The central theme of this research proposal is to further elucidate the mechanism of insulin resistance in obesity and NIDDM, with particular emphasis on post-receptor defects in insulin's action on glucose disposal. To accomplish this, we plan a broadly based in vitro and in vivo approach. We will determine the in vivo Km and Vmax for overall glucose disposal in both obesity and NIDDM and will combine this with in vitro studies of adipocytes in which glucose transport Km and Vmax is assessed along with the number and distribution of cellular glucose carriers, the level of insulin mediator substance, and insulin receptor kinase activity. Detailed studies of insulin receptor structure, internalization, processing, and degradation will be conducted in cells from obese and NIDDM patients will also be treated with a 3 week period of CSII, to normalize glucose levels. After this, the effects of insuliln therapy on the various in vivo and vitro aspects of insulin resistance will be assessed by repeat studies. In this proposal we will also examine the mechanisms of various therapies such as insulin treatment, sulfonylurea treatment, and weight reduction in obese or NIDDM patients. We also propose that abnormalities in the kinetics of insulin action play a role in insulin resistance and plan to test this by measuring the rate of activation and deactivation of insulin's effects to stimulate glucose disposal and inhibit hepatic glucose production. The role of intermittant versus sustained hyperinsulinemia in causing post-receptor defects will also be assessed, and new methods to measure the rate of non-insulin mediated glucose disposal in vivo are proposed for NIDDM. We also plan to re-examine the Randle hypothesis by measuring the effects of elevated FFA levels on in vivo insulin action and the potential beneficial effects of medium chain triglycerides. Finally, the influence of CSII treatment on the therapeutic effects of sulfonylureas in NIDDM will be explored. Since insulin resistance is a major characteristic feature of obese and NIDDM patients, it is hoped that a better understanding of the in vivo and in vitro mechanisms underlying this metabolic abnormality will lead to better knowledge of the pathogenesis of these disorders, and a more rationale of therapeutic modalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033649-04
Application #
3232057
Study Section
(SSS)
Project Start
1983-08-01
Project End
1989-05-31
Budget Start
1986-06-01
Budget End
1987-05-31
Support Year
4
Fiscal Year
1986
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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