Diet and Metabolic Syndrome: An Overview

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Diet and Metabolic Syndrome: An Overview Deirdre Keane, Stacey Kelly, Niamh P. Healy, Maeve A. McArdle, Kieran Holohan and Helen M. Roche* Nutrigenomics Research Group, Food for Health Ireland, UCD Conway Institute & UCD Institute of Food and Health, University College Dublin, Dublin 4, Ireland Abstract: The metabolic syndrome (MetS) is a complex multifactorial disorder and its incidence is on the increase worldwide. Due to the definitive link between obesity and the MetS weight loss strategies are of prime importance in halting the spread of MetS. Numerous epidemiological studies provide evidence linking dietary patterns to incidence of MetS symptoms. As a consequence of the epidemiology studies, dietary intervention studies which analyse the effects of supplementing diets with particular nutrients of interest on the symptoms of the MetS have been conducted. Evidence has shown that lifestyle intervention comprising changes in dietary intake and physical activity leads to an improved metabolic profile both in the presence or absence of weight loss thus highlighting the importance of a multi-faceted approach in combating MetS. Nutritional therapy research is not focused solely on reducing energy intake and manipulating macronutrient intake but is investigating the role of functional foods or bioactive components of food. Such bioactives which target weight maintenance and /or insulin sensitivity may have a potentially positive effect on the symptoms of the MetS. However the efficacy of different functional nutrients needs to be further defined and clearly demonstrated.

Keywords: Diets, fatty acids, functional foods, glycaemic index, metabolic syndrome, nutrition. 1. DEFINITION OF METS The term “Metabolic Syndrome” (MetS) is used to describe a combination of medical disorders which confer an increased risk on individuals of coronary heart disease (CHD) [1], stroke and type 2 diabetes mellitus (T2DM) [2]. A single definition of the MetS has yet to find worldwide acceptance. In the absence of this “gold standard” there were a number of closely related but individual definitions put forward by various respected worldwide organisations. In 2001 the National Cholesterol Education Program (NCEP) published the results of their Adult Treatment Panel III (ATP III) including their definition of MetS [3]. The NCEP diagnosed MetS when three or more of the following risk factors occurred together; abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, pro-inflammatory state and/or pro-thrombotic state [3]. The International Diabetes Federation (IDF) defined MetS as being central obesity in addition to any two of the following factors, raised triacylglycerol (TAG) levels, reduced HDL-cholesterol, hypertension or elevated fasting plasma glucose [4]. Despite the coordinated work of many organisations in defining the MetS there is ongoing controversy over whether the term should be in use at all. The American Diabetes Association (ADA) in conjunction with the European Association for the Study of Diabetes (EASD) put forward the assertion that there was no need for the term MetS due to the fact that all its associated factors are treated individually as a *Address correspondence to this author at the Nutrigenomics Research Group, Food for Health Ireland, UCD Conway Institute & UCD Institute of Food and Health, University College Dublin, Dublin 4, Ireland; Tel: +353 1 7166845; E-mail: [email protected]

1570-1611/13 $58.00+.00

matter of course once diagnosed [5]. Notwithstanding the debate over the use of the term MetS as a clinical diagnosis – which the World Health Organisation (WHO) has also commented on recently [6], what is not disputed is that the factors that contribute to the MetS are increasing worldwide [7, 8]. More recently there has been an attempt to reconcile these definitions [9]. This integrated definition of the MetS assigns equal levels of importance to the elements involved and removes central obesity as a core component. This most up to date definition includes abdominal obesity as measured by waist circumference, elevated TAG, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels [9]. 2. AETIOLOGY & PATHOGENESIS OF THE METS 2.1. Obesity The precise molecular mechanisms which lead to the pathogenesis and progression of the MetS have yet to be fully defined. Obesity, T2DM and the MetS are complex multi-factorial disorders with no single derangement driving the epidemic. What is clear is that there are both genetic and environmental influences (See Fig. 1). As there are numerous symptoms of the MetS so too are there numerous causes – all inextricably linked. Traditionally adipose tissue was thought of purely as an energy store – wherein excess nutrients were stored principally in the form of TAG. More recently our knowledge of adipose tissue has expanded with the demonstration that adipose tissue is not simply an energy sink but a functioning endocrine organ. Correct adipose tissue function to allow for both these roles is a crucial aspect of whole body glucose and fatty acid (energy) homeostasis. Obesity is the result of a © 2013 Bentham Science Publishers

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Fig. (1). Representation of the main features of the MetS.

pathological increase in adipose tissue mass, either as the result of adipocyte hyperplasia or hypertrophy. Concurrent with this increase in adipose tissue mass there are important and detrimental changes in adipose tissue function which are important in the etiology of MetS. Obesity is an important risk factor for the MetS which shows strong inheritance patterns [10], and increases the chances of developing type 2 diabetes [11] and MetS [3, 4, 12]. The environmental factors associated with development of insulin resistance and MetS include obesity, poor diet excessive in energy, lack of physical activity and age. Obesity is not an isolated disorder. When adipocyte biology is perturbed, important systemic effects and alterations in adipose derived cytokines (or adipokines) are evident. Obesity impedes adiponectin secretion. On the other hand leptin secretion is seemingly unaltered – resistance to its signalling is associated with obesity and also with increased fatty acid release. The current literature states that obesity is associated with elevated release of free fatty acids (FFA) or non-esterified fatty acid (NEFA). The conventional wisdom in this area of obesity is starting to be questioned. Whilst recent studies are exploring the possibility of normalised plasma NEFA levels in some obese patients, elevated NEFA in the peripheral tissues still exists [13]. Immune cell infiltration with subsequent chronic low grade inflammation promotes insulin resistance in adipose and other peripheral tissues. The term meta-inflammation is used to describe the situation of chronic low grade inflammation associated with an obese and MetS phenotype [14]. Chronic low grade inflammation is associated with increased levels of IL-1, IL-6, TNF- and C-Reactive Protein (CRP), among other pro-inflammatory cytokines upon macrophages infiltration of the adipose tissue. There is also a decrease in the secretion of anti-inflammatory cytokines and so called “protective” adipokines e.g. adiponectin [15].

2.2. Insulin Resistance Insulin resistance results in impaired glucose uptake by the peripheral tissues e.g. muscle and adipose while at the liver gluconeogenesis is unchecked resulting in hyperglycemia and possibly at a later stage diabetes [16, 17]. Insulin resistance exists when a normal concentration of insulin elicits a subnormal biological response [18]. Many years prior to manifestation of the MetS or diabetes, insulin resistance is detectable in the body [19]. It was during his Banting award lecture in the 1980’s that Reaven put forward insulin resistance as the fundamental cause of what he described as “Syndrome X” [20]. However Reaven did not recognise that obesity was a core component due to the fact that he identified insulin resistance in patients who were not obese [20]. Obesity and IR both cause and exacerbate each other. There is no clear evidence that the presence of one of these factors alone is the cause of the MetS. 2.3. Peripheral Tissues & Biomarkers In obesity, there is a significant increase in the production and release of free fatty acids from adipose, leading to lipotoxic effects at peripheral tissues. Elevated FFA levels impair insulin signalling and increase the risk of MetS and type 2 diabetes (See Fig. 2). FFA do this by causing insulin resistance at the muscle and liver and they have the added potential for damaging pancreatic -cell function [21]. Insulin resistance in the adipose leads to no suppression of hormone sensitive lipase (HSL) which in turn leads to increased lipolysis exacerbating the elevated FFA situation. Lipotoxicity can result not only in insulin resistance at the peripheral tissues but also oxidative stress and inflammation as demonstrated by elevating FFA levels in healthy individuals [22]. Analysis of data from the United Kingdom Prospective study

Diet and Metabolic Syndrome

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Fig. (2). Multiple organs illustrating the pathophysiology of the MetS.

and the Paris Prospective Study emphasized the role of dyslipidaemia amongst risk factors for CHD & therefore MetS particularly amongst women [23, 24]. Elevated plasma TAG and reduced HDL-cholesterol are recognised across all definitions as factors of the MetS [3, 25]. Hypertriacylglycerolemia is associated with increased hepatic output of verylow-density lipoprotein (VLDL) particles. This hepatic production of VLDL is increased in cases of lipotoxicity [26]. Insulin resistance also leads to a reduction in lipoprotein lipase (LPL) activity. Without LPL, VLDL particles are not metabolised resulting to continued elevation of TAG levels [27]. Reduced levels of HDL-cholesterol alone is classified as a risk factor for cardiovascular disease (CVD) [28]. This reduction in HDL-cholesterol is thought to be due to increased HDL catabolism in the presence of insulin resistance [29]. Correlations between LDL-cholesterol and abdominal obesity are less obvious. The Framingham study could not define LDL-cholesterol as being associated with increased risk of deaths from CVD in patients with MetS [30]. However the same study identified LDL-cholesterol levels as being elevated in the MetS and this was correlated with elevated TAG levels [30].

risk of developing T2DM and CVD. This concept is known as “primordial prevention” a term coined in 1978 by Strasser and approved by the American Heart Association [31]. Unfortunately the number of people who manage to achieve primordial prevention is very low – less than 5% of middle aged Americans have what is defined as ideal cardiovascular health as set out by the American Heart Association [31]. Primordial prevention is an ideal situation which when obtained is capable of conferring an additional 10 years of life to an individual [32, 33]. However given that atherosclerosis has an early age of onset and also that childhood obesity is increasing worldwide the likelihood is that primordial prevention percentages will not rise in the near future. With this in mind reversal of existing risk factors becomes of critical importance. Pharmacological agents to treat the symptoms of the MetS are aimed at reducing LDL-cholesterol, hypertension and impaired glucose tolerance. The drug therapies aimed at reducing these metabolic risk factors include statins, fibrates, nicotinic acid, angiotensin- converting enzyme (ACE) inhibitors, metformin, thiazolidinediones or acarbose [34]. The remainder of this review will focus on the role of diet in treating the MetS and its symptoms due to the principal role played by obesity in the aetiology of the MetS.

3. TREATMENT OF THE METS The principal aim of the clinical management plan of the MetS is to reduce the risk of T2DM and CVD. The ideal situation would be to avoid the MetS, thereby reducing the

4. INFLUENCE OF DIET ON THE METS While primordial prevention and pharmacological intervention represent extreme ends of the treatment spectrum for


Table 1.

