Compared with control subjects, non-insulin-dependent diabetes mellitus (NIDDM) subjects had both quantitative and qualitative abnormalities in blood insulin and glucose concentrations. The purpose of this study was to determine whether and to what extent normally observed multiphasic patterns of insulin and glucose responses to mixed meals are deranged in NIDDM. A total of 24 volunteers were studied while eating three meals of identical composition at 0745, 1145, and 1645. Twelve had NIDDM, and the remainder were healthy nondiabetic age- and weight-matched control subjects. Blood was withdrawn every 10 min from 0630 to 1930 for measurement of C-peptide, insulin, and glucose concentrations. Peaks were analyzed by computer-based algorithms. Diabetic volunteers displayed several differences from control subjects. First, although the number of insulin peaks was similar, there was a consistent delay of 20-30 min in the appearance of the first postprandial peak. Second, insulin concentrations after lunch were higher than after breakfast, whereas the reverse pattern occurred in control subjects. Third, integrated glycemia was greater after breakfast than after lunch. Fourth, glucose concentrations decreased during the first 30 min after lunch, suggesting accelerated glucose disposal and/or enhanced suppression of endogenous glucose production at this time of day. These data demonstrate that insulin secretion and action and glucose homeostasis in NIDDM are more complex than commonly appreciated. This dynamic state is undetected unless there is frequent blood sampling for measurement of insulin and glucose. The quantitative and qualitative abnormalities that we observed in these parameters are independent of obesity and suggest the need to expand the pathophysiological definition of NIDDM.