Our previous investigation showed that hyperinsulinemia incompletely suppressed the transcription of the gene encoding L-serine dehydratase (SDH) (EC 4.2.1.13), a gluconeogenic enzyme, in newborn dogs. To test another hypothesis that insulin resistance in newborn mammals may be partially due to counterregulatory factors, such as epinephrine, euglycemic hyperinsulinemic clamps, hyperglycemic hyperinsulinemic clamps, and hyperglycemic hyperinsulinemic hyperepinephrinemic clamps were performed in newborn dogs in the present study. The infusion rates of insulin and epinephrine were 30 m U/kg/min and 150 ng/kg/min, respectively; the glucose infusion rate was adjustable. The SDH mRNA levels in kidney and liver of newborn dogs were quantitatively analyzed by using rat SDH cDNA probe and by a personal densitometer. The results showed that insulins, glucose, and epinephrine did not change the kidney SDH mRNA level; hyperinsulinemia and hyperglycemia reduced the liver SDH mRNA level by 8.5 and 29.2%, respectively; in the presence of hyperglycemia and hyperinsulinemia, epinephrine was able to increase the liver SDH mRNA by 27.8%, almost offsetting the reduction of the liver SDH mRNA level induced by the combination of insulin and glucose. We conclude that the enhanced regulatory effect of epinephrine counteracting insulin on SDH gene transcription in liver of newborn dogs may be one of the mechanisms responsible for the neonatal insulin resistance which contributes to neonatal hyperglycemia.