| First Author | Song MY | Year | 2016 |
| Journal | Sci Rep | Volume | 6 |
| Pages | 30321 | PubMed ID | 27457971 |
| Mgi Jnum | J:254113 | Mgi Id | MGI:6101624 |
| Doi | 10.1038/srep30321 | Citation | Song MY, et al. (2016) Insulin secretion impairment in Sirt6 knockout pancreatic beta cells is mediated by suppression of the FoxO1-Pdx1-Glut2 pathway. Sci Rep 6:30321 |
| abstractText | Sirtuin 6 (Sirt6), a chromatin associated class III deacetylase, controls whole-body energy homeostasis and has a critical role in glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells. However, its underlying molecular mechanism remains poorly understood. To gain further insights, we studied the pathway by which Sirt6 regulates GSIS utilizing mice lacking Sirt6 in their beta cells (betaS6KO). Further, we overexpressed wild type or deacetylase-inactive mutant Sirt6 in isolated islets as well as in MIN6 cells. We confirmed that betaS6KO mice developed glucose intolerance with severely impaired GSIS. Gene expression analysis of knockout islets and overexpression studies demonstrated that Sirt6 deacetylates forkhead box protein O1 (FoxO1) to trigger its nuclear export and releases its transcriptional repression of key glucose sensing genes such as Pdx1 and Glut2. Ectopic overexpression of Sirt6 in knockout islets resulted in rescue of the defective insulin secretion and restoration of the expression of Pdx1 and Glut2. These results show that Sirt6 in pancreatic beta cells deacetylates FoxO1 and subsequently increases the expression of Pdx1 and Glut2 to maintain the glucose-sensing ability of pancreatic beta cells and systemic glucose tolerance. |
