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Role of phytochemicals in the management of metabolic syndrome.

ABSTRACT

Background: The World Health Organization (WHO) for some years has been focusing on what is now commonly referred to as an "epidemic of obesity and diabetes" ("diabesity"): behind this outbreak, there are several risk factors grouped in what is called "metabolic syndrome" (MetS). The basis of this "epidemic" is either a diet too often characterized by excessive consumption of saturated and trans- esterified fatty acids, simple sugars and salt, either a sedentary lifestyle.

Purpose: The aim of this review is to focus on the phytochemicals that have a more positive effect on the treatment and/or prevention of MetS.

Chapters: Treatment strategies for MetS include pharmacologic and non-pharmacologic options, with varying degrees of success rate. The first is indicated for patients with high cardiovascular risk, while the second one is the most cost-effective preventive approach for subjects with borderline parameters and for patients intolerant to pharmacological therapy. MetS non-pharmacological treatments could involve the use of nutraceuticals, most of which has plant origins (phytochemicals), associated with lifestyle improvement. The chapter will discuss the available evidence on soluble fibres from psyllium and other sources, cinnamaldehyde, cinnamic acid and other cinnamon phytochemicals, berberine, corosolic acid from banaba, charantin from bitter gourd, catechins and flavonols from green tea and cocoa. Vegetable omega-3 polyunsaturated fatty acids, alliin from garlic, soy peptides, and curcumin from curcuma longa.

Conclusion: Some nutraceuticals, when adequately dosed, should improve a number of the MetS components.

Keywords:

Metabolic syndrome

Hypertension

Dyslipidaemia

Nutraceuticals

Insulin resistance

Obesity

Introduction

Metabolic syndrome (MetS) is a clinical entity substantially heterogeneous, represented by the coexistence of multiple alterations, in particular abdominal obesity, insulin-resistance, hypertension and dyslipidaemia (high TG and low HDL-C values), associated with an increased risk to develop cardiovascular diseases, type 2 diabetes and for all-cause mortality (Wu et al. 2010).

The most commonly accepted definition of MetS includes three or more of the following signs: waist circumference > 102 cm (male) or > 88 cm (female), TG > 1.7 mmol/1, HDL cholesterol < 1.0 mmol/1 (male) or <1.3 mmol/1 (female), blood pressure > 135/85 mmHg on medication, fasting plasma glucose (FPG) > 6.1 mmol/1 (Malik et al. 2004; Grundy et al. 2005).

The cornerstone in the treatment of MetS is based on an improvement of lifestyle, promoting physical activity and a balanced low-energy diet, which is also the most cost-effective approach to this condition. When life-style modification has improved the MetS features, but further improvement is required, before to begin a (often multiple) pharmacological therapy, some phytochemicals could be also useful tools in the treatment of one or more MetS components (Table 1) (Graf et al. 2010). In some cases, the use of nutraceuticals could also be considered in already pharmacologically treated patients in support to drugs when the therapeutic target has not been reached (Grundy et al. 2005; NCEP expert panel 2001).

Giving the large number of phytochemicals with proposed positive effects on Mets, the purpose of this review is to analyse those that have had a demonstrated impact on more than one MetS components in clinical trials, and in particular those having an effect on insulin-resistance, the pathophysiological background of MetS.

Data selection

A systematic search strategy was developed to identify trials in both MEDLINE (National Library of Medicine, Bethesda, MD; January 1970 to May 2015) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). The terms 'nutraceuticals' 'dietary supplements', 'herbal drug', 'insulin-resistance', 'metabolic syndrome', 'diabetes', 'dyslipidaemia', 'hypertension' and 'obesity' were incorporated into an electronic search strategy. The bibliographies of all identified studies and review articles were reviewed to look for additional studies of interest. The authors reviewed all of the citations retrieved from the electronic search to identify potentially relevant articles for this review. We excluded in vitro data and animal studies because focusing on human data, in order to limit our report to phytochemicals and nutraceutical for which safety and tolerability in humans are already known. So, we preferably selected papers reporting recent comprehensive reviews or meta-analyses, or original clinical trials on substance with action on at least two or more components of MetS at the same time.

Soluble fibres from psyllium and other sources

Dietary fibres with significant metabolic effect are the soluble ones (NCEP expert panel 2001). Psyllium husk has maybe the largest scientific evidence of efficacy. Although true psyllium comes from Plantago psyllium, the husks and seeds of Plantago ovata (Plantaginaceae) are commonly referred to as psyllium (Petchetti et al. 2007). Psyllium is one of the most widely used fibre supplements because it is reasonably cheap and is better tolerated than other fibre supplements (Pal and Radavelli-Bagatini 2012). Psyllium has mild lipid-lowering, anti-obesity, anti-diabetic and anti-hypertensive effects in humans (Cicero et al. 2010).

In humans, soluble fibres, and in particular psyllium husk, reduce the plasma LDL-cholesterol level by decreasing bowel cholesterol absorption and increasing the fractional turnover of both chenodeoxycholic acid and cholic acids (Everson et al. 1992). Animal studies also suggest that psyllium increases activity of cholesterol 7-alpha hydroxylase, the rate-limiting enzyme for bile acid synthesis, more than twice than cellulose or oat bran and pectin (Vergara-Jimenez et al. 1998), but this effect has never been adequately investigated in humans.

Different meta-analyses suggest that psyllium supplementation has a mild but significant dose- and time-dependent cholesterol-lowering effect in hypercholesterolemic patients, with a mean decrease in LDL-cholesterolemia of 7% for 10 g/d of supplemented fibre, without significant effect on other lipid fractions (Wei et al. 2009). Psyllium also increases the lipid-lowering efficacy of bile acid sequestrant drugs (even reducing their bowel side effects), phytosterols (Cicero et al. 2014), and statins (Agrawal et al. 2007).

Psyllium husk and other soluble fibres have also a positive global impact on post-prandial glycaemia and other insulin-resistance related parameters (Bajorek and Morello 2010).

Randomized clinical studies also showed that psyllium has significant beneficial effects on both systolic and diastolic blood pressures with doses of 3.5 g t.i.d. taken 20 mins before two main meals (Cicero et al. 2007). It was also shown to improve vascular function measured through augmentation index (Pal et al. 2012). Its effect on weight reduction is encouraging, probably because of its positive effect on satiety and decreased intestinal absorption, but more confirming clinical data are needed (Pittler and Ernst 2004).

