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Insulin Continues to Induce Plasminogen Activator Inhibitor 1 Gene Expression in Insulin-Resistant Mice and Adipocytes

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Abstract

Background

Although the association between insulin resistance and cardiovascular risk is well established, the underlying molecular mechanisms are poorly understood. The antifibrinolytic molecule plasminogen activator inhibitor 1 (PAI-1) is a cardiovascular risk factor that is consistently elevated in insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). The strong positive correlation between this elevated PAI-1 and the degree of hyperinsulinemia not only implicates insulin itself in this increase, but also suggests that PAI-1 is regulated by a pathway that does not become insulin resistant. The data in this report supports this hypothesis.

Materials and Methods

We show that insulin stimulates PAI-1 gene expression in metabolically insulin-resistant ob/ob mice and in insulin-resistant 3T3-L1 adipocytes. Moreover, we provide evidence that glucose transport and PAI-1 gene expression are mediated by different insulin signaling pathways. These observations suggest that the compensatory hyperinsulinemia that is frequently associated with insulin-resistant states, directly contribute to the elevated PAI-1.

Conclusions

These results provide a potential mechanism for the abnormal increases in cardiovascular risk genes in obesity, NIDDM, and polycystic ovary disease.

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Acknowledgments

This work was supported in part by grants from the NIH (HL 47819 and HL 59549) and Novartis to DJL. The authors thank T. Thinnes for technical assistance and M. McRae for her expert secretarial skills. TSRI Manuscript No. 12576-VB.

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Authors and Affiliations

  1. Department of Vascular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, VB-3, La Jolla, California, 92037, USA

    Fahumiya Samad, Manjula Pandey & David J. Loskutoff Ph.D.

  2. Metabolic and Cardiovascular Research, Novartis Pharmaceuticals, Summit, New Jersey, USA

    Philip A. Bell

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  1. Fahumiya Samad
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  2. Manjula Pandey
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  3. Philip A. Bell
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  4. David J. Loskutoff Ph.D.
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Correspondence to David J. Loskutoff Ph.D..

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Samad, F., Pandey, M., Bell, P.A. et al. Insulin Continues to Induce Plasminogen Activator Inhibitor 1 Gene Expression in Insulin-Resistant Mice and Adipocytes. Mol Med 6, 680–692 (2000). https://doi.org/10.1007/BF03402048

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