Nutraceutical approaches to metabolic syndrome

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Nutraceutical approaches to metabolic syndrome

Cesare R. Sirtori, Chiara Pavanello, Laura Calabresi & Massimiliano Ruscica

To cite this article: Cesare R. Sirtori, Chiara Pavanello, Laura Calabresi & Massimiliano Ruscica (2017) Nutraceutical approaches to metabolic syndrome, Annals of Medicine, 49:8, 678-697, DOI:

10.1080/07853890.2017.1366042

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Published online: 22 Aug 2017.

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Nutraceutical approaches to metabolic syndrome

Cesare R. Sirtori^a, Chiara Pavanello^b, Laura Calabresi^band Massimiliano Ruscica^c

aCentro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy;^bDipartimento di Scienze Farmacologiche e Biomolecolari, Centro E. Grossi Paoletti, Universita degli Studi di Milano, Milan, Italy;^cDipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy

ABSTRACT

Metabolic Syndrome (MetS), affecting at least 30% of adults in the Western World, is characterized by three out of five variables, from high triglycerides, to elevated waist circumference and blood pressure. MetS is not characterized by elevated cholesterolemia, but is rather the consequence of a complex interaction of factors generally leading to increased insulin resistance. Drug treatments are of difficult handling, whereas well-characterized nutraceuticals may offer an effective alternative. Among these, functional foods, e.g. plant proteins, have been shown to improve insulin resistance and reduce triglyceride secretion. Pro- and pre-biotics, that are able to modify intestinal microbiome, reduce absorption of specific nutrients and improve the metabolic handling of energy-rich foods. Finally, specific nutraceuticals have proven to be of benefit, in particular, red-yeast rice, berberine, curcumin as well as vitamin D. All these can improve lipid handling by the liver as well as ameliorate insulin resistance. While lifestyle approaches, such as with the Mediterranean diet, may prove to be too complex for the single patient, better know- ledge of selected nutraceuticals and more appropriate formulations leading to improved bioavailability will certainly widen the use of these agents, already in large use for the management of these very frequent patient groups.

KEY MESSAGES

Functional foods, e.g. plant proteins, improve insulin resistance.

Pro- and pre-biotics improve the metabolic handling of energy-rich foods.

Nutraceutical can offer a significant help in handling MetS patients being part of lifestyle recommendations.

ARTICLE HISTORY Received 10 July 2017 Revised 4 August 2017 Accepted 7 August 2017

KEYWORDS Metabolic syndrome;

nutraceuticals; probiotics;

berberine and vitamin D

Introduction

Metabolic syndrome (MetS) is present as a common clinical condition in countries where obesity and Western unhealthy dietary patterns prevail. The incidence of MetS is increasing to epidemic proportions thus entailing substantial health care costs. Indeed, MetS associates with an elevated risk of cardiovascular disease and type 2 diabetes (T2D), as well as other conditions, such as non-alcoholic fatty liver disease.

After the first formal definition of MetS introduced in 1998 by the World Health Organization (WHO), several expert panels have attempted to introduce diag- nostic criteria. In 2001 the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) [1] recognized for the first time the clusteriza- tion of the metabolic risk factors, these being also cardiovascular risk factors. In 2003, the American Association of Clinical Endocrinologists modified the

ATP III criteria highlighting the central role of insulin resistance in the pathogenesis of the syndrome [2]. In 2005, the International Diabetes Federation (IDF) issued a consensus document aimed at producing a clinically useful definition of Mets to identify individuals at high risk of cardiovascular disease and T2D on a worldwide basis [3]. In the same year, the American Heart Association (AHA)/National Heart, Lung and Blood Institute (NHLBI) suggested criteria for the diagnosis of MetS [3]. Finally, IDF, NHBLI, AHA, World Heart Federation and the International Association for the Study of Obesity produced a joint statement called the“Harmonization definition”, which, as of today, represents the most common recognized criteria for the clinical diagnosis of MetS [4], summarized inTable 1.

The present review will address the management of MetS by the use of specific nutraceuticals, in particularly plant proteins, pro/prebiotics, curcumin,

CONTACTCesare R. Sirtori cesare.sirtori@icloud.com, [email protected] Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy; Massimiliano Ruscica massimiliano.ruscica@unimi.it Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy

ß 2017 Informa UK Limited, trading as Taylor & Francis Group https://doi.org/10.1080/07853890.2017.1366042

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berberine, red yeast rice and vitamin D. The activity of these substances will be analyzed based on the described major MetS features. While in many cases, e.g. MetS linked to elevated blood pressure, drug treatments may be of higher efficacy, the present favourable view of nutraceuticals by patients and by the medical community, makes it mandatory to carefully analyze what these products may offer in terms of improvement of metabolic health in MetS. The major features of MetS will be hereafter outlined.

Metabolic syndrome: a deep overview Body variables

Abdominal obesity is a prominent feature of MetS contributing to an elevation of cardiovascular risk. Indeed, excess abdominal adipose tissue releases large amounts of FFAs via the portal system to the liver, and may interfere with hepatic insulin clearance [5], thus contributing to IR [6]. In addition, it is an active endocrine organ, secreting different adipokines, including leptin, adiponectin, resistin, interleukins (IL), and tumour necrosis factor (TNF)-a [7]. In the case of excess abdominal weight, there is evidence of macrophage infiltration into the adipose tissue [8], contributing to the inflammatory profile reported in MetS patients. As opposed to proinflammatory adipokines, adiponectin levels are instead reduced in patients with excess visceral adiposity [9].

Arbitrary cut-offs based on epidemiological studies have been adopted for an elevated waist circumference (WC) [10] rated by all as an appropriate maker of central obesity with a strong association with the metabolic components of cardiovascular disease.

However, cut-offs for WC varied for sexes, ethnic groups and even countries [1,3]. The IDF proposed a WC 94 cm for men and 80 cm for women as a threshold for abdominal obesity [3]; these thresholds were, however, not found to be applicable to most Western populations. Higher thresholds are generally

used to define abdominal obesity in the United States [11] and the AHA/NHLBI (ATPIII) guidelines for MetS recognize an increased cardiovascular and diabetic risk at WCs of 102 cm for men and 88 cm for women [4].

In view of the difficulty in agreeing on a common threshold, in addition to the general unavailability of an accurate WC measurement, other variables, such as BMI [12,13] and the waist-to-height ratio (WHtR) have been suggested. This latter, in addition to WC, is being adopted as a more accurate indicator of obesity- related cardiovascular risk. The WHtR has the advan- tage of being similar in most populations, i.e. generally below 0.5 for both men and women, as well as for ethnical subgroups [14].

Atherogenic dyslipidemia

Carriers of MetS are characterized by a triad of metabolic perturbations called “atherogenic dyslipidemia”.

Such perturbations, frequently linked to insulin-resistance (IR), the hallmark of pre-diabetes and T2D, are comprehensive of (i) high levels of apolipoprotein B (apoB)-containing lipoproteins, including very- low-density lipoprotein (VLDL) remnants, (ii) small low- density lipoprotein (sLDL), and (iii) reduced high- density lipoprotein (HDL) levels [15]. In particular, IR affects the activities of enzymes and transfers proteins that play a key role in lipoprotein metabolism, such as lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP). IR may also affect hepatic lipase (HL), phospholipid transfer protein (PLTP), and endothelial lipase (EL) [16].

