Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome

Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP), has recently been linked to obesity, insulin resistance syndromes such as polycystic ovary syndrome (PCOS), and an increased risk of cardiovascular disease. Because the insulin sensitizer metformin has been shown to improve metabolic disturbances in PCOS, it was of particular interest to examine serum CRP levels during metformin therapy. Twenty nonobese women [body mass index (BMI) /==" BORDER="0"> 27 kg/m(2)) with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months) or ethinyl estradiol (35 micro g)-cyproterone acetate (2 mg) oral contraceptive pills. The serum concentrations of CRP were significantly higher in obese than in nonobese subjects at baseline [4.08 +/- 0.53 (SE) vs. 1.31 +/- 0.28 mg/liter; P < 0.001] and correlated to BMI and to a lesser extent waist-hip ratio, suggesting that the elevated CRP levels may be related to obesity and not only to PCOS itself. During metformin treatment, serum CRP levels decreased significantly from 3.08 +/- 0.7 mg/liter to 1.52 +/- 0.26 mg/liter at 6 months in the whole study population (P = 0.006) and especially in obese subjects. In contrast, the treatment with ethinyl estradiol-cyproterone acetate increased serum CRP levels from 2.91 +/- 0.68 mg/liter to 4.58 +/- 0.84 mg/liter (P < 0.001). Whether this effect is related to estrogen action in the liver or whether it reflects increased inflammation process and possible risks for cardiovascular disease remains unclear. The decrease of serum CRP levels during metformin therapy is in accordance with the known beneficial metabolic effects of this drug and suggests that CRP or other inflammation parameters could be used as markers of treatment efficiency in women with PCOS.     

Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors

OBJECTIVE:. To examine the hypothesis that patients with systemic lupus erythematosus (SLE) have increased concentrations of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) and that these cytokines are associated with coronary risk factors and atherosclerosis. METHODS: Plasma IL-6, MCP-1, and serum IL-8 (pg/ml) concentrations were measured in 74 patients with SLE and in 85 controls. Clinical characteristics, homocysteine, lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and coronary artery calcification as detected by electron beam computed tomography were measured. RESULTS: IL-6 (13.2 +/- 13.8 pg/ml vs 6.7 +/- 3.2 pg/ml, p < 0.001) and MCP-1 (264.2 +/- 581.8 pg/ml vs 131.0 +/- 63.7 pg/ml, p < 0.001) concentrations were higher in patients with lupus than in controls. IL-8 concentrations did not differ between patients and controls (p = 0.86). In patients, IL-6 concentrations were correlated with CRP (p < 0.001), ESR (p < 0.001), SLE disease activity index (SLEDAI, p = 0.003), and body mass index (BMI, p = 0.003). IL-6 concentrations were inversely correlated with HDL cholesterol (p = 0.01). MCP-1 concentrations were correlated with SLEDAI (p = 0.01), ESR (p = 0.04), and triglycerides (p = 0.03). After controlling for age, sex, disease activity, SLICC damage index, smoking status, and systolic blood pressure, IL-6 was associated with coronary calcification (odds ratio, OR = 1.07, p = 0.035). Similar models found no association between MCP-1 or IL-8 with coronary artery calcification. CONCLUSION: Patients with SLE have increased concentrations of IL-6 and MCP-1. These cytokines are associated with increased inflammation, BMI, and adverse lipid profiles. IL-6 is associated with burden of atherosclerosis in SLE.     

The effect of orlistat-induced weight loss on interleukin-6 and C-reactive protein levels in obese subjects

OBJECTIVE: Inflammation plays a major role in the pathogenesis of atherosclerosis. Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue. The aim of this study is to investigate changes in the inflammatory markers interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) during weight reduction with orlistat treatment in obese patients. METHODS AND RESULTS: Thirty-six obese (BMI: 36.1 +/- 3.4 kg/m2) and II non-obese (BMI: 22.9 +/- 1.7 kg/m2) subjects were studied. IL-6 and hs-CRP levels were evaluated at baseline. In obese subjects after treatment of orlistat 120 mg three times daily for 6 months, IL-6 and hs-CRP levels were repeated. Levels of circulating IL-6 (p < 0.05) and hs-CRP (p < 0.01) were significantly higher in the obese group than in the non-obese group. Plasma IL-6 (r = 0.29 and p < 0.05) and CRP (r = 0.35 and p < 0.05) concentrations correlated positively with the level of obesity assessed by BMI at baseline. After 6 months of orlistat treatment in obese subjects, the mean weight of the patients decreased by 6.8 kg, the BMI by 3.2 kg/m2. Compared with baseline, weight loss was associated with significant reductions of IL-6 (p < 0.001) and hs-CRP (p < 0.001) levels. CONCLUSION: In summary plasma IL-6 and hs-CRP levels were increased in obese patients. Orlistat-induced weight reduction was associated with decreasing levels of both IL-6 and hs-CRP in obese subjects. Because inflammatory mediators may be directly involved in atherogenesis, this would suggest that interventions to reduce IL-6 and CRP levels could be cardioprotective.     

