Potential role of phytochemicals in metabolic syndrome prevention and therapy

Figures & data

Table 1 Definitions of metabolic syndrome

WHO 1999	IGT or DM, and/or IR, together with two or more of the following criteria: HDL-cholesterol <0.9 mmol/L (35 mg/dL) in men, <1.0 mmol/L (40 mg/dL) in women Triglycerides >1.7 mmol/L (150 mg/dL) Waist/hip ratio >0.9 (men) or >0.85 (women) or BMI > 30 kg/m Blood pressure >140/90 mmHg
NCEP ATP III 2001	Three or more of the following criteria: Blood glucose greater than 5.6 mmol/L (100 mg/dL) or drug treatment for elevated blood glucose HDL-cholesterol <1.0 mmol/L (40 mg/dL) in men, <1.3 mmol/L (50 mg/dL) in women or drug treatment for low HDL-C Blood triglycerides >1.7 mmol/L (150 mg/dL) or drug treatment for elevated triglycerides Waist >102 cm (men) or >88 cm (women) Blood pressure >130/85 mmHg or drug treatment for hypertension
AHA/NHLBI 2004	Three or more of the following criteria: Waist circumference >102 cm in men and >88 cm in women Blood pressure ≥130/≥85 mmHg or specific medication Triglyceride plasma level ≥150 mg/dL (1.7 mmol/L) HDL-cholesterol <40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women Fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or history of diabetes mellitus or taking antidiabetic medications
IDF 2005	IDF definition are very similar to NCEP ATP III except in the waist parameter of 102 vs 94 cm in men and 88 vs 80 cm in women.

Abbreviations: AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol; IDF, International Diabetes Federation; IGT impaired glucose tolerance; IR, insulin resistance; NCEP ATP III, Cholesterol Education Program Adult Treatment Panel III.

