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The objective of the study was to find the prevalence of metabolic syndrome along with identifying the atrial arrhythmias, QT C interval, and coronary artery disease among these patients during follow-ups. Among 171 subjects who were implanted with permanent pacemakers, metabolic syndrome was present in 90 (52.6 %). Prevalence of Arrhythmias was 49 (28.7 %), atrial tachycardia (AT)/atrial fibrillation (AF) was seen in 29 (17 %) patients. Our study showed that there is a strong association between metabolic syndrome and atrial arrhythmias. Metabolic syndrome, age, coronary artery disease and Systolic blood pressure were good independent predictors of atrial arrhythmias among patients with pacemaker implantation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier, a division of RELX India, Pvt. Ltd.)

Background: Indian Diabetic Risk Score (IDRS) and Community Based Assessment Checklist (CBAC) are easy, inexpensive, and non-invasive tools that can be used to screen people for Metabolic Syndrome (Met S). The study aimed to explore the prediction abilities of IDRS and CBAC tools for Met S., Methods: All the people of age ≥30 years attending the selected rural health centers were screened for Met S. We used the International Diabetes Federation (IDF) criteria to diagnose the Met S. ROC curves were plotted by taking Met S as dependent variables, and IDRS and CBAC scores as independent/prediction variables. Sensitivity (SN), specificity (SP), Positive and Negative Predictive Value (PPV and NPV), Likelihood Ratio for positive and negative tests (LR+ and LR-), Accuracy, and Youden's index were calculated for different IDRS and CBAC scores cut-offs. Data were analyzed using SPSS v.23 and MedCalc v.20.111., Results: A total of 942 participants underwent the screening process. Out of them, 59 (6.4%, 95% CI: 4.90-8.12) were found to have Met S. Area Under the Curve (AUC) for IDRS in predicting Met S was 0.73 (95%CI: 0.67-0.79), with 76.3% (64.0%-85.3%) sensitivity and 54.6% (51.2%-57.8%) specificity at the cut-off of ≥60. For the CBAC score, AUC was 0.73 (95%CI: 0.66-0.79), with 84.7% (73.5%-91.7%) sensitivity and 48.8% (45.5%-52.1%) specificity at the cut-off of ≥4 (Youden's Index, 2.1). The AUCs of both parameters (IDRS and CBAC scores) were statistically significant. There was no significant difference (p = 0.833) in the AUCs of IDRS and CBAC [Difference between AUC = 0.00571]., Conclusion: The current study provides scientific evidence that both IDRS and CBAC have almost 73% prediction ability for Met S. Though CBAC holds relatively greater sensitivity (84.7%) than IDRS (76.3%), the difference in prediction abilities is not statistically significant. The prediction abilities of IDRS and CBAC found in this study are inadequate to qualify as Met S screening tools., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gupta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Reactive carbonyl species (RCS) may originate from the oxidation of unsaturated fatty acids and sugar in conditions of pathology. They are known to have high reactivity towards DNA as well as nucleophilic sites of proteins, resulting in cellular dysfunction. It has been considered that various pathological conditions are associated with an increased level of RCS and their reaction products. Thus, regulating the levels of RCS may be associated with the mitigation of various metabolic and neurodegenerative disorders. In order to perform a comprehensive review, various literature databases, including MEDLINE, EMBASE, along with Google Scholar, were utilized to obtain relevant articles. The voluminous review concluded that various synthetic and natural agents are available or in pipeline research that hold tremendous potential to be used as a drug of choice in the therapeutic management of metabolic syndrome, including obesity, dyslipidemia, diabetes, and diabetes-associated complications of atherosclerosis, neuropathy, and nephropathy. From the available data, it may be emphasized that various synthetic agents, such as carnosine and simvastatin, and natural agents, such as polyphenols and terpenoids, can become a drug of choice in the therapeutic management for combating metabolic syndromes that involve RCS in their pathophysiology. Since the RCS are known to regulate the biological processes, future research warrants detailed investigations to decipher the precise mechanism.

Background: Metabolic Syndrome (MetS) is a cardio-metabolic cluster that increases the risk of type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Whilst it affects 35% of the American adult population, its pathogenesis remains to be elucidated. Both insulin resistance and increased inflammation appear to be pivotal mechanisms. The NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome, an intracellular multi-protein complex, is crucial in the activation of Caspase 1, resulting in an increase in both IL-1and IL-18. In this preliminary report we examined the relationship between metabolites from our exploratory metabolomics studies with the NLRP3 inflammasome activity in the adipose tissue of patients with nascent MetS., Patient and Methods: This study comprised patients with nascent MetS matched with controls. All patients in this study had normal renal and hepatic function. Metabolites were analyzed from frozen early morning urine samples and correlated with adipose tissue Caspase 1, interleukin-1, and interleukin-18 density., Results: Caspase 1, a marker of NLRP3 inflammasome activity, was significantly elevated in patients with nascent MetS compared to controls. Isoleucine, GABA, Carnitine and PC34: 2 were also significantly increased in patients with MetS. Caspase1 correlated positively with Isoleucine, GABA, Carnitine, and PC34:2., Conclusion: We make the novel observation that the NLRP3 inflammasome activity is correlated with certain metabolites (Isoleucine, GABA, Carnitine and PC34:2) and hypothesize that they could trigger increased NLRP3 Inflammasome activity in MetS. However, these preliminary ,hypothesis generating novel findings need confirmation in larger studies of the metabolome and inflammasome., Competing Interests: Declaration of competing interest No conflicts of interest, financial or otherwise, are declared by any of the authors., (Published by Elsevier Inc.)

Aims: The metabolic syndrome (MetS) is an inflammatory disorder associated with an increased risk for diabetes and atherosclerotic cardiovascular disease (ASCVD). Studies in patients and animal models of obesity and diabetes have shown increased NOD-like receptor family pyrin domain containing 3 (NLPR3) inflammasome activity. However, there is scanty data on the activity of the NLRP3 inflammasome in patients with nascent MetS. The aim of this study was to determine the status of the inflammasome in subcutaneous adipose tissue (SAT) of patients with nascent MetS without concomitant diabetes, ASCVD and smoking., Materials and Methods: Patients with nascent MetS and controls were recruited from Sacramento County. Fasting blood samples were collected for biomediators of inflammation and SAT was obtained by biopsy for immunohistochemical (IHC) staining for caspase 1, IL-1β and IL-18., Results: Caspase1, a marker of inflammasome activity and its downstream mediators IL-1β and IL-18 were significantly increased in SAT of patients with MetS compared to controls. Significant positive correlations of caspase 1 were obtained with certain cardio-metabolic features, biomediators of inflammation and markers of angiogenesis and fibrosis in SAT. Both mast cell and eosinophil abundance but not macrophage density correlated with caspase1., Conclusions: We make the novel observation that the SAT of patients with nascent MetS displays increased NLRP3 inflammasome activity manifest by increased caspase 1 in SAT and this may contribute to increased insulin resistance, inflammation and SAT fibrosis in these patients., (2020 John Wiley & Sons Ltd.)