All the available trials and meta-analysis conclude for an overall safety of psyllium supplements. However, it could have transient gastrointestinal side effects which are usually not severe and only mildly decrease compliance to treatment, especially when micronized fibre is used (Cicero et al. 2012). Entire seeds, used for the treatment of constipation, did not demonstrate a lipid-lowering action and they could exacerbate diverticulitis in patients affected by chronic diverticulosis.

A main safety concern about soluble fibres use as cholesterol-lowering agents is the risk of drug interaction that regards oral anti-diabetic drug, digoxin, warfarin, lithium, iron, oral steroids, tricyclic antidepressants, carbamazepine and other molecules (Mechanick et al. 2003).

Other soluble fibres with positive effects on more than one MetS component are guar gum, fenugreek, chitosan and glucomannan.

The dietary fibre guar gum has beneficial effects on dyslipidaemia, insulino-resistance and obesity in both humans and animals (Den Besten et al. 2015). In mice, the intake of guar gum with the diet decreased the markers of MetS (body weight, adipose weight, triglycerides, glucose and insulin levels and HOMA-IR) in a dose-dependent manner. An important role have been suggested to be played by the short-chain fatty acids, that act through a signalling cascade that inhibits the peroxisome proliferator-activated receptor y and that activates AMP-activated protein kinase (Den Besten et al. 2014). In humans, diets enriched sufficiently in guar gum may improve overall glycaemic control in type 2 diabetes mellitus and increase satiety (Mello and Laaksonen 2009). Furthermore, a randomized controlled clinical trial demonstrated that guar gum has an anti-hypertensive, lipid-lowering and hypoglycaemic effect, supporting a role for guar in the treatment of the MetS (Landin et al. 1992).

Dietary fibre from fenugreek (Trigonella foenum-graecum) blunts glucose and lipids after a meal and regulates the production of cholesterol in the liver, but some interesting central metabolic effects are also under study (Roberts 2011). Chitosan, a deacetylated chitin, is associated to a short-term improvement in body weight and blood pressure Gull et al. 2008), plasma lipids (Choi et al. 2012) and insulin-resistance (Hernandez-Gonzalez et al. 2010), as well. Moreover, the intake of glucomannan, in a meta-analysis of randomized clinical trials, significantly lowered TG (weighted mean difference (WMD): 11.08 mg/dl; 95% CI: -22.07, -0.09), body weight (WMD: -0.79 kg; 95% CI: -1.53, -0.05), and fasting plasma glucose (WMD: -7.44 mg/dl; 95% CI: -14.16, -0.72), but not blood pressure (Sood et al. 2008).

Cinnamaldehyde, cinnamic acid and other cinnamon phytochemicals

Cinnamon (Cinnamon zeylanicum) is a very old spice and several cultural practices have been using it for centuries. In addition to its culinary uses, cinnamon has a rising popularity due to its stated health benefits (Varker et al. 2012). Out of the large number of cinnamon species available, Cinnamomum aromaticum (Cassia) and Cinnamomum zeylanicum have been subjected to extensive research.

Cinnamon primarily contains vital oils and other derivatives, such as cinnamaldehyde, cinnamic acid and cinnamate (Rao and Gan 2014).

In vitro and in vivo available evidence indicates that cinnamon may have multiple health benefits, mainly in relation to glucose- and lipid-lowering activity. Furthermore, the therapeutic potential of cinnamon is brought about by its anti-microbial, anti-fungal, antiviral, anti-oxidant, anti-tumour, blood pressure-lowering, and gastro-protective properties (Bandara et al. 2012).

Studies carried out on streptozotocin-induced diabetic rats show that oral intake of cinnamon reversibly and competitively inhibits alpha-glucosidase enzyme and improves postprandial hyperglycaemia (Mohamed Sham Shihabudeen et al. 2011). Cinnamaldehyde administration to diabetic rats for 2 months significantly improves muscle and hepatic glycogen content: moreover it increases glucose uptake through GLUT-4 translocation in peripheral tissues (Anand et al. 2010). Cinnamic acid also reduces blood-glucose levels in a dose-dependent manner in non-obese type 2 diabetic rats: the improvement by 10 mg/kg of cinnamic acid has been comparable to that of the sulphonylurea glibenclamide (5 mg/kg); furthermore, in vitro it significantly enhances glucose-stimulated insulin secretion in isolated pancreas islets (Hafizur et al. 2015).

Cinnamon may also improve insulin resistance by preventing and reversing impairments in insulin signalling in skeletal muscle and adipose tissue, such as increasing the expression of peroxisome proliferator-activated receptor (PPAR)-gamma, genes coding for adipokines, increased glucose transporter (GLUT)-1 mRNA levels, meanwhile decreasing the expression of further genes encoding insulin-signalling pathway proteins (Kim and Choung 2010; Cao et al. 2010). Moreover it can act as a dual activator of PPAR-gamma and alpha, and may be an alternative to PPAR-gamma activator in managing obesity-related diabetes and hyperlipidaemia (Sheng et al. 2008). PPAR-related mechanisms account for antiadipogenic effects of cinnamaldehyde, as well (Huang et al. 2011).

Moreover, together with cinnamaldehyde, cinnamon polyphenols are active in increasing GLUT-4 levels, insulin receptor-(IR) beta and tristetraprolin (Cao et al. 2007).

Several phenolic compounds, such as catechin, epicatechin, and procyanidin B2, and phenol polymers identified from the subfractions of aqueous cinnamon extract has shown significant inhibitory effects on the formation of advanced glycation end-products, suggesting a potential in the prevention of diabetes complications (Peng et al. 2008).

However, it is not yet clear which cinnamon active components have the higher bioavailability in humans.

In a recent meta-analysis of randomized clinical trials including 435 patients enrolled in trials with follow-up between 40 days and 4 months and doses ranging from 1 g to 6 g per day, a significant decrease in mean HbAlc (0.09%; 95% Cl was 0.04-0.14) and mean FPG (0.84 mmol/1; 95% CI 0.66-1.02) has been observed (Akilen et al. 2012). Similar data have been confirmed also in prediabetic subjects (Davis and Yokoyama 2011).

