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

Jakob Hansen, Morten Tonnesen, Andreas Madsen, Peter Hagedorn, Josefine Friberg, Lars Grunnet, Rs Heller, Anja Nielsen, Joachim Storling, Luc Baeyens, Leeat Anker-Kitai, Klaus Qvortrup, Luc Bouwens, Shimon Efrat, Mogens Aalund, Nancy Andrews, Nils Billestrup, Allan Karlsen, Birgitte Holst, Flemming PociotThomas Mandrup-Poulsen

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

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-1b induces divalent metal transporter 1 (DMT1) expression correlating with increased beta 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, beta cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications.
Original languageEnglish
Pages (from-to)449-461
Number of pages13
JournalCell Metabolism
Volume16
Issue number4
DOIs
Publication statusPublished - 2012

Keywords

  • Animals
  • Apoptosis
  • Cation Transport Proteins
  • Diabetes Mellitus, Experimental
  • Diet, High-Fat
  • Glucose Intolerance
  • Homeodomain Proteins
  • Insulin-Secreting Cells
  • Interleukin-1beta
  • Iron
  • Mice
  • Mice, Knockout
  • Models, Biological
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Trans-Activators
  • Journal Article
  • Research Support, Non-U.S. Gov't

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