Hepatic Steatosis, Obesity, Polycystic Ovarian Syndrome
Conditions
Brief summary
Women with polycystic ovarian syndrome (PCOS) have increased rates of hepatic steatosis compared to weight similar women with regular menses. It is unclear if this is related to high testosterone or insulin resistance. The investigators will assess hepatic glucose release, rates of lipolysis and hepatic de novo lipogenesis in the fasted and postprandial state to determine if alterations in the processes contribute to hepatic steatosis. Participants will be overweight, sedentary girls with or without PCOS. Those with PCOS will either be medication naive, or must be taking metformin or combined oral contraceptives (COCPs) for a period of at least 6 months prior to study procedures.
Detailed description
Hepatic glucose release will be assessed with a stable isotope glycerol tracer, lipolysis with a glycerol tracer, and hepatic de novo lipogenesis with an acetate tracer. Data will be collected fasting and after a glucose challenge. The degree of hepatic steatosis and abdominal fat partitioning will be assessed with Magnetic Resonance Imaging (MRI), and total body composition with Dual-energy X-ray absorptiometry (DEXA).
Interventions
DRUGByetta 5Mcg Pen Injection
10 participants will receive 2 doses of Byetta, one at 7 PM the night prior to metabolic study and the second 30 min before ingestion of glucola
Sponsors
National Center for Advancing Translational Sciences (NCATS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
12 Years to 21 Years
Healthy volunteers
Yes
Inclusion criteria
* Females * 2 years post-menarche * BMI percentile \>90%
Exclusion criteria
* Type 2 diabetes * Anemia * Liver disease * Medications known to effect insulin sensitivity * Cause of oligomenorrhea or hirsutism other than PCOS, * \>3 hours a week of moderate exercise.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Glucose Release | Measured up to 4 months from enrollment | Hepatic glucose release will be measured by the rate of appearance of a glucose tracer. Glucose rate of appearance reflects the amount of glucose being release by primarily the liver during fasting. A higher glucose rate of appearance is often seen with dysglycemia |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Lipolysis | Measured up to 4 months from enrollment | Rate of lipolysis will be measured by the rate of appearance of a glycerol tracer. Glycerol rate of appearance reflects the amount of glycerol being released into the blood stream as a results of lipolysis. Higher rates of lipolysis are thought to be associated with insulin resistance. |
| Hepatic Phosphate Concentrations | Measured up to 4 months from enrollment | Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy. The ratio of the following will be reported over total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG) |
| Hepatic Fat Fraction | Measured up to 4 months from enrollment | Amount of fat in the liver measured by 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 in the liver. |
| Hepatic de Novo Lipogenesis | Measured up to 4 months from enrollment | Hepatic de novo lipogenesis will be measured by with an acetate tracer by mass spectroscopy. De novo lipogenesis can contribute to non-alcoholic fatty liver disease, so having a lower value is better. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Sleep Duration | Measured up to 4 months from enrollment | Sleep duration will be assessed using home actigraphy using the Philips Actigraph wrist-worn watch, and collects 7 days of data. |
| Sleep Quality | Measured up to 4 months from enrollment | Apnea Hypopnea Index (AHI) will be measured using WatchPAT. 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 | Measured up to 4 months from enrollment | 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 SAMM II software. This software uses participant weight, glucose and insulin concentrations at various time points during the oral glucose tolerance test to calculate the participant insulin sensitivity. The higher the Si value means more insulin sensitivity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Up to 25 girls without PCOS | 24 |
| PCOS Medication Naive Up to 45 girls with PCOS with no exposure to hormone therapy or metformin in the preceding 6 months. | 42 |
| PCOS, Medication Naive + Byetta PCOS, medication naive; 10 girls with PCOS will receive 2 doses of Byetta.
