The Protective Effect Of GLP-1 On Islet Function Of Obese Ratsand Relationship With TLR4 Signal Pathway

Objective:To investigate the protective effect of GLP-1 analog Exenatide on islet function of obese rats and its relationship with TLR4 inflammation signal pathway.Methods:1.Male SD rats and TLR4 knockout SD rats were randomly divided into normal diet feeding group and high-sugar high-fat diet feeding group.After 16 weeks of feeding,the HSFD group was randomly divided into two subgroups.One group was given subcutaneous injection of the GLP-1 analogue Exenatideand the other group was given subcutaneous injections of the same amount of physiological saline for 16 weeks.2.After the intervention of Exenatide,glucose tolerance test(IPGTT)and insulin tolerance test(ITT)were performed.3.Rats abdominal aortic blood were collected from each group and serum BG,INS,FFA,FetA,IL-1,IL-6,TCHO,TG,and LDL levels were measured.4.Pancreatic tissue was isolated to detect the protein expression levels of TLR4,NF-?B and insulin-related genes GPR40 and PDX-1 in the pancreas;after fixing and sectioning the pancreas,HE staining and pancreatic islet ?-cell and ?-cell immunofluorescence dual-label staining were performed,and TUNEL was used to detectislet cells apoptosis.Results:1.The rat model of obese and insulin resistance can be established by high-sugar and high-fat diet for 16 weeks.2.GLP-1 reduced the level of FBG,FFA,FetA,AUC of IPGTT and ITT,HOMA-IR,IL-1,IL-6 of obese rats,and increased INS secretion(P<0.05).3.GLP-1 can down-regulate the expression of TLR4 and NF-?B protein,and up-regulate the expression of GPR40 and PDX-1 proteins(P<0.05).4.GLP-1 reduced the inflammatory infiltration of pancreatic tissues in obese rats in the HE staining(P<0.05);GLP-1 improved the ratio of insulin-positive cells to glucagon-positive cells.But there was no significant difference in islet cell apoptosis rate between the each group(P> 0.05).5.Compared with the high-sugar and high-fat groups of wild mice,TLR4 gene knockout can ameliorate the weight and Lee's index rised by high-sugar and high-fat diet,and increase INS secretion,up-regulate the expression of GPR40 and PDX-1 proteins,reduce the inflammatory infiltration of pancreatic islets,and down-regulate the expression of NF-?B protein(P <0.05),increase the number of pancreatic islet ? cells.6.After TLR4 knockout,GLP-1 can amelioratethe level of blood glucose,insulin,FetA and HOMA-IRin obese rats(P<0.05),but there was no significant difference in the level of body weight,Lee'sindex,FFA,GPR40 and PDX-1 protein expression,as well as the morphology of pancreatic islets,islet inflammation infiltration and the number of pancreatic ?-cells in the immunofluorescence staining of the pancreas(P>0.05),suggesting that the knockdown of TLR4 gene significantly reduced GLP-1's intervention.Conclusions:GLP-1 can increase insulin levels,reduce inflammation,and improve the function of islet ? cellsin obese rats,and its mechanism of action may be related to TLR4 inflammation signaling pathway.