| Chronic ethanol consumption-induced pancreatic {beta}-cell dysfunction and apoptosis through glucokinase nitration and its down-regulation. | |
| | |
MedLine Citation:
|
PMID: 20855893 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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:
|
Ji Yeon Kim; Eun Hyun Song; Hyun Jung Lee; Yeo Kyoung Oh; Yoon Shin Park; Joo-Won Park; Bong Jo Kim; Dae Jin Kim; Inkyu Lee; Jihyun Song; Won-Ho Kim |
Related Documents
:
|
20351753 - A low-risk znt-8 allele (w325) for post-transplantation diabetes mellitus is protective... 17709883 - Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2... 11347743 - Unchanged incidence of lower-limb amputations in a german city, 1990-1998. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-20 |
Journal Detail:
|
Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Nov |
Date Detail:
|
Created Date: 2010-11-24 Completed Date: 2010-12-30 Revised Date: 2011-12-21 |
Medline Journal Info:
|
Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 37251-62 Citation Subset: IM |
Affiliation:
|
Divisions of Metabolic Diseases, National Institutes of Health, Eunpyeong-gu, Seoul 122-701, Korea. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Alcoholism
/
enzymology*,
genetics,
metabolism,
physiopathology Animals Apoptosis* Cell Line Disease Models, Animal Down-Regulation* Ethanol / adverse effects, metabolism* Glucokinase / genetics, metabolism* Glucose Transporter Type 2 / genetics, metabolism Humans Insulin-Secreting Cells / cytology*, enzymology, metabolism Male Mice Mice, Inbred C57BL Nitrites / metabolism* Peroxynitrous Acid / metabolism* Protein Processing, Post-Translational |
| Chemical | |
Reg. No./Substance:
|
0/Glucose Transporter Type 2; 0/Nitrites; 0/Slc2a2 protein, mouse; 14691-52-2/Peroxynitrous Acid; 64-17-5/Ethanol; EC 2.7.1.2/Glucokinase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Whole body deletion of AMP-activated protein kinase {beta}2 reduces muscle AMPK activity and exercis...
Next Document: Potentiation of ligand binding through cooperative effects in monoamine oxidase B.