Glucokinase (GK) is a key regulatory enzyme in whole-body glucose homeostasis. Dorzagliatin is a novel GK activator that has been shown to decrease blood glucose levels and improves GK activity and insulin resistance. Two hours after a single intragastric administration of 10 mg/kg or 30 mg/kg dorzagliatin decreased glucose levels in diabetic rats by ~25% and 31%, respectively, compared with the levels measured before dorzagliatin treatment. After 27 days of treatment, a significant reduction in fasting plasma glucose levels was observed in dorzagliatin-treated diabetic rats compared to the vehicle-treated group. Also, rats administered with 10 mg/kg or 30 mg/kg dorzagliatin showed a reduction in glucose levels (~18% and 23%, respectively) measured 2h after HMS5552 administration compared with the levels detected before dorzagliatin administration. Treatment of diabetic rats with 10 mg/kg and 30 mg/kg dorzagliatin also significantly decreased the levels of fasting insulin compared with the diabetic group. Rats treated with dorzagliatin (10 mg/kg and 30 mg/kg) for one months showed significantly decreased Km value of GK (5.9 ± 0.43mmol/L and 5.6 ± 0.27mmol/L, respectively) compared to the diabetic group (9.9 ± 0.55mmol/L). After dorzagliatin treatment, the number of GK- and insulin-immunopositive cells was also significantly increased in diabetic rats. The protein and mRNA expressions of GK in dorzagliatin-treated rats were significantly higher than those observed in the diabetic group.[3]
作用机制
Dorzagliatin is a fourth-generation GK activator with a structurally novel amino-acid-based chemical scaffold, which improves GK activity in a rat model of T2DM induced by a high-fat diet and streptozotocin.[3]
Dorzagliatin 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse pancreatic islet β-cells
10 µM
30 minutes
To evaluate the effect of Dorzagliatin on glucose-stimulated insulin secretion. Results showed that Dorzagliatin alone had minimal effects on insulin secretion in wild-type and GckKI/+ mouse islets, but significantly enhanced insulin secretion when combined with Exendin-4, particularly in male GckKI/+ mice.
To evaluate the effect of Dorzagliatin on PI3Ki-induced hyperglycemia and hyperinsulinemia. Results showed that Dorzagliatin significantly reduced blood glucose levels and C-peptide levels, indicating effective mitigation of hyperinsulinemia.
Mol Metab. 2025 Jun;96:102151
Mouse
GckKI/+ and GckKI/KI mice
Intraperitoneal injection
1 mg/kg Dorzagliatin and 1 nmol/kg Exendin-4
Single dose
To evaluate the effects of Dorzagliatin and Exendin-4 on glucose tolerance. Results showed that in male GckKI/+ mice, Dorzagliatin significantly potentiated the action of Exendin-4, restoring glucose tolerance to wild-type levels. In female mice, Exendin-4 alone improved glucose tolerance, but Dorzagliatin did not show additional effects.
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