Cyanidin-3-rutinoside stimulated insulin secretion through activation of L-type voltage-dependent Ca2+ channels and the PLC-IP3 pathway in pancreatic β-cells

Abstract

Cyanidin-3-rutinoside (C3R) is an anthocyanin with anti-diabetic properties found in red-purple fruits. However, the molecular mechanisms of C3R on Ca²⁺-dependent insulin secretion remains unknown. This study aimed to identify C3R's mechanisms of action in pancreatic β-cells. Rat INS-1 cells were used to elucidate the effects of C3R on insulin secretion, intracellular Ca²⁺ signaling, and gene expression. The results showed that C3R at 60, 100, and 300 µM concentrations significantly increased insulin secretion via intracellular Ca²⁺ signaling. The exposure of cells with C3R concentrations up to 100 μM did not affect cell viability. Pretreatment of cells with nimodipine (voltage-dependent Ca²⁺ channel (VDCC) blocker), U73122 (PLC inhibitor), and 2-APB (IP₃ receptor blocker) inhibited the intracellular Ca²⁺ signals by C3R. Interestingly, C3R increased intracellular Ca²⁺ signals and insulin secretion after depletion of endoplasmic reticulum Ca²⁺ stores by thapsigargin. However, insulin secretion was abolished under extracellular Ca²⁺-free conditions. Moreover, C3R upregulated mRNA expression for Glut2 and Kir_6.2 genes. These findings indicate that C3R stimulated insulin secretion by promoting Ca²⁺ influx via VDCCs and activating the PLC-IP₃ pathway. C3R also upregulates the expression of genes necessary for glucose-induced insulin secretion. This is the first study describing the molecular mechanisms by which C3R stimulates Ca²⁺-dependent insulin secretion from pancreatic β-cells. These findings contribute to our understanding on how anthocyanins improve hyperglycemia in diabetic patients.

Keywords: Cyanidin-3-rutinoside; Insulin secretion; Intracellular Ca(2+) signaling; PLC-IP(3) pathway; Pancreatic β-cells; Voltage-dependent Ca(2+) channel.