Redox Balance, Mitohormesis, and Organ Stress in Type 2 Diabetes Mellitus: Mechanistic Insights and the Therapeutic Role of SGLT2 Inhibitors

Oxidative stress and chronic low-grade inflammation are recognized key drivers of diabetic complications. Lysosomal dysfunction, cellular senescence, and inter-organ stress signaling further aggravate the Redox–Inflammation–Organ Stress Axis in type 2 diabetes mellitus (T2DM). Recent studies suggest that reactive oxygen species (ROS) are not always harmful. Through mitohormesis, mild and transient increases in ROS levels can trigger antioxidant defenses, strengthen mitochondrial function, and limit chronic inflammation. Evidence from caloric restriction, exercise, and ketone body studies supports this adaptive redox balance, underscoring the importance of maintaining a “hormetic window” rather than indiscriminate antioxidant supplementation. In our prospective study, sodium-glucose cotransporter 2 inhibitor treatment significantly reduced albuminuria and serum levels of inflammatory markers, e.g., tumor necrosis factor receptors 1 and 2, while paradoxically increasing urinary 8-hydroxy-2′-deoxyguanosine levels and biological antioxidant potential (BAP), suggestive of adaptive ROS responses consistent with mitohormesis. Concomitant glucagon-like peptide-1 receptor agonist use emerged as an independent explanatory factor for increased urinary levels of oxidative stress markers, suggesting that multiple metabolic therapies converge on shared hormetic pathways. Emerging evidence that stressed adipocytes can communicate mild ROS signals via extracellular vesicles expands this paradigm to inter-organ mitohormesis. Collectively, these insights caution against indiscriminate antioxidant use and underscore the therapeutic potential of controlled redox modulation to disrupt the vicious cycle of senescence, inflammation, and organ stress. Incorporating redox biomarkers like urinary 8-hydroxy-2′-deoxyguanosine, reactive oxygen metabolite derivatives, and BAP into clinical monitoring, alongside pharmacological and lifestyle interventions, may facilitate the realization of precision metabolic medicine for multi-organ protection in T2DM.