To examine the effects of prolonged infusions of somatostatin in maturity-onset diabetes, we administered five-hour infusions to eight patients. This infusion resulted in a 45 to 55 per cent decline in plasma insulin and glucagon. Plasma glucose initially fell by 20 to 25 mg per 100 ml, but later rose despite continuing hypoglucagonemia. After five hours, plasma glucose concentration was 40 to 50 mg per 100 ml higher than that observed with saline infusion (P less than 0.001). The degree of hyperglycemia and plasma insulin levels correlated inversely at completion of the infusion (P less than 0.01). In addition, somatostatin resulted in a fivefold increase in beta-hydroxybutyrate and a 40 to 45 per cent rise in branched-chain amino acids (P less than 0.005). Our findings suggest that glucagon is not essential for the development and maintenance of fasting hyperglycemia. Furthermore, accentuation by somatostatin of hyperglycemia, hyperketonemia and hyperaminoacidemia in maturity-onset diabetes argues against its use in patients with residual insulin secretion.