Grape Seed Proanthocyanidins Protects Pancreatic β Cells against Ferroptosis via the Nrf2 Pathway in Type 2 Diabetes

Abstract

Abstract Objective Pancreatic β cell damage is a core cause of type 2 diabetes mellitus (T2DM), but the mechanism has not yet been fully elucidated. This study explored the role of ferroptosis in pancreatic β cell damage and the protective effects of grape seed proanthocyanidins (GSPE). Methods T2DM rat model was established. In T2DM rats, the blood glucose, water intake, urine volume, HbA1c, and homeostasis model assessment-insulin resistance were significantly increased, while the body weight and the insulin level were significantly decreased, indicating the successful establishment of T2DM model. MIN6 mouse insulinoma β cells were cultured in high glucose and sodium palmitate conditions to obtain glycolipid damage model, which was administrated with GSPE, Ferrostatin-1 (Fer-1) or nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering (si) RNA. Results GSPE and Fer-1 treatment significantly improved pancreatic β cell dysfunction and protected against cell death. Both treatments increased the superoxide dismutase and glutathione activity, reduced the malondialdehyde and reactive oxygen species levels, and improved the iron metabolism. Furthermore, both treatments reversed the expression of ferroptosis markers cysteine/glutamate transporter (XCT) and glutathione peroxidase 4 (GPX4) caused by glycolipid toxicity. Moreover, GSPE treatments activated the expression of Nrf2 and related proteins. These effects were reversed when co-transfected with si-Nrf2. Conclusion These results demonstrate that GSPE inhibits ferroptosis by activating the Nrf2 signaling pathway, thus reducing β cell damage and dysfunction in T2DM. GSPE could be a potential agent for T2DM treatment.