| Diazoxide-induced beta-cell rest reduces endoplasmic reticulum stress in lipotoxic beta-cells. | |
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MedLine Citation:
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PMID: 18644846 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of beta-cell function and impaired insulin secretion observed in these individuals. A strategy to improve beta-cell function in individuals with T2DM has been intermittent administration of K(ATP) channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of K(ATP) channels improve beta-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in beta-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic beta-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and beta-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves beta-cell function. |
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Authors:
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Ernest Sargsyan; Henrik Ortsäter; Kristofer Thorn; Peter Bergsten |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2008-07-21 |
Journal Detail:
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Title: The Journal of endocrinology Volume: 199 ISSN: 1479-6805 ISO Abbreviation: J. Endocrinol. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-09-25 Completed Date: 2009-07-10 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0375363 Medline TA: J Endocrinol Country: England |
Other Details:
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Languages: eng Pagination: 41-50 Citation Subset: IM |
Affiliation:
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Department of Medical Cell Biology, Uppsala University, SE-75123, Uppsala, Sweden. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Activating Transcription Factor 6
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metabolism Alternative Splicing / drug effects, genetics Animals Apoptosis / drug effects Blotting, Western Cell Line, Tumor DNA-Binding Proteins / genetics Diazoxide / pharmacology* Endoplasmic Reticulum / drug effects*, metabolism Endoribonucleases / metabolism Eukaryotic Initiation Factor-2 / metabolism Glucose / pharmacology Insulin / metabolism, secretion Insulin-Secreting Cells / cytology, drug effects*, metabolism* Islets of Langerhans / drug effects, metabolism Male Palmitates / pharmacology Phosphorylation / drug effects Protein-Serine-Threonine Kinases / metabolism Rabbits Rats Signal Transduction / drug effects, physiology Transcription Factor CHOP / metabolism Transcription Factors / genetics eIF-2 Kinase / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Activating Transcription Factor 6; 0/Atf6 protein, mouse; 0/DNA-Binding Proteins; 0/Ddit3 protein, mouse; 0/Eukaryotic Initiation Factor-2; 0/Palmitates; 0/Transcription Factors; 0/regulatory factor X transcription factors; 11061-68-0/Insulin; 147336-12-7/Transcription Factor CHOP; 364-98-7/Diazoxide; 50-99-7/Glucose; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/Ern1 protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/eIF-2 Kinase; EC 3.1.-/Endoribonucleases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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