Effect Of Liraglutide On Improving The Glucose Metabolism By Inhibiting Toll-like Recpter4/Toll-like Recpter4Signaling Pathway In Type2Diabetes Rats

Objective:To investigate the effect of Liraglutide on improving the glucose metabolism,gastrointestinal hormone levels, islet cells structure and function, TLR4/NF-κBmRNA levels in Pancreas, and its mechanism, we use type2diabetic rats as studyobject。Methods:1、The rats were administrated with high-carbonhydrate-fat diet for4weeks, andthen intraperitoneal injected with30mg/kg streptozotocin(dissolved in the0.1mmol·L-1citrate buffer solution) to induce type2Diabetes Mellitus (T2DM). Thenthe T2DM rats were randomly divided into two groups: type2diabetic group (T2DM),Liraglutide treatment group (T2DM+LIRA)；2、 Fasting blood glucose(FBG) were detected regularly. After8weeks,Intraperitoneal glucose tolerance test (IPGTT) was carried out in these rats; The serumconcentration of glycosylated hemoglobin(HbA1c), C-peptide(C-P), glucagon(GLu),gastrin(GAS), cholecystokinin(CCK) glucagon-like peptide-1(GLP-1) andTriglycerides(TG) were measured; The expressions of insulin and glucagon inpancreas were measured; Islet cells apoptosis were measured by TUNEL. RT-PCRwas used to detect the NF-κB mRNA and TLR4mRNA in pancreas.Results: 1、The concentration of FBG，HbA1c，TG in groups LIRA were significantlydecreased than those in group T2DM （p＜0.01）; IPGTT：The abnormal level ofIPGTT in group T2DM+LIRA improved significantly;2、Gastrointestinal hormone: The serum concentrations of C-p, GLP-1, GAS,CCK in groups T2DM+LIRA were significantly higher than those in group T2DM（p＜0.01）. The serum concentrations of GLu in groups T2DM+LIRA were significantlylower than those in group T2DM（p＜0.01）;3、Pancreatic immunohistochemistry: Compared with T2DM group, the ratio ofinsulin positive area in islet cells was significantly increased in T2DM+LIRA group（p＜0.01）. Compared with T2DM group, the ratio of glucagon positive area in islet cellswas significantly decreased in T2DM+LIRA group（p＜0.01）;4、Islet cells apoptosis index：Compared with T2DM group, the Islet cellsapoptosis index significantly decreased in T2DM+LIRA group（p＜0.01）;5、Real time-PCR：Compared with T2DM group, the expression of TLR4mRNAand NF-κB mRNA in pancreatic tissue signifieantly decreased in T2DM+LIRA group（p＜0.01）;6、Correlation Analysis:①Gastrointestinal hormone: After8weeks, the serumconcentration of C-P was positively correlated with GAS（r=0.781，p＜0.01）, CCK（r=0.779，p＜0.01） and GLP-1（r=0.930，p＜0.01）,but was negatively correlatedwith GLu（r=-0.726，p＜0.01）; The serum concentration of GLu was negativelycorrelated with GAS （r=-0.806，p＜0.01），CCK（r=-0.558，p＜0.01）and GLP-1（r=-0.705，p＜0.01）.②Apoptotic index and The relative expression of genes: theapoptotic index of islet cells was positively correlated with the expression of TLR4mRNA（r=0.611，p＜0.01）and NF-κB mRNA（r=0.817，p＜0.01）.Conclusions:1、 The therapy of Liraglutide could increase the concentration of multiplegastrointestinal hormones，and regulate the β together with α cells function in islet oftype2diabetes rats, thus the glucose metabolism could be improved； 2、With the progress of T2DM, the expression of TLR4and NF-κB in pancreatictissue increased significantly, So the inflammatory reaction of TLR4/NF-κB signalingpathway plays an important role in the occurrence and development of diabetesmellitus. the treatment of Liraglutide can inhibit toll-like recpter4/nuclear factor-κBsignaling pathway;3、Our study provide evidence that Liraglutide can inhibit Islet cells apoptosisinduced by inhibiting TLR4/NF-κB signaling pathway in type2diabetes rats；4、This study revealed that Liraglutide could improve glucose metabolism byprevent Islet cells apoptosis in a TLR4/NF-κB pathway-dependent manner.