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

Without internal affiliation

  • Author: Hansen, Jakob Bondo

    University of Copenhagen, Denmark

  • Author: Tonnesen, Morten Fog

    Novo Nordisk A/S, Denmark

  • Author: Madsen, Andreas Nygaard

    University of Copenhagen, Denmark

  • Author: Hagedorn, Peter H.

    Technical University of Denmark

  • Author: Friberg, Josefine

    University of Copenhagen, Denmark

  • Author: Grunnet, Lars Groth

    Novo Nordisk A/S, Denmark

  • Author: Heller, R. Scott

    Novo Nordisk A/S

  • Author: Nielsen, Anja Østergren

    Novo Nordisk A/S, Denmark

  • Author: Størling, Joachim

    Copenhagen University Hospital, Denmark

  • Author: Baeyens, Luc

    Vrije Universiteit Brussel

  • 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

    University of Copenhagen, Denmark

  • Author: Bouwens, Luc

    Vrije Universiteit Brussel

  • 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.

    Duke University

  • Author: Billestrup, Nils

    University of Copenhagen, Denmark

  • Author: Karlsen, Allan E.

    Novo Nordisk A/S, Denmark

  • Author: Holst, Birgitte

    University of Copenhagen, Denmark

  • Author: Pociot, Flemming

    Lund University, Sweden

  • Author: Mandrup-Poulsen, Thomas

    Karolinska Institute, 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
Issue4
Pages449-461
ISSN1550-4131
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 13
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