Regulation of Hepatic Glycogen Synthesis

Miller, Thomas

Abstract

The long-term goal of this research has been and continues to be an attempt to increase our understanding of how glycogen metabolism is regulated by hormones and other effectors and of the effects of diabetes mellitus on regulation of hepatic glycogenesis. Specifically, I will study the effects of glucose and insulin on hepatic glycogen metabolism at the molecular level and determine how their effects are altered by diabetes. Hepatic glycogen metabolism will be studied using the isolated perfused rat liver and collagenase-dispersed isolated hepatocytes, both of which have the advantage over in vivo preparations of allowing studies virtually eliminating secondary effects. Glycogen synthesis and degradation will be assessed by determining the actions of effector molecules and insulin-deficiency on tissue levels of glycogen, cyclic AMP, and other metabolic intermediates and by studying their effects on labeled substrate incorporation. Enzymatic activities of glycogen synthase, phosphorylase, synthase kinase and synthase (phosphorylase) phosphatase will be determined. I will also study the effects of various effector molecules and diabetes on cyclic nucleotide turnover to assess the role of cyclic AMP in glucose and insulin regulation of glycogenesis. Current studies using DEAE and Sephadex column chromatography for separation of enzymatic activities from crude liver extracts will be extended to determine if the diabetic state alters structure of phosphatase, kinase, synthase and phosphorylase or some phase of the reaction(s) catalyzed. This study should increase current understanding of how hormones work, how liver glycogenesis is regulated, and how diabetes affects these processes.