Insulin resistance has been reported to partially explain the clinical appearance of neonatal hyperglycemia. To determine the relative resistance to insulin of glucose production vs. glucose utilization, the euglycemic hyperinsulinemic clamp technique was employed for the first time in the human neonate and was combined with stable isotopic determination of glucose production and glucose utilization. The basal rates of glucose production and glucose utilization were determined, after which each neonate was clamped at his or her own euglycemic glucose concentration while receiving regular human insulin at one rate of 0.2, 0.5, 1.0, 2.0, or 4.0 mU. kg-1.min-1. Persistent glucose production (> or = 1 mg.kg-1.min-1) during the clamp was recorded for all groups. A significant increase in the glucose infusion rate (P < 0.001) and in percent glucose utilization (P < 0.01) occurred in the 2.0 and 4.0 mU.kg-1.min-1 insulin groups. Metabolic clearance rate of insulin was significantly greater in the neonate compared with the adult at the 2.0 mU.kg-1.min-1 insulin infusion rate (P = 0.036). Our results indicate that, in contrast to the adult, the neonate has persistent glucose production (P = 0.001) and greater peripheral sensitivity to insulin (P = 0.015).