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Metabolic diseases are associated with chronic low-grade inflammation, which has been indicated as a potential mediator of endothelial dysfunction and cardiovascular disease. Visceral adiposity is thought to be the starting condition of the inflammatory state through the release of inflammatory cytokines, including TNF-alpha, CRP, and IL-6, which in turn promote endothelial dysfunction, endothelial expression of chemokines (IL-1) and adhesion molecules (ICAM-1, VCAM-1, and P-selectin), and the inhibition of anti-atherogenic factors (adiponectin). Obesity, metabolic diseases, and diabetes, all conditions characterized by abdominal fat, are well-recognized risk factors for sexual dysfunction in both sexes. Evidence from randomized-controlled trials supports the association between inflammatory milieau and erectile dysfunction in men suffering from metabolic diseases, whereas, in women, this has to be confirmed in further studies. A healthy lifestyle based on dietary pattern with high content of whole grain, fruit, nuts and seeds, and vegetables and low in sodium and saturated fatty acids plus regular physical activity may help to modulate the pro-inflammatory state associated with metabolic diseases and the related burden of sexual dysfunctions.

In the past decades, dietary guidelines focused on reducing saturated fat as the primary strategy for cardiovascular disease prevention, neglecting the many other potential effects of diet on health, in particular the harmful effects of sugar. A greater intake of soft drinks (sugar-sweetened beverages), for example, is associated with a 44% increased prevalence of metabolic syndrome, a higher risk of obesity, and a 26% increased risk of developing diabetes mellitus. Carbohydrates comprise around 55% of the typical western diet, ranging from 200 to 350 g/day in relation to a person's overall caloric intake. For long-term weight gain, food rich in refined grains, starches, and sugar appear to be major culprits. Low-carbohydrate diets restrict daily carbohydrates between 20 and 50 g, as in clinical ketogenic diets. The results of controlled trials show that people on ketogenic diets (a diet with no more than 50 g carbohydrates/day) tend to lose more weight than people on low-fat diets. Moreover, there is no good evidence for recommending low-fat diets, as low-carbohydrate diets lead to significantly greater weight loss (1.15 kg) than did low-fat interventions. However, the magnitude of such a benefit is small. As the quality of ingested carbohydrates seems more important than the quantity for health outcomes, people with metabolic disorders should avoid or substantially reduce low-fiber, rapidly digested, refined grains, starches, and added sugars. So, the consumption of the right carbohydrates (high-fiber, slowly digested, and whole grains), in a moderately lower amount (between 40 and 50% of daily energy content), is compatible with a state of good health and may represent a scientifically-based and palatable choice for people with metabolic disorders.

Background: The epidemiological evidence supporting a causal link between Mediterranean diets and body weight is contrasting. We evaluated the effect of Mediterranean diets on body weight in randomized controlled trials (RCTs) using a meta-analysis., Methods: We searched English and non-English publications in PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials from inception to January, 2010. Two evaluators independently selected and reviewed eligible studies. Sixteen randomized controlled trials, with 19 arms and 3,436 participants (1,848 assigned to a Mediterranean diet and 1,588 assigned to a control diet) were included., Results: In a random-effects meta-analysis of all 19 arms, the Mediterranean diet group had a significant effect on weight [mean difference between Mediterranean diet and control diet, -1.75 kg; 95% confidence interval (CI), -2.86 to -0.64 kg] and body mass index (mean difference, -0.57 kg/m², -0.93 to -0.21 kg/m²). The effect of Mediterranean diet on body weight was greater in association with energy restriction (mean difference, -3.88 kg, -6.54 to -1.21 kg), increased physical activity (-4.01 kg, -5.79 to -2.23 kg), and follow up longer than 6 months (-2.69 kg, -3.99 to -1.38 kg). No study reported significant weight gain with a Mediterranean diet., Conclusions: Mediterranean diet may be a useful tool to reduce body weight, especially when the Mediterranean diet is energy-restricted, associated with physical activity, and more than 6 months in length. Mediterranean diet does not cause weight gain, which removes the objection to its relatively high fat content. These results may be useful for helping people to lose weight.

Introduction: Although epidemiological evidence seems to support a role for lifestyle factors in the pathogenesis of erectile dysfunction (ED), limited data are available suggesting that dietary changes may improve ED., Aim: To provide an update on clinical evidence regarding the role of dietary factors in ED., Methods: A systematic literature search was performed using MEDLINE and other database (EMBASE, SCOPUS) with MeSH terms and keywords for "erectile dysfunction", "diet", "dietary patterns", "Mediterranean diet", and "lifestyle"., Main Outcome Measures: To examine the data relating to erectile dysfunction with dietary factors, its relationship and the impact of dietary treatment., Results: Only few studies assessed the role or the effect of diet on ED. A dietary pattern which is high in fruit, vegetables, nuts, whole grains, and fish but low in red and processed meat and refined grains is more represented in subjects without ED. Mediterranean diet has been proposed as a healthy dietary pattern based on evidence that greater adherence to this diet is associated with lower all-cause and disease-specific survival. In type 2 diabetic men, those with the highest adherence to the Mediterranean diet had the lowest prevalence of ED and were more likely to be sexually active. In clinical trials, Mediterranean diet was more effective than a control diet in ameliorating ED or restoring absent ED in people with obesity or metabolic syndrome., Conclusion: The adoption of a Mediterranean diet may be associated with an improvement of erectile dysfunction.

