Protective action of pomegranate peel polyphenols in type 2 diabetic rats via the translocation of Nrf2 and FoxO1 regulated by the PI3K/Akt pathway

The aim of this study is to investigate the protective mechanism of pomegranate peel polyphenols (PPPs) in in vivo and in vitro rat models of T2DM. Our results showed that PPPs markedly improved the symptoms of diabetes, such as insulin resistance, impaired insulin secretion, and pancreatic oxidative damage, which contributed to the attenuation of the symptoms of hyperglycemia in a high-fat diet (HFD) combined with streptozocin (STZ) induced type 2 diabetes mellitus in rats. On the one hand, PPPs promoted the translocation of Nrf2 from the cytoplasm to the nucleus, the key protein down-regulated by the PI3K/Akt pathway, activating its downstream phase 2 antioxidant enzyme system. On the other hand, the positive effect was associated with another downstream protein of the PI3K/Akt pathway, FoxO1. With the activation of Akt phosphorylation, the phosphorylated FoxO1 protein transferred from the nucleus to the cytoplasm, releasing the block of Pdx-1 and its downstream genes. The inhibitor of the PI3K/Akt pathway was also studied in INS-1 cells in order to verify the mechanism observed in vivo. Altogether, we presented evidence that PPPs activated the translocation of Nrf2 into the nucleus and resulted in increased antioxidant activity, and PPPs promoted the translocation of FoxO1 out of the nucleus resulting in an increase in insulin synthesis in vivo and in vitro. Pomegranate extracts may show great potential and application prospects as functional foods or preventive drugs to improve pancreatic beta cell dysfunction and provide a reference for future development in health care.