Adipose tissue macrophages

It is now broadly accepted that low-grade chronic inflammation associated with obesity leads to the onset of insulin resistance and type 2 diabetes mellitus. Obesity-associated inflammation is characterized by an increased abundance of macrophages in adipose tissue along with production of inflammatory cytokines. Adipose tissue macrophages (ATMs) are suspected to be the major source of inflammatory mediators such as TNF-alpha and IL-6 that interfere with adipocyte function by inhibiting insulin action. However, ATMs phenotypically resemble alternatively activated (M2) macrophages and are capable of anti-inflammatory mediator production challenging the concept that ATMs are simply the "bad guys" in obese adipose tissue. Triggers promoting ATM recruitment, ATM functions and dysfunctions, and stimuli and molecular mechanisms that drive them into becoming detrimental to their environment are subject to current research. Strategies to interfere with ATM recruitment and adverse activation could give rise to novel options for treatment and prevention of insulin resistance and type 2 diabetes mellitus.     

Obesity, inflammation and diabetes

Integration of metabolism and immunity in normal physiology is beneficial to maintain homeostasis. It can also become deleterious under conditions such as the immunosuppression observed among the malnourished. With the increase of excess weight and obesity, a new set of problems and complications has emerged at the intersection of metabolic activity and immunity. As examples of the latter we find obesity associated with inflammatory diseases, diabetes, fatty liver disease and atherosclerosis. Obesity is characterized by inflammation; there are common factors at the crossroads of inflammation and metabolic disease. Obesity is characterized by an inflammatory response and many inflammatory mediators exhibit expression patterns that interfere with insulin action. The high level of coordination of inflammatory and metabolic pathways is highlighted by the overlapping biology of macrophage and adipocite function observed in obesity. The intracellular signaling pathways activated by inflammatory and stress responses inhibit insulin signaling and the loss of inflammatory mediators prevents insulin resistance. In the absence of obesity, an infusion of inflammatory cytokines or lipids causes insulin resistance. Understanding the mechanisms leading from obesity to inflammation will have important implications to help reduce the morbidity and mortality associated with obesity by preventing its association with inflammatory disorders.     

The major inflammatory mediator interleukin-6 and obesity

Adipose tissue is one of the main sources of inflammatory mediators, with interleukin-6 (IL-6) among them. Although high systemic levels of inflammatory mediators are cachectogenic and/or anorexic, today it is a widely propagated thesis that in the background of obesity, a low level of chronic inflammation can be found, with IL-6 being one of the many suggested mediators. This paper reviews the studies describing elevated IL-6 levels in obese patients and the role of adipocytes and adipose-tissue macrophages in the production of IL-6. The secretion of IL-6 is regulated by several physiologic or pathologic factors: hormones, cytokines, diet, physical activity, stress, hypoxia, and others. Adipose tissue-derived IL-6 may have an effect on metabolism through several mechanisms, including adipose tissue-specific gene expression, triglyceride release, lipoprotein lipase downregulation, insulin sensitivity, and so on. Having a better understanding of these mechanisms may contribute to the prevention and treatment of obesity.     

An update on immune dysregulation in obesity‐related insulin resistance

Obesity is associated with chronic low‐grade inflammation of the adipose tissue (AT) that might develop into systemic inflammation, insulin resistance (IR) and an increased risk of type 2 diabetes mellitus (T2DM) in severe obese rodents and humans. In the lean state, small normal adipocytes and AT macrophages interact with each other to maintain metabolic homeostasis but during obesity, enlarged adipocytes secrete inflammatory mediators and express immune receptors to recruit immune cells and aggravate the inflammation. The better understanding of the obesity‐related inflammatory milieu and the sequential events leading to IR could be helpful in designing new preventive and therapeutic strategies. The present review will discuss the cellular and molecular abnormalities participating in the pathogenesis of obesity in obese individuals as well as high‐fat diet (HFD)‐fed mice, a mouse model of obesity.     