Background and Aims: Obesity is associated with an increased risk of developing atherosclerosis. Interleukin-20 (IL-20) is a pleiotropic cytokine thought to be involved in the onset and progression of atherosclerosis. The aim of this study was to determine whether circulating levels of IL-20 are elevated in obese women and whether they could be affected by a substantial decrease in body weight., Methods and Results: Fifty obese and 50 age-matched, normal weight, premenopausal women participated in the study. Obese women entered into a medically supervised weight loss program aimed at reducing body weight to 90% of baseline. We measured anthropometric, glucose and lipid parameters, and IL-20, C-Reactive Protein (CRP) and interleukin-10 (IL-10) circulating levels. Circulating IL-20 and CRP levels were significantly higher in obese than control women (P=0.01), while IL-10 levels were significantly lower; IL-20 levels were positively associated with body weight (r=0.35; P=0.02) and visceral fat (waist-hip ratio; r=0.32; P=0.025). Caloric restriction-induced weight loss (>10% of original weight) over 6 months reduced IL-20 levels from 152 (112/184) to 134 (125/153)pg/ml (median and 25%/75%; P=0.03), and it was positively associated with changes in body mass index and waist-hip ratio., Conclusion: In premenopausal obese women, IL-20 levels are higher than matched normal weight control women, are associated with body weight and waist-hip ratio, and are reduced by weight loss., ((c) 2009 Elsevier B.V. All rights reserved.)

Introduction: Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the peripheral blood and are involved in endothelial homeostasis and repair., Aim: The aim of this study was to assess the circulating levels of different EPC phenotypes in overweight men with or without erectile dysfunction (ED). As endothelial dysfunction is considered a necessary link with ED, endothelium-dependent vasodilation and its relation with EPCs were also investigated., Methods: We studied 30, otherwise healthy, overweight subjects with symptomatic ED for at least 6 months, and 30 age- and weight-matched subjects without ED. Erectile function was assessed by completing the International Index of Erectile Function (IIEF-5), which consists of items 5, 15, 4, 2, and 7 from the full-scale IIEF-15., Main Outcome Measures: Seven subpopulations of EPCs were determined by flow cytometry on the basis of the surface expression of CD34, CD133, and KDR antigens: CD34(+), CD133(+), KDR(+), CD34(+)CD133(+), CD34(+)KDR(+), CD133(+)KDR(+), and CD34(+)CD133(+)KDR(+). Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the right brachial artery with a high-resolution ultrasound machine following reactive hyperemia., Results: CD34(+)KDR(+) cell count was significantly lower in men with ED as compared with men without ED (63.1 +/- 4 vs. 92.4 +/- 6 cells/10(6) events, mean +/- standard error, P < 0.01). There was a significant direct correlation between circulating CD34(+)KDR(+) cells and the IIEF score (r = 0.44; P = 0.01): men with the severe form of ED presented the lowest level of circulating EPC CD34(+)KDR(+) cells. No significant correlation was found between the circulating levels of the other EPC phenotypes and the IIEF score. There was a significant correlation between CD34(+)KDR(+) cell count and FMD (r = 0.45; P = 0.01), but not between FMD and the other phenotypes., Conclusions: Circulating levels of CD34(+)KDR(+) EPC are reduced in overweight subjects with ED and correlate with the severity of ED. Other EPC phenotypes are not related to ED, suggesting that the CD34(+)KDR(+) phenotype of EPCs may be preferred in future studies.

Obesity has become a worldwide public health problem of epidemic proportions, as it may decrease life expectancy by 7 years at the age of 40 years: excess bodyweight is now the sixth most important risk factor contributing to the overall burden of disease worldwide. Overweight and obesity may increase the risk of erectile dysfunction (ED) by 30-90% as compared with normal weight subjects. On the other hand, subjects with ED tend to be heavier and with a greater waist than subjects without ED, and also are more likely to be hypertensive and hypercholesterolemic. The metabolic syndrome, characterized by a clustering of risk factors associated with insulin resistance and abdominal obesity, associates with ED. Moreover, women with the metabolic syndrome have an increased prevalence of sexual dysfunctions as compared with matched control women. Lifestyle changes aimed at reducing body weight and increasing physical activity induce amelioration of both erectile and endothelial functions in obese men. Moreover, preliminary evidence suggests that a Mediterranean-style diet might be effective in ameliorating sexual function in women with the metabolic syndrome. Lifestyle changes, mainly focussing on regular physical activity and a healthy diet, are effective and safe ways to reduce cardiovascular diseases and premature mortality in all population groups; they may also prevent and treat sexual dysfunctions in both sexes.

Purpose of Review: The objective of this article is to present evidence illustrating the relationship between Mediterranean diets and metabolic diseases, including obesity, type 2 diabetes, and the metabolic syndrome, and to briefly discuss potential mechanisms by which these diets can help in disease prevention and treatment., Recent Findings: Although the Mediterranean diet has long been celebrated for its impact on cardiovascular health, mounting evidence indicates a favorable effect on obesity and type 2 diabetes, as well. While health promotion strategies aimed at preventing adult obesity are emphasizing components of Mediterranean dietary patterns, a role for Mediterranean diets in attenuating the inflammatory burden associated with type 2 diabetes is also emerging. Moreover, a lower prevalence of the metabolic syndrome is associated with dietary patterns rich in fruits, vegetables, whole grains, dairy products, and unsaturated fats. Both epidemiological and interventional studies have revealed a protective effect of the Mediterranean diet against mild chronic inflammation and its metabolic complications., Summary: Mounting evidence suggests that Mediterranean diets could serve as an anti-inflammatory dietary pattern, which could help fighting diseases that are related to chronic inflammation, including visceral obesity, type 2 diabetes and the metabolic syndrome.

