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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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 1

β Cells switch from mTORC1 to AMPK-dependent signaling during postnatal maturation.

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β Cells switch from mTORC1 to AMPK-dependent signaling during postnatal ...
(A) Experimental paradigm for RNAseq on sorted pancreatic β cells in mice at P6 and P45. (B) Heatmap, showing the expression profile of genes related to mTORC1/AMPK signaling in β cells at P6 and P45. In this comparison, deepening colors represent progressively lower (blue) or higher (red) mRNA levels for any given gene (P < 0.05). (C) Representative pancreatic sections from WT mice at P6, P18, and 2 months of age stained for insulin (green) and p-rpS6 (red). Nuclei were counterstained with DAPI (blue). Scale bars: 50 μm. (D) Quantification (FACS) of the number of cells positive for both insulin and p-rpS6 in P7 and 2-month-old WT mice. Data shown are representative of 3 separate experiments. *P = 0.0178 (2-tailed unpaired t test). (E) Immunoblot representing an experiment repeated 3 times (n = 3 for each), showing total rpS6, p-rpS6 (Ser240/244), p-AMPK (Thr172), and total AMPK in neonatal and adult islets treated with either 2.8 mM or 16.7 mM glucose. β-Tubulin was used as loading control. Corresponding p-AMPK and total AMPK normalized to β-tubulin quantifications are adjacent. Five to 7 P6 mice and 1 adult mouse were used for each replicate. *P < 0.01 (unpaired t test corrected for multiple comparison using the Holm-Sidak method). (F) Representative pancreatic sections from WT mice at P6 and 2 months of age stained for Pdx1 (green) and p-AMPK (red), with DAPI (blue) counterstaining the nuclei. Scale bars: 50 μm.