Cask methylation involved in the injury of insulin secretion function caused by interleukin1-β.

Islet inflammation severely impairs pancreatic β-cell function, but the specific mechanisms are still unclear. Interleukin1-β (IL-1β), an essential inflammatory factor, exerts a vital role in multiple physio-pathologic processes, including diabetes. Calcium/calmodulin-dependent serine protein kinase (CASK) is an important regulator especially in insulin secretion process. This study aims to unveil the function of CASK in IL-1β-induced insulin secretion dysfunction and the possible mechanism thereof. Islets of Sprague-Dawley (SD) rats and INS-1 cells stimulated with IL-1β were utilized as models of chronic inflammation. Insulin secretion function associated with Cask and DNA methyltransferases (DNMT) expression were assessed. The possible mechanisms of IL-1β-induced pancreatic β-cell dysfunction were also explored. In this study, CASK overexpression effectively improved IL-1β-induced islet β-cells dysfunction, increased insulin secretion. DNA methyltransferases and the level of methylation in the promoter region of Cask were elevated after IL-1β administration. Methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) and si-DNMTs partially up-regulated CASK expression and reversed potassium stimulated insulin secretion (KSIS) and glucose-stimulated insulin secretion (GSIS) function under IL-1β treatment in INS-1 and rat islets. These results reveal a previously unknown effect of IL-1β on insulin secretion dysfunction and demonstrate a novel pathway for Cask silencing based on activation of DNA methyltransferases via inducible nitric oxide synthase (iNOS) and modification of gene promoter methylation.