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J. Biol. Chem., Vol. 282, Issue 52, 37501-37507, December 28, 2007

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Increased Glucose Disposal and AMP-dependent Kinase Signaling in a Mouse Model of Hemochromatosis^*

Jingyu Huang¹, J. Scott Gabrielsen¹, Robert C. Cooksey^¶, Bai Luo, László G. Boros^||, Deborah L. Jones, Hani A. Jouihan, Yudi Soesanto, Lauren Knecht, Mark W. Hazel, James P. Kushner, and Donald A. McClain^¶2

From the Departments of Biochemistry and Medicine, the University of Utah School of Medicine, Salt Lake City, Utah 84132, the ^¶Research Service of the Veterans Affairs Medical Center, Salt Lake City, Utah 84132, and ^||SIDMAP, Los Angeles, California 90064

Hereditary hemochromatosis is an inherited disorder of increased iron absorption that can result in cirrhosis, diabetes, and other morbidities. We have investigated the mechanisms underlying supranormal glucose tolerance despite decreased insulin secretion in a mouse model of hemochromatosis with deletion of the hemochromatosis gene (Hfe^–/–). Hfe^–/– mice on 129Sv or C57BL/6J backgrounds have decreased glucose excursions after challenge compared with controls. In the C57BL/6J/ Hfe^–/–, for example, incremental area under the glucose curve is reduced 52% (p < 0.001) despite decreased serum insulin, and homeostasis model assessment insulin resistance is decreased 50% (p < 0.05). When studied by the euglycemic clamp technique 129Sv/Hfe^–/– mice exhibit a 20% increase in glucose disposal (p < 0.05) at submaximal insulin but no increase at maximal insulin compared with wild types. [1,2-¹³C]D-glucose clearance from plasma is significantly increased in Hfe^–/– mice (19%, p < 0.05), and lactate derived from glycolysis is elevated 5.1-fold in Hfe^–/– mice (p < 0.0001). Basal but not insulin-stimulated glucose uptake is elevated in isolated soleus muscle from Hfe^–/– mice (p < 0.03). Compared with controls Hfe^–/– mice exhibit no differences in serum lipid, insulin, glucagon, or thyroid hormone levels; adiponectin levels are elevated 41% (p < 0.05), and the adiponectin message in adipocytes is increased 83% (p = 0.04). Insulin action measured by phosphorylation of Akt is not enhanced in muscle, but phosphorylation of AMP-dependent kinase is increased. We conclude that supranormal glucose tolerance in iron overload is characterized by increased glucose disposal that does not result from increased insulin action. Instead, the Hfe^–/– mice demonstrate increased adiponectin levels and activation of AMP-dependent kinase.

Received for publication, May 2, 2007 , and in revised form, October 15, 2007.

^* This work was supported by the Research Service of the Veterans Administration and National Institutes of Health Grant DK59512. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Endocrinology, University of Utah School of Medicine, 30 N. 2030 East, Salt Lake City, UT 84132. Tel.: 801-585-0954; Fax: 801-585-0956; E-mail: donald.mcclain{at}hsc.utah.edu.

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