title: Iron overload and diabetes risk: a shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis.
abstract: OBJECTIVE
  Excess tissue iron levels are a risk factor for diabetes, but the mechanisms underlying the association are incompletely understood. We previously published that mice and humans with a form of hereditary iron overload, hemochromatosis, exhibit loss of β-cell mass. This effect by itself is not sufficient, however, to fully explain the diabetes risk phenotype associated with all forms of iron overload.
  
  
  METHODS
  We therefore examined glucose and fatty acid metabolism and hepatic glucose production in vivo and in vitro in a mouse model of hemochromatosis in which the gene most often mutated in the human disease, HFE, has been deleted (Hfe⁻(/)⁻).
  
  
  RESULTS
  Although Hfe⁻(/)⁻ mice exhibit increased glucose uptake in skeletal muscle, glucose oxidation is decreased and the ratio of fatty acid to glucose oxidation is increased. On a high-fat diet, the Hfe⁻(/)⁻ mice exhibit increased fatty acid oxidation and are hypermetabolic. The decreased glucose oxidation in skeletal muscle is due to decreased pyruvate dehydrogenase (PDH) enzyme activity related, in turn, to increased expression of PDH kinase 4 (pdk4). Increased substrate recycling to liver contributes to elevated hepatic glucose production in the Hfe⁻(/)⁻ mice.
  
  
  CONCLUSIONS
  Increased hepatic glucose production and metabolic inflexibility, both of which are characteristics of type 2 diabetes, may contribute to the risk of diabetes with excessive tissue iron.
authors.affiliation: Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Huang
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.forename: Bai
authors.initials: B
authors.lastname: Luo
authors.forename: Michael
authors.initials: M
authors.lastname: Sanderson
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cooksey
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D000818:Animals; D021983:Cyclophilins / Q000235:genetics; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000453:epidemiology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology; D019190:Iron Overload / Q000150:complications*; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010101:Oxygen Consumption; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics; D012307:Risk Factors
chemical_list: D017931:DNA Primers; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D012269:Ribosomal Proteins; C520792:Rpl13a protein, mouse; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D021983:Cyclophilins; D005947:Glucose