β-cell senescence in type 2 diabetes

of type 2 diabetes mellitus (T2D). However, the understanding of how cellular aging contributes to diabetes pathogenesis is incomplete and as a result, current therapies do not target this aspect of the disease. Pancreatic β-cells play a central role in the development of T2D; healthy β-cells compensate for insulin resistance, and β-cell dysfunction causes the progression to overt diabetes. Normal β-cell compensatory mechanisms include an increase in mass through cellular proliferation and increased function, which manifests as hyperinsulinemia to maintain normal blood glucose levels. Over time, β-cell compensation for insulin resistance may fail, resulting in a progressive decline of insulin secretion [1]. As a consequence, subjects progress from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and, finally, to established T2D. Even after diagnosis, β-cell function continues to worsen. Early interventions to save β-cell function are a promising strategy to halt the progression of diabetes. In recent work [2, 3] we showed that insulin resistance induced the expression of aging markers, suggesting that β-cell aging could accelerate the progression toward diabetes. Therefore, reversing the hallmarks of cellular aging presents a potential avenue for novel T2D therapies; in particular, transcriptomic analysis of aged β-cells pointed us toward cellular senescence as a promising target. Senescent cells enter a state of longterm growth inhibition and replicative arrest after exposure to environmental insults, including genomic damage, oncogene activation, and reactive oxygen species [4]. The resulting changes in gene expression impair cell function and proliferation while modifying intercellular signaling through the senescenceassociated secretory phenotype (SASP) [5]. The potential paracrine effects of senescent β-cells highlight the importance of the β-cell SASP in driving metabolic dysfunction. Along these lines, we demonstrated that senescent βcells downregulated hallmark identity genes, upregulated disallowed genes, and secreted proinflammatory cytokines [2]. We established two models of insulin resistance in mice: one using the delivery of the insulin receptor antagonist S961, and the other using a more physiologically representative high fat diet. In both cases, the metabolic stress increased the number of Editorial