Effects Of Visfatin On Insulin Resistance In Skeletal Muscle Of Diabetic Mice Via PI3k/aKt/FoxO1 Signaling Pathway

Objective:To investigate the effects of Visfatin on glycolipid metabolism and insulin resistance in skeletal muscle of diabetic KKAy mice,and preliminarily analyze the possible mechanism of its action through PI3K/Akt/FoxO1 on skeletal muscle tissue of diabetic mice.Methods:The 8-week-old male C57BL/6J mice were randomly divided into a normal diet group and a high-fat diet group,of which the normal diet group was randomly divided into a normal diet?ND?group and a normal diet+Visfatin?ND+V?group.The high-fat diet group was randomly divided into a high-fat?HFD?group and a high-fat+Visfatin?HFD+V?group.After 8-week-old male KKAy mice were fed high-fat for 8 weeks,two consecutive fasting blood glucose?FBG??13.9mmol/L was defined as diabetes model.When the model was made,KKAy mice were randomly divided into the diabetes mellitus?DM?group and diabetes mellitus+Visfatin?DM+V?group.ND+V group,HFD+V group and DM+V group were intraperitoneally injected with recombinant lipoprotein for 3 consecutive days,and the other groups were injected with the same amount of normal saline.FBG,postprandial blood glucose?PBG?,total cholesterol?TC?,triglyceride?TG?,free fatty acid?FFA?and fasting insulin?FIns?were detected in each group of mice.The glucose tolerance test?GTT?and insulin tolerance test?ITT?were measured,meanwhile,the area under curve of glucose tolerance test(AUC_GTT),the area under curve of insulin tolerance test(AUC_ITT)and homeostasis model assessment for insulin resistance?HOMA-IR?were calculated.At the same time,the gene expression levels of phosphatidylinositol 3 kinase?PI3K?,protein kinase B?Akt?and Forkhead box transcription factor 1?FoxO1?were detected by RT-qPCR;Western blot was used to detect the protein expression levels of PI3K/Akt signaling pathway and downstream FoxO1,PDK4 and other related molecules.Results:Compared with the ND group and the HFD group,the body weight,food intake,FBG,PBG,TC,TG,FFA,FIns,AUC_GTT,AUC_ITT and HOMA-IR levels in the DM group were significantly increased?P<0.05?.While the body weight,TC and FFA levels of mice in HFD group were remarkably higher than the ND group?P<0.01?.Compared with DM group,FBG,TC,TG,AUC_GTT,AUC_ITT and HOMA-IR levels in DM+V group were significantly reduced?P<0.05?.Compared with the ND group and the HFD group,the mRNA expression levels of PI3K and Akt in the DM group were significantly decreased?P<0.001?,but the mRNA expression levels of FoxO1 were increased?P<0.05?.Compared with the ND group,the mRNA expression of FoxO1 in the ND+V group was reduced?P<0.05?.The mRNA expression of Akt in ND group was higher than the HFD group?P<0.05?.Compared with the DM group,the mRNA expression of PI3K and Akt in the DM+V group was obviously increased,but the mRNA expression of FoxO1 was significantly reduced?P<0.01?.Compared with the ND group,the protein expression levels of PI3K_110?,and p-Akt in the DM group were reduced,and the protein expression levels of FoxO1,p-FoxO1,and PDK4were increased;while the expression of FoxO1 protein in the HFD group was reduced,the protein expression of p-FoxO1 increased?P<0.05?.The expression level of FoxO1 protein in ND+V group was lower than the ND group?P<0.001?.Compared with the HFD group,the p-Akt,and p-FoxO1 protein levels were lower in the DM group,and the protein expression levels of FoxO1,PDK4,and PEPCK were increased?P<0.05?.Compared with the DM group,the protein expression of PI3K_110?,p-Akt,and p-FoxO1 were increased in the DM+V group,but the protein expression levels of FoxO1,PDK4,and PEPCK were reduced?P<0.05?.Conclusion:Visfatin may down-regulate the expression of FoxO1 and PDK4 in skeletal muscle of diabetic mice through the PI3K/Akt pathway and play the role in improving glucolipid metabolism and insulin resistance.