The modern interleukin-1 superfamily: Divergent roles in obesity

Obesity is now recognised as a chronic, low-grade inflammatory disease contributing to insulin resistance, type 2 diabetes (T2D) and cardiovascular disease (CVD). Multiple mechanisms leading to the low grade inflammation in this setting have been suggested. Due to the complexity and interconnection of inflammatory and metabolic responses, there also remains a need to fully elucidate the inflammatory mechanisms that control obesity and associated metabolic disorders. One important avenue in the field that has gained great attention is the interleukin (IL)-1 superfamily of cytokines that consist of IL-1β, IL-18 and IL-33. IL-1β is well known for its contribution as an inflammatory mediator in obesity contributing to insulin resistance and T2D, whereas the IL-18 and IL-33 cytokines have been shown to oppose metabolic dysregulation. This review will focus on the current understanding of the IL-1 superfamily of cytokines in the setting of obesity and discuss how endogenous feedback loops can be exploited for therapeutic approaches to fight obesity and subsequent cardiometabolic disorders.     

Effect of redox status of peripheral blood on immune signature of circulating regulatory and cytotoxic T cells in streptozotocin induced rodent model of type I diabetes

Diabetes mellitus is an autoimmune chronic inflammatory disease manifested by hyperglycemia and associated with imbalance in redox status and inflammatory response. Oxidative stress has been reported to affect functions of T cell repertoire- regulatory T cells (T_regs) and cytotoxic lymphocytes (CTLs). T_regs are involved in prevention against autoreactive T cells and controlling inflammation while CTLs are major mediators of tissue injury. Hence the present study is novel as it contemplates to understand oxidative stress in diabetes vis-à-vis T cells. Comparative analysis was carried out between two groups, i.e., healthy Sprague Dawley (SD) and Streptozotocin (STZ) induced SD rat model of type1 diabetes (T1D). Various hematological, biochemical and oxidative stress parameters were assessed in plasma samples in the study. Peripheral blood mononuclear cells (PBMCs), T_regs and CTLs were evaluated for intracellular oxidative stress using 2′,7′–dichlorofluorescin diacetate (DCFDA), mitochondrial ROS using Mitosox-red, mitochondrial membrane potential using JC-1 in PBMCs. T_reg populations expressing IL-4, IL-6 and IL-10 and CTLs expressing αβ-T cell receptor (αβ -TCR), interferon- γ (IFN-γ), perforin and granzyme were also considered. We found decreased activity of enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and reduced glutathione(GSH) and increased lipid peroxidation (LPO) in plasma indicated altered redox state in diabetic animals. Elevated intracellular reactive oxygen species (ROS) and mitochondrial superoxide was observed in T1D group confirming oxidative stress in cell specific manner. Cell population with hyperpolarized mitochondrial membrane potential was found to be elevated in T1D group. We found a decrease in T_reg population in T1D group in comparison to healthy group. T_reg population expressing IL-4, IL-6 were increased and those expressing IL-10 were found to be reduced in diabetic group. The CTL numbers were dropping whereas αβ-TCR, IFN-γ, perforin and granzyme expressing CTLs were on the rise in diabetic group. Our finding suggested an increased oxidative stress in T_regs and CTLs which might be responsible for progressive inflammatory environment built up due to persistent hyperglycemia. This was fortified by the statistical analyses where strong correlation between LPO and CTLs expressing TCR, IFN-γ, perforin and granzyme was noted. Lipid peroxidation was also found to be correlated to intracellular ROS in T_regs and CTLs along with other important revelations. The present study gives important insights into the significance of oxidative stress on immune system and its mediators in diabetes.     

Chronic inflammation in psoriasis and obesity: implications for therapy

A recent study has shown an indisputable relationship between psoriasis and obesity. Obesity leads to a higher risk in developing psoriasis and a poorer long-term clinical outcome of psoriasis. Furthermore, loosing weight may improve the psoriasis. A network of pro-inflammatory cytokines (especially tumour necrosis factor alpha (TNF-alpha)) is believed to play an important role in the pathophysiology of both obesity and psoriasis. The chronic low-level inflammation- as seen in obesity--may contribute to the extent of psoriatic lesions in obese patients. TNF-alpha in obesity is presumed to be derived from inflammatory cells (macrophages) in the adipose tissue and in psoriasis from activated T cells. Several drugs, such as peroxisome proliferator activated receptor (PPAR)-gamma agonists and TNF-alpha blocking agents, that target the pro-inflammatory pathways involved in both psoriasis and obesity have proven their benefit in the treatment of these entities. Furthermore, changes in levels of metabolic hormones as ghrelin and leptin in obesity may also play a role in the pathogenesis of deterioration of psoriasis by their potency to release pro-inflammatory mediators (e.g. interleukin (IL) 6 and TNF-alpha). We hypothesize that the treatment of obese psoriasis patient could be focused on reducing the obesity-induced inflammation. Reducing this obesity-induced inflammation may finally lead to a better clinical outcome. Weight loss could lead to a less inflammatory state by reducing concentrations of TNF-alpha, IL-6, leptin and improving insulin sensitivity.     

