Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release
Caroline E. Geisler,
Susma Ghimire,
Chelsea Hepler,
Kendra E. Miller,
Stephanie M. Bruggink,
Kyle P. Kentch,
Mark R. Higgins,
Christopher T. Banek,
Jun Yoshino,
Samuel Klein,
Benjamin J. Renquist
Affiliations
Caroline E. Geisler
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Susma Ghimire
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Chelsea Hepler
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA; Robert H. Lurie Medical Research Center, Northwestern University, Chicago, IL 60611, USA
Kendra E. Miller
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Stephanie M. Bruggink
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Kyle P. Kentch
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Mark R. Higgins
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Christopher T. Banek
Department of Physiology, University of Arizona, Tucson, AZ 85721, USA
Jun Yoshino
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Samuel Klein
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Benjamin J. Renquist
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA; Corresponding author
Summary: Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. 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 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.
