Berry Fruit Consumption and Metabolic Syndrome

Metabolic Syndrome is a cluster of risk factors which often includes central obesity, dyslipidemia, insulin resistance, glucose intolerance, hypertension, endothelial dysfunction, as well as a pro-inflammatory, pro-oxidant, and pro-thrombotic environment. This leads to a dramatically increased risk of developing type II diabetes mellitus and cardiovascular disease, which is the leading cause of death both in the United States and worldwide. Increasing evidence suggests that berry fruit consumption has a significant potential in the prevention and treatment of most risk factors associated with Metabolic Syndrome and its cardiovascular complications in the human population. This is likely due to the presence of polyphenols with known antioxidant and anti-inflammatory effects, such as anthocyanins and/or phenolic acids. The present review summarizes the findings of recent dietary interventions with berry fruits on human subjects with or at risk of Metabolic Syndrome. It also discusses the potential role of berries as part of a dietary strategy which could greatly reduce the need for pharmacotherapy, associated with potentially deleterious side effects and constituting a considerable financial burden.


Metabolic Syndrome: General Overview
Metabolic Syndrome is characterized by the simultaneous presence of multiple risk factors, which are a direct or indirect consequence of both insulin resistance and overweight/obesity [1]. Although it is not a disease in itself, this combination of health problems dramatically increases the risk of developing type II diabetes mellitus and cardiovascular disease [2].
The US National Cholesterol Education Program-Adult Treatment Panel III (ATPIII) defines Metabolic Syndrome as the combined occurrence of at least three of the following five risk factors: abdominal obesity (waist circumference ≥102 cm in males, ≥88 cm in females); high blood triglycerides (≥150 mg/dL); low HDL cholesterol (≤40 mg/dL in males, ≤50 mg/dL in females); high diastolic and/or systolic blood pressure (≥130/85 mmHg) and high fasting blood glucose (≥100 mg/L) [2].
Together with these diagnostic parameters, which were selected because of their widespread use in the clinical setting, a plethora of other dysfunctional states are often associated with Metabolic Syndrome. Although they are not used for diagnostic purposes, they significantly contribute to the increased cardiovascular risk and the onset of type II diabetes mellitus [2]. In particular, Metabolic Syndrome is associated with a pro-oxidant, pro-inflammatory, and pro-thrombotic state [3,4].
Flavonols, 3-hydroxyflavones and tannins are also widespread in berries. Flavan-3-ols are a complex subclass of polyphenols without glycoside residues and with different levels of polymerization ranging from monomeric, oligomeric, and polymeric forms. Tannins include both condensed non-hydrolysable tannins known as proanthocyanidins, and esters of gallic and ellagic acids called hydrolysable tannins. Tannins play an essential role in defining the sensory properties of fresh fruit and fruit-derived products. They are responsible for the taste and changes in the color of fruit and fruit juice. Moreover, tannins stabilize ACNs by binding to form co-polymers. The amount of flavan-3-ols and proanthocyanidins in chokeberries, blueberries, and strawberries varies from 150 mg to 700 mg/100 g, while in blackberries and raspberries the amount is about 300 mg/100 g [13].
During recent years, a multitude of clinical research studies have focused on the health properties of berries. In particular, increasing attention has been devoted to the role of berries and their components in the modulation of oxidative stress [14], vascular function [15], inflammation, and lipid metabolism [16]. In addition, research studies have explored the role of berries on chronic diseases such as cardiovascular diseases, diabetes, and obesity with promising, albeit preliminary, results. Several studies have also investigated the effect of berry consumption on their ability to modulate/attenuate risk factors associated with Metabolic Syndrome.
A search of the literature on intervention studies investigating the effect of berry consumption in the modulation of Metabolic Syndrome and/or related risk factors was carried out. Abstracts and full texts from human acute and chronic intervention studies were screened. PUBMED, ScienceDirect, and ScholarGoogle databases were searched to identify articles published later than 1 January 2000. The searches used the following terms and text words alone and in combination: "berry", "Metabolic Syndrome", "overweight", "obesity", "hypertension", "hypercholesterolemia", "hyperlipemia", "Type II diabetes", and "humans". Interventions conducted in healthy subjects (not presenting any of the risk factors characterizing Metabolic Syndrome) were excluded. Reference lists of the obtained articles were also searched for related articles. The search was limited to English-language articles. A total of 45 articles were obtained from the database searches and from their reference lists. Four papers were excluded because studies were performed with a mix of fruits and vegetables and other foods in which berries did not constitute the main food [17][18][19][20]. Therefore after exclusions, a total of 41 studies were included in the review ( Figure 1). Thirty-four explored a medium-long term intervention, four were post-prandial while three investigated both or performed a chronic intervention followed by an acute study. Here, we summarize the main results of the human studies. The results obtained are also reported in Table 1, describing the type of food or supplement, number of intervention days, number of subjects and their characteristics, dose/day of test food, the use of control/placebo food, and the significant findings.

