Semaglutide alleviates the pancreatic β cell function via the METTL14 signaling and modulating gut microbiota in type 2 diabetes mellitus mice.

AIMS: Semaglutide, a novel long-acting GLP-1RA, stimulates insulin and suppresses islet-secreted glucagon to reduce glucose levels. It has been unveiled that m6A mRNA modification plays a pivotal role in regulating β cell function. However, it remains unclear whether semaglutide can elicit protective effects through manipulating m6A modification and the underlying mechanism. We aimed to elucidate the role played by semaglutide in m6A modification, and to explore its specific regulatory targets. Furthermore, we also delve into its effects on gut microbiota. MAIN METHODS: Five-week-old male C57BL/6 mice were assigned to two dietary groups and fed a control or high-fat diet for 4 weeks. Then T2DM was induced in high-fat diet-fed mice via streptozotocin (STZ), the main groups were resampled to include treatment with semaglutide (SEM, 40 μg/kg) for another 4 weeks, totaling three groups: Control, Model (T2DM), T2DM + SEM. Additionally, we elucidated specific regulatory targets and signaling pathways in palmitic acid (PA)-stimulated beta-TC-6 cells. Immunofluorescence, Western blot, and RT-qPCR were used in the study. KEY FINDINGS: Semaglutide mitigated pancreatic damage, enhanced islet cell proliferation, and restored islet size and alpha- and beta-cell masses. It also improved the expression of METTL14, pancreatic duodenal homeobox 1 (PDX-1), and protecting mitochondria, and modulated the PDX1 expression in an m6A-dependent manner. Concurrently, semaglutide significantly decreases the abundance of Firmicutes, Actinobacteriota, and Lactobacillus, while increasing the Bacteroides and norank_f_Muribaculaceae content, and the production of short-chain fatty acids (SCFA). SIGNIFICANCE: Semaglutide positively influences by regulating m6A modifications to alleviate pancreatic beta cell dysfunction and modulate the gut microbiome.