Changes in MicroRNA Expression Contribute to Pancreatic β-Cell Dysfunction in Prediabetic NOD Mice
- Elodie Roggli1,
- Sonia Gattesco1,
- Dorothée Caille2,
- Claire Briet3,4,
- Christian Boitard3,4,
- Paolo Meda2 and
- Romano Regazzi1⇓
- 1Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- 2Department of Cell Physiology and Metabolism, School of Medicine, University of Geneva, Geneva, Switzerland
- 3Institut National de Santé et de Recherche Médicale U986, Paris, France
- 4Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Corresponding author: Romano Regazzi, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1086/-/DC1.
See accompanying commentary, p. 1661.
- Received August 4, 2011.
- Accepted March 5, 2012.
- © 2012 by the American Diabetes Association.
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