Alpha cell dysfunction in type 1 diabetes is independent of a senescence program

Type 1 Diabetes (T1D) is caused by insulin deficiency, due to progressive autoimmune destruction of pancreatic beta cells. Glucagon-secreting alpha cells become dysfunctional in T1D and contribute to pathophysiology, however, the mechanisms involved are unclear. While the majority of beta cells are destroyed in T1D, some beta cells escape this fate and become senescent but whether alpha cell dysfunction involves a senescence program has not been explored. Here we addressed the question of whether alpha cells become senescent during the natural history of T1D in the non-obese diabetic (NOD) mouse model and humans. NOD mice had several distinct subpopulations of alpha cells, but none were defined by markers of senescence at the transcriptional or protein level. Similarly, alpha cells of human T1D donors did not express senescence markers. Despite the lack of senescence in alpha cells in vivo, using a human islet culture model, we observed that DNA damage-induced senescence led to alterations in islet glucagon secretion, which could be rescued by inhibiting the senescence-associated secretory phenotype (SASP). Together our results suggest that alpha cell dysfunction in T1D is not due to activation of a senescence program, however, senescent beta cell accumulation in the islet microenvironment may have a negative effect on alpha cell function.