IR may cause these metabolic changes in the presence of suppressed hormone-sensitive lipase (HSL) in visceral adipocytes; this process raises free fatty acids (FFA) mobilization from adipose tissue, leading to hepatic triglyceride (TG) overload [17]. HSL is an intracellu- lar neutral lipase that hydrolyzes triacylglycerols, diacylglycerols, monoacylglycerols and cholesteryl esters. The increased efflux of FFA from adipose tissue Table 1. Risk factors for the clinical diagnosis of metabolic syndrome.

Value Alternative indicator

Waist circumference ^a> 94 cm in males, >80 cm in females

b>102 cm in males, >88 cm in females

Raised blood pressure Systolic130 and/or diastolic 85 mm Hg Treatment of previously diagnosed hypertension

Raised FPG 100 mg/dl (5.6 mmol/l) Previously diagnosed of T2DM

Raised TG >150 mg/dl (1.7 mmol/l) Specific pharmacological treatment

Reduced HDL-C <40 mg/dl (1.0 mmol/l) in males

<50 mg/dl (1.3 mmol/l) in females Specific pharmacological treatment

aBased on the International Diabetes Federation (IDF) threshold for Europid population.

bBased on the AHA/NHLBI (ATP III) threshold for USA population.

FPG: fasting plasma glucose; TG: triglycerides; HDL-C: high-density lipoprotein-cholesterol; T2DM: type 2 diabetes mellitus.

Conversion factors: (i) mg/dl cholesterol¼ mmol/l 38.6; (ii) mg/dl triglycerides ¼ mmol/l 88.5 and (iii) mg/dl glucose ¼ mmol/l 18. Reproduced with permission of Elsevier [64].

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and their reduced skeletal muscle uptake raises FA flux to the liver [18], thus raising VLDL secretion and consequent plasma TG levels [19].

Insulin may further affect TG-rich lipoprotein metabolism by inhibiting the microsomal transfer protein (MTP), responsible for the lipidation of nascent apoB during their translocation into the lumen of the endo- plasmic reticulum [20]. Notably, TGs lipidating apoB are derived from the FFA released from the adipocyte, from VLDL remnants and from de novo lipogenesis [21]. The reduced activity of LPL [22], impairing the metabolism of TG-rich lipoproteins, may lead to hyper- triglyceridemia and will, in turn, increase the CETP- mediated exchange of VLDL TG for HDL-CE. This step will raise the atherogenic cholesterol-rich VLDL rem- nant particles and the TG-rich, cholesterol-depleted HDL particles [23].

Specifically, in the condition of “atherogenic dyslipidemia” excess TGs in HDL become a substrate for HL and LPL, enzymes that convert HDL to smaller particles filtered by the renal glomeruli and degraded in renal tubular cells [24]. Besides the decrement in HDL concentrations, in the presence of hypertriglyceride- mia, the higher activity of cholesteryl ester transfer protein (CETP) accounts for a marked reduction of cholesterol carried in LDL [25]. sLDL particles are rated as being more atherogenic, easily undergoing glyca- tion and oxidation, compared with the larger LDL.

sLDL (i) possess a higher capacity to penetrate the arterial wall, (ii) show prolonged plasma half-life, and (iii) lower affinity for the LDLR [26].

Thus, a point to note is that in carriers of MetS, LDL-C is not the only lipid goal: the 2016 European guidelines point out to monitor atherogenic TG-rich lipoproteins (VLDL, IDL and remnants), recommending the achievement of specific cut-offs for non-HDL-C and apoB [27]. Indeed, non-HDL-C may be used to estimate the total amount of atherogenic lipoproteins in plasma, being well related to apoB levels.

Elevated blood pressure

High blood pressure is one of the most relevant independent risk factors for cardiovascular disease; indeed, worldwide, suboptimal blood pressure accounts for around 7.6 million premature deaths annually [28]. At ages 40–69 years, a reduction of 20 mmHg in systolic blood pressure (SBP), halves the risk of coronary heart diseases [29]. Based on the European guidelines, hypertension is defined as values>140mmHg SBP and/or>90mmHg DBP, whereas a SBP goal<140 mmHg is recommended in patients with diabetes. Moreover, a diastolic blood pressure (DBP)

target of<90 mmHg is always recommended, except in patients with diabetes, in whom the recommended objective is reduced to<85 mmHg [30]. A recent meta-analysis of randomized trials of blood pressure- lowering agents in>100,000 patients with T2D confirmed that lowering blood pressure reduces the risk of cardiovascular events, coronary artery disease, stroke as well as of all-cause mortality [31].

Most recently there has been a heated debate on the blood pressure target values. The SPRINT study on drug treated hypertensives indicated that an SBP below 120 mmHg should be the appropriate target for an optimal risk reduction [32]. This was not accepted by other investigators [33], but a most recent large- scale study indicated that outcomes after therapy may differ according to the achieved blood pressure targets in specific patient subgroups [34] and the lowest targets may not always be the most appropriate. In MetS, blood pressure elevation is linked to IR, possibly to the elevated WC. It is a common practice to note that blood pressure reduction occurs in the presence of reduced body weight and improved glucose control [35].

Elevated glycaemia

Elevated plasma glucose as well as increased immu- noreactive insulin are in general the major features of what was earlier called “chemical diabetes” [36].

Increased insulin response to an elevated glucose has been, from then on, generally linked to a higher cardiovascular risk, in particular hyperinsulinemia being found in the majority of hypertensives and constituting a common feature of the triad: obesity/glucose- intolerance/hypertension [37]. Hyperglycemia per se leads to an increased risk of reduced fibrinolysis and T2D [38]; eventually leading to a definition of elevated fasting glucose as a risk factor in the Framingham OFFSPRING Study [39].

In view of the poor practicality of evaluating IR or even insulin levels per se, investigators aimed to define an optimal correlation between glycaemia and IR to obtain a reliable indicator of the presence of MetS.

Initially, high significance was given to the condition of “impaired fasting glucose” (IFG), i.e. a fasting glycaemia above 110 mg/dl [40] and the best threshold for fasting glucose based on correlations between glucose and insulin was 110–115 mg/dl [41]. Later, it was suggested that this fell short of properly diagnosing a syndrome characterized by hyperinsulinaemia, and an adequate information could be provided by a fasting glycaemia above 100 mg/dl, resulting in the

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classification of 20.4% of patients in their study group as IR, with a predictive value of 63% [42].

A fasting glucose 100 mg/dl has thus been selected as the basis for the diagnosis of MetS. The possible overlap between IFG and MetS has been clearly outlined: in a non-diabetic population50 years of age, about twice as many individuals have IFG and MetS versus those with IFG alone Grundy [43]. A sizable portion of non-diabetics have MetS without IFG and vice versa. With these considerations, it appears that the MetS is a pre-diabetic state and MetS treatment of hyperglycaemia should aim to the prevention of microvascular disease [44]. In the absence of specific treatments aimed only to glucose reduction, prior- ity must be given to reduce IR. The efficacy of this approach may be lifestyle intervention, weight reduction and increased physical activity as well established by the results of the DPP trial [45].

