Objective: Although proinsulin misfolding in the endoplasmic reticulum (ER) initiates beta cell death response during the pathogenesis of type 2 diabetes, the mechanism(s) remains unknown. We have studied the role of unfolded protein response (UPR) underlying the death/dysfunction of pancreatic beta cell. Methods: To provide insight into how protein misfolding may cause beta cell failure we analyzed mice deleted for P58IPK/DnajC3, an ER luminal co-chaperone, Akita mice that express mutant misfolded proinsulin, and as db/db obese diabetic mice. For in vitro experiments, we generated beta cell lines which are deficient of P58IPK, followed by treatment with several ER stress inducers. Results: P58IPK-/- mice become diabetic due to decreased beta cell function and mass accompanied with induction of oxidative stress and cell death. Treatment with chemical chaperone, as well as deletion of Chop, improved beta cell function and ameliorated the diabetic phenotype in P58IPK-/- mice, suggesting P58IPK deletion causes beta cell death through ER stress. Significantly, feeding mice chow supplemented with antioxidant dramatically and rapidly restored beta cell function in P58IPK-/- mice. Antioxidant feeding also preserved beta cell function in Akita mice that express mutant misfolded proinsulin as well as db/db obese diabetic mice. Therefore, defective protein folding in the beta cell causes oxidative stress as an essential proximal signal required for apoptosis in response to ER stress. Remarkably, these findings demonstrate that antioxidant feeding restores ER function in cells deleted of an ER molecular chaperone. Conclusion: In conclusion, antioxidant or chemical chaperone treatment may be a promising therapeutic approach for type 2 diabetes.