# data[].attributes.headline
Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome

# data[].attributes.subject
Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome

# data[].attributes.body
Metabolic diseases have been studied extensively in animals. It has been proven that restrictive diets reverse the symptoms in various species. However, this study was conducted using human subjects, and observed the effects of a restrictive diet on patients suffering from metabolic syndrome. This study was done over the course of twelve weeks and proved to be a success. It has warranted the need for more extensive research of the diets of metabolic syndrome patients and how what they eat affect their symptoms. Not only did these patients experience extensive weight loss, but they also improved their cardiovascular health and their overall quality of life. The study calls for a restrictive diet to be implemented into the basic treatment of all metabolic syndrome patients. However, more studies should be done to further solidify these findings. This study was a positive, strong first step into changing the treatment plan for metabolic syndrome and its symptoms.

Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, Wang X, Fleischer JG, Navlakha S, Panda S, Taub PR. Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome. Cell Metab. 2020 Jan 7;31(1):92-104.e5. doi: 10.1016/j.cmet.2019.11.004. Epub 2019 Dec 5. PMID: 31813824; PMCID: PMC6953486.

# data[].attributes.headline
Impact of Mediterranean diet on metabolic syndrome, cancer and longevity

# data[].attributes.subject
Impact of Mediterranean diet on metabolic syndrome, cancer and longevity

# data[].attributes.body
As we know, obesity is associated with adipose tissue dysfunction and increased rates of metabolic syndrome diagnosis. High levels of stored adipose tissue results in increased systemic low-grade bodily inflammation and can trigger over activation of the immune system. This paper presents the impact of the Mediterranean diet and how it can help elongate the lives of those living with metabolic syndrome and help reduce the risk of developing cancer. Those people who live in countries that border the Mediterranean sea, who follow this diet, have much lower incidence rates of cancer.

Areas of chronic low-grade inflammation produce pro-inflammatory cytokines that act on surrounding tissue. Reactive oxygen species are constantly being produced and can play a hand in increased oxidative stress. This diet, antioxidants in particular, help play a role in reducing these reactive oxygen species and helps reduce the risk of cancer.  Polyphenols are organic compounds that are reducing agents found in pants. This study show that polyphenols down regulates angiogenesis, prostaglandins, cellular proliferation, nitric oxide, and oxidative stress. They are known to up-regulate autophagy and help balance pro- and anti-inflammatory cytokines. This is important clinically because early population diet intervention is important in reducing the incidence of metabolic syndrome, cancer, and increasing patient longevity.

Di Daniele, N., Noce, A., Vidiri, M. F., Moriconi, E., Marrone, G., Annicchiarico-Petruzzelli, M., D'Urso, G., Tesauro, M., Rovella, V., & De Lorenzo, A. (2017). Impact of Mediterranean diet on metabolic syndrome, cancer and longevity. Oncotarget, 8(5), 8947–8979. https://doi.org/10.18632/oncotarget.13553

# data[].attributes.attachment_link.readable_text
INTRODUCTION

Obesity and metabolic syndrome (MetS) showed a significant increase in the last decades, becoming a public health problem due to high hospitalization rates, treatment costs and impaired quality of life.

Both obesity that MetS are characterized by insulin resistance that expose the patients to an increased risk of cardiovascular disease and cancer, despite the healthy nutritional habits [ 1]. In fact only 5-10% of cancer cases are linked to genetic causes while 90-95% can be attributed to environment and lifestyle [ 2].

The Mediterranean Diet (MD) is characterized by an adequately balanced combination of fruit and vegetables, fish, cereals, and polyunsaturated fats, with a reduced consumption of meat and dairy products and moderate intake of alcohol, primarily red wine. The value of this diet lies in its ability to preserve the state of health and improve longevity, as United Nations Educational, Scientific and Cultural Organization (UNESCO) declared in 2010 [ 3].

Scientific evidence has showed that the adoption of the Mediterranean diet is a protective factor against the onset of various types of cancer, cardiovascular disease, aging and obesity. As shown by the Epic (European Prospective Investigation into Cancer and Nutrition) study, the MD is the most effective in the prevention of several chronic diseases, including cancer.

The nutrients that are found in abundance in the Mediterranean diet have anti-cancer, anti-inflammatory, anti-obesity properties and contribute together to the maintenance of health status. The anti-tumor effects of the Mediterranean diet are mostly due to the combination of antioxidant elements, fiber and polyunsaturated fats. This dietary pattern is therefore essential as a preventive measure against the onset of cancer and other chronic diseases but also to reduce health care costs.

MEDITERRANEAN DIET, METABOLIC SYNDROME (METS) AND OBESITY

Definition and classification of Mets

Overweight and obesity are highly prevalent worldwide. One billion people in the world are overweight and 300 million are considered obese. Several studies estimate that in 2030, approximately 2 billion people will be overweight and 1,12 billion obese [ 4]. In the United States, abdominal obesity has tripled during the past 40 years [ 5]. More than 25% of the US population can be classified as having the MetS [ 6]. MetS prevalence has increased from 34.3% to 38.5% during the past 15 years [ 7, 8]. Given the prevalence of the phenomenon, obesity is considered an important public health problem, with a strong impact on health status, economy and quality of life. The accumulated adipose tissue, particularly central adiposity, generates a chronic low-grade inflammatory state that is the basis of metabolic disturbances, such as insulin resistance, dyslipidemia and hyperuricemia. Insulin resistance is the "core" of the MetS and abdominal obesity plays a central role in this syndrome.

MetS is characterized by dyslipidemia and arterial hypertension, which are associated with increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) [ 9]. The relationship between obesity and T2DM is so strong that the new term "diabesity" has been introduced. It is a global pandemic favoured by an obesogenic environment that promotes consumption of energy-dense foods and discourages energy expenditure, with the result of weight gain. In recent years there has been an increase in the incidence of obesity in young people, with the result that T2DM and MetS are not exclusive to adulthood but are increasingly observed in childhood [ 10].

Several definitions for MetS have been proposed. In 1988, Reaven first spoke of "the syndrome X," which is currently defined "Metabolic Syndrome". Reaven noticed a close link between risk factors of CVD (glucose intolerance, hyperinsulinemia, high serum triglycerides, low serum high-density lipoprotein cholesterol) and arterial hypertension. Moreover, a prothrombotic and chronic inflammatory state, often is associated with MetS and added subsequently to its definition [ 16, 17]. As late as the 1990s, World Health Organization (WHO) defined MetS as insulin resistance or diabetes or impaired glucose tolerance or impaired fasting glucose, plus two of these conditions: body mass index ≥30kg/m ² or waist/hip ratio >0,9 (man) / >0,85 (woman); blood pressure ≥140/90 mmHg or antihypertensive treatment; triglycerides ≥1,7 mmol/l (150 mg/dl) or lipid-lowering treatment; HDL<0,9 mmol/l (35 mg/dl) (man)<1,0 (39 mg/dl) (woman); albuminuria [ 18].

Later the National Cholesterol Education Program's Adult Treatment Panel III report (NCEP ATP III) and International Diabetes Federation (IDF) proposed a new set of criteria with ethnic/racial specific cut-offs to define MetS. This study group gave less attention to the criteria albuminuria and focused on abdominal obesity expressed as waist circumference. In particular, IDF considers waist circumference as essential criteria of MetS. The main difference between NCEP-ATP III and IDF MetS definition consists in the cut-offs chosen. The definitions of the MetS are summarized in Table 1. The concept of MetS has been disputed [ 19, 20], it is still recognized as a major risk factor cluster for CV disease, even in older subjects in whom MetS confers a 38% higher risk of myocardial infarction and stroke [ 21- 23].
Table 1: Main definitions of Metabolic Syndrome

Insulin resistance or diabetes or impaired glucose tolerance or impaired fasting glucose, plus two of these conditions

At least 3 of the following:

Abdominal obesity defined as waist circumference ≥ 94 cm in men and ≥80 cm in women
Plus at least two of the following criteria:

✓ Body mass index ≥30kg/m ² or waist ratio >0,9 man/ 0,85woman;

✓ Waist circumferences ≥ 102cm man and 88 woman;

✓ Increased fasting tryglicerides > 150 mg/dl (≥1,7 mmol/l) or lipid lowering treatment;

Legend Table 1:

HDL: High Density Lipoprotein

IDF: International Diabetes Federation

NCEP ATP III: National Cholesterol Education Program's Adult Treatment Panel III report

T2DM: type 2 diabetes mellitus

WHO: World Healt Organization

Main definitions drawn up by the WHO, NCEP/ ATP III and IDF of MetS recognized by the scientific world.

Despite the increased urinary albumin excretion (UAE) is not currently reported in diagnostic criteria of the MetS, recent studies had showed that albuminuria is considered an important indicator of cardiovascular risk. Actually, albuminuria and estimated glomerular filtration rate (eGFR) are considered not only biomarkers of progression and diagnosis of chronic Kidney disease (CKD) but also are significantly correlated with MetS and its components [ 24, 25]. In particular, a recent study proposed to reintroduce, in the diagnostic criteria of MetS, the albuminuria and elevated high-sensitive C- Reactive Protein (hs-CRP) [ 26]. In fact, albuminuria and hs-CRP are widely recognized as biomarkers of systemic endothelial dysfunction and low-grade chronic inflammation, respectively. According to guidelines, elevated UAE was defined as UAE ≥30 mg/24h and high hs-CRP as a hs-CRP≥3 mg/l [ 22, 23]. Elevated UAE is associated to higher risk of new-onset T2DM, CVD and CKD, whereas hs-CRP is only correlated to new onset CVD and CKD, but not with the onset of T2DM [ 27]. In fact albuminuria is not only a complication of T2DM but also can precede it [ 27- 30]. In line with these studies, it has been suggested that since the birth, UAE levels are genetically determined and influenced by factors present in the intra-uterine environmental. These values represent both the state vascular and the individual susceptibility to organ damage [ 26- 31].