Nutraceutical approach to metabolic syndrome Functional foods: plant proteins

Functional foods are characterized by the presence of components with a clear activity on metabolite levels that may be associated to specific clinical syndromes [46]. In the case of MetS, plant proteins deserve a spe- cial consideration. Indeed, protein-enriched diets have become a popular strategy to enhance weight management and weight loss [47]. Increasing protein intake may also have a potential for the prevention of T2D [48]. Although optimal amount and quality of proteins for these indications are still controversial, there are strong indications that, e.g. high intake of red meat is associated with an increased risk of T2D [49], whereas plant proteins are generally associated with some improvement in diabetes risk and also in the general management of hyperlipidaemia.

Very recently, Virtanen et al. [50] in a follow up of the Kuopio Ischemic Heart Disease Risk Factor Study clearly indicated that plant proteins are associated with a decreased risk of T2D. Data on MetS are less extensive but two types of proteins, i.e. lupin and soy, have been studied more in details in patients with MetS providing clinical evidence of potential benefit [51]. In addition, other plant proteins, in particular pea and wheat protein, have shown some potential benefit.

Lupin

Lupin is a protein-rich grain legume. It commonly represents four domestic species, i.e. Lupinus albus (white lupin), L. luteus (yellow lupin), L. mutabilis (pearl lupin) and L. angustifolius (sweet leaf lupin). In Europe,

both L. angustifolius, available as a protein concentrate, and L. albus are widely available. Lupin seeds have the interesting feature of a limited, close to nil, content of antinutritional factors such as phytate, tannins, lectins, protease inhibitors and oligosaccarides [52]. Lupin seeds contain two classes of proteins, i.e. the 7S and 11S globulins, (also conglutinsa and b) in addition to two minor distinct proteins, conglutinc and d..

Lupin proteins have been studied for a number of years mainly for their activity on plasma cholesterol reduction, attributable in large part to an LDL-receptor (LDL-R) activating mechanism [53]. Moreover, conglutin c has been shown to reduce glycemia both in animal models and, moderately, in humans, particularly in the postprandial condition [54]. In animal models, similar to soy proteins, lupin proteins have displayed hypolipi- demic and a remarkable antiatherosclerotic effect [55].

In order to investigate the mechanism/s of the possible activity on plasma glucose, recently different soy and lupin proteins were hydrolyzed by pepsin and trypsin and the resulting peptides separated and screened for their capacity to inhibit dipeptidyl peptid- ase IV (DPP-IV). This new molecular target is correlated to the development of T2D; a number of pharmacological inhibitors have been developed and are currently being used [56]. In the post-hydrolysis study [57], two small peptides were isolated and identified as Soy 1 and Lup 1, both with efficient inhibitory capacity on DPP-IV, with IC50s equal to 106 and 228lm, respectively, thus indicating that both proteins may be sources of DPP-IV inhibitory peptides.

Clinically, lupin proteins have been tested in different conditions, predominantly in hypercholesterolemia.

Within this context, possibly due to the mechanism exerted on the LDL-R, a positive effect on LDL-C and on the LDL:HDL cholesterol ratio was reported in two studies, i.e. one with supplementation [58] and another with a mixed diet enriched with lupin [59].

Our group showed instead that lupin protein combina- tions with cellulose led to a remarkable hypocholester- olemic effect; a similar range of cholesterolaemia reduction was noted after a pea protein/fibre combination [60].

A TG reduction was noted in rodent studies, apparently associated with reduced fatty acid synthesis and increased TG hydrolysis [61]. This was not noted in studies in hypercholesterolemic individuals. However, in a randomized study in patients predominantly with MetS, Pavanello et al. [62] reported that a lupin protein concentrate, compared with a lactose-free milk powder diet, led to a reduction, in addition to the LDL cholesterol (8.0%), also of non-HDL cholesterol (7.5%). This study also reported that lupin proteins,

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in men, lead to a 12.7% reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9), the key regula- tor of LDLR [63,64]. A direct modulation of the protein–protein interaction of PCSK9 with the LDL-R has been shown [65].

Further, lupin proteins can provide a potential T2D treatment, possibly also due to the recently described modulatory effect of conglutynb on the insulin signal- ing pathways [66]. It can be, thus, concluded that lupin protein supplemented diet or a well-designed whole diet with lupin proteins can provide an effective dietary tool for the management of the biochemical alterations characteristic of MetS.

Soy proteins

Soy proteins are the most widely evaluated dietary proteins for metabolic control. Proteins from Glycine max are the prototype plant proteins and, as such, have reached the attention, as reported in the recent systematic review on the effects of plant versus animal protein sources on features of MetS [51].

In addition to proteins, glycine max provides components such as isoflavones or phytoestrogens, with a potential estrogenic activity and possibly antiatherosclerotic effects [67]. Isoflavones may be of potential risk for, particularly growing children, but, so far, there is no clear evidence of a significant activity on the major components of MetS [68]. Indeed, careful extrac- tion of isoflavones from soy did not change their lipid lowering and LDL-R stimulating activity in an experimental animal model [69]. While there is clear evidence that soy proteins per se can raise the activity of LDL-R in different animal models and in familial hypercholesterolemic patients [70], decreased triglyceridaemia and changes in other MetS-associated variables have been reported in a lower number of studies.

Some reports have shown an improvement of glucose homeostasis after soy proteins. In post-meno- pausal women with MetS, soy proteins and soy nuts were compared (nuts have somewhat reduced protein and slightly higher phytoestrogen content). The soy nut regimen reduced fasting glucose more significantly than the soy protein, in addition to an improved LDL- cholesterol reduction (5.0 ± 0.6% versus protein and

9.5%±0.6% versus control diet, both p <.01) [71]. The HOMA index was also reduced, somewhat more, by soy nuts (7.4 ± 0.8% versus protein and 12.9 ± 0.9%

versus control diet, both p< .01).

Changes of triglyceridaemia were reported in a number of studies. In individuals with mildly elevated plasma TG, the reduction was in the range of 15–20%, independent of isoflavone content [72]. In a detailed study in patients with moderate hypercholesterolemia treated with the bile acid binding resin colesevelam,

25 g/d of an insoluble fraction of partially hydrolyzed soy proteins were compared with a similar intake of milk proteins [73]. There was a clear benefit of soy proteins on LDL-cholesterol (10.9 ± 1.8 versus

5.9 ± 2% with milk proteins, p < .01) and a somewhat higher rise of HDL-cholesterol. The difference in TG levels was modest, but non-HDL-cholesterol, was reduced to a highly significant extent with soy proteins (10.8 ± 1.7% versus 3.9 ± 1.8% with milk protein, p< .01). There was also a highly significant difference in apo B levels, whereas faecal sterol excre- tion was reduced by milk proteins and significantly raised by soy proteins.

In a single study, a direct comparison of the acute intake of soy versus lupin protein on glycaemia was evaluated [74] in T2D patients. A soy or lupin-based beverage containing 50 g glucose significantly reduced glycaemia for 4 h post- beverage, with no significant difference between lupin and soy. The insulin response was somewhat higher for lupin and soy, compared with controls.

While blood pressure changes following plant protein sources, compared with animal proteins, have been mainly inconsistent, body changes have been generally characterized by some weight reduction [51].

