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

Type 2 diabetes is characterized by insulin resistance and a progressive loss of beta-cell function induced by a combination of both beta-cell loss and impaired insulin secretion from remaining beta-cells. Here, we review the fate of the beta-cell under chronic hyperglycaemic conditions with regard to beta-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 (beta V59M mice). We suggest that insulin staining using standard histological methods may not always provide an accurate estimation of beta-cell mass or number. We consider how beta-cell identity is best defined, and whether expression of transcription factors normally found in islet progenitor cells, or in a-cells, implies that mature beta-cells have undergone dedifferentiation or transdifferentiation. We propose that even in long-standing diabetes, beta-cells predominantly remain beta-cells-but not as we know them.