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Prospective Cohort Studies Identifying The role of Diet in the MetS Study Name

Author

Year

Voluneers

Framingham Study

Wolongevicz et al.

2010

General Population

INTERHEART Study

Iqbal et al. Mente et al.

2008 2010

General Population

CARDIA Study

Carnethon et al.

2004

Young Adults

TLGS

Mirmiran et al.

2008

General Population

ARIC

Lutsey et al.

2008

General Population

Amsterdam Growth & Health Longitudinal Study

Ferreira et al.

2005

Young Adults

NURSES Health Study

Field et al. Oh et al.

2007 2005

Female Nurses

the vast majority of cases of the MetS changes to diet and lifestyle are suitable. In fact one study in particular highlighted that a change in lifestyle – including increased exercise and dietary changes was more effective than metformin in reducing the risk of developing type 2 diabetes [35]. The idea that diet can influence health is not a new one, “let food be thy medicine and medicine be thy food” is a phrase attributed to Hippocrates the Ancient Greek father of modern medicine. There are numerous studies both ongoing and concluded which are providing evidence for the role that diet plays in the development or prevention of the MetS (Table 1). The Framingham study is the primary source of information for markers of MetS. Framingham has demonstrated that diet quality is inextricably linked with obesity and therefore the MetS particularly in women. A diet low in energy, carbohydrates and micronutrients but high in saturated fatty acids and alcohol was found to correlate with increased obesity. In addition women who consumed a diet which was high in energy, derived from protein, carbohydrates and fat were also at risk of increased obesity. On the other hand a high intake of energy, based on high fibre and vitamin E was inversely related to obesity [36]. The Framingham study is a local study and fails to take into account dietary patterns based on global location – which is precisely what the INTERHEART study has attempted to do. One method which this study has made use of is the classification of diets into “Oriental”, “Western” or “Prudent”. The oriental diet contains tofu and soy and various other sauces. The western diet is high in fried foods, salty snacks, eggs and meat. The Prudent diet depends on large amounts of fruit and vegetables. What they demonstrated based on this classification system is that the Oriental diet had no association with acute myocardial infarction (AMI), while the Prudent diet in addition to no association with AMI had a protective effect at higher levels. The Western diet in comparison was associated with AMI [37]. As it is the INTERHEART study which has highlighted a link between AMI and MetS similar to the levels in type 2 diabetes the link between a Western diet and MetS prevalence is hard to ignore [38].

There has been an increase in the number of national and multinational prospective cohort studies all emphasising the influence of diet on the risk of MetS, type 2 diabetes and CVD. The coronary artery risk development in young adults (CARDIA) study correlated increased BMI and weight gain due to a diet high in carbohydrate and low in crude fibre with increased risk of MetS [39]. The following years have seen at least one study published per year which emphasises the role that diet plays in prevalence of MetS. The Amsterdam Growth and Health Longitudinal Study established a link between increased energy intake rather than any one macro or micronutrient and the MetS [40]. The Framingham study highlighted the link between 1 soft drink daily and increased waist circumference, altered glucose tolerance and MetS [41]. The Tehran Lipid and Glucose Study (TLGS) highlighted a dose dependent relationship between dietary intake of carbohydrates and fats and the incidence of MetS [42]. Confirmation of the role played by a western diet based on meat and fried foods and the incidence of MetS was demonstrated in the Atherosclerosis risk in communities (ARIC) study – this also offered further evidence of the possible protective role to be played by the prudent diet high in vegetables, fruit, fish, and poultry [43]. 5. ROLE OF DIETARY COMPONENTS ALONE OR IN CONJUNCTION WITH EXERCISE IN TREATING THE METS What all these prospective cohort studies have in common is that they are pointing the way towards new dietary guidelines and a nutritional strategy to reduce the prevalence of obesity, type 2 diabetes and the MetS and thereby reduce the number of deaths from CVD. The evidence outlined to date provides a convincing argument for the adverse effects of the western diet and two macronutrients in particular –fats and carbohydrates. 5.1. Fats Despite the recognised role of fats and fatty acids as a vital fuel source (37 kJ or 9 kcal per gram), research shows their potentially deleterious effects. Convention dictates that fatty acids are classified based on double bonds within their


Table 2.


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Dietary Intervention Studies analysing the effects of PUFA on factors of the MetS

Author

Year

Diet

Participants

Duration (Weeks)

Outcome

Tierney

2011

Replacing SFA with PUFA

Patients with MetS

12

PUFA improved TAG levels

Meyer

2009

Seal oil and Fish oil Supplements

General Population

6

Seal Oil & Fish Oil supplementation reduced plasma TAG and blood pressure

Cicero

2006

PUFA diet

Metanalysis

Dangardt

2010

PUFA Supplementation

Obese Adolescents

McEwen

2010

Diets higher in Fish and PUFA

Patients with Diabetes

Vessby

2001

Moderate -3 Supplementation

General Population

structure. In so doing saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) are associated with certain biological effects. 5.1.1. Trans Fats Trans fats, for example, are unsaturated fatty acids that are created during the industrial process of partial hydrogenation; converting vegetable oils to semi-solids. Trans fats are positively correlated with plasma CRP, TNF, Eselectin, sICAM-1 and sVCAM-1 [44, 45]. Trans fats have been shown to be inversely related to HDL and LDL:HDL in women [45] and positively related to total cholesterol and serum LDL [46] and so, increased consumption of trans fats raises the risk of CHD [46]. 5.1.2. Saturated Fatty Acids & Polyunsaturated Fatty Acids SFA are acknowledged as “bad” fats associated with an increased risk of MetS. The most abundant SFA in the diet and in the body are palmitate and stearate. Studies have shown that replacing SFA with a diet enriched with PUFA decreases LDL-cholesterol and total cholesterol:HDLcholesterol ratio [47] and reduce the risk of MetS developing [48, 49]. There is also evidence that substituting SFA with low-GI foods (or wholegrain carbohydrates) could lead to a reduction in MetS incidence [50] however high GI foods or refined carbohydrates may have the opposite effect [48]. As opposed to SFA and MUFA, dietary intake of n-3 and n-6 PUFA are essential for normal growth and development. Of all fatty acids n-3 PUFA are the longest recognised as having beneficial effects on human health (Table 2) [51]. There is strong evidence that n-3 PUFA can reduce TAG levels [5254], and also may improve hypertension [53, 55, 56]. Increased intakes of n-3 PUFA are inversely related to plasma CRP, IL-6 and E-selectin [57]. EPA and DHA are inversely related to the soluble adhesion molecules, sICAM-1 and sVCAM-1 [57] Thus, n-3 PUFA reduce inflammation [58] and decrease cardiovascular risk in diabetic patients [59]. However, despite PUFA reducing the risk of CHD, there is no evidence that increased consumption of LC-n-3 fatty acids reduces the risk of T2DM in men and women [60].

PUFA improve hypertension 17

PUFA supplementation reduced inflammation as measured by certain cytokines PUFA can be recommended as part of a diabetes management programme

12

No effect of PUFA supplementation on insulin secretion

5.1.3. Monounsaturated Fatty Acids Little is known about the nutritional implications of MUFA however, there is increasing interest into the potential of MUFA and, in particular oleate, in benefiting health. The MUFA in Obesity (MUFObes) study was a 6 month dietary intervention study comparing Willet’s Healthy Eating Pyramid (a high MUFA diet), the current recommended diet (a low fat diet) and a control diet (typical Western diet) [61, 62]. The 6 month intervention, significantly reduced the LDL:HDL ratio in the MUFA group with no change in the other two groups [63] Studies into the effect of a diet enriched with MUFA on healthy individuals has identified beneficial effects on MetS risk factors including reductions in LDL-cholesterol, TAG and elevated HDL-cholesterol levels [64, 65]. Furthermore as part of the KANWU study, MUFA are associated with a reduction in blood pressure in healthy subjects [66]. From the MUFObes study, it was seen that the MUFA group had reduced fasting glucose and insulin concentrations while the low-fat group and control group had increased concentrations of glucose and insulin [61, 63]. The large scale KANWU study determined the effect of substituting SFA for MUFA on insulin sensitivity in healthy individuals [67]. KANWU demonstrated that insulin sensitivity was reduced on the SFA diet but, contrary to the initial hypothesis, insulin sensitivity was not improved by replacing SFA with MUFA. What was interesting to note, that post hoc analysis determined that the positive effects of the MUFA diet were only discernible in individuals with a reduced total dietary fat intake (< 37% of total energy) [67]. The LIPGENE project concluded similarly – indicating that there was no difference in the effect of a high MUFA diet compared to a high SFA diet as the total fat intake at 36% of total energy was too high regardless of quality of fat [52]. Moving on from dietary intervention studies in healthy volunteers, there has been evidence to suggest that substitution of SFA with MUFA or carbohydrates in insulin resistant individuals, can lead to increased insulin sensitivity associated with elevated postprandial adiponectin levels [68]. Adiponectin and its association with improved insulin sensitivity at the peripheral tissues in animal models [69]. This effect on


adiponectin levels is in addition to the positive effects of MUFA on body fat distribution as seen in diabetic patients [70], highlighting the importance of including MUFA in a dietary intervention for the symptoms of the MetS. 5.1.4. Mediterranean Diet With the positive effects of MUFA being recognised there is a renewed interest in the so called “Mediterranean Diet” as an optimal healthy eating approach. It is rich in foods common to the Mediterranean region with an emphasis on olive oil which is approximately 75% MUFA. The Mediterranean diet is also high in fruits, vegetables, cereals, beans, nuts and seeds. There is a very low amount of red meat consumed. Red meat is associated with an increased risk of CVD and the risk for CVD in vegetarian populations is reduced relative to non-vegetarians [71]. The evidence in favour of the Mediterranean Diet over the traditional Western Diet points to a reduction in LDL-cholesterol and an increase in HDL-cholesterol and improved insulin sensitivity in healthy [72] and insulin resistant patients [73]. Whilst these intervention studies are positive, long-term dietary intervention studies in high-risk groups are required to confirm the efficacy of a Mediterranean type diet as a long term healthy eating approach. 5.1.5. Total Fat What the studies mentioned above have highlighted is the importance of total fat in the diet. Several studies have shown no association between total fat intake and obesity and the markers of the MetS [74-77], while only one prospective cohort study has demonstrated a link between total fat intake and CHD incidence [78]. While the number of prospective cohort studies linking fat intake with MetS symptoms may be limited there are studies which demonstrate a loss in weight and an improvement in metabolic parameters in response to reduced total fat intake. A metaanalysis conducted by Astrup which included 16 low fat intervention studies found a maintenance of weight in normal weight individuals and a reduction in weight of obese/overweight individuals [79]. What is important to bear in mind is that in order to prevent essential fatty acid deficiency and to maintain normal absorption of fat soluble vitamins and maintain energy levels it is recommended that fats should account for minimum 15% of total energy intake [80]. As for the maximum dietary intake of fats a recent comprehensive study compiled by the Food and Agriculture Organisation of the United Nations (FAO) and the World Health Organisation (WHO) approved a maximum of 3035% of total energy intake to be derived from fats to be acceptable for most individuals [81]. The value of this maximum cut off is seen in the results of the KANWU and LIPGENE studies [52, 67]. 5.2. Carbohydrates 5.2.1. Glycaemic Index & Glucose Load Carbohydrates are another macronutrient which have been investigated on the basis of their contribution to MetS incidence. In 1981 Jenkins introduced the concept of the glycaemic index (GI) as a classification of carbohydrates according to their postprandial effects on blood glucose lev-

