Extracellular Vesicles Mediate Glucose Regulation by GLUT4-Overexpressing Engineered Muscle Tissue in T2D Mice

Type 2 diabetes (T2D) is characterized by impaired glucose uptake in skeletal muscle and adipose tissues, which contributes to systemic hyperglycemia. GLUT4 is a crucial component in insulin-stimulated glucose uptake, and its expression and translocation are impaired in T2D onset. This study explored the role of extracellular vesicles (EVs) derived from GLUT4-overexpressing engineered muscle constructs (G4OE-EMC) in glucose metabolism. G4OE-EMC-derived EVs enhanced glucose uptake and insulin sensitivity both in vitro, when tested on wild-type (WT) engineered muscle constructs, and in vivo, using the diet-induced obesity (DIO) mouse model. Proteomic and transcriptomic analyses revealed that the EVs were enriched in IGF1 and contained reduced levels of miRNAs, such as miR-122-5p, miR-16-5p, and miR-486-5p, which target IGF1R. The multiomic approach used here combined with in vivo and in vitro results suggest a mechanism whereby G4OE-derived EVs enhance glucose metabolism via IGF1 signaling and miRNA-mediated regulation of IGF1R expression, offering a path for potential therapeutic strategy for T2D.