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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.