Background-Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-␣ (TNF-␣) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-␣, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results-Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-␣, and IL-18 levels rose (PϽ0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (PϽ0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-␣ levels higher (PϽ0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, PϽ0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (PϽ0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses. Conclusions-Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.

Context Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue. Objective To determine the effect of a program of changes in lifestyle designed to obtain a sustained reduction of body weight on markers of systemic vascular inflammation and insulin resistance. Design and Setting Randomized single-blind trial conducted from February 1999 to February 2002 at a university hospital in Italy. Patients One hundred twenty premenopausal obese women (body mass index Ն30) aged 20 to 46 years without diabetes, hypertension, or hyperlipidemia. Interventions The 60 women randomly assigned to the intervention group received detailed advice about how to achieve a reduction of weight of 10% or more through a low-energy Mediterranean-style diet and increased physical activity. The control group (n=60) was given general information about healthy food choices and exercise. Main Outcome Measures Lipid and glucose intake; blood pressure; homeostatic model assessment of insulin sensitivity; and circulating levels of interleukin 6 (IL-6), interleukin 18 (IL-18), C-reactive protein (CRP), and adiponectin. Results After 2 years, women in the intervention group consumed more foods rich in complex carbohydrates (9% corrected difference; PϽ.001), monounsaturated fat (2%; P=.009), and fiber (7 g/d; PϽ.001); had a lower ratio of omega-6 to omega-3 fatty acids (−5; PϽ.001); and had lower energy (−310 kcal/d; PϽ.001), saturated fat (−3.5%; P=.007), and cholesterol intake (−92 mg/d; PϽ.001) than controls. Body mass index decreased more in the intervention group than in controls (−4.2; PϽ.001), as did serum concentrations of IL-6 (−1.1 pg/mL; P=.009), IL-18 (−57 pg/mL; P=.02), and CRP (−1.6 mg/L; P=.008), while adiponectin levels increased significantly (2.2 µg/mL; P=.01). In multivariate analyses, changes in free fatty acids (P=.008), IL-6 (P=.02), and adiponectin (P=.007) levels were independently associated with changes in insulin sensitivity. Conclusion In this study, a multidisciplinary program aimed to reduce body weight in obese women through lifestyle changes was associated with a reduction in markers of vascular inflammation and insulin resistance.

Background-Visceral fat is a key regulator site for the process of inflammation, and atherosclerotic lesions are essentially an inflammatory response. Methods and Results-Fifty-six healthy premenopausal obese women (age range 25 to 44 years, body mass index 37.2Ϯ2.2, waist to hip ratio range 0.78 to 0.92) and 40 age-matched normal weight women were studied. Compared with nonobese women, obese women had increased basal concentrations of tumor necrosis factor-␣ (TNF-␣, PϽ0.01), interleukin-6 (IL-6, PϽ0.01), P-selectin (PϽ0.01), intercellular adhesion molecule-1 (ICAM-1, PϽ0.02), and vascular adhesion molecule-1 (VCAM-1, PϽ0.05). Vascular responses to L-arginine (3 g IV), the natural precursor of nitric oxide, were impaired in obese women: reductions in mean blood pressure (PϽ0.02), platelet aggregation to adenosine diphosphate (PϽ0.05), and blood viscosity (PϽ0.05) were significantly lower as compared with those in the nonobese group. Concentrations of TNF-␣ and IL-6 were related (PϽ0.01) to visceral obesity, as well as to adhesin levels and responses to L-arginine. After 1 year of a multidisciplinary program of weight reduction (diet, exercise, behavioral counseling), all obese women lost at least 10% of their original weight (9.8Ϯ1.5 kg, range 7.5 to 13 kg).

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Context Healthy lifestyle factors are associated with maintenance of erectile function in men.Objective To determine the effect of weight loss and increased physical activity on erectile and endothelial functions in obese men.Design, Setting, and Patients Randomized, single-blind trial of 110 obese men (body mass index Ն30) aged 35 to 55 years, without diabetes, hypertension, or hyperlipidemia, who had erectile dysfunction that was determined by having a score of 21 or less on the International Index of Erectile Function (IIEF). The study was conducted from October 2000 to October 2003 at a university hospital in Italy. InterventionsThe 55 men randomly assigned to the intervention group received detailed advice about how to achieve a loss of 10% or more in their total body weight by reducing caloric intake and increasing their level of physical activity. Men in the control group (n=55) were given general information about healthy food choices and exercise. Main Outcomes MeasuresErectile function score, levels of cholesterol and tryglycerides, circulating levels of interleukin 6, interleukin 8, and C-reactive protein, and endothelial function as assessed by vascular responses to L-arginine.Results After 2 years, body mass index decreased more in the intervention group (from a mean [SD] of 36.9 [2.5] to 31.2 [2.1]) than in the control group (from 36.4 [2.3] to 35.7 [2.5]) (PϽ.001), as did serum concentrations of interleukin 6 (P=.03), and Creactive protein (P=.02). The mean (SD) level of physical activity increased more in the intervention group (from 48 [10] to 195 [36] min/wk; PϽ.001) than in the control group (from 51 [9] to 84 [28] min/wk; PϽ.001). The mean (SD) IIEF score improved in the intervention group (from 13.9 [4.0] to 17 [5]; PϽ.001), but remained stable in the control group (from 13.5 [4.0] to 13.6 [4.1]; P=.89). Seventeen men in the intervention group and 3 in the control group (P=.001) reported an IIEF score of 22 or higher. In multivariate analyses, changes in body mass index (P=.02), physical activity (P=.02), and C-reactive protein (P=.03) were independently associated with changes in IIEF score. ConclusionLifestyle changes are associated with improvement in sexual function in about one third of obese men with erectile dysfunction at baseline.