Endocrine Abstracts

Cellular senescence is a stress response marked by the upregulation of anti-apoptotic pathways and loss of cellular function while maintaining an active secretory profile. Senescent pancreatic β-cells contribute to the development of Type 2 Diabetes and secrete a unique senescence-associated secretory phenotype (SASP) with potential effects on surrounding cells. Removing senescent β-cells leads to their functional recovery. scRNASeq analysis of mouse and human islets identified different subpopulations of senescent β-cells based on the expression of two cyclin-dependent kinase inhibitors: Cdkn1a⁺ β-cells had reduced expression of functional and hallmark identity genes. In contrast, Cdkn2a⁺ β-cells had a specific SASP profile. In vitro, SASP factors induced senescence and impaired insulin secretion, making senescent cells and its SASP a therapeutic target. JAK inhibitors were used to inhibit SASP secretion (senomorphic effect) and were compared to ABT263, which induced apoptosis in senescent cells (senolytic effect). SASP inhibition was confirmed with proteomic analysis of conditioned media from human β-cells, while senolytic action was shown through morphological analysis. In a mouse high-fat diet model of insulin resistance, senomorphic drugs improved blood glucose levels, increased insulin levels, restored glucose responsiveness, and decreased senescence and SASP genes while restoring the β-cell specific transcriptome. Human islets from donors with and without T2D were treated in vitro with senomorphic drugs, which preferentially decreased the CDKN1A⁺ human subpopulation, increased survival, decreased SASP secretion, and improved GSIS in humans. In conclusion, the non-cell autonomous effects of SASP in β-cells can be pharmacologically inhibited to restore β-cell function and identity.