The Effect of Vigabatrin on Insulin Sensitivity
Phase: PHASE2
Conditions: NAFLD, Obesity
Sponsor: Washington University School of Medicine

1 
 
 
 
 
 
The effect of Vigabatrin on Insulin Sensitivity 
 
NCT04321395 
 
 
 
Principal Investigator: 
 
Samuel Klein, MD 
Washington University School of Medicine in St. Louis, Missouri 
 
 
 
Version 7 
December 15, 2022 
  
 
 
 

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SPECIFIC AIMS 
Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity and is associated with 
hyperinsulinemia, mutli-organ insulin resistance and an increased risk of developing type 2 diabetes (T2D). 
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 cause insulin resistance through signaling by 
the hepatic vagal afferent nerve (HVAN). 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). In lean rodents GABA-T acts to break down high levels of GABA to produce 
succinate semialdehyde and glutamate, but in the livers of obese mice, the opposite reaction occurs with 
increased succinate semialdehyde and glutamate availability driving the GABA-T reaction toward GABA 
production, rather than breakdown. Pharmacological inhibition of GABA-T in obese mice by treatment with 
vigabatrin, an irreversible inhibitor of GABA-T that is approved by the FDA to treat seizure disorders, improves 
glucose tolerance and reduces hyperinsulinemia, hyperglycemia, and insulin resistance. It is not known if 
vigabatrin can also improve metabolic function in people.   
The overall goals of this pilot study are to determine the potential effect of vigabatrin on insulin 
sensitivity, insulin secretion and glycemic control in people with obesity and NAFLD (IHTG content ≥5.6%). 
Accordingly, we will 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:  
 
Aim 1: Determine the effect of GABA-T inhibition on insulin sensitivity in people with NAFLD. We will 
perform hyperinsulinemic-euglycemic clamp procedures plus stable isotope tracer infusions to assess skeletal 
muscle insulin sensitivity before and after treatment.  
 
Aim 2: Determine the effect of GABA-T inhibition on oral glucose tolerance and glucose-stimulated 
insulin secretion. We will perform oral glucose tolerance tests to simultaneously assess glucose control and 
oral glucose-stimulated insulin secretion before and after treatment.  
 
 
BACKGROUND 
Nonalcoholic fatty liver disease (NAFLD) affects about one-third of the adult population in the United 
States1.  Insulin resistance is a key feature of NAFLD central to many of the cardiometabolic complications 
associated with excess adiposity because insulin is a key regulator of liver glucose production, liver triglyceride 
(TG) synthesis and plasma TG concentration2-8.  Accordingly, insulin resistance is implicated in the 
pathogenesis of T2D, dyslipidemia, hypertension, and coronary heart disease2-5,7-9. Moreover, the degree of 
hepatic lipid accumulation is positively related to the magnitude of hyperinsulinemia and insulin resistance and 
the severity of T2D10-15.  
Hepatocyte Depolarization Regulates Glucose Homeostasis: Hepatic lipid accumulation depolarizes 
hepatocytes16,17. Expression of ligand-gated ion channels in hepatocytes through use of an adeno-associated 
virus (AAV), increases hepatocyte depolarization (Fig. 1A), inhibits activity of the HVAN (Fig. 1B) and induces 
hyperinsulinemia (Fig. 1C). Further, AAV mediated delivery of a plasmid encoding for hepatocyte specific 
expression of a hyperpolarizing Kir2.1 channel prevents obesity induced hyperinsulinemia and insulin 
resistance (Fig. 1D and 1E). In addition, hepatic vagotomy decreases insulin-mediated skeletal muscle glucose 
clearance18,19 potentially due to skeletal muscle parasympathetic acetylcholine signaling, which limits 
acetylcholine mediated vasodilation and resulting improved skeletal muscle blood perfusion and increased 
interstitial insulin and glucose concentrations.  These increased insulin and glucose concentrations encourage 
GLUT4 translocation to the cell surface and glucose uptake. The HVAN also tonically suppresses activity of 
parasympathetic nerves that project to the pancreas20. Severing the HVAN increases activity of these 
pancreatic projections and acetylcholine release onto β-cells thereby stimulating increased insulin release20,21. 
In turn, stimulation of the HVAN decreases acetylcholine signaling at the β-cell and depresses insulin 
release20,21. Moreover, obese Kir2.1 expressing mice, which prevented hepatocyte depolarization in obesity, 
did not exhibit hyperinsulinemia despite similar hepatic lipid accumulation as controls (Kir2.1: 94.2±10.6 mg 
triglycerides/g liver versus eGFP control: 98.4±6.6 mg triglycerides/g liver; P = 0.73). Importantly, a hepatic-

3 
 
specific vagotomy eliminates signals originating from the liver but does not alter basal signaling in the nucleus 
tractus solitarii (NTS)22-24. Taken together these data suggest hepatocyte depolarization is an important 
mediator of the relationship between hepatic lipid accumulation and dysregulated glucose homeostasis, and 
that prevention of NAFLD-induced hepatic depolarization lowers circulating plasma insulin concentrations and 
improves insulin sensitivity.  
 
Obesity increases hepatic GABA release due to increased GABA-T activity: Gamma aminobutyric acid (GABA) 
is an inhibitory neurotransmitter released in the liver.  In ex vivo liver slices from rodents, diet-induced obesity 
increases release of GABA, and decreases release of aspartate, an excitatory neurotransmitter (Fig. 1G and 
1H). Because the liver does not 
express measurable levels of the 
glutamate decarboxylase enzymes 
(i.e. GAD65 and GAD67) that 
synthesize GABA in the nervous 
system, Renquist and colleagues 
sought another mechanism by which 
GABA could be formed.  They found 
obesity increases the expression of 
GABA-transaminase 
(GABA-T) 
mRNA at the liver (Fig. 1F) and 
expression of genes involved in 
ketogenesis 
and 
Figure 
1. 
Hepatic 
Regulation 
of 
Glucose 
Homeostasis. 
Ligand- 
induced 
hepatocyte 
depolarization 
(A) 
decreases hepatic vagal 
afferent nerve activity (B) 
and exacerbates glucose 
stimulated 
insulin 
(C). 
Increased hepatic Kir2.1 
channel 
expression 
prevents high fat diet-
induced hyperinsulinemia 
(D) and insulin resistance 
(E). Diet induced obesity 
increases 
liver 
GABA-
transaminase 
(GABA-T) 
mRNA 
expression 
(F), 
increases hepatic slice 
GABA (G) release and 
decreases hepatic slice 
aspartate 
(H) 
release. 
Kir2.1 channel expression 
in obese mice decreases 
hepatic slice GABA (G) 
release 
and 
increases 
hepatic slice aspartate 
release (H). The GABA-T 
inhibitors 
ethanolamine-
O-sulfate 
(EOS) 
and 
Vigabatrin 
limit 
diet-
induced 
obesity 
hyperinsulinemia (I), and 
hyperglycemia (J), while 
improving oral glucose 
tolerance (K) and insulin 
tolerance (L). 
Figure 2. GABA-T inhibition by knockdown of the ABAT gene (A) or pharmacologically with 
EOS (B) increases GABA levels in lean rodents but decreases GABA levels in obese rodents 
B
A