Figure 1.
A flow chart highlighting study selection. * Studies were identified according to the following keywords: "berry", "Metabolic Syndrome", "overweight", "obesity", "hypertension", "hypercholesterolemia", "hyperlipemia", "Type II diabetes", and "humans". ** Studies were excluded because they used a mix of fruit and vegetables and other foods in which berries were not the main food.

Blueberry
Depending on the size of the shrubs, blueberries are classified as either lowbush ('wild') or highbush: Vaccinium corymbosum, a highbush blueberry, is the most commonly cultivated species around the world, while Vaccinum angustifolium, native to North America, is the most widespread species of wild blueberry [62]. Anthocyanins are the distinctive and most abundant class of phenolic compounds in blueberries, and wild blueberries contain higher amounts of anthocyanins compared to highbush blueberries. Blueberries also contain significant amounts of phenolic acids, flavonols and flavan-3-ols, as well as manganese [63].
In an 8-week, controlled, randomized intervention, 48 middle-aged, obese subjects with Metabolic Syndrome were given a daily blueberry drink made with 50 g freeze-dried blueberries, resulting in significantly lower systolic and diastolic blood pressure, plasma oxidized LDLs, and malondialdehyde (MDA) and 4-hydroxynonenal (HNE) concentrations. No significant changes were observed for cholesterol and triglyceride levels, inflammatory markers CRP, adiponectin and IL-6, or adhesion molecules ICAM-1 and VCAM-1 [25].
In a 6-week, placebo-controlled, randomized intervention, 27 obese, insulin-resistant subjects received a daily smoothie made with 45 g of blueberry powder, which resulted in improved insulin sensitivity but did not affect markers of inflammation, blood pressure, and blood lipid profile [24]. In a subsequent 6-week intervention with the same experimental design on 44 obese subjects with Metabolic Syndrome, endothelial function measured as peripheral arterial tone, significantly improved Figure 1. A flow chart highlighting study selection. * Studies were identified according to the following keywords: "berry", "Metabolic Syndrome", "overweight", "obesity", "hypertension", "hypercholesterolemia", "hyperlipemia", "Type II diabetes", and "humans". ** Studies were excluded because they used a mix of fruit and vegetables and other foods in which berries were not the main food.

Blueberry
Depending on the size of the shrubs, blueberries are classified as either lowbush ('wild') or highbush: Vaccinium corymbosum, a highbush blueberry, is the most commonly cultivated species around the world, while Vaccinum angustifolium, native to North America, is the most widespread species of wild blueberry [62]. Anthocyanins are the distinctive and most abundant class of phenolic compounds in blueberries, and wild blueberries contain higher amounts of anthocyanins compared to highbush blueberries. Blueberries also contain significant amounts of phenolic acids, flavonols and flavan-3-ols, as well as manganese [63].
In an 8-week, controlled, randomized intervention, 48 middle-aged, obese subjects with Metabolic Syndrome were given a daily blueberry drink made with 50 g freeze-dried blueberries, resulting in significantly lower systolic and diastolic blood pressure, plasma oxidized LDLs, and malondialdehyde (MDA) and 4-hydroxynonenal (HNE) concentrations. No significant changes were observed for cholesterol and triglyceride levels, inflammatory markers CRP, adiponectin and IL-6, or adhesion molecules ICAM-1 and VCAM-1 [25].
In a 6-week, placebo-controlled, randomized intervention, 27 obese, insulin-resistant subjects received a daily smoothie made with 45 g of blueberry powder, which resulted in improved insulin sensitivity but did not affect markers of inflammation, blood pressure, and blood lipid profile [24]. In a subsequent 6-week intervention with the same experimental design on 44 obese subjects with Metabolic Syndrome, endothelial function measured as peripheral arterial tone, significantly improved with blueberry consumption, while blood pressure and insulin sensitivity did not significantly change [22].
