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
- Jingyu Huang1,
- Deborah Jones1,
- Bai Luo1,
- Michael Sanderson1,
- Jamie Soto1,
- E. Dale Abel1,
- Robert C. Cooksey1,2 and
- Donald A. McClain1,2
- 1Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah;
- 2Research Service, VA Medical Center, Salt Lake City, Utah.
- Corresponding author: Donald A. McClain, .
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.
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.
- Received April 26, 2010.
- Accepted September 20, 2010.
- © 2011 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.