Tissue sensitive to insulin and insulin binding to monocytes were evaluated in 15 nonobese maturity-onset diabetics and in 16 healthy controls. Insulin sensitivity was determined by the insulin clamp technique in which the plasma insulin is acutely raised and maintained 100 muU/ml above the fasting level and plasma glucose is held constant at fasting levels by a variable glucose infusion. The amount of glucose infused is a measure of overall tissue sensitivity to insulin. In the diabetic group, the fasting plasma glucose concentration (168+/-4 mg/dl) was 85% greater than controls (P < 0.01) whereas the plasma insulin level (15+/-1 muU/ml) was similar to controls. During the insulin clamp study, comparable plasma insulin levels were achieved in the diabetics (118+/-5) and the controls (114+/-5 muU/ml). However, the glucose infusion rate in the diabetics (4.7+/-0.4 mg/kg.min) was 30% below controls (P < 0.01). Among the diabetics, the glucose infusion rate correlated directly with the fasting plasma glucose level (r = 0.57, P < 0.05). In five diabetic subjects, glucose metabolism was similar to controls, and these diabetics had the highest fasting glucose levels. When they were restudied after prior normalization (with insulin) of the fasting plasma glucose (100+/-1 mg/dl), the glucose infusion rate during the insulin clamp was 30% lower than observed in association with hyperglycemia (P < 0.01). Studies that employed tritiated glucose to measure endogenous glucose production indicated comparable 90-95% inhibition of hepatic glucose production during hyperinsulinemia in the diabetic and control subjects.(125)I-insulin binding to monocytes in the diabetics (5.5+/-0.6%) was 30% below that in controls (P < 0.01). Insulin binding to monocytes and insulin action as determined with the insulin clamp were highly correlated in both control (r = 0.67, P < 0.01), and diabetic subjects (r = 0.88, P < 0.001). We conclude that (a) tissue sensitivity to physiologic hyperinsulinemia is reduced in most maturity-onset diabetics; (b) this decrease in sensitivity is located, at least in part, in extrahepatic tissues; (c) the resistance to insulin may be mediated by a reduction in insulin binding; and (d) in maturity-onset diabetics with normal tissue sensitivity to insulin, hyperglycemia may be a contributing factor to the normal rates of insulin-mediated glucose uptake.