Impaired Hepatic Glycogenolysis Related to Hyperinsulinemia in Newborns from Hyperglycemic Pregnant Rats

Abstract

ABSTRACT. We have investigated the respective roles of insulin and glucagon in the initiation of hepatic glycogen degradation during the early postnatal period in rats, with special regard on the inhibitory effect of insulin on this process. Pregnant rats were rendered either slightly (8.5 mM) or highly hyperglycemic (22 mM) by infusing glucose during the last week of pregnancy. Fasted, newborn rats were studied from delivery to 16 h postpartum. At birth, newborns from slightly hyperglycemic rats showed higher glvcemia and insulinemia and lower plasma glucagonemia --compared with controls. Newborns from highly hyperglycemic rats were still more hyperglycemic and exhibited low plasma glucagon concentrations, but they were not hyperinsulinemic. In control newborns, hepatic glycogen breakdown was triggered by 2 h after delivery. By contrast, hyperglycemic-hyperinsulinemic newborns (newborns from slightly hyperglycemic rats) were unable to mobilize liver glycogen before 8-10 h after delivery. In hyperglycemicnormoinsulinemic newborns (newborns from highly hyperglycemic rats), hepatic glycogen concentration significantly started to decline 2 h after delivery and was no longer different from controls at 8 h. Anti-insulin serum injection at delivery promoted a prompt decrease in liver glycogen stores in controls as well as in newborns from slightly hyperglycemic rats. Phosphorylase alsynthase a ratio rose rapidly after delivery in controls and in newborns from highly hyperglycemic rats (maximum 4 h), whereas in newborns from slightly hyperglycemic rats, it rose much more slowly than in the two other groups (maximum 16 h). These data suggest that, in newborns from hyperglycemic mothers, hyperinsulinemia during late fetal and early neonatal life is the main factor preventing postnatal hepatic glycogenolysis. glucose homeostasis in newborn mammals. The breakdown of the large glycogen stores that have been accumulated in the fetal liver during late pregnancy represents the more rapidly available endogenous source of glucose (1, 2).Hepatic glycogen metabolism is primarily controlled by the respective concentrations of insulin and glucagon in the plasma (3), and it could be assumed that even a slight change in the secretion of one or both hormones during the fetal life may hamper the metabolic adaptation of the newborn to extrauterine life. This is suggested by the situation of infants of poorly controlled diabetic women in whom the severe postnatal hypoglycemia is mainly due to defective glucose production (4).We have previously shown that newborn rats of dams rendered slightly hyperglycemic by continuous glucose infusion during the last third of pregnancy were hyperglycemic at birth, but were profoundly hypoglycemic in the early postnatal period. This hypoglycemia seemed to be due, in a major part, to a defective postnatal hepatic glycogen breakdown, in contrast to control newborns, which exhibited sustained postnatal hepatic glycogenolysis (5). Concurrently, in newborns from hyperglycemic rats, the insulin/glucagon molar ...

Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats

“…However, several lines of evidence indicate that high plasma insulin levels at delivery and during the early postnatal period impair hepatic glucose output. On one hand, the crucial role played by hyperinsulinemia in preventing glycogen breakdown is supported by the ability of anti-insulin serum injected at delivery to promote a prompt decrease in liver glycogen concentration, not only in normal newborns, but also in the offspring of diabetic mothers which are characterized by elevated levels of circulating insulin 37 . Moreover, it has been described that insulin plays a dominant role over glucagon in controlling liver autophagy because, even under high plasma glucagon levels, autophagy is only induced when circulating insulin levels drop 33 .…”

“…However, both a decrease in glycemia and a shift in circulating insulin and glucagon levels have also been reported in the human newborn 43 . The secretory behavior of the human islet a- and b-cells at birth may thus be relevant to normal extrauterine adaptation, and altered secretion might contribute to abnormal states of glucoregulation, as demonstrated in the infants of diabetic mothers 37 , 38 , 44 . In this regard, the herein reported failure of glycogen mobilization seems to be associated with a delay in neonatal maturation of the hepatic mechanisms necessary for endogenous glucose production.…”