Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS (ORANGE)

The Investigators will measure hepatic glucose and fat metabolism in obese girls with Polycystic Ovarian Syndrome (PCOS) and hepatic steatosis (HS) after taking 4 weeks of an essential amino acid (EAA) supplement or placebo and test whether the EAA supplement can improve hepatic glucose metabolism in these girls.

Study Overview

• Status: Completed
• Conditions: Obesity; Polycystic Ovarian Syndrome; Hepatic Steatosis
• Intervention / Treatment: Dietary supplement: Essential Amino Acid (EAA) Supplement; Other: Placebo

Detailed Description

Girls with Polycystic Ovarian Syndrome (PCOS) and hepatic steatosis (HS) will complete a 12 week double-blinded placebo controlled cross-over study with 4 weeks each of an essential amino acid (EAA) supplement and placebo, and will complete metabolic studies after each intervention. There will be a 4 week wash out period in-between. The metabolic tests after each intervention (EAA/placebo) will include an oral sugar tolerance test (OSTT) and an oral U-C13 glycerol tracer that is paired with Nuclear Magnetic Resonance (NMR) isotopomer analysis of serum samples to describe flux through the hepatic pentose phosphate pathway, tricarboxylic acid (TCA) cycle and fatty acid synthesis pathways in girls with PCOS and HS. Hepatic steatosis will be measured with magnetic resonance Imaging (MRI) and hepatic phosphate concentrations with magnetic resonance (MR) spectroscopy.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado, Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Females
2. Ages 12-21
3. Sedentary- less than 2 hours of moderate (jogging, swimming etc) exercise a week.
4. BMI equal or greater than the 90th percentile for age and gender
5. PCOS per the most stringent NIH criteria adapted for adolescents (irregular menses >24 months post-menarche and clinical or biochemical hypertestosteronemia)
6. HS per FibroScan ultrasound, with CAP score of >225 (will be measured at screening visit)

Exclusion Criteria:

1. Use of medications known to affect insulin sensitivity: metformin, oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, HIV medications, hormonal contraception. Dermal patch or vaginal ring contraception methods.
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. Weight >325 lbs or <84 lbs.
6. Anemia, defined as Hemoglobin < 11 mg/dL
7. Diagnosed major psychiatric or developmental disorder limiting informed consent
8. Implanted metal devices that are not compatible with MRI
9. Use of blood pressure medications
10. Known liver disease other than NAFLD or AST or ALT >125 IU/L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Essential Amino Acid (EAA) Supplement; 4 weeks: Essential Amino Acid Supplement- 15g 2/day	Dietary supplement: Essential Amino Acid (EAA) Supplement; Powder supplement
Placebo Comparator: Placebo; 4 weeks: Placebo- 15g 2/day	Other: Placebo; Powder that will be similar to the essential amino acid supplement

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hepatic Fat Fraction	Change from baseline in presence/severity of hepatic fat fraction will be measured with MRI, and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%.	4 weeks after completing the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Rate of De Novo Lipogenesis	Change from baseline of the rate of overnight de novo lipogenesis will be measured utilizing stable isotope methods with deuterated water, and expressed as the rate of newly synthesized lipids in the serum triglyceride fraction.	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Evaluation of Mitochondrial function via change in ratios of direct to indirect hepatic carbon flux in newly synthesized triglycerides	OSTT with UC13 glycerol after each intervention	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in the hepatic phosphate profile	hepatic phosphate profile via 31 Phosphorus MR spectroscopy after each intervention	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in Whole Body Insulin Sensitivity	Participants will undergo a 75 gram oral glucose tolerance test, and the change from baseline in whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model.	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in Adipose Insulin Sensitivity	Change from baseline of adipose insulin sensitivity will be calculated as the percent suppression of free fatty acids during the oral glucose tolerance test.	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in Sleep duration	Sleep duration will be assessed after each intervention using home actigraphy	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in Apnea Hypopnea Index (AHI)	Apnea Hypopnea Index (AHI) will be measured using WatchPAT after each intervention. 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.	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in Amino Acid Metabolomics: glutamate, valine, leucine, alanine	Targeted amino acid metabolomics will be performed after each intervention	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change in Lipid Metabolomics: 16n1	Targeted lipid metabolomics will be performed after each intervention to look at changes in lipid profiles	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Change Bile Acid Metabolomics: sphingosine-1-phospate	Targeted bile acid metabolomics will be performed after each intervention	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2018
• Primary Completion (Actual): January 14, 2022
• Study Completion (Actual): January 14, 2022

Study Registration Dates

• First Submitted: June 15, 2018
• First Submitted That Met QC Criteria: October 22, 2018
• First Posted (Actual): October 24, 2018

Study Record Updates

• Last Update Posted (Actual): March 8, 2022
• Last Update Submitted That Met QC Criteria: March 4, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: hepatic de novo lipogenesis
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Liver Diseases; Polycystic Ovary Syndrome; Fatty Liver
• Other Study ID Numbers: 18-0803

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Data will only be shared with IRB approved personnel.

Drug and device information, study documents

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