Control of glycogen synthesis in health and disease.

Abstract

Investigations in our laboratory have shown that the activity of glycogen synthase phosphatase in the liver is shared by at least two functionally distinct proteins: a G-component, which is tightly associated with glycogen particles, and a soluble S-component. Most preparations of glycogen synthase-b that are isolated from the liver of fed glucagon-treated animals require the presence of both components in order to be converted to synthase-a. The G-component is subject to control mechanisms that do not affect the S-component. Its activity is strongly inhibited by phosphorylase-a. This feature explains why glycogen synthesis and glycogenolysis do not normally occur simultaneously, except in the glycogen-depleted liver, where a futile cycle may occur. Experiments in vitro have shown that a minimal glycogen concentration is required to ensure the interaction between the G-component and phosphorylase-a. The G-component is also selectively inhibited by Ca2+, and the magnitude of this inhibition depends markedly on the glycogen concentration. The latter inhibition is probably one of the mechanisms by which cyclic adenosine monophosphate (cAMP)-independent glycogenolytic agents achieve the inactivation of glycogen synthase in the liver. Glucocorticoid hormones and insulin are required for the induction and/or maintenance of the G-component in the liver. During the development of the fetal rat, glucocorticoids induce the G-component in the liver. This is an essential event in the glucocorticoid-triggered deposition of glycogen in the fetal liver. A functional adrenal cortex is also required in the adult animal to prevent a loss of the capacity for hepatic glycogen storage during starvation. The latter capacity depends on the concentration of functional G-component in the liver. Chronic diabetes causes a similar functional loss. However, the effect of glucocorticoids is not mediated by a putative secretion of insulin.