Pancreatic β-cell identity in diabetes

Abstract

Recovery of functional β-cell mass continues to be an ongoing challenge in treating diabetes. Initial work studying β-cells suggested apoptotic β-cell death as a main contributor for the loss of β-cell mass in diabetes. Restoration of β-cells either by transplant or stimulating proliferation of remaining β-cells or precursors would then logically be a viable therapeutic option for diabetes. However, recent work has highlighted the inherent β-cell plasticity and the critical role of loss of β-cell identity in diabetes, and has suggested that β-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 β-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 β-cell identity in diabetes, the current understanding of mechanisms involved in altering this mature functional β-cell state and potential progresses to identify novel therapeutic targets providing better opportunities for slowing or preventing diabetes progression.

Keywords: KATP; apoptosis; dedifferentiation; diabetes; differentiation; environmental; factors; fate; glibenclamide; glucose; glucotoxicity; glyburide; hormones; human; identity; insulin; mice; monogenic; obesity; progenitor; proliferation; redifferentiation; regeneration; stem; sulfonylureas; therapy; transdifferentiation; treatment; type 1; type 2; β-cell.

Figure 1. Metabolic state influences cell fate decisions in adult β-cells

At rest (1) β-cells secrete insulin in response to glucose. In cases where insulin supply is insufficient to respond to metabolic demand (2), β-cells begin to prime themselves to both proliferate and relieve stress. At this point, the functionality of β-cells can be recovered completely with interventions (brown arrow). With sufficiently high blood glucose (3) however, the cells begin to undergo changes induced by glucotoxicity, at which point they may encounter a fate decision (4) between altering their terminally differentiated state and undergoing apoptosis. As changes in cell transcription factor expression occur (5), the β-cells can degranulate, undergo dedifferentiation to more progenitor-like cell fate, or transdifferentiate to an alternative, terminally-differentiated state. Whether this plays a role in further cell susceptibility to apoptosis is not well understood. With therapies (6) that alter cell fate such as intensive insulin therapy to relieve glucotoxicity (pink arrows), gene therapy to restore transcription factors, or treatment with other metabolic modulators (gray arrows), the cells undergo re-differentiation and regain markers of mature β-cell identity as well as insulin content. Under physiological conditions or in the presence of certain stimuli, β-cells can proliferate and grow (7).