Post-Prandial Liver Glucose Metabolism in PCOS

Study Overview
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Brief Summary
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The Investigators will measure if hepatic metabolism is upregulated in obese girls with PCOS and hepatic steatosis (HS), compared to PCOS without HS and obese controls without HS.

Detailed Description
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This will be a cross-sectional study with 4 groups of youth. A 6 hour OSTT (Oral Sugar Tolerance Test) with an oral U-C13 glycerol tracer will be paired with nuclear magnetic resonance spectroscopy (NMR) isotopomer analysis of serum samples to describe flux through the hepatic pentose phosphate pathway, TCA cycle and FAS pathways in girls with PCOS receiving lifestyle only, metformin or oral contraceptive treatment, and obese girls with regular menses receiving lifestyle therapy. Hepatic steatosis will be measured with MRI. Please note that 3 study groups: PCOS on metformin, PCOS on oral contraceptive treatment, and obese girls with regular menses were not funded in the study, so no participants were enrolled in these 3 arms of the study.

Official Title
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Post-Prandial Liver Glucose Metabolism in Polycystic Ovarian Syndrome (PCOS) and Understanding Standard of Care Medications

Conditions
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Obesity, Polycystic Ovarian Syndrome, Hepatic Steatosis

Intervention / Treatment
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* Diagnostic Test: oral glucose tolerance test
* Diagnostic Test: MRI of liver


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female Ages 12-21 Sedentary- less than 2.5 hours of moderate (jogging, swimming etc) exercise a week. BMI equal or greater than the 90th percentile for age and gender For PCOS groups: (NIH definition) irregular menstrual cycles at least 1.5 years after menarche, and either clinical evidence of hyperandogenism, or elevated Testosterone (above the norms for age/tanner stage) at time of screening, or documented prior to initiation of therapy for OCP and metformin groups. For PCOS groups: patients un-treated or currently treated with either Metformin 1500-2000 mg a day, or oral contraception (30-35 mcg ethynyl estradiol a day) for at least 6 months, with > 80% adherence confirmed via refill frequency from pharmacy. For non-PCOS groups: regular menstrual cycles at least 1.5 years after menarche, and no clinical evidence of hyperandrogenism. Exclusion Criteria: Use of medications known to affect insulin sensitivity: oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, HIV medications. Nexplanon, Depo-Provera or Mirena progesterone only contraceptives. Dermal patch or vaginal ring contraception methods. For controls only: metformin or oral contraception. Currently pregnant or breastfeeding women. Development of pregnancy during the study period will necessitate withdrawal from the study. Severe illness requiring hospitalization within 60 days Diabetes, defined as Hemoglobin A1C > 6.4% BMI percentile less than the 90th percentile for age and sex. Weight >325 lbs or <84 lbs. Anemia, defined as Hemoglobin < 10 mg/dL Diagnosed major psychiatric or developmental disorder limiting informed consent Implanted metal devices that are not compatible with MRI Use of blood pressure medications Known liver disease other than NAFLD or AST or ALT >150 mg/mL -

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Untreated PCOS<br>PCOS per NIH criteria. Obese Lifestyle treatment only. | Diagnostic Test: oral glucose tolerance test<br>* 6 hours OGTT<br>Diagnostic Test: MRI of liver<br>* MRI of the liver and use of DIXON method<br>|
| Metformin PCOS-(Study arm not funded)<br>PCOS per NIH criteria. Obese Taking 1500 mg of metformin or more per day for at least 6 months. | Diagnostic Test: oral glucose tolerance test<br>* 6 hours OGTT<br>Diagnostic Test: MRI of liver<br>* MRI of the liver and use of DIXON method<br>|
| Oral Contraceptive PCOS-(Study arm not funded)<br>PCOS per NIH criteria. Obese Taking 30 mcg of ethanyl estradiol or more per day for at least 6 months. | Diagnostic Test: oral glucose tolerance test<br>* 6 hours OGTT<br>Diagnostic Test: MRI of liver<br>* MRI of the liver and use of DIXON method<br>|
| Obese Control group-(Study arm not funded)<br>Obese Regular menses at least 18 months post-menarche Females only | Diagnostic Test: oral glucose tolerance test<br>* 6 hours OGTT<br>Diagnostic Test: MRI of liver<br>* MRI of the liver and use of DIXON method<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic fat fraction | Amount of fat in the liver | Within 4 months from Screening Visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic metabolism ratios | Ratio of pentose phosphate pathway, TCA cycle and fatty acid synthesis metabolites following an OGTT | Within 4 months from Screening Visit | 
| Whole Body Insulin Sensitivity | 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. | Within 4 months from Screening Visit | 
| Sleep duration | Sleep duration will be assessed using home actigraphy | Within 4 months from Screening Visit | 
| Sleep quality | 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. | Within 4 months from Screening Visit | 
| Stool microbiome profile | Stool microbiome profiles will be determined | Within 4 months from Screening Visit | 
| Hepatic phosphate concentrations | 31 phosphorus spectroscopy will be utilized to measure hepatic phosphate concentrations | Within 4 months from Screening Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatic de novo lipogenesis