Abstract: Objective: To study the regulatory effects of sitagliptin phosphate on mitochondrial homeostasis and function in hepatocytes of type 2 diabetic rats.Methods: The rat model of type 2 diabetes mellitus was established by high fat and high sugar diet combined with 45 mg·kg^-1 streptozotocin feeding.The rats in sitagliptin phosphate group were administrated with 10 mg·kg^-1 sitagliptin phosphate (n=8) and the rats in model group were given an equal volume of PBS (n=8).After 12 weeks, the body weight and blood glucose level of rats were measured, and the degree of liver fibrosis was evaluated by HE staining and Masson staining; TUNEL staining was used to detect apoptotic cells in hepatocytes; ATP content in hepatocytes was determined by chemiluminescence method; the ratio of mitochondrial genome DNA to nuclear genome DNA was determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR); the levels of mitochondrial marker proteins TOMM20, HSP60 and VADC were determined by semi-quantitative western blotting; after HepRG was treated with sitagliptin phosphate, JC-1 staining was used to observe mitochondrial membrane potential changes, ATP content was determined, and RT-qPCR was used to detect transcription levels of mitochondrial coding genes, including COX 1, COX3, ND 1 and Cyb.Results: Sitagliptin phosphate improved weight loss, blood glucose increase, liver damage and liver fibrosis in type 2 diabetic rats.Compared with model group (0.22±0.03) pmol/min·mg^-1, ATP content in liver tissue of sitagliptin phosphate group (0.43±0.03) pmol/min·mg^-1increased (P＜ 0.05).Compared with model group (1.58±0.36), the ratio of mitochondrial genome DNA to nuclear genome DNA in hepatocytes in sitagliptin phosphate group (2.89±0.62) increased (P＜ 0.05).Compared with model group, mitochondrial marker proteins TOMM20, HSP60 and VADC in hepatocytes in sitagliptin phosphate group were significantly higher.JC-1 staining showed that high glucose caused significant loss of HepRG mitochondrial membrane potential in hepatocytes, but the mitochondrial membrane potential was obviously recovered after sitagliptin was added; meanwhile, ATP content and transcription level in hepatocytes increased (P＜ 0.05).Conclusion: Sitagliptin phosphate may be involved in reducing the degree of liver fibrosis in type 2 diabetic rats by regulating mitochondrial membrane potential, ATP production and mitochondrial transcriptional activity.