The concept of the metabolic syndrome, although controversial, continues to gain acceptance. Whereas each risk factor of the metabolic syndrome (visceral obesity, atherogenetic dyslipidemia, elevated blood pressure, and dysglycemia) can be dealt with individually, the recommended initial therapeutic approach is to focus on reversing its root causes of atherogenetic diet, sedentary lifestyle, and overweight or obesity. No single diet is currently recommended for patients with the metabolic syndrome, although epidemiologic evidence suggests a lower prevalence of the metabolic syndrome associated with dietary patterns rich in fruit, vegetables, whole grains, dairy products, and unsaturated fats. We conducted a literature search to identify clinical trials specifically dealing with the resolution of the metabolic syndrome by lifestyle, drugs, or obesity surgery. Criteria used for study selection were English language, randomized trials with a placebo or control group (except for surgery), a follow-up lasting>or=6 mo, and a time frame of 5 y. We identified 3 studies based on lifestyle interventions, 5 studies based on drug therapy, and 3 studies based on laparoscopic weight-reduction surgery The striking resolution of the metabolic syndrome with weight-reduction surgery (93%) as compared with lifestyle (25%) and drugs (19%) strongly suggests that obesity is the driving force for the occurrence of this condition. Although there is no "all-inclusive" diet yet, it seems plausible that a Mediterranean-style diet has most of the desired attributes, including a lower content of refined carbohydrates, a high content of fiber, a moderate content of fat (mostly unsaturated), and a moderate-to-high content of vegetable proteins.

Objectives: To discuss present knowledge about the relation between sexual dysfunction, metabolic factors and the Mediterranean-style diet., Design: Review of the literature and personal perspectives., Setting and Results: Sexual problems appear to be widespread in society, influenced by both health-related and psychosocial factors, and are associated with impaired quality of life. Epidemiological studies suggest that modifiable health behaviours, including physical activity and leanness, are associated with a reduced risk for erectile dysfunction (ED) among men. Data from other surveys also indicate a higher prevalence of impotence in obese men. Obesity and the metabolic syndrome may be a risk factor for ED. The high prevalence of ED in patients with cardiovascular risk factors suggests that abnormalities of the vasodilator system of penile arteries play an important role in the pathophysiology of ED. We have shown that one-third of obese men with ED can regain their sexual activity after 2 years of adopting health behaviours, including a Mediterranean-style diet associated with regular exercise., Conclusions: Western societies actually spend a huge part of their health care costs on chronic disease treatment and interventions for risk factors. The adoption of healthy lifestyles can reduce the prevalence of obesity and the metabolic syndrome, and hopefully the burden of sexual dysfunction.

Objectives: To discuss present knowledge about the relation between adipose tissue, inflammation and the Mediterranean-style diet., Design: Review of the literature and personal perspectives., Setting and Results: Recent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, which play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation which is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. An increased release of proinflammatory adipokines from the visceral adipose tissue, associated with a reduced secretion of anti-inflammatory adipokines and cytokines, could determine a low-grade chronic inflammatory state which might play a role in the future development of the metabolic syndrome, diabetes and atherosclerosis through both insulin resistance and endothelial dysfunction. Interventions aimed at decreasing weight loss and improving adherence to a Mediterranean-style diet in people with obesity or metabolic syndrome decrease the inflammatory milieu and ameliorate both insulin resistance and endothelial dysfunction., Conclusions: Appropriate dietary patterns, as those associated with the eating model of Mediterranean-type diets, represent therapeutic strategies to reduce inflammation and the associated metabolic and cardiovascular risk.

During the past 10 years, there has been a dramatic increase in the prevalence of obesity in the United States and other developed nations. Recent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, that play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation. Inflammation is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. According to a hypothesis, stimuli such as overnutrition, physical inactivity, and aging would result in cytokine hypersecretion and eventually lead to insulin resistance and diabetes in genetically or metabolically predisposed individuals. This article discusses the current understanding of important adipokines thought to be involved in the metabolic and cardiovascular risk associated with obesity. Available evidence linking fat removal by liposuction to modification of cardiovascular risk and vascular inflammatory markers in the obese patient is also presented. Most studies have shown that liposuction produces beneficial effects on insulin resistance and vascular inflammation in the obese patient, reducing its cardiovascular risk. Besides having a significant role in body contouring of the obese patient at the end of the lengthy process of bariatric surgery and massive weight loss, plastic surgery should be incorporated into a multifaceted program of lifestyle changes that allows the obese patient to obtain weight loss and, more importantly, to maintain the reduced weight in the long term.