Keane et al.

els [82]. Refined grains are classed as high GI foods due to their rapid digestion and the large fluctuations that they cause in blood glucose and insulin. On the other hand wholegrain foods are classed as low GI, they are digested slowly and therefore cause a gradual increase in glucose levels and as a result a more controlled insulin response [82]. In addition to GI measurement, studies involving carbohydrates in the diet also take into consideration the glucose load (GL). The GL is defined as the carbohydrate content times the GI [83]. There is no accepted definition for dietary fibre however it is often referred to as non starch polysaccharides and sources include whole grain cereals, legumes, fruits and vegetables and they are associated with possible prevention of the MetS and T2DM [84, 85]. 5.2.2. Relationship between Glycaemic Index and MetS In an eight year follow-up of 91,249 female nurses, a diet high in rapidly absorbed, high GI foods was strongly associated with an increased risk of T2DM and this association remained high after adjusting for BMI and other lifestyle factors [85]. The same relationship between high GI foods and incidence of T2DM has been demonstrated in men [86]. In a prospective study of EPIC-NL participants, diets high in GL, GI, and starch and low in fibre were associated with an increased diabetes risk [87]. High GI foods are positively correlated with haemorrhagic stroke and replacing high GI foods with low GI foods could reduce the risk [88]. A metaanalysis of 37 prospective studies on GI and GL reported that diets with a high GI or GL independently increased the risk of T2DM and heart disease [89]. Plasma C-peptide is a marker of insulin secretion and higher concentrations are associated with IR. High intakes of high GI foods are associated with higher concentrations of plasma C-peptide than low GI foods. A diet enriched in cereal fibre, demonstrated reduced levels of plasma C-peptide [90]. High-GI is also associated with an increase in highsensitivity-C-reactive protein (hsCRP) concentration. hsCRP is a sensitive marker for inflammation, Liu et al. investigated whether this association was modified by BMI [91]. The Women’s Health Study showed that GL was significantly associated with hs-CRP and this positive association was significantly modified by BMI [91]. 5.2.3. Glycaemic Index Intervention Studies These association studies have demonstrated a clear need for intervention studies to establish if substituting high GI with low GI alternatives is capable of reversing the incidence of T2DM and the numerous symptoms of the MetS (Table 3). Some intervention studies have been carried out in healthy individuals, however reducing the GI content of the diet had little to no effect on the markers of the MetS. However it is important to note that these studies have been short in duration and perhaps a more sustained low-GI diet is necessary. In high-risk subjects, the impact of a low-fat, highcarbohydrate diet, in which carbohydrate was either low-GI or high-GI, on energy intake, body weight, composition and risk factors for T2DM and ischemic heart disease (IHD) in overweight healthy subjects was examined by Sloth et al. [92]. High- versus low-GI diets had no significant effect on fasting serum insulin, TAG and NEFA and HDL-cholesterol concentrations, homeostasis model assessment for relative


Table 3.


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Dietary intervention studies investigating the benefits of a low GI diet with regard to factors of the MetS

Author

Year

Diet

Participants

Duration

Outcome

(Weeks) Wolever

1992

Alternating Low GI and High GI

Patients with Type1 & 2 Diabetes

2

Reduction in Blood Glucose Levels & Serum cholesterol levels

Frost

1996

Low Vs High GI

Patients with CHD

4

Improved Insulin Sensitivity

Frost

1998

Low Vs High GI

Female – Family history of CHD

3

Improved Insulin Sensitivity

Jarvi

1999

Alternating Low GI and High GI

Patients with Type 2 Diabetes

3

Lowers Blood Glucose & Insulin Levels Improved Lipid Profile – Reduced LDL & HDL-cholesterol

Heilbronn

2002

Low GI Vs High GI


8

Reduction in LDL-cholesterol but no change in glucose management on Low GI diet

Sloth

2004

Low GI Vs High GI

Overweight but Healthy

10

No change in -cell function, TAG, NEFA or HDL-cholesterol. Decrease in LDL and Total cholesterol with the Low GI.

Wolever

2008

High GI, Low GI & Low Carbohydrate


52

HbA1c not altered. Sustained reduction in postprandial glucose on Low GI diet.

Shikany

2009

Low GI/GL Vs High GI/GL

Overweight but Healthy Men

4

No Significant effects on markers for MetS

Larsen

2010

Varied Protein Content & GI

Overweight but Healthy who achieved initial targeted weight loss

26

Diet high in protein but low GI was most successful @ maintaining weight loss.

2011

Varied Protein Content & GI

Overweight but Healthy who achieved initial targeted weight loss

26

Diet low in protein or low GI reduced hsCRP

Diogenes Gogebakan Diogenes

insulin resistance (HOMA) levels or homeostasis model assessment for cell function. However, a 10% decrease in LDL-cholesterol and a trend towards a greater reduction in TC was demonstrated in the low-GI group relative to the high-GI subjects. Shikany et al. determined the effect of high- or low- GI/GL diets in 24 overweight or obese men who were otherwise healthy and showed that neither intervention had a significant effect on glucose metabolism, inflammatory markers (CRP, IL-6, TNF- or TNF-RII) or coagulation factors (plasminogen activator inhibitor-1 (PAI-I) or fibrinogen) [93]. Fat mass reduction and an increase in lean mass with high-GI/GL diet was significant relative to the low-GI/GL diet, however the absolute differences between the groups was small. The high-GI/GL diet resulted in a significant reduction in TC, LDL-cholesterol and HDLcholesterol compared with the low-GI/GL diet. The reduction in TC and LDL-cholesterol with the high-GI/GL intervention may be attributed to the higher PUFA and lower SFA content of this diet. Jarvi et al. compared the effects of high-GI versus lowGI diets in a cross-over study conducted over two consecutive 24 day periods and noted that insulin sensitivity im-

proved significantly with both diets but particularly with the low-GI diet; in addition serum TC and LDL-cholesterol were significantly reduced with the low-GI diet relative to the high-GI diet, however HDL-cholesterol was reduced in both groups [94]. Heilbronn et al. determined the effect of a high SFA diet run-in for 4weeks, followed by an 8 week low- or high-GI intervention in T2DM patients with low, median or high glucose tolerance. Both diets induced weight loss and lowered fasting glucose and TAG concentrations however this was not significant between intervention groups. The low-GI diet resulted in a greater reduction in LDLcholesterol concentrations in subjects with low glucose tolerance [95]. Overall the low-GI intervention studies in T2DM patients have been limited to small cohorts and therefore further research is needed to establish whether or not a low-GI diet can have a positive effect. To date, studies have shown that the glycaemic index of a diet alone is not sufficient to resolve the symptoms of the MetS. The most recent attempt to target obesity and its various associated risk factors has involved a combination of altered protein intake and altered GI levels. Diogenes (Diet, obesity and Genes), investigated the


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efficacy of moderate fat diets that vary in protein content and glycaemic index in preventing weight gain and obesity related factors following an initial weight loss phase [96]. Diogenes aimed to investigate if improvements in hs-CRP, TAG, TC, LDL-cholesterol, HDL-cholesterol and blood pressure all factors involved in the MetS that were achieved during the initial weight-loss phase of the study, could be maintained or indeed improved with the intervention diets and additionally whether these diets elicit additional weight loss–independent effects [97]. hsCRP levels decreased significantly during the run-in phase and continued to decrease during the 26-week intervention, there were distinct changes between the dietary groups, the low-GI group displayed greater reduction in hsCRP when compared to the high-GI group, a combination of low-protein and low-GI was most beneficial in respect to hsCRP reduction. This result corroborates that of a prospective Canadian study [98] and a cross-sectional study of a Dutch population [99]. In this study of a Dutch population, GI was shown to have a significantly inverse association with HDL-cholesterol. A low-GI diet (high in dairy and fruit, but low in potatoes and cereals) was assoicated with improved insulin sensitivity and lipid metabolism and with a reduction in chronic inflammatory factors This was in agreement with a study conducted in a female US cohort [100]. However the findings of van Dam et al. and Oxlund et al. do not support these associations [101, 102].

5.4. Lifestyle Interventions Combining Exercise and Dietary Advice

5.3. General Healthy Eating Advice

The results of the Diabetes Prevention Study were complimented by a similar lifestyle intervention the Diabetes Prevention Programme (DPP) in the US, which focused on the relative efficacy of lifestyle intervention versus pharmacological therapy (metformin) to prevent or delay the onset of diabetes in individuals with impaired glucose tolerance [121]. The DPP showed that for every 5% reduction in dietary fat intake (%fat) during follow-up, diabetes incidence was reduced by 25% [122]. The DPP suggest that lifestyle intervention may have the potential to preserve -cell function and prevent T2DM. Weight loss in the lifestyle intervention group was particularly associated with increased adiponectin levels [123] [124]. Persons with impaired glucose tolerance have elevated levels of C-reactive protein which has been shown to predict the development of type 2 diabetes and MetS [125, 126]. In the DPP study, levels of CRP were reduced in the lifestyle intervention and in response to metformin treatment but not in the control group [127]. The control group had increased prevalence of hypertension and dyslipidemia the lifestyle intervention was more successful even than the metformin treatment in reducing hypertension and dyslipidemia [128, 129]. The results show that a reduction in diabetes incidence by either lifestyle intervention or metformin treatment persists for at least ten years [130].

