Journal article
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
Diabetes (New York, N.Y.), Vol.60(1), pp.80-87
2011
DOI: 10.2337/db10-0593
PMCID: PMC3012200
PMID: 20876715
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.
Research design and 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.
Details
- Title: Subtitle
- 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
- Creators
- Jingyu Huang - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesDeborah JONES - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesBai Luo - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesMichael SANDERSON - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesJamie SOTO - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesE Dale Abel - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesRobert C COOKSEY - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United StatesDonald A MCCLAIN - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.60(1), pp.80-87
- Publisher
- American Diabetes Association; Alexandria, VA
- DOI
- 10.2337/db10-0593
- PMID
- 20876715
- PMCID
- PMC3012200
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 2011
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024511902771
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