Pancreatic 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.
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
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