Voltage-Gated Na+ Channels are Modulated by Glucose and Involved in Regulating Cellular Insulin Content of INS-1 Cells

Background/Aims: Islet beta cells (β-cells) are unique cells that play a critical role in glucose homeostasis by secreting insulin in response to increased glucose levels. Voltage-gated ion channels in β-cells, such as K + and Ca 2+ channels, contribute to insulin secretion. The response of voltage-gated Na + channels (VGSCs) in β-cells to the changes in glucose levels remains unknown. This work aims to determine the role of extracellular glucose on the regulation of VGSC. Methods: The effect of glucose on VGSC currents (I Na ) was investigated in insulin-secreting β-cell line (INS-1) cells of rats using whole-cell patch clamp techniques, and the effects of glucose on insulin content and cell viability were determined using Enzyme-Linked Immunosorbent Assay (ELISA) and Methylthiazolyldiphenyl-tetrazolium Bromide (MTT) assay methods respectively. Results: Our results show that extracellular glucose application can inhibit the peak of I Na in a concentration-dependent manner. Glucose concentration of 18 mM reduced the amplitude of I Na , suppressed the I Na of steady-state activation, shifted the steady-state inactivation curves of I Na to negative potentials, and prolonged the time course of I Na recovery from inactivation. Glucose also enhanced the activity-dependent attenuation of I Na and reduced the fraction of activated channels. Furthermore, 18 mM glucose or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited the activity of VGSC and also improved insulin synthesis. Conclusion: These results revealed that extracellular glucose application enhances the insulin synthesis in INS-1 cells and the mechanism through the partial inhibition on I Na channel is involved. Our results innovatively suggest that VGSC plays a vital role in modulating glucose homeostasis.