Abdominal Obesity, Insulin Resistance, Hypertriglyceridemia
Conditions
Brief summary
The purpose of the study is to examine whether a medication called acipimox can improve your body's mitochondria. Mitochondria are the power house of the cell and make energy for your body. Obesity is associated with increased risk for developing diabetes. However, the investigators do not know how obesity leads to diabetes. Previous studies have shown levels of fat in the blood (free fatty acids or FFA) are higher in obesity, and elevated FFA can affect how our body uses glucose and responds to insulin. Recent studies have shown that changes in mitochondria may be involved in the development of diabetes and may be affected by FFA. The investigators propose to improve the function of mitochondria in obese people with pre-diabetes by treating with acipimox, a medication which decreases FFA. The investigators will use state of the art techniques to evaluate the mitochondria, including a new magnetic resonance imaging (MRI) technique to measure function of mitochondria in muscle.
Interventions
DRUGAcipimox
250 mg by mouth (PO) three times daily
DRUGPlacebo
0 mg by mouth (PO) three times daily
Sponsors
American Diabetes Association
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women age 18-55 years old 2. Body Mass Index (BMI) ≥ 30 kg/m2 3. Waist circumference ≥ 102 cm in men and ≥ 88 cm in women 4. Hypertriglyceridemia defined as triglycerides ≥ 150 mg/dl OR Insulin resistance defined as elevated fasting glucose (≥ 100 mg/dl but \<125 mg/dl) or hyperinsulinemia defined as fasting serum insulin ≥ 10 uU/ml.
Exclusion criteria
1. Subjects on any hormonal treatment including estrogen, hormone replacement therapy, oral contraceptives, testosterone, glucocorticoids, anabolic steroids, GH, GH releasing hormone or Insulin like growth factor (IGF)-1 within 3months of enrollment. 2. Subjects who have a known history of diabetes, using any anti-diabetic drugs, or fasting blood glucose of ≥ 125 mg/dl. 3. Use of cholesterol lowering medication including niacin or fish oil. 4. Changes in anti-hypertensive regimen within 3months of screening. 5. Chronic illness including HIV, anemia (Hgb \<12 g/dL), chronic kidney disease (Creatinine \> 2 mg/dL), or liver disease (SGOT \> 2.5 x upper limit normal). 6. Use of Aspirin, Clopidogrel (Plavix), Warfarin (Coumadin) or other anti-coagulants 7. History of or active peptic ulcer disease 8. History of any recent cardiovascular event including myocardial infarction (MI; heart attack), cerebral vascular accident (CVA; or stroke) or transient ischemic attack (TIA; or mini-stroke) within 3 months of screening visit, unstable angina pectoris, oxygen-dependent severe pulmonary disease 9. Subjects with contraindication for an MRI study including any significant metal in their body including surgical clippings, or pacemakers and known claustrophobia. 10. History of recent alcohol or substance abuse (\< 1 year) 11. Positive pregnancy test or lactating females 12. Women of child-bearing potential not currently using non-hormonal birth control methods including barrier methods (intra-uterine device or IUD, condoms, diaphragms) or abstinence 13. Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Phosphocreatine Recovery (ViPCr) at 6-months | Change from Baseline to 6-months Visit | The rate of recovery of phosphocreatine concentration after depletion by exercise is considered a measurement of mitochondrial function. Change in phosphocreatine recovery from baseline to 6 months will therefore give a measurement of change in mitochondrial function. ViPCR is given -- a higher value indicates better mitochondrial function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Sensitivity at 6-months | Change from Baseline to 6-months visit | Change in insulin resistance assessed by hyperinsulinemic-euglycemic clamp study at Baseline and at 6-months. Change in insulin-stimulated glucose uptake (M) during 40 mU/m2/min insulin clamp is given. |
| Change From Baseline in Mitochondrial Density at 6 Months | Change from Baseline to 6-months | Muscle tissue obtained from biopsy will be used to assess mitochondrial number and morphology by microscopes at Baseline and at 6-months. The change in mitochondrial density from 6 months to baseline is given. |
| Change From Baseline in Intramyocellular Lipid Content at 6-months | Change from Baseline to 6-months | Change in tibialis intramyocellular lipid (IMCL) normalized to creatinine is given. |
| Change From Baseline in Lipid Profile at 6-months | Change from Baseline to 6-months | Change in direct low density lipoprotein (LDL) cholesterol is given |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acipimox Treatment with the study drug Acipimox
Acipimox: 250 mg by mouth (PO) three times daily | 20 |
| Placebo Treatment with Placebo control.
