HCV has been identified within
Caronia S et al. (1999) observed diabetes in 23.6% pancreas, evidence of b-cell damage by HCV directly or
cases of HCV positive cases and in 9.4% cases of HBV- indirectly by immune response is questionable. Piquer
related cirrhosis. Fasting insulin level in 30 cases out of 127 et al. studied this hypothesis and could not find higher
HCV-related cirrhosis patients was significantly higher, incidence of glutamic acid decarboxylase (GAD) antibody,
consistent with insulin resistance. Reduced acute insulin tyrosine phosphatase antibody or islet cell antibody in
response indicating β-cell dysfunction was observed in patients with HCV infection as compared to normal popu­
all these cases.26 Narita et al.35 demonstrated that, using lation.40 However, increasing incidence of Type 1 DM is
homeostatic model assessment (HOMA) methods, both seen after interferon therapy in HCV infection probably
insulin resistance and β-cell dysfunction contributed to due to amplification of previously existing autoimmune
glucose intolerance in chronic hepatitis C patients. response to b-cells.41 Moreover interferon therapy in
healthy volunteer is reported to induce insulin resistance.42
Insulin Deficiency
Grimbert et al. found lower value of serum insulin and C Non-alcoholic Fatty Liver Disease
peptide amongst 17 cases of HCV chronic infection and
This is a known entity for developing DM and is associated
diabetes but when compared to 9 HCV-negative patients
with HCV infection. However, obesity and dyslipidemia
with diabetes the result appeared not to be statistically
determine the risk of steatosis produced by HCV infec­
significant probably because of low sample size.15
tion.43 Metabolic steatosis and viral steatosis are both
Pancreatic Infection by HCV probably responsible in this condition.

A number of viruses including coxsackie virus, CMV, HSV,

Increased Iron Stores
mumps, varicella zoster virus, HBV and HCV have been
recognized as causes of pancreatic infection. Most viruses Excess iron store is a known factor for developing
with the exception of HCV have been implicated in the secondary diabetes. Forty percent cases of HCV-infected
pathogenesis of Type 1 diabetes mellitus.36 However, persons have higher iron stores. Serum ferritin was
Masini et al, have proposed that direct cytopathic effect studied by Hernandez C in 123 patients infected with
of HCV at the islet cell level causes b-cell dysfunction HCV (55 diabetic, 68 non-diabetic). Serum ferritin was
resulting in Type 2 diabetes mellitus.37 It has been sugges­ 4 times higher in the diabetic group suggesting etiological
ted that, insulin resistance may be caused by a direct effect correlation for diabetes in HCV infection.44
 Chronic Infections and Diabetes Mellitus 833

Risk Factors HCV Infection and Diabetic Complications

The common risk factors for the development of diabetes According to data from Giordanino et al.22 the presence
in patients with HCV are: of HCV seems to play a protective role toward the
• Older age complications of DM. It has been previously suggested
• Obesity that, in patients with viral cirrhosis, DM is not associated
• Hepatitis C virus genotype 3 with an increased risk of peripheral macroangiopathy,54

chapter
• Severe liver fibrosis microangiopathy,54-56 coronary artery disease (CAD),54,56

56
• Family history of diabetes cerebrovascular disease55,56 or carotid intima-media thick­
• Liver transplantation ness;57 given that 40% of the chronic hepatitis C diabetics
• Kidney transplantation were cirrhotic. The coagulation abnormalities and throm­
bocytopenia58,59 as well as the low serum cholesterol
Effect of DM on HCV-Positive levels60 and low arterial blood pressure frequently seen
Chronic Liver Disease in cirrhosis, are probably the protective factors. A recent
study61 has shown that only HCV-positive cirrhosis is
Retrospective cross-sectional study of 1,195 patients with negatively related to CAD, supporting the information
chronic HCV demonstrated synergistic liver damaging from previous studies showing a decreased prevalence of
effects of DM and HCV. The three way interaction CAD in cirrhosis of viral origin.
between the stages of chronic liver disease, diabetes and To conclude, association of HCV infection and DM
enzymatic cholestasis suggests that diabetes is a risk factor is not uncommon. In a patient of diabetes, when liver
for the progression of viral liver disease at least in part enzymes are raised, the possibility of fatty liver as well as
by induction of cholestasis.45 High blood glucose in HCV HCV infection should be considered. Necessary changes
infected person leads to advanced and increased fibrosis. in terms of treatment of both diseases should be adopted.
This effect is mediated via receptors for advanced glycation
end (AGE) products situated in hepatic stellate cells and DIABETES MELLITUS AND TUBERCULOSIS
increased oxidative stress through key inflammatory genes
Tuberculosis in diabetes is 2–5 times higher, usually
such as TNF-a, IL-6, etc.46
diagnosed late, asymptomatic and is mostly due to reac­
When diabetes is present, it accelerates the course
tivation of an old focus and not a fresh infection. The risk
of chronic hepatitis C (CHC)47 and also influence the
of acquiring TB was found to be 4.8% in a study of 1,529
response to antiviral therapy.48 HCV interferes with
diabetic patients.62 The risk was highest (24%) in Type 1
glucose metabolism independently of age and stage of
DM patients.
liver disease. But during the cirrhotic stage multiple factors
contribute to insulin resistance and mask the HCV-related
Epidemiology
effect.49
If HCV is directly involved in the development of In a large cohort of 8,793 patients, Patel in India reported
insulin resistance and DM, it is reasonable to hypo­thesize TB to be the most common associated illness (5.9%)
that its clearance may result in a parallel decrease in the with DM.63 Swai et al. in a prospective 7 year follow-up of
risk of DM incidence. Recent studies50-52 reported a signi­ 1,250 diabetes patients found that 5.4% cases developed
ficantly reduced incidence of DM amongst sus­ tained pulmonary TB and 0.2% spinal tuberculosis. In 25.7%
responders to antiviral therapy, irrespective of their base­ cases, TB was detected before DM, in 45.7% after DM and
line predisposing factors. But, Giordanino et al. have in 20.6% simultaneously.64 He noted a greater prevalence
suggested53 that the eradication of HCV does not signi- of tuberculosis (TB) in young patients, in those with low
ficantly reduce the risk of DM in predisposed individuals. BMI, in those with Type 1 diabetes (compared to those
The clinical impact of a successful antiviral therapy on the with Type 2 diabetes, 9% vs 2.7%) and in those with
long-term outcome of DM in diabetics with CHC remains poorly controlled diabetes. He also noted higher mortality
unclear. compared to general population.
 834 Complications

Recent studies from India have shown that about • Pituitary and adrenocortical hyper-reactivity
18.4% (12.5–29.9%) of people with pulmonary TB (both • Vitamin D deficiency
smear-positive and smear-negative) have diabetes. Out Diabetic state usually improves with antituberculous
of the smear-positive group, diabetes prevalence is 23.5% drugs. But Rifampicin can produce alimentary glycosuria
(12.1–44%).65 and early phase hyperglycemia due to augmented glucose
Though chances of TB are higher in diabetes, infection absorption from the intestine as intravenous glucose
rate by Mycobacterium tuberculosis and tuberculin sen­ tolerance test (GTT) in normal.70
section

sitivity are not higher compared to non-diabetics.66 In active pulmonary TB immunoreactive insulin,
10

Higher sputum positivity, more incidences of lung C-peptide and glucose levels before and after glucagon
involvement, particularly cavitations than other lung injection demonstrated insulin deficiency.71 Anti­-tuber­
changes are noted. Though lower lobe involvement was culous therapy is also detrimental to insulin secretion
claimed to be more in diabetes in earlier reports, recent as reported by Egarova IL and suggests insulin therapy
always.72 Purified protein derivative of TB are also potent
observations are in consensus that distribution of lung
cytotoxic to islet cells.
affection are same as in non-diabetes (involving upper
Bacakoğlu F et al. (2000) studied 927 cases of culture
zone predominantly).67
positive TB and found DM in 12.3% persons.73 This study
Causes of increased susceptibility to TB in diabetes are
showed that DM does not alter the symptomatology, TB
as follows:
reactivity, rate of drug response, resistance or localization
• Neutorphilic dysfunction (discussed earlier)
of the lesion in upper or lower zones of lung. But in persons
• Lowered production of interleukin-1b and TNF-a from over 40 years and in female gender, lower lung field
monocytes, more so in poorly controlled groups. involvement is significantly high. Smear positive cases
• Thickened alveolar epithelium and pulmonary basal and radiologically reticulonodular appearance were less
lamina leading to reduction of lung diffusion capacity, in TB with DM than opacity, cavitation, pleural involve­
lung capacity and elastic recoil. ment. Cavitary lesions were higher in Type 1 DM than
• Reduced bronchial reactivity and dilation due to Type 2 DM.
diabetic autonomic neuropathy. Whereas in one series, 20% of patients with DM had
Bacteriological conversion, relapse rate are same with lower-lobe involvement,74 in other studies, lower-lobe
diabetics and non-diabetics. But relapse in diabetes is involvement was only seen in 1.8% (8 of 438 patients) and
mostly due to resistant strain and has poor prognosis.68 8.3% (1 of 12 patients).75,76 The older individuals are more
Correlation of relapse with diabetic control is still a likely to have lower-lobe involvement, and preferential
conflicting issue. changes in lower-lobe alveolar oxygen tension related to
age or DM has been suggested to favor lower lobe disease
Tuberculosis and Diabetes Mellitus in these groups.77,78 In most series, multilobar disease or
As diabetics are well-known to develop TB, TB affected the presence of multiple cavities was more common in
patients have also higher prevalence of DM with pre­va­ diabetic patients.79,80
lence rates varying from 1.9% to 41% in different studies.62 Although the cavitary lesions maintain high bacterial
Jawad et al. reported DM and impaired glucose population, less smear positivity is noted in diabetes
tolerance in 20% each amongst cases of TB.69 50% of them because this may be related to muscle weakness due to
recovered with antituberculosis therapy. Association bet­ uncontrolled glycemia and less effective expectoration.
ween diabetes and TB have been reported by different Higher frequency of lower lobe disease in elderly may be
investigators. due to immunological alteration or higher frequency of
Probable causes of higher prevalence of DM in TB primary TB, increased alveolar oxygen pressure in lower
• Reciprocal worsening of the two processes by each lobes.
other Mona Bashar found 36% cases to suffer from multi-
• Malnutrition and low BMI drug-resistant tuberculosis (MDR-TB) amongst diabetics
• Pancreatic TB in rare cases compared to 10% in non-diabetics (p < 0.01).81 Out of
• Stress-induced DM due to TB these 36%, 23% never received antitubucular drugs. Upper
 Chronic Infections and Diabetes Mellitus 835

Table 56.4: Incidence of diabetes mellitus in tuberculosis86 Table 56.5: Incidence of tuberculosis amongst diabetics86
Author Total Tuberculosis % Author % of diabetes Total cases
Himsworth 1938 230 6.8% Landis et al 1919 .017–0.33 68
Bencot et al. 1952 3,106 4% Weiner & Karea 14.2% 305
Neogi and Roy, 1952 1,862 3.3% Nichols 1957 11.0% 851
Turner & Warnick, 1957 1,851 1.8% Deshmukh, et al. 1966 14.0% 200

chapter
Deshmukh et al. 1966 241 8.35 Nanda & Tripathy 1968 12% 875

56
Dehmkar et al. 1975 400 7.8% Bahulkar 1975 4.5% 470
Bhatia 1975 14% 150

lobe cavitation or cystic changes were present in 95% Management Strategy in

than 94% cases of non-diabetic TB cases. 14% of diabetic Tuberculosis and Diabetes
group and 1% of non-diabetic group died of active TB.
Management requires some special alterations as follows:
Twenty percent of diabetic group had extrapulmonary
• Requirement of high calorie and high protein diet
TB than 5% of the non-diabetic group. The study strongly
(2,000–2,400 cal/day)
recommended DOT (directly observed therapy) therapy to
–– Compensate negative nitrogen balance
avoid MDR-TB by using at least four drugs while sensitivity
–– Prevent further infection or reactivation
report is awaited. If Rifampicin and INH resistance is –– Better insulin secretion
detected two new drugs including one injectable should • Problems with antitubercular drugs in DM
be recommended. –– Rifampicin
One hundred and ninety-two new patients (60 DMTB, ǃǃ Accenuates destruction of sulfonylurea by drug
132 TB) were regularly treated for a full course (≥ 6 interaction through P450 cytochrome oxidase
months) and prospectively followed for more than 1 year. enzyme
The DMTB patients had more severe infections (p < 0.01), ǃǃ Increases insulin requirement
higher mycobacterial loads (p < 0.01), higher treatment ǃǃ Augments intestinal glucose absorption
failure rates (17% vs 2%, p < 0.01) and longer delayed –– Isoniazid
clearance of mycobacteria than did the TB patients ǃǃ Antagonizes sulfonylurea action
(p < 0.01). After 1 year, three DMTB patients and one TB ǃǃ Rarely causes pancreatitis
patient had MDR-TB (5.0% vs 0.8%, p = 0.056). Bacterial –– Biguanides
genotyping revealed that the proportion of mycobacterial ǃǃ Loss of appetite and weight
strains was not significantly different in DMTB and TB ǃǃ Malabsorption of glucose
patients.82 • Choice of antidiabetic agents: Sulfonylurea and bigua­
nides have its real problems in TB. Moreover, to
In Hong Kong, in a 5-year study of 42 000 elderly
control diabetes in spite of high caloric intake and
individuals, the adjusted hazard of active TB was only
because of the possibility of pancreatic TB, pancreatic
present in those with HbA1c concentrations greater
secretagogues should be avoided. Insulin is the only
than 7%.83
mode of treatment effective for lowering any degree
The insulin dependence, as a marker for severity of of blood sugar within minimum time as a few days
disease, predicts increased TB risk because TB is more of hyperglycemia may affect the antituberculosis
common in Type 1 diabetes than Type 2 diabetes. In a response. Insulin also helps in inflammatory response
cohort of 1,529 diabetic individuals in Chile, the 10-year and healing process. Distribution of diabetes in TB
probability of developing TB was 24% in IDDM and 4.8% patients (Table 56.4) and TB in diabetic patients
in NIDDM.84 In a prospective study of diabetic patients (Table 56.5) studied before 1980 are as follows.86
followed for 1–7 years in Tanzania, 9.0% of patients with Anorexia, weakness, sweating and weight loss are
IDDM and 2.7% of patients with NIDDM developed com­mon to both TB and diabetes. So appearance of any
pulmonary TB.85 one illness over another is detected very late.
 836 Complications

