To determine whether cyclic somatostatin (GH-RIH) interferes with glucose utilization and gluconeogenesis we studied levels of blood glucose (BG), immunoreactive insulin (IRI), immunoreactive glucagon (IRG) and of human growth hormone (GH) after iv glucose (330 mg/kg) and iv arginine (0.5 g/kg) in healthy subjects (n=8) and in maturity onset diabetics (n=8; fasting BG less than 200 mg/dl) both in the presence and in the absence of GH-RIH (500 microng/h iv). GH-RIH caused a reduction of glucose utilization in healthy subjects as shown by the decrease of the k-value from 2.08+/-0.22 (SE) % per min to 0.61+/-0.06 (SE) % per min (P less than 0.0005). No significant change of the glucose disappearance rate was observed in maturity onset diabetics by GH-RIH (kI=0.55+/-0.14 (SE) % per min; kII=0.42+/-0.03 (SE) % per min). The response of insulin to glucose was abolished by GH-RIH. The glucose induced suppression of IRG was in part significantly enhanced by GH-RIH in maturity onset diabetics (P less than 0.01). BG rises seen after iv arginine were increased by the administration of GH-RIH both in healthy subjects (P less than 0.001) and in maturity onset diabetics (P less than 0.05). Somatostatin abolished IRI and GH responses to arginine in both groups studied (P less than 0.001). IRG increases after arginine administration were diminished by GH-RIH in both groups (P less than 0.01). Our data demonstrate that GH-RIH impairs the iv carbohydrate tolerance in healthy subjects and facilities an increased hepatic glucose output upon administration of arginine both in controls and in maturity onset diabetics. We attribute the diabetogenic effect of somatostatin to suppression of IRI release rather than to changes in the IRG/IRI ratio in favor of IRG.