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

Loss of mature ß cell function and identity, or ß cell dedifferentiation, is seen in all types of diabetes mellitus. Two competing models explain ß cell dedifferentiation in diabetes. In the first model, ß cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated ß cells resemble ß cell progenitors. In the second model, ß 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, ß 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 ß cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of ß cell transcriptional trajectories during the normal course of ß 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 ß cells, ß cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes. Overall design: Mouse ß 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)