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

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posted on 15.06.2021, 22:57 by Sutichot D. Nimkulrat, Matthew N. Bernstein, Zijian Ni, Jared Brown, Christina Kendziorski, Barak Blum
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-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.

Funding

This work was funded in part by grants number 1R56DK115837 from the NIDDK and 2-SRA-2018-621-S-B from the JDRF to BB, and grant number 1S10RR025483-01 to the University of Wisconsin-Madison School of Medicine and Public Health Flow Cytometry Core.

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