Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.

Autor:	Geisler CE; 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., Ghimire S; School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA., Hepler C; 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., Miller KE; School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA., Bruggink SM; School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA., Kentch KP; School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA., Higgins MR; School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA., Banek CT; Department of Physiology, University of Arizona, Tucson, AZ 85721, USA., Yoshino J; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA., Klein S; Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA., Renquist BJ; School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA. Electronic address: bjrenquist@email.arizona.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Jun 29; Vol. 35 (13), pp. 109298.
DOI:	10.1016/j.celrep.2021.109298
Abstrakt:	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. Competing Interests: Declaration of interests The results presented in this paper have resulted in patent cooperation treaty Application No. 62/511,753 and 62/647,468: METHODS AND COMPOSITIONS FOR REGULATING GLUCOSE HOMEOSTASIS, which has been licensed by Livendocrine, LLC founded by Benjamin Renquist. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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