Objective To explore the effects of high fat diet on insulin resistance (IR) and the expression of liver insulin receptor substrate (IRS)1 and 2 in Tibet minipigs.Methods Ten Tibet minipigs were randomly divided into 2 groups,normal control (Ctr,n=5) group was fed with normal diet,and IR model (n=5) group fed with high fat/cholesterol diet for 12 weeks.After the establishment of pig models for 12 weeks,the body weight and body length were measured and body mass index (BMI) was calculated,and the changes of total cholesterol (TC),low density lipoprotein (LDL-C),high density lipoprotein (HDL-C),triglyceride (TG),free fatty acids (FFA),fasting blood glucose (FBG),fasting insulin (insulin) and homeostasis model assessment-insulin resistance (HOMA-IR) were detected.Glucose tolerance test was performed,the area under the curve of glucose tolerance (AUC) was also calculated,and the expressions of IRS-1 and IRS-2 gene and protein in liver tissue were detected.The lipid deposition,liver glycogen and pathological changes were examined by pathology using oil-red O,PAS and HE staining,respectively.Results Compared with the control group,the body weight,BMI index,TC,LDL-C,HDL-C,FFA,FBG,insulin and HOMA-IR were significantly increased (P<0.05,P<0.01).Intravenous glucose tolerance test showed that the curve of blood glucose and insulin levels were slowed down,while AUC_glucose and AUC_insulin were significantly increased (P<0.05,P<0.01).Lipid deposition and liver glycogen were increased,and partial hepatocyte swelling,part of the nuclei disappeared or were pushed to one end,occasionally scattered infiltration of lymphocytes in the liver tissue.Furthermore,the expressions of IRS-1 and IRS-2 mRNA and protein were significantly decreased (P<0.05,P<0.01).Conclusions High fat diet can induce insulin resistance in Tibet minipigs.The decreased IRS-1 and IRS-2 expression in the liver may be one of the molecular mechanisms involved in the effects of high fat diet on insulin sensitivity in Tibet minipigs.