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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Feb 26, 2015; 6(1): 1-15
Published online Feb 26, 2015. doi: 10.4331/wjbc.v6.i1.1
Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction
Ji Yeon Kim, Dae Yeon Lee, Yoo Jeong Lee, Keon Jae Park, Kyu Hee Kim, Jae Woo Kim, Won-Ho Kim
Ji Yeon Kim, Dae Yeon Lee, Yoo Jeong Lee, Keon Jae Park, Kyu Hee Kim, Won-Ho Kim, Division of Metabolic Diseases, Center for Biomedical Science, National Institute of Health, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, South Korea
Jae Woo Kim, Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, South Korea
Author contributions: All authors contributed to this manuscript.
Supported by A grant from the Korean National Institute of Health, No. 4845-302-201-13.
Conflict-of-interest: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Won-Ho Kim, PhD, Division of Metabolic Diseases, Center for Biomedical Science, National Institute of Health, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, South Korea. jhkwh@nih.go.kr
Telephone: +82-43-7198691 Fax: +82-43-7198602
Received: June 29, 2014
Peer-review started: June 29, 2014
First decision: September 18, 2014
Revised: November 19, 2014
Accepted: December 3, 2014
Article in press: December 10, 2014
Published online: February 26, 2015
Processing time: 221 Days and 10.2 Hours
Abstract

Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic β-cell and the exact mechanisms associated with ethanol-mediated β-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic β-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic β-cell dysfunction and metabolic syndrome.

Keywords: Ethanol consumption; Type 2 diabetes; Pancreatic β-cells; Glucokinase; Metabolic syndrome

Core tip: Chronic ethanol consumption induces Glucokinase (GCK) downregulation and inactivation through Tyr nitration, resulting in pancreatic β-cell apoptosis and dysfunction. Additionally, GCK proteins nitrated following ethanol treatment may be more susceptible to ubiquitination and consequent degradation than are native proteins of control cells. Peroxynitrite-mediated GCK downregulation or inactivation may perturb glucose metabolism and cellular antioxidant defense mechanisms, increasing susceptibility to insulin resistance and type-2 diabetes. Furthermore, peroxynitrite-generated activating transcription factor 3 may play as a major upstream regulator of GCK downregulation in β-cell dysfunction and apoptosis.