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To determine the secretion of insulin, C-peptide, and proinsulin after oral glucose loading in healthy elderly subjects compared with middle-aged subjects with and without obesity and with NIDDM.Subjects fell into four groups: nonobese middle-aged normal control subjects (CNT group; n = 38, 40-64 years old); obese normal subjects (OB group; n = 18, 40-64 years old); nonobese NIDDM subjects (NIDDM group; n = 28, 40-64 years old); and nonobese elderly subjects (OL group; n = 17, 65-92 years old). Insulin, C-peptide, and proinsulin were determined by radioimmunoassay in plasma samples taken at 0, 30, 60, and 120 min during a 75-g oral glucose tolerance test (OGTT).There were no differences in plasma glucose during the OGTT among the three nondiabetic groups. Hyperinsulinemia was significant in the OB and NIDDM groups but not in the OL group. On the other hand, absolute hyperproinsulinemia was significant in the OL and NIDDM groups compared with the CNT group. Increased proinsulin was rather dominant in the OL group, especially late after glucose loading. Molar ratios of proinsulin to insulin or C-peptide thus were significantly higher in the OL and NIDDM groups.Alteration of pancreatic beta-cell function independent of that seen with NIDDM occurred in relation to aging. This may be a predisposing factor to the development of impaired glucose tolerance or NIDDM in elderly subjects, that is, independent of obesity.