SummaryPersistent endogenous hepatic glucose production is characteristic of the newborn lamb in response to exogenous glucose infusion. The hypothesis that decreased hepatic sensitivity for insulin may be a major mechanism accounting for the imprecision in glucose homeostasis was tested in 28 unanesthetized, mixed breed, term lambs. Either 0, 5.7, 6.2, or 12.5 mg glucose/kg/min was infused for a period of 2 hr after which simultaneous infusion of 0, 1.25, or 6.25 mU porcine insulin/kg/min was administered for 4 hr to produce a euglycemic, hyperinsulinemic steady state. Gluconeogenesis from lactate was measured by determining the ratio of14C to3H in plasma glucose during the simultaneous infusion of14Cu-lactate and3H6-glucose. Endogenous hepatic glucose production was determined by the prime-constant infusion technique of Steele using3H6radio-labeled glucose during a 50-min turnover period after the infusions. All animals maintained a constant plasma glucose concentration and glucose specific activity during the turnover period. Gluconeogenesis was significantly suppressed when insulin levels were in the 49–61 μU/ml range although endogenous glucose production was not affected. When plasma insulin concentrations were above 200 μU/ml, both gluconeogenesis and endogenous glucose production were significantly suppressed. These changes were observed irrespective of the steady state blood glucose concentration. Plasma glucagon concentrations were the same in all experimental groups and were not affected by glucose and insulin infusion nor were they responsive to differences in plasma glucose or insulin concentrations. Our data indicates that insulin may be the major hormone for the control of glucose homeostasis in the neonatal lamb and that there is a quantitative difference in the response of the various glucose homeostatic mechanisms to insulin.SpeculationRegardless of the plasma glucose concentration and the resultant counter-regulatory responses that may occur during prolonged continuous glucose infusion, endogenous glucose production in the neonatal lamb may be primarily controlled by insulin.