Phenotypes of obesity

Obesity can be categorised according to four phenotypes: 1) Normal weight obese (NOW) [ 32]; 2) Metabolically obese normal weight (MONW) [ 33, 34]; 3) Metabolically healthy obese (MHO); and 4) Metabolically unhealthy obese (MUO) or "at risk obese" with MetS [ 35]. Furthermore, the sarcopenic obesity was described and related to all these obesity phenotypes [ 36]. NWO syndrome was defined firstly by De Lorenzo et al, in order to indicate subjects with normal Body Mass Index (BMI) (18.5-24.9 kg/m ²) and high body fat percentage (PBF%) (man ≥ 23.5%, woman ≥ 29.2%). They develop early oxidative stress and chronic inflammatory status and they have higher risk of cardio-metabolic diseases and sarcopenic obesity [ 37]. The inflammation is explained by the presence of single nucleotides polymorphisms (SNPs) in specific genes, such as -174G/C promoter polymorphism of the IL-6 gene that correlates to insulin resistance [ 38, 39], polymorphism in IL-15 receptor alpha, in methylenetetrahydrofolate reductase (MTHFR) genes [ 40] and in G/A -308 Tumor Necrosis Factor-alpha (TNF-α). The latter is associated to sarcopenic obesity [ 41]. MONW subjects have a normal weight but metabolic alterations typical of MetS (such as high blood pressure, low insulin sensitivity and dyslipidemia) [ 42, 43]. The higher amount of visceral fat in this phenotype leads to higher blood levels of inflammation cytokines (TNF-α and Interleukin-6 (IL-6) [ 44]. MHO, although have an excess of body fat, are metabolically healthy individuals. In fact, 20-30% of obese adults do not show the metabolic complication associated with obesity. MHO individuals have high insulin-sensitivity, normal blood pressure, no signs of chronic inflammation and normal lipid profile. Therefore, the inflammation is correlated to increasing of adipose tissue but is not always linked to obesity [ 45, 46]. MUO, are also called "at risk" obese subjects. They are obese for both anthropometric parameters (BMI ≥ 30 kg/m ²) and fat mass percentage (PBF > 30%) and develop metabolic abnormalities such as MetS, T2DM and atherosclerotic CVD [ 47, 48]. This phenotype is linked to higher visceral adiposity than subcutaneous adiposity and consequently to a greater fatty acids release into the portal circulation and major deposition in liver [ 49].

The concept of Sarcopenic Obesity was introduced firstly by Roubenoff and co-workers [ 36], who suggested that the inflammation of visceral fat promotes muscle catabolism leading to a loss of muscle mass and muscle weakness [ 50]. Schrager et al demonstrated that sarcopenic obesity was directly related to higher levels of IL-6, CRP, IL-1 receptor antagonist and IL-7; consequently these cytokines were involved in both the development and progression of sarcopenic obesity [ 51]. The identification of obesity phenotypes can allow early detection the subjects at risk to develop the MetS in order to carry out timely personalized diet and drug treatment intervention.

Adiposopathy and inflammation

During positive caloric balance, adipocytes initially become hypertrophic, trigging paracrine adipogenic signaling in order to recruit other fat cells and to maintain AT physiologic functions during increased energy storage [ 62- 64]. When the positive energy balance persists, adipogenesis is impaired causing adipocyte dysfunction [ 65]. The anatomic/functional alterations of AT, promoted by positive caloric balance, in genetically and environmentally susceptible individuals, are responsible of "adiposopathy" or "sick fat". The endocrine and immune responses caused by the "adiposopathy" increase and/or exacerbate metabolic disorders and CVD risk factors (such as T2DM, high blood pressure and dyslipidemia) [ 66]. Furthermore, an increased fat storage induces adipocyte hypertrophy and intracellular hypoxia, causing the release of FFA in the blood. The "spill over" of lipids from dysfunctional adipocyte [ 67] lead to ectopic fat deposition in non adipose tissue/organ (such as liver, muscle, pancreas, kidney and blood vessels) causing "lipotoxicity". In the muscle, lipotoxicity causes IR and in the pancreas reduces insulin secretion [ 66]. This process is the base of "meta-inflammation", a chronic low-grade inflammatory state caused by obesity [ 68]. The lipid storage capacity decrease inhibits preadipocytes differentiation and increases lipolysis. In particular, TNF-α stimulates lipolysis in adipocyte by impairing the function of two enzymes, the hormone-sensitive lipase (HSL) and the fatty triglyceride lipase (ATGL). In this scenario, the macrophage infiltration in AT grows proportionally to BMI, fat mass and adipocyte hypertrophy and is a reversible process in obese patients who lose weight. The chemo-attractant factors such as monocyte-chemotactic protein-1 (MCP-1), chemerin, progranulin and colony stimulating factor-1 (CSF-1) allow the recruitment of macrophages from the bloodstream into AT [ 69] and the shift from a profile mainly anti-inflammatory (M2 macrophages) to a pro-inflammatory profile (M1 macrophages) [ 68]. M1 macrophages induce aerobic glycolysis and they are linked to inflammation and IR. M2 macrophages active oxidative metabolism and release anti-inflammatory cytokines [ 70].

The greater availability of circulating FFA produces storages outside the AT, causing cell dysfunction and cell death. This process (lipotoxicity) is involved in beta cell loss during the progression of T2DM (contributing to insulinopenia) and in the pathogenesis of complications related to T2DM injuring cardiomyocytes, hepatocytes, kidney parenchimal cells and endothelial cells [ 71, 72]. Recently, several deposits of adipose ectopic tissue are discovered in transgenic animal models [ 73]. One of the most involved organs in ectopic fat deposition is the liver, that is fundamental for oxidation and metabolism of FFA. During a positive caloric balance adipocyte hypertrophy and accumulation of VAT may contribute to enhance the flow of FFA to the liver, causing liver steatosis. Patients "inflexible" to hepatic metabolism of fatty acids are more prone to the accumulation of lipids in the liver and, consequently, the development of IR and dyslipidemia [ 64, 74]. Ectopic fats depots are also localized in the renal sinus (RS), where they may compress the renal vein and artery, increase kidney interstitial pressure and decrease sodium excretion. This condition is responsible for both arterial hypertension and CKD [ 75- 77]. Several studies [ 78, 79] have recently demonstrated an ectopic adipose depot in epicardial region. The Epicardial Adipose Tissue (EAT) is metabolically active and located between the heart and pericardium. Anatomically it presents a prevalent localization around the right ventricle [ 80]. EAT produces several bioactive adipokines, as well as pro-inflammatory cytokines and pro-atherogenic substances such as TNF-α, IL-6, resistin, visfatin, omentin, leptin, PAI-1 and angiotensinogen. EAT is also associated with T2DM and obesity [ 81]. Under physiological conditions, the EAT plays a cardio-protective role through the local secretion of adipokines with anti-inflammatory and anti-atherogenic proprieties, as adiponectin and adrenomedullin. However in pathological conditions, the increase in thickness of the epicardial fat reflects the expansion of adipose tissue and visceral infarction, contributing to the development of MetS and coronary artery disease. Given its significant clinical implication, the evaluation of the EAT has been proposed as therapeutic target during the diet therapy or during pharmacological treatments directly or indirectly in order to weight loss [ 82]. During the redistribution of fat depots, adiposity is located undereath the deep fascia of the thigh and inside the muscles. This ectopic fat depot, called intermuscular adipose tissue (IMAT), is linked to insulin sensitivity in obese individual [ 83]. IMAT is also a significant predictor of both muscle and mobility function in older adults [ 84]. In this scenario, MetS cannot be related only to the increase in BMI but also to quantitative and qualitative enhancement of the AT and its localization.

Nutrigenetics and nutrigenomic

Nutrition is probably the principal environmental factor that conditions the expression of genes involved in MetS. Nutrigenomics is defined as a prospective analysis of the differences between nutrients in relation to their impact on gene expression and finally on human health. Nutrigenomics allows us to study the interactions between nutrients and genes in order to establish a diet program according to the individual genetic profile and represents a tool to understand how the components of a particular diet (bioactive compounds) can alter gene expression, through their down and-or up regulation. The Nutrigenomics is a useful instrument in the prevention of Non-Transmissible Chronic Diseases (NTCDs) [ 85]. Nutrigenetics is a retrospective analysis of people genetic variations and their clinical response to specific nutrients. The term nutrigenetics was introduced by Brennan in 1975 [ 86]. Nutrigenetics approach was widely studied: the inter-individual differences in response to dietary factors underline the role of genes. Nutrient intake is manipulated or optimized according to an individuals' genetic profile in order to reduce the risk to onset disease. The relationship between nutrigenetics and obesity, MetS and T2DM is largely based on data relating to dietary fat [ 87- 89]. Sedentary lifestyle behaviour and a greater availability by high-calorie foods, in particular high fat food, are associated to obesity and CVD. The "thrifty genes" play a central role in the development of obesity and metabolic disorders. In the past, these genes promoted fat deposition as energy storage during times of food deprivation. Actually, in a modern environment of physical inactivity and excessive caloric consumption, the thrifty genes are associated to obesity and T2DM [ 90, 91]. Several studies support the interaction between genes and environment. The different nutritional responses are caused by SNPs mutations that occur in a single code base of a gene. They are very frequent: 1 SNP for 1,91 Kb DNA sequence and 5% of all cases of obesity and diabetes has been associated with monogenic disorders. The mutated genes, related to obesity, include leptin (LEP), leptin receptor (LEPR), pro-opiomelanocortin (POMC) and melanocortin-4 receptor (MC4R) [ 92]. Genome-wide association studies (GWAS) have evaluated susceptibility genes of T2DM and obesity. In particular, Calpain 10 (CAPN10), that encodes cysteine protease calpain 10, has been the first identified T2DM susceptibility gene [ 93]. Also, two Single Nucleotides polymorphism (SNPs) are associated with T2DM risk: transcription factor 7-like 2 (TCF7L2) and fat mass and obesity-associated (FTO) gene on chromosome 16. TCF7L2 polymorphisms is related to high risk of dyslipidemia and increased waist circumference. While the homozygous mutation of FTO gene (FTO rs9939609 mutation) is associated to 3 kg heavier and had 1,7 fold increased risk of obesity than the homozygous non-risk allele carriers [ 94]. Actually, FTO rs9939609 SNP is considered one of the most important gene variants predisposing to obesity [ 95] and the LIPGENE-SU.VI MAX study showed that FTO rs9939609 is also associated with overweight and abdominally obesity [ 96].

