Glucose Regulation by Isolated Near Term Fetal Monkey Liver

Abstract

ExtractNear term fetal monkey livers were perfused with a closed recirculating system and a defined perfusion medium. Livers from normal fetal animals were able to release glucose rapidly into the perfusate when they were exposed to glucagon, cyclic AMP, or an aglycemic perfusate, but they did not remove glucose rapidly from the perfusate, synthesize glycogen, or activate liver glycogen synthetase in response to hyperglycemia (Figs. 1,2, and 3; Table I ). Insulin decreased glucose mobilization in response to aglycemia, but did not stimulate glucose uptake during hyperglycemia; insulin activated glycogen synthetase (Table 1; Figs. 1 and 3). Livers from fetuses of streptozotocin-treated mothers and livers from 2-week-old neonates released more glucose into the perfusate in response to aglycemia then did livers from normal fetal monkeys (Fig. 4). These observations support the possibility that neonatal monkey liver is capable of rapidly mobilizing glucose during periods of hypoglycemia but is unable to take up glucose and store glycogen rapidly during periods of hyperglycernia. SpeculationIncomplete development of glycogen synthetic mechanisms in early postnatal life may contribute to decreased liver glycogen reserves. These decreased reserves may then be inadequate for maintaining normoglycemia during periods of increased glucose uptake or utilization by peripheral tissue. (9,10,27,29) support the possibility that at birth hormonal regulation of glycogen metabolism is competent, but direct glucose regulation of glycogen synthesis has not developed.In humans, development of rapid glucose and glycogen mobilizing responses precedes birth (1, 13, 26), and liver glycogen levels, high at birth, decline rapidly during the first few hours of life (3,28). Idiopathic neonatal hypoglycemia does not appear to be associated with impaired glycogenolytic mechanisms since it usually occurs when liver glycogen stores are depleted (3, 28). Consequently, we considered that incomplete development of glycogen synthetic mechanisms in early postnatal life might contribute to decreased liver glycogen reserves and that these inadequate reserves are incapable of maintaining normoglycemia.We now provide additional support for this possibility based on studies with isolated perfused rhesus monkey livers from near term fetuses of normal mothers and mothers with streptozotocin-induced glucose intolerance, and from normal monkey neonates. In all three groups, hepatic glucose removal rates were low in the presence of high glucose concentrations in the perfusion solution. Changes in circulating glucose concentration did not modify glycogen synthetase activity, but in all instances liver glucose was released in response to hypoglycemia. Direct effects of exogenous glucagon and insulin on hepatic glucose output and glycogen cycle enzyme activity were demonstrated in the near term fetus group. METHODS ANIMALSOne of the primary functions for liver is to maintain blood glucose levels. This is achieved by changes in gluconeogenic Pregnant Macaca mulatt...

Effects of Euglycemic Hyperinsulinemia on Neonatal Canine Hepatic and Muscle Metabolism

“…Insulin has been demonstrated to modulate the reciprocal activities of glycogen synthase and phosphorylase toward net glycogen synthesis in various models (7). Nonetheless, glucose may also produce enzyme activation in concert or independently of ambient insulin concentrations (6,28). In the present investigation, sustained euglycemic hyperinsulinemia had no effect on neonatal hepatic or muscle glycogen metabolism.…”

“…Under varying experimental conditions, hormones or substrates have been demonstrated to regulate the activation-inactivation cycle of the enzymes of hepatic glycogen synthesis and gluconeogenesis. I n utero, insulin and glucose or glucose alone have been demonstrated to stimulate the enzymes of glycogen synthesis or to enhance hepatic glycogen content (6)(7)(8)(9).…”

Glucose Production in Pregnant Women at Term Gestation

“…Early in gestation, the isolated, human fetal liver can release glucose in response to aglycemia (37). A similar response has been shown in isolated monkey liver preparation near term gestation (38). Furthermore, the human fetal liver has the necessary enzymes for gluconeogenesis, and the fetal liver explant can incorporate [14C]alanine into glucose (39,40).…”

Fetal metabolism and fetal growth

“…In such infants the weights of most organs, particularly adipose tissue, are increased and this is reflected in an increase in body protein, fat and glycogen (Fee & Weil, 1963; Naeye, 1965;Osier, 1965;Glinsmann, Eisen, Lynch & Chez, 1975). The increased growth rate in utero is thought to result largely from the maternal and concomitant fetal hyperglycaemia (Cornblath & Schwartz, 1966;Pedersen, 1967;Baird, 1969;Adam, 1971).…”