Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Influence of peripheral insulin resistance and hepatic lipogenesis on liver fat in obese PCOS girls

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? DESCRIPTION (provided by applicant): Polycystic Ovary Syndrome (PCOS), a condition characterized by high levels of male hormones, 3 affects 6-10% of women, is psychosocially difficult in teens due to increased acne and hair growth, costs $4 4 billion a year, and is increasing in prevalence in parallel with the obesity epidemic. PCOS is associated with an 5 increased risk of nonalcoholic fatty liver disease (NAFLD) and as a result, type 2 diabetes and cardiovascular 6 disease, which start to develop in adolescence. Our preliminary data indicates that adolescent girls with PCOS 7 have three-fold higher rates of hepatic steatosis (HS), a pre-NAFLD condition, relative to non-PCOS girls of 8 similar weight. These girls also already have evidence of a pre-diabetes state, insulin resistance (IR). Despite 9 the high prevalence and serious early morbidity associated with PCOS, effective therapeutic options are 10 currently lacking. Development of new therapeutics is limited by the lack of comprehensive, minimally invasive 11 methods to assess how the body normally responds to feeding. 12 Candidate: The candidate is a K12 BIRCWH scholar and Instructor in the Division of Pediatric Endocrinology. 13 She has experience in stable isotope tracer methodology and in cross sectional studies in girls with PCOS. 14 Training: To become an independent investigator, the investigator needs training in advanced stable isotope 15 methodology, mathematical modeling, and in regulations surrounding medical intervention clinical trials. 16 Research: The goals of this application are three-fold: 1) to develop a unified, non-invasive method to measure 17 tissue-specific IR following an oral challenge while simultaneously measuring hepatic fat production; 2) using 18 this method, measure the differences in metabolism between obese girls with and without PCOS, and finally, 19 3) determine if up-regulated hepatic fat production is more related to IR or alterations in post-prandial 20 hormones. 21 Environment: The research environment for this project in excellent, and draws on the mentorship strengths in 22 endocrinology (Kristen Nadeau, Jane Reusch), tracer methodology (Wendy Kohrt, Elizabeth Parks, Robert 23 Eckel, Bryn Bergman), hepatic metabolism and steatosis (Elizabeth Parks, Robert Eckel) and mathematical 24 and statistical modeling (Cecilia Diniz Behn, Laura Pyle). The Colorado CTSI which includes a pediatric 25 specific facility is also a major institutional strength for the proposed training. 26 Impact: A better understanding of IR and mechanisms of hepatic fat production after a meal in PCOS is critical, 27 and may lead to new and improved ways to treat PCOS. This work will then inform the therapeutic choice for 28 future interventional trials to help improve the immediate and long-term health of obese girls with PCOS. This 29 is critical, as so many girls are affected by PCOS, yet treatment options are so limited. Additionally, these 30 methods can also be employed to study therapies in other patient populations with HS.
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