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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number109298
JournalCell Reports
Volume35
Issue number13
DOIs
StatePublished - Jun 29 2021

Keywords

  • GABA
  • GABA transporter
  • GABA-transaminase
  • NAFLD
  • Type 2 diabetes
  • hyperinsulinemia
  • insulin resistance
  • membrane potential
  • obesity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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