Transcriptional control of pancreatic β-cell identity and plasticity during the pathogenesis of type 2 diabetes

Abstract

Type 2 diabetes (T2D) is caused by insulin resistance and insufficient insulin secretion. Evidence has increasingly indicated that pancreatic β-cell dysfunction is the primary determinant of T2D disease progression and remission. High plasticity is an important feature of pancreatic β-cells. During T2D development, pancreatic β-cells undergo dynamic adaptation. Although β-cell death/apoptosis in later-stage T2D is the major cause of β-cell dysfunction, recent studies have revealed that β-cell dedifferentiation and reprogramming, which play critical roles in β-cell functional regulation in the early and middle T2D progression stages, are characterized by (i) a loss of mature β-cell-enriched genes; (ii) dedifferentiation to a progenitor-like state; and (iii) transdifferentiation into other cell types. The roles of transcription factors (TFs) in the establishment and maintenance of β-cell identity during pancreatic development have been extensively studied. Here, we summarize the roles and underlying mechanisms of TFs in the maintenance of β-cell identity under physiological and type 2 diabetic conditions. Several feasible approaches for restoring islet functions are also discussed. A better understanding of the transcriptional control of β-cell identity and plasticity will pave the way for developing more effective strategies, such as β-cell regeneration therapy, to treat T2D and associated metabolic disorders.

Keywords: Dedifferentiation; Pancreatic β-cell; Redifferentiation; Transcription factors; Transdifferentiation; Type 2 diabetes.