Metabolic syndrome is characterized by central obesity, insulin resistance, elevated blood pressure, and dyslipidemia. Metabolic syndrome is a significant risk factor for several common cancers (e.g., liver, colorectal, breast, pancreas). Pharmacologic treatments used for the components of the metabolic syndrome appear to be insufficient to control cancer development in subjects with metabolic syndrome. Murine models showed that cancer has the slowest progression when there is no food consumption during the daily activity phase. Intermittent fasting from dawn to sunset is a form of fasting practiced during human activity hours. To test the anticancer effect of intermittent fasting from dawn to sunset in metabolic syndrome, we conducted a pilot study in 14 subjects with metabolic syndrome who fasted (no eating or drinking) from dawn to sunset for more than 14 h daily for four consecutive weeks. We collected serum samples before 4-week intermittent fasting, at the end of 4th week during 4-week intermittent fasting and 1 week after 4-week intermittent fasting. We performed serum proteomic analysis using nano ultra-high performance liquid chromatography-tandem mass spectrometry. We found a significant fold increase in the levels of several tumor suppressor and DNA repair gene protein products (GP)s at the end of 4th week during 4-week intermittent fasting (CALU, INTS6, KIT, CROCC, PIGR), and 1 week after 4-week intermittent fasting (CALU, CALR, IGFBP4, SEMA4B) compared with the levels before 4-week intermittent fasting. We also found a significant reduction in the levels of tumor promoter GPs at the end of 4th week during 4-week intermittent fasting (POLK, CD109, CAMP, NIFK, SRGN), and 1 week after 4-week intermittent fasting (CAMP, PLAC1) compared with the levels before 4-week intermittent fasting. Fasting from dawn to sunset for four weeks also induced an anti-diabetes proteome response by upregulating the key regulatory proteins of insulin signaling at the end of 4th week during 4-week intermittent fasting (VPS8, POLRMT, IGFBP-5) and 1 week after 4-week intermittent fasting (PRKCSH), and an anti-aging proteome response by upregulating H2B histone proteins 1 week after 4-week intermittent fasting. Subjects had a significant reduction in body mass index, waist circumference, and improvement in blood pressure that co-occurred with the anticancer, anti-diabetes, and anti-aging serum proteome response. These findings suggest that intermittent fasting from dawn to sunset actively modulates the respective genes and can be an adjunct treatment in metabolic syndrome. Further studies are needed to test the intermittent fasting from dawn to sunset in the prevention and treatment of metabolic syndrome-induced cancers.

Aims: Metabolic Syndrome (MetS) is a common global disorder that predisposes to both Type 2 diabetes mellitus (T2DM) and cardiovascular disease (ASCVD). Adipose tissue (AT) contributes significantly to increased inflammation and insulin resistance (IR) in MetS which appear to be the crucial underpinnings of MetS. Compared to macrophages and lymphocytes in human subcutaneous AT (SAT), there is sparse data on the role of other immune cells, especially eosinophils (EOS). In this study, we investigated the abundance of EOS in the SAT of 19 patients with MetS without diabetes, ASCVD, smoking or any inflammatory condition, and matched controls., Methods: SAT EOS were quantified by immunohistochemistry., Results: Both circulating and SAT EOS were significantly increased 2-fold in MetS and correlated with each other. Circulating EOS correlated significantly with triglycerides (TG), high-sensitivity CRP, leptin, and IL-6. SAT EOS correlated significantly with plasma glucose, TG, FFA, adipose-IR, leptin, IL-6, endotoxin, chemerin and inversely with adiponectin. They also correlated with SAT markers of fibrosis: collagen and Sirius red staining of SAT., Conclusion: We make the novel and seminal observation that eosinophils are increased in SAT of MetS patients, and are associated with the pro-inflammatory state. Hence, in humans, they appear to contribute to the dysregulation of SAT biology in MetS., (Published by Elsevier Inc.)

Metabolic Syndrome (MetS) affects 35% of American adults > 40 yr and portends an increased risk for both atherosclerotic cardiovascular disease (ASCVD) and diabetes. The role of mast cells in the proinflammatory state of MetS is not well elucidated. We propose that mast cells in subcutaneous adipose tissue (SAT) of MetS patients without diabetes or clinical ASCVD contribute to insulin resistance and inflammation. Matched controls ( n = 15) and MetS ( n = 19) subjects were recruited from Sacramento, CA, and selected based on Adult Treatment Panel III criteria. SAT biopsy was performed on all subjects and processed for immunohistochemistry. The SAT sections were stained using Astra Blue stain and tryptase stain for mast cells. Fasting blood was obtained for chemistries and biomarkers. Abundance of mast cells (Astra Blue stain) in SAT of MetS subjects compared with controls was increased 2.5-fold ( P < 0.0001). Mast cells correlated positively and significantly with waist circumference, glucose, triglycerides, homeostatic model of assessment-insulin resistance (HOMA-IR), AT insulin resistance, leptin, interleukin (IL)-1β, IL-6, chemerin, p38 MAPK activity, and nuclear factor κB activity in circulating monocytes. Mast cells also correlated significantly with markers of fibrosis and angiogenesis. Tryptase staining of mast cells in AT revealed a significant increase ( P = 0.008) with similar correlations. We make the novel observation that there are increased mast cells in SAT of MetS, and these mast cells correlate with insulin resistance (hepatic and adipose tissue), inflammation, and AT fibrosis. Hence, these immune cells appear to occupy a pivotal role in the pathogenesis of MetS.

Purpose of Review: Obesity and diabetes are worldwide epidemics. There is also a growing body of evidence relating the gut microbiome composition to insulin resistance. The purpose of this review is to delineate the studies linking gut microbiota to obesity, metabolic syndrome, and diabetes., Recent Findings: Animal studies as well as proof of concept studies using fecal transplantation demonstrate the pivotal role of the gut microbiota in regulating insulin resistance states and inflammation. While we still need to standardize methodologies to study the microbiome, there is an abundance of evidence pointing to the link between gut microbiome, inflammation, and insulin resistance, and future studies should be aimed at identifying unifying mechanisms.

