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[email protected] Current Vascular Pharmacology, 2013, 11, 906-919
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Inflammation, Oxidative Stress and Metabolic Syndrome: Dietary Modulation José C. Fernández-García1,3,* Fernando Cardona2, 3 and Francisco J. Tinahones1,3 1
Department of Endocrinology, Virgen de la Victoria University Hospital, Málaga, Spain; 2Research laboratory, Virgen de la Victoria University Hospital, Málaga, Spain; 3Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBERObn CB06/003), Instituto de Salud Carlos III, Madrid, Spain Abstract: The metabolic syndrome (MetS) is a cluster of risk factors for the development of cardiovascular disease and type 2 diabetes mellitus. These risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. MetS has become a serious public health and clinical problem whose prevalence and incidence are increasing along with the worldwide rise in rates of obesity and sedentary lifestyles. A number of studies have shown that MetS is associated with a state of low-grade inflammation, characterized by abnormal pro-inflammatory cytokine production, increased acute-phase reactants, and activation of a network of inflammatory signalling pathways. Moreover, MetS has also been linked to oxidative stress, a consequence of a reduction in the antioxidant systems and an increase in the production of reactive oxygen species. Nevertheless, agreement exists that dietary intervention may modulate the pro-inflammatory state and lessen oxidative stress related to MetS, thereby decreasing the cardiovascular risk. In this review we address the current available evidence regarding dietary modulation of inflammation and oxidative stress associated with MetS.
Keywords: Dietary modulation, inflammation, mediterranean diet, metabolic syndrome, oxidative stress, polyphenols, resveratrol. INTRODUCTION Most countries are currently experiencing the highest life expectancy rates ever recorded. Technical medical advances are reaching unimaginable heights and with the advanced therapies now available for most diseases, the era of infectious pandemics is gone. However, a new epidemic, referred to as obesity, is on the increase; so much so that it has become the most serious public health issue in developed countries. Recent data show that 1.46 billion people worldwide are overweight and nearly 502 million are obese. Furthermore, in the past 3 decades the prevalence of obesity has doubled and the mean body mass index (BMI) has increased by 0.4 kg/m2 per decade [1]. Obesity is clearly associated with the development of type 2 diabetes mellitus (T2DM), hypertension, impaired lipid metabolism, cancer, musculoskeletal disorders and cardiovascular diseases [2]. Obesity and overweight are responsible for 44% of the T2DM burden, 23% of the ischemic heart disease burden and between 7% and 41% of certain cancers. Overweight and obesity are considered the fifth leading risk for global deaths and 2.8 million adults die each year as a result of excess body weight [3]. Rising obesity rates could even reverse life-expectancy gains in highincome nations [4].
*Address correspondence to this author at the Department of Endocrinology, Virgen de la Victoria University Hospital, Campus de Teatinos s\n, 29010 Málaga, Spain; Tel: +34 951 034 016; Fax: + 34 951 92 46 55; E-mail:
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A cluster of risk factors for cardiovascular disease and T2DM, which occur together more often than by chance alone, have become known as the metabolic syndrome (MetS). These risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein [HDL] cholesterol), raised fasting glucose, and central obesity. MetS has now become a serious public health and clinical problem, and its prevalence and incidence are increasing along with rising rates of obesity and sedentary lifestyles worldwide [5]. MetS has been estimated to affect ~34% of American adults and up to 36% of adult Europeans [6]. The elevated prevalence of MetS is related with a significant burden of morbidity and mortality. Epidemiological studies have reported that MetS is associated with a 5-fold increase in the risk for T2DM, a 2-fold increase for cardiovascular disease, and a 1.5-fold increase for all-cause mortality [7]. Increasing evidence suggests that MetS is associated with chronic low-grade inflammation and increased oxidative stress [8, 9]. This pro-inflammatory state and the concomitant raised oxidative stress, which in turn lead to endothelial dysfunction, are clearly related to increased cardiovascular morbidity and mortality [10, 11]. Strategies should therefore be sought to ameliorate this inflammation and elevated oxidative stress. Several epidemiological, pre-clinical and clinical studies have reported that certain dietary modifications, including antioxidants, micronutrients, vitamins or polyphenols might be useful to lessen the proinflammatory state and decrease oxidative stress related to MetS [12, 13]. In this review we summarize current knowledge about the dietary © 2013 Bentham Science Publishers
