Anti-Senescence Effect of Inhibiting Sodium-Glucose Cotransporter 2 and α-Glucosidase in a Type 2 Diabetes Mellitus Animal Model

Abstract

Background: The prevalence of type 2 diabetes mellitus (T2DM) increases with age, and cellular senescence of pancreatic β-cells plays a key role in T2DM pathogenesis. As canagliflozin and acarbose have been shown to increase lifespan in mice, we investigated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, α-glucosidase inhibitor or both on the cellular senescence of β-cells in a T2DM mouse model. Methods: Enavogliflozin (0.3 mg/kg), acarbose (10 mg/kg), or vehicle was orally administered daily to db/db mice for 6 weeks. The levels of senescence markers (p16, p21, and p53) in the pancreas and kidney were measured through real-time polymerase chain reaction (PCR), immunofluorescence staining, and Western blot. In an in vitro analysis, isolated pancreatic islets were exposed to H2O2 to induce cellular senescence, then treated with β-hydroxybutyrate (β-HB), and subsequently assessed for levels of senescent markers. Results: Enavogliflozin alone or combined with acarbose effectively lowered blood glucose levels in db/db mice. The combined treatment resulted in the greatest increase in β-cell function calculated using insulinogenic index and homeostasis model assessment of β-cell function compared to the vehicle. Additionally, the combined treatment significantly reversed the increase in p16, with a similar trend observed in p21 and p53 in the islets. Treatment increased circulating β-HB and in vitro analysis suggested the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by β-HB in reducing senescence in the islets. Conclusion: The combined administration of enavogliflozin and acarbose significantly reduced blood glucose, improved β-cell function, and reduced senescent β-cells in db/db mice. This combination therapy holds potential as a senotherapeutic strategy for managing T2DM.