AGING AND PERIPHERAL AND HEPATIC GLUCOSE METABOLISM

In this proposal We hypothesize that derangement's in carbohydrate metabolism of aging is associated with parallel changes in body composition. We plan to demonstrate these changes during the life span of rats, focusing mainly on muscle and hepatic glucose metabolism and intracellular pathways. We also hypothesize that caloric restriction may reverse many of the derangement's in glucose metabolism of aging rats. Our Specific Aims are to study in aging rats: 1) The effects of body composition and plasma FFA concentration on insulin- and glucose-mediated glucose disposal, glycolysis, and glycogen synthesis. 2) The effects of body composition and plasma FFA concentration on in vivo hepatic glucose fluxes, glycogenolysis, gluconeogenesis. 3) The correlation between the specific alterations in in vivo hepatic and skeletal muscle glucose fluxes and the in vitro kinetics of the rate-determining enzymes of these metabolic pathways, such as glycogen synthase, glucokinase and glucose-6-phosphatase. 4) The impact of early intervention by caloric restriction on body composition and peripheral and hepatic glucose fluxes. Studies will be conducted in 2 rat models: Fischer 344 and Sprauge-Dawley, in 4 different age groups. The significance of this proposal is two fold. First it will quantify the role of increased fat mass on glucose metabolism in aging. Second, if not all impairment is fat mass related, it may point to the mechanisms that are true senescence.