This competitive renewal application for a K24 Mid-Career Investigator Award in Patient-Oriented Research is to provide continued support for the development of Dr. John E. Nestler as a clinical investigator and, most importantly, as a research mentor. Dr. Nestler is Professor of Medicine at Virginia Commonwealth University's Medical College of Virginia, and has been a productive patient-oriented investigator whose research focus has been the pathophysiologic role of insulin resistance in the polycystic ovary syndrome (PCOS), a disorder that affects 6-10% of women of childbearing age. Dr. Nestler has an established track record of mentorship of young clinical investigators, and has been highly successful in providing research training to young investigators during the 4 year tenure of the active K24 grant. The broad long-term objective of Dr. Nestler's studies has been to conduct both mechanistic and translational studies exploring the role of insulin resistance in PCOS. The specific studies proposed in this application, which are currently funded by an NIH R01 grant, are designed to determine: 1) if decreasing circulating insulin directly by inhibition of islet insulin release with diazoxide in obese women with PCOS (i) decreases renal clearance of D-chiro-inositol (uCIDCI) and (ii) increases the circulating concentration of DCI;2) if decreasing circulating insulin indirectly, by improving insulin sensitivity with pioglitazone, in obese women with PCOS (i) decreases uCIDCI, (ii) increases the circulating concentration of DCI, and (iii) enhances the insulin-stimulated release of the putative DCI-inositolphosphoglycan mediator during an OGTT [oral glucose tolerance test];and 3) if acutely increasing circulating insulin in non obese women with PCOS increases uCIDCI and/or the metabolic clearance rate of DCI. These studies will be conducted on the General Clinical Research Center (GCRC) using state of the art methodologies, such as the modified minimal model FSIVGTT [frequently-sampled intravenous insulin tolerance] to determine insulin sensitivity. The K24 renewal will allow Dr. Nestler to continue his increased mentorship of young investigators and to enhance his personal growth as a clinical investigator. It will do so by continuing to provide Dr. Nestler with increased protected time and to maintain decreases in administrative duties and clinical service responsibilities. As a result of the K24 renewal, Dr. Nestler will be able to devote 75-85% effort to research, personal development in clinical research, and, most importantly, the training and mentorship of young investigators.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HD040237-08
Application #
7618017
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Parrott, Estella C
Project Start
2001-04-01
Project End
2013-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$154,473
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
Le, Trang N; Nestler, John E; Strauss 3rd, Jerome F et al. (2012) Sex hormone-binding globulin and type 2 diabetes mellitus. Trends Endocrinol Metab 23:32-40
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
Essah, Paulina A; Arrowood, James A; Cheang, Kai I et al. (2011) Effect of combined metformin and oral contraceptive therapy on metabolic factors and endothelial function in overweight and obese women with polycystic ovary syndrome. Fertil Steril 96:501-504.e2
Cheang, Kai I; Essah, Paulina A; Sharma, Susmeeta et al. (2011) Divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women. Fertil Steril 96:353-359.e1
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
Essah, P A; Levy, J R; Sistrun, S N et al. (2010) Effect of weight loss by a low-fat diet and a low-carbohydrate diet on peptide YY levels. Int J Obes (Lond) 34:1239-42
Cheang, Kai I; Huszar, Jessica M; Best, Al M et al. (2009) Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome. Diab Vasc Dis Res 6:110-9
Cheang, Kai I; Nestler, John E; Futterweit, Walter (2008) Risk of cardiovascular events in mothers of women with polycystic ovary syndrome. Endocr Pract 14:1084-94
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

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