Inflammation, Oxidative Stress and Metabolic Syndrome
modulation of inflammation and oxidative stress associated with MetS. METABOLIC SYNDROME AND INFLAMMATION Various diagnostic criteria have been proposed over the past decade by different organizations, and several expert groups have set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of MetS. The first formal definition of MetS came from the World Health Organization (WHO) in 1998. The WHO diagnostic criteria emphasized insulin resistance as the major underlying risk factor and evidence of insulin resistance was required for diagnosis. A diagnosis of the syndrome according to the WHO criteria could be made on the basis of several markers of insulin resistance plus 2 additional risk factors, including obesity, hypertension, a high triglyceride level, a reduced HDL cholesterol level, or microalbuminuria [14]. In 2001, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) established new criteria for MetS and proposed the presence of 3 of the following 5 factors as the basis for establishing the diagnosis: abdominal obesity (which is highly correlated with insulin resistance), elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, and elevated fasting glucose (impaired fasting glucose or T2DM). The demonstration of insulin resistance, though, was not needed [15]. In 2005, the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) both published diagnostic criteria for MetS. In the IDF criteria, the presence of abdominal obesity was considered indispensable for diagnosis of MetS; the remainder of the criteria were essentially identical to those provided by ATP III [16]. The AHA/NHLBI modified the ATP III criteria slightly and did not mandate abdominal obesity as a required risk factor. The remaining 4 risk factors were identical in definition to those of the IDF [17]. A consensus scientific statement from several major organizations has recently been published in an attempt to unify the criteria for MetS [5]. This joint scientific statement agreed that the diagnosis of MetS derives from the presence of any 3 of the following 5 risk factors: abdominal obesity (not a prerequisite for diagnosis but 1 of 5 criteria), raised blood pressure, raised triglycerides, lowered HDL cholesterol and elevated fasting glucose. Although the diagnostic criteria of MetS have varied considerably since its initial description, and there are currently no mandatory criteria for diagnosis, it seems clear that MetS is largely related to increasing obesity and sedentary lifestyles. Imbalance between calorie intake and metabolic expenditure causes excess body fat which is stored in the adipose tissue. Moreover, recent interest has focused on the possible involvement of insulin resistance as a linking factor in MetS [5, 17]. An important recent development in our understanding of obesity, insulin resistance and MetS is the emergence of the concept that they are characterized by a state of chronic low-
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grade inflammation. Conversely to the traditional view of adipose tissue as a mere passive storage organ, adipose tissue is now considered a complex and highly active metabolic and endocrine organ, releasing several factors involved in metabolism regulation [18]. Adipose tissue expresses and secretes a variety of bioactive peptides, known as adipocytokines, which act at both the local (autocrine/paracrine) and systemic (endocrine) level. The most important of these adipokines are tumor necrosis factor alpha (TNF-), IL-6, IL1, leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), and proteins of the renin angiotensin system [19, 20]. When obesity and MetS develop, the complex and delicate hormonal balance described above becomes impaired and results in a pro-inflammatory condition with abnormal cytokine production, increased acute-phase reactants and activation of a network of inflammatory signaling pathways [21]. The first link connecting obesity and inflammation (and subsequently insulin resistance) came to light in the early 1990s. A seminal study by Hotamisligil et al. found that TNF-, a cytokine secreted by both immune cells and adipocytes, is a major mediator of inflammation in general and of obesity and insulin resistance in particular. TNF- was overexpressed in the adipose tissue of obese mice compared with wild-type controls and TNF- caused a significant decrease in the peripheral uptake of glucose in response to insulin [22]. These results were soon replicated in humans; TNF- levels were increased in adipose tissue of obese individuals compared with lean subjects, and TNF- levels correlated positively with insulin resistance [23] and with C-reactive protein (CRP) levels, this latter a marker of systemic inflammation [24]. Later, the mechanisms by which TNF- produces