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

• DOI: 10.2337/db10-0593
• Publication Date: 2010-09-29T02:36:25Z
• Authors: Jingyu Huang; Deborah Jones; Bai Luo; Michael Sanderson; Jamie Soto; E. Dale Abel; Robert C. Cooksey; Donald A. McClain
• Keywords: Hereditary hemochromatosis

OBJECTIVE Excess tissue iron levels are a risk factor for diabetes, but the mechanisms underlying association incompletely understood. We previously published that mice and humans with form of hereditary overload, hemochromatosis, exhibit loss β-cell mass. This effect by itself is not sufficient, however, to fully explain diabetes phenotype associated all forms overload. RESEARCH DESIGN AND METHODS therefore examined glucose fatty acid metabolism hepatic production in vivo vitro mouse model hemochromatosis which gene most often mutated human disease, HFE, has been deleted (Hfe−/−). RESULTS Although Hfe−/− increased uptake skeletal muscle, oxidation decreased ratio increased. On high-fat diet, hypermetabolic. The muscle due pyruvate dehydrogenase (PDH) enzyme activity related, turn, expression PDH kinase 4 (pdk4). Increased substrate recycling liver contributes elevated mice. CONCLUSIONS metabolic inflexibility, both characteristics type 2 may contribute excessive iron.