Vigabatrin and Insulin Sensitivity

Phase 2

Completed

Conditions: NAFLD
Obesity

Interventions: Drug: Vigabatrin

Registration Number: NCT04321395

Lead Sponsor: Washington University School of Medicine

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 4

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Vigabatrin	Vigabatrin	-

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity	3 weeks after initiation of treatment	Measured by hyperglycemic euglycemic clamp

Secondary Outcome Measures

Name	Time	Method
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.