Background: Metabolic Syndrome (MetS) is a cardio-metabolic cluster that confers an increased risk of developing both diabetes and atherosclerotic cardiovascular disease (ASCVD). The mechanisms governing the increased ASCVD risk remains to be elucidated. Moreover, lipidomics poses as an exciting new tool that has potential to shed more light on the pathogenesis of MetS., Objective: The aim of this study was to explore the lipidome in an unbiased fashion in patients with nascent MetS uncomplicated by diabetes and CVD., Methods: Patients with nascent MetS (n = 30) without diabetes or ASCVD and controls (n = 20) who participated in the study had normal hepatic and renal function. Early morning urine samples from patients were collected and frozen at -70° until analysis. Lipidomic analyses were undertaken at the National Institute of Health Western Metabolomics Center., Results: Phosphatidylcholine 34:2, PC (34:2) was significantly increased in patients with MetS compared to controls. PC (34:2) had a significant positive correlation with waist circumference, plasma glucose, free fatty acid, and triglyceride levels. It had a significant positive correlation with pro-inflammatory markers such as plasma hs CRP, IL-1b, and IL-8. Additionally, PC (34:2) significantly correlated positively with Leptin and inversely with adiponectin. Levels of various acyl carnitines and PC34:1 were not significantly altered., Conclusion: We propose that PC (34:2) could emerge as a novel biomarker in MetS that promotes a pro-inflammatory state., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: The effect of waist circumference (WC) on cardio-metabolic features and biomarkers of oxidative stress and inflammation and adipose tissue dysregulation is poorly defined in Metabolic Syndrome (MetS). Hence the aim of this study was to examine the effect of increasing tertiles of WC on the cardio metabolic risk profile, pro-oxidant state, pro-inflammatory state and adipose tissue dysregulation in nascent MetS patients (n = 59) without diabetes or CVD., Methods and Results: None of the main cardio-metabolic features including blood pressure, blood glucose, HDL-cholesterol, triglycerides, HOMA-IR, and free fatty acids increased with increasing WC tertiles except for hsCRP. In addition, none of the biomarkers of oxidative stress increased with increasing WC. Other circulating and cellular bio-mediators of inflammation and adipokines did not show significant increase with increasing WC. Using the waist to height ratio (WHtR) also did not reveal any major findings with increasing tertiles., Conclusion: In conclusion, in a well-defined cohort of MetS we failed to show any superiority of either WC or WHtR compared to BMI in capturing the cardio-metabolic cluster, adipose tissue dysregulation and the increased burden of oxidative stress and inflammation in this pilot study. These observations need confirmation in larger studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Metabolic syndrome (MetS) is a common global problem that comprises the cardio-metabolic cluster and predisposes to both diabetes and cardiovascular diseases. Although the pathogenic mechanisms have not been elucidated, both increased inflammation and insulin resistance play a pivotal role. It appears that both monocyte/macrophages and adipose tissue (AT) conspire to accentuate both the pro-inflammatory state and increased insulin resistance. Whilst there are scant data on visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) biology, there are data on subcutaneous adipose tissue (SAT) dysregulation. There is a significant increase in macrophages and crown-like structures in the SAT of patients with MetS. With respect to adipokines, there is an increase in plasma leptin, plasminogen activator inhibitor-1, retinol-binding protein-4 (RBP-4), chemerin, serum amyloid-A, C-reactive protein (CRP), interleukin-1, -6, -8, lipopolysaccharide, fetuin A (FetA) and a decrease in adiponectin and omentin-1. All of the abnormalities in plasma were also confirmed for SAT-secreted adipokines except for adiponectin and RBP-4 which derive largely from VAT. As many of these biomediators correlate with both insulin resistance and increased inflammation, we can posit that dysregulation of SAT is detrimental and contributes to both the pathogenesis of MetS and its sequalae. Furthermore, as future directions, much work is needed with respect to VAT/EAT biology, autophagy, sirtuins, the gut microbiome, browning of AT, to further elucidate this common syndrome and identify potential therapeutic targets to forestall its serious complications.

Metabolic syndrome (MetS), a common cardio-metabolic cluster, predisposes to both increased cardiovascular disease and diabetes. Both adipose tissue and monocyte/macrophages contribute to the increased inflammation in MetS. However there are sparse data on factors that determine macrophage recruitment into adipose tissue (AT). In this preliminary report in patients with MetS, without the confounding of diabetes and cardiovascular diseases, we show that plasma resistin, soluble CD14 and monocyte p38 MAP kinase activity correlate significantly with AT macrophage density and hence could be important biomediators of macrophage homing to AT in MetS. However larger studies are required to confirm these novel findings and elucidate other important factors., (Published by Elsevier Inc.)

Objective: Metabolic syndrome (MetS), a common disorder, predisposes to both cardiovascular disease and diabetes. There is a paucity of data on monocyte cell adhesion molecule receptors in MetS. This study determined monocyte Mac-1 (CD11b) and VLA4 (CD49d) in patients with MetS and controls. Research design and methods In isolated monocytes (n=58 MetS and n=40 healthy controls), both CD11b and CD49d expression were assayed by flow cytometry and correlated with features of MetS, and biomarkers of inflammation., Results: Monocyte CD11b was significantly increased in patients with MetS compared to controls, median [25(th)-75(th) percentile] 34.2 MFI/10,000 cells [26.3-56.2] versus 25.3 [20.9-32.4], even following adjustment for adiposity. Furthermore, CD11b increased with increasing features of MetS (p for trend 0.005.) CD11b significantly correlated with glucose, triglycerides, Toll-like receptor 4 and p38 MAP kinase activity., Conclusions: This is the first report showing increased monocyte CD11b expression in MetS possibly mediated by TLR4 and could contribute to the increased risk of atherosclerosis by promoting monocyte adhesion to endothelium., (Copyright © 2015 The Canadian Society of Clinical Chemists. All rights reserved.)

