Pima Indians have the highest reported prevalence rate of noninsulin-dependent diabetes mellitus (NIDDM) in the world, so that metabolic comparisons with caucasians, who have a much lower rate, should provide insights into the pathogenesis of NIDDM. We have compared 81 caucasians with 211 Pima Indian nondiabetic subjects similar in age, sex, degree of obesity, and glucose tolerance. During a hyperinsulinemic euglycemic clamp at physiological insulin concentrations, Pima Indians were 17% more insulin resistant than caucasians after accounting for any differences in degree of obesity (P less than 0.0001). During oral glucose tolerance testing, mean plasma insulin concentrations were 33% higher in the Pimas (P less than 0.0001), but these differences were largely explained by the greater insulin resistance in the Pimas. Insulin clearance did not differ between the races. However, early insulin responses were exaggerated in the Indians and not explained by insulin resistance. After accounting for differences in insulin action, plasma insulin concentrations in Pima Indians were 50% higher than those in caucasians 3-5 min after iv glucose (P less than 0.0001), 38% higher 10 min after the end of a meal (P less than 0.0001), and 20% higher 30 min after an oral glucose load (P less than 0.006). These data suggest that in addition to insulin resistance, Pima Indians have exaggerated early insulin release and either increased beta-cell mass or enhanced beta-cell sensitivity to glucose. The data argue against low or delayed insulin secretion as primary factors leading to NIDDM in Pima Indians and favor insulin resistance as the underlying and initiating cause of the disease.