Weaning Triggers a Maturation Step of Pancreatic β Cells

Abstract

Because tissue regeneration deteriorates with age, it is generally assumed that the younger the animal, the better it compensates for tissue damage. We have examined the effect of young age on compensatory proliferation of pancreatic β cells in vivo. Surprisingly, β cells in suckling mice fail to enter the cell division cycle in response to a diabetogenic injury or increased glycolysis. The potential of β cells for compensatory proliferation is acquired following premature weaning to normal chow, but not to a diet mimicking maternal milk. In addition, weaning coincides with enhanced glucose-stimulated oxidative phosphorylation and insulin secretion from islets. Transcriptome analysis reveals that weaning increases the expression of genes involved in replication licensing, suggesting a mechanism for increased responsiveness to the mitogenic activity of high glucose. We propose that weaning triggers a discrete maturation step of β cells, elevating both the mitogenic and secretory response to glucose.

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

“…Furthermore, recent work has observed that mice prematurely weaned to a high-fat diet resembling milk showed a lower increase in plasma insulin in response to glucose compared with mice prematurely weaned to a normal chow diet (Stolovich-Rain et al 2015). These data point to the leading role of diet over age in the maturation of the beta-cell GSIS.…”

“…Previous works had shown that a physiological critical window that consists of the suckling and weaning periods plays a significant role in rat beta-cell development and lifespan function (Aguayo-Mazzucato et al 2006, CabreraVasquez et al 2009, Stolovich-Rain et al 2015. Research on the development, including the postnatal period, of pancreatic beta-cells could generate significant knowledge to, on one hand, improve the generation of mature insulin-producing cells as a source for diabetes cell-based therapies and, on the other hand, to stimulate in situ beta-cell division to overcome insulin deficiency observed during diabetes.…”

Dynamics and Regulation of Insulin Secretion in Pancreatic Islets from Normal Young Children

“…Human β-cells therefore have reached functional maturity by the age of 1 year, before expansion of their mass is complete. Closer timing of postnatal β-cell maturation and elucidation of its mechanisms will require studies of islets from infants between birth and the age of 1 year, particularly around weaning [45]. Ideally, functional and genetic approaches should be combined to determine whether increased expression or silencing of the same genes as in rodent β-cells [45–47] impact on the secretory process.…”

“…Closer timing of postnatal β-cell maturation and elucidation of its mechanisms will require studies of islets from infants between birth and the age of 1 year, particularly around weaning [45]. Ideally, functional and genetic approaches should be combined to determine whether increased expression or silencing of the same genes as in rodent β-cells [45–47] impact on the secretory process. The endeavor will be challenging owing to the rarity of infant donors, but should prove valuable for the numerous laboratories currently attempting to derive well-functioning β-cells from human pluripotent stem cells.…”

MiRNAs in β-Cell Development, Identity, and Disease

“…Further supporting a role for miRNAs in mediating the effects of nutrients on β-cell differentiation and function, Regazzi et al have recently demonstrated that the expression of several miRNAs such as miR-29b, miR-17 and miR-25, changes during the post-natal β-cell maturation that occurs at weaning (Jacovetti et al, 2015). Nutrient changes associated with weaning have been demonstrated to trigger complete β-cell maturation, at least in mice, required for adequate β-cell secretion and compensatory proliferation (Stolovich-Rain et al, 2015). …”