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

Jakob Bondo Hansen, Morten Fog Tonnesen, Andreas Nygaard Madsen, Peter Hagedorn, Josefine Friberg, Lars Groth Grunnet, R Scott Heller, Anja Østergren Nielsen, Joachim Størling, 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

87 Citationer (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-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.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind16
Udgave nummer4
Sider (fra-til)449-61
Antal sider13
ISSN1550-4131
DOI
StatusUdgivet - 3 okt. 2012

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