Mechanism and Significance of Insulin Resistance in Non-insulin-dependent Diabetes Mellitus

To determine whether receptor and/or postreceptor abnormalities of insulin action were responsible for insulin resistance in nonobese patients with non-insulindependent diabetes mellitus (NIDDM) and to assess the role of insulin resistance in their impaired glucose tolerance, insulin dose-response characteristics, insulin binding to monocytes, and insulin secretion were compared in 10 nonobese patients with NIDDM and six age-weight-matched nondiabetic volunteers. The insulin resistance of the diabetics was characterized by a shift to the right of their insulin dose-response curve (K_m 81 ± 4 μU/ml vs. 58 ± 2 μU/ml in the nondiabetics P < 0.001) but a normal maximal response to insulin. Although monocyte insulin binding was decreased in the diabetics (P < 0.01), their response to insulin was appropriate for the number of insulin receptors occupied indicating normal postreceptor function. Insulin secretion was markedly reduced in diabetic subjects (52 ± 22 vs. 471 ± 90μu.U · ml⁻¹ · 10 mirr1 in the nondiabetic subjects, P < 0.001) and was more strongly correlated with fasting plasma glucose (r = 0.92, P < 0.001) and intravenous glucose tolerance (Kivgtt) (r = 0.98, P < 0.001) than was insulin sensitivity (K_m) (r = 0.23, NS, and r = 0.57, P < 0.05, respectively). We conclude that in nonobese patients with NIDDM, insulin resistance is characterized by a shift to the right of the insulin dose-response curve, which can be accounted for solely by an insulin receptor defect. However, in these patients, impaired insulin secretion rather than insulin resistance appears to be the predominant metabolic abnormality.