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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

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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 4

AMPK activation triggers a switch to oxidative metabolism in mature islets.

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AMPK activation triggers a switch to oxidative metabolism in mature isle...
(A) Heatmap, profiling mitochondrial genes and genes related to ox-phos metabolism in P6 and P45 β cells (P < 0.05). (B) qPCR, showing the ratio of mtDNA to nuclear DNA in P6 and adult islets (n = 4–5). ****P < 0.0001 (2-tailed unpaired t test). (C) Relative Ppargc1a and Ppargc1b mRNA levels in P6 and adult islets (n = 4). *P = 0.016, **P = 0.0029 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). (D) Oxygen consumption rates for cultured neonatal and adult islets (Seahorse XF24), with data presented relative to baseline (n = 7–8). *P < 0.01, **P < 0.001, ***P < 0.0001 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method). Oligo, oligomycin; Rot, rotenone; AA, antimycin A. (E) Heatmap, showing the transcriptional profile of mitochondrial genes those related to ox-phos metabolism in AMPKdKO control islets (P < 0.05). (F and G) Morphometric analysis of mitochondria in AMPKdKO and control β cells, showing (F) the number of mitochondria per 70 μm2 (n = 32–36), and (G) the volume density (mL%). n = 29–33 β cells per group. ****P < 0.0001 (2-tailed unpaired t test). (H) qPCR, showing the ratio of mtDNA to nuclear DNA in WT adult islets treated with 10 μM compound C (CC) (n = 3). ***P = 0.0003 (2-tailed unpaired t test). (I) Ppargc1a and Ppargc1b mRNA levels in the islets of control mice vs. those receiving milk fat throughout their development into adulthood (n = 3). MFD, milk fat–supplemented diet. **P = 0.0013 (unpaired t test corrected for multiple comparisons using the Holm-Sidak method).
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