No New Islet Formation after Neonatal Islet Fission

Abstract

Glucose homeostasis is regulated by the islets of Langerhans, a cluster of micro-organs embedded in the exocrine pancreas. These pancreatic islets range in size from a few to several thousand endocrine cells independent of species over a range of body sizes, suggesting an optimal functional size. Humans have more but not larger islets than mice. To examine the developmental processes that produce this size range of islets, we used a novel method that images all the islets in an intact pancreas of the transgenic mice expressing a fluorescent protein specifically in beta cells. Based on changes of the islet size distribution from postnatal day 1 to week 20, we analyzed islet developmental processes such as birth, growth and fission with mathematical modeling. No new islets were formed after postnatal week 3. At early postnatal days, islet growth was size-dependent with more active cell proliferation in smaller islets than in larger islets. In adulthood, however, every beta cell in an islet of arbitrary size ultimately has an equally small proliferation potential. In addition to this limited islet growth, fission of large islets occurred most actively at postnatal week 3, and contributed to maintaining a limited range of islet sizes. On the other hand, in a tumor (insulinoma) progression model, we found unlimited islet growth, with especially accelerated cell proliferation in larger islets. We conclude that islet size is constrained by preferential growth of small islets and fission of large islets in the early postnatal period, and a low rate of proliferation in maturity.