Objective To observe the effect of liraglutide on the expression of glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxylase (PEPCK) in the diabetic mouse liver and explore the underlying mechanisms of these effects. Methods Mice were divided into three groups: the normal control group ( male C57 mice, n= 5) received intraperitoneal injection of normal saline, the model control group ( male KK-Ay mice, n= 5) received intraperitoneal injection of normal saline, and the Liraglutide group (male KK-Ay mice+ drug intervention, n= 5) received intraperitoneal injection of liraglutide. All three groups of mice were raised in the same feeding environment. After 8 weeks of intervention, the blood glucose of mice was detected; the expression levels of the FOXO1, cryptochrome 1, the E3 ubiquitin ligase DDB1, G6pase, and PEPCK in the liver were detected by Western blotting. Results Compared with the model control group, blood glucose was significantly reduced in the intervention group. The expression levels of DDB1, FOXO1, G6Pase and PEPCK decreased in the intervention group, while the expression level of Cryptochrome 1 ( CRY1) increased. Conclusions Liraglutide can downregulate the expression of G6Pase and PEPCK, key gluconeogenesis enzymes, in the diabetic mouse liver; this may be related to downregulation of the E3 ubiquitin ligase DDB1.