Pancreatic β-cell identity in diabetes

Recovery of functional beta-cell mass continues to be an ongoing challenge in treating diabetes. Initial work studying beta-cells suggested apoptotic beta-cell death as a main contributor for the loss of beta-cell mass in diabetes. Restoration of beta-cells either by transplant or stimulating proliferation of remaining beta-cells or precursors would then logically be a viable therapeutic option for diabetes. However, recent work has highlighted the inherent beta-cell plasticity and the critical role of loss of beta-cell identity in diabetes, and has suggested that beta-cells fail to maintain a fully differentiated glucose-responsive and drug-responsive state, particularly in diabetic individuals with poorly controlled, long-lasting periods of hyperglycaemia. Understanding the underlying mechanisms of loss of beta-cell identity and conversion in other cell types, as well as how to regain their mature differentiated functional state, is critical to develop novel therapeutic strategies to prevent or reverse these processes. In this review, we discuss the role of plasticity and loss of beta-cell identity in diabetes, the current understanding of mechanisms involved in altering this mature functional beta-cell state and potential progresses to identify novel therapeutic targets providing better opportunities for slowing or preventing diabetes progression.