In human hereditary hemochromatosis (HH), as well as in a mouse model with deletion of the hemochromatosis gene (Hfe−/−), iron excess in beta cells results in oxidant stress and decreased insulin secretory capacity. In mice, unlike humans, this is insufficient to cause diabetes, but both mice and humans with HH are resistant to obesity. We therefore examined fuel homeostasis in these mice. Hfe−/− mice on 129Sv or C57BL/6J backgrounds, or wild-type mice fed excess dietary iron all have supranormal glucose tolerance. In the C57BL/6J/Hfe−/− , incremental area under the glucose curve is 52% reduced (p < .001) despite decreased serum insulin (40%, p < .05) and no difference in body weights. Insulin resistance determined by the HOMA method is decreased 50% (p < .05) in C57BL/6J/Hfe−/−. Hfe−/− mice studied by the glucose clamp technique exhibited a 20% increase in total glucose disposal (p < .05) but also a 36% increase in hepatic glucose production at submaximal insulin (p < .05) compared with wild types. The results of the clamp studies were confirmed by determining the fate of absorbed [1,2-13C2]-d-glucose. In Hfe−/− mice, glucose clearance from plasma was significantly increased (19%, p < .05), whereas there was also a 36% increase in the reappearance of [1-13C1]-d-glucose via hepatic glucose production. Much of this appeared to be due to increased lactate cycling to the liver from skeletal muscle: lactate derived from glycolysis was elevated 5.1-fold in the Hfe−/− mice (p < .0001), suggesting a defect in peripheral glucose oxidation, consistent with our previous description of decreased mitochondrial function in the model. These results also conform to an observed 11% decrease in heat production (p < .05) in Hfe−/− mice studied by indirect calorimetry. The Hfe−/− mice are resistant to weight gain in the face of a high-fat diet or aging. There are no differences between Hfe−/− and wild-type mice in terms of serum lipid, glucose, insulin, glucagon, or thyroid hormone levels; adiponectin levels are modestly elevated in the Hfe−/− mice (29%, p < .05). Insulin action is enhanced in liver but not muscle as determined by a twofold increase (p < .02) in basal and insulin stimulated levels of phosphorylated Akt. We conclude that hemochromatosis is characterized by supranomal glucose tolerance that is associated with increased insulin sensitivity in liver and increased glucose disposal. This results at least in part from a novel mechanism of increased hepatic glucose production and recycling from lactate, that is, futile Cori cycling. This is likely substrate-driven secondary to mitochondrial dysfunction.
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