2043-LB: hERG Potassium Channels as Novel Targets for GLP-1 and GIP Secretagogue Therapies in Diabetes and Obesity

Le résumé fourni par la source

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), derived from enteroendocrine cells (EECs), play critical roles in blood glucose regulation as incretin hormones. While medications targeting GLP-1 analogues and GLP-1 receptor activators are widely used for managing type 2 diabetes (T2D) and obesity, there remains a need for agents that stimulate endogenous incretin secretion. In this study, we uncover the pivotal role of hERG potassium channels in regulating incretin secretion. Co-localization of hERG channels with EECs in the intestinal epithelium of rodents underscores their significance. Intestine-specific knockout of hERG in mice enhances glucose tolerance and augments GLP-1 and GIP secretion triggered by oral glucose intake. Moreover, primary intestinal epithelial cells deficient in hERG exhibit heightened incretin secretion upon glucose stimulation. Mechanistically (see Figure 1), (1) hERG deficiency leads to reduced Kv currents and (2) prolonged repolarization in enteroendocrine cells, (3) resulting in increased Ca2+ influx and intracellular Ca2+ accumulation, (4) ultimately leading to augmented incretin secretion. Given the therapeutic benefits associated with GLP-1 and GIP, these findings underscore the potential of hERG as an auspicious novel target for addressing obesity and diabetes therapeutically. Disclosure Y. Yuan: None. H. Wang: None. J. Yang: None.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.