Objective:To explore the improvement effect of rhein lysinate (RHL)on the insulin resistance in the KK/HlJ diabetes mellitus (DM ) mice induced by streptozotocin (STZ ), and to elucidate its mechanism. Methods:The KK/HlJ diabetic mouse models were made by intraperitoneal injection of STZ (50 mg· kg-1 )and fed with DM diet.A total of 48 mice were divided into normal control group,model group,low dose of RHL group (25 mg·kg-1 )and high dose of RHL group (50 mg·kg-1 ) (n= 12).All the mice were treated for 16 weeks. The levels of fasting glucose (FBG),total cholesterol (TC)and triglyceride (TG)of the mice were measured by glucose oxidase method.HE staining was used to observe the morphology of pancreas tissue of the mice.The insulin level in pancreas islet tissue was detected by immunohistochemistry method.The levels of insulin and of C reactive protein (CRP)in serum and tumor necrosis factorα(TNF-α)and interleukin 6 (IL-6)in liver tissue of the mice were detected by enzyme linked immunosorbent assay (ELISA)method.The expression levels of glycogen synthesis related genes (PI3K,AKT and GSK-3β)phosphorylation were detected by Western blotting method. Results:Compared with model group,the levels of FBG,TG and TC of the mice in low and high doses of RHL groups were significantly decreased (P < 0.05),but there was no significant difference in the insulin level (P >0.05).Compared with model group,the levels of CRP in serum and the levels of TNF-αand IL-6 in liver tissue of the mice in low and high doses of RHL groups were significantly decreased (P <0.01).The HE staining results showed that compared with model group,the islet morphology of the mice in low and high doses of RHL groups was partially restored,and the occasional inflammatory infiltration was observed.The immunohistochemical staining results showed that compared with model group,the brown granular substance in the islets of the mice in low dose of RHL group was significantly reduced,which was disappeared in high dose of RHL group.Compared with model group,the expression levels of glycogen synthesis related genes (PI3K,AKT and GST-3β)phosphorylation of the mice in low and high doses of RHL groups were increased (P <0.01).Conclusion:RHL has improvement effect on the insulin resistance in the KK/HlJ DM mice induced by STZ,and the mechanism may be related to promoting the glycogen synthesis.