The 2010 Dietary Guidelines for Americans recommend the DASH diet for reaching and sustaining a healthy weight and for the prevention of diet-induced diseases. The DASH diet was established as a means of reducing blood pressure by dietary patterns as opposed to nutrients alone [103]. The control diet represented a typical Western style diet and was compared to a high fruit and vegetable diet and the DASH diet which consisted of increased consumption of low-fat dairy, fruit and vegetables, dietary fibre and whole grains and decreased intake of refined grains, saturated fat and total fat [103]. The DASH diet significantly reduced blood pressure especially in African Americans and those with existing hypertension [104-106]. The DASH diet also had favourable effects on blood lipids by lowering total, LDL and HDL cholesterol but it had no effect on TAG concentrations in overweight people [107]. Blood pressure and blood lipids were markedly improved in diabetic patients [108]. Among diabetic individuals, the DASH diet reduced the inflammatory markers CRP, fibrinogen, alanine aminotransferase and aspartate aminotransferase more so than the standard diet for diabetic patients after just eight weeks [109]. A longer-term study showed that the DASH diet may prevent the occurrence of T2DM, but the effect was greater for white individuals than for minority groups [110]. Positive outcomes were noted for weight and fasting blood glucose as well as for blood pressure and HDL cholesterol among men and women with existing MetS [111]. The DASH could prove to be effective at not only preventing the risk factors associated with the MetS but also treating them.

Alterations to diet alone have demonstrated an improvement in markers of the MetS as outlined above. Further studies investigated the role of dietary intervention in conjunction with physical activity as a treatment option for MetS [35, 112-115]. One of the first controlled, individually randomised trials to test the effect of lifestyle intervention on components of the Metabolic Syndrome was the Diabetes Prevention Study, a multi-centre study based in Finland [116]. In the intervention group, a frequent individual consultation with a nutritionist was provided and subjects were recommended to follow a lifestyle intervention (Table 4). There was a significant reduction in body weight and waist circumference in response to intervention compared to the control cohort in years 1, 2 and 3 [116, 117]. The incidence of the MetS and risk factors associated with the MetS, including abdominal obesity, blood pressure, HDLcholesterol and TAG concentrations were significantly improved in the intervention but not in the control group [118]. Importantly, the diet and lifestyle intervention led to a reduced number of patients with MetS and T2DM at the end of 3, 4 or 6 years [117] [118] [119]. The most significant dietary predictor for achieving large weight reduction was energy density. In particular low-fat and high-fibre intakes predicted decreased diabetes risk independently of body weight change and physical activity [120].

The positive effects of lifestyle intervention seen in the DPS and DPP studies were corroborated further by another detailed study “The study on lifestyle-intervention and impaired glucose tolerance Maastricht (SLIM)” [131]. Dietary recommendations were based on the Dutch guidelines for a healthy diet (Dutch Nutrition Council 1992). Lifestyle intervention again led to a reduction in weight and BMI [131, 132]. Total cholesterol, HDL and LDL concentrations did not change over time within the two groups. Prevalence of


Table 4.


9

Outline of dietary and physical interventions to achieve goals of the DPS study.

Dietary Intervention

Carbohydrate

•

>50 % of energy derived from carbohydrate

Fat

•

Amount of total fat 30 % of energy

•

10 years) benefits of lifestyle intervention and the fundamental role of physical activity in conjunction with dietary modifications in reducing the prevalence of the MetS. 5.5. Functional Foods – bioactives for Treating MetS

Long chain (LC) n-3 PUFA, derived from fish oils, may also be considered as bioactives as they have multiple potential health benefits which when incorporated into a food matrix that would not usually contain LC n-3 PUFA can also be classed as functional foods. Evidence from in vitro studies has demonstrated that LC n-3 PUFA have anti-inflammatory potential which results in improved insulin sensitivity in adipose tissue [141]. With the rising health costs associated with the MetS and the recognised links between food and the symptoms of the MetS there have been attempts to identify bioactive compounds and functional foods which might be able to attenuate the risk factors for MetS. The bioactive components of various functional foods have been found to have beneficial effects on risk factors associated with MetS. For example, beta-glucan a soluble dietary fibre readily found in oat and barley bran has been associated with reduced insulin resistance, dyslipidemia, hypertension and obesity [142].

5.5.1. Definition of Functional Food

5.5.2. Animal Derived Bioactives

The term functional food was first coined in Japan to describe foods which were fortified to have a positive physiological effect [133-135]. Therefore a functional food can be defined as a food that contains bioactive compounds present as natural constituents or added as fortificants which have the potential to exert health benefits beyond the basic nutritional value of the product [136]. The “bioactive” compound is defined as an “extranutraceutical” and is where the potential for health benefits lies [137]. Bioactive compounds normally occur naturally in small quantities and they can be isolated from marine, animal or plant sources [136, 138, 139]. The bioactive components of functional foods are released either by digestion processes in vivo or through food processing methods. Functional food research is being driven by commercial benefits for the food industry and a need to reduce healthcare costs in an increasingly ageing population. What is important to note is that the power of foods to have physiological effects both positive and negative has been realised and therefore worldwide there is an effort to define these foods more rigidly and to formulate and apply legislation to their production [140]. The original bioactives were what we know of as micronutrients – vitamins and minerals which were used to “fortify” existing food stuffs in order to maintain or enhance normal physiological functions [140].

Bioactive peptides from milk, meat, soy and plant sources have also shown favourable effects on risk factors associated with MetS [143]. For example, milk casein BPs such as Val-Pro-Pro and Ile-Pro-Pro both have shown antihypertensive effects through inhibiting angiotensin Iconverting enzyme (ACE) [144, 145]. Furthermore, lactoferrin, a bioactive component of the whey fraction of milk has shown anti-inflammatory activity in vitro and, in clinical studies has been found to reduce visceral fat in men and women with abdominal obesity [146-148]. Studies have also assessed the effects of glycomacropeptide (GMP), a -casein fragment on weight loss and cardiovascular disease risk. Total and LDL-cholesterol, TAG, glucose, insulin, and systolic and diastolic blood pressure have been shown to decrease at 6 and 12 months compared to baseline with an additional increase in HDL-cholesterol at 12 months compared with baseline using meal replacements containing GMPenriched whey protein isolate (GMP-WPI) containing 90% GMP [149]. Whey-born multifunctional peptides called lactorphin and -lactorphin affect adipocyte lipogenesis due to their ACE-inhibitory activities and also they may reduce food intake via peripheral opioid receptors, similarly to casein and soy protein hydrolysates [150, 151]. Meat derived


Keane et al.

BPs have also shown anti-thrombotic, anti-inflammatory and antihypertensive properties in rodent models [152-154].

glucuronide and sulfate conjugates would be more effective due to the fact that they are absorbed as conjugates [178].

5.5.3. Plant Derived Bioactives

Bioactive compounds are reinforcing the concept of “you are what you eat”. There is rapid progress being made in isolating and understanding bioactive compounds and the list of functional foods is being added to at pace. Functional foods occupy the market between traditional foods and what we consider to be medicine. They have demonstrated that they have the potential to reduce the risk of disease or improve markers of health. However there is much more work to do to classify these compounds and regulatory bodies are putting in place the necessary legislation to ensure that there are no health scares as a result of functional foods cross reaction with “normal” foods or prescribed medication. There are a number of ongoing studies evaluating the benefit or risk of foods and functional foods e.g. BEPRARIBEAN, PLANTLIBRA and BRAFO. In the USA, functional foods are under the regulation of the Food and Drug Administration (FDA). In Europe, the European Food Safety Authority (EFSA) is responsible for evaluating health and nutritional claims for functional foods. Aside from issues of food safety further research is needed to establish scientific proof of efficacy and bioavailability of the bioactive components of functional foods in human studies. Human intervention studies into functional foods must take into consideration – subject selection, background diets, length of intervention, maximum effective dose of the active ingredient, possible food matrices, appropriate controls, methods of establishing compliance and finally the biological markers of the endpoint [179].

Phytochemical –or plant derived bioactives such as cinnamon, green tea, berberine and ginseng have all demonstrated an ability to modulate signalling pathways in metabolically challenged in vitro cell models and animal studies [155-160]. Cinnamon extract decreased oxidative stress, body fat and improved fasting glucose levels in glucose intolerant subjects, however these studies involved a relatively small cohort and due to the reliance on self reported food diaries it is not clear if those involved had reduced their energy intake thus the reduction in body fat observed [161, 162]. Epigallocatechingallate (EGCG), the major bioactive in green tea, lowered cholesterol and improved insulin sensitivity in obese mice, and lowered blood pressure in spontaneous hypertensive rats [163, 164]. Epidemiological studies have found that regular consumption of green tea is inversely associated with cardiovascular mortality, risk of hypertension and of diabetes, and with percent body fat and body fat distribution [165]. Supplementation of an exercise regime based on walking with the same green tea extract has demonstrated improvement in glycaemic control and a reduction in heart rate in overweight females however this study recognised that the dose given was not sufficient to induce fat loss [166]. Berberine has traditionally been recognised for its antibiotic properties however recent studies have demonstrated that supplementation with berberine can improve blood glucose levels and improve dyslipidemia in diabetic patients [167, 168]. Two bioactive polyphenols found in fruits, resveratrol and quercetin have been noted for their favourable effects on components of MetS. Both bioactives improved insulin sensitivity and glucose metabolism in cell culture models, including 3T3-L1 adipocytes and adipose tissue isolated from rats and cultured ex vivo [142, 169, 170]. Quercetin given to obese rats improved inflammation, dyslipidemia, hypertension, and hyperinsulinemia [171]. In a human study, quercetin supplements given to overweight subjects with MetS traits reduced systolic blood pressure and LDL-cholesterol concentration [172]. Mice fed a high fat diet and supplements of resveratrol lived longer, weighed less and, had increased insulin sensitivity compared to control mice. In another study, obese rats given supplements of resveratrol had lowered blood pressure, plasma glucose, cholesterol and TAG compared to control animals [139]. Recent evidence in healthy obese adults has corroborated the early work conducted in animal models of obesity [173]. Epidemiological and experimental studies have revealed that drinking red wine attenuates cardiovascular risk factors, highlighting resveratrol as a protective agent [174, 175]. Human intervention studies have demonstrated a beneficial effect of resveratrol supplements (10mg) on symptoms of CAD [176], and an improvement in insulin sensitivity [177]. However there are questions about the bioavailability of resveratrol and quercetin, with evidence that even massive supplementation doses may not be able to achieve the concentrations needed for biological effects to occur. This research also questions the use of polyphenols alone but rather stresses that their