Interleukin-6 and Oxidative Stress in Plasma of Alloxan-Induced Diabetic Rabbits after Pioglitazone Treatment

There is evidence that oxidative stress might be implicated in promoting a state of systemic inflammation in diabetic patients. Understanding the role of reactive oxygen species in the inflammatory response in diabetes becomes essential in finding preventive treatments. Pioglitazone is a new oral antidiabetic agent with potent antioxidant and anti-inflammatory properties. The drug is a high affinity ligand of peroxisome proliferator-activated receptor gamma. This receptor seems to be involved in the control of inflammation by modulating the production of inflammatory mediators. In the present study, the changes in some markers of enhanced oxidative stress and in the level of pro-inflammatory interleukin-6 (IL-6) were examined in plasma of diabetic rabbits after 4 and 8 weeks of pioglitazone treatment. Ascorbic acid (AA) concentration and total antioxidant status (TAS) in plasma of diabetic animals were diminished and significantly elevated after pioglitazone treatment (p < 0.05). Protein carbonyl groups (PCG) content and IL-6 concentration were elevated in plasma of diabetic animals and significantly diminished after pioglitazone treatment. The results obtained in the present study confirm the relations of cytokine systems with oxidative stress in plasma of diabetic subjects. They also suggest the antioxidative and antinflammatory properties of pioglitazone.     

Interleukin-6 and oxidative stress in plasma of alloxan-induced diabetic rabbits after pioglitazone treatment

There is evidence that oxidative stress might be implicated in promoting a state of systemic inflammation in diabetic patients. Understanding the role of reactive oxygen species in the inflammatory response in diabetes becomes essential in finding preventive treatments. Pioglitazone is a new oral antidiabetic agent with potent antioxidant and anti-inflammatory properties. The drug is a high affinity ligand of peroxisome proliferator-activated receptor gamma. This receptor seems to be involved in the control of inflammation by modulating the production of inflammatory mediators. In the present study, the changes in some markers of enhanced oxidative stress and in the level of pro-inflammatory interleukin-6 (IL-6) were examined in plasma of diabetic rabbits after 4 and 8 weeks of pioglitazone treatment. Ascorbic acid (AA) concentration and total antioxidant status (TAS) in plasma of diabetic animals were diminished and significantly elevated after pioglitazone treatment (p < 0.05). Protein carbonyl groups (PCG) content and IL-6 concentration were elevated in plasma of diabetic animals and significantly diminished after pioglitazone treatment. The results obtained in the present study confirm the relations of cytokine systems with oxidative stress in plasma of diabetic subjects. They also suggest the antioxidative and antinflammatory properties of pioglitazone.     

Phlebodium decumanum is a natural supplement that ameliorates the oxidative stress and inflammatory signalling induced by strenuous exercise in adult humans

