Post-Prandial Liver Glucose Metabolism in PCOS (PLUM)

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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Polycystic Ovarian Syndrome; Hepatic Steatosis
• Intervention / Treatment: Diagnostic test: oral glucose tolerance test; Diagnostic test: MRI of liver

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.

• Study Type: Observational
• Enrollment (Actual): 19

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anshutz Medical Campus/Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Girls age 12-21. Obese >90th percentile for BMI for age.

Description

Inclusion Criteria:

1. Female
2. Ages 12-21
3. Sedentary- less than 2.5 hours of moderate (jogging, swimming etc) exercise a week.
4. BMI equal or greater than the 90th percentile for age and gender

5. 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.

6. 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.

7. For non-PCOS groups:

   • regular menstrual cycles at least 1.5 years after menarche, and
   • no clinical evidence of hyperandrogenism.

Exclusion Criteria:

1. 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.
2. Currently pregnant or breastfeeding women. Development of pregnancy during the study period will necessitate withdrawal from the study.
3. Severe illness requiring hospitalization within 60 days
4. Diabetes, defined as Hemoglobin A1C > 6.4%
5. BMI percentile less than the 90th percentile for age and sex.
6. Weight >325 lbs or <84 lbs.
7. Anemia, defined as Hemoglobin < 10 mg/dL
8. Diagnosed major psychiatric or developmental disorder limiting informed consent
9. Implanted metal devices that are not compatible with MRI
10. Use of blood pressure medications

11. Known liver disease other than NAFLD or AST or ALT >150 mg/mL

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Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Untreated PCOS; PCOS per NIH criteria. Obese Lifestyle treatment only.	Diagnostic test: oral glucose tolerance test; 6 hours OGTT; Diagnostic test: MRI of liver; MRI of the liver and use of DIXON method
Metformin PCOS-(Study arm not funded); 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; 6 hours OGTT; Diagnostic test: MRI of liver; MRI of the liver and use of DIXON method
Oral Contraceptive PCOS-(Study arm not funded); 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; 6 hours OGTT; Diagnostic test: MRI of liver; MRI of the liver and use of DIXON method
Obese Control group-(Study arm not funded); Obese Regular menses at least 18 months post-menarche Females only	Diagnostic test: oral glucose tolerance test; 6 hours OGTT; Diagnostic test: MRI of liver; MRI of the liver and use of DIXON method

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic Fat Fraction	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.	Measured up to 4 months from enrollment

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Melanie Cree-Green, MD, PhD, University of Colorado, Denver

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2017
• Primary Completion (Actual): August 29, 2018
• Study Completion (Actual): September 29, 2018

Study Registration Dates

• First Submitted: January 31, 2017
• First Submitted That Met QC Criteria: January 31, 2017
• First Posted (Estimated): February 2, 2017

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: hepatic de novo lipogenesis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Liver Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Syndrome; Fatty Liver
• Other Study ID Numbers: 16-2399

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No