The polycystic ovary syndrome (PCOS) affects approximately 6-10% of women of reproductive age and is characterized by chronic anovulation and hyperandrogenism. Most women with PCOS are also characterized by insulin resistance, and our long-term goal is to elucidate the relationship between insulin resistance and PCOS. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action, and evidence suggests that a deficiency in a specific D-chiro-inositol-containing IPG (DCI-IPG) may contribute to insulin resistance in women with PCOS. We successfully refined and validated a bioactivity assay for DCI-IPG, and assessed DCI metabolism and insulin sensitivity in both women with PCOS and a group of normal control women. We found that women with PCOS, when compared to normal women, had a 1) greater than 5-fold increase in the renal clearance of DCI, 2) 50% reduction in the circulating concentration of DCI, and 3) decreased insulin-stimulated release of DCI-IPG during an OGTT. Moreover, insulin sensitivity (as determined by FSIVGTT) correlated inversely with renal clearance of DCI in all women. These findings are consistent with abnormal handling of DCI in PCOS that results in impaired release of the DCI-IPG mediator and, consequently, insulin resistance. We propose to test the hypothesis that DCI metabolism itself is regulated by insulin in PCOS, such that hyperinsulinemia increases renal clearance of DCI, resulting in deficiencies in DCI and DCI-IPG, and that this is specific for PCOS and does not occur in normal women. If this proves correct, it would suggest that an initial """"""""insult"""""""" producing insulin resistance/hyperinsulinemia in a woman with PCOS would be amplified by a """"""""vicious cycle"""""""" in which renal clearance of DCI is increased, yielding a deficiency in the DCI-IPG mediator, which in turn further decreases insulin sensitivity. Such a mechanism could account for the observation that insulin resistance in women with PCOS is substantially greater than that of age- and BMI-matched healthy women.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035629-11
Application #
7575763
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Parrott, Estella C
Project Start
1997-08-01
Project End
2012-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
11
Fiscal Year
2009
Total Cost
$302,992
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Gupta, Anshu; Jakubowicz, Daniela; Nestler, John E (2016) Pioglitazone Therapy Increases Insulin-Stimulated Release of d-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome. Metab Syndr Relat Disord 14:391-396
Randeva, Harpal S; Tan, Bee K; Weickert, Martin O et al. (2012) Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev 33:812-41
Nestler, John E; Reilly, Elizabeth R; Cheang, Kai I et al. (2012) A pilot study: effects of decreasing serum insulin with diazoxide on vitamin D levels in obese women with polycystic ovary syndrome. Trans Am Clin Climatol Assoc 123:209-19; discussion 219-20
Wickham 3rd, Edmond P; Cheang, Kai I; Clore, John N et al. (2011) Total and high-molecular weight adiponectin in women with the polycystic ovary syndrome. Metabolism 60:366-72
Baillargeon, Jean-Patrice; Iuorno, Maria J; Apridonidze, Teimuraz et al. (2010) Uncoupling between insulin and release of a D-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women With polycystic ovary syndrome. Metab Syndr Relat Disord 8:127-36
Baillargeon, Jean-Patrice; Nestler, John E; Ostlund, Richard E et al. (2008) Greek hyperinsulinemic women, with or without polycystic ovary syndrome, display altered inositols metabolism. Hum Reprod 23:1439-46
Nestler, John E (2008) Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril 90:14-6
Cheang, Kai I; Baillargeon, Jean-Patrice; Essah, Paulina A et al. (2008) Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism 57:1390-7
Nestler, John E (2008) Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 358:47-54
Baillargeon, Jean-Patrice; Diamanti-Kandarakis, Evanthia; Ostlund Jr, Richard E et al. (2006) Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Diabetes Care 29:300-5

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