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.