Nutrient integration by mTOR signaling regulates neonatal beta cell function

A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires functional changes in the metabolic system. Despite their central role in metabolic homeostasis, little is known about how pancreatic beta cells adjust to the new nutritional program. Here, we describe a role of nutrient-sensing in controlling beta cell maturation. Our experiments show that after birth beta-cells undergo a functional shift from amino acid- to glucose-stimulated insulin secretion that correlates with the nutritional environment of the animal. This metabolic adaptation is mediated by a switch in nutrient sensitivity of the mTORC1 pathway, which leads to intermittent mTORC1 signaling activity after birth. Disrupting nutrient sensitivity of mTORC1 in mature beta cells, via deletion of upstream nutrient-responsive inhibitors, affects insulin secretion and reverts them to an immature functional state. Finally, we show that manipulating the nutrient sensitivity of mTORC1 in stem cell-derived beta cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrient sensing and mTORC1 signaling regulate mature beta cell function, thereby enabling a metabolic adaptation for the newborn.