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

Authors
  • Helman, Aharon1
  • Cangelosi, Andrew L2
  • Davis, Jeffrey C3
  • Pham, Quan3
  • Rothman, Arielle3
  • Faust, Aubrey L3
  • Straubhaar, Juerg R3
  • Sabatini, David M4
  • Melton, Douglas A5
  • 1 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: [email protected]
  • 2 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 4 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected]
  • 5 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell metabolism
Publication Date
May 05, 2020
Volume
31
Issue
5
Identifiers
DOI: 10.1016/j.cmet.2020.04.004
PMID: 32375022
Source
Medline
Keywords
Language
English
License
Unknown

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. Published by Elsevier Inc.

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