Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS

Not Applicable

Completed

Conditions: Polycystic Ovarian Syndrome
Obesity
Hepatic Steatosis

Interventions: Dietary Supplement: Essential Amino Acid (EAA) Supplement
Other: Placebo

Registration Number: NCT03717935

Lead Sponsor: University of Colorado, Denver

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 27

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Essential Amino Acid (EAA) Supplement	Essential Amino Acid (EAA) Supplement	4 weeks: Essential Amino Acid Supplement- 15g 2/day
Placebo	Placebo	4 weeks: Placebo- 15g 2/day

Primary Outcome Measures

Name	Time	Method
Hepatic Fat Fraction	4 weeks after completing the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)	Hepatic Fat Fraction measured after completing placebo and amino acid therapy measured with 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

Secondary Outcome Measures

Name	Time	Method
Amino Acid Metabolomics: Alanine, Glutamate, Leucine, Valine Levels After 4 Weeks of Placebo and 4 Weeks of EAAs	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 and the levels of these 4 amino acids will be reported after each intervention.
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 measure 16n1 lipids after completing 4 weeks of essential amino acid therapy and 4 weeks of placebo.
Bile Acid Metabolomics: Sphingosine-1-phospate After 4 Weeks of Placebo and 4 Weeks of EAAs	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 to measure levels of sphingosine-1-phospate
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)	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 measured after 4 weeks of placebo and after 4 weeks of EAA intervention.
Evaluation of Mitochondrial Function	4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)	Mitochondrial function will be assessed via change in direct hepatic carbon flux in newly synthesized triglycerides (TGs) using an oral sugar tolerance test with an oral UC13 glycerol tracer after each intervention. Data from 180 minutes post-tracer drink is shown below. A higher direct percent means less indirect futile cycling through the TCA cycle.
Hepatic Phosphate Profile After EAA and Placebo Supplement	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 Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy after each intervention. The Total phosphate (TP) concentration will be reported after each intervention and the ratio of the following phosphate metabolites will be reported over the total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG)
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 (FFAs) during the oral glucose tolerance test.
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. 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	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 whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model using 4 hour glucose and insulin data during the OGTT after each phase of the study (placebo vs EAA).
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 completing placebo and essential amino acid therapy using home actigraphy. Change in sleep duration reported in minutes.