331-LB: A Switch in Nutrient Sensing Controls Functional Maturation of Pancreatic Beta Cells

Abstract

A drastic transition at birth, from constant maternal nutrient supply in-utero to intermittent postnatal feeding, requires functional changes in the metabolic system. Considering their central role in controlling metabolic homeostasis, little is known about how beta-cells adjust to the new nutritional challenge. Our experiments show that after birth beta-cells undergo a functional shift from amino acids- to glucose-stimulated insulin secretion. Moreover, a change in mTORC1 activity, from dependence on amino acids in the amino acid-rich environment in-utero to a postnatal dependence on glucose, corresponds with the initiation of glucose-responsive insulin secretion. Disrupting nutrient sensitivity of mTORC1 in mature beta-cells, via deletion of leucine-responsive inhibitors Sestrin1 and Sestrin2, reverts beta-cells to an immature state. Finally, manipulating mTORC1 nutrient sensitivity in stem-cell-derived beta-cells in-vitro shifts them from constitutive to glucose-dependent insulin secretion. These results reveal a post-transcriptional mechanism where nutritional environment and mTORC1 signaling regulate glucose responsiveness, thereby promoting beta-cell maturation. Disclosure A. Helman: None.