title: Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic β cell fate in response to cytokines.
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-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.
authors.affiliation: Center for Medical Research Methodology, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Jakob Bondo
authors.initials: JB
authors.lastname: Hansen
authors.forename: Morten Fog
authors.initials: MF
authors.lastname: Tonnesen
authors.forename: Andreas Nygaard
authors.initials: AN
authors.lastname: Madsen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hagedorn
authors.forename: Josefine
authors.initials: J
authors.lastname: Friberg
authors.forename: Lars Groth
authors.initials: LG
authors.lastname: Grunnet
authors.forename: R Scott
authors.initials: RS
authors.lastname: Heller
authors.forename: Anja Østergren
authors.initials: AØ
authors.lastname: Nielsen
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.forename: Luc
authors.initials: L
authors.lastname: Baeyens
authors.forename: Leeat
authors.initials: L
authors.lastname: Anker-Kitai
authors.forename: Klaus
authors.initials: K
authors.lastname: Qvortrup
authors.forename: Luc
authors.initials: L
authors.lastname: Bouwens
authors.forename: Shimon
authors.initials: S
authors.lastname: Efrat
authors.forename: Mogens
authors.initials: M
authors.lastname: Aalund
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
authors.forename: Allan E
authors.initials: AE
authors.lastname: Karlsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D059305:Diet, High-Fat; D018149:Glucose Intolerance; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D018398:Homeodomain Proteins; D053583:Interleukin-1beta; D007501:Iron; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D000099236:Solute Carrier Family 11, Member 2; C084010:pancreatic and duodenal homeobox 1 protein