Background: Metabolic syndrome (MetS) predisposes to both diabetes and cardiovascular disease, and inflammation is pivotal in MetS. The Toll-like receptors (TLRs), TLR2 and TLR4, are implicated in both diabetes and atherosclerosis, are increased in MetS, and contribute to the inflammatory burden. Recent studies also suggest an evolving role of endosomal TLRs in diabetic complications. However, there is a paucity of data with regard to the expression of endosomal TLRs such as TLR3, 7-9 in MetS., Aim: Thus, in this short report, we examine expression of monocytes TLR3 and TLR9 in our cohort of subjects with nascent MetS compared to matched controls., Subjects and Methods: Monocytes were isolated from subjects with MetS (n = 45) and matched controls (n = 37), respectively, and TLR3 and TLR9 expression was assessed by intracellular flow cytometry and correlated with nuclear factor (NF)-κB expression., Results: We demonstrate increased endosomal TLR9 expression in MetS compared to controls that correlate with increased nuclear NF-κB expression in the monocytes of these subjects, with no change in TLR3 protein., Conclusion: Future studies are required to confirm these findings and determine the role of TLR9 in the increased cardiovascular risk in MetS.

Objective: Adipose Tissue (AT) dysregulation contributes to the pro-inflammatory state and insulin resistance of Metabolic Syndrome (MetS). We examined AT secretion of the hepatokine, Fetuin-A, LBP, sCD14 and HMGB-1, and toll-like receptor 2 and 4 protein levels in MetS and controls., Design and Methods: Secreted levels of Fetuin-A, LBP, HMGB-1 and sCD14 and TLR2 and TLR4 protein in AT of controls and MetS patients were assayed. Also mRNA and protein for Fetuin-A, LBP, sCD14 and HMGB-1 were studied in subcutaneous fat depot of mice and during adipocyte differentiation., Results: Secretion of Fetuin-A, LBP and HMGB-1 from AT were significantly increased in MetS (n = 28) compared to controls (n = 25), even after adjustment for adiposity. There were no significant differences in sCD14. Both LBP and Fetuin-A correlated significantly with HOMA-IR and increased significantly with increasing features of MetS. There was a significant increase in AT TLR2 and TLR4 protein in MetS compared to controls. Expression of Fetuin-A and LBP were significantly higher in subcutaneous white adipose tissue of HFD fed mice as well as in ob/ob mice compared to C57BL6/J control mice (n = 6 per group). Additionally mRNA and protein levels of FetA, LBP and HMGB-1 increased during differentiation of 3T3-L1 adipocytes., Conclusions: We make the novel observation of increased secretion of Fetuin A, LBP and HMGB-1 from AT and hypothesize that these engage TLRs in AT and other tissues contributing to the pro-inflammatory state and insulin resistance of MetS., (Published by Elsevier Ireland Ltd.)

Background: Although hepatic insulin resistance has been documented in patients with metabolic syndrome using homeostasis model assessment of insulin resistance (HOMA-IR) as a measure, there is scanty data on adipose insulin resistance (Adipo-IR) and its relationship with the dysregulation of adipokines in metabolic syndrome. Thus, we examined whether Adipo-IR is increased in metabolic syndrome as well as its correlation with circulating adipokines., Methods: In 42 individuals including controls and participants with metabolic syndrome, we measured fasting plasma insulin and free fatty acids (FFA). Adipo-IR was calculated as the product of FFA×insulin. We examined the association between Adipo-IR, metabolic syndrome variables, and circulating adipokines, including leptin, adiponectin, chemerin, omentin-1, and retinol-binding protein-4., Results: Adipo-IR was higher in metabolic syndrome (n=19; median 68.7 mmol/L·pmol/L; 25(th)-75(th) percentile, 50.0-104.7) compared to controls (n=23; 22.9 mmol/L·pmol/L; 6.8-36.1; P<0.0001), and this difference was similar following adjustments for waist circumference or body mass index (BMI). Adipo-IR correlated significantly with certain adipokines: Leptin, r=0.45, P=0.004; adiponectin, r=-0.33, P<0.05; chemerin r=0.55, P=0.0008; omentin-1, r=-0.46, P=0.04, and with all features of metabolic syndrome., Conclusions: Adipo-IR is increased in metabolic syndrome following adjustment for adiposity and may be an important biomarker of adipose tissue dysregulation, including adipokine secretion and a potential relevant therapeutic target.

Background: The metabolic syndrome is a highly prevalent state affecting one in three US adults and comprises a cluster of cardiometabolic risk factors. While metabolic syndrome is a proinflammatory state, there is a paucity of studies examining monocyte/macrophage phenotype in metabolic syndrome subjects. This was the aim of this study., Methods: Following informed consent, metabolic syndrome and age- and gender-matched healthy subjects (n=15/group) were recruited, and monocytes were obtained for phenotypic characterization of the classical M1 phenotype and alternative M2 phenotype. Biomarkers of inflammation, C-reactive protein (CRP), and proinflammatory cytokines were examined., Results: Metabolic syndrome subjects had significantly higher waist circumference (WC), significantly increased systolic blood pressure, higher fasting glucose, triglycerides, and free fatty acids levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to matched controls. Also, CRP and endotoxin levels were significantly elevated in metabolic syndrome compared to controls. Metabolic syndrome subjects had significantly higher levels of the M1 phenotype and significantly decreased levels of the M2 phenotype compared to controls, even after adjusting for WC. Among the other biomarkers of inflammation, there were significant increases in the proinflammatory cytokines and chemokines interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 (MCP-1) and decreased IL-10 in metabolic syndrome compared to controls. The M1 phenotype was significantly correlated to levels of CRP, endotoxin, MCP-1, and WC and negatively with HDL-C., Conclusions: Monocytes from metabolic syndrome subjects display a proinflammatory M1 phenotype that could promote the increased cardiometabolic burden in these subjects.

Context: The prevalence of both obesity and metabolic syndrome (MetS) is increasing at alarming rates globally. Both predispose to diabetes, cardiovascular disease, fatty liver disease, obstructive sleep apnea, and certain cancers. Understanding the mechanisms contributing to increased cardiometabolic risk in obesity and MetS is of utmost importance., Evidence Acquisition: For this review, we performed a detailed literature search on PubMed of all publications related to Toll-like receptors (TLRs) and obesity and MetS for the last 20 years., Evidence Synthesis: The TLRs are well-characterized immune receptors that enhance inflammation. The recognition of pathogen-associated molecular patterns and endogenous (host-derived) ligands released by various cell types triggers activation and expression of TLRs. TLRs, especially TLR2 and TLR4, induce insulin resistance, which is pivotal in the pathogenesis of obesity and MetS. Both obesity and MetS are characterized by low-grade chronic inflammation, possibly triggered by activation of TLR2 and TLR4. TLRs, especially TLR4, are activated by fatty acids and endotoxinemia (a marker of gut permeability), features of both obesity and MetS, resulting in activation of nuclear factor-κB and increased release of inflammatory biomediators such as IL-6, IL-1β, TNF-α, and monocyte chemotactic protein-1, which play a role in the pathophysiology of obesity and MetS. Reduction of calories, exercise, and nutraceutical and pharmacological agents can modulate TLRs., Conclusions: In this review, we present evidence for a pivotal role of TLR-induced inflammation in both obesity and MetS and speculate that targeting these TLRs can forestall their adverse sequelae of diabetes and cardiovascular disease.

