Purpose: To analyze the effect and potential therapeutic targets of liraglutide in type 2 diabetes through miRNA expression profiling.
Methods: Ten of 30 SPF Wistar rats, males at 4 weeks old, were randomly selected as the control group and given conventional feed, the other rats adopted high-sugar and high-fat diet combined with an intraperitoneal injection of streptozotocin to establish a T2DM model. One unsuccessful rat was excluded, and the remaining rats were randomized to the model and the liraglutide group. Liraglutide group was subcutaneously injected with liraglutide 0.11 mg/kg for 8 weeks. The biochemical indicators and staining HE were detected. The expression of miRNA in pancreatic tissue was detected by miRNA sequencing. The intersection of miRNA difference was used to predict the target gene, then functional enrichment was performed to identify its possible biological functions and signal transduction paths. Finally, qRT-PCR was used to verify the results.
Results: Compared to the model group, the level of fasting blood glucose (FBG), glucagon and insulin resistance index (HOMA-IR) in the liraglutide group were significantly decreased, fasting insulin (FINS) and insulin sensitivity index (ISI) were increased. Nine differential miRNAs (miR-135a-5p, miR-144-5p, miR-21-3p, miR-215, miR-451-5p, miR-486, miR-122-5p, miR-181d-5p and miR-345-5p) were identified at the intersection through two miRNA sequencing. A total of 3359 related target gene predictions were obtained. GO and pathway analyses demonstrated that differentially expressed genes were closely related to cell proliferation, angiogenesis, and proteolysis. Significant signaling pathways included PI signaling system, autophagy, FoxO and HIF-1 signaling pathway.
Conclusion: Liraglutide could improve islet function by regulating nine miRNAs, and the related signaling pathways included PI signaling system, autophagy, FoxO and HIF-1 signaling pathway. Our study provided the basis and direction for further exploring the molecular mechanism of liraglutide on T2DM.
Keywords: liraglutide, type 2 diabetes, miRNA expression profile, target gene, signaling pathway