Table 2 Phytochemicals and metabolic syndrome: clinical trials

Aim	Treatment	Result	Reference
Catechins
To evaluate the effect of catechins on body fat reduction	Oolong tea with green tea extract (690 mg catechins daily) or oolong tea containing (22 mg catechins daily) for 12 weeks	BW, BMI, waist circumference, body fat mass and subcutaneous fat area were significantly lower in the green tea extract group than in the control group	^Citation32
To compare the effects of supplementation of green tea on BW, blood glucose and lipid profile, and oxidative stress in obese subjects with MetS	Green tea (4 cups daily), or green tea extract (2 capsules and 4 cups water/d) for 8 weeks	Green tea beverage consumption or extract supplementation significantly decreased BW and BMI. Green tea beverage lowered lipid peroxidation versus controls	^Citation34
To evaluate the effects of green tea extract on the lipid profile, blood glucose and antioxidant status of obese patients	379 mg of green tea extract (EGCG 208 mg) daily for 3 months	Green tea extract supplementation induced the reduction of BMI, waist circumference, TC, LDL-C, TG, and increased the total antioxidant level	^Citation35
To investigate the effect of dietary supplementation with EGCG on IR and associated metabolic risk factors in man	400 mg capsules of EGCG twice daily for 8 weeks	EGCG treatment had no effect on insulin sensitivity, IR or glucose tolerance but reduced diastolic BP	^Citation41
To investigate the effect of a green tea–caffeine mixture on BW maintenance after BW loss in moderately obese subjects	Green tea–caffeine mixture (EGCG 270 mg +150 mg caffeine per day) or placebo.	High caffeine intake was associated with BW loss. In habitual low caffeine consumers, the green tea–caffeine mixture improved BW maintenance, partly through thermogenesis and fat oxidation	^Citation45
Anthocyanins
To evaluate the freeze-dried strawberry supplementation in improving BP, plasma glucose level, and dyslipidemia in obese subjects with MetS	4 cups of freeze-dried strawberry beverage (50 g freeze-dried strawberries approximately 3 cups fresh strawberries) daily for 8 weeks	Strawberry supplementation significantly decreased TC and LDL-C, small low-density lipoprotein particles, and circulating levels of vascular cell adhesion molecule. Serum glucose, TG, HDL-C, BP and waist circumference were not affected	^Citation56
To investigate the apple and blackcurrant polyphenol-rich drinks in reducing postprandial blood glucose, insulin, C-peptide and GIP concentration	2 polyphenol-rich drinks containing fruit extracts: either apple polyphenols 1200 mg or apple polyphenols 600 mg + blackcurrant anthocyanins 600 mg	Polyphenol-rich drinks significantly decreased postprandial blood glucose, insulin, C-peptide and GIP	^Citation61
To determine the modulation of lipid and glucose metabolism, oxidative stress and inflammation, by an açaí beverage	25 mL twice per day of a placebo control or açaí beverage (1139 mg/L gallic acid equivalents of total polyphenolics) for 12 weeks	Plasma level of interferon gamma and urinary level of 8-isoprostane, were significantly decreased after 12 weeks of açaí consumption compared to the placebo control. No significant modification of biomarkers for lipid and glucose metabolism was observed	^Citation63
Proanthocyanidins
To evaluate the acute effects of solid dark chocolate and liquid cocoa intake on endothelial function and BP in overweight adults	In phase 1: solid dark chocolate bar (containing 22 g cocoa powder) or a cocoa-free placebo bar. In phase 2: sugar-free cocoa (containing 22 g cocoa powder), sugared cocoa (containing 22 g cocoa powder) or a placebo	Solid dark chocolate and liquid cocoa ingestion improved endothelial function (measured as flow-mediated dilatation). BP decreased after the ingestion of dark chocolate and sugar-free cocoa compared with placebo	^Citation68
To compare the effects of either dark or white chocolate bars on BP and glucose and insulin responses to an oral-glucose-tolerance test in healthy subjects	100 g dark chocolate bars, which contained approximately 500 mg polyphenols, or 90 g white chocolate bars for 15 days	HOMA-IR was significantly lower and QUICKI was significantly higher after dark than after white chocolate ingestion. Systolic BP was lower after dark than after white chocolate ingestion	^Citation74
To evaluate the effects of 3-month treatment with epicatechin-rich cocoa in oxidative stress.	18 g of natural cocoa powder (100 mg epicatechin) daily for 3 months	Treatment with with epicatechin-rich cocoa increased the glutathione levels and decreased the nitrotyrosilation and carbonylation of proteins	^Citation76
To examine the effects of chocolate on lipid profiles, weight and glycemic control in individuals with type 2 diabetes	45 g chocolate with or without a high polyphenol content for 8 weeks	HDL-C increased significantly with high polyphenol chocolate with a decrease in the TC:HDL-C ratio. No changes were seen in BW nor in glycemic control	^Citation77
Curcumin
To evaluate the effect of a curcumin extract for 12 weeks on BW, blood glucose, and lipid profiles in patients with MetS	Turmeric extract capsule (630 mg of curcumin) thrice daily	HDL-C and TG significantly increased and the LDL-C significantly reduced after 12 weeks of treatment. BW and glucose homeostasis did not improve	^Citation85
To evaluated the effect of curcuminoids plus piperine on glycemic, hepatic and inflammatory biomarkers in type 2 diabetes patients	Curcuminoids 500 mg/day co-administered with piperine (5 mg/day) or placebo for 3 months	Significant reduction in serum levels of blood glucose, HbA1c, C-peptide and transaminases in curcuminoids compared with the placebo group	^Citation90
To test the effect of phosphatidylserine- and piperine-containing curcumin phytosomes on metabolic parameters related to IR	Phytosomal curcumin (curcumin 200 mg, phosphatidylserine 120 mg, phosphatidylcholine 480 mg and piperine 8 mg) for 8 weeks	In the curcumin group fasting plasma insulin, HOMA-IR, BW, TG, HDL-C, liver transaminases, gamma-GT, index of liver steatosis and serum cortisol improved compared to the baseline. Fasting plasma insulin, TG, liver transaminases, fatty liver index and serum cortisol level also significantly improved compared with the placebo-treated group	^Citation91

Abbreviations: BMI, body mass index; BP, blood pressure; BW, body weight; EGCG, epigallocatechin gallate; GIP, gastrointestinal peptide; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment insulin resistance; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.