Animal protein intake was positively associated with BMI and WC but plant proteins were instead inversely associated with BMI only in males and with WC in both genders [75]. In the recent longitudinal EPIC- PANACE study [76], increasing dietary plant source proteins by 5% at the expense of animal-source proteins in an isoenergetic diet reduced weight gain by nearly 1 kg per year in men over a 5-year period, not in women. In another study, in children, an increase in weight and BMI was noted after consumption of animal proteins, especially dairy (for periods of up to 7 years) versus vegetable proteins [77].

A study by our group specifically investigated patients with clinical features of MetS; they received 30 g/d soy proteins in parallel group versus animal food. A significant reduction of body weight (1.5%

and BMI 1.5%) was observed [78]. The expected reductions of total and LDL-cholesterol as well as of non-HDL-C (7.14%) versus milk proteins were found (Figure 1). Thirteen out of the 26 participating subjects had a reduction of MetS indexes, bringing them to normality.

Other plant protein sources (without isoflavones) have been tested in individuals with MetS. Among these, pea, fava bean proteins and wheat gluten did not show any further beneficial effect on fasting lip- emia compared with proteins of animal sources.

However, wheat gluten ingestion resulted in a larger

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postprandial TG response compared with wheat proteins [79]. In general, studies comparing diets from plant versus animal sources with a positive metabolic effect had a longer duration [51].

Probiotics, prebiotics and synbiotics

In humans, microbial density comprises a biomass of 1.5–2.0 kg and increases from the proximal to the dis- tal end of the intestine; in the body, the ratio of bacteria to human cells is close to 1:1 [80]. Recently, numerous studies in humans and in animal models have reported how gut microbiota, established within the first 3 years of life, converts dietary and endogen- ous molecules into metabolites, that allow communi- cation with peripheral organs and tissues in the host [81].

Among microbial metabolites, short-chain fatty acids, i.e. acetate, butyrate and propionate, are known to exert several health benefits, including reduction of the luminal pH, inhibition of enteropathogens, increased absorption of some nutrients and mainten- ance of gut barrier function [82]. Conversely, a rise in the absorption of branched-chain amino acids, as in the case of alterations in the intestinal barrier (e.g.

high-fat diets), is associated with a higher risk of T2D [83,84]. Indeed, dysbiosis, i.e. the alteration of gut homeostasis, is associated to obesity, T2D and IR, all traits of MetS that can lead to atherosclerosis and heart failure [85]. It has been, further, proposed an

“Interaction Model”, demonstrating that, at least in permissive genetic backgrounds, gut microbiota plays a significant role in modulating key metabolic traits, such as obesity, diabetes and IR [86] (Figure 2).

Since diet shapes the composition of gut microbiota, restoring its diversity and activity, nutrients and particularly nutraceuticals can represent a promising approach to improve metabolic features of MetS [81].

Moreover, in older people, in which microbiota is sus- ceptible to a larger inter-individual variation, dietary supplements with defined food ingredients promoting specific components of microbiota may be useful in maintaining the best health status [87].

Consumption of some nutraceuticals i.e. probiotics, prebiotics and synbiotics should be of primary consideration. Probiotics are living micro-organisms that when administered in adequate amounts confers beneficial health effects to the host (i.e. Lactobacillus rhamnosus GG, L. reuteri, Bifidobacteria certain strains of L. casei or the L. acidophilus group) [88].

Prebiotics are defined as selectively non-digestible plant-derived carbohydrates, allowing specific changes, both in the composition and in the activity of gastrointestinal microflora; indeed, these food ingredients (i.e., inulin and its hydrolysis product oligofructose, and (trans)galactooligosaccharides) confer health benefits by stimulating growth and/or activity of a limited number of bacteria within the colon [89]. The definition of“prebiotic” should include (a) resistance to gastric acidity, hydrolysis by mammalian enzymes and gastrointestinal absorption; (b) fermentation by intestinal microflora; (c) selective stimulation of the growth and/or activity of intestinal bacteria associated with health and wellbeing [89]. Synbiotics are a synergistic combination of pro- and prebiotics [90].

A detailed summary of data from randomized controlled studies (RCTs) related to the use of these Figure 2. The development of obesity, insulin resistance, type 2 diabetes and metabolic syndrome in general are the consequence of a complex multidirectional interaction between host genetics, environment, diet and the gut microbiota [with permission of Elsevier [86]].

Figure 1. Percentage median changes of non-HDL-C. Subjects randomly assigned to receive the experimental diet, containing whole soy foods corresponding to 30 g/day soy protein in sub- stitution of animal foods containing the same amount of protein or the control diet containing the animal foods, for 12 weeks [with permission of Elsevier [78]].

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nutraceuticals should also consider that results may be affected by different biases, since the majority of the RCTs (i) did not follow the same design, (ii) were small in terms of participants, (ii) were of short duration and (iii) used probiotics from multiple strains as well as different delivery methods (i.e. yogurt, cheese or capsules) [91]. Thus, RCTs studies with a variety of sources, daily doses and different durations of intervention are required to confirm health benefits and specific roles of probiotics, prebiotics and synbiotics on the metabolic components of the MetS.

Probiotics and traits of metabolic syndrome Weight and BMI

Data from a meta-analysis of 15 RCTs reported, in obese, that the administration of 2.710¹⁰ Colony Forming Units (CFU)/day of Lactobacilli probiotics for 2–3 months reduced body weight (kg) by 0.54 (95%

CI 0.83, 0.25; p < .001); when BMI (kg/m²) was instead considered, reduction in the Lactobacilli arms was0.43 (95% CI 0.67, 0.20; p ¼ .005). Conversely, upon probiotic supplementation, a slight increment in body weight was observed in children (þ0.20 kg; 95%

CI 0.04, 0.36) and infants (þ0.30 kg; 95% CI 0.01, 0.62; p¼ 0.05) [92]. Another meta-analysis, on four RCTs, showed no significant effects of probiotics on body weight, BMI and visceral fat of obese subjects [93].

In line with the above-described findings, reporting a weak (<3%) or absent effect of probiotics on body components [94], in obese with elevated cardiovascular risk, probiotic supplementation reduced BMI by 0.52 kg/m² (95% CI 0.81, 0.25; p < .001) and waist circumference by 2.11 cm (95% CI 3.54, 0.68;

p¼ .004) [95]. A further contribution to the under- standing of this complex issue has come from a meta- regression analysis reporting that the effects of probiotics on BMI depend on the duration of intervention ( 8 weeks), number of species of probiotics and baseline BMI25 kg/m², thus highlighting the effect- iveness of probiotics in reducing BMI, especially in overweight or obese subjects [96].

A possible mechanism explaining the effects on weight loss are the improvement of the intestinal barrier function that may reduce metabolic endotoxemia [97], thus ameliorating levels of lipopolysaccharides (LPS). In the adipose tissue, endotoxins from LPS trig- ger systemic and local inflammation with an increase in reactive oxygen species (ROS) [97]. As a possible associated event, bacterial fragments can increase the number of preadipocytes [98]. Among other proposed mechanisms linking probiotics and body weight

reduction there are the ability (i) of the microbioma to extract energy from the diet [99] and (ii) to increase the secretion of the gut hormone glucagon-like peptide (GLP-1) enhancing satiety and reducing energy intake [100].

