β Cell Stress and Endocrine Function During T1D: What Is Next to Discover?

Canonically, type 1 diabetes (T1D) is a disease characterized by autoreactive T cells as perpetrators of endocrine dysfunction and β cell death in the spiral toward loss of β cell mass, hyperglycemia, and insulin dependence. β Cells have mostly been considered as bystanders in a flurry of autoimmune processes. More recently, our framework for understanding and investigating T1D has evolved. It appears increasingly likely that intracellular β cell stress is an important component of T1D etiology/pathology that perpetuates autoimmunity during the progression to T1D. Here we discuss the emerging and complex role of β cell stress in initiating, provoking, and catalyzing T1D. We outline the bridges between hyperglycemia, endoplasmic reticulum stress, oxidative stress, and autoimmunity from the viewpoint of intrinsic β cell (dys)function, and we extend this discussion to the potential role for a therapeutic β cell stress-metabolism axis in T1D. Lastly, we mention research angles that may be pursued to improve β cell endocrine function during T1D. Biology gleaned from studying T1D will certainly overlap to innovate therapeutic strategies for T2D, and also enhance the pursuit of creating optimized stem cell-derived β cells as endocrine therapy.