ORANGE: Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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 Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- Change in Hepatic Fat Fraction [4 weeks after completing the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
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%.
Secondary Outcome Measures
- Change in Rate of De Novo Lipogenesis [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
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.
- Evaluation of Mitochondrial function via change in ratios of direct to indirect hepatic carbon flux in newly synthesized triglycerides [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
OSTT with UC13 glycerol after each intervention
- Change in the hepatic phosphate profile [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
hepatic phosphate profile via 31 Phosphorus MR spectroscopy after each intervention
- Change in Whole Body Insulin Sensitivity [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
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.
- Change in Adipose Insulin Sensitivity [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
Change from baseline of adipose insulin sensitivity will be calculated as the percent suppression of free fatty acids during the oral glucose tolerance test.
- Change in Sleep duration [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
Sleep duration will be assessed after each intervention using home actigraphy
- Change in Apnea Hypopnea Index (AHI) [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
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.
- Change in Amino Acid Metabolomics: glutamate, valine, leucine, alanine [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
Targeted amino acid metabolomics will be performed after each intervention
- Change in Lipid Metabolomics: 16n1 [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
Targeted lipid metabolomics will be performed after each intervention to look at changes in lipid profiles
- Change Bile Acid Metabolomics: sphingosine-1-phospate [4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)]
Targeted bile acid metabolomics will be performed after each intervention
Eligibility Criteria
Criteria
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.
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Severe illness requiring hospitalization within 60 days
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Diabetes, defined as Hemoglobin A1C > 6.4%
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BMI percentile less than the 90th percentile for age and sex. Weight >325 lbs or <84 lbs.
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Colorado, Anschutz Medical Campus | Aurora | Colorado | United States | 80045 |
Sponsors and Collaborators
- University of Colorado, Denver
Investigators
- Principal Investigator: Melanie Cree-Green, MD, PhD, Department of Endocrinology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 18-0803