Divalent Metal Transporter 1 Regulates Iron-Mediated ROS and Pancreatic β Cell Fate in Response to Cytokines

Publication: Research - peer-reviewJournal article – Annual report year: 2012

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  • Author: Hansen, Jakob Bondo, Denmark

    1Center for Medical Research Methodology, Department of Biomedical Sciences, University of Copenhagen, Denmark

  • Author: Tonnesen, Morten Fog, Denmark

    5Diabetes Biology and Hagedorn Research Institute, Novo Nordisk, Denmark

  • Author: Madsen, Andreas Nygaard, Denmark

    Rodent Metabolic Phenotyping Center, University of Copenhagen, Denmark

  • Author: Hagedorn, Peter H.

    Biosystems Department, Risø National Laboratory, Technical University of Denmark, 4000 Roskilde, Denmark

  • Author: Friberg, Josefine, Denmark

    Department of Biomedical Sciences, University of Copenhagen, Denmark

  • Author: Grunnet, Lars Groth, Denmark

    Diabetes Biology and Hagedorn Research Institute, Novo Nordisk, Denmark

  • Author: Heller, R. Scott

    Imaging Team, Novo Nordisk, 2760 Måløv, Denmark

  • Author: Nielsen, Anja Østergren, Denmark

    Diabetes Biology and Hagedorn Research Institute, Novo Nordisk, 2820 Gentofte, Denmark, Denmark

  • Author: Størling, Joachim, Denmark

    Glostrup Research Institute, Glostrup Hospital, Denmark

  • Author: Baeyens, Luc

    Diabetes Research Center, Vrije Universiteit Brussel-Free University of Brussels, 1090 Brussels, Belgium

  • Author: Anker-Kitai, Leeat

    Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel

  • Author: Qvortrup, Klaus, Denmark

    Core Facility for Integrated Microscopy, Department of Biomedical Sciences University of Copenhagen, Denmark

  • Author: Bouwens, Luc

    Diabetes Research Center, Vrije Universiteit Brussel-Free University of Brussels, 1090 Brussels, Belgium

  • Author: Efrat, Shimon

    Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel

  • Author: Aalund, Mogens

    Neurotech A/S, 2200 Copenhagen, Denmark

  • Author: Andrews, Nancy C.

    Department of Pediatrics and Pharmacology and Department of Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA

  • Author: Billestrup, Nils, Denmark

    Department of Biomedical Sciences, University of Copenhagen, Denmark

  • Author: Karlsen, Allan E., Denmark

    Diabetes Biology and Hagedorn Research Institute, Novo Nordisk, Denmark

  • Author: Holst, Birgitte, Denmark

    Rodent Metabolic Phenotyping Center, University of Copenhagen, Denmark

  • Author: Pociot, Flemming, Sweden

    Clinical Research Center, University of Lund, Sweden

  • Author: Mandrup-Poulsen, Thomas, Sweden

    Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden

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Reactive oxygen species (ROS) contribute to target-cell damage in inflammatory and iron-overload diseases. Little is known about iron transport regulation during inflammatory attack. Through a combination of in vitro and in vivo studies, we show that the proinflammatory cytokine IL-1β induces divalent metal transporter 1 (DMT1) expression correlating with increased β cell iron content and ROS production. Iron chelation and siRNA and genetic knockdown of DMT1 expression reduce cytokine-induced ROS formation and cell death. Glucose-stimulated insulin secretion in the absence of cytokines in Dmt1 knockout islets is defective, highlighting a physiological role of iron and ROS in the regulation of insulin secretion. Dmt1 knockout mice are protected against multiple low-dose streptozotocin and high-fat diet-induced glucose intolerance, models of type 1 and type 2 diabetes, respectively. Thus, β cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications.
Original languageEnglish
JournalCell Metabolism
Publication date2012
Volume16
Journal number4
Pages449-461
ISSN1550-4131
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 9
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