Insulinotropic and Anti-Apoptotic Effects of Nobiletin in INS-1D Β-Cells

To determine the mechanism underlying anti-diabetic effects of nobiletin, a citrus flavonoid, the effects of nobiletin on insulin secretion and β-cell apoptosis were investigated in the INS-1D β-cell line. Nobiletin increased glucose-induced insulin secretion (GSIS), and inhibited thapsigargin-induced apoptosis. Nobiletin also potentiated forskolin-induced cAMP accumulation. The insulinotropic effect was significantly suppressed by the EPAC inhibitor ESI-09, but not by the PKA inhibitor KT-5720. Conversely, the anti-apoptotic effect was inhibited by KT-5720, but not by ESI-09. Nobiletin also inhibited thapsigargin-induced increases in cleaved caspase-3 and JNK phosphorylation, but had no effect on the expression of CHOP. Similar insulinotropic and anti-apoptotic effects were also observed with the extract from Ponkan peels containing nobiletin. These results suggest that nobiletin exerts anti-diabetic effects by increasing GSIS and preventing β-cell apoptosis via cAMP-dependent mechanisms; the former is primarily mediated by EPAC, whereas the latter is due to PKA-induced alleviation of JNK-mediated ER stress.