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

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

来源：Cell Metabolism, 2012, 16(4): 449-461.

DOI：10.1016/j.cmet.2012.09.001

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-1 beta 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.

• 出版日期2012-10