Objective: This investigation is to observe the effects of sitagliptin (SIT) on epithelial-mesenchymal transition (EMT) of human renal tubular epithelial cells (HK-2) under high glucose involving AKT signaling pathway, and elucidate the possible mechanism of SIT in the prevention and treatment of early diabetic nephropathy. Methods: Human renal tubular epithelial cells were randomly divided into normal group (NG, 5.56 mmol/L glucose), high glucose group (HG, 60 mmol/L glucose) and sitagliptin group (SIT, 60 mmol/L glucose +1, 5, 10 μmol/L sitagliptin), TGF-β1 inhibitor group (60 mmol/L glucose +5 μmol/L SB-431542). Cell viability was determined by MTT assay. The secretion of TGF-β1 was detected by ELISA. Western blot analysis was used to monitor the phosphorylated AKT and EMT indicator proteins. Results: Under high glucose, the viability of renal tubular cells was increased. Meanwhile, increased secretion of TGF-β1, up-regulated phosphorylated AKT, down-regulated E-cadherin as well as up-regulated α-SMA were observed. However, in the presence of sitagliptin, the viability of renal tubular cells was reduced. Accordingly, TGF-β1 and α-SMA were down-regulated, AKT was inactivated, while E-cadherin was up-regulated. Conclusion: Sitagliptin improves the epithelial-mesenchymal transition of HK-2 cells under high glucose, which may be closely associated with the inhibition of TGF-β1/AKT signaling pathway.