Context: Cell-derived microparticles are supposed to be involved in atherogenesis., Objective: This study aimed to evaluate circulating microparticles in obese women and their relation with anthropometric measures and endothelial dysfunction., Design, Setting, and Participants: Forty-one obese [body mass index (BMI) > 30 kg/m(2)] women and 40 normal weight (BMI < 25 kg/m(2)) age-matched women were studied. Flow cytometry was used to assess microparticles by quantification of circulating endothelial microparticles (EMP, CD31+/CD42b-) and platelet microparticles (PMP, CD31+/CD42b+) in peripheral blood; endothelium-dependent flow-mediated vasodilation (FMD) was evaluated in the right brachial artery after reactive hyperemia., Results: Compared with lean women, obese women presented significantly higher numbers of EMP and PMP, and reduced FMD. BMI did not correlate with either EMP (r = 0.02, P = 0.9) or PMP (r = -0.07, P = 0.645), whereas waist-to-hip ratio (WHR) showed significant correlation with both microparticles (r = 0.699, P < 0.001; r = 0.373, P = 0.016, respectively). Both EMP and PMP counts positively correlated with impairment of FMD in obese women. Multivariate analysis correcting for age, anthropometric indices, lipid parameters, and PMP identified EMP as the only independent predictor for impaired endothelial-dependent vasodilation (P = 0.003)., Conclusions: EMP are elevated in obese women and independently involved in the pathogenesis of endothelial dysfunction. WHR is the anthropometric measure more closely related to EMP and endothelial dysfunction.

Sexual problems in both sexes appear to be widespread in society, influenced by both health-related and psychosocial factors, and are associated with impaired quality of life. Epidemiological studies suggest that modifiable health behaviors, including physical activity and leanness, are associated with a reduced risk for erectile dysfunction (ED) among men. Data from other surveys also indicate a higher prevalence of impotence in obese men. Obesity may be a risk factor for sexual dysfunction in both sexes; the data for the metabolic syndrome are very preliminary and need to be confirmed in larger epidemiologic studies. The high prevalence of ED in patients with cardiovascular risk factors suggests that abnormalities of the vasodilator system of penile arteries play an important role in the pathophysiology of ED. We have shown that one-third of obese men with ED can regain their sexual activity after 2 y of adopting health behaviors, mainly regular exercise and reducing weight. Western societies actually spend a huge part of their health care costs on chronic disease treatment and interventions for risk factors. The adoption of healthy lifestyles can reduce the prevalence of obesity and the metabolic syndrome, and hopefully the burden of sexual dysfunction.

Erectile and endothelial dysfunction may have some shared pathways through a defect in nitric oxide activity. We evaluated associations between erectile function, endothelial function and markers of systemic vascular inflammation in 80 obese men, aged 35-55 yr, divided into two equal groups according to the presence/absence of erectile dysfunction. Compared with non-obese age-matched men [no.=50, body mass index (BMI)=24 +/- 1], obese men (all) had impaired indices of endothelial function as suggested by the reduced mean blood pressure and platelet aggregation responses to L-arginine, and higher circulating concentrations of the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-18 (IL-18), as well as C-reactive protein (CRP). The mean erectile function score was 14 +/- 4 (range 7-19) in obese men with erectile dysfunction and 23.5 +/- 1 (range 22-25) in obese men without erectile dysfunction. Endothelial function showed a greater impairment in impotent obese men as compared with potent obese men. The mean blood pressure and platelet aggregation decreases following L-arginine were -1.5 +/- 1.1 mmHg and -1.1 +/- 1.2%, respectively, in obese men with erectile dysfunction, and -3.4 +/- 1.2 mmHg and -5.6 +/- 2.1%, respectively, in obese men without erectile dysfunction (p < 0.01). Circulating CRP levels were significantly higher in obese men with erectile dysfunction as compared with obese men without erectile dysfunction (p < 0.05). Erectile function score was positively associated with mean blood pressure responses to L-arginine and negatively associated with BMI, waist-to-hip ratio (WHR), and CRR Erectile and endothelial dysfunction associate in obese men and may contribute to their raised cardiovascular risk through impaired nitric oxide availability elicited by a low-grade inflammatory state.

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 > or =30) 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., Interventions: The 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 Measures: Erectile function score, levels of cholesterol and triglycerides, 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]) (P<.001), as did serum concentrations of interleukin 6 (P =.03), and C-reactive protein (P =.02). The mean (SD) level of physical activity increased more in the intervention group (from 48 [10] to 195 [36] min/wk; P<.001) than in the control group (from 51 [9] to 84 [28] min/wk; P<.001). The mean (SD) IIEF score improved in the intervention group (from 13.9 [4.0] to 17 [5]; P<.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., Conclusion: Lifestyle changes are associated with improvement in sexual function in about one third of obese men with erectile dysfunction at baseline.

Background: Hyperinsulinemia/insulin resistance and elevated plasma free fatty acids (FFA) levels are involved in the hypertension and cardiac sympathetic overactivity. Metformin improves insulin action and lower plasma FFA concentrations. We investigate the possible effect of metformin on arterial blood pressure (BP) and cardiac sympathetic nervous system., Methods: One hundred twenty overweight type 2 diabetic patients were treated by placebo (n = 60) + diet or metformin (850 mg twice daily) (n = 60) + diet for 4 months, to evaluate the effect of metformin treatment on the cardiac autonomic nervous system. Insulin resistance was measured by the Homeostasis Model Assessment (HOMA) index. Heart rate variability (HRV) assessed cardiac sympathovagal balance., Results: Metformin treatment, but not placebo treatment, was associated with a decrease in fasting plasma glucose (P <.05), insulin (P <.05), triglyceride (P <.05), and FFA (P <.03) concentrations and HOMA index (P <.03). Metformin treatment was also associated with a significant improvement in cardiac sympathovagal balance but not in mean arterial BP. Furthermore, in a multivariate analysis, delta change in sympathovagal balance index (LF/HF ratio) were associated with delta change in plasma FFA concentrations and HOMA index independently of gender and delta change in plasma triglyceride and HbA1c concentrations., Conclusions: Our study demonstrated that metformin treatment might be useful for improving cardiac sympathovagal balance in obese type 2 diabetic patients.