Context: The metabolic syndrome (MetS) confers an increased propensity for diabetes and cardiovascular disease. C-reactive protein (CRP) levels are increased in MetS and predict cardiovascular events. Fc-γ receptors (FcgRs) are immune receptors on macrophages and include FcgRI (CD64), FcgRII (CD32), and FcgRIII (CD16)., Objective: CRP has been shown to be processed by CD32 and CD64 in human monocytes. Although MetS is characterized by increased CRP and monocyte proinflammatory activity, data on FcgR expression on monocytes in patients with MetS compared with those of control subjects are sparse. Thus, the aim of the study was to examine this expression and the correlation with CRP., Design and Setting: After informed consent was given, patients with MetS (n = 50) and control subjects (n = 40) were studied. CD32 and CD64 expression on monocytes was examined by both flow cytometry and Western blotting. Immunoprecipitation studies were performed to examine spleen tyrosine kinase (Syk) activity as a measure of CD32 and CD64 activity., Results: Surface expression of CD32 and CD64 was significantly increased in patients with MetS compared with that in control subjects even after adjustment for body mass index and waist circumference. Expression of these FcgRs increased significantly with the number of features of MetS (Ptrend < .001) and correlated with levels of high-sensitivity CRP (P < .01). CRP after engagement of CD32 and CD64 signals via Syk. Syk phosphorylation was increased in monocytes of patients with MetS compared with that in control subjects., Conclusions: We provide novel evidence of increased FcgR expression and activity in monocytes of patients with MetS that correlates with the number of features of MetS and with high-sensitivity CRP.

Context: Adipose tissue dysregulation causing aberrant adipokine secretion contributes toward the proinflammatory state of metabolic syndrome (MetS). However, there are scant data on the role of novel adipokines in MetS., Objective: The aim of this study was to determine the levels of circulating and adipose tissue-secreted adipokines, chemerin, omentin-1, resistin, and visfatin in nascent MetS patients without diabetes or cardiovascular disease and to determine their relation with features of MetS., Design and Setting: Subjects with MetS and gender- and age-matched controls were recruited after informed consent. Fasting blood samples and gluteal subcutaneous adipose tissue (SAT) biopsies were obtained., Main Outcome: SAT-secreted and plasma levels of chemerin, omentin-1, resistin, and visfatin were quantitated., Results: There was significantly higher circulating as well as SAT-released chemerin in nascent MetS compared to controls, which persisted after adjustment for body mass index, waist circumference, and age. Also, both SAT-released and plasma levels of omentin-1 were significantly lower in MetS compared to controls, and the significant differences persisted after adjustment for age, body mass index, or waist circumference. No significant differences were observed in the levels of circulating visfatin as well as SAT-secreted resistin and visfatin. Chemerin correlated significantly with high-sensitivity C-reactive protein, homeostasis model of assessment for insulin resistance, triglycerides, and blood pressure, and inversely with omentin and high-density lipoprotein cholesterol. Omentin correlated significantly with high-density lipoprotein cholesterol and inversely with glucose and triglycerides., Conclusions: We make the novel observation of abnormal circulating and gluteal SAT-secreted chemerin and omentin-1 levels in nascent MetS, which could confer a higher risk for diabetes and cardiovascular disease.

Background: Metabolic syndrome affects 1 in 3 U.S. adults. The primary target of treatment of patients with metabolic syndrome is therapeutic lifestyle change. Numerous animal trials have reported positive effects of Aloe vera in in vivo models of diabetes, but there is a paucity of controlled clinical trials in patients with prediabetes. Thus, the objective of this pilot study was to examine the effect of aloe compared to placebo on fasting blood glucose, lipid profile, and oxidative stress in subjects with prediabetes/metabolic syndrome., Methods: This was a double-blind, placebo-controlled Institutional Review Board (IRB)-approved pilot study of two aloe products (UP780 and AC952) in patients with prediabetes over an 8-week period. A total of 45 subjects with impaired fasting glucose or impaired glucose tolerance and having two other features of metabolic syndrome were recruited (n=15/group). Parameters of glycemia [fasting glucose, insulin, homeostasis model assessment (HOMA), glycosylated hemoglobin (HbA1c), fructosamine, and oral glucose tolerance test (OGTT)] and oxidative stress (urinary F2-isoprostanes) were measured along with lipid profile and high-sensitivity C-reactive protein (hsCRP) levels before and after supplementation., Results: There were no significant baseline differences between groups. Compared to placebo, only the AC952 Aloe vera inner leaf gel powder resulted in significant reduction in total and low-density lipoprotein cholesterol (LDL-C) levels, glucose, and fructosamine. In the UP780 Aloe vera inner leaf gel powder standardized with 2% aloesin group, there were significant reductions in HbA1c, fructosamine, fasting glucose, insulin, and HOMA. Only the UP780 aloe group had a significant reduction in the F2-isoprostanes compared to placebo., Conclusions: Standardized aloe preparations offer an attractive adjunctive strategy to revert the impaired fasting glucose and impaired glucose tolerance observed in conditions of prediabetes/metabolic syndrome.

Context: Metabolic syndrome (MetS) confers a greater risk for both cardiovascular disease (CVD) and diabetes. Oxidative stress (OS) could contribute to this excess risk. However, there are few data examining both cellular and circulating biomarkers of OS in MetS uncomplicated by diabetes and CVD., Objective: The aim of the study was to evaluate both cellular and circulating biomarkers of OS in MetS uncomplicated by diabetes or CVD., Design and Setting: At an academic medical center, we compared MetS (n=43) vs. control subjects (n=33). Fasting blood was collected for monocyte isolation and assay of OS biomarkers., Main Outcome: Monocyte nicotinamide adenine dinucleotide phosphate oxidase activity (p22 phox and p47), superoxide anion release, oxidized-low-density lipoprotein (Ox-LDL), nitrotyrosine, and nuclear factor erythroid 2-related factor were measured., Results: There was significantly increased release of superoxide from the monocytes (basal and after activation) of MetS compared with controls adjusted for body mass index. Body mass index-adjusted plasma levels of Ox-LDL and nitrotyrosine were significantly increased in MetS. There was a linear trend between biomarkers of oxidative stress and increasing number of features of MetS. Also, there was a significant increase in nicotinamide adenine dinucleotide phosphate oxidase membrane expression of p22 phox and p47 phox in MetS. The major cellular antioxidant defense, nuclear factor erythroid 2-related factor was significantly decreased. There were significant correlations between homeostasis model assessment insulin resistance index and both Ox-LDL and nitrotyrosine and superoxide and Ox-LDL., Conclusions: Collectively, nascent MetS is associated with increased OS as evidenced by both circulating and cellular biomarkers, and this could contribute to the risk for both diabetes and CVD.

