Effects Of Visfatin On Glucose Metabolism In Skeletal Muscle Of Diabetic Mice Via PI3K/Akt/mTORC1

Objective:To explore the effect of Visfatin overexpression on glucose metabolism and insulin resistance in KKAy diabetic mice,and analyze its mechanism of action on skeletal muscle insulin resistance in diabetic mice via PI3K/Akt/m TORC1.Methods:The thirty-six 8-week-old male C57BL/6J mice were randomly divided into normal diet（n=18）and high-fat diet（n=18）.The eighteen 8-week-old male KKAy mice were fed high-fat diet.After 8 weeks of modeling,two consecutive fasting blood glucose（Fasting blood glucose,FBG）≥13.9mmol/L is considered to be established as a diabetes model.After modeling,KKAy mice are randomly divided into diabetes group（DM）,diabetes+Visfatin overexpression Group（DM）and diabetes+Visfatin overexpression+Akt inhibition group（DV+A）;C57BL/6J mice fed with normal diet were randomly divided into general food group（ND）,general food+Visfatin overexpression group（NV）and general food+Visfatin overexpression+Akt inhibition group（NV+A）;C57BL/6J mice fed with high fat diet were randomly divided into high fat diet group（HFD）,high fat+Visfatin overexpression group（HFV）and high fat+Visfatin overexpression+Akt inhibition group（HFV+A）.Tail vein injection of empty vector adeno-associated virus（AAV）in ND group,HFD group and DM group;Tail vein injection of Visfatin overexpressing AAV in NV group,HFV group and DV group;Tail vein injection of Visfatin overexpressing and Akt inhibition AAV in NV+A group,HFV+A group and DV+A group.Measure body weight,FBG,triglyceride（TG）,total cholesterol（TC）,low density lipoprotein-cholesterol（LDL-C）,high density lipoprotein cholesterol（HDL-C）,free fatty acid（FFA）,fasting insulin（FIns）,Resp Ins Ratory exchange ratio（RER）,and perform intraperitoneal glucose tolerance test（IPGTT）and Insulin tolerance test（ITT）.The area under curve of IPGTT(AUC_IPGTT)and the area under curve of ITT(AUC_ITT)were calculated to evaluate the function of pancreatic isletβ-cells,and the Homeostasis model assessment of insulin resistance（HOMA-IR）to evaluate the insulin sensitivity of mice in each group.Western blot was used to determine the protein expression of Visfatin,Phosphatidylinositol 3-kinase（PI3K）,Protein kinase B（Akt）,tuberous sclerosis protein complex 1（TSC1）,mechanistic target of rapamycin complex 1（m TORC1）,Phospho-p70 S6 Kinase（p70S6K）in the skeletal muscle of each group mice.Results:Compared with the ND and HFD groups,the body weight,FBG,TG,TC,LDL-C,FFA,FIns,HOMA-IR,AUC_IPGTTand AUC_ITTin the DM group were increased significantly（P<0.05）,HDL-C and RER were decreased significantly（P<0.05）;Compared with the DM group,the body weight,FBG,TG,TC,LDL-C,FFA,FIns,HOMA-IR,AUC_IPGTTand AUC_ITTin the DV group were decreased significantly（P<0.05）,HDL-C and RER were significantly increased（P<0.05）;Compared with the DV group,the body weight,FBG,TG,TC,LDL-C,FFA,FIns,HOMA-IR,AUC_IPGTTand AUC_ITTin the DV+A group were significantly increased（P<0.05）,HDL-C And RER decreased significantly（P<0.05）;compared with ND group,the protein expression of Visfatin,PI3K,p-Akt,Akt,p-m TORC1,m TORC1,p-p70S6K and p70S6K in the DM group were significantly decreased（P<0.05）,The protein expression of TSC1,G6Pase and PEPCK were significantly increased（P<0.05）;compared with the DM group,the protein expressions of PI3K,p-Akt,Akt,p-m TORC1,m TORC1,p-p70S6K and p70S6K in the DV group were increased significantly（P<0.05）,the protein expressions of TSC1,G6Pase and PEPCK were decreased significantly（P<0.05）;compared with the DV group,the protein expressions of p-Akt,Akt,p-m TORC1,m TORC1,p-p70S6K and p70S6K in the DV+A group were significantly decreased（P<0.05）,the protein expressions of TSC1,G6Pase and PEPCK were increased significantly（P<0.05）.Conclusion:Visfatin up-regulates the expression of m TORC1 and p70S6K in skeletal muscle of KKAy diabetic mice through the PI3K/Akt pathway to improve glucose metabolism and insulin resistance.