Type 2 diabetes (T2D) is a complex, heterogeneous disease characterized by peripheral insulin resistance (IR) and islet β-cell dysfunction. Recent evidence suggests that early β-cell dysfunction, rather than IR, may be a primary driver of dysglycemia in some individuals. Regardless of the initial event, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may contribute to T2D onset and progression. Oxidative stress, defined by the generation of reactive oxygen species (ROS), is mediated by hyperglycemia and lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress leads to inter-tissue miscommunication, often mediated by extracellular vesicles (EVs), including mitochondria-containing EVs (Mito-EVs). Under metabolic stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely triggers mitochondrial anomalies, leading to prediabetes and T2D. This review discusses the molecular mechanisms underlying ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress, and explores potential therapeutic avenues to attenuate oxidative damage, reverse prediabetes, and prevent T2D progression. Key findings include the role of STX4 in mitophagy and the potential of boosting mitophagy as a preventive treatment. Additionally, the review highlights the importance of inter-organ communication through EVs, particularly Mito-EVs, in mediating prediabetes and T2D progression.Type 2 diabetes (T2D) is a complex, heterogeneous disease characterized by peripheral insulin resistance (IR) and islet β-cell dysfunction. Recent evidence suggests that early β-cell dysfunction, rather than IR, may be a primary driver of dysglycemia in some individuals. Regardless of the initial event, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may contribute to T2D onset and progression. Oxidative stress, defined by the generation of reactive oxygen species (ROS), is mediated by hyperglycemia and lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress leads to inter-tissue miscommunication, often mediated by extracellular vesicles (EVs), including mitochondria-containing EVs (Mito-EVs). Under metabolic stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely triggers mitochondrial anomalies, leading to prediabetes and T2D. This review discusses the molecular mechanisms underlying ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress, and explores potential therapeutic avenues to attenuate oxidative damage, reverse prediabetes, and prevent T2D progression. Key findings include the role of STX4 in mitophagy and the potential of boosting mitophagy as a preventive treatment. Additionally, the review highlights the importance of inter-organ communication through EVs, particularly Mito-EVs, in mediating prediabetes and T2D progression.