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bioRxiv · 10.1101/2021.02.16.431507

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

Nimkulrat, S. D.·Ni, Z.·Brown, J.·Kendziorski, C.·Blum, B.
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Abstract

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.

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Nimkulrat, S. D., Ni, Z., Brown, J., Kendziorski, C., Blum, B.. 2021-02-17. The Anna Karenina model of beta cell maturation in development and their dedifferentiation in type 1 and type 2 diabetes. https://doi.org/10.1101/2021.02.16.431507

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