Positive effects of cinnamon on fasting TG and HDL cholesterol, and postprandial hypertriglyceridemia have also been confirmed in animal models (Qin et al. 2009) and diabetic patients (Khan et al. 2003).

Blood pressure has been also reduced by cinnamon treatment in diabetic patients (Akilen et al. 2010; Wainstein et al. 2011). Cinnamaldehyde also averts the progress of hypertension in types 1 and 2 diabetes by abridging vascular contractility (El-Bassossy et al. 2011).

In animal studies the median lethal dose (LD50) of cinnamaldehyde could not be obtained even at 20 times (0.4 g/kg bw) of its effective dose, showing a high margin of safety (Ranasinghe et al. 2012), confirmed by the high tolerability shown in the available clinical trials (Akilen et al. 2012; Davis and Yokoyama 2011).

Berberine

Berberine is a quaternary plant ammonium salt extract, which has lipid-lowering, hypoglycaemic, anti-inflammatory and antihypertensive effects, beyond a low systemic bioavailability (Cicero and Ertek 2009).

Berberine stabilizes the mRNA of liver LDL receptor (by the activation of AMP-activated protein kinase (AMPK), the inhibition of mitogen-activated protein kinase MAPK) and modulatory effects on PPAR-gamma and alpha (Brusq et al. 2006). The most relevant mechanism of action of berberine is however the inhibition of the transcription of the mRNA encoding the proprotein convertase subtilisin/kexin type 9 (PCSK9): it is an enzyme which facilitates the detachment of the hepatic LDL receptor from the cell surface to the lysosomes where it is degraded(Cameron et al. 2008).

Patients with mixed hyperlipidaemia treated with berberine experienced a mean reduction of 25% in LDL and TG levels, by using doses of 500-1500 mg daily (Zhang et al. 2008; Yin et al. 2008a).

Berberine has also an insulin-sensitizer effect comparable to that of metformin, through a mechanism involving retinol binding protein-4 (RBP-4) (Zhang et al. 2008) and GLUT-l(Kim et al. 2007) and an insulinotropic effect different from sulfonylureas by increasing both mRNA expression of hepatic nuclear factor 4-alpha (HNF-4-alpha) and glucokinase activity (Wang et al. 2008). Moreover it increases the levels of glucagon like peptide-1 (GLP-1), acting directly on pancreas (Yin et al. 2008b).

A recent meta-analysis confirmed the lipid-lowering power of berberine, with an average reduction in total cholesterol of 0.61 mmol/1, TG of 0.50 mmol/1 and LDL cholesterol of 0.65 mmol/1 (Dong et al. 2013).

Standard doses of berberine (500-1000 mg/day) are usually well tolerated and adverse reactions are rare and mild (mainly gastrointestinal discomfort). On the contrary, high doses (more than 1000 mg/day) have been associated to arterial hypotension, dyspnoea, flu-like symptoms, gastrointestinal discomfort, constipation and cardiac damage (Derosa et al. 2012; Vuddanda et al. 2010).

The main concerns are about berberine interactions: berberine displaces bilirubin from albumin about ten-fold more than phenylbutazone, thus it should be avoided in jaundiced infants and pregnant women (Chan 1993). Berberine also displaces warfarin, thiopental and tolbutamide from their protein binding sites, increasing their plasma levels (Tan et al. 2002). Meanwhile, it can markedly increase the blood levels of cyclosporine A by the inhibition of the cytochrome P450 3A4 in the liver and of the P-glycoprotein in the gut wall and by increasing the gastric emptying time, thus causing its increased bioavailability and reduced metabolism (Xin et al. 2006).Therefore, berberine should not be used in patients assuming drugs with narrow therapeutic range.

Corosolic acid from banaba

Lagerstroemia speciosa, in Philippines folk medicine known as "banaba", seems to have anti-diabetic and anti-obesity effects (Klein et al. 2007). Although its mechanism of action is still not clear, the increase of cellular uptake of glucose, the inhibition of the hydrolysis of sucrose and starches, the decreased gluconeogenesis and the regulation of lipid metabolism, mediated by PPAR, MAPK, nuclear factor kappa-B (NF-[kappa]B) and other transduction signal factors, could be responsible for its effects (Stohs et al. 2012). The main active components of banaba extract may be corosolic acid, ellagitannins, tannic acid and penta-O-galloyl-glucopyranose (PGG) (Liu et al. 2005; Saumya and Basha 2011). The bioavailability of corosolic acid in humans has not yet investigated.

In mice, banaba suppresses blood glucose elevation and plasma total cholesterol (Kakuda et al. 1996), decreases hepatic lipid content and body weight (Suzuki et al. 1999). Moreover, banaba extract inhibits adipocyte differentiation in preadipocytes in a dose-dependent manner (Liu et al. 2001).

In humans, the antidiabetic activity of a banaba extract (Kouzi et al. 2015), standardized to 1% corosolic acid, has been examined and a 30% decrease in blood glucose levels has been reported after 2 weeks' administration Qudy et al. 2003). In another study, 31 subjects has taken 10 mg of corosolic acid or placebo, 5 mins before an oral 75-g glucose tolerance test (OGTT) in a double-blind and cross-over design: corosolic acid treatment subjects has shown lower glucose levels from 60 min until 120 min and have reached statistical significance at 90 min (Fukushima et al. 2006). Overall, controlled human studies and animal data reported no adverse effects when using this compound, even if effects on other components of the MetS than FPG and post-prandial glycaemia have yet to be assessed in humans.

There is strong evidence that these effects are determined by both corosolic acid and ellagitannins of banaba and also valoneic and oleanolic acids have anti-hyperglycaemic properties (Miura et al. 2012). However further clinical trials are needed to evaluate their effectiveness and tolerability in humans, in particular focusing on dose-dependent effects of corosolic acid and banaba.

Charantin from bitter gourd

Bitter gourd (Momordica charantia L.) is a common tropical vegetable that has been used in traditional or folk medicine to treat diabetes (Chaturvedi 2012).

In mice, M. charantia (200 mg/kg/day of charantin-rich extract of M. charantia for 8 weeks) has potential for increasing insulin sensitivity in animals with type 2 diabetes mellitus more than protecting the ones with type 1 diabetes against [beta]-cell dysfunction (Wang et al. 2014).