Objective: Obesity is an important risk factor for heart failure in both women and men. Dyssynchrony between right and left ventricular contraction and relaxation has been identified as an independent predictor of heart failure. We examined the relationship of ventricular synchronization abnormalities with the concentration of proinflammatory cytokines in obese women at baseline and after sustained weight loss., Research Design and Methods: Echocardiographic parameters of ventricular dyssynchrony, circulating levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18, and C-reactive protein (CRP) were investigated in 67 healthy, premenopausal obese women and 40 age-matched normal-weight women., Results: Compared with nonobese women, obese women had increased concentrations of CRP (P < 0.01), TNF-alpha (P < 0.01), IL-6 (P < 0.01), and IL-18 (P < 0.01). Moreover, obese women had a higher myocardial performance index (P < 0.02) and lower transmitral Doppler flow (P < 0.05), pulmonary venous flow analysis (P < 0.02), and ejection fraction (P < 0.05), indicating ventricular dyssynchrony. Concentrations of CRP, TNF-alpha, and IL-6 were related to anthropometric indexes of obesity and to echocardiographic parameters of ventricular dyssynchrony. After 1 year of a multidisciplinary program of weight reduction, obese women lost at least 10% of their original weight. This was associated with reduction of cytokine (P < 0.01) and CRP (P < 0.02) concentrations and with improvement of echocardiographic parameters of ventricular dyssynchrony, which correlated with changes in adiposity, particularly visceral adiposity., Conclusions: In obese women, ventricular dyssynchrony correlates with body fat, possibly through inappropriate secretion of cytokines. Weight loss represents a safe method for downregulating the inflammatory state and ameliorating cardiac function in obese women.

Objective: We describe associations among the heart-rate-corrected QT (QTc) interval, QTc dispersion (QTc-d), circadian BP variation, and autonomic function in obese normotensive women and the effect of sustained weight loss., Research Methods and Procedures: In 71 obese (BMI = 37.14 +/- 2.6 kg/m(2)) women, 25 to 44 years of age, circadian BP variations (24-hour ambulatory BP monitoring), autonomic function (power spectral analysis of RR interval oscillations), and cardiac repolarization times (QTc-d and QTc interval) were recorded at baseline and after 1 year of a multidisciplinary program of weight reduction., Results: Compared with nonobese age-matched women (n = 28, BMI = 23 +/- 2.0 kg/m(2)), obese women had higher values of QTc-d (p < 0.05) and QTc (p < 0.05), an altered sympathovagal balance (ratio of low-frequency/high-frequency power, p < 0.01), and a blunted nocturnal drop in BP (p < 0.01). In obese women, QTc-d and the QTc interval correlated with diastolic nighttime BP (p < 0.01) and sympathovagal balance (p < 0.01). Waist-to-hip ratio, free fatty acids, and plasma insulin levels correlated with QT intervals and reduced nocturnal drops in both systolic and diastolic BP and sympathovagal balance (p < 0.01). After 1 year, obese women lost at least 10% of their original weight, which was associated with decrements of QTc-d (p < 0.02), the QTc interval (p < 0.05), nighttime BP (p < 0.01), and sympathovagal balance (p < 0.02)., Discussion: Sustained weight loss is a safe method to ameliorate diastolic nighttime BP drop and sympathetic overactivity, which may reduce the cardiovascular risk in obese women.

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 > or =30) 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; P<.001), monounsaturated fat (2%; P =.009), and fiber (7 g/d; P<.001); had a lower ratio of omega-6 to omega-3 fatty acids (-5; P<.001); and had lower energy (-310 kcal/d; P<.001), saturated fat (-3.5%; P =.007), and cholesterol intake (-92 mg/d; P<.001) than controls. Body mass index decreased more in the intervention group than in controls (-4.2; P<.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 microg/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.

Obesity is associated with an increased risk of developing atherosclerosis and atherosclerotic lesions are essentially an inflammatory response. The aim of this study was to evaluate the effect of a medically supervised, multidisciplinary weight loss program on endothelial functions and circulating levels of proinflammatory cytokines in obese women. Twenty healthy pre-menopausal obese women and 20 age-matched normal weight women were studied. Endothelial functions were assessed by evaluating the response of blood pressure and platelet aggregation to an intravenous bolus of L-arginine (3 g), the natural precursor of nitric oxide. In obese women, the vascular and rheological responses to L-arginine were significantly lower (p < 0.05) at baseline, as compared with non-obese women, indicating endothelial dysfunction; on the contrary, basal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were significantly higher (p < 0.01). After one year of a multidisciplinary program of weight reduction consisting of diet, exercise and liposuction surgery, all obese women lost at least 10% of their original weight (10.5 +/- 1.7 kg, range 7.9-13.9 kg). Compared with baseline, sustained weight loss was associated with reduction of cytokine (p < 0.01) concentrations and with improvement of vascular responses to L-arginine. In conclusion, a multidisciplinary approach aimed at inducing a sustained reduction of body weight in obese women is feasible and is associated with improvement of endothelial functions and reduction of circulating proinflammatory cytokine concentrations.

