NAFLD, Obesity
Conditions
Brief summary
Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity and is associated with an increased risk of developing type 2 diabetes. The hallmark feature of NAFLD is an increase in intrahepatic triglyceride (IHTG) content. Data from studies conducted in rodent models suggest increased IHTG content can alter hepatic vagal afferent nerve (HVAN) activity. In rodent models of obesity and NAFLD, HVAN activity is reduced leading to impaired insulin sensitivity and glucose control. The reduction in HVAN activity is likely due to increased hepatic release of GABA, an inhibitory neurotransmitter, attributable to increased expression of GABA-Transaminase (GABA-T). Pharmacological inhibition of GABA-T in obese mice by treatment with vigabatrin, an irreversible inhibitor of GABA-T improves glucose tolerance and reduces hyperinsulinemia, hyperglycemia, and insulin resistance. It is not known if vigabatrin can also improve metabolic function in people. We propose to conduct a 3-week, single-arm trial to assess the effect size of treatment with vigabatrin on the following specific aims with the larger goal of determining whether a large, randomized controlled trial investigating the effect of vigabatrin is warranted.
Interventions
DRUGVigabatrin
Vigabatrin - Pill, 500 mg twice daily for 7 days (days 0-6), 1000 mg twice daily for 7 days (days 7-13), 1500 mg twice daily for 10 days (days 14-23), 1000 mg twice daily for 7 days (days 24-30), 500 mg twice daily for 7 days (days 31-37) and will discontinue treatment on day 38.
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Participants will receive vigabatrin
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* age 25-60 years old * BMI 30.0-49.9 kg/m2 * IHTG content ≥5.6 * Homeostatic Model of Insulin Resistance (HOMA-IR) Score\>2.5.
Exclusion criteria
* previous bariatric surgery * structured exercise ≥250 min per week (e.g., brisk walking) * unstable weight (\>4% change during the last 2 months before entering the study) * significant organ system dysfunction (e.g., diabetes, severe pulmonary, kidney or cardiovascular disease) * cancer * polycystic ovary syndrome * major psychiatric illness (including suicidal ideation or previous suicide attempts) * conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders) * regular use of tobacco products * excessive consumption of alcohol (≥3 drinks/day for men and ≥2 drinks/day for women) * use of medications that are known to affect the study outcome measures or increase the risk of study procedures and that cannot be temporarily discontinued for this study * pre-existing visual field deficits; or those at high risk of irreversible vision loss, including patients with retinopathy or glaucoma * pregnant or lactating women * conditions that render subject unable to complete all testing procedures (e.g. aversion to needles, metal implants that prevent magnetic resonance imaging * persons who are unable or unwilling to follow the study protocol * persons who are not able to grant voluntary informed consent * patients at risk for severe anemia (hemoglobin \< 14 g/dL (men) or \<12.0 g/dL (women) and/or hematocrit \<40% in men or \< 37% in women) * patients with history of lower limb edema (risk of heart failure) * patients with mild or more severe renal insufficiency (CrCl \<100 mL/min (men) or \<80 mL/min (women)) * patients with existing peripheral neuropathy * women who have active menstrual cycles but are not using birth control (acceptable contraception includes barrier/hormonal/IUD)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | 3 weeks after initiation of treatment | Measured by hyperglycemic euglycemic clamp |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oral Glucose Tolerance | 3 weeks after initiation of treatment | Measured by 75 gram oral glucose tolerance test |
| Oral Glucose Insulin Sensitivity | After 3 weeks on drug | Insulin sensitivity based on oral glucose tolerance. Values are calculated using glucose and insulin from a 3-hour 75 gram oral glucose tolerance test at 0, 2, and 3 hours. Higher values are indicate better insulin sensitivity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vigabatrin Vigabatrin: Vigabatrin - Pill, 500 mg twice daily for 7 days (days 0-6), 1000 mg twice daily for 7 days (days 7-13), 1500 mg twice daily for 10 days (days 14-23), 1000 mg twice daily for 7 days (days 24-30), 500 mg twice daily for 7 days (days 31-37) and will discontinue treatment on day 38. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Vigabatrin |
|---|---|
| 2 Hour OGTT | 139.5 mg/dL STANDARD_DEVIATION 7.9 |
| Age, Continuous | 36.2 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Glucose infusion rate | 6.61 (mg/kg FFM/min) STANDARD_DEVIATION 1.7 |
| Oral Glucose Insulin Sensitivity | 294 ml/min/m^2 of body surface area STANDARD_DEVIATION 56 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
Insulin Sensitivity
Measured by hyperglycemic euglycemic clamp
Time frame: 3 weeks after initiation of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vigabatrin | Insulin Sensitivity | 6.82 mg/kg FFM/min | Standard Deviation 1.7 |
Secondary
Oral Glucose Insulin Sensitivity
Insulin sensitivity based on oral glucose tolerance. Values are calculated using glucose and insulin from a 3-hour 75 gram oral glucose tolerance test at 0, 2, and 3 hours. Higher values are indicate better insulin sensitivity.
Time frame: After 3 weeks on drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vigabatrin | Oral Glucose Insulin Sensitivity | 294 ml/min/m^2 of body surface area | Standard Deviation 56 |
Secondary
Oral Glucose Tolerance
Measured by 75 gram oral glucose tolerance test
Time frame: 3 weeks after initiation of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vigabatrin | Oral Glucose Tolerance | 155.5 mg/dL | Standard Deviation 19.2 |