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This study aimed to describe the plasma EV miRNA profiling of type 2 diabetes mellitus (T2DM) and evaluate the association between differentially expressed miRNAs and T2DM. The subjects were from the Henan Rural Cohort. The miRNA profiling of plasma EVs was quantified by the next-generation sequencing of RNA in the discovery sets to identify differentially expressed miRNAs. The association between differentially expressed miR-3120-5p and T2DM was validated in 75 pairs of newly diagnosed T2DM and controls using logistic regression and a generalized linear model. In vitro experiments were performed in HepG2 cells to explore the mRNA and protein expression levels of glucose-related transcription factors and glucose consumption by transfecting miR-3120-5p mimic or inhibitor. We found that in the discovery set, the first phase identified 73 upregulated and 44 downregulated miRNAs, followed by 41 upregulated and 23 downregulated miRNAs in the second phase. miR-3120-5p showed upregulation in the two phases. In the validation set, the miR-3120-5p level in plasma EVs was positively associated with the risk of T2DM (OR: 1.22, 95% CI: 1.05, 1.44). In vitro experiments demonstrated that glucose consumption was reduced in HepG2 cells overexpressing miR-3120-5p compared to mimic negative controls, and that expression of the glucose uptake factor GLUT2 protein was also decreased. We conclude that plasma EV miR-3120-5p was associated with T2DM in the rural populations with limited resources, and might contribute to the pathological process by directly or indirectly inhibiting hepatocyte GLUT2 expression and glucose consumption.<\/jats:p>","DOI":"10.1530\/jme-25-0060","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T19:12:33Z","timestamp":1762629153000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":0,"title":["Profiling of plasma extracellular vesicle miRNA reveals the association of miR-3120-5p with type 2 diabetes 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