Introduction and Objective: A short-term study in obese T2D patients showed that the combination of dorzagliatin, a glucokinase activator (GKA) and sitagliptin improved glucose controls with increased GLP-1 secretion. This study aims to assess the impact of long-term administration of dorzagliatin and the combination of dorzagliatin/sitagliptin on glucose homeostasis in high-fat diet-induced obesity/diabetes (DIO) mice.Methods: DIO mice were developed following a 6-month high-fat diet. Prior to treatment, mice were evaluated. Mice were then administered dorzagliatin at a dosage of 30 mg/Kg/day, or a combination of dorzagliatin (same dose) and sitagliptin (20 mg/Kg/day) for 30 days. Mice on a standard diet serve as controls.Results: Compared to controls, DIO mice have elevated random and fasting glucose levels, along with higher insulin and glucagon, decreased GLP-1/glucose ratio. On day 30, the glucose levels were all reduced compared to pre-treatment, and the combination therapy was more effective than dorzagliatin alone. Dorzagliatin alone elevated insulin and GLP-1 secretion, the combination resulted in a further increase. The blood chemistry analysis indicated that DIO mice exhibit increased levels of ALT, AST, lipid profiles, and glycated serum protein (GSP). Drug therapy has significantly improved GSP and AST. The combined therapy also improved the LDL levels.Conclusion: DIO mice have impaired GLP-1 secretion, elevated glucose, insulin and glucagon levels. Following 30 days of treatment, glucose levels were improved with increased secretion of insulin, the combination of GKA and DPP4i was superior to dorzagliatin alone with the improved GLP-1 secretion. Those data indicated that, in addition to increased insulin secretion by GKA, the enhanced GLP-1 secretion also played a significant role in improving glucose homeostasis, and the addition of DPP4i amplified these effects.
D. Han: None. S. Meng: None. R. Li: None. L. Feng: None. L. Chen: None. C. Li: None.
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