In a 6-week, placebo-controlled, cross-over, randomized intervention on 18 subjects with risk factors for cardiovascular disease receiving a daily blueberry drink made of 25 g wild blueberry powder, endogenous and ex vivo oxidatively-induced DNA damage in blood mononuclear cells was found to be significantly lower, but no changes were observed in blood lipid profile, markers of inflammation, and endothelial function [23].
In an 8-week, placebo-controlled, cross-over, randomized intervention on 48 overweight or obese hypertensive women, administration of a daily drink made with 22 g of blueberry powder resulted in significantly lower systolic and diastolic blood pressure and brachial-ankle pulse wave velocity, and higher plasma levels of nitric oxide, but no changes in the inflammatory marker CRP [21].
In conclusion, the effect of blueberries in the modulation of Metabolic Syndrome-related risk factors has been investigated in five interventions, documenting an effect on blood pressure, oxidative stress, endothelial function, and insulin sensitivity, but not on inflammatory marker levels or blood lipid profile.

Bilberry
Bilberries (Vaccinium myrtillus), the wild European blueberries, have a phenolic profile and content which is comparable to that of blueberries, and are also exceptionally rich sources of anthocyanins.
In a 4-week, controlled, randomized intervention, 62 subjects with risk factors for cardiovascular disease received 330 mL/day of bilberry juice, resulting in decreased serum concentrations of inflammatory markers CRP, IL-6, IL-15 and TNF-α, while markers of antioxidant status and oxidative stress remained unaffected [28].
When 100 g/day of fresh bilberries were given to 80 overweight or obese women with or without Metabolic Syndrome for 5 weeks, body weight, waist circumference and concentrations of VCAM-1 and TNF-α, but also adiponectin, significantly decreased, insulin and glycated hemoglobin concentrations increased, while fat percent, blood pressure, blood lipids, and IL-6 levels were not affected [27].
In an 8-week, controlled, randomized intervention, in 27 overweight or obese subjects with Metabolic Syndrome receiving 200 g/day of fresh bilberry purée and 40 g/day of dried bilberries, serum concentrations of inflammatory markers hs-CRP, IL-6, IL-12, and LPS decreased, with no changes in blood glucose and lipid profile [26].
Thus, the effect of bilberries on Metabolic Syndrome has not been fully investigated. To our knowledge, only three interventions focused on this berry, finding a consistent effect on reducing inflammation levels.
A randomized, placebo-controlled intervention administering six daily capsules of cranberry powder (equivalent to 240 mL cranberry juice) for 12 weeks to a group of 27 subjects with type 2 diabetes, did not detect any significant effect on blood glucose levels, glycated hemoglobin HbA1c, triglyceride or cholesterol levels [40].
A 2-week intervention on 21 dyslipidemic men with abdominal obesity, reported improved total plasma antioxidant capacity, and decreased BMI and plasma oxidized LDL levels following daily consumption of 7 mL/kg BW of cranberry juice. Blood pressure, plasma lipid profile, and inflammatory markers were not significantly affected [39].
When the effects of three different doses (125, 250, and 500 mL/day) of cranberry juice administered sequentially for four weeks each, were tested on a group of 30 middle-aged men with abdominal obesity, a significant reduction in body weight, BMI, waist circumference, total/HDL-cholesterol ratio and apolipoprotein B, and a significant improvement in plasma total antioxidant capacity were reported after 250 mL and/or 500 mL consumption. A significant decrease in plasma nitrite and nitrate, and increase in HDL cholesterol were reported only after the highest dose. No significant effect was observed at the lowest dose, and no effect on total, LDL and VLDL cholesterol was observed at any dose [38].
The same experimental design was tested on 30 middle-aged abdominally obese men, nine of which with Metabolic Syndrome. HDL cholesterol and oxidized LDLs improved after 250 and 500 mL cranberry juice consumption, while systolic blood pressure and plasma ICAM-1 and VCAM-1 concentrations decreased only at the highest dose, with a stronger effect in the subset of subjects with Metabolic Syndrome. No significant effect was observed at the lowest dose, and no effect on cholesterol, triglycerides, diastolic blood pressure, and plasma E-selectin was observed at any dose [35].
