کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2792780 | 1155085 | 2012 | 13 صفحه PDF | دانلود رایگان |
SummaryReactive 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.
Graphical AbstractFigure optionsDownload high-quality image (112 K)Download as PowerPoint slideHighlights
► IL-1 induces β cell iron uptake via DMT1, ROS formation, and apoptosis
► DMT1 deletion or iron chelation prevents β cell ROS formation and apoptosis
► Glucose-stimulated insulin secretion is decreased in DMT1 null islets
► DMT1 knockout improves β cell function in models of type 1 and type 2 diabetes
Journal: - Volume 16, Issue 4, 3 October 2012, Pages 449–461