A study considering subjects with MetS has shown that the 12% of them no more responded to the diagnostic criteria after 7 weeks' treatment with 4.8 g/d of lyophilized bitter gourd, mainly because of an improving effect on FPG and waist circumference (Tsai et al. 2012).

Bitter gourd 2 g/day had a modest hypoglycaemic effect among patients with newly diagnosed type 2 diabetes when compared to that of metformin 1000 mg/day (Fuangchan et al. 2011), but more efficacious than rosiglitazone in the global management of type 2 diabetes (Huang et al. 2011).

A clinical trial controlled with placebo has examined the effects of the association of bitter gourd with other nutraceuticals, in particular red yeast rice, chlorella, soy protein, and licorice, and have evaluated their effectiveness in subjects with MetS, which have received the active treatment or placebo for 12 weeks: the plant extractives has shown to be effective in reducing low-density lipoprotein (3.4 [+ or -] 0.7 to 2.7 [+ or -] 0.5 mmol/1, P < 0.001) and triglyceride (-0.5 [+ or -] 0.8 versus -0.2 [+ or -] 1.0 mmol/1, P = 0.039), improving blood pressure level, as well (Lee et al. 2012).

Bitter gourd supplementation appears to be safe, since it did not induce acute hypoglycaemias or other negative metabolic effects in non-diabetic subjects (Kasbia et al. 2009).

Catechins and flavonols from green tea and cocoa

Consumption of green tea as well as cocoa can be beneficial in patients with MetS. In fact these nutraceuticals are rich in phytochemicals, including catechins and phenols, which have significant antioxidant properties with clear benefits for cardiovascular health (USDA database for the flavonoid content of selected foods 2011; Grassi et al. 2012). Animal studies have shown that green tea lowers blood pressure by suppressing the activity of NADPH oxidase and reducing the reactive oxygen species (Ihm et al. 2012).

The green tea extract has demonstrated lipid-lowering activity in hypercholesterolemic rats, with a reduction of 21% in LDL-C and 13% in TG. In hyperglycaemic rats the reduction in blood glucose has been of 13%: if confirmed in humans, these results would be a further evidence of the effectiveness of green tea in subjects with MetS (Yousaf et al. 2014).

A meta-analysis of 20 randomized clinical trials, with a total of 1536 participants who received green tea regularly, has shown a slight decrease in systolic blood pressure (MD: -1.94 mmHg; 95% CI: -2.95 to -0.93; 12 = 8%; p = 0.0002), as well as a moderate reduction of LDL cholesterol (MD: -0.19 mmol/1; 95% Cl: -0.3 to -0.09; 12 = 70%; p = 0.0004) (Onakpoya et al. 2014).

Moreover, green tea extracts reduces adipogenesis in patients with MetS by decreasing expression of transcription factors C/EBP[alpha] and PPAR-gamma (Yang et al. 2014).

The flavonoids of cocoa are the most studied in the clinical field: in particular it has been shown that the flavonols content in some types of cocoa, improves the endothelial function in healthy subjects and in hyperglycaemic or hypertensive patients with or without glucose intolerance, increasing the flow-mediated vasodilation (Grassi et al. 2008).

A recent meta-analysis of 20 randomized, double-blind, placebo-controlled, which involved a total of 856 participants mostly healthy, has revealed a statistically significant decrease in blood pressure in patients taking products made from cocoa rich in flavonoids (average value of flavonoids 545 mg/day) for a period from 2 to 18 weeks; the average decrease in systolic blood pressure has been of -2.77 mmHg (95%CI: -4.72, -0.82; p = 0.005), while the average decrease in diastolic blood pressure has been of -2.20 mmHg (95% CI: -3.46, -0.93; p = 0.006) (Ried et al. 2012).

In addition to the hypotensive effects, cocoa flavonols could stimulate thermogenesis, lipolysis and consequently reduce the adipose tissue, with a reduction of body weight, especially in response to high fat intake diets (Osakabe et al. 2014).

Vegetable omega-3 polyunsaturated fatty acids

Lipid-lowering action of omega-3 polyunsaturated fatty acids (PUFAs) has been clearly demonstrated in several clinical trials and meta-analyses (Wei and Jacobson 2011), however the most part of available clinical data have been obtained through the use of marine omega-3 PUFAs.

Nuts, vegetables with green leaves, linseed, flaxseed, walnuts and vegetable oils, including canola, soybean and hemp oil, are rich in alpha-linoleic acid (ALA), which is the principle vegetable omega-3 fatty acid. Moreover, some microalgae are rich in docosahexaenoic acid (DHA) and in particular the diatom Odontella aurita (Mimouni et al. 2012). Omega-3 PUFAs enhance prostaglandins formation, suppress angiotensin converting enzyme (ACE) activity, reduce angiotensin II formation, enhance nitric oxide (NO) formation and suppress transforming growth factor (TGF)-beta expression (Mohan and Das 2001). It's probable that ALA has a hypotensive effect acting as a precursor for eicosanoids that can generate the production of prostaglandins and leukotrienes and reduce vascular tone (Salonen et al. 1988; Djousse et al. 2005).

Alph[alpha]-linolenic acid seems to have beneficial effects on MetS and type 2 diabetes, because of its action on dyslipidaemia, inflammation, hypertension, platelet aggregation and prothrombotic effects (Douglas 2007) and to reduce the risk factors of cardiovascular disease (Poudyal et al. 2011). The cardioprotective effects of ALA have been attributed to its precursor role in converting to EPA in the body (Rajaram 2014). A clinical trial that evaluated the efficacy of a 6-months hypoenergetic diet enriched with a high MUFA content and an ALA intake of 3.5 g/die in patients with metabolic syndrome: systolic blood pressure, insulin levels, total and LDL cholesterol and also body weight were reduced in both groups (P < 0.05), while diastolic blood pressure and serum TAG were significantly reduced after the high ALA intake, but not in the control group (P < 0.05) (Baxheinrich et al. 2012).

