Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS

Conditions
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Polycystic Ovarian Syndrome, Obesity, Hepatic Steatosis

Intervention / Treatment
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* Dietary Supplement: Essential Amino Acid (EAA) Supplement
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females Ages 12-21 Sedentary- less than 2 hours of moderate (jogging, swimming etc) exercise a week. BMI equal or greater than the 90th percentile for age and gender PCOS per the most stringent NIH criteria adapted for adolescents (irregular menses >24 months post-menarche and clinical or biochemical hypertestosteronemia) HS per FibroScan ultrasound, with CAP score of >225 (will be measured at screening visit) Exclusion Criteria: 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. 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 < 11 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 >125 IU/L

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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) | 

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