Plasma glucagon response to glucose in diabetic subjects was observed before and after treatment. In normal subjects, plasma glucagon concentrations decreased substantially after an oral glucose load. In all diabetic patients before treatment, plasma glucagon was not suppressed and rather tended to rise paradoxically despite pronounced hyperglycemia. In diabetics treated with sulfonylurea or insulin, basal plasma glucagon concentrations were significantly lower than those in patients who were not treated. However, plasma glucagon response to an oral glucose load was not normalized by successful treatment with sulfonylurea or insulin, in spite of improvement of glucose tolerance. These results suggest that the insensitivity of the A-cell to hyperglycemia exists after treatment, and this abnormal plasma glucagon response to glucose after treatment may be caused either by impaired response of endogenous insulin to glucose, which is sustained even after treatment, or by an intrinsic defect of the A-cell.