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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
27
Powder supplement
Powder that will be similar to the essential amino acid supplement
University of Colorado, Anschutz Medical Campus
Aurora, Colorado, United States
Hepatic Fat Fraction
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
Time frame: 4 weeks after completing the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Rate of De Novo Lipogenesis
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.
Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Evaluation of Mitochondrial Function
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.
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 After EAA and Placebo Supplement
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)
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Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Whole Body Insulin Sensitivity
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).
Time frame: 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 (FFAs) during the oral glucose tolerance test.
Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Sleep Duration
Sleep duration will be assessed completing placebo and essential amino acid therapy using home actigraphy. Change in sleep duration reported in minutes.
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)
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
Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Amino Acid Metabolomics: Alanine, Glutamate, Leucine, Valine Levels After 4 Weeks of Placebo and 4 Weeks of EAAs
Targeted amino acid metabolomics will be performed after each intervention and the levels of these 4 amino acids will be reported after each intervention.
Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Lipid Metabolomics: 16n1
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.
Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)
Bile Acid Metabolomics: Sphingosine-1-phospate After 4 Weeks of Placebo and 4 Weeks of EAAs
Targeted bile acid metabolomics will be performed after each intervention to measure levels of sphingosine-1-phospate
Time frame: 4 weeks after the first intervention, and approximately 8 weeks later (4 weeks washout and 4 weeks of second intervention)