Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It is associated with profound insulin resistance resulting in a markedly increased risk for non-insulin dependent diabetes mellitus (NIDDM) at a strikingly early age (3rd-4th decades). The overall hypothesis of this research is that insulin resistance in PCOS is the result of several distinctive defects in insulin receptor-mediated signaling. Further, we propose that each defect has a unique genetic basis compared to defects producing insulin resistance associated with typical NIDDM, with obesity, or with the rare syndromes of extreme insulin resistance. We have found a novel abnormality of insulin- receptor signaling (increased insulin-independent insulin receptor serine phosphorylation and decreased insulin-stimulated insulin receptor tyrosine phosphorylation) in association with insulin resistance in approximately 50% of PCOS women. This defect is present in the major insulin target tissue, muscle, and persists in cultured cells suggesting a genetic abnormality.
The Specific Aims of this proposal are, thus: 1) To determine the role of insulin receptor serine phosphorylation in the pathogenesis of insulin resistance in PCOS. We hypothesize that increased insulin- independent insulin receptor serine phosphorylation inhibits insulin- induced receptor-mediated signaling in PCOS. This will be investigated by examining the effects of dephosphorylation on the kinase activity of insulin receptors partially-purified from muscle and from fat, using serine specific (e.g. phosphatase type-2A) as well as nonspecific (e.g. alkaline phosphatase) phosphatases. 2) To determine whether there are post-insulin receptor signaling defects in PCOS. In PCOS there is a marked shift to the right in the insulin dose-response curve for glucose uptake in fat and in muscle as well as a decrease in adipocyte GLUT4 content. However, approximately 30% of such insulin resistant PCOS women have normal insulin receptor phosphorylation, and we hypothesize that these women have downstream signaling defects. Moreover, we hypothesize that 50% of PCOS women with defects in insulin receptor phosphorylation will also have decreased insulin-receptor mediated downstream signaling. This will be investigated by assessing insulin stimulation, in vivo and in intact adipocytes, of phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity. Glucose uptake and GLUT4 content will also be determined. The ED50 insulin and Vmax for glucose use and for PtdIns 3-kinase activation will be examined. 3) To determine whether defects in insulin action in PCOS are genetic. If insulin resistance in PCOS is a genetic defect, first degree relatives should be affected. This will be investigated by determining total body and cellular insulin action in brothers of PCOS probands. We will screen for mutations in the insulin receptor and IRS-1 genes of PCOS women with denaturing gradient gel electrophoresis or single stranded conformation polymorphisms. Lean and obese PCOS women, brothers of PCOS women and age-, weight-, ethnicity- and sex-matched normal control subjects will participate in these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK040605-10
Application #
2831924
Study Section
Metabolism Study Section (MET)
Program Officer
Smith, Philip F
Project Start
1989-07-01
Project End
2001-07-31
Budget Start
1997-08-03
Budget End
2001-07-31
Support Year
10
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Diamanti-Kandarakis, Evanthia; Dunaif, Andrea (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981-1030
Sam, Susan; Sung, Yeon-Ah; Legro, Richard S et al. (2008) Evidence for pancreatic beta-cell dysfunction in brothers of women with polycystic ovary syndrome. Metabolism 57:84-9
Sam, Susan; Coviello, Andrea D; Sung, Yeon-Ah et al. (2008) Metabolic phenotype in the brothers of women with polycystic ovary syndrome. Diabetes Care 31:1237-41
Corbould, Anne; Dunaif, Andrea (2007) The adipose cell lineage is not intrinsically insulin resistant in polycystic ovary syndrome. Metabolism 56:716-22
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
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
Palmert, Mark R; Gordon, Catherine M; Kartashov, Alex I et al. (2002) Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab 87:1017-23
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

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