7890 Combination of Dorzagliatin and Canagliflozin Improves β-cell Function and Alleviates Hepatic Steatosis in db/db Mice

Abstract Disclosure: Z. Zhang: None. S. Chen: None. S. Ji: None. Q. Zhao: None. J. Qiao: None. M. Liu: None. Introduction: Early combination of anti-hyperglycemic medications with different targets is an optimal choice for patients with type 2 diabetes (T2D) who do not achieve targeted HbA1c with monotherapy. Dorzagliatin is a novel dual-acting glucokinase activator that has been shown to be effective in both drug-naive and metformin-treated patients with T2D. However, the effect of combination of dorzagliatin and sodium-glucose cotransporter-2 inhibitor (SGLT2i) remains unknown. Methods: Ten-week-old db/db mice were treated daily with either dorzagliatin (30mg/kg of body weight) alone, or canagliflozin (30mg/kg of body weight) alone, or dorzagliatin plus canagliflozin, or vehicle only by gavage for 6 weeks. Body weight and fasting blood glucose were monitored weekly. Plasma insulin, triglyceride, and cholesterol were measured every two weeks. The morphology of islets and liver was evaluated by chemical staining and immunofluorescence. Results: The 6-week treatment of dorzagliatin had no significant effect on fasting blood glucose and fasting plasma insulin but reduced body weight in db/db mice compared to those treated with vehicle. It also caused a significant decrease of islet size and β-cell number. Surprisingly, dorzagliatin alleviated hepatic steatosis but did not affect serum lipid levels. The combination of dorzagliatin and canagliflozin lowed fasting blood glucose and improved glucose tolerance without affecting bodyweight, and the anti-diabetic effect was stronger than the canagliflozin-only treatment group. Combination treatment group also showed an increased islet size and β-cell number, and alleviated liver steatosis compared with vehicle group. Conclusion: The combination of dorzagliatin and canagliflozin had better antidiabetic effects than single-agent administration, providing clinical guidance for the combination therapy of dorzagliatin and SGLT2i in the treatment of type 2 diabetes. Presentation: 6/2/2024