Effective lipid-lowering doses of omega-3 PUFAs range from 2 to 4 g/die, which can only be obtained consistently by supplementation. At present, it seems that both eicosapentaenoic acid (EPA) and DHA have similar triglyceride (TG)-lowering properties, but in comparative studies DHA caused greater reduction in TG and increase in LDL-C and HDL-C than EPA (Wei and Jacobson 2011). Also ALA has modest but short lived LDL-C lowering effect, reduces Lp(a) and improves insulin sensitivity in hyperlipidaemic adults (Bloedon et al. 2008). An intake of 4 g/die of ALA seems to have biological effects similar to those of 0.3 g/die of long-chain [omega]-3 PUFA: comparatively, EPA and DHA produce more rapid effects than ALA, but the role of ALA could be more effective in terms of long-term dietary intake (Simopoulos 2000).

Moreover, omega-3 PUFAs seem to have a small, dose-dependent hypotensive effect, the extent of which seems to be dependent on the degree of hypertension, as shown in some animal and clinical studies (Cicero et al. 2009a).

These results suggest that a diet with a high intake of ALA can be an effective strategy in the therapy of subjects with MetS, but data about appropriate dosage and evidence for PUFAs protective role are still insufficient to suggest them as effective antihypertensive drug and further clinical trial are needed to confirm these results(Sanders et al. 2006).

Alliin from garlic

Allium sativum (garlic), and in particular alliin, is well known for its anti-diabetic, hypotensive, anti-inflammatory and lipid-lowering properties suggesting a significant role in the management of MetS (Hosseini and Hosseinzadeh 2015).

Garlic extracts have mainly a significant blood pressure lowering effect (Ried and Fakler 2014).The dry aged garlic extract has an inhibitory activity on ACE and acts as calcium channel blocker, which reduces the sensitivity to catecholamines; it also increases the levels of bradykinin and nitric oxide and consequently improves arterial compliance (Butt et al. 2009).A recent meta-analysis of randomized clinical trials controlled with placebo has shown an average reduction in systolic blood pressure of 4.6 [+ or -] 2.8 mmHg in the group of patients treated with garlic (p = 0.001); moreover, in the subgroup of patients with hypertension it has been found a mean reduction in systolic blood pressure of 8.4 [+ or -] 2.8 mmHg (p < 0.001) and diastolic pressure of 7.3 [+ or -] 1.5 mmHg (p < 0.001). These effects seems to be additive to the ones of the antihypertensive drugs (Reid et al. 2010).

Data from different trials suggest that garlic extract could also exert variable effects on human lipid metabolism, reducing the serum level of apolipoprotein B and increasing the one of HDL-cholesterol (Jung et al. 2014).

In a recent study of 43 subjects (Gomez-Arbelaez et al. 2013), the intake of aged garlic extract for 12 weeks has proved to be effective in increasing the levels of adiponectin, an adipokine secreted by adipose tissue, whose serum level is inversely associated to both body weight and cardiovascular disease risk (Kumada et al. 2003). This effect is probably related to a kind of insulin-sensitizing effects exerted by garlic extract that, in diabetic patients, reduce fasting plasma glucose, fructosamine and TG levels (Sobenin et al. 2008).

Soy peptides

Soy have received international recognition about its preventive and therapeutic activity on cardiovascular risk and there is a consensus document drawn up in 2006 by the American Heart Association Nutrition Committee on the benefits of soy on cardiovascular health (Sacks et al. 2006).

Torres et al. highlighted the normalizing effect of soy on lipid profile, with decreased synthesis of LDL also in subjects with MetS, and its preventive role in diabetes (Villegas et al. 2008).

Soy proteins lower the insulin/glucagon ratio, reducing the synthesis of LDL by liver (Davidson 2008) and increasing the expression of the receptors for the Apolipoprotein B100 Qones et al. 2009). The reduction of LDL in response to soy intake is expected to be between 7.9% and 10.3% (Jenkins et al. 2010).

Soy proteins presents also a hypotensive effect, in addition to induce weight-loss, due to their low caloric value and their ability to induce satiety (Singh et al. 2014). Moreover, they contain isoflavones that have a regulating action on glucose metabolism (Nanri et al. 2010).

These multiple effects of soy proteins make them a potential tool to prevent MetS, to treat the first alterations in patients with borderline values or to increase the effectiveness of medical therapies.

The intake of 25 g/day of lupine proteins has shown a marked lipid lowering activity (Bahr et al. 2015), due to a presumed inhibition of Hydroxy-methyl-glutaryl-coenzyme A reductase and to an increased expression of hepatic LDL receptor and SREBP2, through the activation of different pathways. (Lammi et al. 2014)

Curcumin from curcuma longa

Studies on extracts of Curcuma longa and their lipid-lowering effects have had mixed results and require further studies (Ghorbani et al. 2014).

Turmeric is obtained from the C. longa L. plant; its main constituent, curcumin, is a polyphenol with multiple effects that can modulate several signalling pathways.

Curcumin contained in the rhizome, could favourably act on all the main components of the MetS including insulin resistance, obesity, hypertriglyceridemia, decreased HDL-C and high blood pressure, and prevent the worst complications of MetS, including diabetes and cardiovascular events. Due to its anti-oxidant and anti-inflammatory activity, curcumin can also exert several pleiotropic effects and improve endothelial dysfunction, adipokines and hyperuricemia imbalances, that usually accompany MetS (Sahebkar 2013).

Curcumin has hypoglycaemic and insulin sensitizing effects; in fact it can lower plasmatic glycaemia, reducing hepatic glucose production and inflammation-induced hyperglycaemia, stimulating glucose uptake by the up-regulation of GLUT4, GLUT2 and genes GLUT3 expressions and the activation of AMP kinase, promoting the activity of PPAR ligand, stimulating insulin secretion from pancreatic tissues, improving the functionality of pancreatic cells and reducing insulin resistance (Panahi et al. 2014; Yao et al. 2014).

Therefore, Curcumin has proven to inhibit 11 [beta]-hydroxysteroid dehydrogenase type 1, with an increase blood levels of cortisol (Hu et al. 2013).

Discussion

Even if cardiovascular diseases are today the leading cause of mortality and one of the first causes of disability in developed countries, we seems to be far from reaching the treatment goals, especially in the setting of primary prevention (Banegas et al. 2011).

