To gain insight into cellular events associated with the progression of obesity to diabetes, we have studied glucose metabolism and insulin responses in adipocytes from monkeys with spontaneous obesity. Over a 3- period, we studied animals which (A) remained relatively lean; (B) became obese (over 30 percent body fat) with normal glucose tolerance; (C) were obese and developed hyperinsulinemia (over 100 microU/ml); and (D) were obese and subsequently developed noninsulin-dependent diabetes (NIDDM) (fasting plasma glucose above 140 mg/dl and abnormal glucose tolerance test). Adipocyte glucose utilization, evaluated by conversion of 14-C-glucose to CO2 and lipids, was measured in the absence and presence of varying concentrations of insulin, using cells prepared from biopsy samples of subcutaneous abdominal fat. The major change in adipocyte metabolism was a decrease in basal and insulin-stimulated glucose utilization in NIDDM, relative to the enhanced responses observed in cells from the obese-hyperinsulinemic monkeys. Longitudinal studies of individual monkeys over 2-3 years led to the following additional observations regarding adipocyte glucose metabolism. Basal and insulin-stimulated glucose utilization dropped markedly as hyperinsulinemia progressed into diabetes. As impairments in glucose tolerance worsened in diabetes, adipocytes showed only a modest or negligible additional impairment in basal and insulin-stimulated glucose oxidation. Insulin binding was reduced in adipocytes from monkeys with obesity as compared to lean controls, and was similar in cells from monkeys with obesity and NIDDM. In the monkeys, obesity was initially associated with enhanced adipocyte metabolism. With the spontaneous development of NIDDM, glucose metabolism in adipocytes was depressed. The progression of metabolic events from hyperinsulinemia to NIDDM in monkeys includes cellular changes in insulin responses at the level of the adipocyte.