Objective: The metabolic syndrome (MetS) is highly prevalent and confers an increased risk for diabetes and cardiovascular disease (CVD). While MetS is a proinflammatory state, there is a paucity of data on cellular inflammation in MetS. Toll-like receptors (TLRs) are classical pattern recognition receptors of the innate immune response., Research Design and Methods: The aim of this study was to examine monocyte TLR2 and TLR4 in MetS patients without diabetes or CVD and control subjects since both of the receptors have been implicated in atherosclerosis and insulin resistance. Fasting blood was obtained for TLR expression and activity., Results: Circulating levels of high-sensitivity C-reactive protein, interleukin (IL)-1β, IL-6, IL-8, and soluble tumor necrosis factor receptor 1 (sTNFR1) were significantly increased in MetS versus control subjects following adjustment for waist circumference. There was a significant increase in both TLR2 and TLR4 surface expression and mRNA on monocytes after adjustment for waist circumference. In addition to increased nuclear factor-κB nuclear binding, there was significantly increased release of IL-1β, IL-6, and IL-8 in MetS versus control subjects following priming of the monocytes with lipopolysaccharides. While both plasma free fatty acids and endotoxin were increased in MetS, they correlated significantly with TLR4 only., Conclusions: In conclusion, we make the novel observation that both TLR2 and TLR4 expression and activity are increased in the monocytes of patients with MetS and could contribute to increased risk for diabetes and CVD.

The metabolic syndrome (MetS) is highly prevalent and confers an increased risk of diabetes and cardiovascular disease. A key early event in atherosclerosis is endothelial dysfunction. Numerous groups have reported endothelial dysfunction in MetS. However, the measurement of endothelial function is far from optimum. There has been much interest recently in a subtype of progenitor cells, termed endothelial progenitor cells (EPCs), that can circulate, proliferate, and dfferentiate into mature endothelial cells. EPCs can be characterized by the assessment of surface markers, CD34 and vascular endothelial growth factor receptor-2, VEGFR-2 (KDR). The CD34(+)KDR(+) phenotype has been demonstrated to be an independent predictor of cardiovascular outcomes. MetS patients without diabetes or cardiovascular diseases have decreased EPC number and functionality as evidenced by decreased numbers of colony forming units, decreased adhesion and migration, and decreased tubule formation. Strategies that have been shown to upregulate and enhance EPC number and functionality include statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and peroxisome-proliferator-activating-receptor gamma agonists. Mechanisms by which they affect EPC number and functionality need to be studied. Thus, EPC number and/or functionality could emerge as novel cellular biomarkers of endothelial dysfunction and cardiovascular disease risk in MetS.

Context: The metabolic syndrome (MetS) is associated with increased risk of diabetes and cardiovascular disease (CVD). Numerous groups have shown increased circulating biomarkers of inflammation in MetS. However, there are scanty data on the cellular sources contributing to this low-grade inflammation., Objective: The aim of this study was to determine the role of sc adipose tissue (SAT) biology in nascent MetS without concomitant diabetes or CVD., Patients and Methods: Subjects with MetS and controls were recruited after informed consent. Fasting blood was collected, and SAT was obtained by biopsy., Results: Circulating biomarkers of inflammation and insulin resistance, high-sensitivity C-reactive protein (hsCRP), IL-6, IL-1β, leptin, serum amyloid A, and retinol-binding protein-4 (RBP-4) concentrations were significantly higher in the MetS subjects than controls, whereas adiponectin concentrations were lower. In SAT, leptin, RBP-4, CRP, serum amyloid A, plasminogen activator inhibitor-1, IL-1, IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) levels were significantly higher in MetS than controls. These differences except for RBP-4 persisted after adjusting for waist circumference. In addition, there were significantly increased numbers of macrophages infiltrating the SAT of MetS and increased numbers of crown-like structures compared with controls. hsCRP correlated positively with homeostasis model assessment and SAT MCP-1 and negatively with adiponectin. Homeostasis model assessment correlated positively with plasminogen activator inhibitor-1, RBP-4, and SAT MCP-1., Conclusions: We make the novel observation that SAT of MetS has increased macrophage recruitment with cardinal crown-like structure features and contributes to the increased cellular inflammation that produces increased levels of biomarkers that are correlated with both insulin resistance and low-grade inflammation. These aberrations could contribute to the progression of MetS and the increased risk for diabetes and CVD.

Much evidence supports a pivotal role for inflammation in atherosclerosis. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a cardiovascular risk marker and may also promote atherogenesis. CRP levels are increased in metabolic syndrome and hypertension and confer increased risk of cardiovascular events in patients in these subgroups. Statins have been shown to lower low-density lipoproteins and CRP independently, and reduce cardiovascular events in subjects with and without metabolic syndrome and hypertension. In this review, we focus on the results from the primary prevention statin trial, Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which showed reductions in LDL, CRP, and cardiovascular events. Post-JUPITER, the new guidelines will now need to consider recommending high-sensitivity CRP testing to intermediate-risk metabolic syndrome patients and those with hypertension and intermediate risk so that we can better identify candidates at greater risk and reduce cardiovascular burden in these subjects with statin therapy.

Endothelial progenitor cells (EPCs) are an emerging biomarker of vascular health. However, there are few data on the biology and mobilizing factors of EPCs in metabolic syndrome (MS). The aim of this study was to assay EPC mobilizing factors, including granulocyte colony-stimulating factor, stem cell factor/c-kit ligand (SCF), vascular endothelial growth factor, and stromal cell-derived factor-1 levels, in patients with MS (n = 36) and age- and gender-matched controls (n = 38). There was a significant reduction of 83% in granulocyte colony-stimulating factor levels in patients with MS. Also, there were decreases in SCF and SCF soluble receptor levels. However, there was no significant difference in stromal cell-derived factor-1 levels, and paradoxically, vascular endothelial growth factor levels were increased, consistent with resistance. In conclusion, in addition to progenitor cell exhaustion as a mechanism for the decrease in EPCs in patients with MS, they also have a mobilization defect, as manifested by decreased levels of granulocyte colony-stimulating factor and SCF, resulting in a decrease in EPCs., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Metabolic syndrome is associated with increased propensity for diabetes and cardiovascular disease. Low-grade inflammation is characteristic of metabolic syndrome. C-reactive protein, the best characterized biomarker of inflammation, is also an independent predictor of future cardiovascular events. This review outlines the role of high-sensitivity C-reactive protein in contributing to increased cardiovascular risk in metabolic syndrome by inducing endothelial cell dysfunction and activating monocytes.

