The vicious cycle of hyperglycemia and oxidative stress: Novel mechanistic insights into a pathogenic alliance

Diabetes mellitus (DM) is a global health concern characterized by chronic hyperglycemia, which drives severe microvascular and macrovascular complications. The reciprocal interaction between hyperglycemia and reactive oxygen species (ROS)-induced oxidative stress represents a fundamental mechanism in diabetic pathogenesis. As recent studies identify novel intracellular pathways and highlight the critical role of mitochondria, re-examining the interplay between oxidative stress and intracellular organelles is essential. Unlike conventional models that view oxidative stress merely as a passive downstream consequence of cellular damage, this review introduces a distinct, integrative perspective. We reframe the hyperglycemia–oxidative stress axis as a highly coordinated, organelle-driven signaling network that physically bridges metabolic dysfunction with sterile inflammation. By synthesizing classical metabolic shunts (mitochondrial dysfunction, the polyol pathway, advanced glycation end products (AGEs), protein kinase C (PKC) activation, and the hexosamine pathway) with modern inflammatory signaling cascades, we delineate how hyperglycemia amplifies ROS production. This amplification triggers β-cell dysfunction, insulin resistance, and progressive tissue damage, ultimately driving complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease. Although cellular antioxidant defenses attempt to maintain redox homeostasis, persistent hyperglycemia continuously compromises these protective mechanisms. By systematically evaluating these cellular interactions, this review elucidates the oxidative stress-related pathogenesis of diabetic complications. Ultimately, we revisit the self-perpetuating mechanisms of the hyperglycemia–oxidative stress vicious cycle, offering a structurally unified and highly integrative framework to guide future research.