title: Ethanol causes endoplasmic reticulum stress and impairment of insulin secretion in pancreatic β-cells.
abstract: Chronic ethanol consumption increases the risk of type 2 diabetes mellitus, and ethanol has been reported to cause insulin resistance and, inconsistently, to reduce insulin secretion. The mechanism(s) underlying the reduction of insulin secretion by ethanol is not known. We used β-cell lines and isolated murine islets to determine the effect of ethanol on insulin content and secretion at low- and high-glucose concentrations, in the presence of KCl, diazoxide, tolbutamide, and regulators of cyclic AMP and protein kinase C (PKC). We also determined the gene expression of insulin; pancreas duodenum homeobox 1; and endoplasmic reticulum (ER) stress markers, such as Chop, ERp57, glucose-regulated protein 78/binding immunoglobulin protein, and inositol 1,4,5-triphosphate receptors. Ethanol reduced insulin secretion by interfering with muscarinic signaling and PKC activation but not the K-ATP channels. In addition, ethanol reduced insulin content and caused ER stress. The deleterious effects of ethanol on β-cells were prevented by 4-methyl pyrazole, an inhibitor of alcohol dehydrogenase, suggesting that ethanol metabolism is required for these effects.
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Khanh Hoa
authors.initials: KH
authors.lastname: Nguyen
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Lee
authors.forename: B L Grégoire
authors.initials: BL
authors.lastname: Nyomba
mesh_terms: D000818:Animals; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000235:genetics; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019704:Protein Disulfide-Isomerases / Q000187:drug effects / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000187:drug effects / Q000235:genetics
chemical_list: D002492:Central Nervous System Depressants; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; C514817:Ins1 protein, mouse; D007328:Insulin; D051742:Transcription Factor CHOP; D000431:Ethanol; D011493:Protein Kinase C; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases; D005947:Glucose