mTORC1-to-AMPK switching underlies β cell metabolic plasticity during maturation and diabetes
Rami Jaafar, … , Suneil K. Koliwad, Anil Bhushan
Rami Jaafar, … , Suneil K. Koliwad, Anil Bhushan
Published October 1, 2019; First published July 2, 2019
Citation Information: J Clin Invest. 2019;129(10):4124-4137. https://doi.org/10.1172/JCI127021.
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Categories: Research Article Endocrinology

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

Abstract

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.

Authors

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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Figure 2

Weaning from maternal milk induces the switch from mTORC1 to AMPK signaling in β cells.

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Weaning from maternal milk induces the switch from mTORC1 to AMPK signal...
(A and B) Representative immunoblots showing p-AMPK, p-rpS6, total AMPK, total rpS6, and β-tubulin in (A) adult human islets and (B) adult mouse islets after treatment with 1 mM AICAR or 40 μM everolimus for the indicated time (n = 3 for both human and mouse islets except only for the 3-hour AICAR treatment condition, where n = 2). (C) Experimental paradigm for the milk fat–supplemented diet (MFD), and immunofluorescence (IF) staining for insulin (green) and p-rpS6 (red) in representative pancreatic sections from P40 mice otherwise fed either standard chow (control) or the MFD. Nuclei were counterstained with DAPI (blue). Original magnification, ×64. (D) Experimental paradigm for the MFD and associated representative Western blots (WB), showing p-AMPK, p-rpS6, total S6, and total AMPK in control and MFD mice. β-Tubulin was used as loading control. Quantification of p-AMPK/AMPK and AMPK/β-tubulin is shown below. **P = 0.0062 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). (E) Intraperitoneal glucose tolerance test in control and MFD mice (n = 7). *P < 0.05 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). (F) Percentage of Ki67+ and insulin+ cells in control and MFD islets (n = 3–5). ***P = 0.0002 (2-tailed unpaired t test).