The potential role of anti-inflammatory cytokines in human obesity is unknown. We tested the hypothesis that low serum IL-10 concentrations associate with the metabolic syndrome in obese women. Compared with 50 matched nonobese women, the prevalence of the metabolic syndrome (>/=3 of the following abnormalities: waist circumference, >88 cm; triglycerides, >1.69 mmol/liter; high density lipoprotein cholesterol, <1.29 mmol/liter; blood pressure, >130/85 mm Hg; glucose, >6.1 mmol/liter) was higher in 50 obese women (52% vs. 16%; P < 0.01). As a group, obese women had higher circulating levels of IL-6, C-reactive protein, and IL-10 than nonobese women. In both obese and nonobese women, IL-10 levels were lower in those with than in women without the metabolic syndrome: obese, 1.3 (0.7/2.1) pg/ml vs. 4.5 (4.3/7.4) pg/ml (median and quartiles; P < 0.01); and nonobese, 0.9 (0.7/1.3) pg/ml vs. 1.3 (0.9/3.3) pg/ml (P < 0.05). After 12 months of a lifestyle program, body weight decreased by 10.9 +/- 1.7 kg and was associated with a significant decrement of IL-6, C-reactive protein, and IL-10 levels; the decrease in IL-10 levels was confined to obese women without the metabolic syndrome. These results show that circulating levels of the anti-inflammatory cytokine IL-10 are elevated in obese women and that low IL-10 levels are associated with the metabolic syndrome.

Prolonged QT intervals and a reduced fall of nocturnal blood pressure (BP) both predict an increased risk of cardiovascular events in obese subjects. We evaluated circadian BP variations (24-h ambulatory BP monitoring), autonomic function (power spectral analysis of RR interval oscillations) and cardiac repolarization times (QTc-dispersion and QTc interval) in 70 obese women, aged 25-44 yr, grouped by WHR into group A (WHR > 0.85, no.=38) and group B (WHR < or = 0.85, no.=32). Compared with non-obese age-matched women (no.=25, BMI=23+/-1.8) and obese women of group B, obese women of group A had higher values of QTc-d (p<0.05) and QTc (p<0.05), an altered sympathovagal balance (ratio of low-frequency/high-frequency power, p<0.01), and a blunted nocturnal drop in BP (p<0.01). In group A, QTc-d and the QTc interval correlated with diastolic night BP (p<0.01) and sympathovagal balance (p<0.01). WHR and plasma insulin levels correlated with QT intervals, reduced nocturnal fall in diastolic BP and sympathovagal balance (p<0.01). Prolongation of cardiac repolarization times and the reduction of nocturnal fall in BP coexist in obese women with visceral obesity, and might contribute to their raised cardiovascular risk. Autonomic dysfunction may be the common mechanism for this association.

Obesity is associated with an increased risk of developing atherosclerosis, which may be mediated, at least in part, by increased secretion of proinflammatory cytokines by adipose tissue. We examined the hypothesis that circulating levels of IL-18 were elevated in obese women and would be reduced by weight loss. In a sample of 40 obese (body mass index, 36.4 +/- 3.1 kg/m(2)) women we found that plasma IL-18 levels were higher than in 40 normal weight control women (P < 0.01) and were positively associated with body weight (r = 0.46; P < 0.01) and visceral fat (waist to hip ratio; r = 0.39; P < 0.01). Caloric restriction-induced weight loss (> or = 10% of original weight) over 1 yr reduced IL-18 levels from 247 (204/309) to 147 (111/210) pg/ml (medians and 25%/75%; P < 0.01), positively associated with changes in body mass index and waist to hip ratio. In obese women, IL-18 levels are associated with body weight and abdominal fat deposition; weight loss is an important intervention to reduce IL-18 levels. IL-18 may be a novel cytokine operating in human obesity.

We evaluated 66 obese patients grouped by waist-to-hip ratio (WHR) into group A (WHR > 0.85, n = 30) and group B (WHR < or = 0.85, n = 36), before and after 1 yr of diet-induced weight loss compared with 25 nonobese women. Before diet, the longest values of QT intervals and the highest levels of FFA and catecholamines were in group A (P < 0.01). In obese women (both groups), the corrected QT (QTc); interval correlated with plasma FFA (P < 0.01) and catecholamine (P < 0.02) concentrations. After 1 yr of diet, at the same levels of body weight reduction, the decrement of the QTc interval (P < 0.02), FFA (P < 0.01) and catecholamine (P < 0.02) levels were significantly greater in-group A than group B. In multivariate analysis, the decline of the QTc interval after weight loss was associated with changes in plasma FFA independently of changes in WHR and plasma catecholamines. Our data suggest that the QTc interval is tightly correlated with plasma FFA levels; shortening of cardiac repolarization times in the course of long-lasting weight reduction may reduce the risk of ventricular electrical instability, especially in women with abdominal adiposity.

