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...

The American Thoracic Society (ATS) published guidelines for the treatment and management of community-acquired pneumonia in 2001, but the impact of adherence on outcomes such as mortality and length of stay is not well defined.A study of 780 patients with community-acquired pneumonia consecutively admitted to hospital over 1 yr was carried out. Nursing home patients were excluded.Overall adherence to antibiotics recommended in the ATS guidelines was 84%. The lowest adherence was found in patients admitted to an intensive care unit (52%), especially those at risk of infection withPseudomonas aeruginosa(ATS group IVb). However, very few patients from this group were indeed infected withP. aeruginosa. This could be explained by the exclusion of the nursing home patients. There was a difference in mortality between patients that received adherent and nonadherent regimens (3versus10.6%). There was a difference in length of stay between patients receiving adherent and nonadherent regimens (7.6versus10.4 days). This result was confirmed on multivariate analysis.Adherence to the 2001 American Thoracic Society guidelines was high except in community-acquired pneumonia patients admitted to an intensive care unit. Length of stay was shorter in patients who received adherent rather than nonadherent antibiotic regimens.

OBJECTIVE -Adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity. In experimental studies, adiponectin has also been found to inhibit vascular smooth muscle cell proliferation. Decreased adiponectin levels have been described in patients with coronary artery disease, and circulating adiponectin predicts cardiovascular death in patients with renal failure. Because adiponectin appears to influence both insulin sensitivity and vessel wall physiology, we examined insulin sensitivity and vascular function in relation with circulating adiponectin.RESEARCH DESIGN AND METHODS -We studied brachial artery vascular reactivity (high-resolution external ultrasound) and insulin sensitivity (minimal model) in 68 healthy subjects. Brachial artery vascular reactivity was also determined in 52 patients with altered glucose tolerance: 30 subjects with impaired fasting glucose (IFG) or glucose intolerance (GIT) and 22 patients with type 2 diabetes.RESULTS -Circulating adiponectin concentration was significantly associated with insulin sensitivity (r ϭ 0.29, P ϭ 0.02) and with fasting serum triglycerides (r ϭ Ϫ0.29, P ϭ 0.02) in healthy subjects. In the latter, adiponectin levels were positively associated with arterial vasodilation in response to nitroglycerin (endothelium-independent vasodilation [EIVD], r ϭ 0.41, P ϭ 0.002) but not with flux-induced, endothelium-dependent vasodilation (EDVD) (r ϭ 0.007, P ϭ NS). In contrast, EIVD was not significantly associated with adiponectin in subjects with IFG, GIT, or type 2 diabetes (r Յ 0.10, P ϭ NS). In a multiple linear regression analysis to predict EIVD in healthy subjects, age (P ϭ 0.012), sex (P ϭ 0.042), and adiponectin concentration (P ϭ 0.045), but not BMI, insulin sensitivity, or fasting triglycerides, contributed to 39% of EIVD variance.CONCLUSIONS -Serum adiponectin concentration appears to be significantly associated with vascular function in apparently healthy humans. This association seems to be independent of its link with insulin sensitivity.

Tumor necrosis factor-α (TNF-α) is increasingly recognized as a key component in the development of insulin resistance and increased blood pressure. In a sample of 368 individuals, the ratio of soluble TNF-α receptors (sTNFR2/sTNFR1) correlated positively with systolic and diastolic blood pressure ( P < 0.01). This ratio was significantly greater in type 2 diabetic subjects (DM-2) than in type 1 diabetic patients and was greater than in control nondiabetic subjects ( P < 0.00001). The TNF-α receptor 1 (TNFR1) density in peripheral blood monocytes was similar in DM-2 patients and in nondiabetic subjects. After phorbol 12-myristate 13-acetate, TNFR1 shedding was significantly decreased in DM-2 compared with control subjects, and it was directly associated with insulin sensitivity ( r = 0.54, P = 0.03). Serum sTNFR1 concentration was also linked to the vasodilatory response to glyceryltrinitrate ( P = 0.01). Conversely, TNF-α receptor 2 shedding was negatively associated with insulin sensitivity ( r = −0.54, P = 0.03), whereas shedding of L-selectin showed no significant association. After exercise-induced lowering of blood pressure, a parallel decrease in sTNFR2/sTNFR1 was observed in DM-2 patients. Our findings suggest that insulin resistance and blood pressure are linked to altered shedding of TNF-α receptors in DM-2. The latter seems reversible and is not genetically determined.