Vitamin D augments insulin secretion via calcium influx and upregulation of voltage calcium channels: Findings from INS-1 cells and human islets

Abstract

Vitamin D (VD) has been implicated in regulating insulin secretion and pancreatic β-cell function. Yet, the underlying molecular mechanism of VD in glucose homeostasis is not fully understood. This study investigates the effect of VD in regulating insulin secretion and pancreatic β-cell function. INS-1 β-cells were treated with VD to assess cell viability, reactive oxygen species production (ROS), insulin secretion, glucose uptake, proliferation, gene expression alterations, mitochondria metabolism, calcium influx, as well as the effects of antidiabetic drugs on VDR expression. Additionally, RNA sequencing from human pancreatic islets were utilized to examine VDR expression in relation to clinical parameters such as HbA1c, BMI, age, and gender. VD treatment enhanced glucose-stimulated insulin secretion and elevated intracellular calcium levels without affecting insulin content, glucose uptake, ROS production, proliferation, or mitochondrial metabolism. Expression levels of key β-cell function genes, including Ins, Pdx1, and Glut2, remained unchanged with VD treatment. However, genes associated with calcium channels were upregulated. Cell exposure to rosiglitazone and dexamethasone elevated VDR expression in INS-1 cells, while metformin and insulin had no effect. RNA-seq analysis in human islets showed that VDR expression levels in human islets were significantly higher than in other metabolic tissues and were notably reduced in hyperglycemic donors compared to normoglycemic individuals. Furthermore, VDR expression positively correlated with several genes regulating voltage-gated calcium channels. In conclusion, the study indicates that VD plays a significant role in enhancing insulin secretion through modulation of intracellular calcium dynamics, highlighting its potential therapeutic implications for managing type 2 diabetes.

Keywords: Antidiabetic drugs; Human islets; Insulin; RNA-Seq; Vitamin D.