6. CONCLUSION AND FUTURE PERSPECTIVES The MetS is a complex disorder involving physiological dysfunction in multiple organs and systems and which is caused by both genetic and environmental influences. The multi-factorial nature of the MetS means that there are numerous targets for therapy which is positive – however it also makes it difficult to treat as no single therapy can possibly hope to affect all available targets. Studies put forward the theory of “primordial prevention” as a way to avoid the symptoms and outcomes of the MetS altogether. However with the worldwide increase in childhood obesity this option is already taken out of most individual’s control. Pharmacological agents can be used to treat the MetS at its latter stages – however they should be a last resort, following lifestyle interventions, as none currently available are an outright cure for the MetS. In the early stages of metabolic disturbance it is possible to reverse the symptoms and prevent outright T2DM development or to reduce the risk of death from cardiovascular complications. As the cost of treating MetS is increasing worldwide and therefore straining already constrained health budgets there has been an increase in the number of studies analysing alternative treatment options. The literature supports weight management through dietary and lifestyle interventions as early as possible to prevent disease progression. While initial studies focused on individual nutrients, the outcomes of these studies were insufficient. There has been considerably more success with the combination of exercise and dietary interventions in treating symptoms of the MetS. The functional food area may have further potential within the context of designing novel foods en-



riched with “bioactives” or compounds which when isolated from their natural source have added health benefits which ameliorate one or more components of the MetS. Whilst there is the potential to develop bioactives that target the insulin resistant component of the MetS and this would attenuate the metabolic risk factors such as T2DM and CVD risk. There is promising data from both in vitro and animal studies. Nevertheless it is very important that efficacy is demonstrated in man in order to support a viable therapeutic strategy to improve health.

TAG

=

Triacylglycerol

TC

=

Total Cholesterol

VLDL

=

Very-low-density lipoprotein

WHO

=

World Health Organisation

CONFLICT OF INTEREST

[2]

REFERENCES [1]

The authors confirm that this article content has no conflicts of interest. [3]

ACKNOWLEDGEMENTS DK, SK, NPH, MAMcA and KH work in the Food for Health Ireland group supported by Enterprise Ireland under Grant Number CC20080001. HMR is a recipient of the Science Foundation Ireland Principal Investigator Programme (11/PI/1119).

11

[4]

[5]

ABBREVIATIONS [6]

ACE

=

Angiotensin Converting Enzyme

ADA

=

American Diabetes Association

AMI

=

Acute Myocardial Infarcation

CHD

=

Coronary Heart Disease

CRP

=

C-reactive protein

CVD

=

Cardiovascular Disease

DHA

=

Docosahexaenoic acid

EASD

=

European Association for the Study of Diabetes

EPA

=

Eicosapentaenoic acid

FFA

=

Free fatty acid

GI

=

Glycaemic Index

GL

=

Glycaemic Load

GMP

=

Glycomacropeptide

HDL

=

High density lipoprotein

HSL

=

Hormone Sensitive Lipase

IDF

=

International Diabetes Federation

[12]

LDL

=

Low density lipoprotein

[13]

LPL

=

Lipoprotein lipase

MetS

=

Metabolic Syndrome

MUFA

=

Monounsaturated fatty acid

NCEP

=

National Cholesterol Education Panel

NEFA

=

Non-esterified fatty acid

PUFA

=

Polyunsaturated fatty acid

SFA

=

Saturated fatty acid

T2DM

=

Type 2 Diabetes Mellitus

[7]

[8] [9]

[10]

[11]

[14] [15]

[16] [17]

Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes care. 2001;24(4):683-9. Epub 2001/04/24. Lorenzo C, Okoloise M, Williams K, Stern MP, Haffner SM. The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. Diabetes care. 2003;26(11):3153-9. Epub 2003/10/28. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA: the journal of the American Medical Association. 2001;285(19):2486-97. Epub 2001/05/23. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet. 2005;366(9491):1059-62. Epub 2005/09/27. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2005;48(9):1684-99. Epub 2005/08/05. Simmons RK, Alberti KG, Gale EA, Colagiuri S, Tuomilehto J, Qiao Q, et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010;53(4):600-5. Epub 2009/12/17. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18-e209. Epub 2010/12/17. Smith SC, Jr. Reducing the global burden of ischemic heart disease and stroke: a challenge for the cardiovascular community and the United Nations. Circulation. 2011;124(3):278-9. Epub 2011/07/07. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-5. Epub 2009/10/07. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic medicine: a journal of the British Diabetic Association. 1998;15(7):539-53. Epub 1998/08/01. Kahn SE, Prigeon RL, Schwartz RS, Fujimoto WY, Knopp RH, Brunzell JD, et al. Obesity, body fat distribution, insulin sensitivity and Islet beta-cell function as explanations for metabolic diversity. J Nutr. 2001;131(2):354S-60S. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881-7. Epub 2006/12/15. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60(10):2441-9. Epub 2011/09/29. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860-7. Epub 2006/12/15. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, et al. Plasma concentrations of a novel, adiposespecific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis, thrombosis, and vascular biology. 2000;20(6):1595-9. Epub 2000/06/10. Peter P, Nuttall SL, Kendall MJ. Insulin resistance--the new goal! J Clin Pharm Ther. 2003;28(3):167-74. Poitout V, Robertson RP. An integrated view of beta-cell dysfunction in type-II diabetes. Annu Rev Med. 1996;47:69-83.

12 Current Vascular Pharmacology, 2013, Vol. 11, No. 00 [18]

[19] [20] [21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30] [31]

[32]

[33] [34]

[35]

[36]

[37]

Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372(6502):182-6. Goldstein BJ. Insulin resistance: from benign to type 2 diabetes mellitus. Rev Cardiovasc Med. 2003;4 Suppl 6:S3-10. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-607. Epub 1988/12/01. Charles MA, Eschwege E, Thibult N, Claude JR, Warnet JM, Rosselin GE, et al. The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia. 1997;40(9):1101-6. Epub 1997/09/23. Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003;52(12):2882-7. Epub 2003/11/25. Empana JP, Ducimetiere P, Charles MA, Jouven X. Sagittal abdominal diameter and risk of sudden death in asymptomatic middle-aged men: the Paris Prospective Study I. Circulation. 2004;110(18):2781-5. Epub 2004/10/20. U.K. Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes care. 1997;20(11):1683-7. Epub 1997/11/14. Ryden L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). European heart journal. 2007;28(1):88-136. Epub 2007/01/16. Chan DC, Barrett HP, Watts GF. Dyslipidemia in visceral obesity: mechanisms, implications, and therapy. American journal of cardiovascular drugs: drugs, devices, and other interventions. 2004;4(4):227-46. Epub 2004/08/03. Couillard C, Bergeron N, Prud'homme D, Bergeron J, Tremblay A, Bouchard C, et al. Postprandial triglyceride response in visceral obesity in men. Diabetes. 1998;47(6):953-60. Epub 1998/05/30. Franceschini G. Epidemiologic evidence for high-density lipoprotein cholesterol as a risk factor for coronary artery disease. The American journal of cardiology. 2001;88(12A):9N-13N. Epub 2002/01/15. Pascot A, Lemieux I, Prud'homme D, Tremblay A, Nadeau A, Couillard C, et al. Reduced HDL particle size as an additional feature of the atherogenic dyslipidemia of abdominal obesity. J Lipid Res. 2001;42(12):2007-14. Epub 2001/12/06. Lindley VA. A new procedure for handling impervious biological specimens. Microsc Res Tech. 1992;21(4):355-60. Epub 1992/06/01. Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613. Epub 2010/01/22. Lloyd-Jones DM, Leip EP, Larson MG, D'Agostino RB, Beiser A, Wilson PW, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113(6):791-8. Epub 2006/02/08. Kullo IJ, Cooper LT. Early identification of cardiovascular risk using genomics and proteomics. Nature reviews Cardiology. 2010;7(6):309-17. Epub 2010/05/05. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-52. Epub 2005/09/15. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England journal of medicine. 2002;346(6):393-403. Epub 2002/02/08. Wolongevicz DM, Zhu L, Pencina MJ, Kimokoti RW, Newby PK, D'Agostino RB, et al. Diet quality and obesity in women: the Framingham Nutrition Studies. The British journal of nutrition. 2010;103(8):1223-9. Epub 2009/11/26. Iqbal R, Anand S, Ounpuu S, Islam S, Zhang X, Rangarajan S, et al. Dietary patterns and the risk of acute myocardial infarction in

Keane et al.