Byetta 5Mcg Pen Injection: 10 participants will receive 2 doses of Byetta, one at 7 PM the night prior to metabolic study and the second 30 min before ingestion of glucola | 10 |
| PCOS on COCPs Up to 10 girls with PCOS and 6 months of therapy with combined oral contraceptives (COCPs) prior to study procedures. | 10 |
| PCOS on Metformin Up to 10 girls with PCOS and 6 months of therapy with metformin prior to study procedures | 6 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Nurse not able to place IV so unable to complete visit | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Screen Failure | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Control | PCOS Medication Naive | PCOS, Medication Naive + Byetta | PCOS on COCPs | PCOS on Metformin | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 23 Participants | 34 Participants | 7 Participants | 9 Participants | 6 Participants | 79 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 8 Participants | 3 Participants | 1 Participants | 0 Participants | 13 Participants |
| Age, Continuous | 15.3 years STANDARD_DEVIATION 1.62 | 15.9 years STANDARD_DEVIATION 1.81 | 15.3 years STANDARD_DEVIATION 2.16 | 15.7 years STANDARD_DEVIATION 1.34 | 15.6 years STANDARD_DEVIATION 1.7 | 15.62 years STANDARD_DEVIATION 1.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 20 Participants | 3 Participants | 6 Participants | 4 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 22 Participants | 7 Participants | 4 Participants | 2 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 24 participants | 42 participants | 10 participants | 10 participants | 6 participants | 92 participants |
| Sex: Female, Male Female | 24 Participants | 42 Participants | 10 Participants | 10 Participants | 6 Participants | 92 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 42 | 0 / 10 | 0 / 10 | 0 / 6 |
| other Total, other adverse events | 0 / 24 | 0 / 42 | 0 / 10 | 0 / 10 | 0 / 6 |
| serious Total, serious adverse events | 0 / 24 | 0 / 42 | 0 / 10 | 0 / 10 | 0 / 6 |
Outcome results
Primary
Hepatic Glucose Release
Hepatic glucose release will be measured by the rate of appearance of a glucose tracer. Glucose rate of appearance reflects the amount of glucose being release by primarily the liver during fasting. A higher glucose rate of appearance is often seen with dysglycemia
Time frame: Measured up to 4 months from enrollment
Population: Not all participants had complete data to analyze the glucose RA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Hepatic Glucose Release | 1.85 mg/kg/min | Standard Deviation 1.24 |
| PCOS Medication Naive | Hepatic Glucose Release | 1.46 mg/kg/min | Standard Deviation 0.21 |
| PCOS, Medication Naive + Byetta | Hepatic Glucose Release | 1.54 mg/kg/min | Standard Deviation 0.38 |
| PCOS on COCPs | Hepatic Glucose Release | 1.88 mg/kg/min | Standard Deviation 0.49 |
| PCOS on Metformin | Hepatic Glucose Release | 1.57 mg/kg/min | Standard Deviation 0.07 |
Secondary
Hepatic de Novo Lipogenesis
Hepatic de novo lipogenesis will be measured by with an acetate tracer by mass spectroscopy. De novo lipogenesis can contribute to non-alcoholic fatty liver disease, so having a lower value is better.
Time frame: Measured up to 4 months from enrollment
Population: Not everyone in the study received the acetate tracer. We had a problem with the analysis of the acetate tracer on 3 participants: 1 from the control group and 2 from the metformin group, so we did not obtain data for those 3 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Hepatic de Novo Lipogenesis | 9.3 mg/dL | Standard Deviation 5.3 |
| PCOS Medication Naive | Hepatic de Novo Lipogenesis | 6.6 mg/dL | Standard Deviation 4.2 |
| PCOS, Medication Naive + Byetta | Hepatic de Novo Lipogenesis | 7.9 mg/dL | Standard Deviation 7.2 |
| PCOS on COCPs | Hepatic de Novo Lipogenesis | 18.2 mg/dL | Standard Deviation 14.9 |
| PCOS on Metformin | Hepatic de Novo Lipogenesis | 19.4 mg/dL | Standard Deviation 17.4 |
Secondary
Hepatic Fat Fraction
Amount of fat in the liver measured by 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 in the liver.