Table 3 Effects of plant substances on the components of metabolic syndrome and associated conditions

Components	Plants/substances	Mechanisms	References
Abdominal obesity	Caffeine	Adrenergic stimulation	^Citation36,Citation38
	Tea (catechins)	Adrenergic stimulation	^Citation33^–^Citation35
Impaired glucose tolerance	Berries (anthocyanins, flavonoids, stilbenes)	Slowing carbohydrate digestion and absorption; stimulating insulin secretion via AMPK pathway; decreasing cell oxidative damage	^Citation62
	Pomegranate (ellagitannins, anthocyanins) Cocoa Curcuma (curcumin) Olive oil (polyphenols)	Inhibition of α-glucosidase; increasing glucose transporter type 4 activity^Citation64 Slowing carbohydrate digestion and absorption; stimulation of incretin response; improvement of insulin signaling, modulation of gut microbiota. Improvement of IR via TNFα reduction Slowing carbohydrate digestion and absorption; improvement of IR via anti-inflammatory activity	^Citation64 ^Citation73,Citation74,Citation78,Citation79 ^Citation87,Citation96 ^Citation95
Hypertriglyceridemia	Olive oil (MUFAs, polyphenols)	Increasing VLDL catabolism	^Citation95,Citation96
Low levels of HDL-C	Curcuma (curcumin)? Olive oil (polyphenols)	-Improvement of HDL metabolism	^Citation85,Citation86,Citation91 ^Citation95^–^Citation97
High blood pressure	Cocoa (catechins, proanthocyanidins, flavonols) Pomegranate (ellagitannins, anthocyanins) Olive oil (polyphenols)	Activation of endothelial NO synthase; inhibition of angiotensin-converting enzyme Reduction of serum angiotensin-converting enzyme (ACE) activity Increasing NO levels Increasing NO levels	^Citation67^–^Citation72 ^Citation95
Associated conditions
Fatty liver	Curcuma (curcumin) Milk thistle	Antioxidant and antiinflammatory effects; inhibition of fibrogenesis	^Citation90,Citation91 ^Citation104
Chronic inflammation	Tea, catechins Berries (anthocyanins, flavonols,stilbenes) Pomegranate (ellagitannins, anthocyanins) Cocoa (catechins, proanthocyanidins, flavonols) Curcuma (curcumin) Olive oil (polyphenols)	Modulation signaling of inflammatory response pathways, antioxidant activity NF-kB suppression Modulating peroxisome proliferator-activated receptor pathways Modulation of toll-like receptor pathway Reduction of TNFα; inhibition of COX and LOS Inhibition of COX; reduction of inflammatory gene expression	^Citation51,Citation52 ^Citation63 ^Citation64 ^Citation69 ^Citation97
LDL-C/small LDL	Tea, catechins Berries (anthocyanins, flavonoids, stilbenes) Phytosterols	Reduction of lipid intestinal absorption, upregulation of LDL receptors; protection of lipid from oxidative damage Inhibition of cholesterol synthesis via activation of AMPK Inhibition of intestinal cholesterol absorption	^Citation34,Citation35,Citation46^–^Citation48 ^Citation60,Citation61,Citation63 ^Citation130,Citation132^–^Citation135

Abbreviations: AMPK, 5ʹ adenosine monophosphate kinase; COX, cyclooxygenase; HDL-C, high-density lipoprotein cholesterol; IR, insulin resistance; LOS, lipooxygenase; MUFAs, monounsaturated fatty acids; NAFLD, nonalcoholic fatty liver disease; NF-kB, nuclear factor kB; NO, nitric oxide; TNFα, tumor necrosis factor alpha; VLDL, very low-density lipoprotein.

Figure 1 Effect of natural bioactive compounds on the main features of MetS.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; cAMP, cyclic adenosine monophosphate; COMT, catechol-O-methyl transferase enzyme; EGCG, epigallocatechin gallate; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment insulin resistance; IR, insulin resistance; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; NAFLD, non alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NF-kB, nuclear factor kB; PAI-1, plasminogen activator inhibitor-1; PC, policosanol; TG, triglycerides; TNFα, tumor necrosis factor alpha.

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