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Completed

NCT Number: NCT03717935

Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS

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.

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Key information

Conditions

Polycystic Ovarian Syndrome Adnexal Diseases Body Weight Cysts Digestive System Diseases Endocrine System Diseases Fatty Liver Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Gonadal Disorders Hepatic Steatosis Liver Diseases Neoplasms Nutrition Disorders Nutritional and Metabolic Diseases Obesity Ovarian Cysts Ovarian Diseases Overnutrition Overweight Pathological Conditions, Signs and Symptoms Polycystic Ovary Syndrome Signs and Symptoms Urogenital Diseases

Age range

12 year–21 year

Sex eligibility

Female

Study type

Interventional

Phase

Not applicable

Primary location

University of Colorado, Anschutz Medical Campus

Aurora, Colorado, 80045, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Essential Amino Acid (EAA) Supplement

Dietary Supplement

Powder supplement

Placebo

Other

Powder that will be similar to the essential amino acid supplement

Primary outcomes

  1. Hepatic Fat Fraction

    Time frame: 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 outcomes

  1. Rate of De Novo Lipogenesis

    Time frame: 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.

  2. Evaluation of Mitochondrial Function

    Time frame: 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.

  3. Hepatic Phosphate Profile After EAA and Placebo Supplement

    Time frame: 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)

  4. Whole Body Insulin Sensitivity

    Time frame: 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).

  5. Change in Adipose Insulin Sensitivity

    Time frame: 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.

  6. Sleep Duration

    Time frame: 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.

  7. Apnea Hypopnea Index (AHI)

    Time frame: 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

  8. Amino Acid Metabolomics: Alanine, Glutamate, Leucine, Valine Levels After 4 Weeks of Placebo and 4 Weeks of EAAs

    Time frame: 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.

  9. Lipid Metabolomics: 16n1

    Time frame: 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.

  10. Bile Acid Metabolomics: Sphingosine-1-phospate After 4 Weeks of Placebo and 4 Weeks of EAAs

    Time frame: 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

Sponsors and collaborators

Lead sponsor

University of Colorado, Denver

Other

Registry information

Acronym: ORANGE

Important dates

Study start
2018
Primary completion
2022
Study completion
2022
First posted
Oct 24, 2018
Registry last updated
Mar 24, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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