Abnormal coupling of insulin receptor binding in noninsulin-dependent diabetes

By use of the glucose clamp sequential insulin infusion technique, we compared the dose-response characteristics of insulin-mediated glucose disposal in 17 patients with noninsulin-dependent diabetes mellitus (NIDDM) and 13 age- and weight-matched nondiabetic volunteers. In terms of plasma insulin concentrations, the dose-response curve in the diabetics was shifted to the right (K(m) 156 with a decreased maximum response (V(max) 320 ± 22 vs. 405 ± 10 mg.m^-2.min^-1 in nondiabetics, P < 0.01). Moreover, coupling between insulin receptor binding and activation of insulin effector units was defective in the diabetic subjects (half-maximally effective insulin receptor occupancy 184 ± 11 vs. 145 ± 12 pg in nondiabetics for monocytes, P < 0.02, and 120 ± 8 vs. 85 ± 4 pg for erythrocytes in nondiabetics, P < 0.01). The presence of defective coupling in itself could explain the abnormal insulin dose-response characteristics for glucose disposal in NIDDM and differentiates the insulin resistance of this condition from that of obesity in which coupling is normal.