MTORC1-to-AMPK switching underlies βcell metabolic plasticity during maturation and diabetes

Rami Jaafar, Stella Tran, Ajit N. Shah, Gao Sun, Martin Valdearcos, Piero Marchetti, Matilde Masini, Avital Swisa, Simone Giacometti, Ernesto Bernal-Mizrachi, Aleksey Matveyenko, Matthias Hebrok, Yuval Dor, Guy A. Rutter, Suneil K. Koliwad, Anil Bhushan

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Pancreatic βcells 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 βcell function, we found that the control of cellular signaling in βcells 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 βcell phenotype. While forcing constitutive mTORC1 signaling in adult βcells 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 βcell 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 βcell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate βcell metabolism may thus offer new targets to improve β cell function in diabetes.

Original languageEnglish (US)
Pages (from-to)4124-4137
Number of pages14
JournalJournal of Clinical Investigation
Volume129
Issue number10
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Medicine(all)

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