Circulating senescence-associated secretory phenotype factors across the stages of type 1 diabetes in a cross-sectional cohort.

Type 1 diabetes (T1D) results from a chronic autoimmune disease that leads to pancreatic beta cell death and states of dysfunction such as senescence. Cellular senescence is a programmed stress response involving cell cycle arrest, apoptosis resistance and secretion of immunogenic molecules referred to as the senescence-associated secretory phenotype (SASP). Histologic evidence indicates the accumulation of senescent beta cells in T1D, however, there are no biomarkers to noninvasively detect senescent beta cells. Circulating SASP factors have been used as a biomarker for senescent cell accumulation in age-related diseases, but a similar approach has not been explored in T1D. Here, we measured a panel of 7 previously identified human islet-secreted SASP factors (GDF15, CXCL1, CXCL5, CXCL8, CCL20, IGFBP4 and TNFRSF10C) in a blinded cohort of pediatric and young adult plasma samples from TrialNet including autoantibody-negative controls, single autoantibody-positive, and clinical stages of T1D progression (n = 20 donors per group). SASP factor concentrations were higher in stages 1, 2 and 3 recent onset T1D donors versus controls and effectively discriminated stages 2 and 3 disease status. SASP factor concentration did not associate with the extent of beta cell dysfunction, autoantibody titre or donor age. Analysis of matched plasma and pancreas samples from an independent cohort of control donors supported a relationship between senescent beta cells and circulating SASP markers. These results suggest that senescent beta cell burden may be reflected by the circulating levels of specific islet-associated SASP factors and could represent a novel biomarker for senescence in T1D.