Inhibiting GABA Transaminase to Relieve Obesity Induced Hyperinsulinemia and Insulin Resistance

NCT04062890 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: ADHS18-201472b
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

50% of Arizonans are diabetic or pre-diabetic resulting in $6.4 billion in health care and productivity costs. The severity and incidence of Type 2 Diabetes Mellitus (T2DM) is directly related to the hepatic lipid concentration. The degree of hepatic lipid accumulation is communicated by the hepatic vagal afferent nerve (HVAN) to regulate pancreatic insulin secretion and whole body insulin sensitivity. We have shown that obesity enhances expression of GABA-Transaminase (GABA-T) decreasing hepatic release of the excitatory neurotransmitter, aspartate, and increasing release of the inhibitor neurotransmitter, GABA. This enhanced inhibitory tone decreases hepatic vagal afferent nerve activity, increasing pancreatic insulin release and decreasing skeletal muscle glucose clearance/insulin sensitivity. Pharmacological inhibition of GABA-T robustly improves glucose homeostasis in diet induced obese mice. We propose 2 clinical objectives that will test the effect of GABA-T inhibition on glucose tolerance and insulin sensitivity in obese, hyperglycemic, hyperinsulinemic patients.

Conditions

Hyperinsulinism; Insulin Resistance; Insulin Sensitivity; Glucose Intolerance; Hypertension

Keywords

Type II Diabetes; Hyperinsulinism; Insulin Resistance; Hypertension

Outcome Measures

Primary Outcomes (4)

• Fasted serum glucose and insulin

  Overnight fasted serum glucose and insulin

  3 weeks after treatment initiation

• Glucose Clearance

  Clearance of glucose during an oral glucose tolerance test

  3 weeks after treatment initiation

• Insulin Sensitivity

  Insulin sensitivity measured by glucose infusion rate required to maintain euglycemia during a hyperinsulinemic clamp

  24 days after treatment initiation

• Blood Pressure

  Measure basal blood pressure both before and 21 days after treatment initiation

  21 days after treatment initiation

Study Arms (2)

Vigabatrin

ACTIVE COMPARATOR

Vigabatrin - Pill, 500 mg twice daily for 7 days (days 1-7), 1000 mg twice daily for 7 days (days 8-14), 1500 mg twice daily for 10 days (days 15-24), 1000 mg twice daily for 7 days (days 25-31), 500 mg twice daily for 7 days (days 32-38).

Drug: Vigabatrin Pill

Placebo

PLACEBO COMPARATOR

Placebo - Pill, 1 pill twice daily for 7 days (days 1-7), 2 pills twice daily for 7 days (days 8-14), 3 pills twice daily for 10 days (days 15-24), 2 pills twice daily for 7 days (days 25-31), 1 pill twice daily for 7 days (days 32-38).

Drug: Placebo oral tablet

Interventions

Vigabatrin Pill DRUG

Oral Vigabatrin Pill

Vigabatrin

Placebo oral tablet DRUG

Oral Placebo Pill

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Participants that have BMI ≥ 25
• Participants that are mildly hypertensive(≥135 mm HG systolic BP) or taking medication for hypertension
• Hyperglycemic, hyperinsulinemic adults (18-60 y) on insulin or metformin only will be recruited based on elevated HbA1c using existing relationships between community partners and the University of Arizona Division of Endocrinology.
• Patients will be stratified into 2 treatments (Vigabatrin or Placebo) based on age, sex, and HbA1c taken at d -24.

You may not qualify if:

• BMI \< 25
• Insulin Sensitive Individuals
• Participants with normal blood pressure (120/80 mm HG)
• Participants on any other diabetes therapy besides metformin and insulin
• If Pregnant or breast feeding
• If participants smoke
• Individuals who have complex partial seizures
• Individuals who are on other drugs to help with retinopathy or glaucoma

Sponsors & Collaborators

• University of Arizona: lead
• Arizona Department of Health Services: collaborator

MeSH Terms

Conditions

Hyperinsulinism; Insulin Resistance; Glucose Intolerance; Hypertension; Diabetes Mellitus, Type 2

Interventions

Vigabatrin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperglycemia; Vascular Diseases; Cardiovascular Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Benjamin J Renquist, PhD

  University of Arizona

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Only the pharmacist and the principle investigator will know the treatments designated to a patient.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be treated with a placebo or vigabatrin

Study Record Dates

• First Submitted: August 15, 2019
• First Posted: August 20, 2019
• Study Start (Estimated): April 15, 2030
• Primary Completion (Estimated): December 30, 2030
• Study Completion (Estimated): December 30, 2030
• Last Updated: July 30, 2025

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share