To determine whether endogenous alphaadrenergic activity contributes to abnormal insulin secretion in nonketotic, hyperglycemic, alpha adrenergic patients, alpha adrenergic blockade was produced in normal and diabetic subjects. The diabetics had a significantly (P < 0.01) greater increase in circulating insulin 1 h after an intravenous phentolamine infusion than did the normal subjects. During the phentolamine infusion, there was also a significant augmentation of acute insulin responses to intravenous glucose (20 g) pulses in normal subjects (P < 0.05) and diabetics (P < 0.02); this augmentation was fivefold greater in the diabetics. Simultaneous treatment with the beta adrenergic blocking agent, propranolol, did not alter these findings. Thus a role for exaggerated endogenous alpha adrenergic activity in abnormal insulin secretion of the diabetic subjects is suggested. To determine whether this alpha adrenergic activity might be related to elevated circulating catecholamines, total plasma catecholamine levels were compared in normal and nonketotic diabetic subjects given intravenous glucose pulses. These levels were significantly greater (P < 0.02) in the diabetic compared to the normal group before the glucose pulse, and increased significantly in both groups (P < 0.02 and < 0.001, respectively) after the pulse. These data suggest that excessive catecholamine secretion may lead to an abnormal degree of endogenous alpha adrenergic activity, which contributes to defective insulin secretion in diabetic subjects.