Numerous genes are also linked to an increased susceptibility to dyslipidemia, particularly peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that regulates adipocyte differentiation, lipid storage, fat-specific gene expression and insulin action. The most prevalent SNPs variants of PPAR γ gene identified is the Pro12Ala, correlated to T2DM, obesity, and other clinical disorders [ 97, 98]. Patients with T2DM carrying the Pro12Ala polymorphism have higher risk of obesity than non-carriers although the same energy intake, perhaps secondary to a better insulin sensitivity [ 99]. LIPGENE-SU.VI.MAX study shows that not only mutation in glucose metabolism but also in fatty acid metabolism cause IR and dyslipidemia, as evidenced by mutations in long-chain acyl CoA synthetase 1 (ACSL1) gene that is an important enzyme for mitochondrial beta-oxidation of long chain fatty acids. The polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745 and rs12503643) in this locus genes increase MetS risk. Furthermore, a low fat dietary or a total dietary polynsatured fatty acids (PUFA) intake higher to 50 th percentile decrease the MetS risk in (G+) carriers [ 100]. The same study indicates that GG homozygotes of rs3790433 SNP at the LEPR gene have higher IR and increased MetS risk. The latter is exacerbated by a diet rich in n-6 PUFA and poor in n-3 PUFA, whereas a high n-3 or low n-6 PUFA background reduces the likelihood of developing MetS [ 101]. Both obesity and the MetS are characterized by a low-grade inflammatory state that causes or exacerbates their co-morbidities. A proper nutrigenomic approach is useful for reducing this inflammation. In fact, foods containing anti-inflammatory bioactives, such as caffeic acid (Yerba mate), tyrosol (olive oil), quercetin (fruits and vegetables), licopene (tomatoes an watermelon) and α-tocoferol (green tea) are able to reduce the inflammation. Its reduction is led by lower expression of ciclo-oxigenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes after the inhibition of Kappa B-nuclear factor's translocation from the cytoplasm to the nucleus [ 102, 103]. Actually nutrigenomics, with the other "omics" sciences (such as Proteomics, Metabolomics and Transcriptomics), represents a pivotal tool in evaluating, treating and preventing different future diseases, especially in the area of NTCDs [ 85].

Nutrigenetic can be used to compose a personalized diet and in this scenario, an interesting study of Arkadianos et al. have shown that the inclusion of genetic information to personalize patient's diet improves the long term BMI reduction and blood glucose levels. In particular, the authors examined in 24 patients, the variants of 19 genes involved in the metabolism, such as methylenetetrahyidrofolate reductase (MTHFR), glutathione S-transferase (GST), superoxide-dismutase (SOD) 2 and 3 and vitamin D receptor (VDR) polymorphisms [ 104].

De Lorenzo et al., in other paper, have demonstrated that T (+) carriers in C677T MTHFR polymorphism have higher cardiovascular disease risk, osteoporosis and sarcopenia. In particular, the authors examined the impact of the C677T MTHFR gene polymorphism on body composition change induced by a balance hypocaloric Italian Mediterranean Diet. Before the nutritional intervention, T (+) carriers patients were fatter than T (-) carriers and after the nutritional intervention T (+) carriers had lower increase in total body lean/total body fat ratio compared to T (-) carriers [ 105]. The increased CV risk for T (+) carriers is due to hyperhomocysteinemia related in turn to lack of 5-methyltetrahydrofolate, necessary to methylate homocysteine (Hcy) into methionine.
Table 2: Interaction genes and nutrients
Personalized diet therapy intervention and nutrients dose change according to genetic polymorphisms.

Impact of mediterranean diet on metabolic syndrome and obesity

The Seven Country Study, an International Cooperative Study on coronary heart disease epidemiology, promoted by the American physiologist Ancel Keys and the Italian Flaminio Fidanza, investigated the benefits of the MD on human health, comparing European rural cohorts (the Mediterranean cohorts Crete, Corfù, Crevalcore, Montegiorgio and Dalmatia) and the non-Mediterranean cohorts (East and West Finland, Slavonia and Velika Krsna).

In order to assess the adhesion to the Healthy Reference National Mediterranean Diet (HRNMD), it was introduced the Mediterranean Adequacy Index (MAI). It is calculated by dividing the sum of total energy percentages of the food groups typical of HRNMD (bread, cereals, legumes, potatoes, vegetables, fresh fruit, nuts, fish, wine, vegetable oil), by the sum of the dietary energy percentage of food groups that are not characteristic of a HRNMD (milk, cheese, meat, eggs, animal fats and margarines, sweet beverages, cakes, pies, cookies and sugar). The membership of food to one of two groups is based on the results of a dietary survey carried out in 1960 in a sub-sample of Nicotera man aged 45-54 years. Nicotera was chosen for low frequency of cardiovascular diseases, T2DM and arterial hypertension [ 111- 113]. The MAI was inversely associated with the 25-year death rates from cardiac heart disease (CHD). In particular, a 2.7point increase of MAI was associated with a CHD mortality decrease of 26% in 20 years of follow-ups and of 21% in 40 years of follow-ups in two Italian rural cohorts of the Seven Countries Study, Crevalcore and Montegiorgio. It was demonstrated that this association is independent from possible confounding factors, such as age, cigarette consumption, systolic blood pressure, serum cholesterol, physical activity and BMI [ 113]. A longitudinal study of Alberti-Fidanza et al. has evaluated how much near or far eating habits of population are from a reference MD. They were investigated men (aged 45-65 years) from rural areas of Italy in the Seven Countries Study for 26 years (Crevalcore and Montegiorgio), elderly men and women from Perugia for 11 years, men and women from Pollica (Salerno) for 32 years and families from Rofrano (Salerno) for 41 years. The median value of MAI among Nicotera's people was 7.2. The examination during four decades has showed that the diet over the years has abandoned the nutritional characteristics of the reference Italian-Mediterranean diet. In particular, in Nicotera, the median MAI of the diet examined in 1996 has decreased to 2.8, while in Crevalcore it was reduced from 2.9 in 1965 to 2.2 in 1991 and in Montegiorgio from 5.6 in 1965 to 3.9 in 1991. In elderly men from Perugia the median value of MAI was decreased from 4.9 in 1976 to 3.2 in 1987, while in women from 3.1 to 2.6 [ 114]. However, many others nutritional indices are proposed to evaluate the efficacy of MD on healthy status. Cholesterol/Saturated Fat Index (CSI) is associated to atherogenicity grade, whereas the Atherogenic Index (AI) and Thrombogenic Index (TI) have been proposed in order to evaluate the possible link between diet and CHD [ 115]. The Mediterranean Diet Score (MDS) was proposed by Trichopoulou et al. in 1995 for the purpose of examine the relationship between MD and CHD in a random sample of 1159 Jewish people in Israel. The study showed that higher MDS correlated to lower risk of myocardial infarction, coronary by-pass, angioplasty and any other cardiovascular disease [ 116]. In 2003 the MDS was modified by Trichopoulou et al., adding moderate fish consumption among the inclusion criteria. A two-points increase in the MDS with fish (t-MED) was associated with a reduction in CHD mortality by 33% [ 117- 119] ( Figure 1).

Figure 1: Representation of Mediterranean Diet by Paestum Temple Modified By De Lorenzo A, Fidanza F [ 89]. As shown in the figure, at the base of the Mediterranean style there is a healthy lifestyle, energy intake equal to the expenditure, extra virgin olive oil and wine. Within the eating habits must be more present: cereals, legumes, fish, fresh fruits, dried fruits and vegetables. While animal foods and simple sugars should be limited use. Moderation should be the focal point of the Mediterranean model.

A US multiethnic population study has compared 4 diet-quality indexes, the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean Diet Score (aMED) and the Dietary Approaches to Stop Hypertension (DASH), in order to evaluate their effectiveness to predict the decrease risk of mortality for all causes. The authors suggested that high scores were inversely related to risk of mortality for CVD and cancer, reinforcing the concept that healthful diet is important to improve the quality of life and to provide a greater longevity [ 120].

A recent meta-analysis conducted by Grosso et al. has linked the association between MD adherence and CVD incidence and mortality. They found an important decrease of incidence of CHD, myocardial infarction and stroke. The most protective effects are associated to higher consumption of olive oil, fruits, vegetables, legumes, nuts and moderate intake of wine (especially red wine) [ 124].

The "ATTICA study" assessed the effect of the MD on total antioxidant capacity in 3042 healthy subjects, selected from the Attica area of Greece. The adherence to MD was evaluated with a diet score. Total antioxidant capacity (TAC) was measured with colorimetric test on serum samples taken from the participants. The study has demonstrated that greater adherence to the MD is associated to higher TAC levels and low oxidized LDL-cholesterol concentrations, suggesting a healthy role of MD on the cardiovascular system [ 125].

It's known that the adherence to MD and the change of unhealthy lifestyle have a great impact on the individual components of the MetS. In fact, the MD can be considered the first step in the treatment of NTCDs [ 126- 128].

