mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume130
DOIs
StatePublished - Jul 2 2019

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Adenosine Monophosphate
Protein Kinases
Insulin
Metabolic Engineering
Phenotype
Glucose
Food
Metabolome
mechanistic target of rapamycin complex 1
Cell Plasticity
Insulin-Secreting Cells
Organelle Biogenesis
Sirolimus
Weaning
Type 2 Diabetes Mellitus

Keywords

  • Diabetes
  • Endocrinology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes. / Jaafar, Rami; Tran, Stella; Shah, Ajit; Sun, Gao; Valdearcos, Martin; Marchetti, Piero; Masini, Matilde; Swisa, Avital; Giacometti, Simone; Bernal-Mizrachi, Ernesto; Matveyenko, Aleksey V; Hebrok, Matthias; Dor, Yuval; Rutter, Guy A.; Koliwad, Suneil K.; Bhushan, Anil.

In: The Journal of clinical investigation, Vol. 130, 02.07.2019.

Research output: Contribution to journalArticle

Jaafar, R, Tran, S, Shah, A, Sun, G, Valdearcos, M, Marchetti, P, Masini, M, Swisa, A, Giacometti, S, Bernal-Mizrachi, E, Matveyenko, AV, Hebrok, M, Dor, Y, Rutter, GA, Koliwad, SK & Bhushan, A 2019, 'mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes', The Journal of clinical investigation, vol. 130. https://doi.org/10.1172/JCI127021
Jaafar, Rami ; Tran, Stella ; Shah, Ajit ; Sun, Gao ; Valdearcos, Martin ; Marchetti, Piero ; Masini, Matilde ; Swisa, Avital ; Giacometti, Simone ; Bernal-Mizrachi, Ernesto ; Matveyenko, Aleksey V ; Hebrok, Matthias ; Dor, Yuval ; Rutter, Guy A. ; Koliwad, Suneil K. ; Bhushan, Anil. / mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes. In: The Journal of clinical investigation. 2019 ; Vol. 130.
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