The vulnerability of pancreatic β-cells to endoplasmic reticulum stress (ER), is a common cause of β-cell apoptosis and dysfunction involving decreased insulin secretory response and a reduction in β-cell mass in type 2 diabetes mellitus. The possible role of naturally occurring polyphenols –known as flavonoids- in treating type 2 diabetes mellitus is a current area of focus. However, there is a dearth of information about the effect of the trihydroxyflavone, apigenin, on pancreatic β-cell functions.
We evaluated the effect of apigenin on glucose-induced insulin secretion (GSIS) and β-cell apoptosis, studying the mechanism underlying its antidiabetic effects, using the INS-ID β-cell line. The results showed that apigenin dose-dependently stimulated GSIS at all concentrations (1, 10, 30 and 100 μM), with a significant peak effect at 30 μM concentration. The downstream ER stress signaling proteins, CHOP and cleaved caspase-3, which were elevated by thapsigargin-induced apoptosis of INS-1 cells, were concentration-dependently and strongly attenuated by apigenin treatment at all concentrations, with peak suppression at concentrations of 30 and 100 μM. These results strongly correlated with the flow cytometric analysis of Annexin V/PI staining and the DNA fragmentation analysis, which is indicative of apoptosis, as determined by DNA laddering. The thapsigargin-induced increase in TXNIP expression was also dose-dependently suppressed by treatment with apigenin. Apigenin also inhibited high concentration of glucose-induced apoptotic increases in cleaved caspase-3 and CHOP expressions.
These results suggest that apigenin is an attractive candidate with remarkable and potent insulinotropic and anti-apoptotic effects on β-cells and that its anti-diabetic effect may be mediated by increasing GSIS and preventing ER stress-mediated β-cell apoptosis mediated by CHOP, cleaved caspase-3 and TXNIP, hence promoting β-cells survival and function.