insulin resistance were discovered; TNF- interferes with insulin signal transduction via serine phosphorylation of insulin receptor substrate-1 (IRS-1) [25]. Since then, TNF- blockade has become an attractive therapeutic target to treat insulin resistance. For example, the anti TNF- drug infliximab restores glucose homeostasis in animal models of obesity and diabetes, and in humans the use of diverse anti TNF- drugs (etanercept, infliximab and adalimumab) has been associated with decreased insulin resistance and improved -cell function [26, 27]. However, despite the major role of TNF- in the development of obesity-induced inflammation, it was rapidly demonstrated that in obesity, adipose tissue not only secretes inadequate levels of TNF-, but also a further wide range of adipocytokines [18]. Among these, the most important are IL-6 and IL-1, and to a lesser degree IL-8 and IL-17D. All these are potent proinflammatory cytokines associated with obesity and insulin resistance [28, 29]. These cytokines are up-regulated in obesity and play an important role in the pathophysiological processes underlying MetS, T2DM and cardiovascular disease. Yet, not all cytokines exert pro-inflammatory effects, and others like IL-2, IL-4 and IL-10 posses anti-inflammatory actions [30]. Other hormones involved in obesity include leptin and adiponectin. Leptin, a peptide hormone expressed mainly by adipose tissue, is associated with appetite regulation, energy expenditure, lipid oxidation and platelet aggregation. Leptin levels are higher in obese individuals and lower in lean individuals. Elevated leptin concentrations in obesity may con-
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tribute to the pro-inflammatory state of obesity and to atherogenesis in the long term [31]. Adiponectin is an antiinflammatory adipocytokine produced and secreted exclusively by white adipocytes. Its levels are decreased in obesity, T2DM, coronary artery disease and MetS. Adiponectin exerts important anti-inflammatory and anti-atherogenic effects and low adiponectin levels are thus a marker for atherosclerosis and coronary heart disease [32]. A number of studies have reported that obesity is linked to activation of a network of inflammatory signaling pathways. Attention has recently focused on NF-B (nuclear factor kappa-light-chain-enhancer of activated B cells) and JNK (c-Jun NH2-terminal kinase), proinflammatory transcription factors related to obesity, insulin resistance, lowgrade inflammation and oxidative stress [33]. NF-B regulates the expression of more than 400 different genes, most of which control the expression of inflammatory gene products. NF-B is found to be chronically active in many inflammatory diseases, such as sepsis, asthma or atherosclerosis, and is related to cancer development [34]. Accumulated evidence suggests that NF-B plays a major role in insulin resistance [19, 35] and that TNF- and IL-6 are its most important activators [36, 37]. The key event in NF-B activation is the phosphorylation of the inhibitor of kappa-B (IB) since IB inactivates NF-B transcription. This phosphorylation is specifically executed by the IB kinase (IKK) enzyme, resulting in the dissociation of IB from NF-B and thereby activating NF-B [38]. JNK is another transcription factor whose activity has been reported to be abnormally elevated in obesity and insulin resistance. JNK, like NF-B, is activated upon exposure to cytokines such as TNF-, but unlike NF-B, its effects are thought to be exerted through the serine phosphorylation of insulin receptor substrate 1 (IRS-1) [21, 39]. An absence of JNK results in decreased adiposity, improved insulin sensitivity and enhanced insulin receptor signaling capacity in two different murine models of obesity [40, 41]. This accumulated evidence suggests that the inhibition of NF-B and JNK pathways by specific inhibitors might be a promising therapeutic avenue for insulin resistance, obesity and MetS [42]. A number of studies have highlighted the role of the immune system in MetS-induced inflammation [33]. Weisberg et al. showed that adipose tissue in obese subjects is characterized by macrophage infiltration. Moreover, the extent of macrophage infiltration has been shown to correlate directly with the degree of obesity [43]. This has been explained through MCP-1 stimulation. MCP-1 is an adipocyteproduced chemokine, which stimulates macrophage recruitment to adipose tissue. Thus, greater MCP-1 levels produce higher macrophage recruitment. These adipose tissueresident macrophages are a source of pro-inflammatory factors and release active molecules such as TNF-, IL-6 or IL1 [44, 45]. Activated macrophages also express increased intranuclear NF-B binding, decreased IB expression and increased transcription of proinflammatory genes regulated by NF-B [9, 46]. Overall, it therefore seems that macrophage infiltration plays a key role in perpetuating the state of low-grade inflammation associated with obesity.
