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Pancreatic ? cell dedifferentiation as a mechanism of diabetic ? cell failure.


ABSTRACT: Diabetes is associated with ? cell failure. But it remains unclear whether the latter results from reduced ? cell number or function. FoxO1 integrates ? cell proliferation with adaptive ? cell function. We interrogated the contribution of these two processes to ? cell dysfunction, using mice lacking FoxO1 in ? cells. FoxO1 ablation caused hyperglycemia with reduced ? cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of ? cell mass was due to ? cell dedifferentiation, not death. Dedifferentiated ? cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient ? cells adopted the ? 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 ? cell failure and suggest that treatment of ? cell dysfunction should restore differentiation, rather than promoting ? cell replication.

SUBMITTER: Talchai C 

PROVIDER: S-EPMC3445031 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.

Talchai Chutima C   Xuan Shouhong S   Lin Hua V HV   Sussel Lori L   Accili Domenico D  

Cell 20120901 6


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  ...[more]

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