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.

Public Health Relevance

Polycystic Ovary Syndrome (PCOS) effects approximately 10% of women, greatly increases the risk of developing type 2 diabetes and fatty liver disease and is the leading cause of infertility in the United States, yet there are very few therapies for PCOS, in part because the pathogenesis of PCOS is not well understood. In particular very little has been studied regarding hepatic steatosis and insulin resistance in PCOS in youth. In this proposal we will develop and implement a more efficient, less invasive and more physiologic method to simultaneously assess for rates of live fat production and tissue specific insulin resistance. Results of this study could inform which new therapeutic may have the best chance of efficacy in future clinical trials, and this model could then be utilized to evaluate the effectiveness of the intervention. Further this model could be applied for studies in other patient populations with hepatic steatosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK107871-01
Application #
9013233
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2015-09-21
Project End
2019-08-31
Budget Start
2015-09-21
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$179,916
Indirect Cost
$13,327
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Cree-Green, Melanie; Stuppy, Jacob J; Thurston, Jessica et al. (2018) Youth With Type 1 Diabetes Have Adipose, Hepatic, and Peripheral Insulin Resistance. J Clin Endocrinol Metab 103:3647-3657
Cree-Green, Melanie; Cai, Ninghe; Thurston, Jessica E et al. (2018) Using simple clinical measures to predict insulin resistance or hyperglycemia in girls with polycystic ovarian syndrome. Pediatr Diabetes 19:1370-1378
Cree-Green, Melanie; Scalzo, Rebecca L; Harrall, Kylie et al. (2018) Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes. Diabetes 67:1369-1379
Bjornstad, Petter; Cree-Green, Melanie; Baumgartner, Amy et al. (2018) Achieving ADA/ISPAD clinical guideline goals is associated with higher insulin sensitivity and cardiopulmonary fitness in adolescents with type 1 diabetes: Results from RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) and Effects of MEtform Pediatr Diabetes 19:436-442
Cree-Green, Melanie; Xie, Danielle; Rahat, Haseeb et al. (2018) Oral Glucose Tolerance Test Glucose Peak Time Is Most Predictive of Prediabetes and Hepatic Steatosis in Obese Girls. J Endocr Soc 2:547-562
Simon, Stacey L; Behn, Cecilia Diniz; Cree-Green, Melanie et al. (2018) Too Late and Not Enough: School Year Sleep Duration, Timing, and Circadian Misalignment Are Associated with Reduced Insulin Sensitivity in Adolescents with Overweight/Obesity. J Pediatr :
Bjornstad, Petter; Cree-Green, Melanie; Baumgartner, Amy et al. (2017) Leptin is associated with cardiopulmonary fitness independent of body-mass index and insulin sensitivity in adolescents with type 1 diabetes: a brief report from the EMERALD study. J Diabetes Complications 31:850-853
Cree-Green, Melanie (2017) Worldwide Dissatisfaction With the Diagnostic Process and Initial Treatment of PCOS. J Clin Endocrinol Metab 102:375-378
Cree-Green, Melanie; Cai, Ninghe; Pyle, Laura et al. (2017) Insulin Resistance in Youth Without Diabetes Is Not Related to Muscle Mitochondrial Dysfunction. J Clin Endocrinol Metab 102:1652-1660