Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure

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