Effects of Glucose on Glycogen Synthetase, Phosphorylase, and Glycogen Deposition in the Perfused Rat Liver

Abstract

Abstract. An increase in the perfusate glucose concentration from near zero to about 11 mM increased glycogen synthesis in the perfused, isolated rat liver from zero to a value about half the maximum seen in the intact animal. Increased synthesis appeared to be due not only to provision of substrate but also to conversion of glycogen synthetase to the active form and of glycogen phosphorylase to the inactive form. These glucose effects, which are apparently independent of changes in levels of hormones or adenosine 3':5'-cyclic phosphate, may be physiologically significant for control of the blood glucose level.The liver plays a central role in the regulation of blood glucose.1' 2 Control appears to be due in part to changes in the tissue level of adenosine 3': 5'-cyclic phosphate (cyclic AMP) resulting from alterations in the activity of the sympathetic nervous system and in the secretion of glucagon and insulin.3 In addition, the liver possesses intrinsic control systems2' 4 which help stabilize the blood glucose. One of these is described in this report.There are several possibilities regarding the nature of these nonhormonal controls. A negative feedback system in which a rise in blood glucose suppresses gluconeogenesis has been proposed by Ruderman and Herrera5 but these workers could show only a small suppression (25%) of gluconeogenesis from alanine by 17 mM glucose in the isolated, perfused liver, and Exton and Park6 could not show any inhibition of gluconeogenesis from lactate by 19 mM glucose in a similar system. A quantitatively significant regulation of glucose utilization through adjustments in the rate of hepatic glycolysis also seems unlikely since the intrinsic rate of this process is very low under aerobic conditions.6 Another possibility, which we have examined in this study, is that glycogen metabolism is affected by the glucose concentration. In this connection, DeWulf and Hers7 found that intravenous injection of glucose into the mouse led to a rapid activation of hepatic glycogen synthetase and suggested that this effect was independent of changes in insulin or glucocorticoid secretion. Holmes and Mansour8 reported that glucose inactivated glycogen phosphorylase in the isolated rat diaphragm in vitro.In the present study, we have found that elevation of the glucose concentration in the medium perfusing the isolated rat liver promotes net synthesis of glycogen by conversion of glycogen synthetase to the active form9 and transformation of glycogen phosphorylase to the inactive form. These effects of glucose appear to be independent of changes in the tissue level of cyclic AMP. 383

The control of glycogen metabolism in the liver

“…As this effect has been obtained in animals made acutely diabetic by the administration of antiinsulin serum [23], it seems not to be mediated by insulin. In agreement with this conclusion, the activation of glycogen synthetase by a glucose load has been recently observed in perfused rat liver [24,25].…”

“…An increase in the concentration of glucose in vivo [26][27][28] or in the isolated perfused liver [24,25] initiates a slight decrease in the amount of active phosphorylase; this effect is much!less striking than that on glycogen synthetase. It is a usual finding that the activity of phosphorylase a measured in a fresh liver homogenate largely exceeds what would be expected from the actual rate of glycogenolysis.…”

Glycogen Regulation in Isolated Perfused Near Term Monkey Liver

“…The present study used an in situ recirculating perfusion system used previously for studies of liver glycogen metabolism in adult rats and near term monkeys (4,(11)(12)(13)20). Perfusate, operative technique, and perfusion conditions are shown in Figure 1.…”

“…The isolated adult rat liver regulates the activities of these two enzymes directly in response to circulating glucose concentration as well as in response to hormones (4,12,13,20). The relative physiologic contributions of glucose and hormonal regulation of glycogen metabolism in vivo are unknown.…”

Insulin Stimulates Protein Synthesis of Glycogen Synthase in Rat Hepatoma H4 Cells Associated with Acceleration of Translation Rate.

“…The stimulatory effect of insulin on glycogen synthesis in various tissues was among the first metabolic actions of this hormone studied in detail [1,2]. Insulin stimulated the activity of the liver glycogen synthase, the rate-limiting enzyme in the pathway from G-6-P to glycogen, and inhibited the glycogen phosphorylase activity [3][4][5][6][7][8][9][10][11]. The activity of glycogen synthase is partially regulated by its state of phosphorylation [1,2,12,13].…”