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 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 Pociot, Thomas Mandrup-Poulsen, Jakob Bondo Hansen, Morten Fog Tonnesen, Andreas Nygaard Madsen, Peter H 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 Pociot, Thomas Mandrup-Poulsen
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Source: PubMed