Blood pressure

A meta-analysis of 9 RTCs relative to the administration of probiotics from different strains (L. reuteri, L.

plantarum, L. helveticus, Enterococcus faecium and Streptococcus thermophilus), with a total daily consumption between 10⁹ and 10¹² CFU, with a duration of 3–9 weeks, showed an overall improvement in blood pressure. A reduction of 3.58 mmHg (95% CI

6.46, 0.66; p < .00001) and 2.38 mmHg (95% CI

3.84, 0.93; p < .0001) was recorded for SPB and DBP, respectively. Interestingly, both SBP and DBP fell further when a sub-analysis was conducted taking into consideration: (i) duration of treatment8 weeks, (ii) BMI30 kg/m², (iii) dairy source of probiotics (versus capsules), (iv) consumption of multiple probiotic species, (v) daily dose consumption10¹¹CFU and (vi) blood pressure at baseline135/85 mmHg [101].

The anti-hypertensive effects of probiotic supplementation were also confirmed in subjects with T2D;

reductions of 3.28 mmHg and of 2.131 mmHg in SBP and DBP, respectively, have been reported. These effects were inversely related to BMI (> 29 kg/m²) and age [102].

The antihypertensive activity of probiotics has been also attributed to the reduction of inflammation-mediated endothelial dysfunction, nitric oxide synthase downregulation [103], and release of angiotensin-con- verting enzyme inhibitory peptides. Among these, the tripeptides Val-Pro-Pro and Ile-Pro-Pro have been the most extensively investigated [104]. As previously reviewed, two major commercial products, based on sour milk, i.e. the Finnish EvolusV^R and the Japanese CalpisV^R are presently available [105]. However, due to the skepticism regarding their cost and possible effect- iveness, they have not reached a wide distribution out- side these countries.

Fasting plasma glucose

The effect of probiotic supplementation on glucose homeostasis is influenced by the basal levels of FPG ( 126 mg/dl), length of intervention ( 8 weeks), baseline BMI values ( 30 kg/m²), administration of multiple species of probiotics, daily dose consumption

10¹⁰ CFU and the selected sources, i.e. supplements and foods instead of fermented milk or yogurt.

Indeed, the presence of lactose in fermented milk may raise FPG. Conversely, if the overall population is considered, a non-statistical FBG reduction of 0.17 mmol/l is observed [106].

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In studies conducted in cohorts of T2D patients, mean reductions of 0.61 mmol/l [107] or 0.98 mmol/l were reported [108]. Interestingly, the higher the number of bacterial species is, the more significant the FPG reduction is [107,109]. Contrasting and inconclu- sive data have been instead reported on the effective- ness of probiotic supplementation on HOMA-IR and glycosylated hemoglobin (HbA1C) levels, two hallmarks of IR [107–109]. The reduction of low-grade inflammation promoted by gut-derived LPS and metabolic endotoxemia has been proposed as mechanisms linking probiotics and glucose metabolism [110]. Indeed, serum endotoxin levels are correlated with fasting insulin [111] and are two-fold higher in T2D patients compared with non-diabetics [112].

HDL and TG

A recent meta-analysis of 30 RCTs, investigating the effect of different strains of probiotics (L. acidophilus, L.

plantarum and L. helveticus) on lipid parameters, reported no changes in HDL-C (0.24 mg/dl; 95% CI

1.6, 1.1) and TG (5.3 mg/dl; 95%CI 11.1, 0.4) levels [91], between subjects taking probiotics and controls.

This has been confirmed in mild-to-moderate hypercholesterolemic individuals in whom probiotic supplementation was ineffective in improving HDL-C (0.01 mg/dl; 95%Cl 0.02, 0.03) and TG (0.01 mg/dl;

95%Cl 0.08, 0.09) levels; these findings were not modified upon correction for baseline BMI (25 kg/

m²), duration (4 weeks), age ( 45 years), preparation (fermented milk products versus probiotic preparations) and bacterial strains [113].

Considering that probiotics exert a hypocholestero- lemic effect by reducing the intestinal absorption of cholesterol or by enhancing the bile salt hydrolase activity, a lack of efficacy in modulating HDL-C and TG, both linked to the atherogenic dyslipidemia, is expect- able [114]. Notably, if only T2D patients are considered, probiotic consumption reduced TG levels by -24.48 mg/dl (95%Cl 33.7, 11.2) with no HDL-C changes [102]. HDL-C may be raised by 16 mg/dl if a longer duration of probiotic administration (>8 versus

8 weeks) is considered [107].

Prebiotics, synbiotics and the major traits of metabolic syndrome

The effects of prebiotics on the metabolic traits of MetS have been evaluated in a limited number of studies investigating comparable outcomes. Their small sample sizes, heterogeneity among trial subjects, disease conditions, prebiotic supplements, intervention duration and outcomes need thus to be carefully considered.

Among the different outcomes evaluated in trials investigating the effects of prebiotic supplementation on metabolic traits, i.e. body weight, glucose homeostasis and TG, evidence indicates that dietary supplementation impacts only on post-prandial glucose (0.76 mmol/l (95%Cl 1.41, 0.12)) and insulin (0.77 UI/l (95%Cl 1.50, 0.04)) levels leaving the other parameters unaffected. Interestingly, although self-reported, an improvement in satiety was found upon prebiotic intake [115]. Not surprisingly, prebiotics have been related to a decrement in Ghrelin levels and to an increment in peptide YY and GLP-1 secretion, all involved in appetite regulation [116,117].

In subjects with a BMI 25 kg/m² and carriers of diabetes, evaluation of the effects of prebiotics compared with placebo showed an improvement in TG and HDL-C levels, 0.72 mmol/l and þ0.49 mmol/l, respectively [118]. The same authors reported that a synbiotic supplementation decreases plasma fasting insulin and TG levels by 0.39 UI/l (95%Cl 0.75,

0.02) and 0.43 mmol/l (95%Cl 0.70, 0.15), respectively. No changes in FPG were noted [118], similar to what reported in a very recent meta-analysis [106].

Vitamin D

Vitamin D has generally been shown to exert a minor role in the control of MetS. However, recent data have indicated vitamin D levels as an important variable, underlying, in some cases, MetS, in addition to being a possibly significant determinant of cardiovascular risk.

Vitamin D has a well-known primary physiological role in regulating calcium homeostasis. However, besides bone metabolism, growing evidence has described the involvement of vitamin D on glucose metabolism, blood pressure and other metabolic traits related to MetS [119].

Being mainly synthesized in the skin upon ultravio- let-B radiation, vitamin D is metabolized by the hepatic 25-hydroxylase enzyme to 25-hydroxyvitamin D [25(OH)D] and by a renal 1a-hydroxylase to the vitamin D hormone calcitriol, also called 1,25-(OH)2 vitamin D; the active form of vitamin D [120]. Since 1,25- (OH)2 vitamin D is active for a maximum of 27 h, 25(OH)D levels are the landmarks for the assessment of vitamin D status [121,122]. Specifically, when circulating levels of 25(OH)D are 30 nmol/l, this is diagnosed as a condition of vitamin D deficiency;

inadequacy is when 25(OH)D levels are between 30 and 50 nmol/l and sufficiency when concentrations are in the range of 50–75 nmol/l [123].

