Vigabatrin and Insulin Sensitivity

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.


Eligibility Criteria:
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)