Adipokine dysregulation in turner syndrome: comparison of circulating interleukin-6 and leptin concentrations with measures of adiposity and C-reactive protein

Women with Turner syndrome (TS) have increased risks of atherosclerosis, diabetes mellitus, and obesity. We hypothesized that women with TS have adverse metabolic or inflammatory markers for cardiovascular disease compared with normal women and estrogen-deficient controls. This was a cross-sectional study conducted at University College London Hospitals, UK. One hundred seventeen estrogen-treated women with TS and normal fasting blood glucose were compared with 30 age-matched normal controls and 31 estrogen-treated women with 46,XX premature ovarian failure (POF). The main outcome measures were markers of the metabolic syndrome, including the adipokines IL-6 and leptin, and C-reactive protein (CRP). TS women were more obese than controls (waist circumference, 79.9 +/- 12.4, 73.5 +/- 6.9, and 74.7 +/- 8.6 cm in TS, normal subjects, and POF controls, respectively; P = 0.005; body mass index, 26.8 +/- 5.8, 23.7 +/- 3.2, and 22.9 +/- 3.4 kg/m2; P < 0.001). This obesity was associated with increased CRP (2.9 +/- 1.5, 0.8 +/- 1.0, and 1.2 +/- 0.9 mg/liter; P < 0.001) and IL-6 concentrations (1.5 +/- 0.7, 1.0 +/- 1.5, and 1.2 +/- 0.5 pg/ml; P = 0.014), but lower fasting serum insulin (4.7 +/- 2.3, 6.3 +/- 3.0, and 6.9 +/- 2.9 mIU/ml; P = 0.004), glucose (83 +/- 11, 90 +/- 7, and 90 +/- 7 mg/dl; P < 0.001), and leptin (10.2 +/- 6.3, 14.4 +/- 7.6, and 14.8 +/- 8.1 ng/ml; P = 0.048). Triglyceride concentrations were similar in TS and POF women and were greater than in normal controls (97 +/- 53, 97 +/- 53, and 71 +/- 27 mg/dl; P = 0.024). We conclude that women with TS have various physical and biochemical features suggestive of the metabolic/insulin resistance syndrome, but there is a discrepancy among CRP, IL-6, and leptin, with leptin and fasting insulin concentrations being lower than expected for the degree of obesity. Obesity and estrogen therapy do not fully explain these findings. Women with TS may have specific metabolic defects contributing to cardiovascular risk.     

Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women

The endogenous nitric oxide-synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is elevated in patients with increased risk for arteriosclerosis. Obesity is a risk factor for cardiovascular disease. We measured plasma ADMA concentrations in morbidly obese women before and after weight loss following gastroplastic surgery. ADMA and symmetrical dimethyl-L-arginine concentrations were analyzed by HPLC from 34 female patients (age 41 +/- 7 yr) with a body mass index (BMI) of 49 +/- 1 kg/m2 before and 14 months after vertical ring gastroplasty. Age-matched healthy women (BMI < 25 kg/m2; n = 24) were studied as controls. After gastroplastic surgery, BMI decreased to 34 +/- 1 kg/m2 in obese women (P < 0.00001), and ADMA concentrations were reduced from 1.06 +/- 0.06 micromol/liter at baseline to 0.81 +/- 0.04 micromol/liter after weight loss (P < 0.00001). Symmetrical dimethyl-L-arginine plasma levels were not affected. ADMA correlated with high-sensitivity C-reactive protein at baseline (r = 0.42; P < 0.05) and after weight loss (r = 0.56; P < 0.005). No association with blood pressure or plasma lipids could be observed. ADMA concentrations were lower in controls (0.68 +/- 0.04 micromol/liter; P < 0.05) compared with obese patients before or after weight reduction. The decrease of highly elevated ADMA concentrations in morbidly obese patients is paralleled by improvement of parameters associated with the metabolic syndrome after weight loss.     

