KCNH6 channel promotes insulin exocytosis via interaction with Munc18-1 independent of electrophysiological processes.

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.

The signaling protein GIV/Girdin mediates the Nephrin-dependent insulin secretion of pancreatic islet ß cells in response to high glucose.

Glucose-stimulated insulin secretion of pancreatic ß cells is essential in maintaining glucose homeostasis. Recent evidence suggests that the Nephrin-mediated intercellular junction between ß cells is implicated in the regulation of insulin secretion. However, the underlying mechanisms are only partially characterized. Herein we report that GIV is a signaling mediator coordinating glucose-stimulated Nephrin phosphorylation and endocytosis with insulin secretion. We demonstrate that GIV is expressed in mouse islets and cultured ß cells. The loss of function study suggests that GIV is essential for the second phase of glucose-stimulated insulin secretion. Next, we demonstrate that GIV mediates the high glucose-stimulated tyrosine phosphorylation of GIV and Nephrin by recruiting Src kinase, which leads to the endocytosis of Nephrin. Subsequently, the glucose-induced GIV/Nephrin/Src signaling events trigger downstream Akt phosphorylation, which activates Rac1-mediated cytoskeleton reorganization, allowing insulin secretory granules to access the plasma membrane for the second-phase secretion. Finally, we found that GIV is downregulated in the islets isolated from diabetic mice, and rescue of GIV ameliorates the ß-cell dysfunction to restore the glucose-stimulated insulin secretion. We conclude that the GIV/Nephrin/Akt signaling axis is vital to regulate glucose-stimulated insulin secretion. This mechanism might be further targeted for therapeutic intervention of diabetic mellitus.

Incidence of Type 1 Diabetes May Be Underestimated in the Chinese Population: Evidence From 21.7 Million People Between 2007 and 2017.

OBJECTIVE: Previous reports of the annual incidence of type 1 diabetes (T1D) in China were conducted using retrospective hospital cases, which may not reflect the reality. This longitudinal study estimated T1D incidence in a Chinese population of 21.7 million from 2007 to 2017. RESEARCH DESIGN AND METHODS: A population-based registry of T1D was performed by the Beijing Municipal Health Commission Information Center. Annual incidence and 95% CIs were calculated by age group and sex. The association of sex with T1D incidence and predicted new cases of T1D were assessed using Poisson regression models. Annual percentage change and average annual percentage of change were assessed using Joinpoint regression. RESULTS: Overall, there were 6,875 individuals who developed T1D from 2007 to 2017 in this population. T1D incidence (/100,000 persons) (95% CI) significantly increased from 2.72 (2.51, 2.93) in 2007 to 3.60 (3.38, 3.78) in 2017 (P < 0.001). The T1D onset peak was in the 10-14-year-old age group. While no significant trend was found in the 0-14- and 15-29-year-old age groups, T1D incidence markedly increased from 1.87 to 3.52 in the ≥30-year-old age group (P < 0.05). The prevalence of diabetic ketoacidosis at diagnosis was highest in the 0-4-year-old age group. We predicted new cases of T1D will increase 1.57-fold over the next decade. CONCLUSIONS: T1D incidence in this large Chinese population is higher than has been reported previously. From 2007 to 2017, although the incidence peak was in the 10-14-year age group, the T1D incidence increased sharply in adults but not in youth.