The role of plasma glucose concentration in the regulation of endogenous glucose production in the human newborn was examined by infusing glucose at 2.6-4.6 mg/kg . min as a continuous infusion to eight normal term appropriate for gestational age infants, five preterm, and six small for gestational age infants. All infants were healthy, had no overt clinical problems and were studied 6 h after their last feed. Glucose production rates were measured during the basal state and during glucose infusion by tracer dilution using [6,6(2)H2]glucose. The rate of glucose production during the basal state was similar in preterm and term appropriate for gestational age infants (appropriate for gestational age 3.53 +/- 0.32, preterm 3.49 +/- 0.38 mg/kg . min, mean +/- SD), while it was higher in the small for gestational age infants (4.25 +/- 0.98, p less than 0.03) as compared with appropriate for gestational age. During glucose infusion, the peak glucose concentration was related to the rate of glucose infusion. The endogenous glucose production rates during glucose infusion were variable in the three groups. However, a negative correlation between peak glucose concentration and endogenous glucose production rate was observed (r = 0.59, p = 0.006). The insulin response to glucose infusion was comparable in all infants. In addition, three small gestational age and one preterm infants, who had become hypoglycemic in the immediate newborn period, were studied while they were receiving parenteral glucose and their plasma glucose had stabilized at 55.5 +/- 10.25 mg/dl. Tracer kinetic studies showed persistence of endogenous glucose production in these infants even though they were receiving high rates of exogenous glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)