Unchanged asymmetric dimethylarginine levels in non-diabetic, premenopausal obese women who have common risk factors for cardiovascular disease

This study was performed to test whether plasma asymmetric dimethylarginine (ADMA) concentrations are related to obesity and obesity complications including decrement in insulin sensitivity and adiponectin levels, dyslipidemia and low-grade inflammation. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations were analyzed by HPLC in 17 overweight (BMI ≥ 25 kg/m²) and 40 obese (BMI ≥ 30 kg/m²) premenopausal women. Age-matched healthy women were studied as controls. Obesity did not give rise to a significant change in circulating ADMA levels but reduced in SDMA levels. As compared with control subjects (0.441 ± 0.102 μM), ADMA values in overweight and obese subjects were found to be as 0.412 ± 0.102 and 0.436 ± 0.093, respectively. No Pearson’s association of ADMA with relevant risk variables for cardiovascular disease, including blood pressure, insulin sensitivity, inflammatory markers, lipid and adiponectin levels. However, in linear regression analysis, BMI, diastolic blood pressure, glucose, insulin, and IL-8 emerged as significant predictors of ADMA. In spite of obese women have elevated hs-CRP, triglyceride levels and decreased insulin sensitivity, adiponectin and HDL-cholesterol levels, all of which is closely linked risk factors for cardiovascular disease, circulating ADMA levels remained unchanged in obese individuals as compared with controls.     

Growth hormone reduces inflammation in postmenopausal women with abdominal obesity: a 12-month, randomized, placebo-controlled trial

CONTEXT: Abdominal obesity is associated with low GH secretion, elevated circulating markers of inflammation, and increased risk of cardiovascular disease. OBJECTIVE: The objective was to study the effect of GH treatment on inflammatory markers and vascular adhesion molecules in postmenopausal women with abdominal obesity. DESIGN: Forty women aged 51-63 yr received GH (0.67 mg/d) in a randomized, double-blind, placebo-controlled, 12-month trial. Measurements of inflammatory markers [highly sensitive C-reactive protein (CRP), IL-6, and amyloid polypeptideA] and markers of endothelial dysfunction (soluble E-selectin, vascular adhesion molecule-1, intercellular molecule-1, and matrix metalloproteinase-9) were performed at baseline and after 6 and 12 months of treatment. RESULTS: After 12 months, the mean IGF sd score was 0.9 +/- 1.5 and -0.8 +/- 0.6 in the GH and placebo groups, respectively. GH treatment reduced CRP and IL-6 levels compared with placebo (P = 0.03 and P = 0.05, respectively), whereas the markers of endothelial dysfunction were unaffected. Within the GH-treated group, a reduction was shown in CRP (4.3 +/- 4 to 3.0 +/- 3 mg/liter; P < 0.05) and in IL-6 (4.4 +/- 2 to 3.3 +/- 2 ng/liter; P < 0.01). In the GH-treated group, the decrease in CRP and IL-6 correlated with a reduction in visceral adipose tissue (r = 0.7, P < 0.001 and r = 0.5, P < 0.05, respectively). CONCLUSION: GH treatment in postmenopausal women with abdominal obesity reduced serum markers of systemic inflammation. Circulating markers of endothelial dysfunction were unaffected by treatment.     

Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C

Obesity and fatty liver are commonly observed among patients with chronic hepatitis C virus (HCV) and are risk factors for increased hepatic fibrosis. Obesity is accompanied by a low-grade, chronic inflammatory response that may contribute to pathogenesis of obesity-related comorbidities. To assess whether obesity and steatosis potentiate expression of inflammatory markers in chronic HCV, serum protein and hepatic messenger RNA (mRNA) levels of c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were measured in 171 patients with chronic HCV. The relationships of body mass index, steatosis, histological features of inflammation and fibrosis with serum and hepatic levels of these factors were determined. In comparison with lean patients, overweight and obese subjects had increased circulating (P < 0.001) and hepatic (P = 0.003) CRP, and there was a significant correlation between serum protein and hepatic CRP mRNA levels (r(s)= 0.51, P < 0.001). Obesity (P = 0.001) and steatosis (P < 0.001) were associated with increased circulating but not hepatic IL-6, and a weak correlation was seen between serum protein and hepatic IL-6 mRNA levels (r(s)= 0.29, P = 0.003). An independent relationship was seen between hepatic TNF-alpha mRNA levels and higher total inflammatory score (P < 0.001) and stage of fibrosis (P = 0.037). Subjects with HCV genotype 3 had lower hepatic TNF-alpha mRNA levels compared with subjects with genotype 1 (P = 0.017), but there was no relationship between serum TNF-alpha protein and hepatic TNF-alpha mRNA levels. CONCLUSION: In patients with chronic HCV, obesity and steatosis are associated with increased expression of selected inflammatory markers; however, circulating levels of IL-6 and TNF-alpha do not reflect hepatic expression. Hepatic TNF-alpha was associated with both increased inflammatory activity and hepatic fibrosis, providing support for the key role of this pro-inflammatory cytokine in liver injury in chronic HCV.     

Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women

OBJECTIVE: Obesity is linked to the insulin resistance syndrome (IRS), type 2 diabetes (T2D) and cardiovascular disease. Markers of chronic subclinical inflammation such as high-sensitive C-reactive protein (hs-CRP) and interleukin 6 (IL-6) are closely related to insulin resistance and obesity. Recent evidence suggests that adiponectin, a protein whose circulating levels are decreased in obesity, has anti-inflammatory properties, and also appears to enhance potently insulin action and therefore appears to function as a signal produced by adipose tissue that influences whole-body glucose metabolism. SUBJECTS AND METHODS: We investigated the cross-sectional and longitudinal association of adiponectin with CRP and IL-6 in 41 morbidly obese women with different stages of glucose tolerance before and 17 months after significant weight loss induced by gastric surgery. Adiponectin was measured by RIA. CRP and IL-6 were determined by commercially available ELISA systems. RESULTS: Weight loss induced a significant shift from T2D (preoperatively 34% vs postoperatively 2%) to impaired glucose tolerance (IGT) (37% preoperatively vs 30% postoperatively) and normal glucose tolerance (NGT) (29% preoperatively vs 68% postoperatively). Preoperatively adiponectin levels were negatively correlated with CRP (r=-0.59, P<0.0006), IL-6 (r=-0.42, P<0.02) and leukocytes (r=-0.41, P<0.007). After gastroplasty, adiponectin concentrations increased significantly (15.4+/-8.2 vs 19.8+/-6.2 microg/ml, P<0.005) associated with changes of weight and body mass index (r=-0.45, P<0.007; r=-0.35, P<0.04). Furthermore, preoperative CRP was significantly associated with changes in adiponectin even after adjustment for sex, age, preoperative body mass index (BMI) impaired glucose metabolism and changes in BMI and changes in BMI (standardized beta 0.61, P=0.005). CONCLUSION: Levels of adiponectin, which are associated with markers of chronic subclinical inflammation, could be significantly increased after weight loss in morbidly obese patients. This increase was more pronounced in patients with NGT compared to those with T2D and IGT. Preoperative levels of CRP are predictive for changes of adiponectin after weight loss.     

CRP reduction following gastric bypass surgery is most pronounced in insulin-sensitive subjects

