Tandem mass tag-based proteomic profiling revealed potential therapeutic targets and mechanisms of liraglutide for the treatment of impaired glucose tolerance

OBJECTIVE: Based on the tandem mass tag (TMT) technique, our study investigated the potential therapeutic targets of Liraglutide (LIRA) on streptozotocin (STZ) induced impaired glucose tolerance (IGT) in rats and discuss the biological mechanism of the drug against IGT. METHODS: 10 rats were randomly selected from 31 male wistar rats of specific pathogen free (SPF) grade as control group and fed with conventional chow, offered the remaining rats a high fat and high sugar (HFSD) diet combined with an intraperitoneal injection of STZ to establish the IGT model, and excluded 2 non-model rats. Specifically, the model rats were randomly divided into Model group (n=10) and LIRA group (n=9). In addition, the LIRA group was subcutaneously injected with 0.06 mg/kg LIRA, during which the metabolic parameters including body weight and fasting blood glucose were recorded. After 8 weeks, samples were taken under anesthesia. Then, the cell morphology was observed using HE staining, and immunofluorescence was performed on the pancreatic tissues of the three groups of rats. Besides, the expression of differential proteins in pancreatic tissues of the three groups of rats was determined by the TMT proteomic labeling. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological function analysis were performed on the intersection of Model and LIRA differential proteins. RESULTS: LIRA could not only significantly reduce blood glucose levels but also improve islet cell morphology and function in IGT rats. Among the differential proteins between the model group and the blank group, 44 were reversed after LIRA treatment, of which 14 were up-regulated, while 30 were down-regulated, including PPIF, MPRIP, CYP51, TXNL1, BCL-2, etc. (FC>1.1 or<0.909, P<0.05). According to the GO and KEGG analysis results, it was related to biological processes such as fatty acid metabolism and adipocyte generation, which involved multiple signaling pathways regulating the function of islet cells, such as MAPK, PI, Ras, FcγR, and unsaturated fatty acids, and pyruvate metabolism. CONCLUSION: To sum up, LIRA participated in anti-IGT therapy through regulation of multiple target proteins and biological functions. This study is of great reference for further exploring the mechanism of action of LIRA at the protein level of IGT.