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bioRxiv · 10.1101/2025.07.08.663248

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

Shoyhet, H.·Cohen, Y.·Bachinsky, Y. H.·Rosenhek-Goldian, I.·Kamyshinsky, R.·Hornstein, E.·Levenberg, S.
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Abstract

1Type 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 as well as 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 multi-omic approach used here suggests a mechanism whereby G4OE-EMC-derived EVs enhance glucose metabolism via IGF1 signaling and miRNA-mediated regulation of IGF1R expression, offering a potential therapeutic strategy for T2D.

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Shoyhet, H., Cohen, Y., Bachinsky, Y. H., Rosenhek-Goldian, I., Kamyshinsky, R., Hornstein, E., Levenberg, S.. 2025-07-11. Extracellular Vesicles Mediate Glucose Regulation by GLUT4-Overexpressing Engineered Muscle Tissue in T2D Mice. https://doi.org/10.1101/2025.07.08.663248

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