Peculiarities of Tuberculosis in Diabetes rifampicin, ethambutol and pyrazinamide. But question

remains whether in the diabetic with extensive cavitary
In Diabetes, TB has got the following characteristics.
disease should an additional drug (possibly a quinolone
• Relative paucity of physical signs and diagnosis made like moxifloxacin) be added to the initial regime to rapidly
at far advanced stage reduce sputum AFB load?
• Extensive caseation of lung tissue and increased num­ Does DM raise the risk of treatment failure or death? In
ber of cavitary lesions (unilateral or bilateral) one study in Egypt, on 119 patients with treatment failure,
section

• Limited pleural involvement. diabetes conferred a 3.9 times increased risk of treatment
10

• Greater tendency of hemoptysis failure in patients receiving directly observed short-

• Less chance of extrapulmonary involvement and course therapy.94 A study from Indonesia showed 6-month
endobronchial TB. sputum cultures to be positive in 22.2% of patients with
• More cases of sputum positive disease. DM and in 6.9% of controls. These differences remained
The intensity of TB depends upon the duration of after adjustment for age, sex, body mass index and other
diabetes in uncontrolled stage and if diabetes is controlled factors.95
judiciously, response of TB is same as in non-diabetic Two retrospective cohort studies of patients with pul­
groups. It has been reported that patients with both monary TB in USA, have shown a 6.5–6.7 times increased
diabetes and TB usually have a prolonged duration of fever risk of death in diabetic patients compared to non-diabetic
and more significant weight loss with coexistent disease controls.96,97 In a study by Wang and colleagues,66 1-year
than with diabetes or pulmonary TB alone.87 all-cause mortality was 17.6% in diabetic patients versus
7.7% in non-diabetic controls, and death specifically attri­
Problems Arising during butable to pulmonary TB was significantly more common
Treatment of DM and TB in diabetic patients (12.2% vs 4.2%). These studies suggest
that treatment failure and death are more frequent in
Given the risk of peripheral neuropathy, pyridoxine
diabetic patients. However, whether aggressive manage­
should be given with isoniazid during TB treatment in
ment of DM would improve treatment response remains
diabetic patients.88 In patients with Type 1 DM, insulin
unclear.
requirements might increase when on rifampicin.89 Just
as TB drug treatment affects diabetes treatment, diabetes
Preventive Management
might alter the pharmacokinetics of antituberculosis
drugs. The diabetic patients with TB had rifampicin serum • Persons who were MT-negative and have recent
concentrations that were 53% lower than in non-diabetic conversion to tuberculin test should have INH pro­
patients with TB and there was an indirect relation between phylaxis, if they are in close contact with an infective
fasting glucose and rifampicin concentrations.90 Diabetes case.
can also cause changes in oral absorption, decreased • All diabetics at the initial diagnosis and every year
protein binding of drugs and renal insufficiency or fatty must have X-ray chest done.
liver with impaired drug clearance.91 • All diabetics with abnormal weight loss, unexplained
cough or sudden increase of insulin requirement
Treatment Failure and Death should have sputum examination and chest X-ray.

Usually it is thought that diabetics have a higher incidence PERIODONTAL DISEASE AND DM
of antituberculosis drug resistance.92
Condos et al. found that there was a significant asso­ Periodontitis or infection of the anchoring tissues surro­
ciation between diabetes and MDR-TB. A greater sus- unding the teeth is usually due to anaerobic Gram-
picion for MDR-TB should be entertained in diabetic negative organisms. Poorly controlled diabetics are likely
patients. But one recent study found no significant to develop this chronic infection as periodontal disease
difference in the incidence of MDR-TB in their diabetic- (PD) and in turn, this has the potential to alter blood sugar
TB population.93 control as well.
At present initial treatment would include the standard Periodontal disease consists of six categories:
four drug regimen with isoniazid along with pyridoxine, • Gingival disease—the most common form
 Chronic Infections and Diabetes Mellitus 837

• Chronic periodontitis increasing both in the general population and HIV-

• Aggressive periodontitis infected population in a similar way. In June 1997, soon
• Periodontitis as a manifestation of systemic disease after introduction of protease inhibitors (PI), as part
• Necrotizing periodontal disease of highly active anti-retroviral therapy (HAART), Food
• Periodontal abscess. and Drug Administration (FDA) issued a warning for
Chronic PD is a slowly progressing disease and remains increasing cases of hyperglycemia with HAART.
undetected for long time. For this reason, regular dental

chapter
check up is necessary for diabetic persons. It has been Epidemiology

56
postulated that subgingival bacterial content are higher
The prevalence of frank DM in people with HIV is low
in DM, leading to more severe disease. This is equally
with study reports from 0.5% to 15%. But IGT is much
true of Type 1 and Type 2 disease but is dependent upon
higher as estimated to be 15–25%. Some degree of insulin
glycemic control. Regardless of the usual causes of higher
resistance is also noted up to 50% cases on PI therapy.102
infection rate in DM, the effect of interaction between
Coinfection with HCV is found in 40% cases of HIV-
AGE monocytes and its receptor (RAGE) results in chronic
positive persons and is more likely to develop DM or
monocyte release of proinflammatory cytokines like IL-1b,
insulin resistance. S Mehta et al. observed that HCV-
TNF-a and IL-6 with resultant matrix metalloproteinases
positive people are four times more likely to develop Type
leading to bone destruction.98
2 DM than HCV-negative persons but no association
Alteration in both neutrophilic cellular and colla-
genase activity by degrading newly formed collagen impair with hepatitis B was found. If HCV infection occurs in
wound healing in diabetes. In Type 1 DM there is increased HIV-positive cases, the risk of developing hyperglycemia
risk of PD with age, duration of DM and glycemic control becomes five times.103 Elevated levels of ALT liver enzyme
when compared to non-diabetics. is an indicator for liver inflammation and predicts insulin
Also, compared to non-diabetics, high incidence of PD resistance in HIV cases with lipodystrophy in presence
was seen amongst Pima Indians with Type 2 DM.99 Severe or absence of hepatitis B and C. Whether HIV-related
degree of PD is also associated with higher risk of diabetic hyperglycemia will have a negative impact on diabetes-
complications like proteinuria, stroke, angina, myocardial related complications remains unknown, however, it may
infarction and heart failure than in diabetic patients with be expected that progression of disease will be similar to
mild PD.100 HIV-negative cases with hyperglycemia.
When treatment of PD with ultrasonic scaling alone The risk factors contributing to the development
or combined with doxycycline was given, significant of metabolic syndrome in such patients are advancing
reduction of HbA1c was noted after 3 months, more in the age, male gender, longer duration of HIV infection, low
doxycline treated group. The effects of doxycline probably CD4 count, high viral burden, high body mass index,
were due to altered host response by inhibition of protein greater waist circumference or waist-to-hip ratio, lower
kinase C and prevailing excess of IL-1b and TNFa.101 On socioeconomic class and certain ethnic backgrounds
the reverse good diabetic control accelerated response to or culture.104,105 HIV-infected subjects with metabolic
treatment for PD. syndrome show disturbances in inflammation and adi­
Finally it can be accepted that, periodontopathic pokines: they have higher CRP (5.5 ± 7.0 vs 3.9 ± 6.0
bacteria increases cytokine release, which may amplify mg/L, P < 0.003) and leptin (9 ± 9 vs 4 ± 6 ng/mL, P <
AGE-mediated cytokine response and vice versa. Thus 0.0001) and lower adiponectin (12 ± 8 vs 15 ± 10 μg/mL,
PD either precipitates or aggravates the diabetic process P < 0.0001) levels. This may contribute to the pathogenesis
and its complications, and PD and DM enjoy a two-way of diabetes.3 Viral factors which contribute to diabetes
relation. Proper dental health is another avenue to diabetic risk are an increase in viral burden of 0.5 log over a
control. 6-month period, a lower CD4 count and longer duration
of HIV infection.104
HIV INFECTION AND DIABETES One interesting fact is that HAART therapy in child­-
ren rarely leads to the development of insulin resistance
Insulin resistance and its clinical associates like DM, like adults, however, it does result in elevated serum fat
impaired glucose tolerance (IGT) and dyslipidemia are levels. Living long with HAART therapy a HIV person can
 838 Complications

acquire DM as age-related problem like other disease.106 NRTI Treated Cases

Common causes of insulin resistance in HIV infection as
No change with blood glucose and lipid are observed
follows (Table 56.6).
with NRTI therapy. The observations with PI therapy are
The patients with diabetes and HIV can be divided
as follows106 (Table 56.7).
in three subgroups: Patients with pre-existing diabetes
Among the PIs, Indinavir, stavudine, zidovudine and
who contract HIV, those who are diagnosed to have
diabetes at onset of HIV infection and others who develop didanosine108 are strongly related to glucose intolerance
section

hyperglycemia after start of therapy. These subgroups and insulin resistance has been detected within
10

need to be managed differently, as the mechanisms of 2–8 weeks of treatment even in HIV-negative persons.
metabolic alteration vary in them. The incidence of diabetes increases with cumulative
exposure to combination ART. All PIs do not have the
Protease Inhibitor Therapy same metabolic effects. Indinavir precipitates insulin
resistance without any effect on lipid metabolism, whereas
Protease inhibitor (PI) therapy directly affects blood lopinavir and ritonavir increase fasting triglycerides and
glucose metabolism due to alteration of body fat gain or free fatty acids, but do not worsen insulin sensitivity.
loss. Indinavir and ritonavir both block glucose transporter
Kathelien Mulligan et al. compared treatment of 20 type 4 (GLUT-4), but amprenavir and atazanzvir do not
HIV-positive cases with PI, nine cases with nucleoside block the GLUT-4. Some degree of alterations in first phase
reverse transcriptase inhibitors (NRTI) and 12 cases with insulin release with a 25% reduction in β-cell dysfunction
no antiretroviral therapy and observed as follows.107 is seen in patients treated for 12 weeks with nelfinavir,
indinavir, liponavir or saquinavir.109,110 The other class of
Protease Inhibitor Treated Cases drugs which is used is the nucleoside analogs (reverse
Features of insulin resistance seen were as follows: transcriptase inhibitors) (NRTIs). In contradiction to
• Elevated fasting insulin and blood glucose, increased earlier thoughts that NRTIs were less likely to cause
triglyceride and low-density lipoprotein (LDL) metabolic abnor­malities, a recent study, which analyzed
• Signs of insulin resistance after an average of 3.4 130, 151 person years of follow-up has shown that these
months without change in body shape in this duration. drugs, too, increase the risk of diabetes.108
Pentamidine, used to prevent and treat P. carinii
associated pneumonia, may cause β-cell toxicity, with
Table 56.6: Common causes of insulin resistance in HIV infection acute hypoglycemia followed by later diabetes. This risk of
• Protease inhibitors (PI) therapy
hypoglycemia depends upon the longer and higher dosage
of pentamidine and presence of renal insufficiency.111
• Lipodystrophy
The probable mechanisms for PI induced blood
• Increased local or systemic inflammatory mediators
glucose abnormalities are:106
• Hepatic lipid accumulation
• Reduced peripheral uptake by interfering with GLUT-
• Muscle lipid accumulation
4 activity in the fat and muscle cells up to 26–45% in
• Hepatitis C infection
pharmacologic dose, within minutes and reversed
• Reduced systemic adiponectin, leptin and increased resistin
after withdrawal which may lead to fat loss in limbs
• Low testosterone
and face.

