Inhibiting GABA Transaminase to Relieve Obesity Induced Hyperinsulinemia and Insulin Resistance

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.

Timeline

Start

2030-04-15

Primary completion

2030-12-30

Completion

2030-12-30

Drugs

Indications