A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion
Name
nihms-1590274.pdf
Description
Accepted version
Size
2.78 MB
Format
Adobe PDF
Checksum (MD5)
66d3dafadfe304fa9bb29b239ef8bfee
Author(s)
Helman, Aharon
Cangelosi, Andrew L
Davis, Jeffrey C
Pham, Quan
Rothman, Arielle
Faust, Aubrey L
Straubhaar, Juerg R
Sabatini, David M
Melton, Douglas A
Date Issued
2020
Journal
Cell Metabolism
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CMET.2020.04.004
