![]() ![]() In type 1 diabetes (T1D), β-cells are targeted by an autoimmune attack. Insulin-secreting pancreatic β-cells are essential for maintaining blood glucose homeostasis, and their loss or dysfunction underlies all types of diabetes. 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. 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 ob/ob). We directly tested the two models using a β-cell–specific lineage-tracing system coupled with RNA sequencing in mice. 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. In the second model, β-cell dedifferentiation depends on the type of diabetogenic stress. This model predicts that dedifferentiated β-cells resemble β-cell progenitors. In the first model, β-cells dedifferentiate in the reverse order of their developmental ontogeny. Two competing models explain β-cell dedifferentiation in diabetes. ![]() Loss of mature β-cell function and identity, or β-cell dedifferentiation, is seen in both type 1 and type 2 diabetes. ![]()
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