Acute insulin release in response to maximal intravenous doses of glucose (0.5 g/kg), tolbutamide (1 g), and glucagon (1 mg) was studied in 10 subjects with non-insulin-dependent diabetes of the young (NIDDY) and 10 age-, sex-, and weight-matched controls. Diabetic subjects had attenuated insulinemic responses to all three stimuli, in comparison with control subjects. However, insulin responses to glucagon and tolbutamide were higher than those obtained with intravenous glucose. This study demonstrates that the pancreatic beta-cell is more responsive to nonglucose secretagogues than to glucose stimuli in individuals with NIDDY.