The Arg⁹⁷²Variant in Insulin Receptor Substrate-1 Is Associated with an Atherogenic Profile in Offspring of Type 2 Diabetic Patients

Abstract

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 Gly(972)Arg 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 Arg(972) 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 Arg(972) IRS-1 (P < 0.03). Carriers of Arg(972) 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 Arg(972) 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.

The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes

“…We analysed an additional group of 25 euglycaemic offspring of type 2 diabetes-affected couples from the EUGENE2 cohort http:// www.eugene2.com, last accessed in August 2006; [20,22,23]. PBL expression levels of PEA15 in these offspring were comparable to those of the other type 2 diabetic FDR investigated in this study ( Table 3).…”

“…For each subject, whole-blood samples were drawn from an antecubital vein in the morning after an overnight fast on two separate occasions. Plasma glucose, total cholesterol, HDL cholesterol, triacylglycerol and serum insulin levels were determined in a centralised facility as described previously [19,20]. Diagnoses of type 2 diabetes and IFG were established according to criteria listed previously [21].…”

“…Studies in euglycaemic offspring of type 2 diabetic patients were performed using the EUGENE2 cohort http://www. eugene2.com, last accessed in August 2006; [20,22,23] at the University of Catanzaro Magna Graecia. The clinical characterisation of these individuals has been previously reported [20,22,23].…”

“…eugene2.com, last accessed in August 2006; [20,22,23] at the University of Catanzaro Magna Graecia. The clinical characterisation of these individuals has been previously reported [20,22,23]. The OGTT and euglycaemic-hyperinsulinaemic clamp procedures have also been previously reported [20].…”

“…The clinical characterisation of these individuals has been previously reported [20,22,23]. The OGTT and euglycaemic-hyperinsulinaemic clamp procedures have also been previously reported [20]. Briefly, for clamp studies, insulin (Humulin; Eli Lilly, Indianapolis, IN, USA) was given as a prime continuous infusion to produce plasma insulin levels of ∼420 pmol/l.…”