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Glucose-dependent partitioning of arginine to the urea cycle protects beta cells from inflammation

Nature Metabolism: May 2020

Glucose/sugar is a pivotal nutrient with beneficial and damaging effects in the context of diabetes. In this paper, we investigated how the molecular breakdown of glucose influences the human pancreatic beta cell’s response to inflammation. Using metabolomic, biochemical and functional analyses, we found that glucose metabolism augments anaplerotic input into the urea cycle and protects beta cells from inflammatory cytotoxicity. These studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways driven by the TCA cycle as a protective mechanism in diabetes. This article was featured in A BAD portion of glucose can be good for inflamed beta-cells

Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets

Pancreatic beta cell function to secrete insulin is impaired in diabetes due to a number of stress paradigms. In this paper, we investigate the metabolic mechanisms that underlie the response to inflammation and oxidative stress and identified a glucose-fueled route to de novo glutathione synthesis in via the TCA cycle enzyme, pyruvate carboxylase (PC). PC is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response in beta cells.

Additional Publications

Mills EL, Harmon C, Jedrychowski MP, Xiao H, Garrity R, Tran NV, Bradshaw GA, Fu A, Szpyt J, Reddy A, Prendeville H, Danial NN, Gygi SP, Lynch L, Chouchani ET. UCP1 governs liver extracellular succinate and inflammatory pathogenesis Nat Metab. 2021 May;3(5):604-617. doi: 10.1038/s42255-021-00389-5. Epub 2021 May 17. Review. PubMed PMID: 34002097; PubMed Central PMCID: PMC8207988.

Wang CH, Lundh M, Fu A, Kriszt R, Huang TL, Lynes MD, Leiria LO, Shamsi F, Darcy J, Greenwood BP, Narain NR, Tolstikov V, Smith KL, Emanuelli B, Chang YT, Hagen S, Danial NN, Kiebish MA, Tseng YH. CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice Sci Transl Med. 2020 Aug 26;12(558). doi: 10.1126/scitranslmed.aaz8664. PubMed PMID: 32848096; PubMed Central PMCID: PMC7704293.

Bird GH, Fu A, Escudero S, Godes M, Opoku-Nsiah K, Wales TE, Cameron MD, Engen JR, Danial NN, Walensky LD. Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor ACS Chem Biol. 2020 Jun 19;15(6):1340-1348. doi: 10.1021/acschembio.0c00308. Epub 2020 May 27. PubMed PMID: 32348108; PubMed Central PMCID: PMC7366314.

Fu A, Danial NN. Grasping for aspartate in tumour metabolism Nat Cell Biol. 2018 Jul;20(7):738-739. doi: 10.1038/s41556-018-0137-9. PubMed PMID: 29941932.

Robitaille K, Rourke JL, McBane JE, Fu A, Baird S, Du Q, Kin T, Shapiro AM, Screaton RA. High-throughput Functional Genomics Identifies Regulators of Primary Human Beta Cell Proliferation J Biol Chem. 2016 Feb 26;291(9):4614-25. doi: 10.1074/jbc.M115.683912. Epub 2016 Jan 6. PubMed PMID: 26740620; PubMed Central PMCID: PMC4813485.

Mailloux R, Fu A, Florian M, Petrov I, Chen Q, Coughlan MC, Laziyan M, Yan J, Caldwell D, Patry D, Lalande M, Wang GS, Willmore W, Jin X. A Northern contaminant mixture impairs pancreas function in obese and lean JCR rats and inhibits insulin secretion in MIN6 cells Toxicology. 2015 Aug 6;334:81-93. doi: 10.1016/j.tox.2015.06.001. Epub 2015 Jun 9. PubMed PMID: 26066519.

Fu A, Robitaille K, Faubert B, Reeks C, Dai XQ, Hardy AB, Sankar KS, Ogrel S, Al-Dirbashi OY, Rocheleau JV, Wheeler MB, MacDonald PE, Jones R, Screaton RA. LKB1 couples glucose metabolism to insulin secretion in mice Diabetologia. 2015 Jul;58(7):1513-22. doi: 10.1007/s00125-015-3579-7. Epub 2015 Apr 16. PubMed PMID: 25874445.

Ljubicic S, Polak K, Fu A, Wiwczar J, Szlyk B, Chang Y, Alvarez-Perez JC, Bird GH, Walensky LD, Garcia-Ocaña A, Danial NN. Phospho-BAD BH3 mimicry protects β cells and restores functional β cell mass in diabetes Cell Rep. 2015 Feb 3;10(4):497-504. doi: 10.1016/j.celrep.2014.12.056. Epub 2015 Jan 29. PubMed PMID: 25640178; PubMed Central PMCID: PMC4991214.

Sakamaki J, Fu A, Reeks C, Baird S, Depatie C, Al Azzabi M, Bardeesy N, Gingras AC, Yee SP, Screaton RA. Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation Nat Cell Biol. 2014 Mar;16(3):234-44. doi: 10.1038/ncb2919. PubMed PMID: 24561619; PubMed Central PMCID: PMC4107453.

Eberhard CE, Fu A, Reeks C, Screaton RA. CRTC2 is required for β-cell function and proliferation Endocrinology. 2013 Jul;154(7):2308-17. doi: 10.1210/en.2012-2088. Epub 2013 May 15. PubMed PMID: 23677932.

Fu A, Eberhard CE, Screaton RA. Role of AMPK in pancreatic beta cell function Mol Cell Endocrinol. 2013 Feb 25;366(2):127-34. doi: 10.1016/j.mce.2012.06.020. Epub 2012 Jul 3. Review. PubMed PMID: 22766107.

Mailloux RJ, Fu A, Robson-Doucette C, Allister EM, Wheeler MB, Screaton R, Harper ME. Glutathionylation state of uncoupling protein-2 and the control of glucose-stimulated insulin secretion J Biol Chem. 2012 Nov 16;287(47):39673-85. doi: 10.1074/jbc.M112.393538. Epub 2012 Oct 3. PubMed PMID: 23035124; PubMed Central PMCID: PMC3501076.

Phu do T, Wallbach M, Depatie C, Fu A, Screaton RA, Oetjen E. Regulation of the CREB coactivator TORC by the dual leucine zipper kinase at different levels Cell Signal. 2011 Feb;23(2):344-53. doi: 10.1016/j.cellsig.2010.10.001. Epub 2010 Oct 19. PubMed PMID: 20940047.

Milman P, Fu A, Screaton RA, Woulfe JM. Depletion of intranuclear rodlets in mouse models of diabetes Endocr Pathol. 2010 Dec;21(4):230-5. doi: 10.1007/s12022-010-9136-5. PubMed PMID: 20922502.

Fu A, Ng AC, Depatie C, Wijesekara N, He Y, Wang GS, Bardeesy N, Scott FW, Touyz RM, Wheeler MB, Screaton RA. Loss of Lkb1 in adult beta cells increases beta cell mass and enhances glucose tolerance in mice Cell Metab. 2009 Oct;10(4):285-95. doi: 10.1016/j.cmet.2009.08.008. PubMed PMID: 19808021.

Fu A, Screaton RA. Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family Cell Cycle. 2008 Dec 15;7(24):3823-8. doi: 10.4161/cc.7.24.7241. Epub 2008 Dec 21. PubMed PMID: 19098422.

Jansson D, Ng AC, Fu A, Depatie C, Al Azzabi M, Screaton RA. Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2 Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10161-6. doi: 10.1073/pnas.0800796105. Epub 2008 Jul 14. PubMed PMID: 18626018; PubMed Central PMCID: PMC2481316.

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