Inhibiting GABA Transaminase to Relieve Obesity Induced Hyperinsulinemia and Insulin Resistance
Status:
Not yet recruiting
Trial end date:
2022-12-30
Target enrollment:
Participant gender:
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.