Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in β Cells.

Zhihong Liu,Peifeng He,Shouan Ren,Yunfeng Liu,Zhihong Lu,Tao Liu,Huan Xue,Huanhuan Yang,Yanli Zhao,Yi Zhang,Lijuan Cui,Linping Zhi

doi:10.3389/fphar.2021.683674

Zhihong Liu, Peifeng He + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2021.683674

Copy DOI

Abstract

Recent studies suggest that Sphingosine 1-phosphate (S1P) plays an important role in regulating glucose metabolism in type 2 diabetes. However, its effects and mechanisms of promoting insulin secretion remain largely unknown. Here, we found that S1P treatment decreased blood glucose level and increased insulin secretion in C57BL/6 mice. Our results further showed that S1P promoted insulin secretion in a glucose-dependent manner. This stimulatory effect of S1P appeared to be irrelevant to cyclic adenosine monophosphate signaling. Voltage-clamp recordings showed that S1P did not influence voltage-dependent Ca2+ channels, but significantly blocked voltage-dependent potassium (Kv) channels, which could be reversed by inhibition of phospholipase C (PLC) and protein kinase C (PKC). Calcium imaging revealed that S1P increased intracellular Ca2+ levels, mainly by promoting Ca2+ influx, rather than mobilizing intracellular Ca2+ stores. In addition, inhibition of PLC and PKC suppressed S1P-induced insulin secretion. Collectively, these results suggest that the effects of S1P on glucose-stimulated insulin secretion (GSIS) depend on the inhibition of Kv channels via the PLC/PKC signaling pathway in pancreatic β cells. Further, S1P improved β cell survival; this effect was also associated with Kv channel inhibition. This work thus provides new insights into the mechanisms whereby S1P regulates β cell function in diabetes.

Highlights

The study and development of medication to safely increase insulin secretion is of great significance for the treatment of type 2 diabetes
Most effects of Sphingosine 1-phosphate (S1P) depend on its five G-protein-coupled receptor (GPCR) subtypes, other studies reported that S1P can act intracellularly as a second messenger (Laychock, et al, 2006; Hahn, et al, 2017), and directly uptake into cell by S1P transporters (Goto, et al, 2021)
As S1P biological effects are mediated by GPCR composed of five subtypes (S1PR15), their cellular effects are highly complex because each receptor subtype could signal via multiple G proteins signaling pathway

Summary

Introduction

The study and development of medication to safely increase insulin secretion is of great significance for the treatment of type 2 diabetes. Sphingosine 1-phosphate (S1P) is a phosphorylated sphingosine metabolite that regulates various cellular functions, from cell differentiation to apoptosis (Olivera, et al, 1993; Hla, 2001) and has been found to exert beneficial effects on several human diseases. S1P Stimulates Insulin Secretion including organ transplantation, multiple sclerosis, cancer and neuroinflammatory disorders (Brinkmann, 2007). Previous research has shown that S1P administration could improve β-cell functions, increase insulin secretion and reduce β-cell apoptosis (Haass, et al, 2015; Hahn, et al, 2017; Shimizu, et al, 2000; Laychock, et al, 2006). As a potential therapeutic target for various diseases, S1P signaling has attracted extensive attention, including for its therapeutic implications in diabetes (Chaudhry, et al, 2017; Lewis, et al, 2016; Liu, et al, 2019)

Methods

Results

Conclusion