Redox Imbalance and Oxidative Stress in Diabetes Mellitus: Mechanistic Insights into Complications and Antioxidant-Based Therapeutic Perspectives

Diabetes mellitus (DM) is a metabolic disorder marked by chronic hyperglycemia and characterized by micro- and macrovascular complications. Oxidative stress, a state of redox imbalance, is an important etiological factor in the pathophysiology of insulin resistance, β-cell glucotoxicity, inflammation, and cardiovascular complications of diabetes, resulting from the accumulation of reactive oxygen and nitrogen species (ROS/RNS). Chronically elevated glucose levels lead to the generation of reactive oxygen species (ROS) through glucose auto-oxidation, advanced glycation end-product formation, and activation of the polyol pathway and protein kinase C (PKC) signaling. Insulin signaling is also compromised by oxidative stress through inhibition of insulin signaling pathways, suppression of GLUT4-dependent glucose uptake, and stimulation of stress kinases and inflammatory pathways. Pancreatic β-cells, owing to their low antioxidant defense, are particularly vulnerable to oxidative damage, ultimately leading to their functional exhaustion. The purpose of this review is to discuss the contribution of exogenous and endogenous antioxidants in maintaining redox homeostasis, protecting β-cells, improving insulin sensitivity, modulating inflammation, and preventing vascular complications. Emerging strategies such as Nrf2-mediated antioxidant signaling, nano-antioxidants, and targeted antioxidant delivery systems show promising potential for improving glycemic control and reducing diabetes-related complications through redox-sensitive therapeutic approaches.