The Anna Karenina model of beta cell maturation in development and their dedifferentiation in type 1 and type 2 diabetes

Loss of mature beta cell function and identity, or beta cell dedifferentiation, is seen in all types of diabetes mellitus. Two competing models explain beta cell dedifferentiation in diabetes. In the first model, beta cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated beta cells resemble beta cell progenitors. In the second model, beta cell dedifferentiation depends on the type of diabetogenic stress. This model, which we call the "Anna Karenina" model, predicts that in each type of diabetes, beta cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular diabetogenic stress. We directly tested the two models using a beta cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of beta cell transcriptional trajectories during the normal course of beta cell postnatal development, and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated beta cells, beta cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes. Mouse beta cell mRNA profiles of E18.5 ICR embryos, P1 ICR neonates, P7 ICR neonates, P10 ICR neonates, ICR adult (wildtype), NOD adult (T1D model), BTBR ob/+, and BTBR ob/ob (T1D model)所有类型的糖尿病均可见成熟β细胞（beta cell）功能与特性丧失，或β细胞去分化现象。目前有两种相互竞争的模型阐释糖尿病中的β细胞去分化机制。第一种模型认为，β细胞去分化遵循发育个体发生（developmental ontogeny）的逆序过程，该模型预测去分化的β细胞与β细胞祖细胞（beta cell progenitors）相似。第二种模型则提出，β细胞去分化取决于致糖尿病应激（diabetogenic stress）的类型，我们将该模型命名为"安娜·卡列尼娜模型"（Anna Karenina model），其预测在每一类糖尿病中，β细胞去分化均有其独特路径，具体取决于特定致糖尿病应激如何破坏其成熟特性。我们通过小鼠体内β细胞特异性谱系示踪系统（lineage-tracing system）联合RNA测序（RNA-sequencing）技术，直接验证了这两种模型。我们构建了β细胞正常产后发育过程，以及1型糖尿病（type 1 diabetes）模型、2型糖尿病（type 2 diabetes）模型中β细胞去分化过程的多维转录轨迹图谱。借助这一无偏研究策略，我们在此证实：尽管未成熟β细胞与去分化β细胞存在部分相似性，但两种小鼠模型中的β细胞去分化并非遵循发育个体发生的逆序过程，且不同类型糖尿病中的β细胞去分化路径存在差异。本数据集包含以下样本的小鼠β细胞mRNA表达谱：E18.5 ICR胚胎、P1 ICR新生鼠、P7 ICR新生鼠、P10 ICR新生鼠、ICR成年野生型小鼠、1型糖尿病模型NOD成年小鼠、BTBR ob/+以及BTBR ob/ob（T1D模型）小鼠。