The central theme of this research proposal is to continue our studies to further elucidate the mechanisms of insulin resistance in obesity and NIDDM, with particular emphasis on post-binding defects in insulin's action on glucose disposal. To accomplish this, we plan a broadly based combined in vitro and in vivo approach. We will carry out studies of the insulin receptor kinase using receptor from adipocytes and skeletal muscle from fact in NIDDM. We also propose detailed studies of the structure and function of adipocyte glucose transporters. These studies will assess the mechanisms of decreased glucose transporter intrinsic activity. We also plan to assess the in vivo Km and Vmax for overall whole body glucose disposal and more importantly, for skeletal muscle glucose disposal using the femoral arteriovenous catheterization technique. Using this arteriovenous difference technique we will also measure time course and dose response curves for insulin stimulated glucose uptake in normal and insulin resistant states. The dose response for extraction of insulin across the leg will also be measured to determine whether insulin leaves the leg plasma circulation via a receptor or non-receptor mediated process. Concomitant measurements of the volume of distribution of glucose and glucose transit time at different insulin and glucose transit time at different insulin and glucose levels will also be made. Finally, we have recently reported a polymorphism in the insulin receptor gene which is associated with the NIDDM phenotype and even more closely associated with insulin resistance. A series of family studies and further population studies are proposed to further explore the genetics of NIDDM and to assess the relationship between the presence of this insulin receptor gene polymorphism and in vivo and in vitro insulin resistance. Molecular studies are also planned to clone and express the receptor gene from a NIDDM subject homozygous for the polymorphism. Since insulin resistance is an important pathophysiologic feature of obesity and NIDDM, it is our hope that a better understanding of the basic mechanisms underlying this metabolic abnormality will lead to the better knowledge of the pathogenesis of these disorders and a more rationale design of therapeutic modalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK033649-10
Application #
3483648
Study Section
Metabolism Study Section (MET)
Project Start
1983-08-01
Project End
1994-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kruszynska, Yolanta T; Olefsky, Jerrold M; Frias, Juan P (2003) Effect of obesity on susceptibility to fatty acid-induced peripheral tissue insulin resistance. Metabolism 52:233-8
Kruszynska, Yolanta T; Worrall, Dorothy Sears; Ofrecio, Jachelle et al. (2002) Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. J Clin Endocrinol Metab 87:226-34
Hevener, Andrea; Reichart, Donna; Janez, Andrej et al. (2002) Female rats do not exhibit free fatty acid-induced insulin resistance. Diabetes 51:1907-12
Frias, J P; Macaraeg, G B; Ofrecio, J et al. (2001) Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women. Diabetes 50:1344-50
Hevener, A L; Reichart, D; Janez, A et al. (2001) Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male wistar rats. Diabetes 50:2316-22
Frias, J P; Yu, J G; Kruszynska, Y T et al. (2000) Metabolic effects of troglitazone therapy in type 2 diabetic, obese, and lean normal subjects. Diabetes Care 23:64-9
Frias, J P; Basabe, L; Macaraeg, G et al. (2000) Lack of effect of a physiological elevation of plasma non-esterified fatty acid levels on insulin secretion. Diabetes Metab 26:133-9
Kruszynska, Y T; Yu, J G; Olefsky, J M et al. (2000) Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes 49:633-9
Yu, J G; Kruszynska, Y T; Mulford, M I et al. (1999) A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 48:2414-21
Kruszynska, Y T; Mukherjee, R; Jow, L et al. (1998) Skeletal muscle peroxisome proliferator- activated receptor-gamma expression in obesity and non- insulin-dependent diabetes mellitus. J Clin Invest 101:543-8

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