De Lorenzo et al had studied the impact of a moderately hypocaloric Mediterranean Diet (MHMD) on body composition and metabolic profile in 19 obese women. After the 2-months MHMD regimen, total fat mass and the segmental fat mass from trunk and legs were significantly decreased, while no significant loss of total and segmental lean body mass was observed. In the metabolic profile, a significant decrease of basal insulin, total and LDL-cholesterol, uric acid and fibrinogen was observed, while any change in fasting blood glucose, HDL-cholesterol and triglycerides was reported. This study has demonstrated that a MHMD with adequate nutritional indices based on foods and food combinations, was associated to a high effectiveness in term of compliance and safety, in particular to prevention of loss of fat-free mass and on metabolic parameters in obese women [ 115]. Andreoli et al. verified the effect of MHMD and physical activity on the body cell mass (BCM) and cardiovascular risk factors in obese women. After 2 and 4 months, the BCM has remained stable while the body composition has improved and major cardiovascular risk factors decreased [ 129, 130]. A recent paper had examined the effect of Italian Mediterranean Diet (IMD) and Italian Mediterranean Organic Diet (IMOD), in healthy subjects and in CKD patients, on body composition and on laboratory parameters. The aims of this study were to evaluate the impact of IMD and IMOD on decrease of cardiovascular risk factors and on the progression of renal disease. The authors demonstrated that the IMOD diet, according to "Nicotera Diet", was able to reduce the total Hcy, phosphorus and albuminuria levels in CKD patients and to ameliorate the cardiovascular risk profile in both population examined [ 131]. Another study of the same authors highlighted that IMD and IMOD diets represent a valid nutritional alternative intervention to low-protein diet in CKD patients on conservative therapy [ 132], since the low protein diet would seem to be a contributory cause of sarcopenia in these patients [ 133]. An interesting study of Di Daniele et al has shown that the IMD promotes weight loss and reduces the growing burden of cardiovascular risk factors that typifies patients with MetS. Specifically, a balanced hypocaloric IMD improves significantly systolic and diastolic blood pressure and fasting glucose in 80 white Italian subjects with MetS. Moreover the authors have observed a resolution of MetS in 52% of treated patients [ 134].
Table 3: Nutritional factors and targets
Ranges of values for the nutritional targets in the general population according to Mediterranean Diet.
* This value is calculated as total fat - (satured fatty acids + polynsatured fatty acids + trans fatty acids)
The Mediterranean Diet is rich of ω-3 PUFA, contained primarily in fish and seafood. Eicosapentaenoic acids (EPA, C20:5, n-3) and docosahexaenoic acid (DHA, C22:6, n-3) are the most important PUFA associated to cardio-protective effects [ 141].

Several intervention studies such as the "Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico" (GISSI- Prevenzione trial and the Cardiovascular Health Study) have demonstrated that enhanced intake of EPA and DHA improves the risk of CHD [ 130- 132]. The cardio-protective effects of EPA and DHA can be explained by their modulate K, Na, and Ca channels activities in myocardial cells, regulating myocyte electrical excitability and contractility. These effects are concentration-dependent [ 142, 143]. The role of n-6 PUFAs on human health is not clearly identified. However, both n-3 and n-6 PUFAs seem to be positive effect on cardiovascular disease, cancer, and depression in humans [ 144]. Many of the characteristic components of the traditional MD are known to have positive effects on the health status and they are called "functional foods". Carotenoids, folic acid and fibers would appear an important role in the prevention of CHD. Consumption vegetables, an important source of phytosterols, is associated with a reduction in the level of cholesterol in serum and cardiovascular risk. The increased consumption of fruits and vegetables, containing phytoestrogenic substances, may offer an alternative to hormonal therapy in menopausal women. In the gut, these residues are converted into estrogens, neutralizing the typical menopausal hormone deprivation. The polyphenols in red wine have antioxidant activity and cytoprotective action and induce a change in the lipoprotein profile, in platelet aggregation, and in redox mechanisms. The wine and other derivatives of red grapes rich in resveratrol (a polyphenol stilbene) determine a vasodilatory effect through the endothelium-dependent up-regulation of nitric oxide (NO) production, and have a significant antioxidant activity. Resveratrol, found in grape skins, is a potent anti-inflammatory by inhibiting iNOS, COX-2 and NF-kB. It was suggested that the histone acetylation, activated by NF-kB, could be suppressed by resveratrol [ 145]. The antioxidant capacity of red wine is higher than antioxidant capacity of white wine because is an excellent source of polyphenolic compounds such as phenolic acids, flavonoids [ 146]. Di Renzo et al have shown that the red wine combined with different meals (such as McDonald's Meal and a Mediterranean Meal) had a positive effect on ox-LDL and antioxidant gene expression (catalase, superoxide dismutase 2, sirtuins 2 and glutathione peroxidase 1). Thanks to its antioxidant capacity the red wine combined with MD may be an essential component of a holistic approach to prevent NTCDs linked to inflammation [ 147]. Several studies confirmed that flavonoids, especially resveratrol, inhibit pre-adipocyte proliferation, adipogenic differentiation and de novo lipogenesis [ 134, 148, 149]. In the PREDIMED population the moderate red wine consumption (≥ 1 drink/d) is associated with a lower prevalence of the MetS in patients at a high cardiovascular risk [ 150].

Another typical food of MD, besides the red wine, with antioxidant capacity is the tomato. Because the lycopene, a carotene phytochemical containing in tomato, induces the up-regulation of anti-oxidant enzymes activity (SOD, GPX and catalase) and shows anti-inflammatory properties and insulin-sensitizing [ 151]. Thanks its characteristics mitigates inflammation related to obesity. Ghavipour et al. have highlighted that daily supplementation with one glass of tomato juice decreases inflammatory cytokines such as TNF-α, IL-6 and IL-8 after 20 days of assumption [ 152]. This result was confirmed by an another study of McEneny et al, in overweight subjects, in which a lycopene supplementation for 12 weeks decreased systemic levels of serum amyloid A [ 153]. Moreover, the daily tomato juice supplementation ameliorates also the body composition: a study on 30 young females with BMI≥20 kg/m ² demonstrated that 280 ml/day of tomato juice for two months significantly reduce body weight, body fat waist circumferences, BMI and serum levels of cholesterol, monocyte chemoattractant protein-1 (MCP-1) while significantly increased serum levels of adiponectin, triglycerides and lycopene [ 154]. The tomato and its products contain some natural compounds (such as chlorogenic, caffeic, ferulic and p-coumaric acids) that may inhibit platelet activation. These anti-platelet and anti-thrombotic activities of tomato were not modified by industrial tomato processing [ 155].

Another potential food promoting the positive effect of the MD is the extra-virgin olive oil, in fact its bioactive components would seem to have endothelium-protective and anti-oxidative properties [ 156]. A systematic review suggested that markers of inflammation such as C-reactive protein, IL-6 and those related to endothelial-function such as flow mediated dilatation and E-selectine, are significantly ameliorated after supplementation of extra-virgin olive oil [ 157]. The polyphenol intake is associated with lower cardiovascular mortality rates [ 158]. Extra-virgin olive polyphenols have strong antioxidant proprieties as demonstrated in experimental studies [ 159]. In healthy subjects and in cardiovascular and dyslipidemic patients, the polyphenols contained in extra-virgin olive oil improved ischemic reactive hyperemia blood pressure and inflammatory status [ 160]. The presence of extra-virgin olive oil in addition to raw vegetables increases the amount of phenolic components as oleuropein, pinoresinol, hydroxytyrosol and tyrosol and improves the contents of vegetable phenolics such as chlorogenic acid and rutin [ 161]. Moreover, olive oil is an excellent MUFA source and improves insulin sensitivity [ 162]. Estruch et al. compared the effects of MD, supplemented with either 1l g/week of virgin olive oil or 30 g/day of nuts and of low-fat diet on CVD markers. After 3 months of diet treatment, in patients with Mediterranean diet plus virgin olive oil or nuts was observed a reduction of ox-LDL levels, whereas any change occurred in low-fat diet group [ 163]. Moreover, MD reduces IR, thanks to the high fibers content [ 164]. In vivo recent study has shown that a diet rich in soluble fibers (20 g/1000 kcal) and a decreased consumption of food items with a high glycemic index decreases the prevalence of MetS by improving blood pressure (BP) and IR [ 165, 166].

Recently the focus has shifted on caffeinated beverages, such as coffee and tea, and their association with the components of MetS. A study conducted on 1889 inhabitants living in Sicily has demonstrated that the intake of coffee and tea reduced the prevalence of MetS and improved the components of MetS, lowering triglycerides and fasting plasma glucose. The antioxidant properties of coffee and tea are associated to the content of polyphenols; in particular, the main polyphenols are the isomers of chlorogenic acid contained in coffee and the catechin chemical family contained in tea [ 167].

The high consumption of fresh fruits, in particular blueberries, is related to anti-inflammatory property. In the human and animal studies, polyphenolic anthocyanins (containing in blueberries) ameliorated systolic BP because of significantly increase of endothelial NO synthase levels and decrease of vasoconstriction, via nitric oxide-mediate pathway, and the reduction of renal oxidative stress [ 168, 169].

The healthy properties of the MD cannot be limited to any single nutrient, food or food component, but they have to be extended to the entire meal pattern and life-style ( Table 4).
Table 4: List of studies about Mediterranean Diet

Healthy volunteers aged 18-65 years and BMI ≥ 19 kg/m ²

The study evaluated if the consumption of a Mc Donald's Meal (McD) and a Mediterranean Meal (MM) with and without the addiction of red wine, reduces oxidized (ox-) LDL and the expression of oxidative and inflammatory genes.

When red wine is associated with McD or MM, values of ox-LDL are lowered, the expression of antioxidant genes is increased, while CCL5 expression is decreased.

Young females with BMI ≥ 30 kg/m ²

This study showed the effect of tomato juice's supplementation on indices linked to metabolic health and adipokine profiles in generally healthy people.

Daily tomato juice supplementation reduces waist circumference, as well as serum cholesterol and inflammatory adipokine levels in young healthy women and these results are unrelated to body fat changes.

