@article{772e400387a842129760c7baeebfab16,
title = "Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation",
abstract = "Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomic, biochemical and functional analyses, we investigate the protective versus non-protective effects of glucose in the presence of pro-inflammatory cytokines. When protective, glucose metabolism augments anaplerotic input into the TCA cycle via pyruvate carboxylase (PC) activity, leading to increased aspartate levels. This metabolic mechanism supports the argininosuccinate shunt, which fuels ureagenesis from arginine and conversely diminishes arginine utilization for production of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. Activation of the PC–urea cycle axis is sufficient to suppress NO synthesis and shield cells from death in the context of inflammation and other stress paradigms. Overall, these studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways via PC-directed ureagenesis as a protective mechanism.",
author = "Accalia Fu and Alvarez-Perez, {Juan Carlos} and Daina Avizonis and Tatsuya Kin and Ficarro, {Scott B.} and Choi, {Dong Wook} and Esra Karakose and Badur, {Mehmet G.} and Lindsay Evans and Carolina Rosselot and Gaelle Bridon and Bird, {Gregory H.} and Seo, {Hyuk Soo} and Sirano Dhe-Paganon and Kamphorst, {Jurre J.} and Stewart, {Andrew F.} and {James Shapiro}, {A. M.} and Marto, {Jarrod A.} and Walensky, {Loren D.} and Jones, {Russell G.} and Adolfo Garcia-Ocana and Danial, {Nika N.}",
note = "Funding Information: We thank G. Yellen, B. Spiegelman, N. Kalaany and members of the Danial laboratory for helpful discussions and the Nikon Imaging Center at Harvard Medical School for access to imaging platforms. RNA expression data for comparing enrichment of genes in purified human β-cells compared to whole islets and non-β-cells (Extended Data Fig. 4) were generously provided by E. Dermitzakis. This work was supported by the US NIH grants R01DK078081 (N.N.D.), R01CA219850 (N.N.D. and J.A.M.), R01DK113079 (A.G.-O.), R01DK105015 and R01DK116873 (A.F.S.), P30DK020541 (Einstein-Sinai Diabetes Research Center) (A.G.-O. and A.F.S.), R35CA197583 (L.D.W.), R50CA211399 (G.H.B.), R01CA222218 (J.A.M.), Juvenile Diabetes Research Foundation Grant 2-SRA-2015-58-Q-R (N.N.D.) and Barry and Mimi Sternlicht Type 1 Diabetes Research Fund (N.N.D.). A.F. was supported by a postdoctoral fellowship from the Juvenile Diabetes Research foundation (JDRF). The Integrated Islet Distribution Program (IIDP) is supported by NIH Grant 2UC4DK098085. The Rosalind and Morris Goodman Cancer Research Centre Metabolomics Core Facility is supported by the Canada Foundation for Innovation, Dr. John R. and Clara M. Fraser Memorial Trust, the Terry Fox Foundation in partnership with the Foundation du Cancer du Sein du Quebec and McGill University. The Blais Proteomics Center is supported by the Dana-Farber Strategic Research Initiative. A.M.J.S. is a Fellow of the Royal Society of Canada, and is supported through a Canada Research Chair in Regenerative Medicine and Transplantation Surgery. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = may,
day = "1",
doi = "10.1038/s42255-020-0199-4",
language = "English",
volume = "2",
pages = "432--446",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "5",
}