A long-standing question in the diabetes field is whether pancreatic beta cell failure is a result of reduced numbers of beta cells or loss of their function. A new study by Chutima Talchai et al. (Cell 150, 1223–1234) may help resolve this issue.

FoxO1 is a key transcription factor that integrates stress responses and regulation of beta cell mass. The authors examined mice that had a beta cell–specific deletion of FoxO1 and found that, when the mice were exposed to physiological stress, they showed hyperglycemia and reduced beta cell mass. Using lineage-tracing studies, the authors showed that this decrease in cell mass resulted from beta cell dedifferentiation rather than from cell death. Importantly, Talchai et al. showed that two other mouse models of type 2 diabetes show progressive loss of FoxO1 expression during diabetes development and also beta cell differentiation, suggesting that dedifferentiation is a shared mechanism.

Investigation of whether beta cell dedifferentiation also occurs in human diabetes will be needed, but the authors suggest that if so, a revised paradigm for therapeutic strategies will be required—promoting beta cell differentiation rather than replication.