The relationship between 25(OH)D levels and risk of MetS has been recently reviewed; a dose–response

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meta-analysis of 16 cross-sectional studies showed a linear and inverse association between the two variables. Moreover, the risk-ratios of MetS, per 25 nmol/l, increment in the serum/plasma 25(OH)D levels, were 0.87 (95%Cl 0.83–0.92). Albeit, somewhat attenuated, this effect was maintained upon correction for sex, age (middle versus elderly), latitude (high versus low), assay detection method, criteria of MetS definition [124]. The same results were obtained when the relative risk for MetS was assessed comparing individuals in the top versus bottom tertiles of baseline 25(OH)D levels [119]. In the context of MetS, obese individuals show a decrement in circulating 25(OH)D, i.e. of 0.27 ng/ml in vitamin D3 for each 1 kg/m² increment in BMI [125]. Among the different suggested hypothe- ses [126], the concept of reverse causality is to be taken into consideration. Indeed, if an inverse correlation between obesity and vitamin D levels is true, on the other hand, vitamin D may be sequestered or stored in the adipose tissue leading to lower 25(OH)D serum levels. Thus, obesity may be a cause and not a consequence of vitamin D deficiency [127].

An inverse association between baseline 25(OH)D levels and incidence of T2D has been also reported.

Comparing the highest to the lowest cutoffs of 25(OH)D levels, a relative risk of 0.62 (95%Cl 0.54–0.70) emerged from a pooled analysis of 21 prospective studies. This finding was not affected by sex, duration of follow-up, sample size, diabetes or 25(OH)D assay method [128]. The same conclusions were reached by Khan et al. showing how individuals in the top versus bottom tertile of baseline 25(OH)D blood levels had a relative risk of 0.81 (95%Cl 0.71–0.92) for T2D incidence [119]. Conversely, when vitamin D supplementation has been taken into consideration, data from RCTs did not show any effect on fasting glucose, HbA1C, insulin resistance or incidence of diabetes [129]. In general, vitamin D may have a direct effect on beta-cell function through the activation of the vitamin D receptor expressed in beta-cells; lack of a functional vitamin D receptor leads to an impairment in glucose metabolism, although a vitamin D-mediated beta-cell survival should not be excluded [129].

The earliest evidence linking vitamin D to blood pressure came from the observation that low UVB exposure was associated with an increased hypertension risk [130]. Among the 12,644 participants of a cross-sectional survey, mean SBP and DBP were 3.0 mmHg and 1.6 mmHg lower for people in the highest 25(OH)D quintile ( 85.7 nmol/l) compared with the lowest (<40.4 nmol/l) [131]. This finding has been confirmed by showing an improvement in blood pressure directly related to the increment in serum

25(OH)D levels; upon correction for sex, age, BMI and physical activity, the differences in SBP and DBP between the lowest (<41.4 nmol/l) and highest (>62.6 nmol/l) serum 25(OH)D quartiles were 3.6 and 1.0 mmHg, respectively [132].

A meta-analysis on 283,537 subjects, examining the association between vitamin D status and hypertension risk, showed that individuals in the top 25(OH)D tertile have a 30% lower risk of developing hypertension compared with those in the lowest tertile [0.70 (95%Cl 0.58–0.86)]. Notably, a 10 ng/ml increment in baseline vitamin D levels corresponded to a 12%

reduction in risk [0.88 (95%Cl 0.81, 0.97)] [133]. In this type of correlations, the importance of baseline 25(OH)D levels are confirmed also for very low refer- ence values; subjects with circulating levels<15 ng/ml compared with those with levels 30 ng/ml have a 3.18 (95%Cl 1.39–7.29) higher relative risk of hypertension development [134].

Overall, the antihypertensive effects of vitamin D may depend on a direct activation of the vitamin D receptor on vascular endothelial and smooth muscle cells or on a modulation of the renin–angiotensin–al- dosterone system [135,136].

Conversely, different conclusions were reached when the vitamin D supplementation was used as a blood pressure-lowering agent. Indeed, no evidence of blood pressure reduction upon vitamin D supplementation was seen on either SBP (0.0 mmHg (95%Cl –0.8 to–0.8)) or DBP (0.1 mmHg (95%Cl –0.6 to 0.5) [137].

Similar results were obtained after a sub-analysis for baseline SBP>140 mmHg or 140 mmHg and for baseline 25(OH)D values >20 ng/ml or 20 ng/ml.

Supplementation with vitamin D (50,000 IU/week) in MetS patients for 16 weeks significantly reduced levels of the vascular adhesion molecule-1 and of E selectin.

However, there was no significant activity on high-sensitivity C-reactive protein and carotid intima media thickness [138].

Curcumin

Curcuminoids are polyphenolic compounds derived from the dried rhizomes of Curcuma longa L. (turmeric) and are responsible for the orange-yellow colour [139].

Curcumin is the major component, i.e. constituting about 5% of turmeric, with the structural analogues demethoxycurcumin and bis demethoxycurcumin.

Unstable at physiological pH, it rapidly degrades to oxidized products, which mediate topoisomerase poi- soning as well as other antioxidant, anti-inflammatory and lipid lowering effects [140].

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Among the multiple pharmacodynamic effects of curcumin are the well-established antioxidant and anti-inflammatory properties, demonstrated by in vitro and in vivo studies. Indeed, this compound proved to increase serum total antioxidant capacity and super- oxide dismutase, together with an increase in glutathi- one concentrations and reduction in lipid peroxides [141,142]. Interestingly, curcumin can also regulate cytokines, protein kinase, adhesion molecules and other enzymes (TNF-a, IL-1, IL-6, TGF-b, MCP-1, etc.) [139,143,144]. Supplementation with curcuminoids was associated with a statistically significant reduction in circulating high-sensitivity (hs)-CRP levels in a meta- analysis (weighed mean difference:6.44 mg/l; 95% CI:

10.77 to 2.11) [145]. A small trial on 14 males showed a significant increase in postprandial flow- mediated dilatation (FMD) (from 5.2% to 6.6%) after a single consumption of curry meal containing curcumin [146], suggesting a potential role in preventing endothelial dysfunction.

Among the multiple properties on a wide range of diseases, curcumin proved to modify almost all features of MetS [147]. The main metabolic effect of curcumin seems to be related to an activity as insulin sensitizer [148,149], well demonstrated in animal models of diabetes [148], and confirmed in human studies. In a dou- ble-blind randomized trial, pre-diabetic patients achieved an improvement of all markers of insulin sensitivity (C-peptide, HOMA-IR and HOMA forb cells) after 9 months with 1500 mg of curcumin compared with placebo [150]. The curcumin extract in the same study also prevented T2D development (0% of curcumin- treated developed DM versus 16.4% of placebo-treated patients). Aþ22.5% increase in adiponectin levels was also detected, later confirmed in a further meta-analysis reporting a 77% rise (95% CI: 6.14–147.42) together with a 26% decrease in leptin (95% CI:70.44-17) [142];

both adiponectin and leptin have been linked to cardiovascular diseases [7]. A shorter treatment period provided no comparable benefit on glucose homeostasis [151], with, however, a significant improvement of HDL- cholesterol (þ6.8%) and a reduction of TG (28.8) and of non-HDL-C (13.6%). A larger study on 117 subjects with MetS provided confirmatory findings, indicating, in addition a significant antioxidant and anti-inflammatory activity with a marked reduction (2.2 mg/l) of CRP concentrations [152].

