TY - JOUR
T1 - Divalent metal transporter 1 regulates iron-mediated Ros and pancreatic β cell fate in response to cytokines
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 Ostergren
AU - Storling, 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
N1 - Funding Information:
We would like to thank Dr. Claes Wollheim for providing the INS-1 cell lines, Drs. Doug Melton and Palle Serup for the Cre-ERT mouse line, Dr. Herbert Y. Gaisano for permission to apply his islet perifusion system, and Dr. Canonne-Hergaux for the anti-mouse DMT1 antibody. Louise Koch, Christine Petersen, Charity MK Graae, and Tine Wille are thanked for technical help with the DMT1 KO animals and in vitro assays. This work was supported by the JDRF Center for Beta Cell Therapy under the EU6FP, grant number LSHB-CT-2005-512145 (M.F.T.), a PhD fellowship from SHARE LIFE, Denmark (J.B.H.), UNIK: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk ) supported by the Danish Ministry of Science, Technology and Innovation, and Novo Nordisk.
PY - 2012/10/3
Y1 - 2012/10/3
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.
UR - http://www.scopus.com/inward/record.url?scp=84867103281&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2012.09.001
DO - 10.1016/j.cmet.2012.09.001
M3 - מאמר
AN - SCOPUS:84867103281
VL - 16
SP - 449
EP - 461
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 4
ER -
