title: Chronic ethanol consumption-induced pancreatic {beta}-cell dysfunction and apoptosis through glucokinase nitration and its down-regulation.
abstract: Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic β-cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic β-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(ΔC) attenuated ethanol-induced pancreatic β-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers N(γ)-monomethyl-L-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down-regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic β-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and β-cell apoptosis.
authors.affiliation: Divisions of Metabolic Diseases, National Institutes of Health, Eunpyeong-gu, Seoul 122-701, Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Eun Hyun
authors.initials: EH
authors.lastname: Song
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Yeo Kyoung
authors.initials: YK
authors.lastname: Oh
authors.forename: Yoon Shin
authors.initials: YS
authors.lastname: Park
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Bong Jo
authors.initials: BJ
authors.lastname: Kim
authors.forename: Dae Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Inkyu
authors.initials: I
authors.lastname: Lee
authors.forename: Jihyun
authors.initials: J
authors.lastname: Song
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: D000437:Alcoholism / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism*; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009573:Nitrites / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D051273:Glucose Transporter Type 2; D009573:Nitrites; C495682:Slc2a2 protein, mouse; D030421:Peroxynitrous Acid; D000431:Ethanol; D005941:Glucokinase