Abstract

Diabetes mellitus arises through a multifaceted network of metabolic derangements, prominently featuring insulin 
resistance, chronic inflammation, and oxidative stress. These three processes do not occur in isolation; rather, they 
form a self-reinforcing triad that accelerates metabolic dysfunction and tissue injury. Insulin resistance increases 
glucose and lipid flux into susceptible tissues, driving mitochondrial overload and excessive generation of reactive 
oxygen species (ROS). Concurrently, hyperglycaemia and dyslipidaemia activate innate immune sensors, 
promoting the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. These inflammatory 
mediators further impair insulin receptor signaling, creating a vicious cycle that sustains metabolic impairment. At 
the same time, antioxidant defenses—including glutathione, superoxide dismutase, catalase, and 
peroxiredoxins—become depleted due to chronic oxidative burden and reduced transcriptional activation of 
protective pathways such as Nrf2. The resulting imbalance intensifies ROS-mediated cellular injury, endothelial 
dysfunction, β-cell exhaustion, and immunometabolic dysregulation. This review synthesizes current mechanistic 
insights into the interconnected roles of insulin resistance, inflammation, and antioxidant depletion in type 1 and 
type 2 diabetes, with emphasis on molecular pathways, clinical implications, and emerging therapeutic targets. 
Understanding these intertwined processes is essential for designing integrated interventions aimed at preventing 
disease progression and reducing complications.