OBJECTIVE: Obesity is frequently associated with insulin resistance, dyslipidemia, hypertension and an increased risk of cardiovascular disease, reflected in elevated markers of inflammation, in particular C-reactive protein (CRP). To what extent the insulin resistance or the obesity per se contributes to increased CRP levels is unclear. In morbidly obese patients, gastric bypass surgery causes marked changes in body weight and improves metabolism, thereby providing informative material for studies on the regulation of inflammatory markers. DESIGN: Prospective, surgical intervention study of inflammatory markers in morbidly obese subjects. SUBJECTS: In total, 66 obese subjects with mean age 39 y and mean body mass index (BMI) 45 kg/m2 were studied prior to and 6 and 12 months following Roux-en-Y gastric bypass (RYGBP) surgery. MEASUREMENTS: Serum concentrations of high sensitivity CRP, serum amyloid A (SAA) and interleukin-6 (IL-6), as well as markers of glucose and lipid metabolism. RESULTS: Prior to surgery, CRP levels were elevated compared to the reference range of healthy, normal-weight subjects. CRP correlated with insulin sensitivity, as reflected by the homeostatic model assessment (HOMA) index, but not BMI, when corrected for age and gender. Surgery reduced BMI from 45 to 31 kg/m2 and lowered CRP, SAA and IL-6 levels by 82, 57 and 50%, respectively, at 12 months. The reduction in CRP was inversely related to HOMA at baseline independently of the change in body weight (r=-0.36, P=0.005). At 12 months, 140 and 40% reductions in CRP were seen in subjects with HOMA < 4 (insulin sensitive) and HOMA>9 (insulin resistant) despite similar reductions in BMI. Reductions in SAA and IL-6 tended to parallel the changes in CRP, but were less informative. CONCLUSION: In morbidly obese subjects, gastric bypass surgery lowers energy intake, reduces inflammatory markers and improves insulin sensitivity. Despite a marked reduction in body weight, only a small effect on CRP levels was seen in insulin-resistant patients, indicating that flexibility of circulating CRP levels is primarily dependent upon insulin sensitivity rather than energy supply.     

Innate immunity in obese asthmatic allergic and nonallergic adults

Obesity is characterized by activation of the innate immune responses and low grade systemic inflammation with increased levels of inflammatory cytokines. In the past two decades, the prevalence of both asthma and obesity has increased dramatically. The aim of the present study is to examine the relationship between innate immunity, obesity and asthma in allergic and non allergic obese persons by estimating interleukin-6 (IL-6) and C-reactive protein (CRP) levels as markers of innate immunity. The study included 2 groups of asthmatic patients; 50 obese asthmatic and 50 lean asthmatic patients. The obese asthmatic group included 25 allergic obese and 25 non-allergic obese asthmatics. Similarly the lean asthmatic group included 25 allergic and 25 non-allergic lean asthmatics. Body mass index (BMI), skin prick test, serum total IgE, peak expiratory flow rate (PEFR), interleukin-6 (IL-6) and C-reactive protein (CRP) levels were all assessed. A significant difference was found between allergic and non-allergic obese asthmatics and between allergic and non-allergic lean asthmatics as regards IgE, IL-6 and CRP (P=0.000). Comparison between allergic obese asthmatics and allergic lean asthmatics as regards BMI, IL-6 and CRP revealed high significant differences (P=0.000). In contrast no significant differences existed between them as regards IgE, PEFR (P=0.621, P=0.321 respectively). Comparison between non-allergic obese asthmatics and non-allergic lean asthmatics as regards BMI, IL-6 and CRP levels revealed highly significant differences (P=0.000). While no significant difference existed between them as regards IgE and PEFR (P=0.14, P=0.336 respectively). A significant negative correlation was found between PEFR and IgE in all groups (P=0.000) and negative correlation between PEFR and IL-6, CRP in all groups (P=0.000) except for allergic obese asthmatics group. Meanwhile, there was a significant positive correlation between BMI and IL-6 and CRP in both allergic and non-allergic obese asthmatics (P=0.000). In conclusion, obesity is associated with activation of the innate immune system leading to release of inflammatory cytokines more in non-allergic obese than allergic obese asthmatics. Control of obesity in such patients may lead to control of asthma.     

C-reactive protein and gestational diabetes: the central role of maternal obesity

