The role of glucagon in diabetes was studied in four patients with juvenile-type diabetes during continuous insulin infusion and a diet containing 150 g per day of carbohydrate. During insulin alone, plasma glucagon, measured at two-hour intervals, averaged 182±34 pg per milliliter, glucose 269±11 mg per deciliter, glucose excretion 52±8 g per 24 hours, ketone excretion 1.3±0.3 mmol per 24 hours, and urea nitrogen 12±2 g per 24 hours (mean ± S.E.M.). Somatostatin (2 mg per day) lowered glucagon to 60±13 pg per milliliter, glucose to 111 ±17 mg per deciliter, glucose excretion to 1 ±0.7 g per 24 hours, ketone excretion to 0.5±0.2 mmol per 24 hours and urea nitrogen excretion to 8±2 g per 24 hours. Replacement of glucagon raised glucagon to 272±30 pg per milliliter, glucose to 202±20 mg per deciliter, glucose excretion to 14±7 g per 24 hours, ketone excretion to 0.8 mmol per 24 hours and urea nitrogen excretion to 11±2 g per 24 hours. In a subsequent study, similar improvement occurred on a diet of 30 g of carbohydrate daily, when absorption of dietary glucose was negligible. Hyperglucagonemia has an important role in diabetes; its correction reduces diabetic abnormalities to or toward normal. (N Engl J Med 299:433–436, 1978)