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 37.2+/-2.2, 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-alpha (TNF-alpha, P<0.01), interleukin-6 (IL-6, P<0.01), P-selectin (P<0.01), intercellular adhesion molecule-1 (ICAM-1, P<0.02), and vascular adhesion molecule-1 (VCAM-1, P<0.05). Vascular responses to L-arginine (3 g IV), the natural precursor of nitric oxide, were impaired in obese women: reductions in mean blood pressure (P<0.02), platelet aggregation to adenosine diphosphate (P<0.05), and blood viscosity (P<0.05) were significantly lower as compared with those in the nonobese group. Concentrations of TNF-alpha and IL-6 were related (P<0.01) 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 (9.8+/-1.5 kg, range 7.5 to 13 kg). Compared with baseline, sustained weight loss was associated with reduction of cytokine (P<0.01) and adhesin (P<0.02) concentrations and with improvement of vascular responses to L-arginine., Conclusion: In obese women, endothelial activation correlates with visceral body fat, possibly through inappropriate secretion of cytokines. Weight loss represents a safe method for downregulating the inflammatory state and ameliorating endothelial dysfunction in obese women.

Background: It has been hypothesized that metformin inhibits food intake, but in humans such effect needs to be demonstrated. Our study aims at investigating the effect of metformin administration on food intake in obese, non-diabetic, normotensive patients., Methods: Thirty patients underwent a double-blind, randomized study. Placebo (P; n = 15) and metformin (M; n = 15) were both given for 15 days, and food intake (FI) was recorded at baseline and in the last 4 days of each treatment period., Results: M administration allowed a stronger decline in body weight (BW) (-2.8 +/- 1.6 vs. -0.3 +/- 0.4 kg P < 0.01), body fat (BF) (-1.4 +/- 1.2 vs. -0.3 +/- 1.1 kg P < 0.01), plasma leptin concentration (-5.2 +/- 8.9 vs. -1.8 +/- 10.4 ng mL-1 P < 0.05) and FI (-642 +/- 491 vs.-70 +/- 1165 kJ per 24 h P < 0.01) than P. In M-treated subjects, changes in FI significantly correlated with those in BW (r = 0.63, P < 0.007) and BF (r = 0.74, P < 0.001). Independently of sex and change in BF, the changes in FI and in fasting plasma leptin concentration (r = 0.58, P < 0.01) were still correlated., Conclusion: Our study suggests that metformin administration is useful to inhibit FI and to lower BW and BF in obese non-diabetic patients.

The involvement of the opioid system in human obesity has been demonstrated, but whether the abnormalities in the endorphinergic system play a primary role in overfeeding and weight gain or represent a simple biochemical feature is still unclear. The objectives of this study were to investigate the effects of both physiological and pharmacological plasma beta-endorphin levels on some metabolic and hormonal parameters in a normal weight, but prone to obesity, young population consisting of first degree relatives of obese subjects and in body mass index-, sex, and age- matched control subjects without a family history of obesity. Each subject underwent a 1-h infusion of synthetic human beta-endorphin at a constant rate of 4.5 ng/kg.min (low rate), then after a 1-week interval, at a rate of 500 micrograms/h (high rate). Under basal conditions, there was no significant difference in plasma glucose and pancreatic hormones (insulin, C peptide, and glucagon) between the two groups, except for plasma beta-endorphin levels, which were significantly (P < 0.01) higher in relatives of obese individuals. The low rate of beta-endorphin infusion induced physiological elevations of plasma opioid levels in both groups; no significant change in plasma glucose and pancreatic products in control subjects; and a significant (at least P < 0.05) rise in plasma insulin, C peptide, and glucagon concentrations in relatives of the obese. The high rate of beta-endorphin infusion produced pharmacological elevations of opioid plasma levels in both groups; significant (at least P < 0.05) increments in plasma glucose and glucagon levels and no appreciable modification of plasma insulin and C peptide levels in the control group; and a significant (at least P < 0.05) positive response of plasma glucose, insulin, C peptide, and glucagon levels in relatives of obese subjects. These findings suggest that 1) opioid peptides at least in part play a primary, rather than secondary, role in some metabolic events of obesity; and 2) both physiological and pharmacological plasma levels of beta-endorphin are able to provoke marked islet hormone release in the early phase of human obesity.

Objective: To determine the effects of metformin on blood pressure, left ventricular mass, and some metabolic and endocrine parameters in nondiabetic, obese, hypertensive women., Research Design and Methods: Twelve obese, nondiabetic, hypertensive women received 850 mg metformin 2 times/day for 12 wk and placebo for another 12 wk, according to a double-blind, cross-over, randomized design. All patients were hospitalized 4 times, i.e., before randomization and after each treatment (metformin or placebo), to conduct metabolic and cardiovascular investigations (oral glucose tolerance test, euglycemic clamp associated with indirect calorimetry, and echocardiography)., Results: Fasting glucose, HbA1c, fasting and glucose-stimulated insulin, blood pressure and left ventricular mass, cholesterol, triglycerides, and fibrinogen decreased significantly after metformin treatment, whereas high-density lipoprotein cholesterol increased. The improvement in glucose metabolism resulted from increased sensitivity to insulin., Conclusions: These findings suggest that metformin treatment in obese, nondiabetic, hypertensive women produces a more favorable cardiovascular risk profile.

The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose -4.1 mmol.l-1; glycosylated haemoglobin A1 decrease -1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These positive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile < 10 mmol.l-1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile > 10 mmol.l-1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (-21.6 U/day). Metformin was well tolerated by all diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.

