A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system of the neonate. Despite their central role in metabolic homeostasis, little is known about how pancreatic β cells adjust to the new nutritional challenge. Here, we find that after birth β cell function shifts from amino acid- to glucose-stimulated insulin secretion in correlation with the change in the nutritional environment. This adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway, which leads to intermittent mTORC1 activity. Disrupting nutrient sensitivity of mTORC1 in mature β cells reverts insulin secretion to a functionally immature state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived β cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrients regulate β cell function, thereby enabling a metabolic adaptation for the newborn. [Display omitted] •Nutritional changes after birth alter β cell function•β cells acquire glucose response via changes in mTORC1 nutrient sensitivity•Glucose response is independent of changes in canonical β cell markers expression•Nutrient-regulated mTORC1 activity controls stem cell-derived β cell function At birth, metabolic adaptations prepare the newborn for its new nutritional environment. Helman et al. demonstrate a role of nutrient sensing by mTORC1 in adjusting insulin secretion in neonatal β cells. Exploiting this adaptative property of β cells results in improved glucose-responsive insulin secretion in human stem cell-derived β cells.