title: Ethanol induced impairment of glucose metabolism involves alterations of GABAergic signaling in pancreatic β-cells.
abstract: Alcohol overindulgence is a risk factor of type 2 diabetes mellitus. However, the mechanisms by which alcohol overindulgence damages glucose metabolism remain unclear. Pancreatic islet β-cells are endowed with type-A γ-aminobutyric acid receptor (GABAAR) mediated autocrine signaling mechanism, which regulates insulin secretion and fine-tunes glucose metabolism. In neurons GABAAR is one of the major targets for alcohol. This study investigated whether ethanol alters glucose metabolism by affecting GABAAR signaling in pancreatic β-cells. Blood glucose level of test mice was measured using a blood glucose meter. Insulin secretion by the pancreatic β-cell line INS-1 cells was examined using a specific insulin ELISA kit. Whole-cell patch-clamp recording was used to evaluate GABA-elicited current in INS-1 cells. Western blot and immunostaining were used to measure the expression of GABAAR subunits in mouse pancreatic tissues or in INS-1 cells. Intraperitoneal (i.p.) administration of ethanol (3.0g/kg body weight) to mice altered glucose metabolism, which was associated with decreased expression of GABAAR α1- and δ- subunits on the surface of pancreatic β-cells. Acute treatment of cultured INS-1cells with ethanol (60mM) decreased the GABA-induced current and reduced insulin secretion. In contrast, treating INS-1 cells with GABA (100μM) largely prevented the ethanol-induced reduction of insulin release. Importantly, pre-treating mice with GABA (i.p., 1.5mg/kg body weight) partially reversed ethanol-induced impairment of glucose homeostasis in mice. Our data suggest a novel role of pancreatic GABA signaling in protecting pancreatic islet β-cells from ethanol-induced dysfunction.
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Shuanglian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada; Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Allen
authors.initials: A
authors.lastname: Feng
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Xupeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada; Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Roy
authors.initials: R
authors.lastname: Nofech-Mozes
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Changhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, PR China. Electronic address: liucy@sdu.edu.cn.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada; Robarts Research Institute, University of Western Ontario, London, ON, Canada. Electronic address: wlu53@uwo.ca.
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D000431:Ethanol / Q000633:toxicity*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546241:Gabra1 protein, mouse; C546242:Gabra1 protein, rat; D007328:Insulin; D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid
keywords: Alcohol overindulgence; GABA receptor; Glucose metabolism; Insulin; Pancreatic islet β-cells