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

52 countries: results of the INTERHEART study. Circulation. 2008;118(19):1929-37. Epub 2008/10/22. Mente A, Yusuf S, Islam S, McQueen MJ, Tanomsup S, Onen CL, et al. Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries. Journal of the American College of Cardiology. 2010;55(21):2390-8. Epub 2010/05/22. Carnethon MR, Loria CM, Hill JO, Sidney S, Savage PJ, Liu K. Risk factors for the metabolic syndrome: the Coronary Artery Risk Development in Young Adults (CARDIA) study, 1985-2001. Diabetes care. 2004;27(11):2707-15. Epub 2004/10/27. Ferreira I, Twisk JW, van Mechelen W, Kemper HC, Stehouwer CD. Development of fatness, fitness, and lifestyle from adolescence to the age of 36 years: determinants of the metabolic syndrome in young adults: the amsterdam growth and health longitudinal study. Archives of internal medicine. 2005;165(1):428. Epub 2005/01/12. Dhingra R, Sullivan L, Jacques PF, Wang TJ, Fox CS, Meigs JB, et al. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation. 2007;116(5):480-8. Epub 2007/07/25. Mirmiran P, Noori N, Azizi F. A prospective study of determinants of the metabolic syndrome in adults. Nutrition, metabolism, and cardiovascular diseases: NMCD. 2008;18(8):567-73. Epub 2007/12/11. Lutsey PL, Steffen LM, Stevens J. Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study. Circulation. 2008;117(6):754-61. Epub 2008/01/24. Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, et al. Consumption of Trans Fatty Acids Is Related to Plasma Biomarkers of Inflammation and Endothelial Dysfunction. The Journal of Nutrition. 2005;135(3):562-6. Mozaffarian D, Pischon T, Hankinson SE, Rifai N, Joshipura K, Willett WC, et al. Dietary intake of trans fatty acids and systemic inflammation in women. The American Journal of Clinical Nutrition. 2004;79(4):606-12. Sun Q, Ma J, Campos H, Hankinson SE, Manson JE, Stampfer MJ, et al. A Prospective Study of Trans Fatty Acids in Erythrocytes and Risk of Coronary Heart Disease. Circulation. 2007;115(14):185865. Astrup A, Dyerberg J, Elwood P, Hermansen K, Hu FB, Jakobsen MU, et al. The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010? Am J Clin Nutr. 2011;93(4):684-8. Epub 2011/01/29. Jakobsen MU, O'Reilly EJ, Heitmann BL, Pereira MA, Balter K, Fraser GE, et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89(5):1425-32. Epub 2009/02/13. Clarke R, Shipley M, Armitage J, Collins R, Harris W. Plasma phospholipid fatty acids and CHD in older men: Whitehall study of London civil servants. The British journal of nutrition. 2009;102(2):279-84. Epub 2008/12/25. Jakobsen MU, Dethlefsen C, Joensen AM, Stegger J, Tjonneland A, Schmidt EB, et al. Intake of carbohydrates compared with intake of saturated fatty acids and risk of myocardial infarction: importance of the glycemic index. Am J Clin Nutr. 2010;91(6):1764-8. Epub 2010/04/09. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA: the journal of the American Medical Association. 2006;296(15):1885-99. Epub 2006/10/19. Tierney AC, McMonagle J, Shaw DI, Gulseth HL, Helal O, Saris WH, et al. Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome--LIPGENE: a European randomized dietary intervention study. Int J Obes (Lond). 2011;35(6):800-9. Epub 2010/10/13. Meyer BJ, Lane AE, Mann NJ. Comparison of seal oil to tuna oil on plasma lipid levels and blood pressure in hypertriglyceridaemic subjects. Lipids. 2009;44(9):827-35. Epub 2009/09/04. Julius U. Fat modification in the diabetes diet. Experimental and clinical endocrinology & diabetes: official journal, German Society of Endocrinology [and] German Diabetes Association. 2003;111(2):60-5. Epub 2003/05/15.

Diet and Metabolic Syndrome [55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69] [70]

[71]

[72]

Cicero AF, Ertek S, Borghi C. Omega-3 polyunsaturated fatty acids: their potential role in blood pressure prevention and management. Current vascular pharmacology. 2009;7(3):330-7. Epub 2009/07/16. Borghi C, Cicero AF. Omega-3 polyunsaturated fatty acids: Their potential role in blood pressure prevention and management. Heart international. 2006;2(2):98. Epub 2006/01/01. Lopez-Garcia E, Schulze MB, Manson JE, Meigs JB, Albert CM, Rifai N, et al. Consumption of (n-3) Fatty Acids Is Related to Plasma Biomarkers of Inflammation and Endothelial Activation in Women. The Journal of Nutrition. 2004;134(7):1806-11. Dangardt F, Osika W, Chen Y, Nilsson U, Gan LM, Gronowitz E, et al. Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. Atherosclerosis. 2010;212(2):580-5. Epub 2010/08/24. McEwen B, Morel-Kopp MC, Tofler G, Ward C. Effect of omega3 fish oil on cardiovascular risk in diabetes. The Diabetes educator. 2010;36(4):565-84. Epub 2010/06/11. Kaushik M, Mozaffarian D, Spiegelman D, Manson JE, Willett WC, Hu FB. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. The American Journal of Clinical Nutrition. 2009;90(3):613-20. Due A, Larsen TM, Hermansen K, Stender S, Holst JJ, Toubro Sr, et al. Comparison of the effects on insulin resistance and glucose tolerance of 6-mo high-monounsaturated-fat, low-fat, and control diets. The American Journal of Clinical Nutrition. 2008;87(4):85562. Sloth B, Due A, Larsen TM, Holst JJ, Heding A, Astrup A. The effect of a high-MUFA, low-glycaemic index diet and a low-fat diet on appetite and glucose metabolism during a 6-month weight maintenance period. British Journal of Nutrition. 2009;101(12):1846-58. Due A, Larsen TM, Mu H, Hermansen K, Stender S, Astrup A. Comparison of 3 ad libitum diets for weight-loss maintenance, risk of cardiovascular disease, and diabetes: a 6-mo randomized, controlled trial. The American Journal of Clinical Nutrition. 2008;88(5):1232-41. Rivellese AA, Maffettone A, Vessby B, Uusitupa M, Hermansen K, Berglund L, et al. Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and postprandial lipid metabolism in healthy subjects. Atherosclerosis. 2003;167(1):149-58. Epub 2003/03/06. Thomsen C, Rasmussen O, Lousen T, Holst JJ, Fenselau S, Schrezenmeir J, et al. Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr. 1999;69(6):1135-43. Epub 1999/06/05. Rasmussen BM, Vessby B, Uusitupa M, Berglund L, Pedersen E, Riccardi G, et al. Effects of dietary saturated, monounsaturated, and n-3 fatty acids on blood pressure in healthy subjects. Am J Clin Nutr. 2006;83(2):221-6. Epub 2006/02/14. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia. 2001;44(3):312-9. Epub 2001/04/25. Paniagua JA, Gallego de la Sacristana A, Romero I, Vidal-Puig A, Latre JM, Sanchez E, et al. Monounsaturated fat-rich diet prevents central body fat distribution and decreases postprandial adiponectin expression induced by a carbohydrate-rich diet in insulin-resistant subjects. Diabetes care. 2007;30(7):1717-23. Epub 2007/03/27. Pajvani UB, Scherer PE. Adiponectin: systemic contributor to insulin sensitivity. Current diabetes reports. 2003;3(3):207-13. Epub 2003/05/24. Walker KZ, O'Dea K, Johnson L, Sinclair AJ, Piers LS, Nicholson GC, et al. Body fat distribution and non-insulin-dependent diabetes: comparison of a fiber-rich, high-carbohydrate, low-fat (23%) diet and a 35% fat diet high in monounsaturated fat. Am J Clin Nutr. 1996;63(2):254-60. Epub 1996/02/01. Key TJ, Fraser GE, Thorogood M, Appleby PN, Beral V, Reeves G, et al. Mortality in vegetarians and non-vegetarians: a collaborative analysis of 8300 deaths among 76,000 men and women in five prospective studies. Public health nutrition. 1998;1(1):33-41. Epub 1999/11/11. Perez-Jimenez F, Lopez-Miranda J, Pinillos MD, Gomez P, PazRojas E, Montilla P, et al. A Mediterranean and a high-


[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80] [81]

[82]

[83]

[84] [85]

[86] [87]

[88]

[89]

[90]

[91]

[92]

13

carbohydrate diet improve glucose metabolism in healthy young persons. Diabetologia. 2001;44(11):2038-43. Epub 2001/11/24. Paniagua JA, de la Sacristana AG, Sanchez E, Romero I, VidalPuig A, Berral FJ, et al. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr. 2007;26(5):434-44. Epub 2007/10/05. Field AE, Willett WC, Lissner L, Colditz GA. Dietary fat and weight gain among women in the Nurses' Health Study. Obesity (Silver Spring). 2007;15(4):967-76. Epub 2007/04/12. He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, et al. Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study. BMJ. 2003;327(7418):777-82. Epub 2003/10/04. Hu FB, Stampfer MJ, Manson JE, Rimm E, Colditz GA, Rosner BA, et al. Dietary fat intake and the risk of coronary heart disease in women. The New England journal of medicine. 1997;337(21):1491-9. Epub 1997/11/20. Koh-Banerjee P, Chu NF, Spiegelman D, Rosner B, Colditz G, Willett W, et al. Prospective study of the association of changes in dietary intake, physical activity, alcohol consumption, and smoking with 9-y gain in waist circumference among 16 587 US men. Am J Clin Nutr. 2003;78(4):719-27. Epub 2003/10/03. Xu J, Eilat-Adar S, Loria C, Goldbourt U, Howard BV, Fabsitz RR, et al. Dietary fat intake and risk of coronary heart disease: the Strong Heart Study. Am J Clin Nutr. 2006;84(4):894-902. Epub 2006/10/07. Astrup A. The role of dietary fat in the prevention and treatment of obesity. Efficacy and safety of low-fat diets. Int J Obes Relat Metab Disord. 2001;25 Suppl 1:S46-50. Epub 2001/07/24. Jequier E. Response to and range of acceptable fat intake in adults. Eur J Clin Nutr. 1999;53 Suppl 1:S84-8; discussion S8-93. Epub 1999/06/12. Fats and fatty acids in human nutrition. Proceedings of the Joint FAO/WHO Expert Consultation. November 10-14, 2008. Geneva, Switzerland. Annals of nutrition & metabolism. 2009;55(1-3):5300. Epub 2009/12/03. Jenkins D, Wolever T, Taylor R, Barker H, Fielden H, Baldwin J, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. The American Journal of Clinical Nutrition. 1981;34(3):362-6. Brand-Miller JC, Holt SH, Pawlak DB, McMillan J. Glycemic index and obesity. Am J Clin Nutr. 2002;76(1):281S-5S. Epub 2002/06/26. Borneo R, Leon AE. Whole grain cereals: functional components and health benefits. Food & function. 2011. Epub 2011/12/03. Schulze MB, Liu S, Rimm EB, Manson JE, Willett WC, Hu FB. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women. The American Journal of Clinical Nutrition. 2004;80(2):348-56. Salmeron J, Ascherio A, Rimm EB, Colditz GA, Spiegelman D, Jenkins DJ, et al. Dietary fiber, glycemic load, and risk of NIDDM in men. Diabetes care. 1997;20(4):545-50. Epub 1997/04/01. Sluijs I, van der Schouw YT, van der AD, Spijkerman AM, Hu FB, Grobbee DE, et al. Carbohydrate quantity and quality and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) study. The American journal of clinical nutrition. 2010;92(4):905-11. Epub 2010/08/06. Oh K, Hu FB, Manson JE, Stampfer MJ, Willett WC. Dietary Fat Intake and Risk of Coronary Heart Disease in Women: 20 Years of Follow-up of the Nurses' Health Study. American Journal of Epidemiology. 2005;161(7):672-9. Barclay AW, Petocz P, McMillan-Price J, Flood VM, Prvan T, Mitchell P, et al. Glycemic index, glycemic load, and chronic disease risk--a meta-analysis of observational studies. Am J Clin Nutr. 2008;87(3):627-37. Epub 2008/03/11. Wu T, Giovannucci E, Pischon T, Hankinson SE, Ma J, Rifai N, et al. Fructose, glycemic load, and quantity and quality of carbohydrate in relation to plasma C-peptide concentrations in US women. Am J Clin Nutr. 2004;80(4):1043-9. Epub 2004/09/28. Liu S, Manson JE, Buring JE, Stampfer MJ, Willett WC, Ridker PM. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr. 2002;75(3):492-8. Epub 2002/02/28. Sloth B, Krog-Mikkelsen I, Flint A, Tetens I, Bjorck I, Vinoy S, et al. No difference in body weight decrease between a low-glycemicindex and a high-glycemic-index diet but reduced LDL cholesterol