When the post-prandial effect of a single-dose of sweetened cranberry juice was compared to unsweetened cranberry juice in a group of 12 obese subjects with type 2 diabetes, only unsweetened cranberry juice resulted in reduced plasma insulin levels and glycemic response, compared to both a sweetened cranberry juice and an unsweetened control drink [37].
With a similar experimental design, the post-prandial effects of either raw cranberries, sweetened dried cranberries or dried cranberries sweetened with less sugar were tested in 13 obese subjects with type 2 diabetes. The effects of raw cranberries were the lowest on glycemic and insulinemic responses, with the less sweetened, dried cranberries significantly lower compared to the fully sweetened ones [34].
In a 12-week, placebo-controlled, randomized intervention, 30 older overweight subjects with type 2 diabetes received a daily capsule of 500 mg cranberry powder extract, resulting in lower total and LDL cholesterol, and total/HDL-cholesterol ratio. Blood glucose, insulin, and glycated hemoglobin HbA1c levels were unaffected, as well as CRP, blood pressure, oxidized LDLs, triglycerides, and HDL-cholesterol [36].
In a placebo-controlled, randomized intervention, 31 obese women with Metabolic Syndrome were given 480 mL/day of cranberry juice for eight weeks, resulting in reduced circulating levels of oxidized LDLs, malondialdehyde (MDA), and 4-hydroxynonenal (HNE), and improved total plasma antioxidant capacity, while blood pressure, blood lipid and glucose levels, and inflammatory markers did not change [33].
When a single-dose of 480 mL cranberry juice was administered to 15 subjects with coronary artery disease, post-prandial endothelial function measured as brachial artery flow-mediated dilation, it significantly improved (Dohadwala et al., 2011). When the same serving of cranberry juice was given daily to a group of 44 subjects with coronary artery disease in a 4-week, placebo-controlled, cross-over intervention, central aortic stiffness, measured as carotid-femoral pulse wave velocity, significantly decreased, as well as HDL-cholesterol levels. However, no changes were reported for total and LDL cholesterol, triglycerides, CRP, ICAM-1, blood pressure, carotid-radial pulse wave velocity or brachial artery flow-mediated dilation [32].
In a 12-week, placebo-controlled, randomized intervention on 58 middle-aged, overweight or obese subjects with type 2 diabetes, receiving 240 mL/day of cranberry juice, blood glucose, ApoB and ApoA1 concentrations significantly decreased, PON-1 activity increased, while lipoprotein(a) concentrations were unaffected [31].
When 56 overweight or obese subjects with Metabolic Syndrome were given 700 mL/day of low-calorie cranberry juice for four weeks, serum folic acid levels significantly increased while serum homocysteine levels, lipid and protein oxidation significantly decreased. Inflammatory markers CRP, TNF-α, IL-1, and IL-6 did not change [30].
Thirty five abdominally obese men with or without Metabolic Syndrome were given 500 mL/day of low-calorie 27% cranberry juice for four weeks in a placebo-controlled, cross-over intervention.
Measures of global endothelial function and arterial stiffness significantly decreased following cranberry consumption compared to baseline, but not compared to post-placebo (Ruel et al., 2013 [29]). Blood pressure and serum markers of endothelial function ICAM-a, VCAM-1 and E-selectin, as well as oxidized LDLs, did not change [29].
In summary, the effects of cranberries on markers of Metabolic Syndrome have been investigated in eleven interventions, resulting in a consistent effect on reducing oxidative stress, and some beneficial effects on BMI, blood cholesterol levels, and vascular function.

Raspberry
Black raspberry (Rubus occidentalis) is a flavonoid-rich member of the Rosaceae family common in Japan, China, and South Korea, where it is traditionally used to treat prostate and urinary diseases. It also contains significant amounts of tyrosol, resveratrol, tannins, and other phenolic acids [42].
In a 12-week, randomized, controlled intervention, a group of 77 Metabolic Syndrome patients received 750 mg/day of black raspberry powder in the form of capsules or a fiber-and sugar-matched control. Raspberry resulted in decreased total serum cholesterol and total/HDL-cholesterol ratio, with no other changes in serum lipid profile. Inflammatory markers IL-6 and TNF-α significantly decreased, and anti-inflammatory adiponectin significantly increased, while CRP, ICAM-1 and VCAM-1 were unaffected. Brachial artery flow-mediated dilation significantly improved [42].
