Maintenance of β-Cell Maturity and Plasticity in the Adult Pancreas

Abstract

Diabetes occurs when the pancreas fails to produce and secrete sufficient insulin for the maintenance of glucose homeostasis. Although many factors required for β-cell development have been elucidated, we know surprisingly little regarding the mechanisms that maintain the differentiated state of adult β-cells. Despite years of fruitful research, many hurdles remain before we can replace failing β-cells in patients. Efforts to produce new β-cells will benefit from detailed knowledge of their differentiation, maturation, maintenance, heterogeneity, and plasticity. Studies of single cells and conditional knockout mice reveal surprising relationships between the different islet cell types and previously unappreciated roles for transcription factors and soluble factors in β-cell maintenance. Herein we highlight numerous innovative efforts made to identify the core mechanisms responsible for β-cell phenotypic maintenance and compare these with other long-lived cell types. In the adult pancreas, physical β-cell mass is determined by the balance of β-cell birth, differentiation, size, and death. The prenatal origins and development of β-cells (1,2), the molecular mechanisms of adult β-cell proliferation (3,4), and programmed β-cell death (5) have all been reviewed recently and will not be revisited here. The maintenance and adaptation of β-cell mass after birth involves the addition of new β-cells (6). Cells with robust staining for insulin have been shown to slowly proliferate in vivo and in vitro (7–9). It has been reported that β-cells have an extremely long life span under typical conditions and proliferation plays a diminishing role with advancing age (7,10,11). The apparent low rate of β-cell replication has led some groups to suggest that adult β-cells arise from a pool of non–β-cell progenitors (12). Because this topic has been hotly debated and reviewed recently (13), we will only briefly discuss studies relevant to other aspects of this review. …