BibTex format
@article{Jaafar:2019:10.1172/JCI127021,
author = {Jaafar, R and Tran, S and Shah, A and Sun, G and Valdearcos, M and Marchetti, P and Masini, M and Swisa, A and Giacometti, S and Bernal-Mizrachi, E and Matveyenko, A and Hebrok, M and Dor, Y and Rutter, GA and Koliwad, SK and Bhushan, A},
doi = {10.1172/JCI127021},
journal = {Journal of Clinical Investigation},
pages = {4124--4137},
title = {mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.},
url = {http://dx.doi.org/10.1172/JCI127021},
volume = {130},
year = {2019}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.
AU - Jaafar,R
AU - Tran,S
AU - Shah,A
AU - Sun,G
AU - Valdearcos,M
AU - Marchetti,P
AU - Masini,M
AU - Swisa,A
AU - Giacometti,S
AU - Bernal-Mizrachi,E
AU - Matveyenko,A
AU - Hebrok,M
AU - Dor,Y
AU - Rutter,GA
AU - Koliwad,SK
AU - Bhushan,A
DO - 10.1172/JCI127021
EP - 4137
PY - 2019///
SN - 0021-9738
SP - 4124
TI - mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.
T2 - Journal of Clinical Investigation
UR - http://dx.doi.org/10.1172/JCI127021
UR - https://www.ncbi.nlm.nih.gov/pubmed/31265435
UR - https://www.jci.org/articles/view/127021
UR - http://hdl.handle.net/10044/1/74605
VL - 130
ER -