Time frame: Measured up to 4 months from enrollment
Population: Unable to analyze 2 participants in the PCOS medication naive group. One screen failed and the second who withdrew from the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Hepatic Fat Fraction | 4.1 percent fat | Standard Deviation 3.1 |
| PCOS Medication Naive | Hepatic Fat Fraction | 7.6 percent fat | Standard Deviation 6.3 |
| PCOS, Medication Naive + Byetta | Hepatic Fat Fraction | 6.9 percent fat | Standard Deviation 5.3 |
| PCOS on COCPs | Hepatic Fat Fraction | 6.8 percent fat | Standard Deviation 9.4 |
| PCOS on Metformin | Hepatic Fat Fraction | 13.3 percent fat | Standard Deviation 12.1 |
Secondary
Hepatic Phosphate Concentrations
Hepatic phosphate relative concentrations will be measured with 31 phosphorus magnetic resonance spectroscopy. The ratio of the following will be reported over total phosphate concentration: Phosphodiesterase (PDE), phosphomonoester (PME), Adenosine triphosphate (ATP), Inorganic Phosphate (Pi),Nicotinamide adenine dinucleotide phosphate (NADPH), Uridine diphosphate glucose (UDPG)
Time frame: Measured up to 4 months from enrollment
Population: The phosphorus coil for the liver was purchased towards the end of the study, so not all participants had the 31p measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | Hepatic Phosphate Concentrations | PME/TP | 0.067905319 ratio over total phosphate | Standard Deviation 0.033816456 |
| Control | Hepatic Phosphate Concentrations | NADPH/TP | 0.097201285 ratio over total phosphate | Standard Deviation 0.043438464 |
| Control | Hepatic Phosphate Concentrations | PDE/TP | 0.167684728 ratio over total phosphate | Standard Deviation 0.056413082 |
| Control | Hepatic Phosphate Concentrations | Pi/TP | 0.041945761 ratio over total phosphate | Standard Deviation 0.02076513 |
| Control | Hepatic Phosphate Concentrations | ATP/TP | 0.592517535 ratio over total phosphate | Standard Deviation 0.038294886 |
| Control | Hepatic Phosphate Concentrations | UDPG/TP | 0.032745372 ratio over total phosphate | Standard Deviation 0.011777685 |
| PCOS, Medication Naive + Byetta | Hepatic Phosphate Concentrations | ATP/TP | 0.566952309 ratio over total phosphate | Standard Deviation 0.061717281 |
| PCOS, Medication Naive + Byetta | Hepatic Phosphate Concentrations | Pi/TP | 0.054581135 ratio over total phosphate | Standard Deviation 0.019288097 |
| PCOS, Medication Naive + Byetta | Hepatic Phosphate Concentrations | UDPG/TP | 0.033326313 ratio over total phosphate | Standard Deviation 0.014030497 |
| PCOS, Medication Naive + Byetta | Hepatic Phosphate Concentrations | PME/TP | 0.077949656 ratio over total phosphate | Standard Deviation 0.02943916 |
| PCOS, Medication Naive + Byetta | Hepatic Phosphate Concentrations | NADPH/TP | 0.068550332 ratio over total phosphate | Standard Deviation 0.028503778 |
| PCOS, Medication Naive + Byetta | Hepatic Phosphate Concentrations | PDE/TP | 0.198640255 ratio over total phosphate | Standard Deviation 0.040933351 |
| PCOS on COCPs | Hepatic Phosphate Concentrations | ATP/TP | 0.565157308 ratio over total phosphate | Standard Deviation 0.042119495 |
| PCOS on COCPs | Hepatic Phosphate Concentrations | PDE/TP | 0.198787476 ratio over total phosphate | Standard Deviation 0.045832565 |
| PCOS on COCPs | Hepatic Phosphate Concentrations | PME/TP | 0.075872089 ratio over total phosphate | Standard Deviation 0.024970918 |
| PCOS on COCPs | Hepatic Phosphate Concentrations | UDPG/TP | 0.046272886 ratio over total phosphate | Standard Deviation 0.023894603 |
| PCOS on COCPs | Hepatic Phosphate Concentrations | Pi/TP | 0.046604505 ratio over total phosphate | Standard Deviation 0.022669904 |
| PCOS on COCPs | Hepatic Phosphate Concentrations | NADPH/TP | 0.067305736 ratio over total phosphate | Standard Deviation 0.033620062 |
| PCOS on Metformin | Hepatic Phosphate Concentrations | ATP/TP | 0.557277652 ratio over total phosphate | Standard Deviation 0.034367129 |
| PCOS on Metformin | Hepatic Phosphate Concentrations | PME/TP | 0.066789803 ratio over total phosphate | Standard Deviation 0.036986035 |
| PCOS on Metformin | Hepatic Phosphate Concentrations | UDPG/TP | 0.039855678 ratio over total phosphate | Standard Deviation 0.012418624 |
| PCOS on Metformin | Hepatic Phosphate Concentrations | NADPH/TP | 0.074693726 ratio over total phosphate | Standard Deviation 0.021031863 |
| PCOS on Metformin | Hepatic Phosphate Concentrations | PDE/TP | 0.186923469 ratio over total phosphate | Standard Deviation 0.039481266 |
| PCOS on Metformin | Hepatic Phosphate Concentrations | Pi/TP | 0.074459672 ratio over total phosphate | Standard Deviation 0.021584936 |
Secondary
Rates of Lipolysis
Rate of lipolysis will be measured by the rate of appearance of a glycerol tracer. Glycerol rate of appearance reflects the amount of glycerol being released into the blood stream as a results of lipolysis. Higher rates of lipolysis are thought to be associated with insulin resistance.