[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

after 10-wk ad libitum intake of the low-glycemic-index diet. Am J Clin Nutr. 2004;80(2):337-47. Epub 2004/07/28. Shikany JM, Phadke RP, Redden DT, Gower BA. Effects of lowand high-glycemic index/glycemic load diets on coronary heart disease risk factors in overweight/obese men. Metabolism: clinical and experimental. 2009;58(12):1793-801. Epub 2009/07/28. Jarvi AE, Karlstrom BE, Granfeldt YE, Bjorck IE, Asp NG, Vessby BO. Improved glycemic control and lipid profile and normalized fibrinolytic activity on a low-glycemic index diet in type 2 diabetic patients. Diabetes care. 1999;22(1):10-8. Epub 1999/05/20. Heilbronn LK, Noakes M, Clifton PM. The effect of high- and lowglycemic index energy restricted diets on plasma lipid and glucose profiles in type 2 diabetic subjects with varying glycemic control. J Am Coll Nutr. 2002;21(2):120-7. Epub 2002/05/10. Larsen TM, Dalskov SM, van Baak M, Jebb SA, Papadaki A, Pfeiffer AF, et al. Diets with high or low protein content and glycemic index for weight-loss maintenance. The New England journal of medicine. 2010;363(22):2102-13. Epub 2010/11/26. Gogebakan O, Kohl A, Osterhoff MA, van Baak MA, Jebb SA, Papadaki A, et al. Effects of Weight Loss and Long-Term Weight Maintenance With Diets Varying in Protein and Glycemic Index on Cardiovascular Risk Factors: The Diet, Obesity, and Genes (DiOGenes) Study: A Randomized, Controlled Trial. Circulation. 2011. Epub 2011/11/23. Wolever TM, Gibbs AL, Mehling C, Chiasson JL, Connelly PW, Josse RG, et al. The Canadian Trial of Carbohydrates in Diabetes (CCD), a 1-y controlled trial of low-glycemic-index dietary carbohydrate in type 2 diabetes: no effect on glycated hemoglobin but reduction in C-reactive protein. Am J Clin Nutr. 2008;87(1):114-25. Epub 2008/01/08. Du H, van der AD, van Bakel MM, van der Kallen CJ, Blaak EE, van Greevenbroek MM, et al. Glycemic index and glycemic load in relation to food and nutrient intake and metabolic risk factors in a Dutch population. Am J Clin Nutr. 2008;87(3):655-61. Epub 2008/03/11. Liu S, Manson JE, Stampfer MJ, Holmes MD, Hu FB, Hankinson SE, et al. Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women. Am J Clin Nutr. 2001;73(3):560-6. Epub 2001/03/10. van Dam RM, Visscher AW, Feskens EJ, Verhoef P, Kromhout D. Dietary glycemic index in relation to metabolic risk factors and incidence of coronary heart disease: the Zutphen Elderly Study. Eur J Clin Nutr. 2000;54(9):726-31. Epub 2000/09/26. Oxlund AL, Heitmann BL. Glycaemic index and glycaemic load in relation to blood lipids - 6 years of follow-up in adult Danish men and women. Public health nutrition. 2006;9(6):737-45. Epub 2006/08/24. Sacks FM, Obarzanek E, Windhauser MM, Svetkey LP, Vollmer WM, McCullough M, et al. Rationale and design of the Dietary Approaches to Stop Hypertension trial (DASH): A multicenter controlled-feeding study of dietary patterns to lower blood pressure. Annals of Epidemiology. 1995;5(2):108-18. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, et al. A Clinical Trial of the Effects of Dietary Patterns on Blood Pressure. New England Journal of Medicine. 1997;336(16):1117-24. Svetkey LP, Simons-Morton D, Vollmer WM, Appel LJ, Conlin PR, Ryan DH, et al. Effects of Dietary Patterns on Blood Pressure: Subgroup Analysis of the Dietary Approaches to Stop Hypertension (DASH) Randomized Clinical Trial. Arch Intern Med. 1999;159(3):285-93. Prather AA, Blumenthal JA, Hinderliter AL, Sherwood A. Ethnic Differences in the Effects of the DASH Diet on Nocturnal Blood Pressure Dipping in Individuals with High Blood Pressure. Am J Hypertens. 2011;24(12):1338-44. Obarzanek E, Sacks FM, Vollmer WM, Bray GA, Miller ER, Lin P-H, et al. Effects on blood lipids of a blood pressureÂ–lowering diet: the Dietary Approaches to Stop Hypertension (DASH) Trial. The American Journal of Clinical Nutrition. 2001;74(1):80-9. Azadbakht L, Fard NRP, Karimi M, Baghaei MH, Surkan PJ, Rahimi M, et al. Effects of the Dietary Approaches to Stop Hypertension (DASH) Eating Plan on Cardiovascular Risks Among Type 2 Diabetic Patients. Diabetes Care. 2011;34(1):55-7.

Keane et al. [109]

[110]

[111]

[112] [113]

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121] [122]

[123]

[124]

[125]

[126]

Azadbakht L, Surkan PJ, Esmaillzadeh A, Willett WC. The Dietary Approaches to Stop Hypertension Eating Plan Affects C-Reactive Protein, Coagulation Abnormalities, and Hepatic Function Tests among Type 2 Diabetic Patients. The Journal of Nutrition. 2011;141(6):1083-8. Liese AD, Nichols M, Sun X, D'Agostino RB, Haffner SM. Adherence to the DASH Diet Is Inversely Associated With Incidence of Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study. Diabetes Care. 2009;32(8):1434-6. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi T, Azizi F. Beneficial Effects of a Dietary Approaches to Stop Hypertension Eating Plan on Features of the Metabolic Syndrome. Diabetes Care. 2005;28(12):2823-31. Kimokoti RW, Brown LS. Dietary management of the metabolic syndrome. Clin Pharmacol Ther. 2011;90(1):184-7. Epub 2011/06/03. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes care. 1997;20(4):537-44. Epub 1997/04/01. Paniagua JA, Perez-Martinez P, Gjelstad IM, Tierney AC, Delgado-Lista J, Defoort C, et al. A low-fat high-carbohydrate diet supplemented with long-chain n-3 PUFA reduces the risk of the metabolic syndrome. Atherosclerosis. 2011;218(2):443-50. Epub 2011/08/16. Roumen C, Corpeleijn E, Feskens EJ, Mensink M, Saris WH, Blaak EE. Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study. Diabet Med. 2008;25(5):597605. Epub 2008/05/01. Lindstrom J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, et al. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity. Diabetes care. 2003;26(12):3230-6. Epub 2003/11/25. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England journal of medicine. 2001;344(18):1343-50. Epub 2001/05/03. Ilanne-Parikka P, Eriksson JG, Lindstrom J, Peltonen M, Aunola S, Hamalainen H, et al. Effect of lifestyle intervention on the occurrence of metabolic syndrome and its components in the Finnish Diabetes Prevention Study. Diabetes care. 2008;31(4):8057. Epub 2008/01/11. Lindstrom J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemio K, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368(9548):1673-9. Epub 2006/11/14. Lindstrom J, Peltonen M, Eriksson JG, Louheranta A, Fogelholm M, Uusitupa M, et al. High-fibre, low-fat diet predicts long-term weight loss and decreased type 2 diabetes risk: the Finnish Diabetes Prevention Study. Diabetologia. 2006;49(5):912-20. Epub 2006/03/17. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes care. 2002;25(12):2165-71. Epub 2002/11/28. Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, Delahanty L, et al. Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes care. 2006;29(9):2102-7. Epub 2006/08/29. Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes. 2005;54(8):2404-14. Epub 2005/07/28. Mather KJ, Funahashi T, Matsuzawa Y, Edelstein S, Bray GA, Kahn SE, et al. Adiponectin, change in adiponectin, and progression to diabetes in the Diabetes Prevention Program. Diabetes. 2008;57(4):980-6. Epub 2008/01/15. Festa A, D'Agostino R, Jr., Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002;51(4):1131-7. Epub 2002/03/28. Devaraj S, Valleggi S, Siegel D, Jialal I. Role of C-reactive protein in contributing to increased cardiovascular risk in metabolic


[127]

[128]

[129]

[130]

[131]

[132]

[133] [134] [135]

[136] [137]

[138]

[139] [140]

[141]

[142]

[143] [144]

[145]

