糖尿病新药靶-细胞背景钾电流KCNK9 (TASK3)的发现和验证

The impairment of β cell in insulin secretion is a major pathophysiological mechanism of type 2 diabetes (T2DM). The background outward potassium current, KCNK9, has a key role in regulating membrane potential and cellular excitability. In previous study, we found significantly increased expression of KCNK9 in the pancreatic β cells of the diabetic db/db mouse. By loweirng the resting membrane potential of β cells and the threshold of glucose-stimulated insulin secretion (GSIS), and extending the active period of current oscillation, KCNK9 may cause high frequency of membrane depolarization and calcium oscillation, and finally lead to elevated basal insulin secretion and impaired GSIS. In contrast, inhibition of KCNK9 could effectively reverse these dysfunctions of β cell. These findings thus hint KCNK9 might take part in the impairment of β cell’s function in diabetes, and it may be a potential drug target for diabetes treatment. However, the exact roles of KCNK9 plays in systemic glucose homeostasis and in the regulation of insulin secretion under condition of T2DM were still unknown. The current study will delve into the roles that KCNK9 plays in the onset and development of diabetes, and the involved regulatory mechanism under insulin resistance and diabetic condition on levels of cell, tissue and whole animal by using the genetic manipulation approach, to uncover whether KCNK9 could be used as a real and effective drug target for developing new therapies. The successful employment of current study undoubtly will contribute to the intervention of diabetes at an early stage and to lay the foundation in finding novel potential therapeutic approach for diabete.

胰岛β细胞功能受损是T2DM发病原因之一。外向开放-整流型漏钾离子通道KCNK9介导细胞背景钾电流，对维持细胞静息膜电位及兴奋性十分重要。我们前期研究发现在db/db小鼠β细胞，特异性高表达的KCNK9可能通过降低β细胞静息膜电位和胰岛素分泌的葡萄糖刺激阈值，延长电流震荡活跃期，引起高频率的膜除极和钙震荡，导致基础状态下胰岛素分泌亢进和糖刺激下胰岛素分泌反应减低；而抑制KCNK9则可显著改善胰岛素分泌受损。提示KCNK9可能参与了T2DMβ细胞功能紊乱，是T2DM的潜在靶点。然而有关KCNK9与糖代谢的关系尚不明确，其是否可以作为治疗靶点有待系统验证，本课题将采用β细胞特异性KCNK9基因操作（减低、敲除、过表达）策略在细胞、组织和整体动物上研究KCNK9在糖代谢和和胰岛素分泌调控中的作用，结合应用KCNK9抑制剂验证KCNK9作为T2DM新药靶的可行性，为寻找新的糖尿病治疗药物奠定基础。

胰岛β细胞功能受损是T2DM发病原因之一。外向开放-整流型漏钾离子通道KCNK9介导细胞背景钾电流，对维持细胞静息膜电位及兴奋性十分重要。本课题采用β细胞特异性KCNK9基因操作（减低/敲除、过表达）策略在细胞、组织和整体动物上研究了KCNK9在糖代谢和和胰岛素分泌调控中的作用,探究了KCNK9作为T2DM新药靶的可行性，为寻找新的糖尿病治疗药物奠定了基础。我们研究发现葡萄糖可以特异性调节KCNK9表达，KCNK9过表达通过影响小鼠β细胞静息膜电位和胰岛素分泌，改变电流震荡周期，影响膜除极和细胞内钙震荡，导致基础状态下胰岛素分泌亢进和糖刺激下胰岛素分泌反应受损；抑制KCNK9则可改善胰岛素分泌受损。同时我们发现一种单基因突变型糖尿病的发生发展与β细胞内KCNK9过表达密切相关，提示KCNK9表达和功能异常可能参与了糖尿病发生时的β细胞功能紊乱，其可能作为糖尿病治疗药物研发的一个潜在新靶点。