Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Beijing Sijiqing Hospital, Beijing, China.
FASEB J. 2020 Nov;34(11):15015-15028. doi: 10.1096/fj.202001218R. Epub 2020 Sep 12.
Adult patients with dysfunction in human ether-a-go-go 2 (hERG2) protein, encoded by KCNH6, present with hypoinsulinemia and hyperglycemia. However, the mechanism of KCNH6 action in glucose disorders has not been clearly defined. Previous studies identified that sustained endoplasmic reticulum (ER) stress-mediated apoptosis of pancreatic β-cells and directly contributed to diabetes. In the present study, we showed that Kcnh6 knockout (KO) mice had impaired glucose tolerance mediated by high ER stress levels, and showed increased apoptosis and elevated intracellular calcium levels in pancreatic β-cells. In contrast, KCNH6 overexpression in islets isolated from C57BL/6J mice attenuated ER stress induced by thapsigargin or palmitic acid. This effect contributed to better preservation of β-cells, as reflected in increased β cell survival and enhanced glucose-stimulated insulin secretion. These results were further corroborated by studies evaluating KCNH6 overexpression in KO islets. Similarly, induction of Kcnh6 in KO mice by lentivirus injection improved glucose tolerance by reducing pancreatic ER stress and apoptosis. Our data provide new insights into how Kcnh6 deficiency causes ER calcium depletion and β cell dysfunction.
成人患者中 hERG2 蛋白（由 KCNH6 编码）功能障碍，表现为低血糖和高血糖。然而，KCNH6 在葡萄糖代谢紊乱中的作用机制尚未明确。先前的研究表明，持续的内质网（ER）应激介导的胰岛β细胞凋亡直接导致糖尿病。在本研究中，我们发现 Kcnh6 敲除（KO）小鼠的葡萄糖耐量受损，这是由高水平的 ER 应激介导的，并且胰岛β细胞中凋亡增加，细胞内钙离子水平升高。相比之下，KCNH6 在 C57BL/6J 小鼠胰岛中的过表达可减轻由他普西龙或棕榈酸引起的 ER 应激。这种作用有助于更好地保护β细胞，体现在β细胞存活增加和增强葡萄糖刺激的胰岛素分泌上。通过评估 KO 胰岛中 KCNH6 的过表达，进一步证实了这些结果。同样，通过慢病毒注射诱导 KO 小鼠中 Kcnh6 的表达，通过减少胰腺 ER 应激和凋亡来改善葡萄糖耐量。我们的数据为 Kcnh6 缺乏如何导致 ER 钙耗竭和β细胞功能障碍提供了新的见解。
