Effect of successful treatment on plasma glucagon response to arginine was studied in patients with diabetes mellitus, Cushing's syndrome and hypothyroidism. Exaggerated response of plasma glucagon to arginine infusion in diabetic subjects was normalized in those successfully treated with sulfonylureas and significantly improved in those treated with insulin. Patients with Cushing's syndrome and hypothyroidism also exhibited excessive responsiveness of plasma glucagon, which were completely normalized following treatment. The results suggest that the metabolic derangement is a main etiologic factor in inducing hyperresponsiveness of plasma glucagon to arginine in these disorders.