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 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 5

T2D induces increased β cell mTORC1 activity and a reversion of pancreatic islets to an immature phenotype.

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T2D induces increased β cell mTORC1 activity and a reversion of pancreat...
(A) Heatmap, showing the transcriptional profile of genes in the AMPK/mTORC1 pathway and those involved in β cell maturation in islets from db/db and control mice (P < 0.05). (B) Immunostaining for insulin (green) and p-rpS6 (red) in representative pancreatic sections from 4-week-old db/db and control mice. Nuclei were counterstained with DAPI (blue). Scale bars: 50 μm. (C) Insulin secretion (% of insulin content) in a perifusion assay on islets from 4-week-old db/db or control mice in the presence of 2.8 mM and 16 mM glucose (n = 4). *P < 0.05, ****P < 0.0001 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). (D) Oxygen consumption rates for db/db and control islets presented relative to baseline (n = 9–10 per group). Rot, rotenone; AA, antimycin A. *P < 0.05 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). (E) GSIS by control and db/db islets treated with 40 μM everolimus or 1 mM AICAR (n = 3) *P < 0.05 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). (F) Immunostaining for insulin (green) and p-rpS6 (red) in representative pancreatic sections from human donors with or without T2D. Nuclei were counterstained with DAPI (blue). Scale bars: 50 μm. (G) Representative immunoblots for p-AMPK, p-rpS6, total AMPK, and total rpS6 in healthy donors (n = 4) or those with T2D (n = 3). GAPDH was used as loading control. Quantifications of p-AMPK and p-rpS6 normalized to total AMPK and rpS6, respectively, and total AMPK or rpS6 normalized to GAPDH are shown below. *P < 0.05, **P < 0.001 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method).