Exercise‐Induced Extracellular Vesicles as Mediators of Mitochondrial Biogenesis and Insulin Sensitivity in Metabolic Adaptation

BACKGROUND: Metabolic diseases like type 2 diabetes and obesity share insulin resistance as a common feature, driven partly by mitochondrial dysfunction. Exercise-induced extracellular vesicles (EVs) have emerged as mediators of inter-organ communication in metabolic regulation. OBJECTIVE: To synthesize evidence on exercise-induced EVs in mitochondrial adaptation and insulin sensitivity, and propose an integrative framework linking EV-mediated communication to systemic metabolic benefits: METHODS: Narrative synthesis of mechanistic, animal, EV transfer/inhibition, translational, and human studies. RESULTS: -dependent, transcriptional, and post-transcriptional pathways to enhance mitochondrial biogenesis and oxidative metabolism. By improving substrate utilization and reducing lipotoxicity, mitochondrial ROS, ER stress, and inflammation, EV-mediated mitochondrial adaptation may boost insulin sensitivity and insulin signaling. EV transfer/inhibition studies support a contributory role for exercise-induced EVs in glucose homeostasis, though evidence remains context-dependent. CONCLUSIONS: Exercise-induced EVs may link exercise stimuli to mitochondrial adaptation and systemic insulin sensitivity. The proposed "exercise-EV-mitochondrial adaptation-insulin sensitivity" framework offers a conceptual basis for understanding systemic metabolic adaptation and highlights translational potential for metabolic diseases. Future work should clarify causality, tissue specificity, pharmacokinetics, and standardization.