Potassium voltage-gated channel subfamily H member 2(KCNH2)is a promising target for incretin secretagogue therapies  

作　　者：Ying-Chao Yuan Hao Wang Ze-Ju Jiang Chang Liu Qi Li Si-Rui Zhou Jin-Kui Yang 

机构地区：[1]Beijing Key Laboratory of Diabetes Research and Care,Department of Endocrinology and Metabolism,Beijing Diabetes Institute,Beijing Tongren Hospital,Capital Medical University,Beijing 100730,China [2]Laboratory for Clinical Medicine,Capital Medical University,Beijing 100069,China [3]Subcenter of State Key Laboratory of Kidney Disease,Beijing Tongren Hospital,Capital Medical University,Beijing 100730,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第9期4079-4090,共12页信号转导与靶向治疗（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(81930019)to Jin-Kui Yang;supported by grants from Beijing Municipal Natural Science Foundation(7232232)to Hao Wang。

摘　　要：Derived from enteroendocrine cells(EECs),glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic peptide(GIP)are pivotal incretin hormones crucial for blood glucose regulation.Medications of GLP-1 analogs and GLP-1 receptor activators are extensively used in the treatment of type 2 diabetes(T2D)and obesity.However,there are currently no agents to stimulate endogenous incretin secretion.Here,we find the pivotal role of KCNH2 potassium channels in the regulation of incretin secretion.Co-localization of KCNH2 with incretin-secreting EECs in the intestinal epithelium of rodents highlights its significance.Gut epithelial cell-specific KCNH2 knockout in mice improves glucose tolerance and increases oral glucose-triggered GLP-1 and GIP secretion,particularly GIP.Furthermore,KCNH2-deficient primary intestinal epithelial cells exhibit heightened incretin,especially GIP secretion upon nutrient stimulation.Mechanistically,KCNH2 knockdown in EECs leads to reduced K+currents,prolonged action potential duration,and elevated intracellular calcium levels.Finally,we found that dofetilide,a KCNH2-specific inhibitor,could promote incretin secretion in enteroendocrine STC-1 cells in vitro and in hyperglycemic mice in vivo.These findings elucidate,for the first time,the mechanism and application of KCNH2 in regulating incretin secretion by EECs.Given the therapeutic promise of GLP-1 and GIP in diabetes and obesity management,this study advances our understanding of incretin regulation,paving the way for potential incretin secretagogue therapies in the treatment of diabetes and obesity.

关 键 词：KCNH2 POTASSIUM elevated 

分 类 号：R587.1[医药卫生—内分泌]