A change in lifestyle, increasing physical activity and improving dietary habits, is the most important step in term of prevention and cost/effectiveness (Saha et al. 2010; King et al. 2011). Weight loss (reduction of 7-10% of weight) and moderate intensity exercise, such as walking, 5-7 days per week) could be useful tools to help blood pressure, LDL cholesterol, and blood glucose control. Quitting smoking habit is recommended, as well. However, life-style programs are often difficult to follow for long periods and some risk parameters, such as cholesterolemia, are relatively resistant to changes in dietary habits and physical activity (Cicero et al. 2009b). On the other hand, a large number of dietary supplements and nutraceudcals have been studied for their supposed or demonstrated ability to safely improve MetS components in humans (Table 1) (Davi et al. 2010). We have above highlighted the possibility that some of them could act simultaneously improving more than one MetS component, such as omega-3 fatty acids, berberine, psyllium and other soluble fibres, cinnamon, banaba, green tea and cocoa, garlic and bitter gourd (Fig. 1).

Other natural compounds like Gymnema sylvestre, Crataegus monogyna, Panax quinquefolium and Eugenia jambolana were demonstrated to have positive effects on glucose metabolism in small clinical trials (Kouzi et al. 2015), but the effects on MetS components haven't been definitively investigated yet.

The consumption of beetroot juice is suitable in hypertensive patients with MetS. In fact beetroot is known for its proven antihypertensive properties (Cicero and Colletti 2015), mainly due to the presence of inorganic nitrates, that in vivo are converted into nitric oxide (NO), which is responsible for vasodilatation of large arteries and resistance vessels (Coles and Clifton 2012). However it is important to evaluate the effects of beetroot on all components of the MetS; in fact are starting new clinical trial to assess its effects on insulin sensitivity.

The largest part of the most widely marketed nutraceuticals was not clearly demonstrated to have positive cardiometabolic effects. The reasons could be different, among the others low bioavailability (also often not tested, thus unknown), scarce tolerability of efficacious dosages, short duration of the studies, low methodology quality of the available clinical trials. The low interest of industries to invest large amounts of money in outcome study on products that could not be exclusive is probably an important reason, as well. In the future, the increased availability and reduced cost of validated and standardized laboratory and instrumental CVD risk biomarkers could improve the possibility to discover new pleiotropic effects of lipid-lowering nutraceuticals. Moreover these compounds, usually easily available in the market, need to be long-term tested and evaluated on larger patient samples in clinical practice setting.

Clinicians should be informed about nutraceuticals efficacy and safety, in order to use them as preventive tools in non-complicated MetS patients or as additive tools to potentiate more conventional treatments in high-risk subjects. They should also be able to give the consumer full information about the product that he is assuming.

Solutions and polypills of nutraceuticals, associated with a healthy lifestyle, can be the future of the prevention of Mets and the next step is to evaluate its cost/effectiveness, appropriate dosages and side effects in the long term.

Conclusions

MetS is a medical priority worldwide that requires better preventive and therapeutic strategies. In addition to a pharmacological treatment for patients with severe MetS, the use of phytochemicals in the prevention and treatment of subjects with borderline parameters can be useful to avoid the progression of the disease as well as to limit the side effects of drug intake.

MetS's risk factors, i.e. hypertension, dyslipidaemia, obesity and insulin-resistance, are biologically interrelated in the development of the pathology and it is consequently necessary to treat all of them to increase the effectiveness of the therapy. Furthermore, patients with MetS can present different patterns of this syndrome and the need of a tailored therapy based on the individual's pathologies and a specific combination of phytochemicals is very important.

Although there are many studies on single nutraceuticals components (Table 2), only a few describe the use of phytochemicals on multiple components of MetS and they have often short duration or low methodology quality. Consequently, further well-designed and sufficiently powered randomized clinical trials with a large and heterogeneous sample of people at risk for MetS are needed to evaluate which are the best nutraceuticals available and to better understand their mechanism of action both alone and in compounds (possible synergistic effects). It is also necessary to evaluate their cost/effectiveness ratio and to confirm their efficacy and safety in the middle-long term.

ARTICLE INFO

Article history:

Received 10 August 2015

Revised 14 November 2015

Accepted 19 November 2015

Conflict of interest

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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Arrigo F.G. Cicero *, Alessandro Colletti

Diseases Research Center, Medicine & Surgery Dept., Alma Mater Studiorum Atherosclerosis and Metabolic University of Bologna, Bologna, Italy

Abbreviations: ACE, angiotensin converting enzyme; ALA, alpha-linoleic acid; AMPK, AMP-activated protein kinase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FPG, fasting plasma glucose; GLP-1, glucagon like peptide-1; GLUT, glucose transporter; HbAlc, glycated haemoglobin; HBF-4-alpha, hepatic nuclear factor 4-alpha, HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; MAPK, mitogen-activated protein kinase; MetS, metabolic syndrome; NFkB, nuclear factor Kappa-B; NO, nitric oxide; OGTT, 75-g glucose tolerance test; PCSK9, proprotein convertase subtilisin/kexin type 9; PGG, penta-O-galloyl-glucopyranose; PPAR, peroxisome proliferator-activated receptor; PUFAs, polyunsaturated fatty acids; RBP-4, retinol binding protein-4; TG, triglcyerides; TGF-beta, transforming growth factor-beta; WMD, weighted mean difference.

* Corresponding author at Sant'Orsola-Malpighi University Hospital, Building 2-IV Floor, Via Albertoni 15,40138 Bologna, Italy. Tel.: +39 512142224; fax: +39 51390646.

E-mail address: arrigo.cicero@unibo.it, afgcicero@gmail.com (A.F.G. Cicero).

http://dx.doi.org/10.1016/j.phymed.2015.11.009

Table 1 Clinical studies on nutraceuticals in diabetes mellitus and
metabolic syndrome.