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gluconeogenesis25,26. In lean rodents, GABA-
T decreases GABA concentrations by 
converting GABA and 2-oxoglutarate to 
produce 
glutamate 
and 
succinate 
semialdehyde; pharmacological inhibition of 
GABA-T by ethanolamine-O-sulfate (EOS) or 
vigabatrin or knockdown of GABA-T (ABAT) 
gene by an anti-sense oligonucleotide (ASO) 
increases GABA levels (Figure 2A).  In 
contrast, in obesity increased gluconeogenic 
flux and an altered hepatic redox state 
(Figure 3A) inhibits the conversion of 
succinate to fumarate in the TCA cycle by the enzyme succinate dehydrogenase and instead drives succinate 
to form succinate semialdehyde by succinic semialdehyde dehydrogenase leading to increase GABA production. 
Inhibiting succinate dehydrogenase replicates this process resulting in increased GABA production (Figure 3B).  
Knockdown of the GABA-T gene by ASO and pharmacological inhibition of GABA-T by EOS treatment both 
reduce GABA levels in in obese mice (Figure 2A and B). This data is supported by the observation that mice 
which lack phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis, are protected from obesity 
induced hyperinsulinemia and insulin resistance27 and lean mice that lack hepatic insulin signaling and have 
unrestricted hepatic gluconeogenic flux display hyperinsulinemia and insulin resistance28.  
Inhibiting GABA-T activity in obesity improves glucose control: Diet induced obese mice treated with one of two 
GABA-T inhibitors, ethanolamine-O-sulfate (EOS) or vigabatrin, display lean state serum glucose and insulin 
concentrations, insulin sensitivity and glucose tolerance after only 3 days (Fig. 1I-1L). In addition, knockdown 
of the GABA-T gene by ASO, in obese mice, improves glucose and insulin tolerance (Figure 4A and B) and 
increase whole-body and muscle specific glucose uptake during hyperinsulinemia (Figure 4 C and D). This 
data supports a role for GABA-T in the development of insulin resistance and hyperinsulinemia in rodents. 
Whether inhibition of GABA-T improves insulin sensitivity and glucose control in humans with obesity and 
increased liver fat is not known.  
 
Summary: Nonalcoholic fatty liver disease is associated with insulin resistance, and is an important risk factor 
for the development of T2D and CVD. Studies conducted in mouse models have shown a mechanistic link 
between NAFLD and insulin resistance; obese animals with NAFLD have an increase in hepatic GABA which 
decreases HVAN activity which in turn induces insulin resistance. Use of vigabatrin, an FDA-approved drug for 
seizure disorders, lowers hepatic GABA release and improves glucose tolerance and insulin sensitivity.  
However, the effect of vigabatrin on glucose tolerance and insulin sensitivity in people with obesity and NAFLD 
is not known.  Accordingly, the goal of this study is to conduct a pilot study to determine whether GABA-T 
inhibition may improve metabolic function in people with obesity and NAFLD and a larger, randomized 
controlled trial investigating the effect of vigabatrin is warranted. 
 
 
 
 
A
B
C
D
A
B
Figure 3. NADH significantly higher in obese livers (A) GABA reduced with 
succinate dehydrogenase inhibitor (B) 
Figure 4. ASO Knockout of GABA-T improves glucose (A) and insulin (B) tolerance and increases whole-body (C) and muscle (D) insulin-stimulated 
glucose uptake.in obese mice. 

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APPROACH 
Study Participants 
A total of 6 adults (18-60 years old) with obesity (BMI 30.0-49.9 kg/m2), NAFLD (IHTG content ≥5.6%), 
and insulin resistance (Homeostatic Model of Insulin Resistance (HOMA-IR) Score29>2.5), of all races and 
ethnic groups will be enrolled in this study.   
 
Exclusion criteria will include: 1) previous bariatric surgery; 2) structured exercise ≥250 min per week 
(e.g., brisk walking); 3) unstable weight (>4% change during the last 2 months before entering the study); 4) 
significant organ system dysfunction (e.g., diabetes, severe pulmonary, kidney or cardiovascular disease); 5) 
cancer; 6) polycystic ovary syndrome; 7) major psychiatric illness (including suicidal ideation or previous 
suicide attempts); 8) 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, aversion to needles, metal implants that prevent magnetic resonance imaging); 9) 
regular use of tobacco products; 10) excessive consumption of alcohol (≥3 drinks/day for men and ≥2 
drinks/day for women); 11) 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; 12) pre-
existing visual field deficits; or those at high risk of irreversible vision loss, including patients with retinopathy or 
glaucoma; 13) pregnant or lactating women; 14) illicit drug use); 15) persons who are unable or unwilling to 
follow the study protocol; 16) persons who are not able to grant voluntary informed consent; 17) patients at risk 
for severe anemia (hemoglobin less than 13.5 gram/100 ml in men or 12.0 grams/100 ml in women or 
hematocrit < 39% in men or < 36% in women); 18) patients with a heart failure or a history of lower limb 
edema; xxii) patients with mild or more severe renal insufficiency (CLcr <80 mL/min/1.73m2); 19) patients with 
existing peripheral neuropathy; 20) and women who have active menstral cycles but are not using birth control 
(acceptable contraception includes barrier/hormonal/IUD). 
 
