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Cell Metab ; 16(4): 449-61, 2012 Oct 03.
Article in English | MEDLINE | ID: mdl-23000401

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-1ß induces divalent metal transporter 1 (DMT1) expression correlating with increased ß 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, ß cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications.


Subject(s)
Apoptosis/drug effects , Cation Transport Proteins/metabolism , Insulin-Secreting Cells/metabolism , Interleukin-1beta/pharmacology , Iron/metabolism , Reactive Oxygen Species/metabolism , Animals , Cation Transport Proteins/antagonists & inhibitors , Cation Transport Proteins/genetics , Diabetes Mellitus, Experimental , Diet, High-Fat , Glucose Intolerance , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Insulin-Secreting Cells/cytology , Mice , Mice, Knockout , Models, Biological , RNA Interference , RNA, Small Interfering/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism
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