An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis.

Abstract Pancreatic β-cells are the insulin factory of the organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β-cell dysfunction and death. Type 1 diabetes (T1D) is a chronic inflammatory disease caused by autoimmune-mediated destruction of β-cells. Although autoimmunity is an essential component of T1D pathogenesis, accumulating evidence suggests that β-cell ER stress and aberrant unfolded protein response (UPR) can play an important role in disease initiation and progression. Here, we review β-cell ER stress in various mouse models, evaluate its involvement in inflammation, and discuss the effects of ER stress on β-cell plasticity and demise, and islet autoimmunity in T1D. Finally, we provide insight into therapeutic targeting of ER stress and the UPR for prevention or treatment of T1D.