Experimental Design  
Overview  
The testing schedule presented in Table 1. All participants will undergo comprehensive outpatient 
screening visits, including medical examination, visual field examination, blood tests, EKG, and an MRI scan to 
assess IHTG content to determine eligibility for the study. Participants who meet the inclusion criteria will be 
admitted to the inpatient Clinical and Translational Research Unit (CTRU) at Washington University School of 
Medicine on two separate occasions to complete baseline testing. After completion of baseline testing, 
subjects will receive vigabatrin to be taken over 30 days. Participants will be instructed to take one 500 mg pill 
2X/day for the first 7 days (days 0-6; 1000 mg/day), one pill in the morning and two pills in the evening for days 
7-13 (1500 mg/day), and two pills twice a day for days 14-23 (2000 mg/day). On day ~21, participants will 
again arrive at CTRU an overnight fast for a repeat modified oral glucose tolerance test (mOGTT) with a 
hyperinsulinemic-euglycemic clamp (HEC) procedure and repeat peripheral vision tests performed on day ~23. 
Throughout the study, participants and the study team will be blinded to treatments. After completing the HEC, 
participants will begin stepping down the vigabatrin dose as recommended by the manufacturer, moving to the 
1 pill 2X/day dose for days 24-30 before discontinuing treatment. Lastly, participants will be seen for repeat 
vision testing that occurred in screening approximately 6 months after initiation (5 months after discontinuation) 
of the drug.  
 
Screening Visits 
 
 
After informed consent is obtained, participants will undergo three separate screening visits to confirm 
eligibility. 
Screening visit 1.  Participants will arrive in the CTRU in the morning after they have fasted for 10h-12h 
overnight at home where they will undergo a comprehensive screening process, including a medical history, 
physical examination, standard blood tests and questionnaires to assess alcohol intake, eating habits, sleeping 
patterns, current level of anxiety, depression (measured with the Beck Depression Inventory-II30), quality of life 
and any potential barriers that could interfere with their ability to complete all study requirements/visits. 

6 
 
Vital signs (blood pressure, heart rate, respirations, temperature) will be collected while patient is 
seated in a comfortable position. The physical exam will include examination of eyes, ears, nose, throat, heart, 
and lungs. Laboratory and blood work will include: pregnancy test (for females only-measures hCG horome); 
urine drug screen; complete blood count with differential (red blood cell count, MCV, MCH, MCVC, platelets, 
MPV, hemoglobin, hematocrit, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, basophils); 
comprehensive metabolic panel (glucose, Sodium, potassium, carbon dioxide, and chloride, calcium, albumin, 
total protein, ALT, AST, ALP, bilirubin, BUN, creatinine);  lipid panel (triglycerides, total-, HDL-and LDL-
cholesterol); Hemoglobin A1C (HbA1C) and Prothrombin time and international normalized ratio (PT/INR). A 
peripheral vision field test will be performed on all participants.  
Screening visit 2. If inclusion criteria for age, body mass index, HOMA-IR score and vision are met, 
subjects will be scheduled to undergo imaging tests approximately 1 week later. As part of these tests, IHTG 
content will be measured by magnetic resonance imaging (MRI) to confirm if the participant is eligible for the 
study. During this visit, MRI will be used to quantify liver volume and abdominal subcutaneous and intra-
abdominal adipose tissue volumes with liver stiffness also determined by magnetic resonance elastography 
(MRE). If participants have any emotional anxiety associated with completing the MRI and MRE procedures 
(e.g., fear of confined spaces), they will have the option of taking Alprazolom or Lorazepam, prescribed by a 
study physician, to allow the MR scans to be completed.   
Screening visit 3. If IHTG content ≥5.6% at screening visit 2 subects will be subjects will be scheduled 
to undergo vision testing approximately 1 week later. Vision monitoring will include best corrected distance 
visual acuity, perimetry and spectral domain optical coherence tomography (sdOCT), sdOCT will include the 
macula. Perimetry will be automated, threshold testing of the central 60 degree. 
 
Baseline Testing Visit 1 
 
 
Subjects will be at the CTRU for approximately 6 hours. During this admission, subjects will complete a 
mOGTT clamp procedure to assess oral glucose tolerance and a dual energy X-ray absorptiometry (DXA) 
scan to measure whole- body composition.   
 
 
Whole-body composition analyses. Total body fat mass, fat-free mass and appendicular fat-free mass 
will be determined using dual energy X-ray absorptiometry (DXA).   
 
 
Modified 3-hour oral glucose tolerance test (mOGTT).  An IV catheter will be inserted into an 
antecubital vein for blood sampling and kept patent with a continuous infusion of saline. Blood samples to 
determine plasma glucose, insulin, and C-peptide concentrations will be collected 15, 10 and 5 min before 
ingesting a 75-gram glucose load and 10, 20, 30, 60, 90, 120, 150, and 180 min after glucose ingestion. The 
total areas under the curve (AUCs) for glucose, insulin, and C-peptide concentrations will be calculated by 
using the trapezoid method.  Insulin sensitivity will be assessed by using the oral glucose insulin sensitivity 
(OGIS) index 31. Indices of β-cell function will be estimated from plasma glucose and C-peptide concentrations 
by using the oral minimal model of C-peptide secretion and kinetics 32,33.  This model calculates the insulin 
secretion rate as a function of time and the following indices of β-cell responsivity: (i) dynamic responsivity 
index (Φd(109)), which is an index of insulin secretion in response to the rate of change in glucose 
concentration; (ii) static responsivity index (Φs(109min-1)), which is an index of insulin secretion in response to 
a given glucose concentration; and (iii) overall responsivity index (Φo (109min-1)), which is a global sensitivity to 
glucose index of postprandial insulin secretion.  
 
Baseline Testing Visit 2   
Subjects will be admitted to the CTRU at 1800 h for ~24 hours. During this admission, subjects will 
complete a HEC procedure to assess insulin sensitivity. Subjects will be given a standard meal the evening 
before the HEC procedure (day 1) and will then fast until the end of the HEC procedure on day 2.   
 