Purpose of Review: Low-grade inflammation is characteristic of the metabolic syndrome (MetS). C-reactive protein (CRP), the best characterized biomarker of inflammation, is also an independent predictor of future cardiovascular events. The purpose of this review is to outline the role of inflammation and high sensitivity CRP in the MetS., Recent Findings: Emerging laboratory and epidemiological data now link inflammation and high sensitivity CRP to insulin resistance and adiposity and other features of MetS. Furthermore, in large prospective studies, increased high sensitivity CRP levels in MetS confer greater cardiovascular risk. CRP has been shown to impair insulin signaling and contributes to atherothrombosis., Summary: Thus, although a high CRP level predisposes to increased cardiovascular risk in MetS, future investigation is warranted on the in-vivo role of CRP in mediating vascular effects and resulting in increased cardiovascular events in MetS patients.

Metabolic syndrome (MS), characterized by low-grade inflammation, confers an increased risk for cardiovascular disease. Statins, in addition to having lipid-lowering effects, have pleiotropic effects and decrease biomarkers of inflammation and oxidative stress. The Treating to New Target Study showed a greater decrease in low-density lipoprotein (LDL) cholesterol and cardiovascular events with atorvastatin 80 mg versus 10 mg in patients with MS with coronary heart disease. However, part of this benefit could be caused by the greater pleiotropic effects of the higher dose of atorvastatin. The dose-response effect of atorvastatin on biomarkers of inflammation and oxidative stress has not been investigated in subjects with MS. Thus, the dose-response effect of atorvastatin on biomarkers of inflammation (high-sensitivity C-reactive protein [hs-CRP], matrix metalloproteinase-9, and nuclear factor-kappaB [NF-kB] activity) and oxidative stress (oxidized LDL, urinary nitrotyrosine, F2-isoprostanes, and monocyte superoxide release) was tested in a randomized double-blind clinical trial in subjects with MS. Seventy subjects were randomly assigned to receive placebo or atorvastatin 10 or 80 mg/day for 12 weeks. A strong dose-response (atorvastatin 10 compared with 80 mg, p <0.05) was observed for changes in total, LDL (32% and 44% reduction), non-high-density lipoprotein (28% and 40% reduction), and oxidized LDL cholesterol (24% and 39% reduction) at atorvastatin 10 and 80 mg, respectively. Hs-CRP, matrix metalloproteinase-9, and NF-kB significantly decreased in the 80-mg atorvastatin group compared with baseline. In conclusion, this randomized trial of subjects with MS showed the superiority of atorvastatin 80 mg compared with its 10-mg dose in decreasing oxidized LDL, hs-CRP, matrix metalloproteinase-9, and NF-kB activity.

The metabolic syndrome (MetS) is associated with an increased incidence of diabetes and coronary heart disease. Postprandial lipemia is a prominent feature of dyslipidemia in both type 2 diabetes mellitus and MetS and is also associated with coronary heart disease. Oxidative stress and inflammation are pivotal in all stages of atherosclerosis; however, there is a paucity of data on postprandial oxidative stress and inflammation in subjects with MetS. Thus, the primary aim of this study was to compare the postprandial effects of an energy-dense, high-fat, fast-food-style (FFS) meal with an American Heart Association (AHA)-recommended heart-healthy meal on biomarkers of oxidative stress and inflammation in subjects with MetS. A total of 11 subjects with MetS completed the study. Glucose levels were significantly increased 2 hours after both FFS and AHA diets (P < .0001), and high-density lipoprotein cholesterol levels significantly decreased in FFS diet but not in the AHA diet (P for interaction < .05). Total triglyceride levels significantly increased postprandially only in the FFS meal but not in the AHA meal (P for interaction = .03). Plasma thiobarbituric acid reactive substances and malondialdehyde + hydroxynonenal increased significantly with time in both dietary groups, and the postprandial increase was greater in the FFS diet compared to the AHA diet (P < .0005). Serum high-sensitivity C-reactive protein, interleukin 6, and tumor necrosis factor levels did not change with time or dietary treatment. The postprandial increase in interleukin 1b was significantly higher with the FFS meal, thus resulting in significant differences between both treatments (P for interaction = .03). Thus, in subjects with MetS, consumption of an energy-dense, fatty meal (FFS breakfast) results in increased postprandial oxidative stress compared to a heart-healthy meal (AHA).

Background: The Metabolic Syndrome (MS) confers an increased risk for diabetes and cardiovascular disease. We previously showed that simvastatin has concomitant benefits in reducing low-density lipoprotein (LDL)-cholesterol and inflammation in MS subjects. The levels of plasminogen activator inhibitor 1(PAI-1), soluble P-selectin (sP-selectin), and soluble CD40 ligand (sCD40L) play an important role in the development and progression of atherosclerosis. Their levels are increased in the MS. The current study was to investigate the effects of simvastatin on PAI-1, sP-selectin, and sCD40 ligand., Methods: Fifty subjects with MS were randomized into either placebo or simvastatin (40 mg/day) group for 8 weeks. Blood samples were obtained at baseline and at the end of the study. PAI-1 activity and sP-selectin and sCD40L levels were measured by enzyme-linked immunosorbent assay (ELISA)., Results: There was no baseline difference in any of the parameters studied. Compared to baseline, simvastatin significantly reduced (P < 0.05) the circulating PAI-1 activity (24.3 +/- 5.2 IU/mL at baseline vs. 21.4 +/- 3.9 IU/mL after 8 weeks of treatment). Simvastatin did not alter (P < 0.05) the levels of sP-selectin (111.4 +/- 35.9 ng/mL at baseline vs. 118.5 +/- 71.2 ng/mL after 8 weeks) or sCD40L (2.0 +/- 1.6 ng/mL at baseline vs. 1.5 +/- 1.0 ng/mL after 8 weeks)., Conclusion: Our data indicate that simvastatin therapy has significant effects on the fibrinolytic system in MS subjects as evidenced in a reduction in PAI-1 activity.

