Divalent metal transporter 1 regulates iron-mediated Ros and pancreatic β cell fate in response to cytokines

Jakob Bondo Hansen, Morten Fog Tonnesen, Andreas Nygaard Madsen, Peter H. Hagedorn, Josefine Friberg, Lars Groth Grunnet, R. Scott Heller, Anja Ostergren Nielsen, Joachim Storling, Luc Baeyens, Leeat Anker-Kitai, Klaus Qvortrup, Luc Bouwens, Shimon Efrat, Mogens Aalund, Nancy C. Andrews, Nils Billestrup, Allan E. Karlsen, Birgitte Holst, Flemming PociotThomas Mandrup-Poulsen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


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
Pages (from-to)449-461
Number of pages13
JournalCell Metabolism
Issue number4
StatePublished - 3 Oct 2012


FundersFunder number
Danish Ministry of Science, Technology and Innovation
JDRF Center for Beta Cell TherapyLSHB-CT-2005-512145
Novo Nordisk


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