Objective: Procyanidol oligomers (PO) are bioactive flavonoid compounds from fruits and vegetables that possess insulinomimetic properties, decreasing hyperglycaemia in streptozotocin-diabetic rats and stimulating glucose uptake in insulin-sensitive cell lines. In this study, we analysed the effect of PO as grape-seed extract on modulating proliferation and the protective effect of PO against lipotoxicity in beta-cells. Methods: INS-1 rat insulinoma cells were exposed to different concentrations of PO. MTT and BrdU assays were performed to evaluate pancreatic β-cell proliferation. The expression of Akt/FoxO1/p38 MAPK was detected by quantitative real-time PCR and Western blotting. Results: The results revealed that in comparison to the non-treatment group, stimulating INS-1 cells with 10 ug/mL PO caused β-cell proliferation to be significantly enhanced. The effect of PO was related with phosphoinositide 3-kinase (PI3K)/AKT-S473 phosphorylation. The increase in pAKT-S473 led to suppression of FoxO-1. PO-induced AKT-S473 activation and FoxO-1 suppression were abolished by the selective inactivation of mTOR complex (mTORC) 2 using small interfering RNA directed towards the rapamycininsensitive companion of mTOR. The protective effect of PO against lipotoxicity was also abolished by PI3K inhibitor. Conclusion: Therefore, we conclude that PO increased the β-cell mass by upregulating β-cell proliferation and that the proliferative action of PO in β cells may be mediated by FoxO-1 suppression through the PI3K/mTORC2/AKT-S473 phosphorylation.