title: Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.
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.
authors.affiliation: Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Elodie
authors.initials: E
authors.lastname: Roggli
authors.forename: Sonia
authors.initials: S
authors.lastname: Gattesco
authors.forename: Dorothée
authors.initials: D
authors.lastname: Caille
authors.forename: Claire
authors.initials: C
authors.lastname: Briet
authors.forename: Christian
authors.initials: C
authors.lastname: Boitard
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.forename: Romano
authors.initials: R
authors.lastname: Regazzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000008:administration & dosage; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011236:Prediabetic State / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014157:Transcription Factors / Q000096:biosynthesis; D033921:Vesicular Transport Proteins / Q000032:analysis
chemical_list: D016207:Cytokines; D018398:Homeodomain Proteins; D007328:Insulin; C579094:Mcl1 protein, mouse; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C117354:ONECUT2 protein, human; C487964:ONECUT2 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C512779:SYTL4 protein, human; C122015:Sytl4 protein, mouse; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D005947:Glucose