| First Author | Tsunekawa S | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 11 | Pages | 2883-91 |
| PubMed ID | 21933986 | Mgi Jnum | J:189478 |
| Mgi Id | MGI:5445857 | Doi | 10.2337/db11-0340 |
| Citation | Tsunekawa S, et al. (2011) FoxO feedback control of basal IRS-2 expression in pancreatic beta-cells is distinct from that in hepatocytes. Diabetes 60(11):2883-91 |
| abstractText | OBJECTIVE: Appropriate regulation of insulin receptor substrate 2 (IRS-2) expression in pancreatic beta-cells is essential to adequately compensate for insulin resistance. In liver, basal IRS-2 expression is controlled via a temporal negative feedback of sterol regulatory element-binding protein 1 (SREBP-1) to antagonize transcription factors forkhead box class O (FoxO)1/FoxO3a at an insulin response element (IRE) on the IRS-2 promoter. The purpose of the study was to examine if a similar mechanism controlled IRS-2 expression in beta-cells. RESEARCH DESIGN AND METHODS: IRS-2 mRNA and protein expression, as well as IRS-2 gene promoter activity, were examined in isolated rat islets. Specific transcription factor association with the IRE on the IRS-2 promoter was examined by chromatin immunoprecipitation (ChIP) assay, and their nuclear translocation was examined by immunofluorescence. A direct in vivo effect of insulin on control of IRS-2 expression in liver and pancreatic islets was also investigated. RESULTS: In IRS-2 promoter-reporter assays conducted in isolated islets, removal of the IRE decreased basal IRS-2 promoter activity in beta-cells up to 80%. Activation of IRS signaling in isolated rat islets by insulin/IGF-I (used as an experimental in vitro tool) or downstream constitutive activation of protein kinase B (PKB) significantly decreased IRS-2 expression. In contrast, inhibition of phosphatidylinositol 3-kinase (PI3K) or PKB significantly increased IRS-2 levels in beta-cells. ChIP assays indicated that transcription factors FoxO1 and FoxO3a associated with the IRE on the IRS-2 promoter in beta-cells in a PI3K/PKB-dependent manner, whereas others, such as SREBP-1, the transcription factor binding to immunoglobulin heavy chain enhancer 3', and the aryl hydrocarbon receptor nuclear translocator (ARNT), did not. However, only FoxO3a, not FoxO1, was capable of driving IRS-2 promoter activity via the IRE in beta-cells. In vivo studies showed insulin was able to suppress IRS-2 expression via activation of SREBP-1 in the liver, but this mechanism was not apparent in pancreatic islets from the same animal. CONCLUSIONS: The molecular mechanism for feedback control of IRS signaling to decrease IRS-2 expression in liver and beta-cells is quite distinct, with a predominant role played by FoxO3a in beta-cells. |
