Objective To observe the effects of cyclosporin A on the expression of phosphorylated AKT in hepatocytes, and to investigate the mechanism of insulin resistance caused by cyclosporin A. Methods This study included two parts. 1. In vitro experiment: Human hepatocyte HL77022 cell line was cultured at different concentrations of cyclosporin A (0.1 μmol/L, 1 μmol/L, 5 μmol/L) for 48 hours. The expressions of phosphorylated AKT (P-AKT) in HL77022 cells were measured by Western blot assay. 2. Rat in vivo experiment: SD rats were randomly divided into 2 groups. The rats in the control group were administrated with distilled water 1 mL/Kg/d. The rats in the cyclosporine group were administrated with cyclosporine 25 mg/Kg/d. The total experiment time was 5 months. The levels of fasting blood glucose and insulin were tested at the end of the experiment. The insulin resistance index and insulin sensitivity index were calculated. The expression of P-AKT in the rat hepatocytes was measured by immunohistochemistry. Results 1. Each group of the HL7702 cells treated by CsA (0.1 μmol/L, 1 μmol/L, 5 μmol/L) showed a significantly decreased expression of P-AKT (P<0.05, P<0.01, and P<0.01). 2. After 5 months of therapy, the fasting blood glucose level of rats in the cyclosporine group was 9.28 mmol/L, indicating that cyclosporine-induced diabetic rat models were established. The insulin sensitivity index in the cyclosporine group was lower than that in the control group (P<0.05). The expression of P-AKT in liver in the cyclosporine group was significantly lower than that in the control group (P<0.05). Conclusions Therapeutic dose of cyclosporine has hyperglycemic effects on rats. Cyclosporine can reduce the expression of phosphorylated AKT in hepatic tissue in rats and also decrease the expression of P-AKT in human hepatocyte HL77022 cells, which indicate that cyclosporine may cause insulin resistance by interfering PI3K/AKT signal transduction pathway.