Alterations in Beta Cell Identity in Type 1 and Type 2 Diabetes

Purpose of Review To discuss the current understanding of beta cell identity and factors underlying altered identity of pancreatic beta cells in diabetes, especially in humans. Recent Findings Altered identity of beta cells due to dedifferentiation and/or transdifferentiation has been proposed as a mechanism of loss of beta cells in diabetes. In dedifferentiation, beta cells do not undergo apoptosis; rather, they lose their identity and function. Dedifferentiation is well characterized by the decrease in expression of key beta cell markers such as genes encoding major transcription factors, e.g., MafA, NeuroD1, Nkx6.1, and Foxo1, and an increase in atypical or disallowed genes for beta cells such as lactate dehydrogenase, monocarboxylate transporter MCT1, or progenitor cell genes (Neurog3, Pax4, or Sox9). Moreover, altered identity of mature beta cells in diabetes also involves transdifferentiation of beta cells into other islet hormone producing cells. For example, overexpression of alpha cell specific transcription factor Arx or ablation of Pdx1 resulted in an increase of alpha cell numbers and a decrease in beta cell numbers in rodents. The frequency of alpha-beta double-positive cells was also prominent in human subjects with T2D. These altered identities of beta cells likely serve as a compensatory response to enhance function/expand cell numbers and may also camouflage/protect cells from ongoing stress. However, it is equally likely that this may be a reflection of new cell formation as a frank regenerative response to ongoing tissue injury. Physiologically, all these responses are complementary. In diabetes, (1) endocrine identity recapitulates the less mature/less-differentiated fetal/neonatal cell type, possibly representing an adaptive mechanism; (2) residual beta cells may be altered in their subtype proportions or other molecular features; (3) in humans, altered identity is a preferable term to dedifferentiation as their cellular fate (differentiated cells losing identity or progenitors becoming more differentiated) is unclear as yet.