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Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome-Tor Vergata (M.A.M., D.M., M.C., R.D., D.L., M.F., R.L.), 00133 Rome, Italy; Department of Internal Medicine, University of Rome-Tor Vergata (S.F., D.B., A.B., M.P., S.G.), 00133 Rome, Italy; and Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia (P.D.N., G.S.), 88100 Catanzaro, Italy
Address all correspondence and requests for reprints to: Giorgio Sesti, M.D., Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia, Via Tommaso Campanella 115, 88100 Catanzaro, Italy. E-mail: sesti{at}unicz.it.
The insulin receptor substrate-1 (IRS-1) gene has been considered a candidate for insulin resistance, type 2 diabetes, and coronary artery disease. To investigate the relationship between the common Gly972Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. There were no differences between Arg972 IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg972 IRS-1 (P < 0.03). Carriers of Arg972 IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). These results suggest that the Arg972 IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.
This work was supported in part by grants from European Community: EuroDiabetesGene QLG1-CT-1999-00674 (to G.S.), Progetto di Ricerca Finalizzata-Ministero della Sanità (to G.S.), and PRIN-COFIN 2001-Ministero dell’Università e Ricerca Scientifica e Tecnologica (to G.S. and R.L.).
M.A.M. and S.F. contributed equally to this manuscript.
Abbreviations: BMI, Body mass index; CAD, coronary artery disease; IRS-1, insulin receptor substrate-1; PI 3-kinase, phosphatidylinositol 3-kinase.
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