Legend Table 4:

CVD: cardiovascular diseases

MHMD: moderately hypocaloric Mediterranean Diet

LDL: Low density lipopretein

HDL: high density liporptein

BCM: Body cellular mass

IMD: Italian Mediterranean Diet

IMOD: Italian Mediterranean Organic Diet

CKD: Chronic kidney disease

LPD: Low protein diet

MTHFR: methylenetetrahydrofolate reductase

McD: Mc Donald's Meal

MM: Medierranean Meal

CCL5:Chemokine (C-C motif) ligand 5

IL-8: interleukin-8

TNF-α: tumor necrosis factor alpha

IL-6: interleukin-6

MD: Mediterranean Diet

TAC: Total antioxidant capacity

MetS: Metabolic Syndrome

SFA: Saturated Fatty Acid

MUFA: Monoinsaturated Fatty Acids

MS: Metabolic Syndrome

IL-12: interleukin-12

LPS: Lipopolysaccharide

The most important studies in the world about the impact of Mediterranean Diet on cardiovascular risk factors: findings suggest the protective role of MD.

MEDITERRANEAN DIET AND CANCER

The cancer, actually, is considered the second cause of death in the world after cardiovascular diseases [ 174].

This energy and anabolic change implies also a significant interplay with autophagy [ 209- 212], a pathway that strongly affects cancer progression, as well as distinct signalling pathways, such as for example JNK [ 212, 213], the p53 family [ 214- 221] death receptors, as well as mechanisms [ 222, 223].

The MD has a preventive action on cancer, because of the anti-proliferative and anti-apoptotic effects on cancer cell [ 236].

In particular, cancer's risk increased from 1.2 to 1.5 in overweight individuals and from 1.5 to 1.8 in obesity people, especially for colon, gastric cardia, liver, gallbladder, pancreas and kidney cancers, while the relative risk for esophageal adenocarcinoma was up to 4.8 in patients with BMI ≥ 40 kg/m ² [ 241- 244].

The worst cancer in women is breast cancer, which accounts for over 25% of all female cancers. Estrogen has a key role in the pathogenesis and progression of this cancer. The MeDiet study investigated the effect of the MD on the levels of endogenous estrogens in healthy postmenopausal women [ 248]. The women enrolled were divided into two different groups: the first group was treated with the MD for six months, while the control group continued the current diet. Urine samples were examined in order to assess the levels of estrogen, which reflect its intra-tissutal content [ 249] The majority of urinary estrogen is represented by hydroxy and methoxy derivatives of estradiol (E2) and estriol (E3). The study revealed that the group receiving MD had reduced levels of hydroxy and keto derivatives of E2 and E3, known as 2-hydroxy E2 (2OHE2), 17EpiE3 and 16KetoE2, respectively 80, 70 and 27% after six months, while they were unchanged in the control group. The study confirmed the protective role of the MD on cancer development, acting on estrogen metabolism.

The MD contributes to the prevention of colorectal cancer through a high intake of fiber. Barera et al. have highlighted the nutraceutical effects of β-glucans, which seem to reduce low-density lipoprotein cholesterol (LDL), IL-6 and advanced glycation end-product (AGE) levels. They are also linked to colon cancer prevention [ 252].

The MD is able to reduce gastric cancer's incidence and mortality in the South areas of selected Mediterranean country, such as France, Greece and Italy when compared with the North areas of the same countries. Higher adherence to MD lower up of 20% the incidence of all gastric cancers [ 253- 255].

The beneficial role of MD has also been confirmed in a large case-control study in Italy. The authors found that an enhanced adherence to MD (high consumption of fruit, vegetables and legumes) reduced risk of both oral cavity and pharynx cancer and larynx cancer [ 256].

Head and neck cancers are currently the sixth cause of death in the world; however, as confirmed by Bosetti et al., a greater adherence to the MD reduces the risk of oral, laryngeal and pharyngeal cancer (by 23 and 29%, respectively) [ 257].

Jacobs et al. have suggested that consumption of whole grain (bran, germ, endosperm) ≥ 4 times / week reduces the risk of cancer by 40% compared to controls, while the Continuous Update Project has determined that the intake of non-starchy vegetables and fruits lowers the risk of mouth, pharynx, larynx, esophagus and stomach cancers [ 258, 259].

On the other hand, the intake of refined cereal grains (bread, pasta or rice) increase the risk of upper digestive tract, stomach, colorectal, breast and thyroid cancer [ 260].

Another pivotal food of the MD is pulses. Thanks to their content in tannins, saponins, protease inhibitor and phytic acid, legumes play an important anti-cancer role [ 261].

Even the consumption of nuts was associated to the reduction of cancer's risk, in particular for those of the digestive tract. The protective role of nuts comes from their content of ellagic acid, anacardic acids, genistein, resveratrol and phytic acid [ 262]. The consumption of peanut products ≥ 2 / week was associated with 58% reduction of colorectal cancer risk in Taiwan women [ 263].

The role of main components of the MD in the prevention of several cancers type has been recently reviewed in several works [ 245, 267, 268, 269] ( Figure 2).

Figure 2: Polyphenols from Mediterranean Diet. Polyphenols protect and reduce inflammation by different pathways (through mechanisms of down-regulation, balance and up-regulation) preventing obesity, cancer and age-related diseases, in which inflammation has an important pathological role [ 240].

MEDITERRANEAN DIET AND LONGEVITY

Tiainen et al. reported that fruit and vegetables consumption was positively linked to leukocyte telomere length in women aged 57-70 years, but not in men with the same age [ 277].

The MDS, together with the Mediterranean Adequacy Index (MDI) and the Healthy Diet Indicator (HDI), were studied during the Healthy Ageing: a European longitudinal study (HALE) that included men and women from ten European countries. The subjects were followed for a 10 years-time observation. The study has confirmed the protective role of MD for elderly subjects with and without baseline chronic diseases [ 277]. A recent prospective study involving 4676 healthy women has demonstrated the relationship between adherence to the MD and telomere length in cells, supporting the concept of the benefits of MD to promote health status and longevity. Any association was noted between the individual MD components and longevity, but was supposed a synergy effect among the nutrients rich foods included in MD [ 278]. In general, subjects who adhere to the traditional MD have a longer life - span [ 275]. Another study confirmed that higher adherence to MD in older adults in the United-States and Israel is linked to better cognitive and physical functions. In fact, in this subjects were detected a faster walking speed and fewer disabilities [ 279]. The PREDIMED trial reports how the MD supplemented with olive oil (1 l/wk) or mixed nuts (30 g/d) is linked to lower cognitive decline, evaluated through standardized neuropsychological tests in older populations [ 280]. In a Greek population cohort study, Trichopoulou et coworkers demonstrated for the first time that higher degree of adherence to MD was correlated with a reduction in total mortality; an increase of two point of MDS was associated with a diminution of 25% mortality of all-causes. This reduction was more evident for CVD respect to cancer [ 281]. A subsequent meta-analysis of prospective studies confirmed a significant protective role of MD against major chronic degenerative disease. In fact, an increase of two-points of MDS induced 8% reduction of death from any causes, a 10% reduction from death and/or incidence of cardio and cerebro-vascular disease and 13% reduction of neuro-degenerative disease [ 246].

The OO protective effect on aging is confirmed by another study that has evaluated the bioactivity of OO compounds on multipotential mesenchymal stem cell (MSC) progenitor differentiation. In fact, osteoblasts and adipocytes derive from the same MSC. Santiago-Mora et al. have demonstrated that oleuropein, one of the most important OO compounds, enhances osteoblastogenesis and inhibits the main adipogenesis regulators, as PPAR-γ2, lowering the incidence of osteoporosis [ 285]. Furthermore, the phenolic compound oleocantale has the same anti-inflammatory effects of ibuprofen, the most common non-steroidal anti-inflammatory. In fact the OO intake decreases inflammation and consequently aging [ 286].

The benefits of MD are evident in the prevention and slowing the progression of chronic degenerative diseases. A meta-analysis highlighted that both men and women who nearest eating habits to MD have a reduced risk of about 10-20% to die for CVD, cancer and other any causes. The MD is significantly inversely associated with both systolic and diastolic BP. A prospective study on 41358 Spanish adult subjects, during 6.5 years of follow-up, evaluated the possible relationship between dietary factors and total mortality. The authors showed that high intakes of fresh fruit and vegetables are associated with decreased mortality, probably related to the high concentration on vitamin C, provitamin A, carotenoids and lycopene. Antioxidant capacity of vitamin C and provitamin A partly explain this effect on mortality [ 287]. The MD, poor in refined sugar and animal proteins, reduces the activity of mTOR and insulin/IGF-1 pathways, lowering the risk of age-related diseases, promoting successful aging and longevity [ 288].

To confirm the protective role of the MD, the Lion Diet Heart Study has shown a reduction in secondary cardiac events, including death and non-fatal myocardial infarction, after a first myocardial infarction. This protective effect remains at least four years after the first heart attack, independent of main cardiovascular risk factors, such as hypertension and dyslipidemia [ 289- 291].

The benefit effect of MD has confirmed also on elderly non-smoking people. In this study 161 nonsmoking individuals, aged 65-90, were separated into two different groups: the first were 65-80 years, the latter > 80 years. The study has demonstrated that the total diet score, based on 8 main components of MD, is positivity associated to higher longevity in patients less 80 years, but not in those greater than 80. The authors have noted also that higher albumin concentration is linked to lower mortality [ 292].

The MD includes a high significantly quantity of foods rich in antioxidant compounds, which can help explain its many benefits. The extra virgin olive oil, vegetables, fresh fruits, nuts, wine and fish, contain molecules with anti-oxidants and anti-inflammatory properties, as monounsaturated fatty acids, fatty acids omega 3, polyphenols, flavonoids, phytosterols, vitamins, antioxidants, minerals and micronutrients. These factors act on longevity and slow the development of chronic diseases associated with aging [ 293].

MD effect on telomere length makes itself a powerful anti-aging tool.