Table 56.7: Other Observations with PI therapy106

Investigators IGT DM Altered Insulin sensitivity
George Behren Rabi Walli, et al. 46% 13% 61%
Goefel F, et al. 55% with PI, 27% with NRTI
WIHS report 2.8 cases per 100 persons years 1.4 cases per 100 persons years on NRTI developed DM also

(DM: Diabetes mellitus; IGT: Impaired glucose tolerance; NRTI: Nucleoside reverse transcriptase inhibitors).
 Chronic Infections and Diabetes Mellitus 839

• Diminished b-cell secretion due to failure to recognize Other Causes for DM

hyperglycemia as GLUT-2, which transports glucose
Human immunodeficiency virus-induced b-cell damage
inside b-cell, are suppressed by PIs and fasting blood
has been thought of but not supported by reasonable
glucose remains high.
experiments. Higher level of cortisol, a hormone seen
• Increased hepatic glucose output by about 47% within
during stress and chronic illness was thought to be a
4 weeks of Indinavir therapy due to increase in both
contributing factor but ruled out in recent experiments.
glycogenolysis and neoglucogenesis.

chapter
HAART therapy produces immune recovery and increased
• Suppression of adipocyte differentiation, defective
numbers of TNF receptors have been observed in HIV-

56
expression of PPAR-g receptors.
positive cases. Mynarcik et al. demonstrated elevated
TNF receptors to be associated with insulin resistance in
Blood Glucose and Lipodystrophy HIV-positive cases.114 Imbalance in other cytokines like
Loss of peripheral fat and gain in visceral or abdominal interleukin (IL)-1, IL-6, IL-10 may also contribute to blood
fat is known to be associated with insulin resistance. glucose abnormality.113 He also observed changes with
The lipodystrophic changes like loss of fat from face and adipocyte hormones, high level of resistin and low levels
limbs are also present in HIV-positive cases, more so on of leptin and adiponectin in cases of lipodystrophy in HIV-
PI treatment.112 Insulin resistance amongst PI therapy positive cases.
is more prevalent in cases with buffalo hump (with fat Recently Natasha M et al. reported resolution of DM
accumulation at the back of neck). Hadigan et al, evaluated after initiation of antiretroviral therapy in two HIV infected
metabolic and clinical features of 71 HIV-infected patients patients, one treated with PIS, another with NNRTI.
with lipodystrophy by comparing them with 213 healthy Probably HIV may directly damage b-cell or produce
control subjects from the Framingham Offspring Study. insulin resistance by cytokines, hormonal disturbances or
This study also included 30 HIV-infected patients without unknown mechanisms.115
fat redistribution who were separately compared with 90
matched control subjects from the Framingham Offspring Type of Diabetes
Study. Data from this study suggests that fasting and post- Impaired glucose tolerance and insulin resistance usually
glucose challenge hyperinsulinemia is more significant precede weight loss in patients with HIV.116 Insulin
in HIV-infected patients with lipodystrophy. Further, this resistance, rather than insulin deficiency, is usually more
study revealed multiple metabolic abnormalities among involved in the pathogenesis of diabetes in HIV-infected
HIV-infected patients with fat redistribution including patients. Evidence of islet cell autoimmunity or β-cell
hyperinsulinemia, hypercholesterolemia, hyper­trigly­ceri­­ destruction has not been reported in HIV patients.117
demia, reduced HDL and truncal obesity. This cluster Autoimmune diabetes has been reported to develop in
of metabolic abnormalities indicates significant insulin some HIV-infected patients after immune restoration
resistance syndrome in HIV-infected patients with during HAART. Three Japanese patients presenting with
lipodystrophy.113 Hadigan et al. found insulin resistance diabetes after receipt of HAART have been shown to
in men with AIDS-related wasting syndrome treated with develop antibodies to glutamic acid decarboxylase, at a
NRTI but not PI. time when CD4 counts shot up suddenly. Hypothetically
it could be postulated that recovery of immune function
Fatty Acid Metabolism predisposes to autoimmune disease, in the form of Type 1
diabetes.118 The type of diabetes associated with HIV may
High blood level of free fatty acids related to visceral fat
be classified as Type 2 DM, rather than Type 1 DM, in the
accumulation and peripheral fat loss interfere with glucose
vast majority of patients.
metabolism and produce insulin resistance. Hadigan
et al. found that HIV-positive cases receiving antiretroviral
therapy had heightened fasting lipolysis which was
Diagnosis and Monitoring of
aggravated after glucose administration (opposite in DM in HIV-Positive Cases
normal persons).113 This indicates presence of higher free Fasting blood glucose, 2 hours after 75G glucose test and
fatty acids and insulin resistance also but not completely fasting serum insulin level can be estimated to assess
excluding role of other factors. the abnormality in most of the cases. International AIDS
 840 Complications

society recommends (2002 guidelines) fasting blood trained regarding the disposal of lancets, glucose strips,
glucose before HAART, 3–6 months after drugs and at insulin syringes, pens and needles to prevent HIV
least annually on PI therapy. For persons with high risk for transmission.
IR, oral glucose tolerance test (OGTT) may be performed.
They do not recommend insulin estimation. Drug Interactions between HAART and OHA
Avoid metformin in patients receiving NRTI (especially
Management of Blood Glucose Changes d4T and ddI) as both precipitate lactic acidosis and more
section

Options so in HIV-positive patients with gross weight loss.

10

Avoid thiazolidinediones in cases with liver damage

1. Lifestyle changes
due to associated hepatitis B or hepatitis C. Fluid overload
2. Substitution of PIs by other antiretroviral drugs if pos­
with pioglitazone should be considered in AIDS patients
sible (e.g. nevirapine or efavienz or abacavir for PIs)
with cardiac and renal compromise. Insulin is reserved
3. Antidiabetic drugs as used in HIV-negative cases, usually
for severe cases of Type 2 DM or adverse situations with
do not require insulin therapy.
OHA, though if started earlier remission of DM is more
frequent.
Oral Hypoglycemic Agents (OHA) In conclusion, diabetic patients are at higher risk for
If lifestyle modification is not adequate or substitution of acquiring HIV infection because of multiple needle pricks
PIs is not possible antidiabetic drugs, e.g. metformin and if improperly sterilized or recycled needles are used.
thiazolidinediones are of choice to control the glycemic Diabetics can also contract HIV from multiple surgical
state. Both of these drugs alone or in combination have interventions or dialysis and blood transfusion when
their effect on improvement in insulin resistance, body fat chronic renal failure develops.
distribution, free fatty acids and lipid profile in HIV-positive Whether HIV infections alone like HCV infection
cases. Sulfonylureas which worsen hyperinsulinemia can produce DM or IGT is not yet clear but it is proved
and produce drug interaction with HAART are better beyond doubt that HAART regimen particularly Indinavir
avoided. Insulin can be used according to the need of the is definitely correlated. Lipodystrophy-associated insulin
situation. Metformin improves insulin sensitivity and is resistance and PI-associated insulin resistance when com­
the first-line drug of choice in most persons with Type 2 pared, the former is more contributory and irreversible
DM, but should be used with caution in HIV because it is than the latter one. The risk of acquiring DM in HIV-
not well tolerated by cachexic patients, is more likely to positive cases is more with HCV infections, obesity and
cause diarrhea than other drugs and is contraindicated genetic background. Screening for DM should be done
in renal or hepatic dysfunction and may lead to cause with PI therapy and more frequently in high risk cases.
lactic acidosis. When it is in combination with drugs Lifestyle modification is the treatment of choice, and
such as stavudine, the risk of lactic acidosis is increased; metformin or glitazones can be added subsequently.
however, it is not the same when metformin is combined
with abacavir, lamivudine and tenofovir.119 For the RHINOCEREBRAL MUCORMYCOSIS
thiazolidinediones the possibility of a slight increase in
subcutaneous fat makes them the preferred drug class Fifty percent cases of rhinocerebral mucormycosis occurs
in patients with lipodystrophy.120 Insulin secretagogues in a diabetic person and it is a life threatening infection.
such as nateglinide, repaglinide, glimepiride, gliclazide, It can flare in a person chronically infected with the
glibenclamide are safe, but may be ineffective in the face fungus, Rhizopus oryzae. During diabetic ketoacidosis
of severe insulin resistance. the inhibitory effect of serum passes away and the disease
Insulin is the drug of choice for management of dia­ flares. But this inhibitory effect is restored after correcting
betes with HIV because it has an anabolic effect, reduces acidosis.122
inflammatory markers, such as TNF-α, has no interactions Early manifestations are facial, ocular or nasal pain
with antiretroviral or other drugs, is not contraindicated with nasal stuffiness and discharge. Subsequent manifes­
with renal or hepatic dysfunction, does not reduce tations are proptosis, chemosis, necrotic black lesions on
appetite or cause gastrointestinal side effects, can correct palate or nasal mucosa, fever, headache, ophthalmoplegia
both insulin deficiency and resistance when given in and visual loss from caverous sinus thrombosis. Hemi­
appropriate doses, and does not increase the risk of paresis may be seen due to thrombosis of carotid artery or
cardiovascular disease.121 HIV-infected patients should be jugular vein.
 Chronic Infections and Diabetes Mellitus 841

For diagnosis, biopsy of necrotic tissue from the drainage or nephrectomy are the modalities of treatment.
nasal passages or palate demonstrating broad, non-sep­ Chronic fungal UTI particularly due to candidiasis is also
tate, haphazardly branching hyphae invading tissue is common in diabetes. It can involve both upper and lower
required. MRI is essential to identify extent of involve­ urinary tracts. Affection localized to the bladder may be
ment. Surgical debridement of infected tissue, drainage of also due to colonization rather than infection but pyuria
the sinuses with amphotericin B injection is the choice of supports the later. Indwelling catheter, if any, should be
therapy. removed. Bladder irrigation with amphotericin B (single

chapter
dose) or oral fluconazole for 4 days is the treatment of

56
CHOLECYSTITIS choice.123

Chronic cholecystitis with or without cholelithiasis is Chronic foot Infections

very common in diabetes, probably because of super­
saturation of bile, chronic infection, impaired gallbladder This is a frequent complication and most neglected
motility, decreased cholecystokinin release and hepatic issue by both the patient and treating physician. This is
impairment. Emphysematous cholecystitis, an uncom­- discussed in a separate chapter (Chapter No. 62).
mon gas producing virulent infection is similar to acute
FUNGAL INFECTIONS IN DIABETES
cholecystitis, but more frequent in males, with higher
mortality due to gangrene or perforation. Thirty- five percent These are very common but most neglected infections
of cases occur in diabetes and 50% contain gallstone. presenting as oropharyngeal candidiasis, candidial valvo­
Crepitus on abdominal palpation, demonstration of gas vaginitis (a common mode of presentation in Type 2 DM),
in X-ray or CT scan helps in diagnosis. Prompt cholecys­ intertriginous candidiasis leading to gangrene of foot and
tectomy with broad spectrum antibiotics like Ampicillin- paronychia.
Sulbactam 3G intravenously every 6 hours are the Infections strongly associated with DM are as follows:
choice of treatment.58 AK Agarwal et al. (2004) from India • Group B streptococcal bacteremia
studied 91 cases of diabetes for gallbladder function • Klebsiella infections
by ultrasonography (USG). Both increased fasting gall­ • Liver abscess
bladder volume and deceased ejection function of • Endophthalmitis
gallbladder were correlated with autonomic neuropathy. • Thyroid abscess
Gallbladder volume showed positive correlation with • Salmonella enteritidis
BMI, age, LDL cholesterol.123 • Tuberculosis
• Hepatitis C
CHRONIC PYELONEPHRITIS AND CYSTITIS • Candidiasis
Chronic urinary tract infection (UTI) is 2–4 times common Prevention of Infections in Diabetes
in diabetes, particularly in women and in the presence
of autonomic neuropathy and retained bladder. Bilateral The methods required for the prevention of infections in
infection is also seen more with diabetes. Emphysematous diabetes are as follows:
pyelonephritis is a severe infection of the renal paren­ • Maintenance of good hygiene
chyma that causes gas accumulation in the tissues and • Standard immunization
it may be life-threatening. More than 90% of these cases • Frequent check-up
are seen in diabetics. It is produced by gas forming orga­ • Foot care
nisms, E coli in 50–70% cases and is complicated by papi­ • Antibiotics usage; catheterization, IV lines with proper
llary necrosis in 21% of cases.122 care.
If there is failure of remission of fever with therapy
SUMMARY
for UTI after 3–4 days in a diabetic, possibility of emphy­
sematous pyelonephritis and perinephric abscess should • Diabetes mellitus is often complicated by acute or
be considered. Abdominal CT is better than other radio­ chronic infections, as it is a secondary immune defi­
logical methods for diagnosis. Vigorous hydration and ciency disorder. DM produces immune alterations of
intravenous antibiotics with percutaneous CT-guided both cellular and humoral type.
 842 Complications

