Senescent beta-cells exhibit a unique secretory phenotype that promotes inflammation and remodeling of the extracellular environment

Type 2 Diabetes (T2D) patients have higher proportions of senescent beta-cells than their non-diabetic counterparts (Aguayo-Mazzucato et al., 2019). Senescent beta-cells may propagate dysfunction in neighboring cells through the paracrine effects of the senescence-associated secretory phenotype (SASP). To address the heterogeneity in beta-cell SASP expression and its role in T2D, we measured expression levels of beta-cell SASP signature genes in a mouse model of acute insulin resistance using the insulin receptor antagonist, S961. We have previously shown that this model induces hyperglycemia and accelerates beta-cell senescence (Aguayo-Mazzucato et al., 2019). Pancreatic islets were isolated from 3 groups of mice: a control group, a treated group of mice with surgically installed osmotic pumps secreting S961 for 2 weeks, and a third group in which mice recovered from S961 treatment for two weeks. During treatment, mice developed marked hyperglycemia and hyperinsulinemia which was completely reversed during the two-week recovery period. Islets were dispersed into single cells and scRNASeq was performed using the 10x Genomics Chromium Single Cell Gene Expression Assay.

2型糖尿病（Type 2 Diabetes, T2D）患者体内的衰老β细胞比例高于非糖尿病个体（Aguayo-Mazzucato等，2019）。衰老β细胞可通过衰老相关分泌表型（senescence-associated secretory phenotype, SASP）的旁分泌效应，在邻近细胞中传播功能异常。为探究β细胞SASP表达的异质性及其在2型糖尿病中的作用，我们利用胰岛素受体拮抗剂S961构建急性胰岛素抵抗小鼠模型，并检测了该模型中β细胞SASP特征基因的表达水平。我们此前已证实，该模型可诱导小鼠出现高血糖并加速β细胞衰老（Aguayo-Mazzucato等，2019）。本实验共设置三组小鼠：对照组、手术植入渗透泵以持续分泌S961两周的处理组，以及经S961处理后恢复两周的恢复组。在S961处理期间，小鼠出现明显的高血糖与高胰岛素血症，上述代谢异常在为期两周的恢复期内完全逆转。随后我们将胰岛分散为单个细胞，采用10x Genomics Chromium单细胞基因表达检测试剂盒完成单细胞RNA测序（single-cell RNA sequencing, scRNASeq）。