CONCLUSION

Abbreviations

a MED: alternate Mediterranean Diet Score; ACSL1: long-chain acyl CoA synthetase 1; AHEI-2010: the Alternative HEI-2010; AI: Atherogenic Index; AT: Adipose tissue; ATGL: fatty triglyceride lipase; BAT: brown adipose tissue; BCM: body cell mass; BMD: bone mineral density; BP: blood pressure; CAPN10: Calpain 10; CHD: cardiac heart disease; CKD: chronic kidney disease; COX: ciclo-oxigenase; CSF1: colony stimulating factor-1; CSI: Cholesterol/Saturated Fat Index; CVD: cardiovascular diseases; DASH: Dietary Approaches to Stop Hypertension; DHA: docosahexaenoic acid; DII: Dietary Inflammatory Index; e-GFR: estimated glomerular filtration rate; EAT: Epicardial Adipose Tissue; EPA: Eicosapentaenoic acids; FFA: free fatty acids; FTO: fat mass and obesity-associated; GISSI: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico; GST: glutathione S-transferase; GWAS: Genome-wide association studies; HALE: Healthy Ageing: a European longitudinal study; Hcy: homocysteine; HDI: Healthy Diet Indicator; HEI-2010: Healthy Eating Index-2010; HRNMD: Healthy Reference National Mediterranean Diet; hs-CRP: high-sensitive C- Reactive Protein; HSL: hormone-sensitive lipase; IDF: International Diabetes Federation; IL-1: interleukin-1; IL-6: interleukin-6; IMAT: intermuscular adipose tissue; IMOD: Italian Mediterranean Organic Diet; iNOS: inducible nitric oxide synthase; IR: insulin resistance; KANWU: Kopio, Aahhus, Naples, Wollongon and Uppsala; LEP: leptin; LEPR: leptin receptor; MAI: Mediterranean Adequacy Index; MC4R: melanocortin-4 receptor; MCP-1: monocyte-chemotactic protein-1; MD: Mediterranean Diet; MDA: malondialdehyde; MDI: Mediterranean Adequacy Index; MDS: Mediterranean Diet Score; MetS: Metabolic Syndrome; MHMD: moderately hypocaloric Mediterranean Diet; MHO: Metabolically Healthy Obese; MONW: Metabolically Obese Normal Weight; MTHFR: methylenetetrahydrofolate reductase; MUFObes: MUFA in Obesity; MUO: Metabolically Unhealthy Obese; NCEP ATP III: National Cholesterol Education Program's Adult Treatment Panel III report; NO: nitric oxide; NOW: Normal Weight Obese; NTCDs: Non-transmissible Chronic Diseases; OO: olive oil; PAI-1: pro-coagulant substances; PBF: body fat percentage; POMC: pro-opiomelanocortin; PPARγ: peroxisome proliferator-activated receptor γ; PREDIMED: PREvenciòn con DIeta MEDiterrànea; PUFA: polyunsaturated fatty acids; ROS: Reactive Oxygen Species ; RS: renal sinus; SAT: subcutaneous adipose tissue; SFA: saturated fatty acid; SNPs: single nucleotides polymorphisms; SOD: superoxide-dismutase; t-MED: MDS with fish; T2DM: type 2 diabetes mellitus; TAC: Total antioxidant capacity; TCF7L2: transcription factor 7-like 2; TI: Thrombogenic Index; TNF-α: tumor necrosis factor alpha; UAE: urinary albumin excretion; UNESCO: United Nations Educational, Scientific and Cultural Organization; VAT: visceral adipose tissue; VCAM1: vascular cell adhesion-1; VDR: vitamin D receptor; WAT: white adipose tissue.

ACKNOWLEDGMENTS

We would like to express gratitude to dr Eleonora Candi for critical reading of the manuscript. This work was supported by grants from Fondazione Roma.

CONFLICTS OF INTEREST

These authors declare no conflicts of interests.

REFERENCES

1. Noto D, Cefalù AB, Barbagallo CM, Ganci A, Cavera G, Fayer F, Palesano O, Spina R, Valenti V, Altieri GI, Caldarella R, Giammanco A, Termini R, et al. Baseline metabolic disturbances and the twenty-five years risk of incident cancer in a Mediterranean population. Nutr Metab Cardiovasc Dis. 2016; 26: 1020-5. doi: 10.1016/j.numecd.2016.07.003.

2. D'Alessandro A, De Pergola G, Silvestris F. Mediterranean Diet and cancer risk: an open issue. Int J Food Sci Nutr. 2016; 67: 593-605. doi: 10.1080/09637486.2016.1191444.

3. Xavier Medina F. Mediterranean diet, culture and heritage: challenges for a new conception. Public Health Nutr. 2009; 12: 1618-20. doi: 10.1017/S1368980009990450.

4. Curti MLR, Jacob P, Borges MC, Rogero MM, Ferreira SRG. Studies of Gene Variants Related to Inflammation, Oxidative Stress, Dyslipidemia, and Obesity: Implications for a Nutrigenetic Approach. Journal of Obesity. 2011; 2011: 1-31. doi: 10.1155/2011/497401.

5. Okosun IS, Chandra KMD, Boev A, Boltri JM, Choi ST, Parish DC, Dever GEA. Abdominal adiposity in U.S. adults: prevalence and trends, 1960-2000. Preventive Medicine. 2004; 39: 197-206. doi: 10.1016/j.ypmed.2004.01.023.

6. Li C, Ford ES, McGuire LC, Mokdad AH. Increasing Trends in Waist Circumference and Abdominal Obesity among U.S. Adults*. Obesity. 2007; 15: 216-216. doi: 10.1038/oby.2007.505.

7. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among u.s. Adults. Diabetes Care. 2004; 27: 2444-9.

8. Ford ES, Li C, Zhao G. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US*: Metabolic syndrome: A harmonious definition. Journal of Diabetes. 2010; 2: 180-93. doi: 10.1111/j.1753-0407.2010.00078.x.

9. Phillips CM, Tierney AC, Perez-Martinez P, Defoort C, Blaak EE, Gjelstad IMF, Lopez-Miranda J, Kiec-Klimczak M, Malczewska-Malec M, Drevon CA, Hall W, Lovegrove JA, Karlstrom B, et al. Obesity and body fat classification in the metabolic syndrome: Impact on cardiometabolic risk metabotype: Obesity and BF Classification in MetS. Obesity. 2013; 21: E154-61. doi: 10.1002/oby.20263.

10. Zimmet P, Alberti G, Kaufman F, Tajima N, Silink M, Arslanian S, Wong G, Bennett P, Shaw J, Caprio S. The metabolic syndrome in children and adolescents. The Lancet. 2007; 369: 2059-61. doi: 10.1016/S0140-6736(07)60958-1.

11. Wolin KY, Carson K, Colditz GA. Obesity and Cancer. The Oncologist. 2010; 15: 556-65. doi: 10.1634/theoncologist.2009-0285.

12. Colditz GA, Atwood KA, Emmons K, Monson RR, Willett WC, Trichopoulos D, Hunter DJ. Harvard report on cancer prevention volume 4: Harvard Cancer Risk Index. Risk Index Working Group, Harvard Center for Cancer Prevention. Cancer Causes Control. 2000; 11: 477-88.

13. Ryan AM, Cushen S, Schellekens H, Bhuachalla EN, Burns L, Kenny U, Power DG. Poor Awareness of Risk Factors for Cancer in Irish Adults: Results of a Large Survey and Review of the Literature. The Oncologist. 2015; 20: 372-8. doi: 10.1634/theoncologist.2014-0453.

14. Kelly T, Yang W, Chen C-S, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. International Journal of Obesity. 2008; 32: 1431-7. doi: 10.1038/ijo.2008.102.

15. De Pergola G, Silvestris F. Obesity as a Major Risk Factor for Cancer. Journal of Obesity. 2013; 2013: 1-11. doi: 10.1155/2013/291546.

16. Reaven GM. Diet and Syndrome X. Curr Atheroscler Rep. 2000; 2: 503-7.

17. Canale MP, Manca di Villahermosa S, Martino G, Rovella V, Noce A, De Lorenzo A, Di Daniele N. Obesity-Related Metabolic Syndrome: Mechanisms of Sympathetic Overactivity. International Journal of Endocrinology. 2013; 2013: 1-12. doi: 10.1155/2013/865965.

18. Alberti KGMM, Zimmet PZ, WHO Consultation. 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. 1998; 15: 539-53. doi: 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.

19. Reaven GM. The Metabolic Syndrome: Requiescat in Pace. Clinical Chemistry. 2005; 51: 931-8. doi: 10.1373/clinchem.2005.048611.

20. Kahn R, Buse J, Ferrannini E, Stern M, American Diabetes Association, European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005; 28: 2289-304.

21. Scuteri A, Najjar SS, Morrell CH, Lakatta EG, Cardiovascular Health Study. The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events: the Cardiovascular Health Study. Diabetes Care. 2005; 28: 882-7.

22. Kondo T, Osugi S, Shimokata K, Honjo H, Morita Y, Yamashita K, Maeda K, Muramatsu T, Shintani S, Matsushita K, Murohara T. Metabolic syndrome and all-cause mortality, cardiac events, and cardiovascular events: a follow-up study in 25,471 young- and middle-aged Japanese men. European Journal of Cardiovascular Prevention & Rehabilitation. 2011; 18: 574-80. doi: 10.1177/1741826710389529.

23. Scuteri A, Tesauro M, Guglini L, Lauro D, Fini M, Di Daniele N. Aortic stiffness and hypotension episodes are associated with impaired cognitive function in older subjects with subjective complaints of memory loss. International Journal of Cardiology. 2013; 169: 371-7. doi: 10.1016/j.ijcard.2013.09.009.

24. Sheen Y-J. Risks of rapid decline renal function in patients with type 2 diabetes. World Journal of Diabetes. 2014; 5: 835. doi: 10.4239/wjd.v5.i6.835.

