Document Detail


Diazoxide-induced beta-cell rest reduces endoplasmic reticulum stress in lipotoxic beta-cells.
MedLine Citation:
PMID:  18644846     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ernest Sargsyan; Henrik Ortsäter; Kristofer Thorn; Peter Bergsten
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-21
Journal Detail:
Title:  The Journal of endocrinology     Volume:  199     ISSN:  1479-6805     ISO Abbreviation:  J. Endocrinol.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-25     Completed Date:  2009-07-10     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0375363     Medline TA:  J Endocrinol     Country:  England    
Other Details:
Languages:  eng     Pagination:  41-50     Citation Subset:  IM    
Affiliation:
Department of Medical Cell Biology, Uppsala University, SE-75123, Uppsala, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Activating Transcription Factor 6 / 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:
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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