Diabetes is associated with β-cell dysfunction. But it remains unclear whether the latter results from reduced β-cell number or function. Purpose of this study is to investigate the hypothesis that β-cell failure is the result of β-cell dedifferentiation, rather than apoptosis or degranutaion. Transcription factor FoxO1 integrates β-cell proliferation with adaptive β-cell function. The rationale for the proposed project arises from the observation that mice lacking FoxO1 in β-cells develop hyperglycemia with reduced β-cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrate that loss of β-cell mass is due to β-cell dedifferentiation, not death. Dedifferentiated β-cells revert into progenitor-like cells expressing Neurogenin3, Hdac1,and L-Myc. They also partly convert into non-β-cells, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We intend to investigate whether humans with type 1 and 2 diabetes develop the same abnormalities observed in Foxo1 β-cell-specific knockouts.