Hyperinsulinemic-euglycemic clamp (HEC). At 0700 h after a 12 hour fast, a primed constant infusion of 
[6,6-2H2]glucose will be started through an intravenous catheter inserted into an antecubital vein. An additional 
catheter will be inserted into a radial artery for blood sampling. 210 min after the start of the tracer infusion 
(after the basal period is completed), a one-stage HEC procedure will be initiated and continued for an 
additional 210 min. During the HEC, insulin will be infused at a rate of 50 mU/m2 body surface area (BSA) after 

7 
 
initiation with a two-step priming dose: 200 mU/m2 BSA/min for 5 min followed by 100 mU/m2 BSA/min for 5 
min. This will result in plasma insulin concentrations of ~100 mU·l-1.  Dextrose, enriched with [6,6,-2H2]glucose, 
to minimize changes in plasma glucose isotopic enrichment 34, will be infused at a variable rate to maintain 
plasma glucose concentration (monitored every 10 min) at ~100 mg/dl during insulin infusion. The [6,6,-
2H2]glucose infusion will be stopped during the clamp because of the expected decrease in hepatic glucose 
production 35. The insulin concentration achieved during the clamp reflects postprandial plasma insulin 
concentrations 36,37 and is ideal to evaluate insulin’s effect on glucose disposal 38. Blood samples for kinetic 
analyses will be collected immediately before the start of the tracer infusions and then every 6-7 min for a 20 
min period at the end of the basal and insulin infusion stages. The data (average values) obtained during these 
times will be used to determine hormone and substrate concentrations and glucose enrichments to calculate 
the glucose rate of appearance (Ra) and disappearance (Rd) from plasma. Endogenous glucose rate of 
appearance (Ra) in plasma will be calculated by dividing the glucose tracer infusion rate by the average 
plasma glucose TTR during the last 20 min of the basal stage and at the end of the HEC procedure. Glucose 
Rd will be calculated as the sum of endogenous glucose Ra and the infusion rate of exogenous glucose. 
Insulin-induced stimulation of glucose Rd during the HEC procedure will be used as an index of skeletal 
muscle insulin sensitivity 39,40.   
 
Sample processing 
Plasma glucose concentration will be determined by using a YSI analyzer (Yellow Springs Instruments 
Co., Yellow Springs, OH) and plasma C-peptide and insulin concentrations will be determined by using 
electrochemiluminescence assays (Elecsys 2010, Roche Diagnostics, Indianapolis, IN).  Plasma FFA 
concentrations will be assessed by gas chromatography 41.  Glucose tracer-to-tracee ratio in plasma will be 
measured by using gas-chromatography/mass-spectrometry as previously described 41-45.   
 
Intervention 
Vigabatrin capsules will be taken by participants daily for 30 days. Drug tablets will be administered 
orally as provided by the manufacturer and dosage matching the FDA label. Specifically, we will provide each 
patient with a total dosage of 44.5 g vigabatrin. Subjects will be instructed to take one 500 mg pill 2X/day for 
the first 7 days (days 0-6; 1000 mg/day), 1 pill in the morning and 2 pills in the evening for days 7-13 (1500 
mg/day), and two pills 2X/day for days 14-23 (2000 mg/day). On day 24, participants will initiate a step-down 
protocol as recommended by the manufacturer, moving to the one pill 2X/day dose for days 24-30, before 
discontinuing treatment. Study participants will meet with the research coordinator or one of the investigators 
weekly to ensure compliance with the study protocol and problem-solve any barriers. Regular medical 
monitoring by the study research coordinator and medical staff will be performed during the entire study period. 
Subjects will be asked to come in weekly while on the drug.  At the visit, a general wellness check (including 
depression screening with the Beck Depression Inventory-II30), vital signs and body weight and a urine drug 
test will be obtained, and blood samples (7 ml of blood (~0.5 tablespoon)) will be obtained at the weekly visit 
for the first two weeks of dose escalation to assess routine laboratory tests. Study participants will be 
instructed to keep their body weight stable (< 2% change) during the treatment period.  
 
Dispensing and accountability 
A medication accountability log will be used to document dispensing of the vigabatrin to the participant 
and the return of unused product by the participant. The medication accountability log will document the 
participant ID, initials, the amount of medication and the date the drug was dispensed to the participant, and 
the amount of medication that the study participant returned. Participants will be instructed to return unused 
medications at every scheduled study visit and study end. The study research coordinator will perform a pill 
count and document this in the medication accountability log at each study visit.  
 
Repeat studies 
The HEC procedure and mOGTT performed at baseline as well as the MRI to determine liver 
triglyceride content at screening will be repeated after 3 weeks of treatment. In addition, depression measured 
with the Beck Depression Inventory-II30 (measured at screening) will be re-assessed at the repeat mOGTT.   

8 
 
Vision testing will be repeated during the clamp visit (day 23).  Vision and depression (Beck Depression 
Inventory-II30) will be assessed approximately 6 months after participants initiated the drug. 

9 
 
 
Table 1. Schedule of tests performed 
 
SCREENING 
BASELINE  
TESTING 
WEEK 3  
TESTING 
STUDY 
COMPLETION 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 1 
Visit 2 
Visit 1 
Visit 2 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Anthropometrics 
Weight 
X 
 
 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Vital Signs 
Blood Pressure 
X 
 
 
X 
X 
X 
X 
X 
Heart Rate (Pulse) 
X 
 
 
X 
X 
X 
X 
X 
Respirations 
X 
 
 
X 
X 
X 
X 
X 
Temperature 
X 
 
 
X 
X 
X 
X 
X 
 
Medical Evaluation 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
Depression Screening 
X 
 
 
 
 
X 
 
X 
 
Lab/Blood Work 
Urine pregnancy test (females only) 
X 
X 
X 
X 
X 
X 
X 
 
Urine drug test 
X 
X 
X 
X 
X 
X 
X 
 
PT/INR 
X 
 
 
 
 
 
 
 
CBC/diff 
X 
 
 
 
 
X 
 
 
CMP 
X 
 
 
 
 
X 
 
 
Lipid panel 
X 
 
 
 
 
X 
 
 
HbA1C 
X 
 
 
 
 
X 
 
 
 
Body composition analysis 
Dual energy X-ray absorptiometry (DXA) 
 