In a controlled, cross-over intervention on a group of 10 older overweight or obese men, the short-term effect of relatively large amounts of lyophilized black raspberry powder (45 g/day for four days) was evaluated in countering the post-prandial inflammatory effects of a high fat meal. Serum IL-6 concentrations significantly decreased, but not TNF-α and CRP concentrations [41].
In conclusion, the impact of raspberry consumption on subjects with risk factor for Metabolic Syndrome has been evaluated in only two interventions, documenting some positive effects on blood cholesterol levels, inflammation and vascular function. Research is needed to investigate more fully the potential of this berry.

Chokeberry
Chokeberry (Aronia melanocarpa) is a violet-black, strongly-flavored berry, common in areas of North America and Eastern Europe. It is a rich source of polyphenols, particularly anthocyanins present in form of cyanidin-glucosides, but also caffeic acid, quercetin, procyanidins, and other flavonoids [46].
An 18-week intervention on a group of 58 overweight or obese men with mild hypercholesterolemia who were given 150 mL/day of chokeberry juice for two, 6-week long periods separated by a 6-week wash-out, resulted in decreased circulating levels of serum total and LDL cholesterol and increased serum HDL 2 cholesterol. Furthermore, serum triglycerides, glucose, homocysteine, and fibrinogen levels also significantly decreased, as well as blood pressure, while inflammatory markers hs-CRP protein and lipid peroxides were not affected [46].
Eight-week administration of 300 mg/day of chokeberry extract to a group of 52 middle-aged individuals with Metabolic Syndrome, resulted in decreased levels of serum total and LDL cholesterol, with no changes in total HDL cholesterol. Serum triglycerides were also significantly decreased, as well as parameters of platelet aggregation and coagulation [45].
A 4-week intervention on 20 middle-aged, obese women with 100 mL/day of a glucomannanenriched chokeberry juice resulted in decreased BMI, waist circumference and systolic blood pressure. However, no changes were observed in diastolic blood pressure, blood glucose levels, serum triglycerides, total and LDL cholesterol, with increased levels of HDL cholesterol. Membrane composition of erythrocytes was affected, with an increase in omega-3 polyunsaturated fatty acids and a decrease in monounsaturated fatty acids [44].
Four week administration of 200 mL/day of chokeberry juice to a group of 23 hypertensive subjects resulted in decreased systolic and diastolic blood pressure, but blood lipid profile, glucose and C-reactive protein levels were unaffected [43].
The effect of chokeberries on Metabolic Syndrome has been investigated in four intervention studies, documenting some positive but not consistent effects on blood cholesterol and triglyceride levels, blood pressure, and erythrocyte membrane fluidity. More research is needed to better investigate the effects of this berry.
Following a controlled 7-week, randomized, cross-over intervention, 28 hyperlipidemic subjects receiving a serving of strawberries (454 g/day) showed reduced LDL oxidative damage and a reduced LDL-cholesterol molar ratio compared to control. No significant effect was observed for plasma levels of conjugated dienes, lipid profile, C-reactive protein, blood pressure, and body weight [57].
An 8-week randomized, controlled trial on 27 subjects with Metabolic Syndrome receiving two cups of a strawberry beverage (composed of 25 g of freeze-dried strawberry powder each) daily for eight weeks, documented a reduction of total and LDL-cholesterol, small LDL particle size, and VCAM-1. No significant effect was observed for glucose, triglycerides, HDL-cholesterol, blood pressure, waist circumference, and ICAM-1 [55].
A 4-week intervention on 16 obese women with Metabolic Syndrome receiving two daily cups of a strawberry drink (composed of 25 g of freeze-dried strawberry powder each), reported a significant reduction in serum total and LDL-cholesterol levels, with no changes in HDL cholesterol, triglycerides, blood glucose levels and blood pressure. Lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (HNE) significantly decreased, but not plasma oxidized LDL, and inflammatory markers hs-CRP and adiponectin [56].
