Insulin resistance in insulin sensitive organ results in metabolic disorder such as hyperglycemia, hyperinsulinemia and hyper triglyceridemia which are common features of type 2 diabetes. Insulin resistance in liver cells mainly causes impaired glycogen synthesis, failed to suppress glucose production which is the major contribution to hyperglycemia. FGF-21 as a new metabolic regulator can control fasting blood glucose. The mechanism of FGF-21 effects on regulating plasma glucose has little to known. In order to establish an in vitro insulin resistant model of liver cells and evaluate the effects and mechanism of FGF-21 on glucose metabolism in the cell model, HepG2 cells were incubated with 10^-7 mol/L insulin for 24 h to build insulin-resistant cell model. To evaluate the cells for insulin resistance, the cells were stimulated with fresh insulin for 24 h and the glucose uptake by these cells was carried out. The insulin-resistant cells were treated with different concentrations of FGF-21 for 24 h and insulin-treated cells were used as a control. The glucose uptake by the cells was detected by the method of glucose oxidizes/peroxides (GOD-POD); the synergy between insulin and FGF-21 was evaluated. The mRNA expression of GLUT1 in the insulin-resistant cells was detected by the real-time PCR. Glycogen synthesis of the cells was examined by the anthrone method. The results showed that HepG2 cells treated with 10^-7 mol/L insulin for 24 h became resistant to insulin and the insulin resistance status was maintained for 48 h without change of cell morphology. FGF-21 could stimulate glucose consumption of the insulin-resistant model in a dose-dependent manner. The glucose consumption and glycogen synthesis of the insulin-resistant model were significantly improved by FGF-21 treatment. FGF-21 showed strong synergy with insulin in glucose uptake and glycogen synthesis of the model cells. While the cells became resistant to insulin, FGF-21 could increase the mRNA expression of GLUT1. Thus, It is concluded that FGF-21 stimulates glucose uptake in insulin resistant HepG2 cells through GLUT1 expression, stimulates glycogen synthesis and improves the glucose metabolism in the insulin resistant liver cell model.