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

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.