Changes in MicroRNA Expression Contribute to Pancreatic β-Cell Dysfunction in Prediabetic NOD Mice
| Autor: | Dorothée Caille, Romano Regazzi, E. Roggli, Sonia Gattesco, Christian Boitard, Paolo Meda, Claire Briet |
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| Rok vydání: | 2012 |
| Předmět: |
0303 health sciences
medicine.medical_specialty Endocrinology Diabetes and Metabolism Insulin medicine.medical_treatment Pancreatic islets 030209 endocrinology & metabolism Biology Proinflammatory cytokine Cell biology 03 medical and health sciences 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 0302 clinical medicine Immune system Endocrinology medicine.anatomical_structure Apoptosis Internal medicine microRNA Gene expression Internal Medicine medicine 030304 developmental biology NOD mice |
| Zdroj: | Diabetes, vol. 61, no. 7, pp. 1742-1751 Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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