Hepatocyte Membrane Potential Regulates Serum Insulin and Insulin Sensitivity by Altering Hepatic GABA Release

The degree of hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type II diabetes mellitus. Herein, we identify GABA as a novel hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.