The Arg972 variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients.

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.

Early autonomic dysfunction in glucose-tolerant but insulin-resistant offspring of type 2 diabetic patients.

In type 2 diabetes, both insulin resistance and hyperglycemia are considered responsible for autonomic dysfunction, but the specific role of these two abnormalities is not clear. To test the specific role of insulin resistance on autonomic dysfunction, we studied 69 glucose-tolerant offspring of type 2 diabetic patients, comparing the most insulin-resistant tertile (IR) with the most insulin-sensitive tertile (IS) and comparable control subjects, all undergoing the oral glucose tolerance test, impedentiometry, 24-hour blood pressure and ECG monitoring, and an intravenous glucose tolerance test (IVGTT) followed by a euglycemic hyperinsulinemic clamp, with continuous blood pressure and ECG measurements. Sympathovagal balance was evaluated as low- to high-frequency ratio (LF:HF) by spectral analysis on R-R intervals. The change of systolic and diastolic blood pressure was calculated as [(day-night/d)]x100. In IR, the changes of systolic and diastolic blood pressure were significantly lower versus IS (9.2+/-5.0% versus 12.4+/-3.6%, P<0.02; 13.2+/-6.5% versus 17.4+/-5.2%, P<0.02). During the night, LF:HF fall was reduced in IR (43.1+/-21.0 versus 61.4+/-16.9, P<0.02). Hyperinsulinemia (IVGTT) rapidly and significantly increased LF:HF in IR (4.9+/-3.3 versus basal: 2.3+/-1.4, P=0.03) but not in IS. In offspring of type 2 diabetic patients with normal glucose tolerance and normal blood pressure values, insulin resistance is associated with abnormal control of blood pressure and sympathetic activation. Insulin resistance may therefore be responsible for some early derangements of the autonomic nervous tone control and thus contributes to increase the incidence of arterial hypertension and/or diabetes.