A placebo-controlled, randomized, crossover 6-week intervention on 24 middle-aged, overweight or obese hyperlipidemic subjects receiving a daily strawberry drink (composed of 10 g of freeze-dried strawberry powder) did not find any differences in fasting triglycerides, cholesterol or plasma oxidized LDL concentrations. However, when the postprandial response to a high-fat meal challenge was evaluated at the end of the intervention, subjects who were on the strawberry group had significantly lower triglycerides as well as total, LDL and HDL-cholesterol levels [54].
A placebo-controlled, randomized, 6-week intervention on 24 overweight subjects receiving the same strawberry drink, found no changes in serum glucose, insulin, hs-CRP, IL-6, PAI-1, IL-1β, and TNF-α concentrations. However, when a high carbohydrate and fat meal was given to the subjects at the end of the intervention, serum PAI-1, IL-1β levels were significantly lower in the strawberry group, but not serum glucose, insulin, hs-CRP, IL-6, and TNF-α levels [53].
When the post-prandial effect of a single-dose of the same strawberry drink was evaluated on a group of 26 overweight individuals consuming a high-carbohydrate moderate-fat meal, without any pre-intervention, serum hs-CRP, IL-6 and insulin levels were found to be significantly lower, but not PAI-1, IL-1β, TNF-α, and blood glucose concentrations [52].
Following a controlled 7-week, randomized, cross-over intervention, 20 obese individuals receiving two servings of strawberry powder (equivalent to 320 g/day of frozen strawberries) showed a significant reduction in serum total and small HDL-cholesterol concentrations and in LDL particle size. No changes in serum triglycerides and inflammatory markers and oxidative stress were observed, but serum fibrinogen concentrations decreased [51].
When a group of 36 overweight subjects with type 2 diabetes received 50 g/day of freeze-dried strawberry for six weeks in a placebo-controlled, randomized intervention, markers of total serum antioxidant status significantly increased while serum malondialdehyde (MDA), glycated hemoglobin HbA1c, and hs-CRP concentrations significantly decreased, and blood glucose levels remained unaffected [50].
In another controlled, randomized intervention, 36 overweight or obese subjects with type 2 diabetes received the same amount of freeze-dried strawberry for six weeks, resulting in a significantly lower diastolic blood pressure, but with no changes in systolic blood pressure as well as serum triglycerides and cholesterol levels [49].
In a 12-week, randomized, controlled intervention, 60 obese volunteers with risk factors for cardiovascular disease were assigned to either a low-dose or high-dose strawberry treatment (25 or 50 g freeze-dried strawberry powder in water, respectively), or a calorie-and fiber-matched control. At the end of the intervention, malondialdehyde (MDA) and 4-hydroxynonenal (HNE) significantly decreased with both doses, but a significant reduction in serum total and LDL-cholesterol, and derived small LDL particles, was only observed in the high-dose group. Serum glucose, glycated hemoglobin HbA1c, insulin, HDL, VLDL-cholesterol, HOMA-IR score, triglycerides, VCAM-1, ICAM-1, and hs-CRP did not change significantly [48].
When a single serving of freeze-dried strawberry powder at different doses (0, 10, 20 or 40 g) was given to a group of 21 abdominally obese subjects with insulin resistance, a significant reduction in post-prandial plasma insulin concentrations, insulin:glucose ratio, and rate of glucose and insulin increase was only observed after consumption of the highest dose. Interestingly, a significant reduction in plasma oxidized LDLs was observed after the 20 g dose, but not after the 40 g dose. Plasma glucose, triglycerides and IL-6 levels did not change at any dose [47].
Thus, ten studies focused on the role of strawberries on Metabolic Syndrome and its risk factors. Overall, strawberry consumption led to some improvements in oxidative stress, inflammatory status, blood lipid profile, and blood pressure, although these effects were not consistent.

Whortleberry
Caucasian whortleberry, or qaraqat (Vaccinium arctostaphylos), is a wild berry, common in Western Asia with high anthocyanin content [58]. In a 4-week, placebo-controlled, randomized intervention on 50 hyperlipidemic subjects, two daily capsules of whortleberry extract containing 45 mg of anthocyanins each, resulted in lower serum concentrations of total and LDL cholesterol, triglycerides, and MDA, without changes in HDL-cholesterol and inflammatory marker hs-CRP [47]. Due to the paucity of data regarding this berry, more research is needed to investigate its effects.

Berry Mix
Considering the positive results obtained from single-berry studies, some research groups tested the effect of a mix of berries in randomized interventions.