Strenuous exercise induces muscle damage due to a highly increased generation of free radicals and inflammatory response and therefore, in this type of exercise, it is important to reduce both oxidative stress and inflammation, at least their negative aspects. The purpose of this study was investigate, for the first time, whether a purified, standard water-soluble fraction obtained from Phlebodium decamanum could reduce the over-expression of inflammation and oxidative stress induced by strenuous exercise. The physical test consisted of a constant run that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing. Biochemical parameters, oxidative stress and inflammatory mediators were assessed. The results showed that oral supplementation of P. decumanum during high-intensity exercise effectively reduces the degree of oxidative stress (decreased 8-hydroxy-2'-deoxyguanosine and isoprostanes generation, increased antioxidant enzyme activities in erythrocyte and total antioxidant status in plasma). The data obtained also indicate that this supplementation is efficient in reducing the inflammatory response through the decrease of TNF-α and increase of sTNF-RII, but kept the levels of IL-6 and IL-1ra. In conclusion, oral supplementation of P. decamanum extract during high-intensity exercise effectively reduces the degree of oxidative stress and has anti-inflammatory protective effects, preventing the over-expression of TNF-α but keeping the levels and effects of IL-6. These findings provide a basis for similar Phlebodium supplementation for both professional and amateur athletes performing strenuous exercise in order to reduce the undesirable effects of the oxidative stress and inflammation signalling elicited during high-intensity exercise.     

Middle ear fluid cytokine and inflammatory cell kinetics in the chinchilla otitis media model

Streptococcus pneumoniae is the most frequent microbe causing middle ear infection. The pathophysiology of pneumococcal otitis media has been characterized by measurement of local inflammatory mediators such as inflammatory cells, lysozyme, oxidative metabolic products, and inflammatory cytokines. The role of cytokines in bacterial infection has been elucidated with animal models, and interleukin (IL)-1beta, IL-6, and IL-8 and tumor necrosis factor alpha (TNF-alpha) are recognized as being important local mediators in acute inflammation. We characterized middle ear inflammatory responses in the chinchilla otitis media model after injecting a very small number of viable pneumococci into the middle ear, similar to the natural course of infection. Middle ear fluid (MEF) concentrations of IL-1beta, IL-6, IL-8, and TNF-alpha were measured by using anti-human cytokine enzyme-linked immunosorbent assay reagents. IL-1beta showed the earliest peak, at 6 h after inoculation, whereas IL-6, IL-8, and TNF-alpha concentrations were increasing 72 h after pneumococcal inoculation. IL-6, IL-8, and TNF-alpha but not IL-1beta concentrations correlated significantly with total inflammatory cell numbers in MEF, and all four cytokines correlated significantly with MEF neutrophil concentration. Several intercytokine correlations were significant. Cytokines, therefore, participate in the early middle ear inflammatory response to S. pneumoniae.     

The role of pioglitazone in antioxidant,anti-inflammatory,and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance

We explored the cascade effects of a high fat-carbohydrate diet (HFCD) and pioglitazone (an anti-diabetic therapy used to treat type 2 diabetes mellitus (T2DM)) on lipid profiles, oxidative stress/antioxidant, insulin, and inflammatory biomarkers in a rat model of insulin resistance. Sixty albino rats (80-90 g) were randomly divided into three dietary groups; 1) standard diet; 2) HFCD diet for 12 weeks to induce an in vivo model of insulin resistance; and 3) HFCD diet plus pioglitazone. Blood and tissue samples were taken to assess hepatic function, lipid profiles, oxidative biomarkers, malondialdehyde (MDA) levels, antioxidant defense biomarkers, including reduced glutathione (GSH), superoxide dismutase (SOD), and the inflammatory markers interleukin-6 (IL-6) and tumor necrotic factor (TNF-α). HFCD-fed rats had significantly (P≤0.05) increased serum triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein (LDL), alanine transaminase (ALT), and bilirubin levels, but decreased high-density lipoprotein (HDL) levels compared with the normal group. Moreover, serum leptin, resistin, TNF-α, and IL-6 levels were increased significantly in HFCD animals compared with controls. Similarly, HFCD-induced insulin resistance caused antioxidant and cytokine disturbances, which are important therapy targets for pioglitazone. Importantly, administration of this drug ameliorated these changes, normalized leptin and resistin and inflammatory markers by reducing TNF-α levels. Metabolic cascades of elevated lipid profiles, oxidative stress, insulin, and inflammatory biomarkers are implicated in insulin resistance progression. HFCD induced metabolic cascades comprising hypertriglyceridemia, hyperglycemia, insulin resistance, obesity-associated hormones, and inflammatory biomarkers may be alleviated using pioglitazone.     