Reference              Intervention             Participants (n)

Vitamin C (ascorbic
acid)

Chenet al. (2006)      Vitamin C (800 mg/day)   Subjects with T2DM
                                                with low plasma
                                                vitamin C (<40/
                                                [micro]M)(32)

Dakhale et al.         Vitamin C (1 g/day)      Type 2 DM subjects
(2011)                 with metformin or        (70)
                       placebo with metformin

Vitamin E ([alpha]-
tocopherol)

The Heart Outcomes     Vitamin E (400 IU        Subjects with high
Prevention             daily) or placebo and    risk for
Evaluation Study       an angiotensin-          cardiovascular
Investigators (2000)   converting-enzyme        disease, in particular
                       inhibitor (ramipril)     with cardiovascular
                       or placebo               disease or diabetes in
                                                addition to one other
                                                risk factor. (9541)

Sesso et al. (2008)    Vitamin E (400 IU        Male physicians
                       every other day) vs.     (14,641)
                       placebo or Vitamin C
                       (500 mg daily) vs.
                       placebo

Vitamin D

Pittas et al. (2007)   Calcium citrate (500     Non diabetic Caucasian
                       mg) + vitamin D3 (700    adults aged > 65 years
                       IU daily)                (314)

Pilz et al. (2015)     Vitamin D3 (2800 IU      Subjects with arterial
                       daily as oily drops)     hypertension and 25-
                       or placebo               hydroxyvitamin D
                                                levels below 30 ng/mL
                                                (200)

Zhouet al. (2014)      Vitamin D3 (0.50         Subjects with T2DM
                       [micro]g daily)          (164)

Flavonoids

Dower et al. (2015)    Epicatechin (100 mg/     Subjects with BP
                       d), quercetin-3-         between 125-160 mm Hg
                       glucoside (160 mg/d)     (37)
                       or placebo

West et al. (2014)     Active group: 37 g/d     Overweight adults(30)
                       of dark chocolate and
                       a sugar/free cocoa
                       beverage (total cocoa
                       = 22 g/d, total
                       flavanols (TF) = 814
                       mg/d); control group:
                       low-flavanol chocolate
                       bar and a cocoa-free
                       beverage with no added
                       sugar (TF = 3 mg/d)

Minket al. (2007)      Total flavonoids         Postmenopausal women
                       intake: 0.6-133.1 mg/    (34,489)
                       day 133.2-201.8 mg/
                       day 201.9-281.9 mg/
                       day 282.0-425.2 mg/
                       day 4253-3524.4 mg/
                       day

Omega-3 fatty acids

Tsitouras et al.       Fatty fish (720 g-       Healthy men and women
(2008)                 week) + sardine oil      (12)
                       (15 mL-day; 4-5 g n-
                       3) or olive and corn
                       oil

Oh et al. (2014)       n-3 fatty acids (1,2     Healthy subjects and
                       or 4 g daily) or         patients with
                       placebo.                 metabolic syndrome,
                                                T2DM (44)

Farsi et al. (2014)    n-3 fatty acids (4 g     Patients with T2DM
                       daily) or placebo        (44)

Chromium

Kleefstra et al.       Chromium picolinate      Type 2 DM subjects
(2006)                 (500 or 1000 [micro]g/   with HbA1C [greater
                       day) or placebo          than or equal to] 8%,
                                                and age <75 years(46)

Magnesium

Rodriguez-Moran        MgC12 5% solution        Metabolically obese,
(2014)                 (equivalent to 382 mg    normal-weight
                       of magnesium) or         individuals (47)
                       placebo

Zinc plus
antioxidants
formulation

Evans and Henshaw      Zinc sulfate 200 mg      Subjects from the
(2008)                 daily                    general population
                                                with AMD at different
                                                stages (969)

[alpha]-Lipoic acid

Jacob et al. (1999)    600 mg/day 1200 mg/      Subjects withT2DM (72)
                       day 1800 mg/day

Huerta et al. (2015)   EPA (1.3 g/d),           Overweight/obese women
                       [alpha]-lipoic acid      (174)
                       (0.3 g/d),
                       EPA+[alpha]-lipoic
                       acid (1.3 g/d+0.3 g/d

Phytoestrogens

Ikeda et al. (2006)    Fermented Soy Bean (40   Pre-and postmenopausal
                       g of natto)              women (944)

Acharjee (2015)        Active group: diet       Postmenopausal women
                       with 0.5 cup of soy      (60)
                       nuts (25 g of soy
                       protein and 101 mg of
                       aglycone isoflavones)
                       that replaced 25 g of
                       nonsoy protein daily.
                       Control group: diet
                       alone.

Dietary fiber
supplements
(soluble)

Wolf et al. (2003)     OGTT (50 g of            Healthy subjects (30)
                       available carbohydrate
                       from maltodextrin and
                       white bread) or the
                       same meal with either
                       5 g of guar gum (3.6 g
                       galactomannan), 5 g of
                       fructose, or 5 g guar
                       gum + 5 g of fructose

Dall'Alba (2013)       Partially hydrolysed     Patients with T2DM
                       guar gum (10 g daily)    (44)

Dietary fiber
supplements
(insoluble)

Gruendel et al.        200 mL water w/50 g      Healthy subjects (20)
(2007)                 glucose and 5, 10, or
                       20 g carob fiber

Reference              Duration of    Outcome measures
                       intervention

Vitamin C (ascorbic
acid)

Chenet al. (2006)      4 weeks        FPG, FPI, Forearm
                                      blood flow

Dakhale et al.         12 weeks       FPG, PPBG, HBA1c
(2011)

Vitamin E ([alpha]-
tocopherol)

The Heart Outcomes     4,5 years      Major CV events
Prevention
Evaluation Study
Investigators (2000)

Sesso et al. (2008)    10 years       CV events

Vitamin D

Pittas et al. (2007)   3 years        FPG, IS

Pilz et al. (2015)     8 weeks        BP, Cardiovascular
                                      risk factors

Zhouet al. (2014)      12 weeks       BMI, WC, FPG, FPI,
                                      HbAlC, HOMA-IR, IR

Flavonoids

Dower et al. (2015)    4 weeks        Vascular function and
                                      cardiometabolic health

West et al. (2014)     4 weeks        CVD risk Endothelial
                                      function

Minket al. (2007)      16 years       CV and all-cause
                                      mortality

Omega-3 fatty acids

Tsitouras et al.       8 weeks        FPG, Insulin
(2008)                                concentration

Oh et al. (2014)       2 months       Tryglicerides, Insulin
                                      sensitivity

Farsi et al. (2014)    10 weeks       Non-esterified fatty
                                      acid concentration,
                                      insulin sensitivity
                                      and resistance,
                                      glucose and lipid
                                      metabolism

Chromium

Kleefstra et al.       6 months       Weight, BP, HbA1c
(2006)                                lipid profile

Magnesium

Rodriguez-Moran        4 months       BP, HOMA-IR, FG,
(2014)                                triglycerides

Zinc plus
antioxidants
formulation

Evans and Henshaw                     Risk of progression to
(2008)                                advanced AMD

[alpha]-Lipoic acid

Jacob et al. (1999)    4 weeks        FPG, IS

Huerta et al. (2015)   10 weeks       Body weight,
                                      anthropometric
                                      measurements, body
                                      composition.

