par Hansen, Jakob Bondo;Baeyens, Luc ;Anker-Kitai, Leeat;Qvortrup, Klaus;Bouwens, Luc;Efrat, Shimon;Aalund, Mogens;Andrews, Nancy Catherine;Billestrup, Nils;Karlsen, Allan Ertman;Holst, Birgitte;Tonnesen, Morten Fog;Pociot, Flemming Michael;Mandrup-Poulsen, Thomas;Madsen, Andreas Nygaard;Hagedorn, Peter;Friberg, Josefine;Grunnet, Lars Groth;Heller, Richard Scott;Nielsen, Anja Ostergren;Størling, Joachim
Référence Cell Metabolism, 16, 4, page (449-461)
Publication Publié, 2012-10
Référence Cell Metabolism, 16, 4, page (449-461)
Publication Publié, 2012-10
Article révisé par les pairs
Résumé : | 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. © 2012 Elsevier Inc. |