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SYNDROME
AND
OXIDATIVE
Oxidative stress is the consequence of a reduction in the antioxidant systems and/or an increase in the production of reactive oxygen species (ROS) [47]. The damage induced by oxidative stress only occurs when the antioxidant defenses are unable to counteract the production of ROS. Under normal physiological conditions, ROS can be eliminated or inactivated in vivo by different antioxidant systems. Thus, superoxide anions (O2·) are enzymatically converted to hydrogen peroxide by superoxide dismutase (SOD), and hydrogen peroxide is reduced by the enzyme glutathione peroxidase (GSH-Px), catalases and peroxiredoxins [48, 49]. Moreover, ROS can be eliminated or inactivated in vivo by various endogenous molecules (albumin, uric acid) or by different exogenous antioxidants derived from the diet (vitamin C or vitamin E) [50]. Interest has recently centered on the idea that oxidative stress occurring in adipose tissue may be the first step in the generation of inflammation and that oxidative stress plays a major role in the genesis of MetS. Furukawa et al. have shown in experimental murine models that obesity is related to increased levels of ROS, increased expression of NADPH oxidase and decreased expression of antioxidative enzymes, and that it exerts significant disturbances in the production of adiponectin, IL-6 and MCP-1. Interestingly, treatment with a NADPH oxidase inhibitor reduces ROS production in adipose tissue, attenuates the dysregulation of adipocytokines, and improves diabetes, hyperlipidemia, and hepatic steatosis [8]. Furthermore, human studies have demonstrated that obese subjects have lower SOD and GSH-Px activity compared with nonobese persons [51, 52] and that, compared to healthy subjects, MetS patients show greater baseline oxidative stress and higher levels of lipid peroxidation products and oxidized glutathione, but conversely they have lower levels of reduced glutathione, GSH-Px activity, glutathione reductase and glutathione transferase [53]. Another important aspect related to oxidative stress is postprandial hyperlipidemia. This is defined as the increase in triglycerides after fat intake. Clinical studies have shown that increased postprandial concentrations of triglycerides are associated with MetS, coronary and arterial disease [54], and insulin resistance [55]. The postprandial state is a fundamental period in the development of lipid oxidation. Different studies have shown that hypertriglyceridemia increases oxidative metabolism, the release of O2· [56] and the concentration of thiobarbituric acid reactive substances (TBARS) [57] and lipid peroxides [58]. In both healthy persons [59] and in morbidly obese persons [57], a high-fat meal produces an increase in the plasma levels of postprandial triglycerides and strong oxidative stress [53]. Studies in healthy volunteers have shown that postprandial hyperlipidemia causes a worsening in endothelial function [60]. Postprandial lipoproteins, especially chylomicrons and very low–density lipoproteins, appear to generate oxygen radicals on the endothelial surface that react with nitric oxide (NO) and reduce its availability [61, 62].
Inflammation, Oxidative Stress and Metabolic Syndrome
Overall, these findings suggest that obesity and MetS are associated with postprandial hyperlipidemia and greater basal and postprandial oxidative stress. DIETARY MODULATION OF INFLAMMATION AND OXIDATIVE STRESS IN THE METABOLIC SYNDROME A number or studies have reported that certain dietary interventions may modulate the components of MetS and improve outcomes. These dietary interventions include vitamins C, E and D, capsaicin, ginger, lipoic acid, lowglycemic index diets, monounsatured and polyunsaturated fatty acids, polyphenols and polyphenol-rich foods (resveratrol, isoflavones, curcumin, cocoa, tomato and tea), and a Mediterranean-style diet. In the following pages we review the available evidence regarding dietary modulation of inflammation and oxidative stress associated with MetS [6365]. Vitamin C L-Ascorbic acid (vitamin C), present as ascorbate in most biological settings, is considered the most important antioxidant in human plasma. Vitamin C has an important role in the immune function and several oxidative and inflammatory processes, such as scavenging ROS and reactive nitrogen species, preventing the initiation of chain reactions that lead to protein glycation and protecting against lipid peroxidation. In addition, ascorbate can recycle vitamin E (another natural antioxidant) and glutathione (involved in oxidative stress) back from their oxidized forms [66]. Various studies have assessed the effect of vitamin C on biomarkers of oxidation, inflammation, and T2DM. Thus, it has been reported that vitamin C significantly improves endothelium-dependent vasodilatation