| First Author | Demozay D | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 11 | Pages | 2892-902 |
| PubMed ID | 21940781 | Mgi Jnum | J:189475 |
| Mgi Id | MGI:5445854 | Doi | 10.2337/db11-0341 |
| Citation | Demozay D, et al. (2011) Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca2+-dependent calcineurin/NFAT signaling in primary pancreatic islet beta-cells. Diabetes 60(11):2892-902 |
| abstractText | OBJECTIVE: Insulin receptor substrate-2 (IRS-2) plays an essential role in pancreatic islet beta-cells by promoting growth and survival. IRS-2 turnover is rapid in primary beta-cells, but its expression is highly regulated at the transcriptional level, especially by glucose. The aim was to investigate the molecular mechanism on how glucose regulates IRS-2 gene expression in beta-cells. RESEARCH DESIGN AND METHODS: Rat islets were exposed to inhibitors or subjected to adenoviral vector-mediated gene manipulations and then to glucose-induced IRS-2 expression analyzed by real-time PCR and immunoblotting. Transcription factor nuclear factor of activated T cells (NFAT) interaction with IRS-2 promoter was analyzed by chromatin immunoprecipitation assay and glucose-induced NFAT translocation by immunohistochemistry. RESULTS: Glucose-induced IRS-2 expression occurred in pancreatic islet beta-cells in vivo but not in liver. Modulating rat islet beta-cell Ca(2+) influx with nifedipine or depolarization demonstrated that glucose-induced IRS-2 gene expression was dependent on a rise in intracellular calcium concentration derived from extracellular sources. Calcineurin inhibitors (FK506, cyclosporin A, and a peptide calcineurin inhibitor [CAIN]) abolished glucose-induced IRS-2 mRNA and protein levels, whereas expression of a constitutively active calcineurin increased them. Specific inhibition of NFAT with the peptide inhibitor VIVIT prevented a glucose-induced IRS-2 transcription. NFATc1 translocation to the nucleus in response to glucose and association of NFATc1 to conserved NFAT binding sites in the IRS-2 promoter were demonstrated. CONCLUSIONS: The mechanism behind glucose-induced transcriptional control of IRS-2 gene expression specific to the islet beta-cell is mediated by the Ca(2+)/calcineurin/NFAT pathway. This insight into the IRS-2 regulation could provide novel therapeutic means in type 2 diabetes to maintain an adequate functional mass. |
