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

Nature Metabolism
Accalia FuNika N Danial

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.

References

Jul 19, 2003·Science·Joseph GrimsbyJoseph F Grippo
Oct 15, 2003·Rapid Communications in Mass Spectrometry : RCM·Bin MaGilles Lajoie
Jul 28, 2004·Diabetes·Antonio L Cuesta-MuñozMarkku Laakso
Feb 15, 2005·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Zandong YangJerry L Nadler
Oct 13, 2005·Molecular & Cellular Proteomics : MCP·Jeffrey C SilvaScott J Geromanos
Nov 10, 2005·Annals of Neurology·Angels García-CazorlaJean-Marie Saudubray
Dec 3, 2005·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Patrick E MacDonaldPatrik Rorsman
Mar 1, 2006·Bioorganic & Medicinal Chemistry Letters·Darren McKerrecherRolf P Walker
Jan 29, 2008·Nature Medicine·Nika N DanialStanley J Korsmeyer
Aug 30, 2008·American Journal of Physiology. Endocrinology and Metabolism·Mette V JensenChristopher B Newgard
Apr 9, 2009·Nature Reviews. Endocrinology·Décio L EizirikFernanda Ortis
Apr 18, 2009·Nature Reviews. Drug Discovery·Franz M Matschinsky
Jul 29, 2009·Molecular Genetics and Metabolism·C FiciciogluV E Shih
Mar 13, 2010·Diabetologia·S JitrapakdeeM J MacDonald
Nov 18, 2010·Proteomics·Manor AskenaziMichal Linial
Apr 29, 2011·Diabetes·Mark A AtkinsonChristopher J Rhodes
Jan 5, 2012·Methods in Molecular Biology·Douglas KerrGhunwa Nakouzi
Aug 14, 2012·Molecular and Cellular Endocrinology·Mohammed BensellamJean-Christophe Jonas
Sep 7, 2012·Diabetes, Obesity & Metabolism·D DadonB Glaser
May 30, 2013·Genome Research·Alexandra C NicaEmmanouil T Dermitzakis
Jun 12, 2013·Cell Metabolism·Diane Mathis
Jun 12, 2013·Cell Metabolism·Marc Y DonathMarianne Böni-Schnetzler
Jun 25, 2013·Cell Metabolism·Marc PrentkiS R Murthy Madiraju
Jul 19, 2013·Nature Communications·Feng ZhouJarrod A Marto
Dec 7, 2013·Cancer & Metabolism·Shawn McGuirkJulie St-Pierre
Dec 10, 2013·Nature Structural & Molecular Biology·Benjamin SzlykNika N Danial
Feb 11, 2014·Cell Metabolism·Alfredo Giménez-CassinaNika N Danial
Jun 25, 2014·Metabolites·Simon-Pierre GravelJulie St-Pierre
Nov 2, 2014·Molecular Systems Biology·Christopher S HughesJeroen Krijgsveld
Mar 10, 2015·Trends in Endocrinology and Metabolism : TEM·Alfredo Giménez-Cassina, Nika N Danial
Aug 25, 2015·Cardiovascular Diabetology·Valeria De NigrisAntonio Ceriello
Jan 8, 2016·The Journal of Biological Chemistry·Karine RobitailleRobert A Screaton
Aug 16, 2016·The Journal of Clinical Investigation·Laetitia KoppeVincent Poitout
Jul 26, 2017·Scientific Reports·Thierry M NordmannMarc Y Donath
Jan 13, 2018·Cell·Yun Sok LeeJerrold M Olefsky
Jan 25, 2018·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Udom Lao-OnSarawut Jitrapakdee

❮ Previous
Next ❯

Citations

Jul 23, 2020·Nature Metabolism·Christian Frezza
May 13, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jeng Yie ChanD Ross Laybutt
Jun 16, 2021·Cell Chemical Biology·Anthony C VarcaSara J Buhrlage
Aug 21, 2021·Molecular & Cellular Proteomics : MCP·Florian MeierMatthias Mann

❮ Previous
Next ❯

Datasets Mentioned

BETA
EGAS00001000442

Methods Mentioned

BETA
fluorescence-activated cell sorting
RNA-seq
flow cytometry
pull-down
Protein assay
electrophoresis
isothermal titration calorimetry
FACS
PCR
fluorescence microscopy

Software Mentioned

Pep2gene tool
NanoAnalyze
multiplierz scripts
PEAKS Studio
Fiji
FACSDiva
MetaMorph
ZEN
Metaboanalyst
GraphPad

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.