Type 1 diabetes (T1D) development is characterized by insulitis, resulting in β–cell stress and progressive β–cell dysfunction and death. However, recent evidence suggest the role of pancreatic β cells in amplifying this immune response through the presentation of immunogenic peptides and secretion of cytokines and chemokines, indicating β cells may be complicit during the development of T1D. In this context, we reasoned that intrinsic β cell stress pathways such as ER–stress, oxidative stress and the integrated stress response (ISR) could play role immune cell activation and destruction of β cells. The ISR is a complex program of gene expression and translational control which is regulated through the selective phosphorylation of ⍺ subunit of the eukaryotic translational initiation factor (eIF2⍺). Chronic activation of ISR can lead to defective RNA translation and generation of abberent proteins or peptides leading to β cell dysfunction or death. Furthermore, ISR influences RNA epitranscriptomic modifications, such as m6A and pseudouridine, which impact transcript stability and translation efficiency during cellular stress. Beyond RNA modifications, the chemicals regulating these processes can also modulate epigenetic mechanisms, including DNA methylation and chromatin remodeling, driving transcriptional reprogramming. Together, these interconnected processes shape cellular adaptation, survival, and disease progression in T1D.
