Cocoa flavonoids improve insulin signalling and modulate glucose production via AKT and AMPK in HepG2 cells.

SCOPE Cocoa and (-)-epicatechin (EC), a main cocoa flavanol, have been suggested to exert beneficial effects in diabetes, but the mechanism for their insulin-like effects remains unknown. In this study, the modulation of insulin signalling by EC and a cocoa phenolic extract (CPE) on hepatic HepG2 cells was investigated by analysing key proteins of the insulin pathways, namely insulin receptor, insulin receptor substrate (IRS) 1 and 2, PI3K/AKT and 5'-AMP-activated protein kinase (AMPK), as well as the levels of the glucose transporter GLUT-2 and the hepatic glucose production. METHODS AND RESULTS EC and CPE enhanced the tyrosine phosphorylation and total insulin receptor, IRS-1 and IRS-2 levels and activated the PI3K/AKT pathway and AMPK in HepG2 cells. CPE also enhanced the levels of GLUT-2. Interestingly, EC and CPE modulated the expression of phosphoenolpyruvate carboxykinase, a key protein involved in the gluconeogenesis, leading to a diminished glucose production. In addition, EC- and CPE-regulated hepatic gluconeogenesis was prevented by the blockage of AKT and AMPK. CONCLUSION Our data suggest that EC and CPE strengthen the insulin signalling by activating key proteins of that pathway and regulating glucose production through AKT and AMPK modulation in HepG2 cells.