DNA Damage in Diabetes: From Molecular Mechanisms to Clinical Implications

A growing body of evidence indicates that diabetes is associated with pronounced DNA damage, ultimately leading to genomic instability. Chronic hyperglycemia induces the production of reactive oxygen and nitrogen species (ROS and RNS), which trigger a cascade of oxidative stress through multiple pathways. These reactive species attack DNA, causing mutations as well as single- and double-strand breaks. Hyperglycemia also promotes the non-enzymatic glycation of DNA causing the formation of advanced glycation end products (AGEs) adducts. Binding of AGEs to the receptors for AGEs (RAGEs) stimulates additional ROS production, thereby amplifying oxidative stress. This state of genomic instability is further promoted by a decline in antioxidant defenses, which allows ROS-induced damage to accumulate, and is sustained by compromised DNA repair mechanisms. Accumulating DNA damage contributes to the development of diabetic micro- and macrovascular complications by triggering destructive mechanisms such as apoptosis, fibrosis, ferroptosis, and pyroptosis that compromise organ function. Additionally, persistent DNA damage elevates the risk of diabetes-associated malignancies and compromises male reproductive health. This review synthesizes current insights into the molecular mechanisms driving hyperglycemia-induced genomic damage and highlights its broad clinical implications. Understanding the multifaceted impact of DNA damage in diabetes provides a comprehensive framework for its role in disease progression and associated comorbidities.