In a 12-week, placebo-controlled study on 133 older, borderline or hypertensive subjects, consumption of 500 mL/day of a juice made from red grapes, cherries, chokeberries, and bilberries resulted in significantly lower systolic blood pressure after six, but not after 12 week consumption , and no effect on diastolic pressure. When only the hypertensive sub-group was considered, the blood pressure lowering effect was more pronounced [59].
In a 12 week intervention on 20 overweight or obese subjects with Metabolic Syndrome risk factors, daily combined consumption of 100 g strawberry purée, 100 g of frozen raspberries, and 100 g of frozen cloudberries, resulted in lower serum leptin levels but did not affect blood pressure, serum lipid profile, resistin, and markers of oxidative stress [60].
In a 20 week intervention on 61 overweight or obese women with Metabolic Syndrome, a daily mix of 163 g of lingonberry, sea buckthorn berry, bilberry, and black currant resulted in higher anti-inflammatory adiponectin plasma concentrations, but did not affect blood pressure, blood lipid or glucose levels, markers of oxidative stress, and other markers of inflammation [61].
More studies investigating the effects of a mix of multiple berries would be useful, since berries are often commercialized in mixes, both as fresh products but above all in juices, smoothies, purees, and other products.

Remarks and Conclusions
In the US, more than one in every five adults meets the diagnostic criteria for Metabolic Syndrome [64]. In turn, this condition dramatically increases the risk of developing type II diabetes and suffering acute cardiovascular events, such as heart attacks or strokes [1]. Thus, finding economic and effective ways to prevent and reverse Metabolic Syndrome is of key importance for public health.
Several lines of evidence suggest that diet, together with regular physical activity and avoidance of smoking, is one of the most manageable ways of preventing the development of Metabolic Syndrome in the human population, and at the same time it is also a tool to mitigate the symptoms and decrease the risk of complications in patients who already suffer from this condition.
Furthermore, diet has the potential to greatly reduce the need for pharmacological treatment, which is inevitably associated with harmful side effects and constitutes a considerable financial burden. Being a multifactorial condition, the pharmacological approach to Metabolic Syndrome requires the use of multiple medications, to control a wide array of metabolic abnormalities ranging from dyslipidemia to hypertension, and from hypercholesterolemia to impaired blood glucose control. Thus, the risk of side effects is multiplied by the need of administering multiple medications, and the opportunity to be able to prevent or even control some of the same metabolic dysfunctions with lifestyle-including diet-becomes especially advantageous.
Mounting evidence suggests that consumption of dietary achievable amounts of berries, whose distinctive nutritional characteristic is the abundance of phenolic compounds, has the potential to affect several metabolic abnormalities related to Metabolic Syndrome.
When results of the dietary interventions reviewed in this article are considered together, it appears that the stronger and most recurrent effects of berry consumption lie in their anti-inflammatory and anti-oxidant effects. They also have a tendency to improve lipid profile, lowering total and LDL-cholesterol as well as triglycerides, but this outcome is not observed consistently. It is reasonable to speculate that inter-individual variability as well as interactions with the rest of the diet, are strong enough to mask the effects of berry consumption on lipid profile, and this seems to be confirmed by the observation that effects on blood lipids tend to reach statistical significance in subjects with particularly abnormal baseline values.
Several studies also report positive effects in attenuating blood pressure, especially systolic blood pressure in hypertensive subjects, and some studies document positive effects on markers of endothelial function.
As far as the effects on glucose and insulin metabolism are concerned, results are mixed and tend to be absent, in a few studies even negative. It is possible that in subjects whose glucose and insulin metabolism is already severely impaired, the benefits of phenolic compounds are outweighed by the sugar content of berries, especially when given in form of juices and not with meals.
Another recurring observation in studies testing multiple doses is that there exists a dose-response effect, and some positive outcomes are only observed at higher levels of consumption or with longer interventions.
Considering the overall positive effects of berry consumption that have been reported in several dietary interventions on multiple metabolic abnormalities related to Metabolic Syndrome, it appears that regular berry consumption is a promising strategy to prevent Metabolic Syndrome and its complications, certainly not by itself as a single-bullet solution, but as part of a varied, balanced, and healthy dietary approach promoting health and preventing disease.

Conflicts of Interest:
The authors declare no conflicts of interest.