 
 
X 
 
 
 
 
Abdominal MRI 
 
X 
 
 
 
X 
 
 
Liver volume, TG content and stiffness by MRI/MRE 
 
X 
 
 
 
X 
 
 
 
Metabolic function 
Modified 3-hour oral glucose tolerance test (mOGTT) 
 
 
 
X 
 
X 
 
 
Hyperinsulinemic-euglycemic clamp (HEC) 
 
 
 
 
X 
 
X 
 
 
Vision Testing 
Peripheral Vision Tests 
 
 
X 
 
 
 
X 
X 

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Statistical Analyses 
 
Statistical Analysis:  The effect size of vigabatrin treatment on insulin sensitivity during the HEC and insulin 
secretion assessed during the mOGTT will be determined by using Cohen’s d tests. Using these effects sizes 
we using G*Power 3.1.9.2 to estimate the number of participants per group that would be required to detect an 
~15% improvement in insulin sensitivity between placebo and vigabatrin groups with >90% power using two-
sided tests at the α=0.05 level if a randomized, controlled trial were to be conducted.  
 
 
 
 

11 
 
PROTECTION OF HUMAN SUBJECTS 
Human Subjects Involvement and Characteristics. A total of 6 men and women of all races and ethnic groups 
will be studied. Subjects will be screened carefully with a medical history and physical examination, and blood 
tests. Exclusion criteria will include: 1) previous bariatric surgery; 2) structured exercise ≥250 min per week 
(e.g., brisk walking); 3) unstable weight (>4% change during the last 2 months before entering the study); 4) 
significant organ system dysfunction (e.g., diabetes, severe pulmonary, kidney or cardiovascular disease); 5) 
cancer; 6) polycystic ovary syndrome; 7) major psychiatric illness (including suicidal ideation or previous 
suicide attempts); 8) 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); 9) regular use of tobacco products; 10) excessive consumption of alcohol (≥3 
drinks/day for men and ≥2 drinks/day for women); 11) 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; 12) pre-existing visual field deficits; or those at high risk of irreversible vision loss, including patients 
with retinopathy or glaucoma; 13) pregnant or lactating women; 14) conditions that render subject unable to 
complete all testing procedures (e.g. aversion to needles, metal implants that prevent magnetic resonance 
imaging); 15) persons who are unable or unwilling to follow the study protocol; 16) persons who are not able to 
grant voluntary informed consent; 17) patients at risk for severe anemia (hemoglobin less than 13.5 gram/100 
ml in men or 12.0 grams/100 ml in women or hematocrit < 39% in men or < 36% in women); 18) patients with a 
heart failure or a history of lower limb edema; xxii) patients with mild or more severe renal insufficiency (CLcr 
<80 mL/min/1.73m2); 19) patients with existing peripheral neuropathy; 20) and women who have active 
menstral cycles but are not using birth control (acceptable contraception includes barrier/hormonal/IUD). 
 
Sources of Materials. All specimens will be obtained solely for research purposes. Although these generally will 
be obtained specifically for the purposes of the study, use will be made, where appropriate, of existing records 
and data obtained as part of routine clinical care. Measures to be obtained include: 1) detailed medical history, 
2) a physical exam, 3) clinical laboratory evaluation consisting of blood specimens to assess complete 
metabolic panel, lipid profile and complete blood count, 4) DXA scan to evaluate body composition, and 5) MR 
scans to evaluate intra-abdominal adipose tissue, intrahepatic triglyceride content. All data from individual 
subjects will be maintained confidentially and their names and identities will not be disclosed in any published 
document. 
 
Potential Risks. We anticipate no psychological, social or legal risks beyond those of participation in health-
related research in general with the exceptions listed below. The potential risks associated with participation in 
this study are moderate and are listed below. They will be explained to all subjects who desire to participate in 
this research project. In addition, subjects will be informed that there is a possibility of unforeseeable risk, 
although from our experience with such studies, we consider this unlikely. The research coordinator, research 
nurse and/or the PI will ensure understanding of the consent and study procedures, as well as laboratory 
results; in addition, the research nurse and/or the PI will explain the different procedures and answer any 
questions the subjects might have before initiating any study-related procedures. Whenever concerns arise, 
subjects will be informed that they are free to withdraw from the study at any time with no bias or prejudice. 
This research involves exposure to radiation from the dual-energy x-ray absorptiometry (DXA) for body 
composition measurements. The amount of radiation from these procedures, when averaged over the entire 
human body, is equivalent to a uniform whole-body dose of <1 mrem. This is equivalent to less than 3% of the 
amount of natural background radiation exposure all people in St. Louis receive each year. 
This research involves collection of blood samples, each of which has potential risks associated. 
Possible side effects of venous catheter insertion are discomfort, bruising, bleeding, and/or infection at the site 
of needle insertion. Occasionally some people experience dizziness or feel faint. A blood clot can occur at the 
site of the arterial catheter insertion which could decrease blood flow to the hand and cause tissue damage 
requiring corrective surgery. However, the risk of this is extremely small because a small size catheter is used.  
Furthermore, before catheter placement, all subjects are examined to make sure that they have adequate 
blood flow to the hand from the other major artery that supplies the hand. Subjects who are judged to have 
insufficient compensatory blood flow will be excluded from the study. Lastly, there is a possibility that 
potentially adverse medical conditions will be identified as a result of the medical evaluation at screening. 