Phytoestrogens

Ikeda et al. (2006)    3 years        Weight BMI

Acharjee (2015)        8 weeks        BP, lipid levels,
                                      adhesion molecules and
                                      inflammatory markers

Dietary fiber
supplements
(soluble)

Wolf et al. (2003)                    Baseline-adjusted peak
                                      glucose response

Dall'Alba (2013)       6 weeks        CV risk factors

Dietary fiber
supplements
(insoluble)

Gruendel et al.                       Plasma glucose Serum
(2007)                                insulin

Reference              Main results

Vitamin C (ascorbic
acid)

Chenet al. (2006)      No significant effect

Dakhale et al.         Significant reduction
(2011)                 in all parameters

Vitamin E ([alpha]-
tocopherol)

The Heart Outcomes     No apparent effect on
Prevention             cardiovascular
Evaluation Study       outcomes.
Investigators (2000)

Sesso et al. (2008)    The supplementation
                       doesn't reduce the
                       risk of major CV
                       events

Vitamin D

Pittas et al. (2007)   The supplementation
                       attenuates the
                       increases in glycemia
                       and IR

Pilz et al. (2015)     No significant effects
                       on blood pressure and
                       CV risk factors

Zhouet al. (2014)      Significant
                       improvement in all
                       parameters

Flavonoids

Dower et al. (2015)    Epicatechin improved
                       FPI and IR. There were
                       not other significant
                       results neither with
                       the supplementation
                       with epicatechin
                       either with quercetin-
                       3-glucoside.

West et al. (2014)     Enhanced vasodilation
                       and significant
                       reductions in arterial
                       stiffness in women.

Minket al. (2007)      Reduced risk in death
                       due to CV and all
                       causes

Omega-3 fatty acids

Tsitouras et al.       No change in FPG and
(2008)                 insulin Improved IR in
                       3 h OGTT (continued on
                       next page)

Oh et al. (2014)       Significantly
                       decreased
                       triglycerides and
                       improved flow-
                       mediated dilation. No
                       improvements of acute-
                       phase reactants and
                       insulin sensitivity

Farsi et al. (2014)    Improved insulin
                       sensitivity, decreased
                       non-esterified fatty
                       acid concentrations.

Chromium

Kleefstra et al.       No differences between
(2006)                 the three groups

Magnesium

Rodriguez-Moran        Improved the metabolic
(2014)                 profile and blood
                       pressure

Zinc plus
antioxidants
formulation

Evans and Henshaw      Modest benefit
(2008)

[alpha]-Lipoic acid

Jacob et al. (1999)    Increase in IS with
                       600 mg/day may be the
                       maximum effective dose

Huerta et al. (2015)   Promote body weight
                       loss

Phytoestrogens

Ikeda et al. (2006)    No effects

Acharjee (2015)        In women with MetS
                       significant reductions
                       in diastolic BP, TG,
                       C-reactive protein and
                       sICAM

Dietary fiber
supplements
(soluble)

Wolf et al. (2003)     The peak of glucose
                       response is reduced
                       with guar gum and
                       increased with
                       fructose

Dall'Alba (2013)       Reduced WC, HbA1c, UAE
                       and serum trans-fatty
                       acids (FA)

Dietary fiber
supplements
(insoluble)

Gruendel et al.        Increase in PPBG and
(2007)                 insulin response with
                       10 g of carob fiber
                       (no further increase
                       with 20 g)

BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose;
FPI, fasting plasma insulin, OGTT, oral glucose tolerance test;, PPBG,
post prandial plasma glucose, DM, diabetes mellitus; CV,
cardiovascular; IR, insulin resistance; IS, insulin sensitivity; AMI,
acute myocardial infarction; AMD, age-related macular degeneration,
UAE= 24 h urinary albumin excretion, WC, waist circumference.

Table 2
Phytochemicals and their effect on MetS.

Phytochemicals   Effects on MetS                  Level of evidence

Psyllium husk    Lipid-lowering, anti-obesity,    Meta-analyses of RCT
                   anti-diabetic,                   in humans
                   anti-hypertensive

Guar gum         Lipid-lowering,                  RCT in humans
                   insulino-resistance,
                   anti-diabetic,
                   anti-hypertensive

Fibres from      Lipid-lowering, hypoglycaemic    RCT in humans
  fenugreek

Chitosan         Lipid-lowering, anti-obesity,    RCT in humans
                   anti-diabetic,
                   anti-hypertensive

Glucomannan      Lipid-lowering, anti-obesity,    Meta-analyses of RCT
                   anti-diabetic                    in humans

Cinnamon         Lipid-lowering, anti-diabetic,   Meta-analyses RCT in
                   anti-hypertensive                humans

Berberine        Lipid-lowering,                  Meta-analyses of RCT
                   insulin-sensitizer,              in humans
                   anti-hypertensive

Corosolic Acid   Lipid-lowering, anti-diabetic,   RCT in humans
                   anti-obesity

Charantin        Insulin-sensitizer,              RCT in humans
                   hypoglycaemic, anti-obesity,

Catechins and    Lipid-lowering,                  Meta-analyses of RCT
  flavonols        anti-hypertensive,               in humans
                   anti-obesity

Omega-3 PUFA     Lipid-lowering,                  Meta-analyses of RCT
                   anti-hypertensive,               in humans
                   insulin-sensitizer,
                   anti-obesity

Alliin           Lipid-lowering, anti-diabetic,   Meta-analyses of RCT
                   insulin-sensitizer,              in humans
                   anti-obesity,
                   anti-hypertensive

Soy peptides     Lipid-lowering, anti-diabetic,   RCT in humans
                   anti-hypertensive,
                   anti-obesity

Curcumin         Lipid-lowering,                  RCT in humans
                   insulin-sensitizer,
                   hypoglycaemic, anti-obesity,
                   anti-hypertensive

RCT, randomized clinical trials.


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Author:Cicero, Arrigo F.G.; Colletti, Alessandro
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Oct 15, 2016
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