Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines

Jakob Bondo Hansen; Morten Fog Tonnesen; Andreas Nygaard Madsen; Peter Hagedorn; Josefine Friberg; Lars Groth Grunnet; R Scott Heller; Anja Østergren Nielsen; Joachim Størling; Luc Baeyens; Leeat Anker-Kitai; Klaus Qvortrup; Luc Bouwens; Shimon Efrat; Mogens Aalund; Nancy C Andrews; Nils Billestrup; Allan E Karlsen; Birgitte Holst; Flemming Pociot; Thomas Mandrup-Poulsen

doi:10.1016/j.cmet.2012.09.001

Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines

Jakob Bondo Hansen, Morten Fog Tonnesen, Andreas Nygaard Madsen, Peter Hagedorn, Josefine Friberg, Lars Groth Grunnet, R Scott Heller, Anja Østergren Nielsen, Joachim Størling, Luc Baeyens, Leeat Anker-Kitai, Klaus Qvortrup, Luc Bouwens, Shimon Efrat, Mogens Aalund, Nancy C Andrews, Nils Billestrup, Allan E Karlsen, Birgitte Holst, Flemming PociotThomas Mandrup-Poulsen

87 Citations (Scopus)

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.

Original language	English
Journal	Cell Metabolism
Volume	16
Issue number	4
Pages (from-to)	449-61
Number of pages	13
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2012.09.001
Publication status	Published - 3 Oct 2012

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Hansen, J. B., Tonnesen, M. F., Madsen, A. N., Hagedorn, P., Friberg, J., Grunnet, L. G., Heller, R. S., Nielsen, A. Ø., Størling, J., Baeyens, L., Anker-Kitai, L., Qvortrup, K., Bouwens, L., Efrat, S., Aalund, M., Andrews, N. C., Billestrup, N., Karlsen, A. E., Holst, B., ... Mandrup-Poulsen, T. (2012). Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines. Cell Metabolism, 16(4), 449-61. https://doi.org/10.1016/j.cmet.2012.09.001

Hansen, JB, Tonnesen, MF, Madsen, AN, Hagedorn, P, Friberg, J, Grunnet, LG, Heller, RS, Nielsen, AØ, Størling, J, Baeyens, L, Anker-Kitai, L, Qvortrup, K, Bouwens, L, Efrat, S, Aalund, M, Andrews, NC, Billestrup, N, Karlsen, AE, Holst, B , Pociot, F & Mandrup-Poulsen, T 2012, 'Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines', Cell Metabolism, vol. 16, no. 4, pp. 449-61. https://doi.org/10.1016/j.cmet.2012.09.001

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title = "Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic {\ss} 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.",

author = "Hansen, {Jakob Bondo} and Tonnesen, {Morten Fog} and Madsen, {Andreas Nygaard} and Peter Hagedorn and Josefine Friberg and Grunnet, {Lars Groth} and Heller, {R Scott} and Nielsen, {Anja {\O}stergren} and Joachim St{\o}rling and Luc Baeyens and Leeat Anker-Kitai and Klaus Qvortrup and Luc Bouwens and Shimon Efrat and Mogens Aalund and Andrews, {Nancy C} and Nils Billestrup and Karlsen, {Allan E} and Birgitte Holst and Flemming Pociot and Thomas Mandrup-Poulsen",

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T1 - Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines

AU - Hansen, Jakob Bondo

AU - Tonnesen, Morten Fog

AU - Madsen, Andreas Nygaard

AU - Hagedorn, Peter

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

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.

U2 - 10.1016/j.cmet.2012.09.001

DO - 10.1016/j.cmet.2012.09.001

M3 - Journal article

C2 - 23000401

SN - 1550-4131

VL - 16

SP - 449

EP - 461

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic ß cell fate in response to cytokines

Abstract

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