Inhibiting GABA Transaminase to Relieve Obesity Induced Hyperinsulinemia and Insulin Resistance

• Status: Not yet recruiting
• Trial end date: 2022-12-30
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Arizona
• Collaborator: Arizona Department of Health Services
• Treatments: Insulin; Vigabatrin

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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