title: Increased glucose disposal and AMP-dependent kinase signaling in a mouse model of hemochromatosis.
abstract: 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-(13)C]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.
authors.affiliation: Department of Biochemistry, the University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Huang
authors.forename: J Scott
authors.initials: JS
authors.lastname: Gabrielsen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cooksey
authors.forename: Bai
authors.initials: B
authors.lastname: Luo
authors.forename: László G
authors.initials: LG
authors.lastname: Boros
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Jones
authors.forename: Hani A
authors.initials: HA
authors.lastname: Jouihan
authors.forename: Yudi
authors.initials: Y
authors.lastname: Soesanto
authors.forename: Lauren
authors.initials: L
authors.lastname: Knecht
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hazel
authors.forename: James P
authors.initials: JP
authors.lastname: Kushner
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006432:Hemochromatosis / Q000235:genetics*; D007501:Iron / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008055:Lipids; D007501:Iron; C118888:AMP-dependent kinase (ATP-forming); D017856:Phosphotransferases (Phosphate Group Acceptor); D005947:Glucose