The Newborn of Diabetic Rat. II. Impaired Gluconeogenesis in the Postnatal Period

Summary: The incorporation of [U-14C] lactate into blood glucose, the alterations in the postnatal development of hepatic phospho-enolpyruvate (P-enolpyruvate) carboxykinase activity, the concentrations of adenine nucleotides and the cytosolic NAD+/NADH ratios were measured in livers of the newborns of untreated and insulin-treated diabetic (streptozotocin induced) rats during the first 6 h of life. The rate of incorporation of [I4C]-lactate-carbon into glucose in the 6-h-old neonates of insulin-treated diabetic rats was about one-half of the rate observed in age-matched pups of normal rats. The rate of gluconeogenesis from labeled lactate in the 3-h-old neonates of untreated diabetic rats was approximately one-half of that observed in the age-matched pups of normal animals; however, the rates of gluconeogenesis in these two groups of neonates at 6 h of age were not significantly different. The levels of hepatic P-enolpyruvate carboxykinase activity were significantly lower in 3.5− and 6.5-h-old neonates of insulin-treated diabetic rats compared to the age-matched pups of normal rats whereas the activity of this enzyme was significantly lower only in livers of 0.5− and 3.5-h-old neonates of untreated diabetic rats compared to the age-matched pups of normal animals. At birth and during the first 3 postnatal h, the concentrations of hepatic ATP and the adenylate energy charge were significantly higher in the newborns of insulin-treated diabetic rats compared to both normal and untreated diabetic rats; however, a significant reduction in these parameters was observed after 3 postnatal h in neonates of insulin-treated diabetic rats compared to both normal and untreated diabetic animals. The postnatal increase in the hepatic cytosolic redox state (NAD+/NADH) in the newborns of insulin-treated diabetic rats was similar to that observed in the newborn pups of normal animals during the first 3 h postnatal period; however, a significant decline in this parameter was observed only in the neonates of insulin-treated diabetic rats after the third postnatal h. The postnatal increase in the hepatic cytosolic redox state (NAD+/NADH) was significantly lower in the neonates of untreated diabetic rats compared to the age-matched pups of normal rats during the entire 9 h experimental period. The time course of the postnatal changes in the induction of Penolpyruvate carboxykinase activity, the concentrations of adenine nucleotides and the cytosolic redox state in livers of the newborn rats shows that attenuated postnatal development of hepatic Penolpyruvate carboxykinase and the energy state are largely responsible for observed impaired gluconeogenesis from lactate in the neonates of insulin-treated diabetic rats. Speculation: Postnatal alterations in the concentrations of adenine nucleotides and the cytosolic redox state in livers of the neonates of insulin-treated diabetic rats suggest an impaired hepatic mitochondrial metabolism in the immediate postnatal period. Studies of the uptake or transport of adenine nucleotides and anions by isolated mitochondria from livers of the neonates of insulin-treated diabetic rats would aid in our understanding of these changes, and possibly would lead to identification of factor(s) responsible for these changes in livers of newborns of diabetic mothers.