Hyperinsulinemia is frequently associated with a variety of insulin-resistant states and has been implicated causally in the development of insulin resistance. This study examines the metabolic consequences of prolonged hyperinsulinemia in humans. Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU · kg⁻¹ · min⁻¹, aimed at elevating plasma insulin levels to ∼30 mU/L) or normal saline, subjects were assessed for 1) glucose turnover with 3-[³H]glucose; 2) insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and 3) monocyte insulin-receptor binding. Hepatic glucose production (Ra) was suppressed by >95% during each euglycemic clamp and during the 20-h insulin infusion. After the insulin infusion, Ra and glucose utilization rate returned to the initial basal level within 1 h, as did insulin levels. At that time, insulin sensitivity was significantly decreased, as measured by the “insulin action” parameter during the 40- to 80-min phase of the clamp (0.049 ± 0.003 vs. 0.035 ± 0.007 min⁻¹ P < .05) and during the 80- to 120-min phase (0.047 ± 0.005 vs. 0.039 ± 0.007 min⁻¹, .05 < P < .1). The IVGTT minimal model analysis revealed a fall in the rate of glucose disposal (KGTT) (2.8 ± 0.6 vs. 1.9 ± 0.2 min⁻¹ P < .05), which was entirely explained by a decrease in insulin sensitivity (SI, 9.4 ± 0.3 vs. 3.8 ± 0.2 min⁻¹ · μU⁻¹ · ml⁻1, P < .02); there was no change in glucose-mediated glucose disposal (SG, 0.029 ± 0.004 vs. 0.029 ± 0.004 min⁻¹) or pancreatic Ybgr;-cell responsiveness (ø1, 2.7 ± 0.4 vs. 2.6 ± 0.5 μU · ml⁻¹ · min mg⁻¹ · dl⁻¹; ø2, 7.8 ± 2.4 vs. 7.8 ± 2.4 μU · ml⁻¹ · min⁻² – mg⁻¹ · dl⁻¹). Monocyte insulin-receptor binding was unaffected by the prolonged hyperinsulinemia.

Our studies indicate that modest sustained hyperin- sulinemia may lead to decreased insulin action in the presence of normal monocyte insulin-receptor binding and normal pancreatic insulin secretion. If the monocyte reflects insulin binding in the key insulin-sensitive tissues, this defect in insulin action probably lies at a postreceptor level.