Acute-phase biomarkers such as C-reactive protein (CRP) and IL-6 have emerged as predictors of incident type 2 diabetes mellitus, implicating chronic subclinical inflammation as a factor in the pathophysiology of diabetes. Gestational diabetes (GDM) identifies a population of women at high risk of subsequent type 2 diabetes mellitus, representing an early stage in the natural history of the disease. In this context, we performed a cross-sectional study to determine whether markers of subclinical inflammation are elevated in patients with GDM. We studied 180 healthy pregnant women undergoing oral glucose tolerance testing in the late second or early third trimester. Based on oral glucose tolerance testing and prepregnancy body mass index (BMI), participants were stratified into four groups: 1) normal glucose tolerance (NGT) lean (BMI, <25 kg/m(2)) (n = 65); 2) NGT overweight (n = 28); 3) impaired glucose tolerance (n = 39); and 4) GDM (n = 48). Median CRP level was highest in overweight NGT subjects (8.8 mg/liter), followed by GDM (5.5 mg/liter), impaired glucose tolerance (4.4 mg/liter), and lean NGT (4.4 mg/liter) (overall P = 0.0297). CRP was significantly correlated with prepregnancy BMI (r = 0.38, P < 0.0001), followed by fasting insulin (r = 0.27, P = 0.0002) and fasting blood glucose (r = 0.18, P = 0.016). In multivariate linear regression analysis, prepregnancy BMI emerged as the most important determinant of CRP concentration, whereas glycemic tolerance status was not a significant factor. Furthermore, the observed stepwise increase in CRP per tertile of prepregnancy BMI was not significantly attenuated by glycemic tolerance status or factors known to be associated with GDM. In summary, we demonstrate that maternal serum levels of CRP are not related to GDM but rather correlate significantly with prepregnancy obesity. An independent contribution of CRP to risk of GDM could not be confirmed. These data suggest a model in which obesity mediates a systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and glucose dysregulation.     

Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome

OBJECTIVE: To investigate the relationship between C-reactive protein (CRP) and various characteristics of the metabolic syndrome. DESIGN: Population-based cross-sectional study. SUBJECTS: A total of 1929 subjects undergoing a medical examination in a preventive medicine clinic (age, 50+/-10 y; 63% males). RESULTS: The proportion of subjects with CRP levels above the cut point generally used to indicate an obvious source of infection or inflammation (>10 mg/l) was 3, 7, and 15% in subjects who were normal weight, overweight, and obese, respectively. Subjects with obesity had markedly higher CRP level compared to patients without obesity regardless of whether they had the metabolic syndrome. However, there was no significant difference in CRP levels between nonobese subjects without the metabolic syndrome and subjects in whom the diagnosis of the metabolic syndrome was based on criteria other than obesity (adjusted geometric mean CRP 1.75 vs 2.08 mg/l, P=0.79). Similarly, CRP levels did not differ among obese subjects with and without the metabolic syndrome (adjusted geometric mean CRP 3.22 vs 3.49 mg/l, P=0.99). There was a linear increase in CRP levels with an increase in the number of metabolic disorders (P(trend) <0.0001), which was substantially diminished after controlling for body mass index (BMI) (P(trend)=0.1). Stepwise multivariate linear regression analysis identified BMI, triglyceride levels, HDL cholesterol levels (inversely), and fasting glucose as independently related to CRP levels. However, BMI accounted for 15% of the variability in CRP levels, whereas triglycerides, HDL cholesterol and fasting glucose levels accounted for only approximately 1% of the variability in CRP levels. CONCLUSION: Obesity is the major factor associated with elevated CRP in individuals with the metabolic syndrome. CRP levels in the range suggesting a source of infection or inflammation (>10 mg/l) are more common among obese subjects than in nonobese subjects.     

Effect of pronounced weight loss on the nontraditional cardiovascular risk marker matrix metalloproteinase-9 in middle-aged morbidly obese women

OBJECTIVE: Obesity is associated with increased morbidity and mortality from atherosclerotic disease. Nontraditional cardiovascular risk factors such as C-reactive protein (CRP) and interleukin-6 (IL-6) are elevated in obese subjects and weight loss is associated with an attenuation of these risk factors. Matrix metalloproteinase-9 (MMP-9) has been linked to plaque rupture, and is, thus, a candidate marker of future myocardial events. The aim of this study was to determine the influence of weight loss on MMP-9 plasma concentrations. METHODS AND RESULTS: CRP, IL-6 and MMP-9 were analyzed from samples of 45 morbidly obese, middle-aged women before gastric banding and 1 y postsurgical treatment in this prospective study. The body mass index (BMI) of subjects decreased from 42.5+/-4.9 to 32.3+/-5.3 kg/m(2) 1 y after gastric banding. In parallel, both MMP-9 and CRP were reduced by 23 and 41%, respectively. A positive relationship was found between BMI and MMP-9 (r=0.312, P<0.05), and between CRP and IL-6 (r=0.508, P<0.05), whereas no correlation was found between CRP and MMP-9. CONCLUSIONS: We conclude that weight loss is associated with a pronounced decrease in the nontraditional cardiovascular risk markers MMP-9 and CRP, which could indicate future beneficial effects of weight loss on the cardiovascular risk in weight loosing subjects.     

