Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.

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Version: author
Serval ID
serval:BIB_614F5BDEAAC9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.
Journal
Diabetes
Author(s)
Roggli E., Gattesco S., Caille D., Briet C., Boitard C., Meda P., Regazzi R.
ISSN
1939-327X (Electronic)
ISSN-L
0012-1797
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
61
Number
7
Pages
1742-1751
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Abstract
During the initial phases of type 1 diabetes, pancreatic islets are invaded by immune cells, exposing β-cells to proinflammatory cytokines. This unfavorable environment results in gene expression modifications leading to loss of β-cell functions. To study the contribution of microRNAs (miRNAs) in this process, we used microarray analysis to search for changes in miRNA expression in prediabetic NOD mice islets. We found that the levels of miR-29a/b/c increased in islets of NOD mice during the phases preceding diabetes manifestation and in isolated mouse and human islets exposed to proinflammatory cytokines. Overexpression of miR-29a/b/c in MIN6 and dissociated islet cells led to impairment in glucose-induced insulin secretion. Defective insulin release was associated with diminished expression of the transcription factor Onecut2, and a consequent rise of granuphilin, an inhibitor of β-cell exocytosis. Overexpression of miR-29a/b/c also promoted apoptosis by decreasing the level of the antiapoptotic protein Mcl1. Indeed, a decoy molecule selectively masking the miR-29 binding site on Mcl1 mRNA protected insulin-secreting cells from apoptosis triggered by miR-29 or cytokines. Taken together, our findings suggest that changes in the level of miR-29 family members contribute to cytokine-mediated β-cell dysfunction occurring during the initial phases of type 1 diabetes.
Keywords
Animals, Apoptosis/drug effects, Cytokines/pharmacology, Diabetes Mellitus, Type 1/metabolism, Exocytosis/drug effects, Female, Glucose/administration & dosage, Homeodomain Proteins/biosynthesis, Humans, Insulin/secretion, Insulin-Secreting Cells/metabolism, Insulin-Secreting Cells/secretion, Male, Mice, Mice, Inbred NOD, MicroRNAs/biosynthesis, Middle Aged, Prediabetic State/metabolism, Proto-Oncogene Proteins c-bcl-2/analysis, Transcription Factors/biosynthesis, Vesicular Transport Proteins/analysis
Pubmed
Web of science
Open Access
Yes
Create date
31/10/2012 14:02
Last modification date
20/08/2019 14:18
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