Oxidative Stress, Post-Translational Modifications, and Type 1 Diabetes Pathogenesis

Abstract

Type 1 diabetes (T1D) is an organ-specific autoimmune disease that destroys insulin-producing beta-cells. Insulin is a vital hormone for regulating glycemia that often undergoes post-translational modifications during processing from pre-proinsulin to biologically active insulin. While necessary for proper glucose homeostasis, insulin is also an autoantigen recognized by autoreactive T cells in T1D. Cellular stress pathways including endoplasmic reticulum stress and oxidative stress mediated by an increase in reactive oxygen species (ROS) synthesis and/or a concomitant decrease in antioxidant function can further drive post-translational modifications of various autoantigens in T1D including insulin. Innate immune-derived ROS generation is an essential frontline defense against microbial infections, but ROS can also function as signaling intermediates to properly stimulate T cell responses. Oxidative stress-induced post-translational modifications are thought to trigger autoreactive T cells in T1D by generating novel neoepitopes, eliciting epitope spreading, or enhancing autoantigen interactions with antigen-presenting cells. With the current technology, detecting post-translationally modified proteins is challenging. In this review, we will explore the role of ROS and other post-translational modifications involved in T1D. We will also discuss islet transplantation strategies being used for patients with T1D including novel cell sources for beta-cell replacement and management of oxidative stress after transplantation.