Iron overload can cause insulin deficiency, but in some cases this may be insufficient to result in diabetes. We hypothesized that the protective effects of decreased iron would be more significant with increased beta-cell demand and stress. Therefore, we treated the ob/ob mouse model of type 2 diabetes with an iron-restricted diet (35 mg/kg iron) or with an oral iron chelator. Control mice were fed normal chow containing 500 mg/kg iron. Neither treatment resulted in iron deficiency or anemia. The low-iron diet significantly ameliorated diabetes in the mice. The effect was long lasting and reversible. Ob/ob mice on the low-iron diet exhibited significant increases in insulin sensitivity and beta-cell function, consistent with the phenotype in mouse models of hereditary iron overload. The effects were not accounted for by changes in weight or feeding behavior. Treatment with iron chelation had a more dramatic effect, allowing the ob/ob mice to maintain normal glucose tolerance for at least 10.5 wk despite no effect on weight. Although dietary iron restriction preserved beta-cell function in ob/ob mice fed a high-fat diet, the effects on overall glucose levels were less apparent due to a loss of the beneficial effects of iron on insulin sensitivity. Beneficial effects of iron restriction were minimal in wild-type mice on normal chow but were apparent in mice on high-fat diets. We conclude that, even at "normal" levels, iron exerts detrimental effects on beta-cell function that are reversible with dietary restriction or pharmacotherapy.

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Hereditary hemochromatosis (HH) is a common genetic disorder characterized by iron overload and diabetes, although the mechanism underlying the diabetes remains controversial. We have previously demonstrated that mice with knockout of the human gene most commonly mutated in HH (Hfe - / -) exhibit decreased beta cell mass and insulin secretion secondary to beta cell apoptosis and a desensitization of glucose stimulated insulin secretion. In the Hfe - / - mice and HH humans the decreased insulin secretion is partially compensated by increased insulin sensitivity. In contrast, iron overload has also been reported in insulin-resistant humans with the metabolic syndrome and/or type 2 diabetes. To study the mechanisms underlying these different phenotypes, we have created a model of mice that are fed excess dietary carbonyl iron in combination with a high-fat diet and compared them to the HH (Hfe - / -) mice also fed a high-fat diet. On high fat, the Hfe - / - mice are resistant to diet-induced obesity (Hfe - / -, 31.9 g, wild type 36.8 g, p < .02). When studied by intraperitoneal glucose tolerance testing (IPGTT), the Hfe-/-mice also exhibit decreased glucose excursions (19% decrease in the area under the glucose curve, p < .01) with decreased insulin levels (38% decrease at 30 min, p < .05). By contrast, compared to mice on a high-fat diet with normal iron, the iron-fed mice weigh more (38.4 vs 35.6 g, p < .05) and have a 45% increase in glucose excursion during IPGTT (p < .002) despite a 50% increase in serum insulin (p = .02). Thus, in a mouse model, excess dietary iron exacerbates aspects of the metabolic syndrome and leads to a phenotype similar to type 2 diabetes, while iron overload resulting from hereditary hemochromatosis results in protection from these markers of the metabolic syndrome and an insulin-deficient phenotype. The protection afforded the Hfe-/- model can be accounted for by thermogenesis resulting from mitochondrial damage, and the difference in the phenotypes likely results from the different tisssue distributions of iron in the two models.NIH DK 59512.