Diabetic β Cells: To Be or Not To Be?

Abstract

β cell dysfunction with subsequent apoptosis is considered a significant contributor to the development of type 2 diabetes. Emerging data from Talchai et al. suggest β cell dedifferentiation as an alternative mechanism of insulin insufficiency that might be more amenable to intervention in at least a subset of patients.

Figure 1. FoxO1 Plays a Role in Maintaining β Cell Identity

Under normoglycemic conditions, FoxO1 primarily localizes to the cytoplasm in mature, insulin-producing β cells. Under conditions of mild hyperglycemia, FoxO1 is seen to partially localize to the nucleus, with an observable reduction in insulin staining. In mouse models that exhibit severe hyperglycemia, FoxO1 is greatly diminished in the β cell, along with reduced insulin. Similarly, genetic ablation of FoxO1, combined with physiological stressors such as aging, leads to islets lacking FoxO1 and insulin expression that continue to be populated by endocrine cells as ascertained by chromogranin positivity. These dedifferentiated β cells re-express, at least transiently, Ngn3, Oct4, and L-myc, suggesting a more progenitor-like state. Lineage tracing demonstrates that a fraction of the remaining endocrine cells are derived from β cells that have repressed the β cell program. Whether such a mechanism of dedifferentiation occurs in human disease remains to be seen. Finally, a reversal of fate, from the dedifferentiated β cell into a fully functional β cell instead of other endocrine cell types, would potentially have great therapeutic value.