The metabolic syndrome (MetS) confers an increased risk for diabetes and cardiovascular disease. Although high-sensitive C-reactive protein (hsCRP) concentrations are higher and adiponectin concentrations lower in MetS, there is no reliable biochemical measure that can capture its various features. We evaluated whether hsCRP, adiponectin, or the ratio of adiponectin or its oligomers, especially the high-molecular-weight (HMW) oligomer, to hsCRP predict MetS in 123 subjects with MetS compared with that in 91 healthy control subjects. MetS subjects had significantly higher hsCRP levels and lower total adiponectin and oligomer levels relative to control subjects (P < .0001). The HMW/total adiponectin and adiponectin/CRP ratios were significantly lower in MetS subjects than control subjects (P < .005). The odds ratio (OR) of MetS using the 75th percentile cutoff for CRP was 3.8 (95% confidence interval [CI], 2.1-6.8) and equivalent to low total adiponectin (OR, 2.5; 95% CI, 1.3-4.5), its oligomers, or the adiponectin/ hsCRP ratio (OR, 2.6; 95% CI, 1.5, 4.8). Thus, measurements of CRP, adiponectin, or its oligomers provide robust biomarkers for predicting MetS.

Metabolic syndrome (MetS) is associated with increased incidence of diabetes and cardiovascular disease (CVD). Prospective clinical trials with alpha-tocopherol (AT) have not yielded positive results. Because AT supplementation decreases circulating gamma-tocopherol (GT), we evaluated supplementation with GT (800 mg/day), AT (800 mg/day), the combination or placebo for 6 weeks alone AT and GT concentrations, biomarkers of oxidative stress, and inflammation in subjects with MetS (n=20/group). Plasma AT and GT levels increased following supplementation with AT alone or GT alone or in combination. AT supplementation significantly decreased GT levels. Urinary alpha- and gamma-CEHC, metabolites of the respective Ts, also increased correspondingly, i.e., alpha-CEHC with AT and gamma-CEHC with GT supplementation, compared to placebo. HsCRP levels significantly decreased in the combined AT+GT group. LPS-activated whole blood release of IL-1 and IL-6 did not change. There was a significant decrease in TNF with AT alone or in combination with GT. Plasma MDA/HNE and lipid peroxides were significantly decreased with AT, GT, or in combination. Nitrotyrosine levels were significantly decreased only with GT or GT+AT but not with AT compared to placebo. Thus, the combination of AT and GT supplementation appears to be superior to either supplementation alone on biomarkers of oxidative stress and inflammation and needs to be tested in prospective clinical trials to elucidate its utility in CVD prevention.

The metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for diabetes mellitus and cardiovascular disease. Statins reduce cardiovascular events in patients with the MS and have pleiotropic effects in addition to lowering low-density lipoprotein cholesterol. Because there is a paucity of data on the effect of statins on adiponectin levels and insulin sensitivity in the MS, this study was conducted to test the effect of simvastatin (40 mg/day) compared with placebo on circulating adiponectin levels and homeostasis model assessment insulin resistance in subjects with the MS in a randomized, double-blind, placebo-controlled study. Simvastatin therapy failed to affect circulating adiponectin levels or insulin sensitivity compared with placebo over 8 weeks. In conclusion, although simvastatin is anti-inflammatory, it failed to affect adiponectin levels or improve insulin sensitivity in subjects with the MS.

Context: Metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular events in MS patients. There is a paucity of data examining the effect of statins on inflammation in MS., Objective: We aimed to test the effect of simvastatin (40 mg/d) compared with placebo on biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and monocytic cytokines TNF, IL-6, and IL-1] in MS subjects., Design and Patients: We conducted a randomized, double-blind, placebo-controlled study at the University of California, Davis, Medical Center., Participants: Participants were subjects with MS., Intervention: Simvastatin (40 mg/d) or placebo was administered for 8 wk., Methods and Results: The hsCRP levels were assayed using a high-sensitivity immunoassay. Monocyte cytokines were assayed by ELISA after activation with lipopolysaccharide. Simvastatin therapy significantly decreased hsCRP levels in MS subjects compared with placebo (P < 0.0005) and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased nuclear factor-kappaB and increased Akt activity in MS subjects compared with placebo. To gain mechanistic insights, human monocytes were pretreated with lovastatin with and without mevalonate or a phosphatidyl-3-kinase inhibitor or Rho kinase inhibitor. Lovastatin significantly decreased Rho kinase and nuclear factor-kappaB activity, significantly increased Akt activity, and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranyl pyrophosphate, indicating direct effects of statins on protein prenylation., Conclusions: Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.

Inflammation and hypercoagulability predispose to atherothrombosis and seem to be important features of the metabolic syndrome. The most convincing evidence is the association with increased levels of C-reactive protein. The hemostatic abnormality that has been most consistently associated with insulin resistance is an elevated plasminogen activator inhibitor-1 level. In contrast, markers of hypercoagulability have been associated inconsistently with hyperinsulinemia and glucose intolerance. Fibrinogen clusters with inflammatory factors, which suggests involvement of adipose tissue-generated inflammatory cytokines. Elevated von Willebrand's factor and factor VIII levels aggregate with indicators of endothelial injury,whereas vitamin K-dependent coagulation proteins correlate with triglyceride levels.

Background: Inflammation plays a pivotal role in atherosclerosis. In addition to being a risk marker for cardiovascular disease, much recent data suggest that C-reactive protein (CRP) promotes atherogenesis via effects on monocytes and endothelial cells. The metabolic syndrome is associated with significantly elevated levels of CRP. Plasminogen activator inhibitor-1 (PAI-1), a marker of atherothrombosis, is also elevated in the metabolic syndrome and in diabetes, and endothelial cells are the major source of PAI-1. However, there are no studies examining the effect of CRP on PAI-1 in human aortic endothelial cells (HAECs)., Methods and Results: Incubation of HAECs with CRP results in a time- and dose-dependent increase in secreted PAI-1 antigen, PAI-1 activity, intracellular PAI-1 protein, and PAI-1 mRNA. CRP stabilizes PAI-1 mRNA. Inhibitors of endothelial NO synthase, blocking antibodies to interleukin-6 and an endothelin-1 receptor blocker, fail to attenuate the effect of CRP on PAI-1. CRP additionally increased PAI-1 under hyperglycemic conditions., Conclusions: This study makes the novel observation that CRP induces PAI-1 expression and activity in HAECs and thus has implications for both the metabolic syndrome and atherothrombosis.