Beta cell stress and endocrine function during T1D: what's next to discover?

Canonically, Type 1 Diabetes (T1D) is a disease characterized by autoreactive T cells as perpetrators of endocrine dysfunction and beta cell death in the spiral towards loss of beta cell mass, hyperglycemia, and insulin dependence. Beta 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 beta 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 beta cell stress in initiating, provoking, and catalyzing T1D. We outline the bridges between hyperglycemia, endoplasmic reticulum (ER) stress, oxidative stress and autoimmunity from the viewpoint of intrinsic beta cell (dys)function, and we extend this discussion to the potential role for a therapeutic beta cell stress-metabolism axis in T1D. Lastly, we mention research angles that may be pursued to improve beta 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 beta cells as endocrine therapy.