[146]

syndrome. Current atherosclerosis reports. 2010;12(2):110-8. Epub 2010/04/29. Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54(5):1566-72. Epub 2005/04/28. Ratner RE. An update on the Diabetes Prevention Program. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2006;12 Suppl 1:20-4. Epub 2006/04/22. Ratner R, Goldberg R, Haffner S, Marcovina S, Orchard T, Fowler S, et al. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes care. 2005;28(4):888-94. Epub 2005/03/29. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677-86. Epub 2009/11/03. Mensink M, Feskens EJ, Saris WH, De Bruin TW, Blaak EE. Study on Lifestyle Intervention and Impaired Glucose Tolerance Maastricht (SLIM): preliminary results after one year. Int J Obes Relat Metab Disord. 2003;27(3):377-84. Epub 2003/03/12. Corpeleijn E, Feskens EJ, Jansen EH, Mensink M, Saris WH, de Bruin TW, et al. Improvements in glucose tolerance and insulin sensitivity after lifestyle intervention are related to changes in serum fatty acid profile and desaturase activities: the SLIM study. Diabetologia. 2006;49(10):2392-401. Epub 2006/08/10. Hardy G. Nutraceuticals and functional foods: introduction and meaning. Nutrition. 2000;16(7-8):688-9. Epub 2000/07/25. Kwak NS, Jukes DJ. Current international approaches to food claims. Nutr Rev. 2000;58(12):370-7. Epub 2001/02/24. Stanton C, Ross RP, Fitzgerald GF, Van Sinderen D. Fermented functional foods based on probiotics and their biogenic metabolites. Current opinion in biotechnology. 2005;16(2):198-203. Epub 2005/04/16. Lordan S, Ross RP, Stanton C. Marine bioactives as functional food ingredients: potential to reduce the incidence of chronic diseases. Marine drugs. 2011;9(6):1056-100. Epub 2011/07/13. Kitts DD. Bioactive substances in food: identification and potential uses. Can J Physiol Pharmacol. 1994;72(4):423-34. Epub 1994/04/01. Marinangeli CP, Jones PJ. Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of metabolic syndrome. Annals of medicine. 2010;42(5):317-33. Epub 2010/05/22. Cherniack EP. Polyphenols: planting the seeds of treatment for the metabolic syndrome. Nutrition. 2011;27(6):617-23. Epub 2011/03/04. Siro I, Kapolna E, Kapolna B, Lugasi A. Functional food. Product development, marketing and consumer acceptance--a review. Appetite. 2008;51(3):456-67. Epub 2008/06/28. Oliver E, McGillicuddy FC, Harford KA, Reynolds CM, Phillips CM, Ferguson JF, et al. Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA. J Nutr Biochem. 2011. Epub 2011/12/06. El Khoury D, Cuda C, Luhovyy BL, Anderson GH. Beta glucan: health benefits in obesity and metabolic syndrome. Journal of nutrition and metabolism. 2012;2012:851362. Epub 2011/12/22. Cam A, de Mejia EG. Role of dietary proteins and peptides in cardiovascular disease. Mol Nutr Food Res. 2012;56(1):53-66. Epub 2011/11/29. Sano J, Ohki K, Higuchi T, Aihara K, Mizuno S, Kajimoto O, et al. Effect of casein hydrolysate, prepared with protease derived from Aspergillus oryzae, on subjects with high-normal blood pressure or mild hypertension. Journal of medicinal food. 2005;8(4):423-30. Epub 2005/12/29. Mizuno S, Matsuura K, Gotou T, Nishimura S, Kajimoto O, Yabune M, et al. Antihypertensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild hypertension. Br J Nutr. 2005;94(1):84-91. Epub 2005/08/24. Puddu P, Latorre D, Carollo M, Catizone A, Ricci G, Valenti P, et al. Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells. PLoS One. 2011;6(7):e22504. Epub 2011/07/30.

Current Vascular Pharmacology, 2013, Vol. 11, No. 00 [147]

[148]

[149]

[150] [151]

[152]

[153]

[154]

[155]

[156]

[157]

[158]

[159]

[160]

[161]

[162]

[163]

[164]

15

Bharadwaj S, Naidu TA, Betageri GV, Prasadarao NV, Naidu AS. Inflammatory responses improve with milk ribonuclease-enriched lactoferrin supplementation in postmenopausal women. Inflammation research: official journal of the European Histamine Research Society [et al]. 2010;59(11):971-8. Epub 2010/05/18. Ono T, Murakoshi M, Suzuki N, Iida N, Ohdera M, Iigo M, et al. Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br J Nutr. 2010;104(11):1688-95. Epub 2010/08/10. Keogh JB, Clifton P. The effect of meal replacements high in glycomacropeptide on weight loss and markers of cardiovascular disease risk. The American journal of clinical nutrition. 2008;87(6):1602-5. Epub 2008/06/11. Pupovac J, Anderson GH. Dietary peptides induce satiety via cholecystokinin-A and peripheral opioid receptors in rats. The Journal of nutrition. 2002;132(9):2775-80. Epub 2002/09/11. Froetschel MA, Azain MJ, Edwards GL, Barb CR, Amos HE. Opioid and cholecystokinin antagonists alleviate gastric inhibition of food intake by premeal loads of casein in meal-fed rats. The Journal of nutrition. 2001;131(12):3270-6. Epub 2001/12/12. Shimizu M, Sawashita N, Morimatsu F, Ichikawa J, Taguchi Y, Ijiri Y, et al. Antithrombotic papain-hydrolyzed peptides isolated from pork meat. Thrombosis research. 2009;123(5):753-7. Epub 2008/10/22. Zhang Y, Kouguchi T, Shimizu K, Sato M, Takahata Y, Morimatsu F. Chicken collagen hydrolysate reduces proinflammatory cytokine production in C57BL/6.KOR-ApoEshl mice. Journal of nutritional science and vitaminology. 2010;56(3):208-10. Epub 2010/07/24. Zhang Y, Kouguchi T, Shimizu M, Ohmori T, Takahata Y, Morimatsu F. Chicken collagen hydrolysate protects rats from hypertension and cardiovascular damage. Journal of medicinal food. 2010;13(2):399-405. Epub 2010/02/23. Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract (traditional herb) potentiates in vivo insulinregulated glucose utilization via enhancing insulin signaling in rats. Diabetes research and clinical practice. 2003;62(3):139-48. Epub 2003/11/20. Imparl-Radosevich J, Deas S, Polansky MM, Baedke DA, Ingebritsen TS, Anderson RA, et al. Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signalling. Hormone research. 1998;50(3):177-82. Epub 1998/10/08. Waltner-Law ME, Wang XL, Law BK, Hall RK, Nawano M, Granner DK. Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. The Journal of biological chemistry. 2002;277(38):34933-40. Epub 2002/07/16. Zhou L, Yang Y, Wang X, Liu S, Shang W, Yuan G, et al. Berberine stimulates glucose transport through a mechanism distinct from insulin. Metabolism: clinical and experimental. 2007;56(3):405-12. Epub 2007/02/13. Lai DM, Tu YK, Liu IM, Chen PF, Cheng JT. Mediation of betaendorphin by ginsenoside Rh2 to lower plasma glucose in streptozotocin-induced diabetic rats. Planta medica. 2006;72(1):913. Epub 2006/02/02. Zhang Z, Li X, Lv W, Yang Y, Gao H, Yang J, et al. Ginsenoside Re reduces insulin resistance through inhibition of c-Jun NH2terminal kinase and nuclear factor-kappaB. Mol Endocrinol. 2008;22(1):186-95. Epub 2007/09/22. Roussel AM, Hininger I, Benaraba R, Ziegenfuss TN, Anderson RA. Antioxidant effects of a cinnamon extract in people with impaired fasting glucose that are overweight or obese. J Am Coll Nutr. 2009;28(1):16-21. Epub 2009/07/03. Ziegenfuss TN, Hofheins JE, Mendel RW, Landis J, Anderson RA. Effects of a water-soluble cinnamon extract on body composition and features of the metabolic syndrome in pre-diabetic men and women. Journal of the International Society of Sports Nutrition. 2006;3:45-53. Epub 2008/05/27. Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr. 2008;138(9):1677-83. Epub 2008/08/22. Potenza MA, Marasciulo FL, Tarquinio M, Tiravanti E, Colantuono G, Federici A, et al. EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood


[165] [166]

[167]

[168] [169]

[170]

[171]

[172]

pressure, and protects against myocardial I/R injury in SHR. Am J Physiol Endocrinol Metab. 2007;292(5):E1378-87. Epub 2007/01/18. Wolfram S. Effects of green tea and EGCG on cardiovascular and metabolic health. J Am Coll Nutr. 2007;26(4):373S-88S. Epub 2007/10/02. Hill AM, Coates AM, Buckley JD, Ross R, Thielecke F, Howe PR. Can EGCG reduce abdominal fat in obese subjects? J Am Coll Nutr. 2007;26(4):396S-402S. Epub 2007/10/02. Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. The Journal of clinical endocrinology and metabolism. 2008;93(7):2559-65. Epub 2008/04/10. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism: clinical and experimental. 2008;57(5):712-7. Epub 2008/04/30. Strobel P, Allard C, Perez-Acle T, Calderon R, Aldunate R, Leighton F. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. Biochem J. 2005;386(Pt 3):471-8. Epub 2004/10/08. Wang A, Liu M, Liu X, Dong LQ, Glickman RD, Slaga TJ, et al. Up-regulation of adiponectin by resveratrol: the essential roles of the Akt/FOXO1 and AMP-activated protein kinase signaling pathways and DsbA-L. The Journal of biological chemistry. 2011;286(1):60-6. Epub 2010/10/29. Rivera L, Moron R, Sanchez M, Zarzuelo A, Galisteo M. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity (Silver Spring). 2008;16(9):2081-7. Epub 2008/06/14. Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, Settler U, PlachtaDanielzik S, et al. Quercetin reduces systolic blood pressure and

Received: ?????? 29, 2012

Revised: ?????? 1, 2012

Accepted: ?????? 15, 2012

Keane et al.

[173]

[174] [175]

[176]

[177]

[178] [179]

plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr. 2009;102(7):1065-74. Epub 2009/05/01. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14(5):612-22. Epub 2011/11/08. Bertelli AA, Das DK. Grapes, wines, resveratrol, and heart health. Journal of cardiovascular pharmacology. 2009;54(6):468-76. Epub 2009/09/23. Opie LH, Lecour S. The red wine hypothesis: from concepts to protective signalling molecules. European heart journal. 2007;28(14):1683-93. Epub 2007/06/15. Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, et al. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clinical hemorheology and microcirculation. 2012. Epub 2012/01/14. Brasnyo P, Molnar GA, Mohas M, Marko L, Laczy B, Cseh J, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. The British journal of nutrition. 2011;106(3):383-9. Epub 2011/03/10. Goldberg DM, Yan J, Soleas GJ. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clinical biochemistry. 2003;36(1):79-87. Epub 2003/01/30. AbuMweis SS, Jew S, Jones PJ. Optimizing clinical trial design for assessing the efficacy of functional foods. Nutr Rev. 2010;68(8):485-99. Epub 2010/07/22.