Abstract: To investigate the effect of mangiferin on the glycolipid metabolism disorder in type 2 diabetes mellitus (T2DM) rats and its underlying mechanism, T2DM rats were randomly divided into model control group, metformin group (100 mg/kg), and low-, medium- and high-dose mangiferin groups (50, 100 and 200 mg/kg), 10 rats in each group, and a normal control group was set (10 healthy rats). The rats were intragastrically administered with the different agents once a day, successively for 8 weeks. The levels of fasting blood glucose (FBG) and fasting insulin (FINS) were determined, the insulin resistance index (HOMA-IR) was calculated, the contents of serum free fatty acid (FFA), triglyceride (TG) and total cholesterol (TC) were measured, the activities of glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in the liver tissue of rats were tested, and the mRNA and proteins related to the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt)/glucose transporter 4 (Glut4) signaling pathway in the liver tissue of rats were detected. The results showed that mangiferin could improve the general status of T2DM rats, including their hair color, activity and spirits, and slow down the trend of weight loss. Compared with those in the model control group, the contents of FBG, FINS, HOMA-IR and serum FFA, TG and TC in the mangiferin-treated groups were significantly or extremely significantly decreased after the intragastric administration of mangiferin for 8 weeks (P<0.05, P<0.01). The activities of GSH-Px, CAT and SOD in the liver tissue of rats in the mangiferin-treated groups were significantly or extremely significantly higher than those in the model control group (P<0.05, P<0.01), while the content of MDA in the liver tissue of rats was extremely significantly lower than that in the model control group (P<0.01). The expression of IRS-1 mRNA in the liver tissue of rats in the low-, medium- and high-dose mangiferin groups was not significantly different from that in the model control group (P>0.05), the expression levels of Akt, Glut4 mRNA, and p-IRS-1 (Tyr), Akt and Glut4 proteins increased significantly or extremely significantly (P<0.05, P<0.01), while the expression of p-IRS-1 (Ser) protein decreased significantly or extremely significantly compared with that in the model control group (P<0.05, P<0.01). The above results indicate that mangiferin can improve the glycolipid metabolism disorder in T2DM rats, which may be related to its antioxidant stress and regulation on the IRS-1/Akt/Glut4 signaling pathway.