The Overall Specific Aims of this research are to determine the mechanisms and pathogenesis of insulin resistance in the polycystic ovary syndrome (PCO). This research will provide insight into the cause(s) of PCO and of non-insulin dependent diabetes mellitus (NlDDM). PCO, a hyperandrogenic disorder of unknown etiology, is one of the most common endocrine diseases of women of reproductive age. Women with PCO are markedly insulin resistant, independent of obesity. But PCO and obesity have a synergistic deleterious effect on glucose tolerance such that 20% of obese PCO women have impaired glucose tolerance or frank NIDDM. Our preliminary epidemiologic, family, and fibroblast insulin binding studies strongly suggest that there is a genetic component to the insulin resistance of PCO. Further, there is a strikingly increased prevalence of NIDDM in families of women with PCO consistent with a causal and/or genetic association of these disorders.
The Specific Aims of this proposal are: 1) To Characterize in Detail the Mechanisms of Insulin Resistance In Vivo in PCO. This will be accomplished by defining the sensitivity and responsiveness to insulin of glucose utilization and hepatic glucose production as well as the feedback inhibition of endogenous insulin secretion by insulin. The effect of gonadal steroids on these parameters will be determined by regression analysis. The sequential multiple insulin dose euglycemic glucose clamp technique will be used to define the in vivo dose-response curve to insulin and the modified frequently sampled intravenous glucose tolerance test will be used to determine C-peptide metabolism. 2) To Determine the Cellular Defects in Insulin Action in PCO. This will be accomplished by investigating in vitro insulin binding and uniformly labeled (14C)- glucose transport in isolated adipocytes. The effect of gonadal steroids on these parameters will also be assessed. 3) To Determine if Decreased Cellular Insulin Binding or Action in PCO is an Acquired or Intrinsic (? Genetic) Defect. This will be accomplished by determining whether there are persistent defects in insulin binding, insulin receptor tyrosine kinase activity, and/or glucose transport in cultured fibroblasts from PCO women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040605-03
Application #
3240983
Study Section
Metabolism Study Section (MET)
Project Start
1989-07-01
Project End
1991-12-31
Budget Start
1991-07-01
Budget End
1991-12-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
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Corbould, Anne; Zhao, Haiyan; Mirzoeva, Salida et al. (2006) Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 55:751-9
Corbould, Anne; Kim, Young-Bum; Youngren, Jack F et al. (2005) Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 288:E1047-54
Legro, Richard S; Urbanek, Margrit; Kunselman, Allen R et al. (2002) Self-selected women with polycystic ovary syndrome are reproductively and metabolically abnormal and undertreated. Fertil Steril 78:51-7
Legro, Richard S; Kunselman, Allen R; Demers, Lawrence et al. (2002) Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab 87:2134-8
Legro, Richard S; Bentley-Lewis, Rhonda; Driscoll, Deborah et al. (2002) Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab 87:2128-33
Solomon, Caren G; Hu, Frank B; Dunaif, Andrea et al. (2002) Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 87:2013-7

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