The discovery of several endogenous substances with morphine-like activity (endorphins and enkephalins) which possess potent behavioral effects, interfering with food and water intake, has led to suggest their implications in the pathogenesis of human obesity. This suggestion is mainly based on: 1) the ability of opiate antagonists naloxone and naltrexone to reduce food intake in some particular situations associated with obesity: 2) the existence of raised plasma levels of beta-endorphin in obese children and adults not corrected by weight loss; and 3) the increased responsiveness to the metabolic and hormonal effects of opiate agonism and antagonism found in obese but not in normal weight subjects. Although the problem still awaits a definite answer, it seems not hazardous to hypothesize a role for beta-endorphin in some pathogenetic events associated with human obesity.

The responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin (0.5 mg/h) were studied in 10 formerly obese subjects who had lost 35 kg by dieting (body mass index less than 25) and compared with those of 10 normal-weight control (body mass index less than 25) and 10 obese (body mass index greater than 30) subjects. The fasting plasma concentrations of beta-endorphin were significantly higher in both the obese and the post-obese group than in the control group. In both obese and post-obese subjects, the infusion of beta-endorphin caused significant increases in peripheral plasma glucose, insulin, C-peptide and glucagon concentrations. In the control group, matched for age, sex and weight with the formerly obese group, there was no appreciable change in plasma insulin and C-peptide concentrations during the infusion of beta-endorphin, but the rise in plasma glucose was more sustained. Thus, 1. the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; and 2. formerly obese, normal-weight subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin infusion. The alteration of the opioid system in human obesity may play some role in the predisposition to weight gain.

Several experimental data have documented the ability of both opiates and opioid peptides to stimulate food intake. On the other hand, the plasma beta-endorphin levels found in obese patients are higher than those observed in normal-weight controls, which may have pathogenetic implications. We have investigated the responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin in formerly obese subjects who had obtained by dieting the normalization of body weight and in lean controls. The data show that: a) the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; b) formerly obese subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin.

Catecholamines and endogenous opioid peptides are released in response to stress. Exogenous infusions of epinephrine and beta-endorphin (both in doses of 15, 50, and 80 ng/kg.min sequentially, each dose lasting 30 min) were used to mimic short term stress in both normal weight (body mass index, less than 25 kg/m2) and obese (body mass index, greater than 30 kg/m2) subjects. Fasting plasma insulin, C-peptide, and beta-endorphin concentrations were significantly higher in the obese than in the normal subjects (P less than 0.01-0.005). In lean subjects epinephrine produced significant increases in plasma glucose levels, but no appreciable changes in plasma insulin, C-peptide, or glucagon. Infusion of beta-endorphin in the same subjects caused plasma glucose and glucagon to rise, but insulin and C-peptide levels did not change. The simultaneous infusion of epinephrine and beta-endorphin produced a glycemic response which, although greater, was not significantly different than the sum of the responses to the individual hormone infusions. However, the two hormones had a synergistic interaction on plasma glucagon levels [total glucagon response, 2275 +/- 370 pg/min.mL (ng/min.L); sum of single effects, 750 +/- 152 (+/- SE) pg/min.mL (ng/min.L); P less than 0.01]. The plasma epinephrine [207 +/- 21, 607 +/- 70, and 1205 +/- 134 pg/mL (1130 +/- 115, 3640 +/- 382, and 6577 +/- 691 pmol/L] and beta-endorphin [875 +/- 88, 1250 +/- 137, and 1562 +/- 165 pg/mL (250 +/- 25, 358 +/- 39, and 447 +/- 47 pmol/L] concentrations attained during the infusions of each single hormone were not different from those recorded during the combined hormonal infusion. In obese subjects epinephrine raised plasma glucose levels and caused dose-related increments of plasma glucagon concentrations. Plasma insulin and C-peptide concentrations remained low and rebounded at the end of the infusions. In the same subjects, beta-endorphin produced elevations of plasma glucose, insulin, C-peptide, and glucagon. When the combined hormonal infusion was given to obese subjects, the plasma epinephrine and beta-endorphin concentrations rose to values not significantly different from those in normal weight subjects. However, there was a dramatic increase in plasma glucose exceeding 200 mg/dL (11.1 mmol/L), which remained elevated 30 min after the infusion. The glucagon response was not greater than the sum of the single effects.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of human beta-endorphin on plasma glucose, insulin, and glucagon concentrations was studied in patients with noninsulin-dependent diabetes mellitus and in normal subjects. The subjects were divided according to their body weight into lean (body mass index, less than 25) and obese (body mass index, greater than 29.5) groups. In lean subjects, infusion of 0.5 mg/h beta-endorphin caused significant increases in peripheral plasma glucose and glucagon levels, but no change in plasma insulin. In obese subjects, there was an immediate marked increase in both plasma insulin and glucagon concentrations during the beta-endorphin infusion, but the plasma glucose response was lower than that of lean subjects. In lean diabetic patients, beta-endorphin produced significant simultaneous increments in both insulin and glucagon concentrations and significantly decreased plasma glucose levels. These hormonal responses to beta-endorphin were amplified in the obese diabetic patients. There was a significant correlation (r = 0.61; P less than 0.01) between fasting plasma glucose levels and the integrated insulin area in response to beta-endorphin. The infusion of a lower dose of beta-endorphin (0.05 mg/h) in diabetic patients produced similar increments in both insulin and glucagon levels and also decreased plasma glucose concentration. These results indicate that beta-endorphin may have important glucoregulatory effects in man depending on the dose administered, the presence of obesity, and the prevailing plasma glucose concentration.