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
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
DOI: 10.2337/db11-1086
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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