The Anna Karenina Model of β-Cell Maturation in Development and Their Dedifferentiation in Type 1 and Type 2 Diabetes

Loss of mature β-cell function and identity, or β-cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β-cell dedifferentiation in diabetes. In the first model, β-cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β-cells resemble β-cell progenitors. In the second model, β-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, β-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 β-cell-specific lineage-tracing system coupled with RNA sequencing in mice. We constructed a multidimensional map of β-cell transcriptional trajectories during the normal course of β-cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lep ). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β-cells, β-cell dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.