Liver and Fat Regulation in Overweight Adolescent Girls (APPLE)

Women with polycystic ovarian syndrome (PCOS) have increased rates of hepatic steatosis compared to weight similar women with regular menses. It is unclear if this is related to high testosterone or insulin resistance. The investigators will assess hepatic glucose release, rates of lipolysis and hepatic de novo lipogenesis in the fasted and postprandial state to determine if alterations in the processes contribute to hepatic steatosis. Participants will be overweight, sedentary girls with or without PCOS. Those with PCOS will either be medication naive, or must be taking metformin or combined oral contraceptives (COCPs) for a period of at least 6 months prior to study procedures.

Hepatic glucose release will be assessed with a stable isotope glycerol tracer, lipolysis with a glycerol tracer, and hepatic de novo lipogenesis with an acetate tracer. Data will be collected fasting and after a glucose challenge. The degree of hepatic steatosis and abdominal fat partitioning will be assessed with Magnetic Resonance Imaging (MRI), and total body composition with Dual-energy X-ray absorptiometry (DEXA).

Up to 10 girls with PCOS and 6 months of therapy with combined oral contraceptives (COCPs) prior to study procedures.

10 participants will receive 2 doses of Byetta, one at 7 PM the night prior to metabolic study and the second 30 min before ingestion of glucola

Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy

Amount of fat in the liver measured by MRI and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. Greater than 5% is considered extra fat in the liver.

Participants will undergo a 75 gram oral glucose tolerance test, and whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model.

Apnea Hypopnea Index (AHI) will be measured using WatchPAT. In children and adolescents the scale that will be used is AHI>5 is considered mild sleep apnea. The higher the AHI, indicates more severe sleep apnea. The AHI is the number of times you have apnea or hypopnea during one night, divided by the hours of sleep. Normal sleep: An AHI of fewer than five events, on average, per hour Mild sleep apnea: An AHI of five to 14 events per hour Moderate sleep apnea: An AHI of 15 to 29 events per hour Severe sleep apnea: An AHI of 30 or more events per hour

Sleep duration will be assessed using home actigraphy using the Philips Actigraph wrist-worn watch, and collects 7 days of data.

Change in expression of stool microbiome species by comparing the PCOS group to samples collected from a control group without PCOS. The 5 species with the most significant will be identified and reported from a Manhattan Plot (% rate of appearance): the values above 0 represent species that are greater in the control group than in PCOS and values below 0 represent species that are greater in PCOS than in the control group.

Inclusion Criteria: Females 2 years post-menarche BMI percentile >90% Exclusion Criteria: Type 2 diabetes Anemia Liver disease Medications known to effect insulin sensitivity Cause of oligomenorrhea or hirsutism other than PCOS, >3 hours a week of moderate exercise.

Carreau AM, Pyle L, Garcia-Reyes Y, Rahat H, Vigers T, Jensen T, Scherzinger A, Nadeau KJ, Cree-Green M. Clinical prediction score of nonalcoholic fatty liver disease in adolescent girls with polycystic ovary syndrome (PCOS-HS index). Clin Endocrinol (Oxf). 2019 Oct;91(4):544-552. doi: 10.1111/cen.14062. Epub 2019 Aug 16.

Simon SL, McWhirter L, Diniz Behn C, Bubar KM, Kaar JL, Pyle L, Rahat H, Garcia-Reyes Y, Carreau AM, Wright KP, Nadeau KJ, Cree-Green M. Morning Circadian Misalignment Is Associated With Insulin Resistance in Girls With Obesity and Polycystic Ovarian Syndrome. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3525-3534. doi: 10.1210/jc.2018-02385.