β-Cell dysfunction in diabetes: a crisis of identity?

Type 2 diabetes is characterized by insulin resistance and a progressive loss of β-cell function induced by a combination of both β-cell loss and impaired insulin secretion from remaining β-cells. Here, we review the fate of the β-cell under chronic hyperglycaemic conditions with regard to β-cell mass, gene expression, hormone content, secretory capacity and the ability to de- or transdifferentiate into other cell types. We compare data from various in vivo and in vitro models of diabetes with a novel mouse model of inducible, reversible hyperglycaemia (βV59M mice). We suggest that insulin staining using standard histological methods may not always provide an accurate estimation of β-cell mass or number. We consider how β-cell identity is best defined, and whether expression of transcription factors normally found in islet progenitor cells, or in α-cells, implies that mature β-cells have undergone dedifferentiation or transdifferentiation. We propose that even in long-standing diabetes, β-cells predominantly remain β-cells-but not as we know them.