Extracellular vesicle miR-425-5p promotes visceral fat reduction via DACT1 suppression in SGLT2i-treated diabetes.

Objective: In type 2 diabetes (T2D), plasma-derived extracellular vesicle (EV)-microRNAs (miRNAs) contribute to insulin resistance and β-cell dysfunction. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower blood glucose by promoting urinary glucose excretion and are associated with weight loss, although the underlying mechanisms remain unclear. Methods: This study was conducted in two phases. In the screening phase, plasma-derived EV miRNA profiles were analyzed by small RNA sequencing in 13 patients with newly diagnosed, treatment-naive T2D at baseline and after 12 months of SGLT2i therapy. In the validation phase, expression of selected miRNAs was quantified by real-time PCR in an independent cohort of 30 patients at baseline and after 6 and 12 months of treatment. The functional roles of candidate miRNAs were examined in 3T3-L1 adipocytes. Results: Small RNA sequencing identified 18 plasma-derived EV miRNAs exhibiting >1.5-fold expression changes after 12 months of SGLT2i therapy. Quantitative PCR confirmed that five EV miRNAs were significantly upregulated post-treatment. Among these, miR-425-5p showed a strong inverse correlation with waist circumference and visceral fat area. Functional assays in 3T3-L1 adipocytes demonstrated that miR-425-5p suppressed adipogenic differentiation and lipid accumulation by downregulating DACT1, one of its predicted target genes, and reducing DACT1-reporter activity. Conclusion: Plasma-derived EV miR-425-5p, increased by long-term SGLT2i therapy in T2D patients, may inhibit adipocyte differentiation and lipogenesis via DACT1 suppression. These findings suggest a possible mechanistic link through which SGLT2i treatment may ameliorate visceral obesity.