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)