• Common infections in diabetes are TB, pylonephritis, of Diabetes Mellitus. 2nd edition, volume 2. In: Alberti KG,
Staphylococcal infections, cholecystitis, candidiasis, Zimmet P, DeFronzo RA, et al. (Eds). John Wiley & Sons;
1997. pp. 1231-41.
viral hepatitis, etc.
4. Gin H, Brottier E, Aubertin J. Influence of glycaemic
• Hepatitis C and diabetes are very commonly asso­ normalization by an artifical pancreas on phagocytic and
ciated. Hepatitis C may be an etiological agent for bacterial functions of granulocytes in insulin-dependent
DM. Hyperglycemia also leads to advanced fibrosis in diabetic patients. J Clin Pathol.1984;37:1029-31.
hepatitis C. 5. Drell DW, Notkins AL. Multiple immunological abnormali­
section

• Tuberculosis in DM is 2–5 times higher. Chances ties in patients with type 1 (insulin-dependent) diabetes
mellitus. Diabetologia. 1987;30:132-43.
10

of recurrence with multidrug resistant bacteria are 6. Pozzilli P, Arduini P, Visalli N, et al. Reduced protection
common. More cavitary lesions, less sputum positivity against hepatitis B virus following vaccination in patients
and relative paucity of symptoms and signs are the with type 1 (insulin dependent) diabetes. Diabetologia.
features. DM with TB should be treated with insulin. 1987;30:817-9.
• Periodonitis is a complication of DM and DM may 7. Hoddinott S, Dornan J, Bear JC, et al. Immunoglobulin
levels, immunodeficiency and HLA in type 1 (insulin
develop from periodontitis. Proper dental care should
dependent) diabetes mellitus. Diabetologia.1982;23:326-9.
be a part of diabetes control. 8. Vergani D, Johnston C, B-Abdullah N, et al. Low serum
• Protease inhibitor therapy in HIV infection can lead to C4 concentrations: an inherited predisposition to insulin
development of insulin resistance. But whether HIV dependent diabetes? Br Med J.1983;286:943-8.
produces b-cell damage is not known. HIV and DM 9. Allison ME, Wreghitt T, Palmer CR, et al. Evidence for a link
between hepatitis C infection and diabetes mellitus in a
may be complicated by HCV infections.
cirrhotic population. J Hepatol. 1994;21:1135-9.
• Rhinocerebral mucormycosis, cholecystitis, chronic 10. Amarapurkar D, Das HS. Chronic liver disease in diabetes
urinary tract infection and candidiasis are other mellitus. Trop Gastroenterol. 2002;23:3-5.
common chronic infections in DM. 11. Wang CS, Wang ST, Yao WJ, et al. Community-based
study of hepatitis C virus infection and type 2 diabetes: an
FURTHER READING association affected by age and hepatitis severity status. Am
J Epidemiol. 2003;158:1154-60.
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of HIV-infected women. J Acquir Immune Defic Syndr. with chronic hepatitis C. Dig Dis Sci. 2002;47:710-5.
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u bol’nykh tuberkulezom legkikh I sakharnym diabetom monary tuberculosis. Am Rev Respir Dis.1973;108:1164-69.
[The incretory function of the pancreas in patients with pul­ 90. Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure to
monary tuberculosis and diabetes mellitus’. Probl Tuberk. rifampicin is strongly reduced in patients with tuberculosis
1991;9:36-8. and type 2 diabetes. Clin Infect Dis. 2006;43:848-54.
 Chronic Infections and Diabetes Mellitus 845

91. Gwilt PR, Nahhas RR, Tracewell WG. The effects of diabetes independent of changes in body composition in patients
mellitus on pharmacokinetics and pharmacodynamics in with HIV infection. J Acquir Immune Defic Syndr. 2000;23:
humans. Clin Pharmacokinet. 1991;20:477-90. 35-43.
92. Bashar M, Alcabes P, Rom WN, et al. Increased incidence 108. De Wit S, Sabin CA, Weber R, et al. Incidence and risk
of multidrug-resistant tuberculosis in diabetic patients on factors for new-onset diabetes in HIV-infected patients.
the Bellevue Chest Service 1987 to1997. Chest. 2001;120: The data collection on adverse events of anti-HIV Drugs
1514-9. (D:A:D). Study Diabetes Care .2008;31:1224-9.
93. Singla R, Khan N, Al-Sharif MO, et al. Influence of diabetes 109. Woerle HJ, Marivz PR, Meyer C, et al. Mechanisms for the

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on manifestations and treatment outcome of pulmonary deterioration in glucose tolerance associated with protease

56
TB patients. Int J Tuberc Lung Dis. 2006;10:74-9. inhibitor regumem. Diabetes. 2003;52:918-25.
94. Morsy AM, Zaher HH, Hassan MH, et al. Predictors of treat­ 110. Lee GA, Rao M, Greenfeld C. The effects of HIV protease
ment failure among tuberculosis patients under DOTS inhibitors on carbohydrate and lipid metabolism. Curr In­
strategy in Egypt. East Mediterr Health J. 2003;9:689-701. fect Dis Resp. 2004;6:471-82.
95. Alisjahbana B, Sahiratmadja E, Nelwan EJ, et al. The effect 111. Bouchard PH, Sai P, Reach G, et al. Diabetes following
of type 2 diabetes mellitus on the presentation and treat­ pentamidine-induced hypoglycemia in humans. Diabetes.
ment response of pulmonary tuberculosis. Clin Infect Dis. 1982;31:40-5.
2007;45:428-35. 112. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, pre­
96. Dooley KE, Tang T, Golub JE, et al. Impact of diabetes diction, and natural course of HIV-1 protease-inhibitor-
mellitus on treatment outcomes of patients with active associated lipodystrophy, hyperlipidaemia, and diabetes
tuberculosis. Am J Trop Med Hyg. 2009;80:634-39. mellitus: a cohort study. Lancet. 1999;353:2093–99.
97. Oursler KK, Moore RD, Bishai WR, et al. Survival of patients 113. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnor­
with pulmonary tuberculosis:clinical and molecular epide­ malities and cardiovascular disease risk factors in adults
miologic factors. Clin Infect Dis. 2002;34:752-9. with human immunodeficiency virus infection and lipo­
98. Lalla E, Lamster IB, Schmidt AM. Enhanced interac­ dystrophy. Clin Infect Dis. 2001;32:130-9.
tion of advanced glycation end products with their cel­ 114. Mynarcik DC, McNurlan MA, Steigbigel RG, et al. Asso­
lular receptor RAGE: implications for the pathogenesis of ciation of severe insulin resistance with both loss of limb
accelerated periodontal disease in diabetes. Ann Perio­ fat and elevated serum tumor necrosis factor receptor
dontol.1998;3:13-9. levels in HIV lipodystrophy. J Acquir Immune Defic Syndr.
99. Pucher J, Stewart J. Periodontal disease and diabetes mel­ 2000;25:312-21.
litus. Curr Diab Rep. 2004;4:46-50. 115. Natasha M, Julio SG Montaner, Gregory Bondy. Resolution
100. Thorstensson H, Kuylenstierna J, Hugoson A. Medical
of diabetes after initiation of antiretroviral therapy in two
status and complications in relation to periodontal disease human immunodeficiency virus-infected patients. Endo­
experience in insulin dependent diabetics. J Clin Periodon­ crine Practice. 2004;10:199-201.
tol.1996;23:1994-202. 116. Mondy K, Oovertan ET, Grubb J, et al. Metabolic syndrome
101. Grossi SG, Skrepcinski FH. Treatment of periodontal
in HIV-infected patients from an urban, Midwestern US
disease in diabetics reduces glycated hemoglobin. J Peri­ outpatient population. Clin Infec Dis. 2007;44:726-34.
odontol.1997;68:713-9. 117. Dagogo-Jack S. HIV therapy and diabetes risk. Diabetes
102. Dubé MP. Disorder of glucose metabolism in patients
Care. 2008;31:1267-8.
infected with human immunodeficiency virus. Clin Infect 118. Takarabe D, Rokukawa Y, Takahashi Y, et al. Autoimmune
Dis. 2000;31:1467-75. diabetes in HIV-infected patients on highly active antiretro­
103. Mehta SH, Moore RD, Thomas DL, et al. The effect of viral therapy. J Clin Endocrinol Metab. 2010;95:4056-60.
HAART and HCV infection on the development of hyper­ 119. Kohli R, Shevitz A, Gorbach S, et al. A randomized placebo-
glycemia among HIV-infected persons. J Acquir Immune controlled trial of metformin for the treatment of HIV lipo­
Defic Syndr. 2003;33:577-84. dystrophy. HIV Medicine. 2007;8:420-6.
104. Fichtenbaum CJ, Hadigan CM, Kotler DP, et al. Treating 120. Schambelan M, Benson CA, Carr A, et al. Management
morphologic and metabolic complications in HIV-infected of metabolic complications associated with antiretroviral
patients on antiretroviral therapy. IAPAC Monthly. 2005. therapy for HIV-1 infection:recommendations of an Inter­
pp. 38-46. national AIDS Society-USA Panel. J Acquir Immune Defic
105. Norris A, Dreher HM. Lipodystrophy syndrome: the
Syndr. 2002;33:257-75.
morphologic and metabolic effects of antiretroviral therapy 121. Rao PV. Persons with type 2 diabetes and co-morbid active
in HIV infection. J Assoc of Nurses in AIDS care. 2004;15: tuberculosis should be treated with insulin. Int J Diab Dev
46-64. Countries. 1999;19:79-86.
106. Liz Highleyman. Insulin Resistance and Diabetes. Bulletin 122. Joshi N, Caputo GM, Weitekamp MR, et al. Infections in
of Experimental Treatments for AIDS. Winter 2003/2004. A patients with diabetes mellitus. NEJM. 1999;341:1906-12.
Publication of the San Francisco AIDS Foundation. 123. Agarwal AK, Miglani S, Singla S, et al. Ultrasono­graphic
107. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia evaluation of gallbladder volume in Diabetics. JAPI. 2004;
and insulin resistance are induced by protease inhibitors 52:962-5.
 Chapter 57
Macrovascular Disease in Diabetes:
Determinants and Pathogenesis
Sidhartha Das

Macrovascular Disease: Pathogenesis

Chapter Outline
♦♦ Burden of Macrovascular Disease in Diabetics ♦♦ Pathogenesis and Determinants of Macrovascular
♦♦ Distribution and Profile of Atherosclerosis in Diabetics Disease
versus Non-diabetics

INTRODUCTION non-diabetics. Such association envisaged the role of

chronic hyperglycemia to be the likely determinant for
The post-insulin era achieved control over acute compli­
developing excess of MVD. Furthermore most other gene­
cations and infections in patients with diabetes mellitus
tic, hormonal and metabolic parameters, thought to be
(DM). Since then macrovascular disease (MVD) emerged
risk factors (RF) or determinants for AS, are dissimilar in
as the most prevalent complication amongst diabetics in
these two protean types of DM. Prospective studies and
the West. Almost two-thirds of deaths in diabetics are due retrospective analyses in families with type 2 diabetes
to coronary artery disease (CAD), cerebrovascular disease had revealed that MVD foreruns the overt development
(CVD) or peripheral vascular disease (PVD). The problem of chronic hyperglycemia by decades, further suggesting
although more marked with type 2 diabetics is also a a likelihood of AS and DM sharing a “common soil” for
major cause of morbidity and mortality in type 1 diabetics, their genesis.
therefore the American Heart Association has designated Studies from USA and other Western countries had
DM as a major risk factor for cardiovascular disease.1 shown that CAD, both chronic stable angina and acute
Studies from the United Kingdom Prospective Diabetes coronary syndrome (ACS), congestive heart failure and
Study (UKPDS) have revealed that patients with type PVD are the most common morbidities associated with
2 DM have a two to three-fold increase in diseases related DM. The situation in Indians is different as compared
to atheroma. Besides, those diabetic subjects who develop to the West because the four major RF for CAD viz.
atheroma related disease in the age range of 40–50 years hypercholesterolemia, hypertension, DM and cigarette
of age, have a two-fold higher rate of mortality.2 smoking are not very prominent among Indians with CAD
as compared to the Framingham cohorts. However, MVD
BURDEN OF MACROVASCULAR is one of the most established complications in diabetics
DISEASE IN DIABETICS in India and further there is steady rise in the incidence
Atherosclerosis (AS) is more prevalent in subjects with of CAD amongst the urban population as well as amongst
DM and the quantum of involvement of vascular channels diabetics (Tables 57.1 and 57.2). The prevalence of PVD
is more profound in diabetic subjects as compared to is much less amongst Indians as compared to diabetics
 Macrovascular Disease in Diabetes: Determinants and Pathogenesis 847

Table 57.1: Prevalence of CAD in urban and rural India Table 57.2: Prevalence of coronary artery disease amongst diabetics
Author Year Place CD (%+SD) in India

