Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had highferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 ؎ 0.9% vs. 6.39 ؎ 1.2%), insulin sensitivity (2.75 ؎ 1.8 vs. 3.2 ؎ 2.1 mg ⅐ dl ؊1 ⅐ min ؊1 ), and area under the curve for C-peptide (AUC C-peptide ; 38.7 ؎ 11.6 vs. 37.6 ؎ 14.1 ng ⅐ ml ؊1 ⅐ min ؊1 ) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA 1c decreased significantly only in group 1 subjects (mean differences, ؊0.61; 95% CI, ؊0.17 to ؊1.048; P ‫؍‬ 0.01). AUC C-peptide decreased by ؊10.2 ؎ 6.3% after blood letting. In contrast, a 10.4 ؎ 6.4% increase in AUC C-peptide was noted in group 2 subjects at 4 months (P ‫؍‬ 0.032). At 12 months, AUC C-peptide returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 ؎ 43.2% vs. ؊8.6 ؎ 9.9% in groups 1 and 2, respectively, P ‫؍‬ 0.049). At 12 months, the differences between the two groups were even more marked (55.5 ؎ 24.8% vs. ؊26.8 ؎ 9.9%; P ‫؍‬ 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 ؎ 1.81 to 3.08 ؎ 2.55 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 3.16 ؎ 1.85 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months; P ‫؍‬ 0,045) in contrast with group 2 subjects (from 3.24 ؎ 1.9 to 3.26 ؎ 2.05 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 2.31 ؎ 1.35 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months). In summary, blood letting led simultaneously to decreased blood HbA 1c levels and to changes in insulin secretion and insulin resistance that were significantly different from those observed in a matched observational group of subjects with high-ferritin type 2 diabetes. The mechanisms for improvement in peripheral insulin sensitivity after blood letting should be investigated further.

OBJECTIVE -In a recent study, iron chelation with deferoxamine led to improvement of endothelial dysfunction in patients with coronary artery disease. We tested the hypothesis that decreasing circulating iron stores might improve vascular dysfunction in patients with type 2 diabetes and increased serum ferritin concentration. RESEARCH DESIGN AND METHODS-A total of 28 type 2 diabetic male patients with serum ferritin levels Ͼ200 ng/ml (ϳ18% of consecutive type 2 diabetic men attending our outpatient clinic) were randomized to iron depletion (three extractions of 500 ml blood at 2-week intervals; group 1A) or to observation (group 1B). C282Y mutation was absent in all patients. Vascular reactivity (high-resolution external ultrasound) was evaluated at baseline and at 4 and 12 months thereafter. The two groups of patients were matched for age, BMI, pharmacological treatment, and chronic diabetic complications.RESULTS -Endothelium-dependent vasodilation remained essentially unchanged in both groups of patients. In contrast, the vasodilation induced by glyceryl trinitrate (GTN) improved significantly after iron depletion (P ϭ 0.006). These changes occurred in parallel to decreases in transferrin saturation index and HbA 1c levels (Ϫ0.6%, P Ͻ 0.05) only in group 1A patients. The best predictor of the modifications in endothelium-independent vasodilation was the change in HbA 1c levels. Changes in endothelium-independent vasodilation also correlated with the change in serum ferritin (r ϭ Ϫ0.45, P ϭ 0.04). At 12 months, transferrin saturation index and GTN-induced vasodilation returned to values similar to those at baseline in both groups of subjects.CONCLUSIONS -Iron depletion improves vascular dysfunction in type 2 diabetic patients with high ferritin concentrations. The mechanisms by which these changes occur should be further investigated. Diabetes Care 25:2249 -2255, 2002F erritin gene expression increases in the course of atherosclerotic plaque formation (1). Iron is a transition metal that can easily become oxidized and thus act as an oxidant. A possible link between iron and atherogenesis has been suggested by the finding that iron chelation blocks oxidation of LDL, whereas iron released from heme and ferritin favors oxidation of LDL (2). In fact, the general effect of catalytic iron is to convert poorly reactive free radicals such as H 2 O 2 into highly reactive ones, such as the hydroxyl radical. In vitro addition of oxygen-derived free radical scavengers or antioxidants can reverse defective endothelium-dependent relaxation in experimental diabetes (3-6) or in diabetic patients (7). Impaired vascular responses to vasodilators, such as acetylcholine and glyceryl trinitrate (GTN), are usually found in patients with type 2 diabetes (8 -10).In experimental models, iron has an adverse effect on endothelium (11) and accelerates the development of atherosclerosis (12,13). In patients with iron overload, midsize arteries are characterized by an eccentric hypertrophy and decreased distensibility (14). These findings s...

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