Resistin was a cytokine associated with insulin resistance. The objective of the study is to investigate the impact of fibroblast growth factor (FGF)-21 on glucose metabolism in resistin-induced insulin resistant liver cells. A stable HepG2 cell line expressing human resistin was developed. The cell line was treated with different concentrations of insulin or FGF-21. The glucose uptake of the treated cells was measured by the method of GOD-POD, and the mRNA expression of GLUT1 and PPAR-γ of the FGF-21-treated cells were examined by real-time PCR. We successfully developed the HepG2 line which stably expressed human resistin. The results of glucose uptake showed that the sensitivity of the cell line to the insulin treatment significantly decreased, but FGF-21 could effectively stimulate the glucose uptake by the same cell line. The mRNA expression of GLUT1 was elevated in the cell line, and the GLUT1 mRNA level of the cells significantly increased after treatment by FGF-21. The expression of PPAR-γ had no significant change. The cell line in which resistin was highly expressed has a reduced susceptibility to insulin. Although the high level of resistin makes cells insulin resistance, FGF-21 can regulate the glycometabolism effectively in the cells.