〔Abstract〕 Objective To investigate the mechanism of gliclazide in improving hepatic insulin resistance of type 2 diabetes mellitus(T2 DM). Methods We established T2 DM animal model by high fat diet combined with intraperitoneal injection of streptozotocin. Fasting blood glucose, serum insulin, glucose tolerance, insulin sensitivity and liver pathology in T2 DM mice were detected. Glucose consumption and glycogen content were measured. The expression of insulin signaling pathway proteins(insulin receptor, insulin receptor substrate1, phosphatidylinositol 3-kinase, glycogen synthesis kinase 3β and glucose transporter 4) in liver tissues and HepG2 cells were detected by WB. Results Compared with T2 DM group, the mice in gliclazide groups showed decreased blood glucose, increased serum insulin, significantly improved glucose tolerance and insulin sensitivity, and reduced hepatocyte necrosis and vacuolation. Gliclazide significantly increased glucose consumption and glycogen content in insulin resistant HepG2 cells. Gliclazide increased insulin receptor, phosphatidylinositol 3-kinase and glucose transporter 4 expression and insulin receptor substrate1 tyrosine phosphorylation. Gliclazide inhibited glycogen synthesis kinase 3β tyrosine phosphorylation. Conclusion Gliclazide can improve glucose metabolism disorder, insulin sensitivity and liver injury in T2 DM mice. Gliclazide can increase glucose consumption and glycogen content in insulin resistant HepG2 cells. The mechanism may be related to the up-regulated insulin signaling pathway.