The lipid-lowering mechanisms of curcuminoids seem to reside in their ability to increase cholesterol efflux via ABCA1 and APOA-I expression [153,154] and to inhibit the expression of Niemann–Pick C1-Like 1 (NPC1L1) via the Sterol regulatory element-binding protein 2 (SREBP2) transcription factor [155]. Curcumin also

downregulates PCSK9 mRNA levels by up to 31–48% in different cell lines, thus promoting LDL-R expression on the cell surface and LDL-C uptake [156]. The mechanism of down-regulation of PCSK9 appears to be linked to the inhibition of the HNF-1a transcription factor: this may lead to an additional anti-inflammatory activity [157]. Curcumin further demonstrated protection against atherosclerosis in LDLR^/mice [154], by modifying peroxisome proliferator-activated receptors (PPAR)-a and c, CETP and LPL expression, therefore, affecting synthesis and catabolism of fatty acids [154,158].

Limitation to a wider use of curcumin is the poor oral bioavailability, representing a major obstacle to clinical development. Although usually well tolerated and safe, curcumin has a low hydrosolubility and undergoes a rapid gastric and intestinal metabolism. A number of new formulations have been described. A formulation with a hydrophilic carrier, cellulose base and natural antioxidants [159] proved to be absorbed at least 30 times better than curcumin base. Recently, a formulation of curcumin encapsulated in milk exo- somes proved to have improved resistance to human digestion and improved cell permeability [160]. A formulation with piperine, an inhibitor of hepatic and intestinal glucoronidation is in advanced development, and the initial clinical tests have given a positive out- come [161]. Development of a curcumin product with an improved bioavailability will probably lead to a better activity on the blood lipid profile, as shown in a study investigating in parallel lipid responses and blood levels [162].

Berberine

It is a natural plant alkaloid, isolated from the Chinese herb Coptis kinensis (Huanglian). In the Far East, it is commonly used for diarrhoea but a potential glucose lowering effect was noted by Chinese medicine way back in the ‘80s. The breakthrough finding was the description of a powerful cholesterol lowering activity (berberine 500 mg bid for 3 months) in hypercholesterolemic patients [163]. This activity was associated with an elevation of the LDL-R expression, independent of the sterol regulatory element binding proteins (SRBPs), but consequent to the activation of an extra signal regulated kinase (ERK). In a later study, Lee et al. [164]

reported that berberine, in addition to stabilizing hepatic LDL-R mRNA in an ERK-dependent way, could increase the transcriptional activity of LDL-R promoter by activating the JNK pathway (Figure 3). Moreover, in endothelial cells, berberine has been reported to coun- teract pro-atherogenic and inflammatory stimuli

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induced by oxLDL and TNF-alpha, a mechanism involv- ing the inhibition of lectin-like OxLDL receptor 1 and the modulation of AMPK and ERK1/2 pathways [165].

These findings stimulated interest in the possible use of berberine in patients with the more classical LDL-R mutations, but Kong et al. findings were not widely confirmed, mainly because berberine was, from then on, mainly given in association with other nutraceuticals affecting cholesterolemia. Instead, the earlier traditional findings reporting an improvement of T2D were confirmed by a number of investigations. At a similar dose, as in the early study [163], patients with newly diagnosed T2D, showed a similar reduction of glucose, hemoglobin A1c and TG; remarkably, fasting insulin and the HOMA index were reduced by 28.1 and 44.7% [166].

The mechanism/s of berberine in addressing lipid targets, particularly, those strictly related to MetS have been extensively evaluated. Huang et al. [167], work- ing on mechanisms related to an improved insulin sensitivity, reported that berberine inhibited 3T3L adipocyte differentiation, through the transcription factors PPARc and c/eBPa, also inhibiting the full length PPARc, PPAR a and their target genes involved on glucose homeostasis and lipid metabolism [168]. In this way, berberine may exert a weight reduction in addition to hypolipidaemic and hypoglycaemic activity.

A comparative study, in patients with T2D, on 13 weeks of berberine treatment (500 mg tid) versus a similar dose of metformin, reported similar hypogly- cemic and HBA1c reducing effects of the two agents, in addition to a 21% TG reduction with berberine, versus no effect of metformin [166]. In the follow-up, 48 adults with poorly controlled T2D, receiving a similar berberine supplementation, showed a marked

decrease of HBA1c (from 8.1% to 7.3%), insulin and HOMA-index; in addition, TG, total and LDL-C were significantly reduced. In a large series of 106 patients with T2D and dyslipidaemia, berberine (1 g/day) for 3 months significantly reduced glycaemia, cholesterolemia, trygliceridemia and, in addition, improved the glucose disposal rate, as assessed by a hyperinsuline- mic euglycemic clamp [169].

The specific activity of berberine in patients with MetS has been complemented by two studies, one in animals and one in humans, both in conditions of IR.

Lee et al. [170] in two models of IR, i.e. the obese db/

db mice and the high fat-fed Wistar rats, reported a clear IR improving effect, associated with marked body weight reduction. The authors also indicated a possible increase of the AMP-activated protein kinase (AMPK) in adipocytes and increased GLUT4 translocation in L6 cells. The potential mechanisms of the improved insulin sensitivity were well evaluated in MetS patients. After receiving 12 weeks of treatment with berberine 300 mg tid, these patients showed a significantly decreased BMI (from 31.5 ± 3.6 to 27.4 ± 2.4 kg/m²) and leptin levels (8.01 versus 5.12lg/l both p< .001), as well of the leptin/adiponectin ratio and HOMA Index [171]. These findings clearly indicate that insulin sensitivity is improved by berberine by adjustment of the adipokine secretion, both in primar- ily cultured adipocytes and in MetS patients. A potential additional mechanism in improving IR is by way of inhibited adipose tissue lipolysis. The antilipolytic activity is exerted by an increased adipose tissue phosphodiesterase (PDE), leading to reduced cAMP and inhibited activation of the HSL [172].

The improvement of IR and the activation of AMPK, this latter similar to the mechanism of metformin

↑ AMPK

↑ Insulin receptor

↑ Glucose uptake

Lipids:

↓ Cholesterol synthesis

↓ Triglycerides synthesis

↓ Fay acids synthesis

↑ LDL receptor

↓ SREBP2 ↓ PCSK9

↑ AMPK

↑ Insulin secreon

↑ GLP-1

↑ AMPK

↓ Inﬂammaon

Figure 3. Main mechanisms of action of berberine on the components of metabolic syndrome. AMPK: 5' AMP-activated protein kinase; GLP-1: gut hormone glucagon-like peptide; LDL: low-density lipoprotein; PCSK9: proprotein convertase subtilisin/kexin type 9; SREBP-2: sterol regulatory element-binding transcription factor 2 [adapted with permission of Elsevier [205]].