12 
 
Vigabatrin limits central nervous system GABA breakdown. Study subjects will be advised to not drive a 
car or operate other complex machinery until they are familiar with the effects of the study drug on their ability 
to perform these activities. Participants will be warned about possible complications and told to contact their 
physician and the study physician should they experience any of the side effects listed for vigabatrin (e.g. 
headache, irritability, dizziness, drowsiness, tiredness, memory problems, intrameylinic edema, weight gain, 
anemia, swelling, numbness/burning pain/tingly feeling in the hands or feet, loss of coordination, joint pain, 
cold symptoms (such as stuffy nose, fever, sneezing, sore throat), nausea, vomiting, diarrhea, sleep problems 
(insomnia), uncontrolled back and forth eye movements, tremors, pale skin, lightheadedness, shortness of 
breath, rapid heart rate, trouble concentrating, confusion, mood or behavior changes, depression, or thoughts 
about suicide). Participants will be given a list with suicide prevention resources at the time of Consent.   
According to vigabatrin FDA label: In U.S. and primary non-U.S. clinical studies of 4,079 SABRIL 
treated patients, the most common (≥5%) adverse reactions associated with the use of SABRIL in combination 
with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, 
upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory 
impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, 
and rash. The adverse reactions most commonly associated with SABRIL treatment discontinuation in ≥1% of 
patients were convulsion and depression. There are potential rare side effects including constriction of the 
visual field which could potentially lead to vision loss. There is no evidence that a cumulative dose <1 kg 
affects vision.  However there is 4% increase in visual field changes in patients that have taken a cumulative 
dose of > 1 kg48. Vigabatrin is FDA approved for use in people with epilepsy and there have been limited 
studies looking at the effects of vigabatrin in people without neuronal disturbance.  One randomized controlled 
trial was conducted to investigate the effect of vigabatrin (total dose 218 grams) on cocaine addiction49.  
Headaches were more commonly reported in the placebo group as compared to vigabatrin, but there were no 
other differences in side effects between the vigabatrin and control groups49. Compliance was only 40-60% for 
subjects on vigabatrin, which could impact experience of side effects49.  Importantly, in a secondary analysis, 
the investigators found no significant differences in vision between the placebo and the compliant vigabatrin 
subjects50.  Similarly, no visual field defects were reported with short term (6 weeks) use of vigabatrin for 
treatment cocaine dependence (total dose 137 grams)51.  For this study participants will be taking total dosage 
of 44.5 grams. Vision tests will be performed prior to starting vigabatrin, at 3 weeks and 6 months after drug 
initiation to ensure no changes. 
 
Adequacy of protection against risks 
Recruitment and Informed Consent. Potential subjects will be recruited from a pool of subjects in the Center 
Human Nutrition database and from the community-at-large. The objectives of the project, all experimental 
procedures, all of the requirements for participation, and any possible discomforts and risks and benefits of 
participation will be clearly explained in writing and orally, in lay terms, to the subject by the PI or research 
coordinator. After all questions have been answered, and the subjects have been informed orally and in writing 
that they are free to withdraw from the study at any time with no bias or prejudice, and agree to participate, 
written informed consent, approved by the Washington University School of Medicine Institutional Review 
Board, will be obtained. The consenting procedure will be conducted in the CTRU at Washington University 
School of Medicine before initiating any study-related procedures (screening tests, body composition analyses, 
etc.). 
 
Confidentiality. All personnel involved in the design and conduct of this research project will receive the 
required education on the protection of human research participants prior to the start of this project. All 
specimens will be obtained solely for research purposes. Study samples and data sheets will be coded with an 
identification number for each subject. All data will be treated confidentially, and the subjects' names and 
identities will not be disclosed in any published reports.  
 
Medical risks related to this study (described above). Complete physical examinations will be performed to 
screen out subjects who may be at increased risk. All procedures will be performed by qualified and 
experienced personnel and subjects will be carefully monitored during all procedures and during the 
intervention. Intravenous tracer solutions will be prepared in a designated, sterile mixing room. Careful aseptic 
techniques will be used when inserting the catheters and when obtaining blood samples to decrease the risk of 

13 
 
infection. The total amount of blood collected during the full set of research procedures will be ~500 mL 
including all screening, baseline, post-treatment and medical monitoring visits . If a participant develops a 
health problem or potential health problem, the PI/study physician and, if necessary a medical consultant who 
is not part of the research team, will decide whether the participant should be continued in the study, and/or 
what further steps regarding medical evaluation/treatment should be performed. The CTRU and hospital 
facilities used for the study are equipped with defibrillators and all appropriate emergency medications. Should 
the need for medical treatment arise, the PI/study physician will arrange for medical evaluation at the 
Washington University School of Medicine, which provides all the resources of a large teaching hospital for 
subject evaluation and treatment. The subject and the primary care physicians will be made aware of any 
abnormal findings while participating in the study. The participants will be given the phone numbers of the 
members of the research team (including an emergency phone number) and told to call a member of the 
research team immediately if they develop any unusual signs or symptoms. Subjects will be screened for 
depressive symptoms before starting treatment, while on treatment and at study completion.  If the subject 
reports significant increase in depression or thoughts of suicidal ideation, the subject will be removed from the 
study and immediately be sent for psychiatric evaluation.  Vision testing will be completed in all subjects at 
baseline, after a week at the maximum dose and then 6 months after drug initiation.  If vision changes are 
noted, subjects will be referred for further testing and evaluation by an ophthalmologist.  
 
Potential benefits of the research to the participants 
Potential benefits to the participants include obtaining information regarding their body composition and a 
medical examination. Participants' basal measures of glucose homeostasis may improve with this treatment.  
These results could support the findings from studies conducted in rodent models and lead to a new approach 
for treating metabolic abnormalities in people. 
 
Importance of the knowledge to be gained 
The information gained from this work has important public health implications in the potential of development 
of a new drug for treatment or prevention of NAFLD. 
 
Data and safety monitoring plan 
Data from the study will be monitored on a continual basis by the PI. All serious adverse events (SAEs), 
adverse events (AEs), and laboratory values will be reviewed by the PI on an ongoing basis. The PI will be 
responsible for annual reports to Washington University School of Medicine’s IRB and for reporting any 
adverse events to the IRB.  
The IRB at Washington University School of Medicine defines unanticipated problems (adverse events) 
as  involving risks to participants or others which are: 1) unexpected (in terms of nature, severity, or frequency) 
given (a) the research procedures that are described in the study-related documents, such as the IRB-
approved research study and informed consent document; and (b) the characteristics of the subject population 
being studied; and 2) are related or possibly related to participation in the research; and 3) suggest that the 
research places participants or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. 
Adverse events will include vision loss, suicidal behavior, anemia, peripheral neuropathy, edema, ear 
disorders: deafness, gastrointestinal disorders, hepatobiliary disorders (cholestasis), nervous system 
disorders (dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis), 
psychiatric disorders (acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorders), 
respiratory disorders (laryngeal edema, pulmonary embolism, respiratory failure, stridor skin), and/or 
subcutaneous tissue disorders (angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome 
(SJS), toxic epidermal necrolysis (TEN)) 
Adverse Event Reporting: All AEs will be graded according to the following scale: 
0 = No adverse events or within normal limits 
1 = Mild; did not require treatment 
2 = Moderate; resolved without treatment 
3 = Severe; required professional medical attention  
4 = Life-threatening or disabling 