URBAN POPULATION Author Year Place Prevalence

of CAD (%)
Mathur KS 1960 Agra 1.05 + 0.3
ICMR 1984–87 Multicentric 8.1% Males
Padmavathi 1962 Delhi 1.04 + 0.3
4.7% Females
Sarvotham SG 1968 Chandigarh 6.60 + 0.6
Mohan V 2001 Chennai 21.4%

chapter
Gupta SP 1975 Rohtak 3.63 + 0.5
Gupta PB 2001 Surat 19%

57
Chaddha SL 1990 Delhi 9.67 + 0.3
Gupta S 2001 Nagpur 33.5% Males
Shety KS 1994 New Delhi 10.9
21.5% Females
Gupta R 1995 Jaipur 7.59 + 0.6
Phatak SR 2002 Ahmedabad 20.2% Males
Singh RB 1995 Moradabad 8.55 + 2.3
26.1% Females
Begom TR 1995 Trivandrum 12.65 + 1.5
Source: Das S, Misra TK. Diabetes, lipids and coronary artery disease
Ramachandran 2001 Chennai 3.9
in Indians. In: Gupta SB, (Ed). Medicine Update. The Assoc Physi-
Mohan V 2001 Chennai 11 cians India: Mumbai; 2005. pp. 227-33.
Gupta R 2002 Jaipur 7.30
RURAL POPULATION Table 57.3: Prevalence of peripheral vascular disease in diabetics
Dewan BD 1974 Haryana 2.06 + 0.4 Authors Country Year Prevalence
Jajoo UN 1988 Vidarbha 1.69 + 0.3 ICMR (Multicentric-9 centers) India 1984–87 0.8%
Kutty VR 1993 Kerala 7.43 + 0.8 Mohan V, Premlatha G et al. India 1995 3.9%
Wander GS 1994 Punjab 3.09 + 0.5 Pendsey SP India 1998 3.8%
Gupta R 1994 Rajasthan 3.53 + 0.3 Premalatha G et al. India 2000 6.3%
Singh RB 1995 U.P. 3.09 + 1.4 Ali SS, Das S et al. India 2005 10% (Foot
Source: Das S, Misra TK. Diabetes, lipids and coronary artery disease in DM)
in Indians. In: Gupta SB, (Ed). Medicine Update. The Assoc Physi- Janka HU, Standl E et al. Germany 1980 16%
cians India: Mumbai; 2005. pp. 227-33. Migdalis IN, Kourti A et al. Greece 1992 44%
Walters DP, Gatting W et al. UK 1992 23.5%
from the West (Table 57.3). Although there has been
Marinelli MR, Beach KW et al. USA 1997 33%
substantial increase in the prevalence of PVD in Indians
where it varies from 0.8% in epidemiological study to (Foot in DM = those diabetics presenting with foot problems, 10% had
10% in hospital based publications, it is substantially low PVD)
Source: Das S, Goenka RK. Diabetic dyslipidemia. In: Bhattacharya
as compared to data published from Germany, Greece,
PK (Ed). Medicine Update, Assam Chapter. The Assoc Physicians
USA and UK, where almost 80–90% of foot lesions in India: Assam Dibrughar; 2003. pp.559-63.
diabetics are due to AS.3-5 (ICMR: Indian council for medical research; DM: Diabetes mellitus).
The prevalence of CVD varies from 3.4% to 9.2% amon­
gst diabetics in India6 (Tables 57.4a and b). However, the descending (LAD) artery, the carotid artery at the
prevalence of DM amongst patient with CVD is much bifurcation in case of cerebral circulation and abdominal
higher as compared to CAD or PVD (Table 57.5). Further aorta at the origin of renal arteries are more susceptible
DM is more common (22.1%) a cause for cerebral to develop AS than the other parts of arterial tree. The
infarction then cerebral hemorrhage (6.35%) as shown by growth of AS plaques does not occur in smooth linear
studies from India.7 pattern, but rather discontinuously with periods of waxing
and waning.8 The process of AS is more widespread
DISTRIBUTION AND PROFILE OF and extensive with rapid progress in patients with DM
ATHEROSCLEROSIS IN as compared to non-diabetics.9 Besides coexistence of
the other three RF like dyslipidemia, hypertension and
DIABETICS VERSUS NON-DIABETICS
smoking can increase the prevalence of AS in a prog­
Atherosclerosis tends to occur in patches with predilec­ ressive manner. Studies on coro­nary angiography had
tion for particular regions in the vascular channels. shown higher prevalence of multivessel disease along
In the coronary circulation the proximal left anterior with more extensive involvement in Indian diabetics
 848 Complications

Table 57.4(a): Incidence of cardiovascular disease in diabetics as Table 57.4(b): Prevalence of cardiovascular disease among
compared to non-diabetics diabetics
Place Incidence Place Prevalence (%)
1. Ethiopia 2.5 (non-DM):0.45 to 1.29 (in DM) 1. Overall in India (1960 to 1970) 0.5 – 9.2
2. Alabama (USA) 3 times higher in DM 2. Cuttack Tripathy BB,1976 3.4
3. Norway 2 times higher in DM
3. Madras, Shanti P,1991 4.66
4. Whitehall Study (UK) 2 times in DM
4. Madras; V Viswanathan,1992 1.2
section

5. Finland 2 times in DM
5. Honkong – 1970 5.6
10

6. Asia and Africa 15.8 (non-DM):54.7 (DM)

6. Honkong – 1976 14.6
Source: Das S, Goenka RK. Diabetic dyslipidemia. In: Bhattacharya
PK (Ed). Medicine Update, Assam Chapter. The Assoc Physicians Source: Das S. Cerebrovascular complications in NIDDM. J Assoc
India: Assam Dibrughar; 2003. pp.559-63. Physicians India. 1993;(Suppl 1)41:57-65.

Table 57.5: Incidence of diabetes mellitus amongst patients with Table 57.6: Risk factors for developing macrovascular disease
cardiovascular disease 1. Hyperglycemia
In % 2. Hyperinsulinemia
1. Study from 11 countries 2 – 28 3. Obesity
2. West KM-, North Carolina (USA) 13.9 4. Dyslipidemia
3. West KM-, Michigan (USA) 18.3 5. Mediators of inflammation
4. West KM-, Africa 4–8 6. Factors causing alteration of Rheology
5. Lam KSL et al. Honkong 33.5
6. Das S , Cuttack 8.0
on the vascular cell walls. These mechanisms can be
7. Saroop KS et al. Mumbai 32.0
summarized as:
8. Saroop KS et al. Puducherry 32.0 • Increase in non-enzymatic glycation of proteins.
9. Toole, Janway and Choi 28.0 Besides excess glycation of intracellular proteins and
10. Sabharwal, Anjaneyula and Mehndiratta 20.0 plasma membranes; glucose forms glycated com­
Source: Das S. Cerebrovascular complications in NIDDM. J Assoc pounds by causing glycation of primary amines of
Physicians India. 1993;(Suppl 1)41:57-65. amino acids in extracellular matrix and fluid. These
glycated products can act on inflammatory cells to
as compared to non-diabetic cohort.10 Similarly studies release cytokines or directly act on vascular cells
from India (Chennai and Cuttack) had shown that at any and cause vascular dysfunction. The keto amine can
given age diabetic subjects had higher values of carotid undergo further modification and degradation to
intimal-medial thickness than non-diabetics where the form insoluble complexes referred to as advanced
difference reached statistical significance after the age glycation end products (AGE). Collagen, present all
of 50 years.11,12 All these factors contribute to accelerated over the body, are rich in lysine, have long biological
and extensive AS in Indian patients with DM. half-life and thus most susceptible to glycation and
The likely determinants or RF for the development of AGE formation. Such changes in the collagen of the
MVD are as follows (Table 57.6). vascular wall lead to excess low density lipoproteins
(LDL) trapping and oxidation. Interestingly, there is a
PATHOGENESIS AND DETERMINANTS OF threshold for the glycation effect in patients with DM
MACROVASCULAR DISEASE i.e. there is correlation between the degree of glycemia
and MVD, whereas among people without DM there
Hyperglycemia is no such correlation as they fall below the glycemia
The contribution of hyperglycemia as an independent threshold.
determinant or RF for developing MVD, CAD in • Activation of polyol pathway: Excess amount of
particular, has become obvious from the UKPDS. Several glucose enters the intracellular compartment with the
biochemical mechanisms consequent to metabolites help of glucose transporters GLUT-1 and also GLUT-4
of glucose can affect numerous cellular pathways both and get metabolized through the sorbitol pathway.
intra and extracellular sites, that can have adverse effect On conversion to excess of sorbitol they cause change
 Macrovascular Disease in Diabetes: Determinants and Pathogenesis 849

in the redox potential or alter signal transudation tissue with less of nitric oxide (NO) production in
pathways viz. activation of diacylglycerol (DAG) and vessel wall. The biological activity of such cells and
protein kinase C (PKC). All these process adversely tissue are altered. In the vascular channel the effect
affect permeability, contractility, extracellular matrix, can be depressed activity of LPL, decreased insulin
cell growth, angiogenesis, cytokine action and leuko­ action with increased peripheral resistance, attenua­
cyte adhesions in vascular cells. ted fibrinolysis, increased production of von Wille­
• Activation of DAG and PKC cascade: Intracellular brand factor (vWF) and endothelin, defective produc­

chapter
DAG is the physiological activator of PKC. DAG is tion of endothelial derived relaxation factor (EDRF)

57
derived from multiple sources including hydrolysis of and increase in oxidized LDL. Oxidation, which is
phosphatidyl inositides, metabolism of phosphatidyl- enhanced in diabetic state, not only modifies the
choline or de novo synthesis. The PKC consists of a phospholipid content of LDL but also the amino acid
family of 11 isomers representing the major targets for side chains of Apoprotein B100 (Apo B100). Such
lipid second messengers. Persistent hyperglycemia oxidized Apo B100 mediates excess of receptor uptake
causes rise in DAG-PKC levels intracellularly in many of LDL by endothelial cell while the oxidized LDL
tissues including aorta, heart, retina, glomeruli and per se is:
even insulin sensitive tissues like liver and skeletal –– More recognized by macrophage scavenger recep­
muscle but not in brain or peripheral nerves. However, tors and readily taken up by foam cells fat ladened
transient rise in blood glucose does not cause this and scavenger cells or smooth muscle cells (SMC) in
such increase in intracellular DAG-PKC may require 3–5 atheromatous lesions. Once taken up by foam cells
days of persistent hyperglycemia. Increased activation the degradation of oxidized LDL is impaired leading
of DAG-PKC cascade leads to multiple cellular and to further accumulation of lipids in these cells.
functional abnormalities in vascular cells. There occurs –– Oxidized LDL increases the adhesion of circulating
increased release of arachidonic acid and prostaglandin monocytes to damaged endothelium, enhancing
E2 production vis-a-vis decreased Na+, K+ ATPase their migration into the vascular intima.
activity which in turn affects cellular integrity as well as –– Oxidized LDL is more immunogenic forming anti­
function like contractility, growth and differentiation. body-lipoprotein complex which stimulate foam-
PKC activation can increase expression of transforming cell formation and platelet aggregation as compared
growth factor β (TGF-β) which increases type IV and to non-oxidized LDL.
type VI collagens and fibronectins which suppress –– Oxidized LDL has an increased affinity for getting
proteoglycans in extracellular matrix. Less production bound to glucose mediated crosslinks present in
of proteoglycans like glycosaminoglycan’s in capillary the matrix of the vascular intima. These are various
endothelial surface leads to defect in lipoprotein lipase hitherto known mechanisms by which increased
(LPL) binding and consequent poor clearance of very oxidative stress can lead to enhanced AS and MVD
low density lipoproteins (VLDL). These metabolic in DM.
defects lead to the typical dyslipidemia of DM –– Increase in plasma cholesterol and its main trans­
(vide infra). Further, increase in collagen, particularly porter LDL is an important risk factor in AS. In
type-IV, leads to expansion of the basement membrane diabetic subjects, LDL tends to get modified due to
with vascular dysfunction. hyperglycemia, oxidative stress and other metabolic
• Increase of flux via the hexosamine metabolism. Non- abnormalities. Small dense LDL is considered to
enzymatic glycation is a process that affects protein at be more prone to oxidation and conformational
any situation whether structural protein, coagulation changes,5 which results in the lowering of LDL
protein, lipoprotein or carrier proteins in circulation. clearance by its receptors, triggering immunological
Hyperglycemia is an important source of free oxygen changes. Some studies have shown the oxidizability
radicals (OFR) production and contributes to glucose of LDL to be associated with early structural
auto oxidants and increased AGE formation. All these changes.7 Studies have shown that diabetic subjects
combine together to increase the oxidative stress in had higher small dense LDL compared to normal.
the diabetic individual. The oxidative stress (manifests • The enhanced flux of glucose into the cells via hexa­
as increase in NADH/NAD ratio) in various cells and mine formation has been discussed above. In general,
 850 Complications

the Na+, K+ pump is defective in diabetic subjects with adipose tissue-expressed tumor necrosis factor-α
uncontrolled hyperglycemia. This allows the excess (TNF-α) both are proinflammatory cytokines and
flux and the likely explanation is through DAG-PKC enhance atherogenesis.
activation. Evidences from studies published in 1979 and 1980
from various parts of Europe and Australia had shown that
Hyperinsulinemia–Insulin Resistance13 HI is a predictor of future development of AS in men while
Insulin in physiological levels has antiatherogenic actions the Atherosclerosis Risk in Communities (ARIC) study
section

whereas in insulin resistance (IR) or hyperinsulinemia revealed the reverse phenomenon i.e. HI was RF for MVD
10

