The proposed research is a continuation of studies completed and in progress in my laboratory which are designed to characterize the regulation of insulin binding, insulin action and insulin receptor processing in the liver in normal and altered metabolic states. Thus, the scope of this grant covers: a) basal and insulin stimulated metabolic pathways in the liver and how alterations in these pathways affect total metabolism and the responsiveness of these pathways to insulin; b) the specific metabolic abnormalities which confer insulin resistance; c) the regulation of the insulin receptor at both cell surface and intracellular sites and how this regulation is alterd in abnormal metabolic states; d) the mechanisms by which insulin and the insulin receptor is processed in the liver and how this processing is altered in abnormal metabolic states. The proposed studies will evaluate metabolic parameters such as glycogen and lipid synthesis, amino acid uptake and complex metabolic pathways and how they are regulated by substrates, insulin and glucocorticoids. We will evaluate isulin receptor kinase activity and the putative mediator of insulin action to further define mechanisms of insulin resistance. Finally, we will evaluate the distribution and movement of insulin receptors in normal and altered metabolic states and how abnormalities in these processes may relate to insulin resistance. These studies will improve our understanding of insulin mediated hepatic metabolism in a defined in vitro system, primary cultures of rat hepatocytes, and should lead to a deeper understanding of the specific sties involved in the insulin resistance of fasting and diabetes mellitus as well as the specific sites of interaction between glucocorticoids and insulin. With a further understanding of insulin action in normal and altered metabolic states one can more closely define the pathophysiology of a group of disorders characterized by insulin """"""""resistance"""""""".