14 
 
5 = Death 
 
The PI will review AEs and notify the IRB of any changes needed to the protocol. The IRB will be 
notified within 24 hours of any SAE (grade 4 or 5) occurring at this site via their online system for reporting 
SAEs, and additional information will be forwarded to the IRB as it becomes available.  AE’s (grades 2-3) will 
be reported by the PI to the IRB within 10 working days. Mild AE’s (grade 1) will be reported at the annual 
continuing review.  In addition, all laboratory values outside of the normal range will be discussed with the 
study participant, and appropriate arrangements will be made for treatment, if necessary. The annual summary 
of all adverse events and any audit reports will be sent to the IRB at the time of continuing review. 
If the data received during the course of the study on a study participant indicate they he or 
she may benefit from (other) medical intervention, then the appropriate recommendation(s) and/or 
consultation(s) will be made. 
A Data and Safety Monitoring Board, chaired by David Carr MD (Professor of Medicine), and including 
Dominic Reeds, MD (Associate Professor of Medicine) will meet every 12 months with the PI, Co-Investigators, 
and the study research coordinator, to review study data, discuss any safety issues, and ensure compliance 
with the protocol. 
 
Study Withdrawal/Discontinuation 
Participants are free to withdraw at any time. Female participants who become pregnant will be 
removed from the study. If the participant’s doctor decides that staying in the study places the participant at 
risk, she/he will be withdrawn. Any condition deemed by the study personnel to interfere with the participant’s 
ability to complete the study will be cause for withdrawal.  Subjects will be removed from study if they no longer 
meet the study criteria, if an SAE occurs, if they do not show up to study visits, or if the study is terminated.   
Subjects that are removed or withdraw from the study will initiate the drug step-down protocol by 
decreasing their drug dose by 1000 mg for one week prior to stopping the drug completely.  
No patient will be withdrawn from one part of the study without being removed from all study parts. 
Blood specimen collected from these subjects will be kept as the samples does not contain any personal 
identifier. The data and specimen collected until withdrawal from the study will be kept for future as these 
samples and data might still be useful. All data and samples will have an assigned identification number given 
to them which are NOT subject's personal identification. This will be explained at the time subjects sign the 
informed consent form. 
 
 
 
 
 

15 
 
REFERENCES 
 
1. 
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of 
nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. 
Hepatology. 2016;64(1):73-84. 
2. 
Liu H, Li J. Aging and dyslipidemia: A review of potential mechanisms. Ageing Res Rev. 2015;19C:43-
52. 
3. 
Vaneckova I, Maletinska L, Behuliak M, Nagelova V, Zicha J, Kunes J. Obesity-related hypertension: 
possible pathophysiological mechanisms. J Endocrinol. 2014;223(3):R63-78. 
4. 
Villareal DT, Apovian CM, Kushner RF, Klein S, American Society for N, Naaso TOS. Obesity in older 
adults: technical review and position statement of the American Society for Nutrition and NAASO, The 
Obesity Society. Obes Res. 2005;13(11):1849-1863. 
5. 
Sikalidis AK, Varamini B. Roles of hormones and signaling molecules in describing the relationship 
between obesity and colon cancer. Pathol Oncol Res. 2011;17(4):785-790. 
6. 
Ryu TY, Park J, Scherer PE. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J. 
2014;38(5):330-336. 
7. 
Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW. Control of the size of the human muscle mass. 
Annu Rev Physiol. 2004;66:799-828. 
8. 
Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 
2015;239(1):192-202. 
9. 
McGregor RA, Cameron-Smith D, Poppitt SD. It is not just muscle mass: a review of muscle quality, 
composition and metabolism during ageing as determinants of muscle function and mobility in later life. 
Longev Healthspan. 2014;3(1):9. 
10. 
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, 
and clinical implications. Hepatology. 2010;51(2):679-689. 
11. 
Kimura Y, Hyogo H, Ishitobi T, Nabeshima Y, Arihiro K, Chayama K. Postprandial insulin secretion 
pattern is associated with histological severity in non-alcoholic fatty liver disease patients without prior 
known diabetes mellitus. J Gastroenterol Hepatol. 2011;26(3):517-522. 
12. 
Wainwright P, Byrne CD. Bidirectional Relationships and Disconnects between NAFLD and Features of 
the Metabolic Syndrome. Int J Mol Sci. 2016;17(3):367. 
13. 
Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: Insulin hypersecretion 
and specific association with the insulin resistance syndrome. Hepatology. 2002;35(2):373-379. 
14. 
Manchanayake J, Chitturi S, Nolan C, Farrell GC. Postprandial hyperinsulinemia is universal in non-
diabetic patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2011;26(3):510-516. 
15. 
Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, Yki-Jarvinen H. Increased liver fat, impaired 
insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology. 
2008;135(1):122-130. 
16. 
Fitz JG, Scharschmidt BF. Regulation of transmembrane electrical potential gradient in rat hepatocytes 
in situ. Am J Physiol. 1987;252(1 Pt 1):G56-64. 
17. 
Chavin KD, Yang S, Lin HZ, et al. Obesity induces expression of uncoupling protein-2 in hepatocytes 
and promotes liver ATP depletion. J Biol Chem. 1999;274(9):5692-5700. 
18. 
Uno K, Katagiri H, Yamada T, et al. Neuronal pathway from the liver modulates energy expenditure and 
systemic insulin sensitivity. Science. 2006;312(5780):1656-1659. 
19. 
Latour MG, Lautt WW. The hepatic vagus nerve in the control of insulin sensitivity in the rat. Auton 
Neurosci. 2002;95(1-2):125-130. 
20. 
Niijima A. Glucose-sensitive afferent nerve fibers in the liver and their role in food intake and blood 
glucose regulation. J Auton Nerv Syst. 1983;9(1):207-220. 
21. 
Lee KC, Miller RE. The hepatic vagus nerve and the neural regulation of insulin secretion. 
Endocrinology. 1985;117(1):307-314. 