(HI) situations it causes attenuation of AS. At physiological in women. There were reports suggesting that HI did not
levels as insulin increases NO production, retards migra­ correlate with AS in non-caucasians. Moreover, the major
tion and growth of SMC from the subendothelial layer of controversy was raised regarding the estimation of insulin
vascular wall. The vascular cells are capable of responding in plasma since most assays also estimated proinsulin
to insulin with a wide variety of action. Insulin in situation along with insulin. It was then thought that the proinsulin
of HI exerts its adverse effects on the vessel wall through was the main culprit for increased prevalence of MVD in
other mediators and mechanisms rather than having a type 2 DM with HI and such HI was spurious due to non-
direct effect like enhancing mitogenicity. specific assay.
In conditions of HI/IR as seen in obese type 2 diabetics, However, two prospective studies, the Quebec Cardio­
insulin may lose its metabolic effect but retain its growth vascular Study and the British Regional Heart Study that
stimulating effect on vascular wall cells.1 In patients used specific immunoassay for insulin have revealed
with HI, insulin exerts its atherogenic effect on SMC by that, there is a threshold for the MVD enhancing effect of
enhancing the mitogenic action of more potential growth insulin and an increase of one standard deviation in
factors like platelet derived growth factor (PDGF) and specific insulin levels conferred a 70% increase in cardio­
insulin-like growth factor (IGF). IR and HI can trigger vascular risk.
various coagulation abnormalities that act as important
factors for development of MVD in diabetics more so Dyslipidemia
with type 2 diabetics. Generation of NO is suppressed in
Dyslipidemia is one of the well-known determinants
patients with HI. In brief, the mechanisms are:
of MVD. There have been great changes in the profile of
• Insulin, proinsulin and oxidized LDL can induce
lipid abnormalities in the population over the decades.
increased expression and secretion of plasminogen
Reports revealing normal values of pre-β lipoproteins vis-
activator inhibitor-l (PAl-l) by endothelial cell lines
a-vis hypercholesterolemia as RF for increased incidence
and hepatocytes. As PAl-l is a fast acting inhibitor of
fibrinolysis it helps in thrombogenesis and vascular of CAD in the 1950 have gradually been replaced by
occlusion. PAl-l is now considered as a part of insulin volumes of publications suggesting hypertri­glyceridemia
resistance syndrome (IRS). and abnormalities in LDL fraction with regards to size
• Concentrations of endothelial cell protein, vWF are of the molecule and glycation of its apoproteins as the
elevated in IRS. This is a marker of endothelial cell underlying dyslipidemia in diabetics with MVD.14
dysfunction/damage and raised levels in plasma Our own findings of raised triglyceride (TG) levels
suggest endothelial cell injury and activation of in DM was originally attributed to the inherent high
atherogenesis. Further, secretion of vWF and other carbohydrate diet in our population. By early 1980s we
procoagulants as well as adhesive molecules indicate had enough published data to emphasize that raised levels
the existing procoagulant state. of TG and VLDL cholesterol (VLDLc) were more charac­
• Levels of fibrinogen are elevated in IRS. This being an teristic lipid abnormalities in DM irrespective of nutritional
acute phase protein synthesized by liver in response status or body mass index (BMI). Current knowledge from
to circulating interleukin-6 (IL-6) suggest role of acute the West reveals that the major abnormality in diabetics
phase cytokines in the abnormalities of coagulation is hypertriglyceridemia with level of cholesterol and
and endothelial function. This is more so in obese LDL being nearly similar to that found in the general
diabetics where the adipose tissue secretes IL-6 and population.
 Macrovascular Disease in Diabetes: Determinants and Pathogenesis 851

produce impaired clearance of VLDL from circulation.

The apoproteins AI, C III and A IV are known to modulate
TG transport and metabolism where AI and A-IV stimulate
while C-III suppresses LPL activity. The genes for these
apoproteins have been found to be located on the long
arm of chromosome 11 and at least 14 mutations have
been detected in patients with type 2 DM. These mutations

chapter
can produce apoproteins and LPL that are defective in

57
function and can slow VLDL clearance with consequent
persistent hypertriglyceridemia. 14
The near normal levels of plasma cholesterol in
diabetics may be in reality misguiding, since at any given
concentration of cholesterol, diabetics are two to four
times more prone to develop CAD as compared to non­
Fig. 57.1: Role of low density lipoproteins in atherosclerosis.
(LDL: Low density lipoprotein; MCP-1: Monocytic chemoattractant pro- diabetics. This could be due to the reason that, the mere
tein). quantitative value of cholesterol or LDL may not be
important as LDL may be modified viz. non-enzymatically
Hypertriglyceridemia is one of the main markers of IR, glycated, undergone oxidation, changed size to smaller
even in diabetics selected to be lean or low bodyweight. or dense particles. Over and above their interaction
It is needless to re-emphasize today that most studies with coexistent no-lipid RFs like AGE, hypertension,
have endorsed the view that hypertriglyceridemia confers changes in the coagulation cascade etc. make them more
an increased risk for MVD and CAD in particular, in the atherogenic in diabetics (Fig. 57.1). Further, plasma levels
general population. This risk of TG is independent of of HDL and its composition has been observed to be
HDL. Hypertriglyceridemia refers to a situation of altered while efficacy with regard to reverse cholesterol
increased TG-rich lipoproteins. On ultracentrifugation transport subdued. The HDL cholesterol levels have been
of plasma from such diabetics, it will be found that three variably reported to be either low, normal or even raised in
fourth of TG-rich lipoprotein molecules are smaller dense diabetics depending on the mode of treatment or state of
particles and float at a density range of 12–60 Sf. All these metabolic control.
particles contain one molecule of ApoB100 and so called The role of lipoprotein (a) [Lp(a)] as a determinant
intermediate density lipoprotein (IDL). The small dense of MVD has been widely studied in non-diabetics. It
IDL level is positively correlated with MVD in men with is genetically determined lipoprotein which varies in
or without DM and is independent of LDL and HDL. distribution and concentration from one ethnic group
Raised TG levels are also associated with increased levels to the other and is supposed to be a RF for CAD in non-
of PAl-1.14 diabetics. Certain studies suggest that Lp(a) has a reduced
Prospective studies have shown that hypertri­ capacity to suppress cellular cholesterol synthesis and
glyceridemia may antedate development of MVD in thus higher quantities of Lp(a) can get internalized into
type 2 diabetics. Plethora of recent data on insulin the endothelial cells through ApoB100 receptors and
sensitivity and CAD suggest that there could be a genetic cause excess intracellular cholesterol deposition. The
predisposition for hypertriglyceridemia in patients with plasma level of Lp(a) is more or less uniform in both type
type 2 DM. Such genetic abnormality is not monogenic 1 and 2 DM but are higher in insulin-treated subjects and
in origin and appears to the determined by genes that subjects with IR. Levels of Lp(a) are not well correlated
cluster in a particular region of one chromosome so as to with incidence of CAD but has a positive correlation with
express concurrently and produce the complex situation circulating insulin levels. Moreover, level of Lp(a) has
of hypertriglyceridemia in type 2 diabetics with increased been found to be raised diabetics with either macro or
propensity for MVD. Mutations have been detected in microvascular disease indicating that it is associated with
LPL gene locus present in chromosome 8 which can generalized vasculopathy in patients with DM.
 852 Complications

mainly C-reactive protein (CRP), Fibrinogen, Plasminogen

activator inhibitor-1 (PAI-1).

Role of C-Reactive Protein

It elicits direct proatherogenic and proinflammatory
effects to act as a direct mediator of endothelial dysfunc­
section

tion. Decreasing NO release, CRP inhibits angiogenesis

10

and stimulates endothelial cell apoptosis. It also stimulates

endothelin-1 which causes upregulation of monocytic
chemoattractant protein (MCP-1) release. It also promotes
Fig. 57.2: Adipokines, leukotrienes and inflammatory mediators pro-
duced by visceral adipocytes. NF-κβ upregulation. CRP upregulates AT-1 receptor in
(TNF-a: Tumor necrosis factor-alpha; IL: Interleukin; PAI-1: Plasmino- vascular smooth muscle (VSM) cells. Thus, it potentiates
gen activator inhibitor-1; NF: Nuclear factor). the effect of angiotensin-II, another proinflammatory
molecule. It also causes increased basal reactive oxygen
Obesity species production in VSM.18
Latest study from India (Table 57.7), revealed a
Obesity makes individual more susceptible to MVD as
significant inflammatory state prevalent in type 2 diabetics
established from population studies as well as clinical
as compared to healthy individuals even at BMI values
trials. Central obesity with increased visceral fat is a
much below the definition of obesity. Type 2 diabetics
major determined of IR and HI. Adipose tissue has been
with MVD had significantly higher hsCRP as opposed to
recognized as an active endocrine organ in addition to its
type 2 diabetics without MVD. Such a proinflammatory
role as the main storage depots for TGs. A large number
state could be an independent determinant of AS in this
of adipocyte-derived secretory factors (adipokines) are
population and hsCRP, an easily measurable marker for
described in current literature. It is well established that
inflammation, is a reasonable marker of MVD in Indian
individuals who are obese and/or suffer from metabolic
subjects with type 2 diabetes.19
syndrome (MS) display a characteristic imbalance of
their adipokine profile. This altered adipokine profile
Rheology
leads to profound changes in insulin sensitivity and
other biochemical alterations of metabolites, making The pathophysiological process underlying atheromatous
an individual more prone to metabolic disorders. Chief plaque is often complicated by the prothrombotic
adipokines are adiponectin, leptin, visfatin, resistin, and state in the blood. The plaque develops over a period of
TNF-α and IL-6, so also other proteins responsible for many years and when uncomplicated may have little
inflammatory response nuclear factor like kappa-beta effect on individual’s mortality or morbidity. But when
(NF-κβ) (Fig. 57.2).15-17 the plaque ruptures, it causes activation of thrombogenic
pathways and subsequently activation of fibrinolytic
Inflammation pathway. The alteration of hemostatic factors is well
documented in number of studies.
In the past decades, AS has been regarded as a bland Clustering of thrombotic RF occur in association with
lipid storage disease but, currently it is understood that insulin resistance in metabolic syndrome. These are the
inflammation plays paramount role in the process of factors playing role in hemostatic alteration:
initiation, progression and complication of AS. • Plasminogen Activator Inhibitor-1(PAI-1)
As CVD can precede the development of type 2 DM, Elevation of PAI-1 level results in hypofibrinolysis,
the notion that both conditions share some common thereby increasing atherothrombotic risk.
genetic and environmental antecedents, has been put • Tissue Plasminogen Activator (t-PA)
forward (The “Common Soil Hypothesis” as mentioned t-PA level is elevated in endothelial dysfunction, leading
earlier) raising the possibility that inflammation could be to instability of the fibrin clot.
the bridging link between MS and AS. • Factor VII:c
Recent studies have confirmed the positive association It activates intrinsic coagulation pathway, thus pro-
between obesity indices and inflammatory markers, thrombotic and associated with increased insulin level.
 Macrovascular Disease in Diabetes: Determinants and Pathogenesis 853

Table 57.7: Inflammatory markers in patients with or without macrovascular disease

Type 2DM with MVD (A) Type 2DM without MVD (B) Healthy controls (C) p value
n = 29 n = 28 n = 14
A VS B A VS C B VS C ANOVA
hsCRP (mg/L) 9.29 ± 5.31 1.47 ± 1.82 0.44 ± 0.12 0.0001 0.0001 0.006 0.0001
Interquartile
range–0.92

chapter
Median–0.63

57
Adiponectin 50.12 ± 20.84 53.07 ± 20.88 66.28 ± 20.34 0.59 0.02 0.058 0.058
(ng/mL)
NFkB (OD) 0.057 ± 0.030 0.045 ± 0.009 0.041 ± 0.006 0.08 0.007 0.10 0.033
Interquartile
range – 0.0175
Median – 0.047
(CRP: C-Reactive protein; MVD: Macrovascular disease; DM: Diabetes mellitus).

