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"""""""".

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK020948-09
Application #
3226848
Study Section
Metabolism Study Section (MET)
Project Start
1978-09-15
Project End
1988-03-31
Budget Start
1986-09-01
Budget End
1988-03-31
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
School of Medicine & Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Salhanick, A I; Schwartz, S I; Amatruda, J M (1991) Insulin inhibits apolipoprotein B secretion in isolated human hepatocytes. Metabolism 40:275-9
Jackson, T K; Salhanick, A I; Elovson, J et al. (1990) Insulin regulates apolipoprotein B turnover and phosphorylation in rat hepatocytes. J Clin Invest 86:1746-51
Salhanick, A I; Leighty, S J; Amatruda, J M (1989) Postreceptor regulation of insulin action in primary cultures of rat hepatocytes by oral hypoglycemic agents: effects of linogliride and chlorpropamide. Horm Metab Res 21:596-601
Salhanick, A I; Chang, C L; Amatruda, J M (1989) Hormone and substrate regulation of glycogen accumulation in primary cultures of rat hepatocytes. Biochem J 261:985-92
Salhanick, A I; Amatruda, J M (1988) Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus. Am J Physiol 255:E173-9