TY - JOUR

T1 - Divalent Metal Transporter 1 Regulates Iron-Mediated ROS and Pancreatic β Cell Fate in Response to Cytokines

A1 - Hansen,Jakob Bondo

A1 - Tonnesen,Morten Fog

A1 - Madsen,Andreas Nygaard

A1 - Hagedorn,Peter H.

A1 - Friberg,Josefine

A1 - Grunnet,Lars Groth

A1 - Heller,R. Scott

A1 - Nielsen,Anja Østergren

A1 - Størling,Joachim

A1 - Baeyens,Luc

A1 - Anker-Kitai,Leeat

A1 - Qvortrup,Klaus

A1 - Bouwens,Luc

A1 - Efrat,Shimon

A1 - Aalund,Mogens

A1 - Andrews,Nancy C.

A1 - Billestrup,Nils

A1 - Karlsen,Allan E.

A1 - Holst,Birgitte

A1 - Pociot,Flemming

A1 - Mandrup-Poulsen,Thomas

AU - Hansen,Jakob Bondo

AU - Tonnesen,Morten Fog

AU - Madsen,Andreas Nygaard

AU - Hagedorn,Peter H.

AU - Friberg,Josefine

AU - Grunnet,Lars Groth

AU - Heller,R. Scott

AU - Nielsen,Anja Østergren

AU - Størling,Joachim

AU - Baeyens,Luc

AU - Anker-Kitai,Leeat

AU - Qvortrup,Klaus

AU - Bouwens,Luc

AU - Efrat,Shimon

AU - Aalund,Mogens

AU - Andrews,Nancy C.

AU - Billestrup,Nils

AU - Karlsen,Allan E.

AU - Holst,Birgitte

AU - Pociot,Flemming

AU - Mandrup-Poulsen,Thomas

PB - Cell Press

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1016/j.cmet.2012.09.001

DO - 10.1016/j.cmet.2012.09.001

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 4

VL - 16

SP - 449

EP - 461

ER -