β cell replication is the primary mechanism for maintaining postnatal β cell mass

Abstract

The endocrine pancreas undergoes major remodeling during neonatal development when replication of differentiated β cells is the major mechanism by which β cell mass is regulated. The molecular mechanisms that govern the replication of terminally differentiated β cells are unclear. We show that during neonatal development, cyclin D2 expression in the endocrine pancreas coincides with the replication of endocrine cells and a massive increase in islet mass. Using cyclin D2 -/-mice, we demonstrate that cyclin D2 is required for the replication of endocrine cells but is expendable for exocrine and ductal cell replication. As a result, 14-day-old cyclin D2 -/-mice display dramatically smaller islets and a 4-fold reduction in β cell mass in comparison to their WT littermates. Consistent with these morphological findings, the cyclin D2 -/-mice are glucose intolerant. These results suggest that cyclin D2 plays a key role in regulating the transition of β cells from quiescence to replication and may provide a target for the development of therapeutic strategies to induce expansion and/or regeneration of β cells. IntroductionThe β cell mass plays an essential role in determining the amount of insulin that is secreted to maintain the body's glucose levels within a narrow range. Increasing evidence suggests that the β cell mass is dynamic and variations in insulin demand can lead to rapid and marked changes in the β cell mass (1-3). The mass of β cells is governed by balancing β cell growth (differentiation and replication) and β cell death (apoptosis). The molecular basis of the parameters regulating β cell mass are not clear (4). Understanding the regulation of β cell mass is especially important because the inability of the endocrine pancreas to compensate for the changing insulin demand can contribute to the pathogenesis of diabetes (5-7).During mouse embryogenesis, β cells are generated from a population of pancreatic progenitor cells (8,9). The β cells that differentiate from progenitor cells are postmitotic, and direct lineage tracing analyses indicate that a population of progenitor cells persists throughout embryogenesis to allow the differentiation of new β cells (10, 11). During postnatal development, however, replication of differentiated β cells can lead to addition of new β cells (12). High rates of β cell replication during the neonatal period results in a massive increase in β cell mass (13,14). How do terminally differentiated β cells transition between quiescence to replication in the neonatal period? Here we examine the role of D-cyclins in regulating cell cycle progression of β cells in postnatal development. The three D-cyclins (cyclins D1, D2, and D3) are key components of the cell cycle machinery encoded by separate genes, but show significant homology at the protein level (15). The levels of D-cyclins are controlled by mitogens and, upon induction, associate with partner cyclin-dependent kinases CDK4 and CDK6 to drive cells into S-phase (16, 17). Here we report that one D-cyclin, cyclin D2, is uniquel...

Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes

“…The fact that this was present in a man 89 years of age shows that there is a lifelong capacity to induce beta cell replication in humans. This finding is also consistent with findings in mice using lineage tracing [17] and cyclin D2 deletion [18], which identified beta cell replication as the primary mechanism for postnatal beta cell expansion.…”

Upregulation of rat Ccnd1 gene by exendin-4 in pancreatic beta cell line INS-1: interaction of early growth response-1 with cis-regulatory element

“…The involvement of CCND1 protein in beta cell proliferation has recently been verified by others: overexpression of either Ccnd1 alone or in combination with Cdk4-induced beta cell proliferation in rat and human pancreatic islets [23], and CCND1 protein was shown to be essential for normal postnatal pancreatic beta cell growth [24]. These studies, together with our results, implicate CCND1 protein in beta cell proliferation, although CCND2 was also reported to trigger the progression of beta cell replication in the early postnatal period [24,25]. We clearly demonstrated that the induction of Ccnd1 expression by exendin-4 occurred predominantly at the transcriptional level.…”

CXCL10 DNA Vaccination Prevents Spontaneous Diabetes through Enhanced β Cell Proliferation in NOD Mice

“…According to these findings, both in vivo-and in vitro-enhanced ␤ cell proliferation seemed to be due to the direct effect of CXCL10 neutralization, although more detailed studies are required to clarify this. Moreover, these results of the present study in which enhanced ␤ cell proliferation by CXCL10 neutralization maintained the ␤ cell mass, resulting in suppression of the onset of diabetes, are consistent with recent reports by others that replication of differentiated ␤ cells is essential to maintain the ␤ cell mass (43,44). Not only in type 1 diabetes, but also in type 2 diabetes, it has been suggested that a reduction in ␤ cell mass is one of the most important factors in disease progression; therefore, CXCL10 neutralization may be useful for maintaining the ␤ cell mass in both types of diabetes.…”