16 
 
22. 
Peters JH, Gallaher ZR, Ryu V, Czaja K. Withdrawal and restoration of central vagal afferents within 
the dorsal vagal complex following subdiaphragmatic vagotomy. J Comp Neurol. 2013;521(15):3584-
3599. 
23. 
Phillips RJ, Baronowsky EA, Powley TL. Regenerating vagal afferents reinnervate gastrointestinal tract 
smooth muscle of the rat. J Comp Neurol. 2000;421(3):325-346. 
24. 
Phillips RJ, Baronowsky EA, Powley TL. Long-term regeneration of abdominal vagus: efferents fail 
while afferents succeed. J Comp Neurol. 2003;455(2):222-237. 
25. 
Geisler CE, Hepler C, Higgins MR, Renquist BJ. Hepatic adaptations to maintain metabolic homeostasis 
in response to fasting and refeeding in mice. Nutr Metab (Lond). 2016;13:62. 
26. 
Geisler CE, Renquist BJ. Hepatic lipid accumulation: cause and consequence of dysregulated 
glucoregulatory hormones. J Endocrinol. 2017;234(1):R1-r21. 
27. 
Gomez-Valades AG, Mendez-Lucas A, Vidal-Alabro A, et al. Pck1 gene silencing in the liver improves 
glycemia control, insulin sensitivity, and dyslipidemia in db/db mice. Diabetes. 2008;57(8):2199-2210. 
28. 
Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling in hepatocytes leads to severe 
insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6(1):87-97. 
29. 
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model 
assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin 
concentrations in man. Diabetologia. 1985;28(7):412-419. 
30. 
Wang YP, Gorenstein C. Psychometric properties of the Beck Depression Inventory-II: a comprehensive 
review. Braz J Psychiatry. 2013;35(4):416-431. 
31. 
Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin 
sensitivity from the oral glucose tolerance test. Diabetes Care. 2001;24(3):539-548. 
32. 
Breda E, Toffolo G, Polonsky KS, Cobelli C. Insulin release in impaired glucose tolerance: oral minimal 
model predicts normal sensitivity to glucose but defective response times. Diabetes. 2002;51 Suppl 
1:S227-233. 
33. 
Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from C-peptide 
levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes. 
1992;41(3):368-377. 
34. 
Finegood DT, Bergman RN, Vranic M. Estimation of endogenous glucose production during 
hyperinsulinemic-euglycemic glucose clamps. Diabetes. 1987;36:914-924. 
35. 
Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction on insulin action and risk 
factors for coronary heart disease. N Engl J Med. 2004;350(25):2549-2557. 
36. 
Kim HS, Abbasi F, Lamendola C, McLaughlin T, Reaven GM. Effect of insulin resistance on 
postprandial elevations of remnant lipoprotein concentrations in postmenopausal women. Am J Clin 
Nutr. 2001;74(5):592-595. 
37. 
Reaven GM. Effect of variations in carbohydrate intake on plasma glucose, insulin, and triglyceride 
responses in normal subjects and patients with chemical diabetes. Adv Exp Med Biol. 1979;119:253-262. 
38. 
Prager R, Wallace P, Olefsky JM. In vivo kinetics of insulin action on peripheral glucose disposal and 
hepatic glucose output in normal and obese subjects. J Clin Invest. 1986;78(2):472-481. 
39. 
Magkos F, Fabbrini E, Korenblat K, Okunade AL, Patterson BW, Klein S. Reproducibility of glucose, 
fatty acid and VLDL kinetics and multi-organ insulin sensitivity in obese subjects with non-alcoholic 
fatty liver disease. Int J Obes (Lond). 2011;35(9):1233-1240. 
40. 
Conte C, Fabbrini E, Kars M, Mittendorfer B, Patterson BW, Klein S. Multiorgan insulin sensitivity in 
lean and obese subjects. Diabetes Care. 2012;35(6):1316-1321. 
41. 
Patterson BW, Zhao G, Elias N, Hachey DL, Klein S. Validation of a new procedure to determine 
plasma fatty acid concentration and isotopic enrichment. J Lipid Res. 1999;40(11):2118-2124. 
42. 
Patterson BW, Zhao G, Klein S. Improved accuracy and precision of gas chromatography/mass 
spectrometry measurements for metabolic tracers. Metabolism. 1998;47(6):706-712. 
43. 
Yoshino J, Conte C, Fontana L, et al. Resveratrol supplementation does not improve metabolic function 
in nonobese women with normal glucose tolerance. Cell Metab. 2012;16(5):658-664. 

17 
 
44. 
Fabbrini E, Yoshino J, Yoshino M, et al. Metabolically normal obese people are protected from adverse 
effects following weight gain. J Clin Invest. 2015;125(2):787-795. 
45. 
Magkos F, Fraterrigo G, Yoshino J, et al. Effects of moderate and subsequent progressive weight loss on 
metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23(4):591-601. 
46. 
Kars M, Yang L, Gregor MF, et al. Tauroursodeoxycholic acid may improve liver and muscle but not 
adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010;59(8):1899-1905. 
47. 
Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates 
differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009;136(5):1552-
1560. 
48. 
Manuchehri K, Goodman S, Siviter L, Nightingale S. A controlled study of vigabatrin and visual 
abnormalities. Br J Ophthalmol. 2000;84(5):499-505. 
49. 
Somoza EC, Winship D, Gorodetzky CW, et al. A multisite, double-blind, placebo-controlled clinical 
trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. JAMA Psychiatry. 
2013;70(6):630-637. 
50. 
Berezina TL, Khouri AS, Winship MD, Fechtner RD. Visual field and ocular safety during short-term 
vigabatrin treatment in cocaine abusers. Am J Ophthalmol. 2012;154(2):326-332 e322. 
51. 
Fechtner RD, Khouri AS, Figueroa E, et al. Short-term treatment of cocaine and/or methamphetamine 
abuse with vigabatrin: ocular safety pilot results. Arch Ophthalmol. 2006;124(9):1257-1262.