Chapter 10 - Diabetes: senescence in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a chronic metabolic disease of insulin deficiency, resulting from organ-specific autoimmunity and destruction of pancreatic beta cells. Emerging clinical approaches to T1D have largely focused on the autoimmune component, while the mechanisms operating in beta cells remain elusive. Our recent work showed that during the natural progression of T1D in humans and mice, pancreatic beta cells undergo a DNA damage response leading to senescence and a senescence-associated secretory phenotype (SASP). Selective ablation of the accumulated senescent beta cells or suppression of SASP prevents T1D in mice by preserving beta cell mass, indicating that senescence is a pathogenic mechanism driving disease onset. Markers of senescence and SASP are expressed in beta cells during the progression of T1D in humans, suggesting avenues for treatment in newly diagnosed persons and prevention in those at risk. Despite the progress made, major questions remain regarding the mechanisms of why senescent beta cells accumulate in T1D and evade immune surveillance. Future studies to address these questions will lay the foundation for developing senescence-targeted therapies for T1D.