Post-Prandial Liver Glucose Metabolism in PCOS

Completed

Interventions: Diagnostic Test: oral glucose tolerance test
Diagnostic Test: MRI of liver

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Metformin PCOS-(Study arm not funded)	oral glucose tolerance test	PCOS per NIH criteria. Obese Taking 1500 mg of metformin or more per day for at least 6 months.
Oral Contraceptive PCOS-(Study arm not funded)	oral glucose tolerance test	PCOS per NIH criteria. Obese Taking 30 mcg of ethanyl estradiol or more per day for at least 6 months.
Oral Contraceptive PCOS-(Study arm not funded)	MRI of liver	PCOS per NIH criteria. Obese Taking 30 mcg of ethanyl estradiol or more per day for at least 6 months.
Untreated PCOS	MRI of liver	PCOS per NIH criteria. Obese Lifestyle treatment only.
Metformin PCOS-(Study arm not funded)	MRI of liver	PCOS per NIH criteria. Obese Taking 1500 mg of metformin or more per day for at least 6 months.
Obese Control group-(Study arm not funded)	oral glucose tolerance test	Obese Regular menses at least 18 months post-menarche Females only
Obese Control group-(Study arm not funded)	MRI of liver	Obese Regular menses at least 18 months post-menarche Females only
Untreated PCOS	oral glucose tolerance test	PCOS per NIH criteria. Obese Lifestyle treatment only.

Primary Outcome Measures

Name	Time	Method
Hepatic Fat Fraction	Measured up to 4 months from enrollment	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.

Secondary Outcome Measures

Name	Time	Method
Hepatic Metabolism Ratios	Measured up to 4 months from enrollment	Percent indirect glucose at 360 minutes following an oral sugar tolerance test (OGTT) with an isotope labeled oral glycerol tracer.
Sleep Duration	Measured up to 4 months from enrollment	Sleep duration will be assessed using home actigraphy using the Philips Actigraph wrist-worn watch, and collects 7 days of data.
Sleep Quality	Measured up to 4 months from enrollment	Apnea Hypopnea Index (AHI) will be measured using WatchPAT. 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
Whole Body Insulin Sensitivity	Measured up to 4 months from enrollment	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.
Hepatic Phosphate Concentrations	Measured up to 4 months from enrollment	31 phosphorus spectroscopy will be utilized to measure hepatic Phosphodiesterase (PDE)/Total phosphate concentration. This is measured in the MRI using a phosphorus coil.