Placebo: 0 mg by mouth (PO) three times daily | 19 |
| Total | 39 |
Baseline characteristics
| Characteristic | Placebo | Acipimox | Total |
|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 7 | 47 years STANDARD_DEVIATION 5 | 46 years STANDARD_DEVIATION 6 |
| Race/Ethnicity, Customized Black | 8 participants | 12 participants | 20 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 10 participants | 8 participants | 18 participants |
| Region of Enrollment United States | 19 participants | 20 participants | 39 participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 20 | 16 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 19 |
Outcome results
Primary
Change From Baseline in Phosphocreatine Recovery (ViPCr) at 6-months
The rate of recovery of phosphocreatine concentration after depletion by exercise is considered a measurement of mitochondrial function. Change in phosphocreatine recovery from baseline to 6 months will therefore give a measurement of change in mitochondrial function. ViPCR is given -- a higher value indicates better mitochondrial function.
Time frame: Change from Baseline to 6-months Visit
Population: all available data used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Change From Baseline in Phosphocreatine Recovery (ViPCr) at 6-months | 1.7 mM/s | Standard Deviation 9.6 |
| Placebo | Change From Baseline in Phosphocreatine Recovery (ViPCr) at 6-months | 1.6 mM/s | Standard Deviation 10.8 |
p-value: 0.97t-test, 2 sided
Secondary
Change From Baseline in Insulin Sensitivity at 6-months
Change in insulin resistance assessed by hyperinsulinemic-euglycemic clamp study at Baseline and at 6-months. Change in insulin-stimulated glucose uptake (M) during 40 mU/m2/min insulin clamp is given.
Time frame: Change from Baseline to 6-months visit
Population: all available data used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Change From Baseline in Insulin Sensitivity at 6-months | 0.1 mg/kg/min | Standard Deviation 1.9 |
| Placebo | Change From Baseline in Insulin Sensitivity at 6-months | 0.2 mg/kg/min | Standard Deviation 1.4 |
p-value: 0.85t-test, 2 sided
Secondary
Change From Baseline in Intramyocellular Lipid Content at 6-months
Change in tibialis intramyocellular lipid (IMCL) normalized to creatinine is given.
Time frame: Change from Baseline to 6-months
Population: all available data used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Change From Baseline in Intramyocellular Lipid Content at 6-months | -0.2 ratio of IMCL peak to Creatinine peak | Standard Deviation 3 |
| Placebo | Change From Baseline in Intramyocellular Lipid Content at 6-months | 0.0 ratio of IMCL peak to Creatinine peak | Standard Deviation 2.3 |
p-value: 0.79t-test, 2 sided
Secondary
Change From Baseline in Lipid Profile at 6-months
Change in direct low density lipoprotein (LDL) cholesterol is given
Time frame: Change from Baseline to 6-months
Population: all available data used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Change From Baseline in Lipid Profile at 6-months | -19 mg/dL | Standard Deviation 26 |
| Placebo | Change From Baseline in Lipid Profile at 6-months | 6 mg/dL | Standard Deviation 22 |
p-value: 0.007t-test, 2 sided
Secondary
Change From Baseline in Mitochondrial Density at 6 Months
Muscle tissue obtained from biopsy will be used to assess mitochondrial number and morphology by microscopes at Baseline and at 6-months. The change in mitochondrial density from 6 months to baseline is given.
Time frame: Change from Baseline to 6-months
Population: all available data used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acipimox | Change From Baseline in Mitochondrial Density at 6 Months | 0.4 percentage of total muscle fiber area | Standard Deviation 1.3 |
| Placebo | Change From Baseline in Mitochondrial Density at 6 Months | 0 percentage of total muscle fiber area | Standard Deviation 1.6 |
p-value: 0.52t-test, 2 sided