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[173], albeit with some contrasting findings [174], are certainly in line with a significant activity of the agent in MetS. Further findings have suggested that berberine can provide an effective association with cholesterol lowering drugs. Berberine reduces the liver expression of PCSK9, a serine protease favouring deg- radation of the LDL-R [175], increased after statin therapy [176]. The reduction of PCSK9 mRNA and protein levels [177] are dependent on a down regulation of the hepatocyte nuclear factor-a (HNF-1a), one of the essential cofactors for the transcriptional regulation of PCSK9 [178,179] and responsible for the regulation of a variety of inflammatory conditions. Inhibited HNF1-a transcription has also been reported after curcumin, possibly leading to a similar reduction of PCSK9 [156,157].

Finally, berberine has a potentially significant activity in upregulating the reverse cholesterol transport, when this is inhibited by the CETP inhibitor torcetra- pib. In this condition, inhibited CETP in dyslipidemic hamsters does not lead to a stimulation of reverse cholesterol transport, whereas this is markedly stimulated in the presence of berberine [180].

The wide availability, relatively low cost and generally adequate tolerability of berberine, make it an important therapeutic addition to the list of nutraceuticals affecting MetS [181]. Berberine has unfortunately a relatively low bioavailability, making it necessary to administer elevated doses, with consequent possible gastrointestinal side effects. Since the reduced bioavailability is consequent to berberine being P-gp substrate [182], association of berberine with a the P-gp inhibitor Silybum marianum extract, apparently improved the lipid activity on lipid and on insulin secretion [183].

Red yeast rice (RYR)

RYR is obtained by the fermentation of the Monascus purpureus yeast in rice (Oryza sativa) and is commonly used in oriental cuisine. The fermentation process enriches rice in bioactive components, including poly- ketides such as monacolins (compactin, monacolin K, M, L, J, X) with documented lipid-lowering effects as inhibitors of THE 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase [184]. The primary monacolin in RYR is monacolin K, with the same chemical structure as lovastatin and, for this reason, classified as a drug by the US Food and Drug Administration (FDA) [185].

The European Food Safety Authority (EFSA) maintains instead the use of monacolin K from RYR preparations as a nutraceutical that can reduce elevated LDL-C concentrations [186].

Beneficial vascular effects in MetS can go beyond cholesterol reduction since 1200 mg/d of RYR showed endothelial protection in 50 coronary patients after 6 weeks of treatment, significantly reducing fasting hsCRP (50% versus 25.4%) and improving post-prandial FMD compared with placebo (7.91 ± 3.16% versus 5.34 ± 2.78%) [187]. Confirming these findings, Cicero et al. found a significant improvement in endothelial function, measured as pulse volume (PV) and arterial stiffness, measured as pulse wave velocity (PWV) in 40 moderately hypercholesterolemic subjects. After 4 weeks of monacolin K 10 mg treatment, PV rose by 6.0% (compared with 0.3% with placebo) and PWV decreased by 4.7% (1.1% with placebo) [188]. These data could be possibly in line with a reduction in plasma concentrations of the matrix metalloprotei- nases (MMPs), MMP-2 (28.05%) and MMP-9 (27.19%) observed by the same authors in a previous clinical study [189]. These effects could be consequent to an up-regulation of eNOS expression and inhibition of oxidative stress in vascular endothelia, as shown in rodents [190].

There is limited evidence, i.e. from a small randomized clinical trial, of a blood pressure lowering effect of 10 mg monacolins (50% monacolin K), combined with 9 mg of hydroxytyrosol, in 50 MetS subjects [191]. A significant drop in SBP and DBP by 10 and 7 mmHg, respectively, compared with placebo, was recorded after 8 weeks. So far, this effect has not been reproduced and a meta-analysis from 21 trials showed only a significant effect on SBP [192].

RYR is currently used predominantly in combination with other nutraceuticals, allowing us to reduce daily doses, and exerting effects beyond cholesterol reduction. Among others, association of RYR with berberine proved to be highly effective in reducing TC by 0.68 mmol/l and LDL-C by 0.61 mmol/l, while raising HDL-C by 0.07 mmol/l, reducing TG and glucose by 0.16 mmol/l and 0.14 mmol/l, respectively [193].

Interestingly, unlike statins [194], this nutraceutical combination improved the leptin-to-adiponectin ratio (17.8%), without changing adiponectin levels [195].

Moreover, the same association led to an improved endothelial function and PWV [189].

In addition, RYR (200 mg), in combination with berberine (500 mg) and policosanols (10 mg), has been shown to improve insulin sensitivity in patients with IR, reducing the HOMA-IR by 24% [196].

Some studies assessed the efficacy of RYR in reducing cardiovascular risk in adults and elderlies in sec- ondary prevention. Lu et al. [197] carried out a prospective study on 5000 Chinese patients with a previous history of myocardial infarction, randomized

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to RYR or placebo and followed for an average of 4 years. RYR reduced the incidence of coronary events (5.7% versus 10.4% in the placebo group (p¼ .001);

deaths from coronary heart disease increased by 30%

(p¼ .04), and all-cause mortality by 33% (p ¼ .01).

These findings were later confirmed by a reduction (43%) of coronary events and all-cause mortality (35.8%) in 2704 hypertensive patients [198].

In addition to the potential of induced statin-like CK elevations and myalgia [199] after prolonged treatment [200], attention should be given to the presence of citrinin, a nephrotoxic mycotoxin metabolite, derived from the fermentation process of Monascus.

For this reason, EFSA has defined a maximum concen- tration to be taken per day of 0.2 mg/kg b.w. [186].

Found in low quality RYR products, citrinin can pose a health risk as it may be mutagenic, as found in animal models, and genotoxic to human lymphocytes [201,202], and may also cause kidney failure in animals, although acute human toxicity is a rare event.

Conclusions

The management of MetS is a major target in atherosclerosis prevention. While treatment of hypercholesterolemia can be successfully handled using drugs affecting in particular cholesterol biosynthesis, in the case of MetS there are a number of diverse metabolic abnormalities more difficult to pursue. In particular, in MetS, insulin resistance appears to be a major abnor- mality that may be only partially handled by drug treatments. Insulin resistance may of course translate into altered body structure, elevated blood pressure and other metabolic and non-metabolic changes.

The very high number of carriers of MetS makes it mandatory to achieve treatment by more widely available nutritional approaches. Nutraceuticals can, thus, offer a significant help in handling MetS patients [203].

They may be part of lifestyle recommendations and may include Mediterranean diet components, olive oil and its anti-oxidant components, natural legumes and

cereals [204]. However, in the daily management of patients, a dietary counselling alone may not be adequate. In this manuscript, we have reviewed highly standardized nutraceuticals that go from functional food components, in particular from plant proteins (e.g. soy and lupin) to probiotics and prebiotics, providing significant benefit by modifying the intestinal microbiome, to natural compounds, frequently achiev- ing a drug-like status, e.g. red yeast rice, berberine and curcumin, as well as vitamin D (Table 2). All these nutraceuticals are easily accessible both to physicians or patients and can easily enter a lifestyle modification for improvement of MetS. Adequate formulations will certainly raise their already large medical use once bioavailability of some of these natural molecules is improved; eventually making them more widely acceptable for the management of common and high- risk metabolic and vascular abnormalities.

Disclosure statement

The authors report no declarations of interest.

ORCID

Massimiliano Ruscica http://orcid.org/0000-0002-0195- 7061

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Table 2. Effects of nutraceuticals on the features of metabolic syndrome: evidence from randomized-controlled trials and meta- analysis.

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