Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Southeast University, Nanjing 210009, China.
Department of Endocrinology, Affiliated Fuyang Hospital of Anhui Medical University, Fuyang 236000, China.
Acta Biochim Biophys Sin (Shanghai). 2018 Mar 1;50(3):281-287. doi: 10.1093/abbs/gmx139.
High-glucose level exerts deleterious effects on pancreatic β cells, but the mechanisms remain unclear. Calcium/calmodulin-dependent serine protein kinase (CASK) plays a vital role in neural development and release of neurotransmitters, and probably plays a role in the anchoring of insulin on pancreatic β cell membrane. Hypoxia-inducible factor 1α (HIF1α) is involved in β-cell dysfunction. The aim of this study was to provide some basic evidence that CASK could be involved in glucotoxicity-induced insulin secretion dysfunction mediated by HIF1α in INS-1E cells. CASK overexpression plasmid, HIF1α agonist (CoCl2), and HIF1α selective inhibitor (KC7F2) were used. The results showed that chronic stimulation with high glucose could induce insulin secretion dysfunction in INS-1E β cells. Overexpression of CASK partially reversed the effects of high glucose on insulin secretion. CoCl2 reduced the expression of CASK, but KC7F2 reversed the glucotoxicity-induced CASK level reduction. These results suggested that glucotoxicity-induced insulin secretion defects in INS-1E cells could be mediated by HIF1α via the down-regulation of CASK.
高糖水平对胰腺β细胞有有害影响，但机制尚不清楚。钙/钙调蛋白依赖性丝氨酸蛋白激酶 (CASK) 在神经发育和神经递质释放中起着至关重要的作用，可能在胰岛素在胰腺β细胞膜上的锚定中发挥作用。缺氧诱导因子 1α (HIF1α) 参与β细胞功能障碍。本研究旨在提供一些基本证据，表明 CASK 可能参与 INS-1E 细胞中由 HIF1α介导的糖毒性诱导的胰岛素分泌功能障碍。使用了 CASK 过表达质粒、HIF1α 激动剂 (CoCl2) 和 HIF1α 选择性抑制剂 (KC7F2)。结果表明，高葡萄糖的慢性刺激可诱导 INS-1E β 细胞胰岛素分泌功能障碍。CASK 的过表达部分逆转了高葡萄糖对胰岛素分泌的影响。CoCl2 降低了 CASK 的表达，但 KC7F2 逆转了糖毒性诱导的 CASK 水平降低。这些结果表明，HIF1α 通过下调 CASK 介导 INS-1E 细胞中的糖毒性诱导的胰岛素分泌缺陷。
