Iron Depletion Up-regulates Glucose Uptake

Published online before print February 2, 2008
(American Journal of Pathology. 2008;172:738-747.)
Iron Depletion by Deferoxamine Up-Regulates Glucose Uptake and Insulin
Signaling in Hepatoma Cells and in Rat Liver
Paola Dongiovanni*, Luca Valenti*, Anna Ludovica Fracanzani*, Stefano
Gatti, Gaetano Cairo and Silvia Fargion*
From the Departments of Internal Medicine,*and Transplantation and
Experimental Surgery,Ospedale Maggiore Policlinico Mangiagalli Regina
Elena Istituto Ricovero e Cura a Carattere Scientifico, and the
Department of General Pathology,University of Milano, Milano, Italy


Iron depletion improves insulin resistance in patients with
nonalcoholic fatty liver disease and diabetes and also stabilizes the
hypoxia-inducible factor (HIF)-1, resulting in increased glucose
uptake in vitro.
This study investigated the effect of iron depletion by deferoxamine
on insulin signaling and glucose uptake in HepG2 hepatocytes and in
rat liver. In HepG2 cells, deferoxamine stabilized HIF-1 and induced
the constitutive glucose transporter Glut1 and the insulin receptor.
Up-regulation of insulin receptor by deferoxamine was mimicked by the
intracellular iron chelator deferasirox and the hypoxia inducer CoCl2
and required the HIF-1 obligate partner ARNT/HIF-1â. Iron depletion
increased insulin receptor activity, whereas iron supplementation had
the opposite effect.
Deferoxamine consistently increased the phosphorylation status of Akt/
PKB and its targets FoxO1 and Gsk3â, which mediate the effect of
insulin on gluconeogenesis and glycogen synthesis, and up-regulated
genes involved in glucose uptake and utilization.
Iron depletion of Sprague-Dawley rats increased HIF-1 expression,
improved glucose clearance, and was associated with up-regulation of
insulin receptor and Akt/PKB levels and of glucose transport in
hepatic tissue.
Conversely, gluconeogenic genes were not affected. In rats with fatty
liver because of a high-calorie and high-fat diet, glucose clearance
was increased by iron depletion and decreased by iron
supplementation.
Thus, iron depletion by deferoxamine up-regulates glucose uptake, and
increases insulin receptor activity and signaling in hepatocytes in
vitro and in vivo.
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© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070097

Copyright © 2008 by the American Society for Investigative Pathology.


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