Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China.
J Cell Mol Med. 2020 Dec;24(24):14247-14256. doi: 10.1111/jcmm.16041. Epub 2020 Nov 14.
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.
胰岛炎症严重损害胰岛β细胞功能，但具体机制尚不清楚。白细胞介素 1-β（IL-1β）是一种重要的炎症因子，在多种生理病理过程中发挥重要作用，包括糖尿病。钙/钙调蛋白依赖性丝氨酸蛋白激酶（CASK）是一种重要的调节剂，尤其是在胰岛素分泌过程中。本研究旨在揭示 CASK 在 IL-1β诱导的胰岛素分泌功能障碍中的作用及其可能的机制。用 IL-1β刺激的 Sprague-Dawley（SD）大鼠胰岛和 INS-1 细胞作为慢性炎症模型。评估与 Cask 和 DNA 甲基转移酶（DNMT）表达相关的胰岛素分泌功能。还探讨了 IL-1β诱导的胰岛β细胞功能障碍的可能机制。在这项研究中，CASK 的过表达有效改善了 IL-1β诱导的胰岛β细胞功能障碍，增加了胰岛素分泌。IL-1β给药后，DNA 甲基转移酶和 Cask 启动子区域的甲基化水平升高。甲基转移酶抑制剂 5-氮杂-2'-脱氧胞苷（5-Aza-dC）和 si-DNMTs 部分上调了 CASK 的表达，并逆转了 INS-1 和大鼠胰岛中 IL-1β 处理下钾刺激胰岛素分泌（KSIS）和葡萄糖刺激胰岛素分泌（GSIS）的功能。这些结果揭示了 IL-1β对胰岛素分泌功能障碍的先前未知影响，并证明了基于诱导型一氧化氮合酶（iNOS）激活和基因启动子甲基化修饰的 Cask 沉默的新途径。