among diabetics and among patients with coronary artery disease through reduced superoxide production and decreased NO inactivation [67]. A low vitamin C status is associated with proinflammatory responses and impaired vascular function in lean and obese men [68]. Ascorbic acid supplementation attenuates IL-10 increase [69] and inhibits NF-B both in vitro and in vivo [70]. Serum ascorbic acid deficiency has been associated with elevated CRP and other factors related to MetS, such as waist circumference, BMI or hypertension [71]. Plasma vitamin C, dietary vitamin C, and fruit intake are inversely correlated with serum CRP and tissue plasminogen activator, a biomarker of endothelial dysfunction [72]. A high intake of food rich in ascorbic acid reduces levels of some indicators of inflammation (PGF2a, CRP, IL-6) and oxidative stress (F2-isoprostanes) [73], and a significant inverse association has been found between plasma levels of vitamin C and the risk of diabetes (OR=0.38) [74]. Given these exciting findings, several clinical trials have evaluated the effects of vitamin C supplementation on various markers of T2DM and MetS. Daily intake of ascorbic acid at 2000 mg/day improves fasting plasma glucose, HbA1c, cholesterol and triglyceride levels in T2DM subjects [75], and 1000 mg/day of vitamin C for 4 months improves LDL and total cholesterol, fasting plasma insulin, and free radicals, not affecting triglyceride or HDL levels [76]. However, other studies have found different results. A trial as-
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sessing supplementation with 3000 mg/day of vitamin C for 2 weeks reported no improvement in fasting plasma glucose and no significant differences in levels of CRP, IL-6, IL-1, or oxidized LDL [77]. Similarly, treatment with 2000 mg/day of vitamin C for 4 weeks had no effect on levels of CRP, IL6, TNF-, or soluble VCAM-1 in T2DM patients [78]. Finally, Chen et al. found no significant changes in either fasting glucose or fasting insulin after intake of 800 mg/day of vitamin C for 4 weeks in T2DM patients [79]. Overall, it remains unclear whether vitamin C intake has an effect on factors related to T2DM and MetS. Although the epidemiologic evidence suggests that vitamin C, whether as a supplement or as part of a diet rich in fruits and vegetables, affects inflammatory markers beneficially, the results of intervention trials are conflicting. Small sample sizes, genetic variation, short intervention duration, insufficient dosage, and disease status of the cohorts assessed may account for the lack of effect and the inconsistent outcomes observed in intervention studies. Therefore, further research and longterm prospective studies are needed to elucidate the role of vitamin C as a modulator of inflammation and to evaluate its potential role as a preventive agent at a population level [13]. Vitamin E Vitamin E, first described by Evans and Bishop in 1922, is a potent, lipid-soluble antioxidant that prevents the propagation of free radical damage in biological membranes. Vitamin E is the collective name for eight naturally occurring molecules, four tocopherols ( and ) and four tocotrienols ( and ). Each type exerts different actions owing to significant differences in their chemical structure and molecular function. The four forms of tocopherols and tocotrienols differ in the number of methyl groups on the chromanol nucleus ( has 3, - and - have 2, and - has 1) and tocotrienols differ from tocopherols in that they have an unsaturated phytyl side chain [80]. Among the compounds derived from vitamin E, tocopherol and -tocopherol have been the most extensively studied. -tocopherol is the predominant form of vitamin E in most human and animal tissues and is considered the most potent lipid-soluble antioxidant in plasma and low-density lipoproteins. -tocopherol is the main source of vitamin E found in supplements and in the European diet, given the high concentrations of -tocopherol found in olive and sunflower oils. In contrast, -tocopherol is the most prevalent form of vitamin E in vegetable oils such as corn, soybean, and sesame, and nuts such as walnuts, pecans, and peanuts. Because of the widespread use of these plant products, tocopherol represents 70% of the vitamin E consumed in the typical US diet [81]. Several studies have addressed the relationship between vitamin E and MetS. It has been reported that insulin resistance is directly correlated to low plasma concentrations of carotenoids, -tocopherol and -tocopherol [82] and that low vitamin E concentrations predict the risk of incident diabetes [83]. Moreover, serum vitamin E concentrations are lower in patients with MetS than in controls [84] and some studies have suggested an association between vitamin E intake (tocopherol mainly) and reduced rates of morbidity and mortality from cardiovascular disease [85].
