[HTML][HTML] Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure

C Talchai, S Xuan, HV Lin, L Sussel, D Accili - Cell, 2012 - cell.com
C Talchai, S Xuan, HV Lin, L Sussel, D Accili
Cell, 2012cell.com
Diabetes is associated with β cell failure. But it remains unclear whether the latter results
from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β
cell function. We interrogated the contribution of these two processes to β cell dysfunction,
using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β
cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-
tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation …
Summary
Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication.
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