Time frame: Measured up to 4 months from enrollment
Population: Not all participants had complete data to analyze the glycerol RA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Rates of Lipolysis | 0.54 mg/kg/min | Standard Deviation 0.17 |
| PCOS Medication Naive | Rates of Lipolysis | 0.49 mg/kg/min | Standard Deviation 0.22 |
| PCOS, Medication Naive + Byetta | Rates of Lipolysis | 0.49 mg/kg/min | Standard Deviation 0.24 |
| PCOS on COCPs | Rates of Lipolysis | 0.78 mg/kg/min | Standard Deviation 0.18 |
| PCOS on Metformin | Rates of Lipolysis | 0.65 mg/kg/min | Standard Deviation 0.19 |
Other Pre-specified
Sleep Duration
Sleep duration will be assessed using home actigraphy using the Philips Actigraph wrist-worn watch, and collects 7 days of data.
Time frame: Measured up to 4 months from enrollment
Population: Watch failed to record data on: 3 participants in the control group, 2 in the PCOS medication naive group, and 1 in the Byetta group. Two participants withdrew from the PCOS medication naive group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Sleep Duration | 430.85 minutes | Standard Deviation 48.38 |
| PCOS Medication Naive | Sleep Duration | 437.88 minutes | Standard Deviation 49.32 |
| PCOS, Medication Naive + Byetta | Sleep Duration | 410.3 minutes | Standard Deviation 58 |
| PCOS on COCPs | Sleep Duration | 438.29 minutes | Standard Deviation 49.76 |
| PCOS on Metformin | Sleep Duration | 414.87 minutes | Standard Deviation 62.29 |
Other Pre-specified
Sleep Quality
Apnea Hypopnea Index (AHI) will be measured using WatchPAT. 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: Measured up to 4 months from enrollment
Population: The WatchPAT device was purchased towards the end of the study, so this was only used on a few participants for which results are reported here.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Sleep Quality | 9.15 Apnea Hypopnea Index | Standard Deviation 4.71 |
| PCOS, Medication Naive + Byetta | Sleep Quality | 31.25 Apnea Hypopnea Index | Standard Deviation 12.09 |
| PCOS on COCPs | Sleep Quality | 19.32 Apnea Hypopnea Index | Standard Deviation 11.85 |
| PCOS on Metformin | Sleep Quality | 19 Apnea Hypopnea Index | Standard Deviation 0.57 |
Other Pre-specified
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 SAMM II software. This software uses participant weight, glucose and insulin concentrations at various time points during the oral glucose tolerance test to calculate the participant insulin sensitivity. The higher the Si value means more insulin sensitivity.
Time frame: Measured up to 4 months from enrollment
Population: We were unable to calculate Si for some of the participants, because we were missing some lab values that are required for the formula.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Whole Body Insulin Sensitivity | 0.000319383 dL/kg/min/μU/mL | Standard Deviation 0.00021025 |
| PCOS Medication Naive | Whole Body Insulin Sensitivity | 0.00021077 dL/kg/min/μU/mL | Standard Deviation 0.000275814 |
| PCOS, Medication Naive + Byetta | Whole Body Insulin Sensitivity | 0.00033516 dL/kg/min/μU/mL | Standard Deviation 0.000366279 |
| PCOS on COCPs | Whole Body Insulin Sensitivity | 0.00021791 dL/kg/min/μU/mL | Standard Deviation 0.000255919 |
| PCOS on Metformin | Whole Body Insulin Sensitivity | 0.0000959833333 dL/kg/min/μU/mL | Standard Deviation 0.0000414436685 |