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In various experimental studies vitamin E supplementation has shown satisfactory results. For example, tocopherol supplementation (1200 IU/day for 3 months) reduces superoxide, IL-1, IL-6, CRP and TNF- levels, and monocyte adhesion to endothelial cells, decreasing several soluble cell adhesion molecules (ICAM, VCAM, and Eselectin) [86, 87] and high doses of -tocopherol supplementation in patients with coronary artery disease significantly reduce TNF- and CRP [88]. However, clinical trials examining vitamin E and cardiovascular disease have produced contradictory results. The first study that evaluated the role of vitamin E in vascular protection was the Cambridge Heart Antioxidant Study (CHAOS) trial. In this study, patients with angiographically proven coronary atherosclerosis were randomized to tocopherol therapy (800-400 IU daily) or placebo. Treatment with -tocopherol significantly reduced the risk of non-fatal myocardial infarction (RR 0.23) [89]. In the GISSIPrevenzione trial, 11,324 patients with a recent myocardial infarction were assigned to vitamin E (300 mg daily), n-3 polyunsaturated fatty acids or placebo. Vitamin E had no effect on a primary combined efficacy endpoint of death, non-fatal myocardial infarction, and stroke [90]. In the Heart Outcomes Prevention Evaluation (HOPE) study, 9541 subjects at high-risk for cardiovascular events were randomized to treatment with 400 IU of vitamin E daily or placebo for a mean of 4.5 years. However, vitamin E treatment did not show any reduction in the incidence of cardiovascular events [91]. In the SPACE trial, hemodialysis patients with prevalent cardiovascular disease were randomized to supplementation with 800 IU/day of vitamin E or placebo. In this group of patients, vitamin E reduced composite cardiovascular disease endpoints and myocardial infarction [92]. Finally, a combination of antioxidants was assessed in one of the largest clinical trials to date, the Heart Protection Study (HPS). In this study, 20,536 high-risk patients were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo during a 5-year follow-up. Although this regimen doubled the plasma concentration of tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene, there were no significant differences in all-cause mortality, deaths due to vascular or non-vascular causes, or any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death, non-fatal or fatal stroke, or coronary or non-coronary revascularization [93]. Taking all these results together, we cannot conclude that supplementation with vitamin E improves cardiovascular morbidity and mortality. Although vitamin E therapy, especially at high doses, decreases the pro-inflammatory state and oxidative stress related to obesity and MetS, the results of randomized clinical trials to date have been inconsistent. As with vitamin C supplementation, the use of different doses of vitamin E or different types of vitamin E, or inadequate patient selection could be responsible for the contradictory results. Consequently, further studies are warranted, with emphasis on careful patient selection and a correct dose and type of vitamin E.
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Vitamin D Vitamin D is a steroid hormone with pleiotropic actions on most tissues and cells in the body. The active form of the vitamin, 1,25-dihydroxyvitamin D, plays an essential role in calcium and phosphorus homeostasis, bone mineralization and skeletal growth. However, increasing data identifying beneficial roles for vitamin D in a spectrum of pathological processes is emerging, including regulation of cell growth, metabolic modulation, autoimmunity, cardiovascular function and malignancies [94]. Despite the key role of vitamin D in all these derangements, there is a global pandemic of vitamin D deficiency [95], which is more pronounced in obese subjects. This has been explained by the fact that adipose tissue acts as a “metabolic well” for vitamin D, reducing its bioavailability. Furthermore, obese subjects are worse respondents to vitamin D intake [96, 97]. In experimental studies, vitamin D reduces inflammation by modulating the expression of several cytokine genes and deactivating NFB [98], improves the cytokine profile and increases IL-10 concentrations [99, 100]. Moreover, a low vitamin D status has been linked to inflammatory endothelial dysfunction in nondiabetic subjects [101]. Vitamin D deficiency has been implicated in susceptibility to the development of hypertension, obesity, insulin resistance, T2DM and MetS [102, 103]. Accordingly, subjects with vitamin D insufficiency (defined as 25-OH vitamin D levels