Relationships between human serum resistin, inflammatory markers and insulin resistance

OBJECTIVE: Data on the association of resistin levels with markers of insulin resistance are highly contrasting in humans and very few studies about its role in inflammation are available. This study investigates associations between serum resistin levels and markers of insulin resistance, inflammation (C-reactive protein (CRP)) and of oxidative stress (nytrotirosine (NT)). SUBJECTS: A randomly collected sample of 300 men from a population-based cohort was analysed, separated into two groups according to body mass index (BMI) and waist values. RESULTS: Correlations between resistin and BMI, waist, triglyceride, uric acid, fasting glucose, insulin and Homeostasis Model Assessment (HOMA) values were significant in subjects with normal BMI, but not in overweight/obese subjects. In a multiple regression model, after multiple adjustments and exclusion of diabetic patients, only fasting glucose remained significantly associated with resistin levels. Otherwise, resistin is associated to CRP levels in all individuals, after multiple adjustments and exclusion of diabetic patients (in normal BMI beta=0.82; 95% CI 0.21, 1.42; in overweight/obese beta=0.43; 95% CI 0.10, 0.76). In the same model, resistin values are negatively related to NT levels in normal weight individuals (beta=-1.61; 95% CI -0.77-2.45). CONCLUSIONS: Serum resistin is weakly associated with metabolic abnormalities in subjects with normal BMI, while in overweight/obese patients this correlation is not significant, perhaps due to the higher fat content in these subjects. Serum resistin is directly correlated with CRP and inversely to NT. An intriguing hypothesis, which needs to be tested, is that resistin is secreted in response to a chronic low-grade inflammation, and has antioxidant properties.     

Obesity is independently associated with impaired quality of life in patients with rheumatoid arthritis

Obesity is a modifiable major cause of morbidity and mortality in the general population, but little is known about the association of obesity and quality of life in patients with rheumatoid arthritis (RA). Thus, we set out a study to test the hypothesis that obesity is independently associated with lower quality of life in patients with RA. Three hundred and fifty nine patients with RA underwent an interview, physical exam, and all clinical charts were reviewed. Based on body mass index (BMI), patients were classified as normal (BMI < 25 kg/m(2)), overweight (BMI = 25-29.9 kg/m(2)), and obese (BMI > or = 30 kg/m(2)). Quality of life was quantified with the Medical Outcomes Study Short Form 36 (SF-36). Data obtained included demographic variables, extra-articular disease, comorbidities, presence of X-ray erosions, rheumatoid factor, and depression. The association between obesity and quality of life was examined with the use of multiple lineal regression models. One hundred and seventy-two patients (47.9%) had normal BMI, 126 (35.1%) were overweight, and 61 patients (17%) were obese. Obese patients had lower quality of life (30.8 +/- 18.1) than overweight patients (43.3 +/- 20.1) and patients with normal weight (43.8 +/- 22.2), P < 0.001. The association between obesity and impaired quality of life was confirmed with a linear regression model (Coef = -12.9, P < 0.001) and remained significant after adjustment for age, sex, disease activity, extra-articular disease, comorbidities, X-ray erosions, presence of rheumatoid factor, depression, education, and disease duration (Coef = -5.3, P = 0.039). In conclusion, obesity is independently associated with the impaired quality of life in patients with rheumatoid arthritis.     

Circulating procoagulant microparticles in obesity

AIM: Obesity is a risk factor for cardiovascular diseases and venous thromboembolism. Circulating procoagulant microparticles (MP) have been described in various clinical situations associated with thrombosis and in diabetic patients. The aim of this preliminary study was to evaluate the presence of MP in obese patients without any other vascular risk factor in particular diabetes. METHODS: Fifty-eight obese women <50 year-old without other cardiovascular risk factors were recruited from a single out-patient nutrition clinic. They were compared to 45 age-matched healthy normal weight controls. Main outcome was MP levels in patients and controls. Relationships between MP concentrations and parameters reflecting insulin resistance in patients were also studied. RESULTS: Obese patients were 33.3 +/- 1.2 years old and had a mean BMI of 42.4 +/- 0.9 kg/m2. There vas a greater proportion of smokers in the obese group (34.5 vs 15.6%). Mean MP levels were markedly higher in obese patients compared to controls (10.6 +/- 0.5 vs 3.2 +/- 0.3 nMPSeq, P < 0.001). There was no difference in MP concentrations between smokers and non smokers. In the obese group, there was a negative correlation between MP and BMI (r = -0.265, P < 0.05) but no relationship could be established between MP concentrations and markers of insulin resistance. CONCLUSION: This increase in circulating MP levels reflects cell activation and could account for the increased risk of thrombotic complications in obesity. Further studies are ongoing to explore the relationships between MP levels and coagulation markers and to assess the effect of weight reduction.     

Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening

OBJECTIVE: We sought to study arterial endothelial function and carotid intima-media thickness (IMT), both early markers of atherosclerosis, in overweight compared to normal children. DESIGN: Case-control comparison. SUBJECTS: A total of 36 asymptomatic overweight children (body mass index (BMI)>23; mean 25+/-3) aged 9-12 y and 36 age- and gender-matched nonobese healthy children (BMI<21) from a school community. MEASUREMENTS: The key parameters were: BMI, arterial endothelial function (ultrasound-derived endothelium-dependent dilation) and carotid artery IMT. The secondary parameters measured included body fat content, waist-hip ratio (WHR), blood pressures, blood lipids, insulin and glucose. RESULTS: The two groups were well matched for blood pressures, cholesterol and glucose levels, but BMI (P<0.0001), body fat (P=0.001), WHR (P<0.05), fasting blood insulin (P=0.001) and triglyceride levels (P<0.05) were higher in obese children. Overweight was associated with impaired arterial endothelial function (6.6+/-2.3 vs 9.7+/-3.0%, P<0.0001) and increased carotid IMT (0.49+/-0.04 mm vs 0.45+/-0.04 mm, P=0.006). The degree of endothelial dysfunction correlated with BMI (P<0.003) on multivariate analysis. CONCLUSION: Obesity, even of mild-to-moderate degree, is independently associated with abnormal arterial function and structure in otherwise healthy young children.     

Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin

The objective of the study was to determine whether plasma migration inhibitor factor (MIF) concentration and mononuclear cell (MNC) mRNA are elevated in obesity and whether treatment with metformin reduces plasma MIF concentration. Forty obese subjects [body mass index (BMI), 37.5 +/- 4.9 kg/m(2)] and 40 nonobese healthy subjects (BMI, 22.6 +/- 3.4 kg/m(2)) had their plasma MIF, glucose, insulin, free fatty acids (FFAs) and C-reactive protein (CRP) concentrations measured. Sixteen obese patients and 16 nonobese healthy subjects had RNA prepared from MNCs. Eight obese subjects with normal glucose concentration were treated with metformin 1 g (Glucophage XR; 1000 mg twice daily) twice daily for 6 wk. Eight obese subjects were used as controls. Plasma concentration of glucose, insulin, FFAs, and MIF was measured by appropriate assays. mRNA for MIF was measured by real-time PCR. Forty obese subjects had a fasting concentration of MIF of 2.8 +/- 2.0 ng/ml, whereas 40 nonobese subjects had a fasting MIF concentration of 1.2 +/- 0.6 ng/ml (P < 0.001). Plasma MIF concentrations were significantly related to BMI (r = 0.52; P < 0.001). mRNA for MIF was correlated to plasma FFAs (r = 0.40; P < 0.05) and plasma CRP (r = 0.42; P < 0.05) concentrations. Eight obese subjects had their fasting blood samples taken before and after taking a slow-release preparation of metformin at 1, 2, 4, and 6 wk. The mean plasma concentration fell from 2.3 +/- 1.4 to 1.6 +/- 1.2 ng/ml at 6 wk (P < 0.05). Obese subjects not on treatment with metformin showed no change. During the period of treatment with metformin, the body weight did not change and the plasma concentration of glucose, insulin, and FFAs did not alter. We conclude that: 1) plasma MIF concentrations and MIF mRNA expression in the MNCs are elevated in the obese, consistent with a proinflammatory state in obesity; 2) these increases in MIF are related to BMI, FFA concentrations, and CRP; 3) metformin suppresses plasma MIF concentrations in the obese, suggestive of an antiinflammatory effect of this drug; and 4) this action of metformin may contribute to a potential antiatherogenic effect, which may have implications for the reduced cardiovascular mortality observed with metformin therapy in type 2 diabetes mellitus.