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.
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.
Huang
Jingyu
J
Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, USA.
Jones
Deborah
D
Luo
Bai
B
Sanderson
Michael
M
Soto
Jamie
J
Abel
E Dale
ED
Cooksey
Robert C
RC
McClain
Donald A
DA
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
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