Oxidative Post‐Translational Modifications of Insulin in Type 1 Diabetes Autoimmunity

ABSTRACT

Type 1 diabetes (T1D) is characterized by T cell‐mediated destruction of insulin producing pancreatic β cells. However, stressed β cells are increasingly recognized as active contributors to disease pathogenesis rather than passive targets of immune attack. In this context, oxidative stress in β cells may promote oxidative post‐translational modifications (oxPTMs) of insulin, generating modified insulin forms that have emerged as potential drivers of neoantigen formation and autoimmune responses. Due to their exceptionally high insulin biosynthetic load, limited antioxidant defenses, and susceptibility to endoplasmic reticulum and mitochondrial stress, β cells operate in an environment permissive to oxidative protein modification. Multiple studies have demonstrated that insulin is susceptible to several oxidative and nonenzymatic modifications, including oxidation, chlorination, nitration, and glycation, generating structurally distinct proteoforms with altered biological and immunological properties. Importantly, oxidatively modified insulin species (oxPTM‐insulin) are recognized by both autoantibodies and autoreactive T cells in individuals with T1D, supporting their role as neoantigens. In this review, we discuss the mechanisms leading to oxPTM‐insulin generation, summarize the biochemical and immunological evidence supporting their relevance in T1D, and examine the methodological challenges and controversies surrounding their identification. Finally, we explore the potential of oxPTM‐insulin as a biomarker and therapeutic target in T1D.