The Role of Muscle Glycogen in Glucose Homeostatis

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

DESCRIPTION (provided by applicant): Diabetes is a polygenic disease that affects roughly 17 million people in the United States. Diabetes is associated with elevated blood glucose levels. Therefore, enzymes involved in the metabolism of glucose are candidate diabetes genes. Excess glucose is normally removed from the circulation where it is stored as glycogen in both liver and muscle. An essential enzyme in this process is glycogen synthase (GS), which catalyzes the formation of the alpha 1, 4-glycosidic linkages of glycogen using UDP-glucose as the donor. This study asks whether defects in glycogen metabolism affect glucose disposal and therefore are contributory to abnormal whole body glucose metabolism. We will study two transgenic models that address this hypothesis. In one model, the gene encoding the muscle isoform of GS is disrupted. Ironically, these animals perform better than wild-type mice in a glucose tolerance test. We will attempt to explain why the lack of muscle glycogen improves the ability of these mice to dispose of glucose. One possibility is that the knockout animals derive their energy via the oxidation of fuel molecules to a greater extent than their wild type littermates. We will examine several factors to test this hypothesis including muscle fiber type and gene expression patterns. In the second model, we will study the effects of mutations to GS that disable regulation by glucose-6-phosphate and/or phosphorylation in transgenic mice. We will analyze glucose disposal and glycogen synthesis to compare the relative importance of the different regulatory mechanisms.