• vonWillebrand factor (vWF) with MVD. The vascular complications consequent to

Elevated levels of vWF indicate endothelial dysfunction. raised levels are due to accentuated coagulability state,
High vWF activity can be a marker of subclinical AS. endothelial cell dysfunction and thrombosis. Studies on
• Fibrinogen diabetics have shown rise in prevalence of CAD and PVD
Though it is a marker for ongoing thrombosis, it has been in those with elevated homocysteine levels irrespective of
shown to have weak association with hyperinsulinemia the type of DM.21
in multivariate analysis.
• Factor XII Further Reading
Elevated level is associated with significant RF of CVD
1. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary
like increased TG level, increased BMI and hyper- artery disease in non-insulin dependent diabetes mellitus:
tension. Its level is strongly correlated with extent of United Kingdom Prospective Diabetes Study (UKPDS: 23).
coronary stenosis and previous history of Myocardial BMJ.1998;316:823-8.
infarction. 2. Mohan V, Ravikumar R, Shanthirani S, et al. Intimal
• Platelets medical thickness of the carotid artery in South Indian dia-
Platelets in persons with insulin resistance are resistant betic and non-diabetic subjects: the Chennai Urban Popu-
to the action of insulin, NO, and PGI2 suggesting platelet lation Study (CUPS). Diabetologia 2000;43:494-9.
3. Dalal PM, Parab PV. Cerebrovascular Disease in Type 2 Dia-
activation is upregulated in setting of IR.20
betes Mellitus Neurol India 2002;50:380-5.
4. Grundy SM. Obesity, Metabolic Syndrome, and Cardio­
Smoking vascular Disease. J Clin Endocrinol Metab. 2004;89:
2595-600.
Smoking enhances risk of PVD more than hundred times as
5. Mishra TK, Das S, Patnaik UK, et al. Relationship of meta-
compared to non-diabetic and non-smokers. Cessation of bolic syndrome with quantum of coronary artery disease
smoking has been associated with decrease in progression in Indian patients with chronic stable angina. Metab Syndr
of atherosclerosis. There is strong evidence that smoking Relat Disord. 2004;2:187-191.
markedly increases the risk of both myocardial infarction 6. Das S, Misra TK. Diabetes, lipids and coronary artery dis-
and complication of PVD in those with diabetes, especially ease in Indians. In: Gupta SB, (Ed). Medicine Update. The
Assoc Physicians India: Mumbai; 2005. pp. 227-33.
women. Smoking is believed to be associated with adverse
7. Stratmann B, Tschoepe D. Heart in Diabetes: Not only a
changes in plasma lipids and lipoproteins, especially with
macrovascular disease. Diabetes Care. 2011;34:S138-44.
low levels of HDL.
REFERENCES
Homocysteine
1. Powers AC. Diabetes mellitus. In: Dan Longo, Anth­
Raised plasma levels of homocysteine has been estab­ ony Fauci, Dennis Kasper (Eds). Harrison’s Principle of
lished as an independent determinant for MVD. Levels Internal Medicine, 18th edition. McGraw Hill Professional:
above 16.2 mmol/L has been found to strongly correlate New York; 2012. pp. 2968-3003.
 854 Complications

2. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary 13. Das S, Baliarsinha AK. Insulin resistance and dyslipidemia
artery disease in non-insulin dependent diabetes mellitus: two way relationship. In: Venkatraman S. (Ed). Medicine
United Kingdom Prospective Diabetes Study (UKPDS: 23). Update. Mumbai: The Association of Physician of India;
BMJ.1998;316:823-8. 2004.pp. 100-5.
3. Das S, Misra TK. Diabetes, lipids and coronary artery dis- 14. Misra A, Vikram NK. Insulin resistance syndrome (Meta-
ease in Indians. In: Gupta SB, (Ed). Medicine Update. The
bolic syndrome) and Asian Indians. Current Science.
Assoc Physicians India: Mumbai; 2005. pp. 227-33.
2002;83:1483-96.
4. Das S, Goenka RK. Diabetic dyslipidemia. In: Bhattacharya
15. Mohan V, Deepa R, Velmurugan K, et al. Association of small
section

PK (Ed). Medicine Update, Assam Chapter. The Assoc Phy-

sicians India: Assam Dibrughar; 2003. pp. 559-63. dense LDL with coronary artery disease and diabetes in
10

5. Ali SS, Das SK, Begum T. Foot involvement in diabetes mel- urban Asian Indians. the Chennai Urban Rural Epidemi-
litus. The Asian J Diabetology. 2005;7:15-20. ology Study (CURES 8). J Assoc Physicians India. 2005;53:
6. Das S. Cerebrovascular complications in NIDDM. J Assoc 95-100.
Physicians India. 1993;41:57-65. 16. Grundy SM. Obesity, Metabolic Syndrome, and Cardiovas-
7. Padma MV, Bajaj JS. Diabetes and Stroke. In: Bansal BC cular Disease. J Clin Endocrinol Metab. 2004;89:2595-600.
(Ed). Recent Concepts in Stroke. The Assoc Physicians 17. Deng Y, Scherer PE. Adipokines as novel biomarkers and
India: Mumbai; 1999. pp. 79-95.
regulators of the metabolic syndrome. Ann N Y Acad Sci.
8. Peter Libby. The pathogenesis of atherosclerosis. Harrison’s
2010;1212:E1-E19.
Principles of Internal Medicine, 16th edition. 2004. p 1425.
9. Fuster V, Corti R. Evolving concepts of atherothrombosis. 18. van Royen N, Hoefer I, Buschmann I, et al. Effects of local
In: Fuster V (Ed). Assessing and Modifying the Vulner- MCP-1 protein therapy on the development of the collat-
able Atherosclerotic Plaques. American Heart Association. eral circulation and atherosclerosis in Watanabe hyperli­
Futura Publishing Company Inc.: New York; 2002. pp. 1-27. pidemic rabbits. Cardiovasc Res. 2003;57:178-85.
10. Mishra TK, Das S, Patnaik UK, et al. Relationship of meta- 19. Misra DP, Das S, Sahu PK. Prevalence of inflammatory
bolic syndrome with quantum of coronary artery disease markers (high-sensitivity C-reactive protein, nuclear factor-
in Indian patients with chronic stable angina. Metab Syndr κB, and adiponectin) in Indian patients with type 2 diabetes
Relat Disord. 2004;2:187-91. mellitus with and without macrovascular complications.
11. Mohan V, Ravikumar R, Shanthirani S, et al. Intimal med­
Metab Syndr Relat Disord. 2012;10:209-13.
ical thickness of the carotid artery in South Indian diabetic
20. Franchini M, Lippi G, Manzato F, et al. Hemostatic abnor-
and non-diabetic subjects: the Chennai Urban Population
Study (CUPS). Diabetiologia. 2000;43:494-9. malities in endocrine and metabolic disorders, Eur J Endo-
12. Das S, Chakrabarty K, Patnaik M, et al. The relationship of crinol. 2010;162:439-51.
carotid plaque, intima media thickness (IMT), resistivity 21. Das S, Reynolds T, Patnaik A, et al. Plasma homocysteine
index (RI) and pulsatility index (PI) in Asian-Indian Concentration in Type-2 diabetes patients in India: rela-
patients with acute ischemic stroke with and without tionship to body weight. J Diabetes Complications. 1999;
Type2 DM. Inter J Clin Med. 2011;2:561-6. 13:200-3.
 Chapter 58
Coronary Heart
Disease in Diabetes
Ashok Kumar Das

Coronary Heart Disease in DM

Chapter Outline
♦♦ Indian Scenario ♦♦ Screening and Investigations
♦♦ Risk Factors for Coronary Artery Disease in Diabetes ♦♦ Management of Coronary Artery Desease in Diabetes
♦♦ Clinical Features ♦♦ Approach

INTRODUCTION to their non-diabetic counterparts.1 The protective female

gender effect is lost in diabetic subjects, and indeed,
Diabetes mellitus (DM) shares many of the risk factors women with diabetes are possibly more prone to develop
with coronary artery disease (CAD), such as obesity, CAD than men with diabetes.8
physical inactivity, age, hypertension and dyslipidemia.1
The presence of DM in any patient hence, marks the risk of INDIAN SCENARIO
future CAD.2 Cardiovascular diseases (CVD), comprising
CAD and cerebrovascular diseases, are currently the In India previously most of the deaths were due to comm­
leading cause of mortality worldwide, accounting for unicable diseases. With increasing literacy levels, financial
21.9% of total deaths, and are projected to increase to security, urbanization and the immunization schemes the
26.3% by 2030.3 Patients with diabetes have two to four onus is now on the non-communicable diseases (NCD) like
fold higher risk of developing coronary disease,4 and CVD CADs, DM, hypertension etc (Figs 58.1 and 58.2).
accounts for 65–75% of deaths in people with diabetes.5,6 Cardiovascular diseases are the largest cause of
CAD in diabetic patients is more severe, more complex, mortality, accounting for around half of all deaths resulting
and results in higher complication rates than in patients from NCD. CVDs are expected to be the fastest growing
without diabetes.6 CAD is often asymptomatic in diabetic chronic illnesses between 2005 and 2015, growing at 9.2%
patients until the onset of myocardial infarction (MI) annually, and accounting for the second largest number
or sudden cardiac death.7 Diabetes is considered a CAD of NCD patients after mental illnesses. By 2020, 85% of the
risk equivalent according to the Adult Treatment Panel of global CVD burden is expected to be borne by developing
the National Cholesterol Education Program guidelines. nations, and the increase in CAD mortality in developing
This means that in a patient with diabetes, the presence countries between 1990 and 2020 is projected to be 120%
of diabetes itself confers a risk of future coronary artery in women and 137% in men.9 India is predicted to bear the
events, which is equivalent to that of patient with a past greatest CAD burden, according to the estimates from the
history of a coronary artery event.1 CAD has been reported Global Burden of Disease Study of more than 9 million
to occur 2–3 decades earlier in diabetic patients as opposed deaths due to CAD in 1990 in developing countries,
 856 Complications
section
10

Fig. 58.1: Mortality from major communicable and non-communicable diseases

Source: Global Burden of Disease 2004. Projected Deaths 2030, Baseline Scenario. World Health Organization, 2008. Number of deaths
in 1000’s

Fig. 58.2: Disease burden in India

Source: Nutrition Transition in India, 1947–2007. Ministry of Women and Child Welfare

2.4 million (25%) occurred in India.10 In the same year, The Chennai Urban Population Study (CUPS) is a
mortality rates in India due to acute MI were 141/100,000 population-based study involving two residential areas
in males and 136/100,000 in females, which was much representing the lower and middle-income groups in
higher than in China (66/100,000 in males and 69/100,000 Chennai in South India. The prevalence of CAD in the CUPS
in females) and Latin American countries (81/100,000 in study was 11% in the total population, with 1.2% patients
males and 76/100,000 in females). The overall CV mortality having had a MI, 1.3% with Q-wave changes, 1.5% with
in Indians is predicted to rise by 103% in men and 90% ST-segment changes, and 7.0% with T-wave abnor­
in women between 1985 and 2015. A matter of serious malities.12,13 This 11% represents a 10-fold increase in CAD
concern is that 52% of the CAD deaths in India occurred in prevalence in urban India since 1970, now approaching
people aged below 70 years, while the same was just 22% those reported in migrant Indians. In the same study, the
in developed countries.11 prevalence of CAD among diabetic subjects was 21.4%
 Coronary Heart Disease in Diabetes 857

Table 58.1: Prevalence of coronary artery disease in South Indian

subjects with and without glucose intolerance
Subjects
NGT IGT Diabetes
Documented MI (%) 0.9% ­­— 3.4%
Overall Q waves (%) 1.2% 1.4% 8.2%
ST‑segment depression (%) 1.1% 5.4% 2.8%

chapter
T‑wave abnormalities (%) 6.6% 8.1% 9.0%

58
Total CAD prevalence (%) 9.1% 14.9% 21.4%

(NGT: Normal glucose tolerance; IGT: Impaired glucose tolerance;

MI: Myocardial infarction; CAD: Coronary artery disease).