First Evidence for the Anti-inflammatory Activity of Fucoxanthin in High-Fat-Diet-Induced Obesity in Mice and the Antioxidant Functions in PC12 Cells

Obesity, characterized as a state of low-level inflammation, is a powerful determinant influencing the development of insulin resistance and progression to type 2 diabetes. The purpose of the present study was to investigate the anti-inflammatory activity of fucoxanthin in experimental high-fat-diet-induced obesity in mice and antioxidant activity in PC12 cells under oxidative stress situation. The anti-inflammatory potential of fucoxanthin in the regulation of maleic dialdehyde (MDA), polymorphonuclear cells (PMNs), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and cyclooxygenase-2 (COX-2) was determined by ELISA. Fucoxanthin significantly inhibited obesity-induced upregulation of the production of IL-1β, TNF-α, iNOS, and COX-2. Moreover, fucoxanthin suppressed MDA and infiltration of PMNs. The protective effects were associated with lack of hypertrophy and crown-like structures in mammary gland. At the same time, fucoxanthin showed an advantage of antioxidant activity in PC12 cells under oxidative stress situation. These results suggest that supplementation of fucoxanthin is a promising strategy for blocking macrophage-mediated inflammation and inflammation-induced obesity and its associated complications.     

Hyperinsulinaemia, a key factor of the metabolic syndrome in postmenopausal women

The metabolic syndrome (MetS) is a complex disorder combining obesity, hypertension, atherogenic dyslipidaemia and insulin resistance, a clustering of factors which markedly enhance the risk of developing cardiovascular disease (CVD) and type 2 diabetes. Main features of the MetS, which are found in many postmenopausal women, are increasing prevalence of insulin resistance and obesity (particularly visceral adiposity). Accordingly, a majority of postmenopausal women comply with criteria defining the MetS, and CVD is the first cause of morbidity/mortality in women, occurring even more frequently than in men. Moreover, obesity-related type 2 diabetes approaches pandemic proportions. Simultaneous occurrence of insulin resistance and obesity are most detrimental for metabolic health, and are also associated with increased oxidative stress, inflammatory and prothrombotic processes as well as with postmenopausal alterations in adipocytokine production. Hormone replacement therapy, provided the selected progestin does not antagonize estrogen action, may improve fat mass and distribution, dyslipidaemia and insulin sensitivity in postmenopausal women.     

Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-alpha, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats

This study examined the hypothesis that curcumin supplementation decreases blood levels of IL-6, MCP-1, TNF-alpha, hyperglycemia, and oxidative stress by using a cell-culture model and a diabetic rat model. U937 monocytes were cultured with control (7 mM) and high glucose (35 mM) in the absence or presence of curcumin (0.01-1 microM) at 37 degrees C for 24 h. Diabetes was induced in Sprague-Dawley rats by injection of streptozotocin (STZ) (i.p., 65 mg/kg BW). Control buffer, olive oil, or curcumin (100 mg/kg BW) supplementation was administered by gavage daily for 7 weeks. Blood was collected by heart puncture with light anesthesia. Results show that the effect of high glucose on lipid peroxidation, IL-6, IL-8, MCP-1, and TNF-alpha secretion was inhibited by curcumin in cultured monocytes. In the rat model, diabetes caused a significant increase in blood levels of IL-6, MCP-1, TNF-alpha, glucose, HbA(1), and oxidative stress, which was significantly decreased in curcumin-supplemented rats. Thus, curcumin can decrease markers of vascular inflammation and oxidative stress levels in both a cell-culture model and in the blood of diabetic rats. This suggests that curcumin supplementation can reduce glycemia and the risk of vascular inflammation in diabetes.     

Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women

PROBLEM: Despite progress in immunobiology, pre-eclampsia (PE) remains one of the most common reasons for women to die during pregnancy. The widespread pathophysiological mechanisms are endothelial dysfunction, oxidative stress and inflammation. The aim of this study was to assess the alteration in the levels of leptin, interleukin (IL)-10 and inflammatory cytokines [tumour necrosis factor (TNF)-alpha, IL-6 & IL-8] in pre-eclamptic (severe and mild), healthy pregnant and non-pregnant women and correlate these parameters with disease severity. METHOD OF STUDY: The levels of leptin, IL-10 and inflammatory cytokines were measured by high sensitivity enzyme-linked immunoabsorbant assay. The study subjects were 54 pre-eclamptic women (ten severe and 45 milder), compared by age matched 50 healthy pregnant and 27 non-pregnant women. Kruskal-Wallis non-parametric analyses of variance followed by Mann-Whitney U-test were used for statistical analysis. RESULTS: The levels of leptin, TNF-alpha, IL-6 & IL-8 in pre-eclamptic subjects were increased significantly when compared with the healthy control pregnant and non-pregnant (P < 0.000). The concentration of IL-10 has shown different pattern as its level decreased significantly (0.001) in pre-eclamptic women (overall) in comparison with control subjects (pregnant & non-pregnant). A combination of 80% or higher sensitivity and specificity was seen in the parameters analysed, except IL-8 and IL-10. CONCLUSION: Our findings suggest a relationship among TNF-alpha, IL-6, IL-8, IL-10 and leptin and indicate that altered levels of above markers in PE might be used as markers of pro-inflammation/anti-inflammation and endothelial dysfunction in pre-eclamptic pregnancies. These results also advocate the abnormal leptin and cytokine responses in mother, which might be involved in the pathogenesis of PE.     

Gestational diabetes induces chronic hypoxia stress and excessive inflammatory response in murine placenta

Metabolic impairments in maternal obesity and gestational diabetes mellitus (GDM) induce an abnormal environment in peripheral blood and cause vascular structure alterations which affect the placental development and function. A GDM model was developed using C57BL/6J female mice fed with high fat food (HF) (40% energy from fat) and a control group with control food (CF) (14% energy from fat) for 14 weeks before mating and throughout the gestation period. A subset of dams was sacrificed at gestational day (GD) 18.5 to evaluate the fetal and placental development. HF-fed dams exhibited significant increase in the maternal weight gain and homeostasis model assessment for insulin resistance index (HOMA-IR), impaired insulin secretion of glucose stimulus and glucose clearance of insulin stimulus before pregnancy; in addition, they also had the increase in the fetal and placental weight. HF-fed dams at GD 18.5 showed the high level of circulating maternal inflammation factors and were associated with increased oxidative stress and hypoxia in the labyrinth, abnormal vascular development with a high level of hypoxia inducible factor-1α (HIF-1α) and VEGF-A expression, but without a parallel increase in CD31 level; were induced an exaggerated inflammatory response in placental vascular endothelial cell. Our findings show that GDM induces more maternal weight gain and fetus weight, with abnormal maternal circulating metabolic and inflammation factors, and forms a placental hypoxia environment and impacts the placental vascular development. Our findings indicate that gestational diabetes induce excessive chronic hypoxia stress and inflammatory response in placentas which may contribute mechanisms to the high risks of perinatal complications of obesity and GDM mothers.     

The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression

Definitions of the metabolic syndrome (MetS) include obesity, dyslipidemia, elevated levels of fasting blood glucose, and blood pressure as criteria, but it is also known that the MetS is associated with chronic, subclinical inflammation. Hyperglycemia (fasting and postprandial) may be important in exacerbating this proinflammatory state. We aimed to assess the impact of oral glucose challenge and in vitro glucose-stimulation on gene expression and secretion of inflammatory parameters in peripheral blood leukocytes and to investigate whether presence of the MetS could "prime" leukocytes to up-regulate proinflammatory markers in response to glucose. Using quantitative real-time PCR, we could show that the expression of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) significantly increased in peripheral blood leukocytes from "MetS" subjects (n=39) compared to "no MetS" subjects (n=35) 2 h after an oral glucose tolerance test (ICAM-1 +52%, TNF-alpha +107%, and IL-6 +38%) and also in vitro after 72 h cultivation in high-glucose medium (ICAM-1 +74%, TNF-alpha +71%, and IL-6 +44%). Using ELISA and Luminex technique, we further observed a trend towards increased immune mediator concentrations in the corresponding cell culture supernatants from MetS patients (ICAM-1 +21%, TNF-alpha +31%, and IL-6 +175%). Thus, the MetS may support peripheral inflammation by sensitizing leukocytes to up-regulate proinflammatory markers in response to glucose, which in turn increases the risk for type-2 diabetes mellitus and cardiovascular disease.