The present proposal contains significant innovations from the progress report. The PI has made an interesting preliminary observation, namely that the generation of oxygen reactive species (ROS) is increased in diabetic patients. While this observation in itself is not novel (for example, Kitahara et al., Diabetes 29: 251, 1980; Hiramatsu et al., Diabetes 37:832, 1988), the PI made the novel observation that this finding can be explained by a decreased ATP generating capacity in the mitochondria. Based on the hypothesis that a mutation of mitochondrial DNA could account for this defect, the PI has identified a novel allele of mitochondrial DNA carrying a mutant haplotype of the ATP synthase 8 subunit. Next, he has shown that white blood cells from NIDDM patients show increased heteroplasmy for this mutant allele. Consistent with this observation, the PI has shown that ATP synthase activity in mitochondria of NIDDM patients is decreased. The PI espouses the view that impaired mitochondrial function may play a role in the pathogenesis of NIDDM, by impairing insulin secretion. Studies of mitochondrial function are proposed using the technique of mitochondria depletion followed by repopulation with mutant mitochondria from NIDDM patients. A clinical correlation with parameter such as insulin resistance, insulin secretion, hepatic glucose production will also be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033649-17
Application #
6176585
Study Section
Special Emphasis Panel (ZRG2-MET (02))
Program Officer
Laughlin, Maren R
Project Start
1983-08-01
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2002-03-31
Support Year
17
Fiscal Year
2000
Total Cost
$285,304
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
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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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