(known diabetes, 25.3%, and newly diagnosed diabetes,

13.1%), which was much higher than the figure of 14.9%
among subjects with impaired glucose tolerance (IGT) and Fig. 58.3: Mean levels of small dense low density lipoproteins in
9.1% among those with normal glucose tolerance NGT. different subjects
(LDL: Low density lipoproteins; CAD: Coronary artery disease).
Prevalence of known MI was three times higher in diabetic
subjects. However, this study showed that the risk for CAD
increased even at the stage of IGT itself (Table 58.1).
These studies also confirm that Asian Indian dia­ RISK FACTORS FOR CORONARY ARTERY
betic subjects have an increased tendency to develop
DISEASE IN DIABETES
premature atherosclerosis compared to their non-diabetic
counterparts. Coronary artery disease is a major macrovascular
Asian Indians have higher prevalence of hyperin‑ complication of DM and reveals high mortality. Men with
sulinemia, insulin resistance, and other components of diabetes are up to three times more likely to die of CVD
metabolic syndrome. Obesity, particularly abdominal than men without diabetes; the relative risk for women
obesity, is considered to contribute to the increased insulin with diabetes is even higher.19
resistance in Indians. Though Indians have low rates of Diabetes is cardiac risk factor for CAD and is
generalized obesity, the prevalence of abdominal obesity independent of other known cardiac risk factors. People
is higher compared to other ethnic groups.14,15 Further, for with type 2 diabetes will die 5–10 years before people
any given degree of obesity, Indians also have higher body without diabetes, are twice as likely to have a heart attack
fat than other ethnic groups, and for any given body mass
or stroke as people who do not have diabetes.20
index (BMI), the waist-to-hip ratio was higher among
The pathogenesis of CAD in diabetes is multifactorial
Indians.16 Finally, for any given body fat, Indians have
and is contributed by several risk factors like traditional
higher insulin resistance compared to other ethnic groups.
risk factors like age, gender, increased total or LDL-C,
Indians are known to have higher abdominal obesity for
decreased HDL-C cigarette smoking and diabetes itself.
the same BMI compared to their western counterparts.
Framingham risk score (FRS) use these traditional CV
It is important to note that, in CUPS, subjects with CAD
had lipid levels that were much lower than the high-risk risk factors for risk assessment in all asymptomatic
category described by NCEP guidelines.17 Indians are adults without a clinical history of coronary heart disease
known to have much lower high density lipoproteins (CHD).21,22 The Framingham risk score predicts major
(HDL)-cholesterol levels, and hence the total cholesterol/ CHD events well in different demographic and ethnic
HDL-C and low density lipoprotein (LDL)/HDL-C rates groups. Hyperglycemia is an independent and modifiable
are higher in Indians. The role of small dense LDL particles risk factor for CAD.22 The risk of CVD increases gradually
in CAD has been well validated in countless studies. The as glucose metabolism deteriorates.23 There is 14–16%
Chennai Urban Rural Epidemiology Study (CURES) decrease in CV events per 1% HbA1c reduction as shown
conducted in South Indians showed that small dense LDL by United Kingdom Prospective Diabetes Study UKPDS.24
levels were higher in diabetic patients and even higher in However in the Action to Control Cardiovascular Risk in
diabetic subjects with CAD (Fig. 58.3).18 Diabetes (ACCORD) trial there was increased CV mortality
 858 Complications

while mortality did not increase in other outcome trials individuals with serum creatinine more than or equal
Veterans Affairs Diabetes Trial (VADT) and Action in to 1.24 mmol/L had 22% risk of MI that exceeded 15.1%
Diabetes and Vascular Disease: Preterax and Diamicron incidence in people with better renal function (p < 0.001)29
MR Controlled Evaluation (ADVANCE) trial. Meta analysis
showed modest reduction in major CV events with Metabolic Syndrome as Risk Factor
reduction in hyperglycemia.25 Metabolic syndrome is cluster of features of abdominal
Patients with diabetes often have clustering of risk obesity, insulin resistance, hypertension and dyslipidemia.
section

factors such as hypertension, dyslipidemia and obesity There is significant increase in risk of CV events and CV
10

and the summation of risk factors leads to much steeper mortality in presence of metabolic syndrome. Metabolic
rise in the mortality in diabetics compared to non-diabetic syndrome is common and is associated with an increased
population. risk for CVD and T2DM in both sexes.30
There are many novel risk factors proposed for CAD as
Blood Pressure given in below (Table 58.2).
Studies have clearly demonstrated a progressive conti­
C-Reactive Protein
nuous relationship between both systolic and diastolic
blood pressure and risk of CV death or MI in diabetes.22 Inflammation plays a role in all stages of atherosclerosis.
In an epidemological analysis of data from UKPDS, a Many inflammatory lipids, and cytokines markers have
10 mm rise in systolic blood pressure (SBP) was associated been associated with CAD risk. CRP as marker for pre­
with 12% rise in heart failure and a 17% rise in diabetes diction of future coronary events in the Asian Indian popu­
related death.24 In ADVANCE trial reduction of 5.6 mm Hg lation was studied in Indian Atherosclerosis Research
Study in which levels of high sensitivity C-reactive protein
in SBP also reduced CV mortality by 18%.26
(hsCRP) were higher among subjects affected by CAD
who suffered a repeat coronary event as compared to
Dyslipidemia
those who remained event free and subjects in the top
High triglyceride (TG) concentrations and low HDL-C quartile of hsCRP (> 3.58 mg/L) were found to have a four-
concentrations are characteristic of diabetic dyslipidemia. fold higher risk.31 In another study, elevated hsCRP levels
In addition, there are qualitative changes in lipid profile along with dyslipidemia and oxidative stress adds to the
in people with diabetes like increased rate of glycosylation predictive value of premature CAD in young Indians.32
of apolipoprotein B which in turn lead to increased
corporation of LDL-C into macrophages also small dense Clinical Features
LDL particles facilitate oxidation and accumulation in
blood vessels. LDL-C is a progressive and continuous CV The CV mortality rate is more than twice as high in diabetic
risk factor in people with diabetes.24 Similar observations men and more than four-fold greater in diabetic women,
have been reported for relationship between low compared with their non-diabetic counterparts. CAD in
Asian Indians occurs prematurely, i.e. at least 10–20 years
HDL-C and high TG level. There is positive relationship
earlier than that seen in Europeans. The excess rate of
between LDL-C and CV risk even at relatively low range
CAD seen among Asian Indians cannot be explained by
of cholesterol values. Lowering LDL-C reduces the risk
the traditional risk factors for CAD seen among Europeans
of CV events.27 Treatment of diabetic dyslipidemia can
—namely, hypertension, high cholesterol, smoking and
improve CV outcomes as shown in Veterans Affairs HDL
obesity.33 Clinically stable type 2 DM patients with CAD
Intervention Trial. (VA-HIT) trial.28
often do not present with the symptoms of typical angina.
Symptoms are more often absent or atypical (shortness
Albuminuria
of breath) in non-diabetic patients. Several studies have
A meta analysis of prospective studies and analysis of shown that in the presence of myocardial ischemia,
data from the Heart Outcomes Prevention Evaluation diabetic patients report angina less frequently than non-
(HOPE) study has shown that microalbuminuria is an diabetic patients and shortness of breath may be the
independent risk factor for CV events as well as heart only symptom of ischemia. The autonomic neuropathy
failure. Studies of macroalbuminuria have documented caused by diabetes has been suggested to be the cause of
an even higher relative risk of CV events. In HOPE study, the high prevalence of silent CAD. Reduced appreciation
 Coronary Heart Disease in Diabetes 859

Table 58.2: Novel risk factors proposed for coronary artery disease
Ankle-brachial index • ApoE genotype
Apolipoproteins A1 and B • Carotid intima media thickness
Angiotensin-converting enzyme genotype • Cystatin C
C-reactive protein • D-dimer
Electrocardiogram findings • Electron beam computed tomography

chapter
Exercise treadmill testing • Fibrinogen

58
Fibrinopeptide A • Factors V, VII, and VIII
Fasting glucose • Homocysteine
High-density lipoprotein subtypes • Heart rate
Infectious agents: Cytomegalovirus, Chlamydia pneumonia, Helicobacter • Insulin resistance
pylori, Herpes viruses
Interleukins (e.g., IL-6) • Periodontal disease
White blood cell count • Lipoprotein(a)
Lipoprotein-associated phospholipase A(2) • Metabolic syndrome
Microalbuminuria • Oxidized LDL
PAI-1 genotype • Physical inactivity
Plasminogen activator inhibitor 1 (PAI-1) • Platelet activity
Platelet aggregation • Platelet size and volume
Prothrombin fragment 1 + 2 • Pulse pressure
Remnant lipoproteins • Serum amyloid A
Soluble CD40 ligand • Tissue-plasminogen activator
Vascular and cellular adhesion molecules • von Willebrand factor antigen
Waist-to-hip ratio

for ischemic pain can impair timely recognition of many from sudden death. Because the typical cardiac
myocardial ischemia or infarction and thereby delay symptoms often are masked in patients with diabetes, the
appropriate therapy. diagnosis of MI commonly is missed or delayed. Effective
Clinical manifestations of autonomic dysfunction strategies for earlier detection of clinical CVD could
and other microvascular complications frequently occur reduce morbidity and mortality in patients with diabetes
concurrently but in inconsistent patterns. The perception (Table 58.3).
of angina was severely impaired in the diabetic patients, Clinicians have been relying on more sophisticated
allowing these individuals to exercise longer after the techniques such as exercise echocardiogram (ECG),
onset of myocardial ischemia even during exercise testing. coronary calcium scoring (CCS), stress ECG, and myo­
The presence of cardiac autonomic neuropathy does not cardial perfusion (MP), single photon emission com­
exclude painful MI among individuals with diabetes. puted tomography (SPECT) (MPS) imaging to detect
Chest pain at any location in a patient with diabetes silent ischemia. The exercise tolerance test with ECG is
should be considered to be of myocardial origin until relatively inexpensive and widely available, and it has
proven otherwise; but, of equal importance, unexplained been an important tool in the evaluation of CVD for
fatigue, confusion, tiredness, edema, hemoptysis, nausea several decades and provide prognostic information in
and vomiting, diaphoresis, arrhythmias, cough or dyspnea the T2DM population echocardiography combined with
should alert the clinician to the possibility of silent MI. pharmacological stress is capable of detecting silent
CAD while avoiding the challenge of exercise and costs
Screening and Investigations of MPS, but there is less published experience in diabetic
patients.34 
Diabetic patients stand a 4–6 times higher risk of MI. At To increase the yield of screening tests, a testing
least 65% of type 2 DM individuals will die from CV causes, strategy will need to focus on those at higher risk. What
 860 Complications

Table 58.3: Detection of clinical and subclinical cardiovascular Coronary Artery Bypass Graft versus
disease in the diabetic patient Percutaneous Coronary Intervention
History: Assess carefully for claudication, angina, dyspnea on
exertion, cerebrovascular disease A series of trials, showed that the Bypass Angioplasty
Physical exam: Routine cardiovascular examination; assess for Revascularization Investigation BARI subgroup had a
carotid and femoral artery bruits; evaluate peripheral artery pulses; significant survival benefit with coronary artery bypass
ratio of ankle-to-brachial artery systolic blood pressure (marker of graft (CABG).36 This heralded the onset of specific
subclinical peripheral vascular disease)
section

coronary strategies for patients with diabetes. Of note, this

Bed side autonomic function tests- Blunting of blood pressure and
10

trial was conducted in the era prior to coronary stenting

heart rate responses
and the poor outcomes with the percutaneous coronary
ECG—Painless ST-segment depression, LV hypertrophy
intervention (PCI) group could be attributed to vessel
Exercise or pharmacological stress201Tl (or99Tc) perfusion scintig-
restenosis. With the introduction of the bare metal stents,
raphy
the equation shifted slightly in favor of the PCI, with the
Ambulatory ECG monitoring for silent ischemia
Arterial Revascularization Therapy study ARTS showing
Echocardiography (with Doppler) and radionuclide ventriculogra-
equivalent outcomes in both the groups.37 However,
phy showing diastolic dysfunction and LV wall motion abnormalities
the PCI group had higher repeat revascularization. In
Laboratory: Check for microalbuminuria
the diabetes subgroup, CABG fared better in terms of
Electron beam CT: Coronary calcium score highly correlated with
major CV outcomes and 1 year repeat revascularization.
total coronary atherosclerosis burden (role in risk assessment
currently under investigation) Stent of Surgery (SOS) trial38 mirrored the results of the
Carotid ultrasound: Detects subclinical carotid atherosclerosis (role ARTS.39 However, both these trials happened prior to the
in risk assessment currently under investigation) routine use of thienopyridines and Gp IIb/IIIa inhibitors.
(ECG: Electrocardiogram; LV: Left ventricle; CT: Computed The addition of Gp IIb/IIIa inhibitors was particularly
tomography) beneficial in patients with diabetes, which was shown in
a meta analysis. The next major breakthrough was the
is needed is a more insightful method for selecting pati­ introduction of drug eluting stents (DES) which greatly
ents who should proceed to testing for atherosclerosis brought down the restenosis rates. The two major classes
or high-risk ischemia. The 2011 guidelines from the of DES are sirolimus eluting stents and paclitaxel eluting
American Diabetes Association (ADA) clearly discourage stents. Regardless of the type of stent used, patients with
routine screening for CAD in the asymptomatic diabetic diabetes have a higher rate of CV events postPCI than
population. However, they concluded that in asymp­ those without diabetes. The same was confirmed by
tomatic patients with very high CHD risk, screening with Synergy Between Percutaneous Coronary Intervention
radionuclide imaging is appropriate. with TAXUS and Cardiac Surgery (SYNTAX) and Coronary
Emerging data on circulating markers such as hsCRP Artery Revascularization in Diabetes (CARDia) trials,40
and high-sensitivity Troponin T (hsTroponin T) and Lp(a) although CARDia was underpowered to reach the
report on aspects of atherosclerosis pathogenesis distinct conclusion. Furthermore, the problem of restenosis could
from traditional risk factors and may ultimately improve be averted by CABG. Future revascularization evaluation
the utility of risk engines in nominating candidates for in patients with diabetes mellitus: optimal management of
further testing.33,35 multivessel disease (FREEDOM) trial has shown CABG to
be superior to PCI for advanced CAD.41
Management of Coronary Artery
Disease in Diabetes Coronary Artery Bypass Graft Outcomes
Management of CAD in diabetes requires careful conside­ As in those without diabetes, internal mammary artery
ration of medication as well as revascularization therapy. (IMA) offers higher long term patency when compared
Drugs used for diabetes also have a major role to play in to reversed saphenous veins. Thus, IMAs are preferred in
the optimal medical management of the patient with diabetes, although the practice of bilateral IMA stenting
diabetes and CAD. should be avoided due to risk of sternal wound infections.