ABSTRACT
Glucose-stimulated insulin secretion (GSIS) in pancreatic islet ß-cells primarily relies on electrophysiological processes. Previous research highlighted the regulatory role of KCNH6, a member of the Kv channel family, in governing GSIS through its influence on ß-cell electrophysiology. In this study, we unveil a novel facet of KCNH6's function concerning insulin granule exocytosis, independent of its conventional electrical role. Young mice with ß-cell-specific KCNH6 knockout (ßKO) exhibited impaired glucose tolerance and reduced insulin secretion, a phenomenon not explained by electrophysiological processes alone. Consistently, islets from KCNH6-ßKO mice exhibited reduced insulin secretion, conversely, the overexpression of KCNH6 in murine pancreatic islets significantly enhanced insulin release. Moreover, insulin granules lacking KCNH6 demonstrated compromised docking capabilities and a reduced fusion response upon glucose stimulation. Crucially, our investigation unveiled a significant interaction between KCNH6 and the SNARE protein regulator, Munc18-1, a key mediator of insulin granule exocytosis. These findings underscore the critical role of KCNH6 in the regulation of insulin secretion through its interaction with Munc18-1, providing a promising and novel avenue for enhancing our understanding of the Kv channel in diabetes mechanisms.
Subject(s)
Exocytosis , Insulin , Animals , Mice , Electrophysiological Phenomena , Glucose , Insulin SecretionABSTRACT
In this study, we established an HPLC-MS method to determine gypenoside XVâ ¡ in biosamples. The methodology results indicated that the linear range was 1-2 500 µgâ¢L⻹ (r=0.996 3); intraday RSD values for high, medium and low concentrations were 9.9%, 3.0% 1.7%; interday RSD values were 16%, 14%, 2.5%; matrix effect ranged between 90.0%-100%, with RSD<15%. The recovery was more than 80.0%, with precision and accuracy in line with request. After the rats were orally and intravenously administered with gypenoside XVâ ¡, the concentrations of gypenoside XVâ ¡ in plasma were determined, and pharmacokinetic parameter was calculated using pharmacokinetic software DAS 2.0. According to the main pharmacokinetic parameters of gypenoside XVâ ¡, tmax was 0.17-0.20 h, t1/2 was 1.94-2.56 h, bioavailability of oral administration was 1.87%. The results indicated that the pharmacokinetic profiles of gypenoside XVâ ¡ were rapid absorption and distribution after oral administration, short time to peak and rapid elimination.