Glucose metabolism was investigated in four infants aged 3-32 months with persistent hypoglycemia and hyperinsulinism of neonatal onset. Fasting hypoglycemia was found to be due both to an insulin-induced decrease in hepatic glucose output to 3.95 +/- 0.30 (SEM) mg/kg X min, a value about two thirds of normal, and to a glucose utilization rate of 4.25 +/- 0.32 mg/kg X min, which exceeded glucose production by about 8%. Simultaneously, and despite hypoglycemia, fasting plasma D-beta-hydroxybutyric acid concentrations were inappropriately low: 406 +/- 146 microM, presumably the result of elevated circulating insulin levels. The infusion of sodium DL-beta-hydroxybutyrate resulted in an increase of plasma glucose (48 +/- 7 vs. 32 +/- 7 mg/dl, P less than 0.01) and lactate (1704 +/- 217 vs. 964 +/- 149 microM, P less than 0.005), without detectable changes in insulin secretion estimated from circulating C-peptide values. Unexpectedly, the increase of plasma glucose was due to the restoration of glucose production up to 6.7 +/- 0.2 mg/kg X min. The individual increments of plasma lactate and glucose production rate were linearly correlated (P less than 0.01). These results together with the known inhibitory effect of ketone bodies on pyruvate dehydrogenation, suggest both increased production of lactate from peripheral recycling of glucose carbon and an increased conversion of this gluconeogenic precursor into glucose.