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