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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 2021-06-15, 22:57 authored by Sutichot D. Nimkulrat, Matthew N. Bernstein, Zijian Ni, Jared Brown, Christina Kendziorski, Barak BlumLoss 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.