β-Cell Growth and Regeneration: Replication Is Only Part of the Story

Abstract

> “I am accordingly of the opinion that the normal regulation of islet content in the pancreas is by interstitial growth of pre-existing islets and by the formation of new islets from the duct epithelium, and not at all by the formation of new islets out of acini.” > > R.R. Bensley Am J Anatomy 1911;12:297–388 For almost a century (for historical review, see 1) both β-cell replication and neogenesis (the differentiation of new islet cells from progenitors or stem cells) have been thought to be responsible for postnatal growth of the endocrine pancreas. Even though doubts have been raised in recent years about the existence and importance of neogenesis, this skepticism may be subsiding. Replication and neogenesis are not mutually exclusive. Both processes often occur simultaneously, as seen during the regeneration that follows pancreatic injury. However, there are important differences in the balance of these two pathways that depend upon species and age. Replication of β-cells is an important mechanism particularly in adult rodents, but there are compelling data that after-birth progenitors also have a role in renewal and growth of islets. Eventually one or both of these pathways may be manipulated for therapeutic treatment of diabetes. Since we and others have extensively reviewed the regulation of β-cell mass (2,3), this Perspective will specifically address the contributions of the neogeneic pathway to new β-cell formation, considering whether postnatal neogenesis occurs, to what extent; possible differences between mammalian species; and whether it might be exploited therapeutically. ### β-Cell expansion in normal growth. The concept that β-cell mass is dynamic and increases and decreases both in function and mass to maintain the glycemic level within a very narrow physiological range (4) is now generally accepted. In both normal and pathophysiological states, the mechanisms responsible are changes in replication and neogenesis, changes in individual cell volume, and changes in cell loss or death rates. In …