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Publication

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

Journal Contribution - Journal Article

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-1b 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.
Journal: Cell Metab
ISSN: 1550-4131
Issue: 4
Volume: 16
Pages: 449-461
Publication year:2012
Keywords:Animals, Apoptosis, Cation Transport Proteins, Diabetes Mellitus, Experimental, Diet, High-Fat, Glucose Intolerance, Homeodomain Proteins, Insulin-Secreting Cells, Interleukin-1beta, Iron, Mice, Mice, Knockout, Models, Biological, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Trans-Activators, Journal Article, Research Support, Non-U.S. Gov't