25. Scheven L, Halbesma N, de Jong PE, de Zeeuw D, Bakker SJL, Gansevoort RT. Predictors of Progression in Albuminuria in the General Population: Results from the PREVEND Cohort. Burdmann EA, editor. PLoS ONE. 2013; 8: e61119. doi: 10.1371/journal.pone.0061119.

26. van der Velde M, Bello AK, Brantsma AH, El Nahas M, Bakker SJL, de Jong PE, Gansevoort RT. Do albuminuria and hs-CRP add to the International Diabetes Federation definition of the metabolic syndrome in predicting outcome? Nephrology Dialysis Transplantation. 2012; 27: 2275-83. doi: 10.1093/ndt/gfr634.

27. Ned RM, Yesupriya A, Imperatore G, Smelser DT, Moonesinghe R, Chang M, Dowling NF. Inflammation gene variants and susceptibility to albuminuria in the U.S. population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994. BMC Medical Genetics [Internet]. 2010 [cited 2016 Dec 15]; 11. doi: 10.1186/1471-2350-11-155.

28. Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt K-U, Nahas ME, Jaber BL, Jadoul M, Levin A, Powe NR, Rossert J, Wheeler DC, et al. Chronic kidney disease as a global public health problem: Approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes. Kidney International. 2007; 72: 247-59. doi: 10.1038/sj.ki.5002343.

29. Lambers Heerspink HJ, Brantsma AH, de Zeeuw D, Bakker SJL, de Jong PE, Gansevoort RT, for the PREVEND Study Group. Albuminuria Assessed From First-Morning-Void Urine Samples Versus 24-Hour Urine Collections as a Predictor of Cardiovascular Morbidity and Mortality. American Journal of Epidemiology. 2008; 168: 897-905. doi: 10.1093/aje/kwn209.

30. Brantsma AH, Bakker SJL, Hillege HL, de Zeeuw D, de Jong PE, Gansevoort RT, PREVEND Study Group. Urinary albumin excretion and its relation with C-reactive protein and the metabolic syndrome in the prediction of type 2 diabetes. Diabetes Care. 2005; 28: 2525-30.

31. Ritz E, Amann K, Koleganova N, Benz K. Prenatal programming-effects on blood pressure and renal function. Nature Reviews Nephrology. 2011; 7: 137-44. doi: 10.1038/nrneph.2011.1.

32. De Lorenzo A, Martinoli R, Vaia F, Di Renzo L. Normal weight obese (NWO) women: An evaluation of a candidate new syndrome. Nutrition, Metabolism and Cardiovascular Diseases. 2006; 16: 513-23. doi: 10.1016/j.numecd.2005.10.010.

33. Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoret R, Poehlman ET. Metabolic and Body Composition Factors in Subgroups of Obesity: What Do We Know? The Journal of Clinical Endocrinology & Metabolism. 2004; 89: 2569-75. doi: 10.1210/jc.2004-0165.

34. Karelis AD, Faraj M, Bastard J-P, St-Pierre DH, Brochu M, Prud'homme D, Rabasa-Lhoret R. The Metabolically Healthy but Obese Individual Presents a Favorable Inflammation Profile. The Journal of Clinical Endocrinology & Metabolism. 2005; 90: 4145-50. doi: 10.1210/jc.2005-0482.

35. Seo MH, Rhee E-J. Metabolic and Cardiovascular Implications of a Metabolically Healthy Obesity Phenotype. Endocrinology and Metabolism. 2014; 29: 427. doi: 10.3803/EnM.2014.29.4.427.

36. Roubenoff R. Sarcopenic obesity: does muscle loss cause fat gain? Lessons from rheumatoid arthritis and osteoarthritis. Ann N Y Acad Sci. 2000; 904: 553-7.

37. De Lorenzo A, Del Gobbo V, Premrov MG, Bigioni M, Galvano F, Di Renzo L. Normal-weight obese syndrome: early inflammation? Am J Clin Nutr. 2007; 85: 40-5.

38. Di Renzo L, Bertoli A, Bigioni M, Del Gobbo V, Premrov MG, Calabrese V, Di Daniele N, De Lorenzo A. Body composition and -174G/C interleukin-6 promoter gene polymorphism: association with progression of insulin resistance in normal weight obese syndrome. Curr Pharm Des. 2008; 14: 2699-706.

39. Di Renzo L, Noce A, De Angelis S, Miani N, Di Daniele N, Tozzo C, De Lorenzo A. Anti-inflammatory effects of combined treatment with acetyl salicylic acid and atorvastatin in haemodialysis patients affected by Normal Weight Obese syndrome. Pharmacological Research. 2008; 57: 93-9. doi: 10.1016/j.phrs.2007.11.005.

40. Di Renzo L, Bigioni M, Bottini FG, Del Gobbo V, Premrov MG, Cianci R, De Lorenzo A. Normal Weight Obese syndrome: role of single nucleotide polymorphism of IL-1 5Ralpha and MTHFR 677C-->T genes in the relationship between body composition and resting metabolic rate. Eur Rev Med Pharmacol Sci. 2006; 10: 235-45.

41. Di Renzo L, Sarlo F, Petramala L, Iacopino L, Monteleone G, Colica C, De Lorenzo A. Association between −308 G/A TNF- α Polymorphism and Appendicular Skeletal Muscle Mass Index as a Marker of Sarcopenia in Normal Weight Obese Syndrome. Disease Markers. 2013; 35: 615-23. doi: 10.1155/2013/983424.

42. Ruderman NB, Schneider SH, Berchtold P. The "metabolically-obese," normal-weight individual. Am J Clin Nutr. 1981; 34: 1617-21.

43. Succurro E, Marini MA, Frontoni S, Hribal ML, Andreozzi F, Lauro R, Perticone F, Sesti G. Insulin Secretion in Metabolically Obese, but Normal Weight, and in Metabolically Healthy but Obese Individuals. Obesity. 2008; 16: 1881-6. doi: 10.1038/oby.2008.308.

44. Esposito K, Giugliano D. The metabolic syndrome and inflammation: association or causation? Nutr Metab Cardiovasc Dis. 2004; 14: 228-32.

45. Lorenzo AD. New obesity classification criteria as a tool for bariatric surgery indication. World Journal of Gastroenterology. 2016; 22: 681. doi: 10.3748/wjg.v22.i2.681.

46. Sims EA. Are there persons who are obese, but metabolically healthy? Metab Clin Exp. 2001; 50: 1499-504. doi: 10.1053/meta.2001.27213.

47. Despres J-P. Body Fat Distribution and Risk of Cardiovascular Disease: An Update. Circulation. 2012; 126: 1301-13. doi: 10.1161/CIRCULATIONAHA.111.067264.

48. Mohamed EI, Maiolo C, Iacopino L, Pepe M, Daniele N, Lorenzo A. The Impact of Body-Weight Components on Forced Spirometry in Healthy Italians. Lung. 2002; 180: 149-59. doi: 10.1007/s004080000089.

49. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med. 2008; 75: 721-8.

50. Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. American Journal of Clinical Nutrition. 2010; 91: 1123S-1127S. doi: 10.3945/ajcn.2010.28608A.

51. Schrager MA, Metter EJ, Simonsick E, Ble A, Bandinelli S, Lauretani F, Ferrucci L. Sarcopenic obesity and inflammation in the InCHIANTI study. Journal of Applied Physiology. 2006; 102: 919-25. doi: 10.1152/japplphysiol.00627.2006.

52. Wang Z, Nakayama T. Inflammation, a Link between Obesity and Cardiovascular Disease. Mediators of Inflammation. 2010; 2010: 1-17. doi: 10.1155/2010/535918.

53. Drubach LA, Palmer EL, Connolly LP, Baker A, Zurakowski D, Cypess AM. Pediatric Brown Adipose Tissue: Detection, Epidemiology, and Differences from Adults. The Journal of Pediatrics. 2011; 159: 939-44. doi: 10.1016/j.jpeds.2011.06.028.

54. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto N-J, Enerbäck S, Nuutila P. Functional Brown Adipose Tissue in Healthy Adults. New England Journal of Medicine. 2009; 360: 1518-25. doi: 10.1056/NEJMoa0808949.

55. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. AJP: Endocrinology and Metabolism. 2007; 293: E444-52. doi: 10.1152/ajpendo.00691.2006.

56. Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? AJP: Endocrinology and Metabolism. 2013; 305: E567-72. doi: 10.1152/ajpendo.00250.2013.

57. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, et al. Dynamics of fat cell turnover in humans. Nature. 2008; 453: 783-7. doi: 10.1038/nature06902.

58. Taveras EM, Rifas-Shiman SL, Belfort MB, Kleinman KP, Oken E, Gillman MW. Weight Status in the First 6 Months of Life and Obesity at 3 Years of Age. PEDIATRICS. 2009; 123: 1177-83. doi: 10.1542/peds.2008-1149.

59. Rolland-Cachera MF, Deheeger M, Bellisle F, Sempé M, Guilloud-Bataille M, Patois E. Adiposity rebound in children: a simple indicator for predicting obesity. Am J Clin Nutr. 1984; 39: 129-35.

60. Klein S, Allison DB, Heymsfield SB, Kelley DE, Leibel RL, Nonas C, Kahn R, Association for Weight Management and Obesity Prevention, NAASO, Obesity Society, American Society for Nutrition, American Diabetes Association. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care. 2007; 30: 1647-52. doi: 10.2337/dc07-9921.

61. Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014; 233: 104-12. doi: 10.1016/j.atherosclerosis.2013.12.023.

62. van Harmelen V, Skurk T, Röhrig K, Lee Y-M, Halbleib M, Aprath-Husmann I, Hauner H. Effect of BMI and age on adipose tissue cellularity and differentiation capacity in women. International Journal of Obesity. 2003; 27: 889-95. doi: 10.1038/sj.ijo.0802314.

63. Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ. The biology of white adipocyte proliferation. Obes Rev. 2001; 2: 239-54.

64. Bays HE, González-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, Rodbard HW, Henry RR. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Review of Cardiovascular Therapy. 2008; 6: 343-68. doi: 10.1586/14779072.6.3.343.

65. Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients? Expert Review of Cardiovascular Therapy. 2006; 4: 871-95. doi: 10.1586/14779072.4.6.871.

66. Bays HE. Adiposopathy. Journal of the American College of Cardiology. 2011; 57: 2461-73. doi: 10.1016/j.jacc.2011.02.038.

67. Liu L, Mei M, Yang S, Li Q. Roles of Chronic Low-Grade Inflammation in the Development of Ectopic Fat Deposition. Mediators of Inflammation. 2014; 2014: 1-7. doi: 10.1155/2014/418185.

68. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. Journal of Clinical Investigation. 2011; 121: 2111-7. doi: 10.1172/JCI57132.

69. Blüher M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract Res Clin Endocrinol Metab. 2013; 27: 163-77. doi: 10.1016/j.beem.2013.02.005.

70. Castoldi A, Naffah de Souza C, Câmara NOS, Moraes-Vieira PM. The Macrophage Switch in Obesity Development. Frontiers in Immunology [Internet]. 2016 [cited 2016 Dec 15]; 6. doi: 10.3389/fimmu.2015.00637.

71. Brookheart RT, Michel CI, Schaffer JE. As a Matter of Fat. Cell Metabolism. 2009; 10: 9-12. doi: 10.1016/j.cmet.2009.03.011.

72. DeFronzo RA. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int J Clin Pract Suppl. 2004; : 9-21.

73. Gao M, Ma Y, Liu D. High-Fat Diet-Induced Adiposity, Adipose Inflammation, Hepatic Steatosis and Hyperinsulinemia in Outbred CD-1 Mice. Stadler K, editor. PLOS ONE. 2015; 10: e0119784. doi: 10.1371/journal.pone.0119784.

74. Nadler ST, Attie AD. Please pass the chips: genomic insights into obesity and diabetes. J Nutr. 2001; 131: 2078-81.

75. Foster MC, Hwang S-J, Porter SA, Massaro JM, Hoffmann U, Fox CS. Fatty Kidney, Hypertension, and Chronic Kidney Disease: The Framingham Heart Study. Hypertension. 2011; 58: 784-90. doi: 10.1161/HYPERTENSIONAHA.111.175315.

76. Chughtai HL, Morgan TM, Rocco M, Stacey B, Brinkley TE, Ding J, Nicklas B, Hamilton C, Hundley WG. Renal Sinus Fat and Poor Blood Pressure Control in Middle-Aged and Elderly Individuals at Risk for Cardiovascular Events. Hypertension. 2010; 56: 901-6. doi: 10.1161/HYPERTENSIONAHA.110.157370.

77. Tesauro M, Mascali A, Franzese O, Cipriani S, Cardillo C, Di Daniele N. Chronic Kidney Disease, Obesity, and Hypertension: The Role of Leptin and Adiponectin. International Journal of Hypertension. 2012; 2012: 1-7. doi: 10.1155/2012/943605.

78. Bertaso AG, Bertol D, Duncan BB, Foppa M. Epicardial Fat: Definition, Measurements and Systematic Review of Main Outcomes. Arquivos Brasileiros de Cardiologia [Internet]. 2013 [cited 2016 Dec 15]; . doi: 10.5935/abc.20130138.

79. Talman AH, Psaltis PJ, Cameron JD, Meredith IT, Seneviratne SK, Wong DTL. Epicardial adipose tissue: far more than a fat depot. Cardiovasc Diagn Ther. 2014; 4: 416-29. doi: 10.3978/j.issn.2223-3652.2014.11.05.

80. Iacobellis G, Willens HJ. Echocardiographic epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr. 2009; 22: 1311-1319-1418. doi: 10.1016/j.echo.2009.10.013.

81. Song DK, Hong YS, Lee H, Oh J-Y, Sung Y-A, Kim Y. Increased Epicardial Adipose Tissue Thickness in Type 2 Diabetes Mellitus and Obesity. Diabetes & Metabolism Journal. 2015; 39: 405. doi: 10.4093/dmj.2015.39.5.405.

82. Iacobellis G, Malavazos AE, Corsi MM. Epicardial fat: From the biomolecular aspects to the clinical practice. The International Journal of Biochemistry & Cell Biology. 2011; 43: 1651-4. doi: 10.1016/j.biocel.2011.09.006.

83. Goodpaster BH, Thaete FL, Kelley DE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr. 2000; 71: 885-92.

84. Addison O, Marcus RL, LaStayo PC, Ryan AS. Intermuscular Fat: A Review of the Consequences and Causes. International Journal of Endocrinology. 2014; 2014: 1-11. doi: 10.1155/2014/309570.

85. Sales NMR, Pelegrini PB, Goersch MC. Nutrigenomics: Definitions and Advances of This New Science. Journal of Nutrition and Metabolism. 2014; 2014: 1-6. doi: 10.1155/2014/202759.

86. Brennan RO, Mulligan WC. Nutrigenetics: new concepts for relieving hypoglycemia. New York; Philadelphia: M. Evans; Distributed by Lippincott; 1975.

87. Phillips C, Lopez-Miranda J, Perez-Jimenez F, McManus R, Roche HM. Genetic and nutrient determinants of the metabolic syndrome: Current Opinion in Cardiology. 2006; 21: 185-93. doi: 10.1097/01.hco.0000221579.25878.11.

88. Phillips CM, Tierney AC, Roche HM. Gene-Nutrient Interactions in the Metabolic Syndrome. Journal of Nutrigenetics and Nutrigenomics. 2008; 1: 136-51. doi: 10.1159/000112461.

89. Roche HM, Phillips C, Gibney MJ. The metabolic syndrome: the crossroads of diet and genetics. Proc Nutr Soc. 2005; 64: 371-7.

90. Phillips C. Nutrigenetics and Metabolic Disease: Current Status and Implications for Personalised Nutrition. Nutrients. 2013; 5: 32-57. doi: 10.3390/nu5010032.

91. Neel JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet. 1962; 14: 353-62.

92. Andreasen CH, Andersen G. Gene-environment interactions and obesity-Further aspects of genomewide association studies. Nutrition. 2009; 25: 998-1003. doi: 10.1016/j.nut.2009.06.001.

93. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PEH, del Bosque-Plata L, Horikawa Y, Oda Y, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genetics. 2000; 26: 163-75. doi: 10.1038/79876.

94. Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, Häring H-U, Stefan N, Fritsche A. Variation in the FTO Gene Influences Food Intake but not Energy Expenditure. Experimental and Clinical Endocrinology & Diabetes. 2009; 117: 194-7. doi: 10.1055/s-0028-1087176.

95. Povel CM, Boer JMA, Reiling E, Feskens EJM. Genetic variants and the metabolic syndrome: a systematic review: Genetics of metabolic syndrome. Obesity Reviews. 2011; 12: 952-67. doi: 10.1111/j.1467-789X.2011.00907.x.

96. Garcia-Rios A, Perez-Martinez P, Delgado-Lista J, Phillips CM, Gjelstad IMF, Wright JW, Karlstrom B, Kiec-Wilk B, van Hees AMJ, Helal O, Polus A, Defoort C, Riserus U, et al. A Period 2 Genetic Variant Interacts with Plasma SFA to Modify Plasma Lipid Concentrations in Adults with Metabolic Syndrome. Journal of Nutrition. 2012; 142: 1213-8. doi: 10.3945/jn.111.156968.

97. Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998; 20: 284-7. doi: 10.1038/3099.

98. Florez JC, Hirschhorn J, Altshuler D. The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu Rev Genomics Hum Genet. 2003; 4: 257-91. doi: 10.1146/annurev.genom.4.070802.110436.

99. Vaccaro O, Lapice E, Monticelli A, Giacchetti M, Castaldo I, Galasso R, Pinelli M, Donnarumma G, Rivellese AA, Cocozza S, Riccardi G. Pro12Ala polymorphism of the PPARgamma2 locus modulates the relationship between energy intake and body weight in type 2 diabetic patients. Diabetes Care. 2007; 30: 1156-61. doi: 10.2337/dc06-1153.

100. Phillips CM, Goumidi L, Bertrais S, Field MR, Cupples LA, Ordovas JM, Defoort C, Lovegrove JA, Drevon CA, Gibney MJ, Blaak EE, Kiec-Wilk B, Karlstrom B, et al. Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome. J Lipid Res. 2010; 51: 1793-800. doi: 10.1194/jlr.M003046.

101. Phillips CM, Goumidi L, Bertrais S, Field MR, Ordovas JM, Cupples LA, Defoort C, Lovegrove JA, Drevon CA, Blaak EE, Gibney MJ, Kiec-Wilk B, Karlstrom B, et al. Leptin Receptor Polymorphisms Interact with Polyunsaturated Fatty Acids to Augment Risk of Insulin Resistance and Metabolic Syndrome in Adults. Journal of Nutrition. 2010; 140: 238-44. doi: 10.3945/jn.109.115329.

102. Daimiel L, Vargas T, Ramírez de Molina A. Nutritional genomics for the characterization of the effect of bioactive molecules in lipid metabolism and related pathways: General. ELECTROPHORESIS. 2012; 33: 2266-89. doi: 10.1002/elps.201200084.

103. Rana S, Kumar S, Rathore N, Padwad Y, Bhushan S. Nutrigenomics and its Impact on Life Style Associated Metabolic Diseases. Current Genomics. 2016; 17: 261-78. doi: 10.2174/1389202917666160202220422.

104. Arkadianos I, Valdes AM, Marinos E, Florou A, Gill RD, Grimaldi KA. Improved weight management using genetic information to personalize a calorie controlled diet. Nutrition Journal [Internet]. 2007 [cited 2016 Dec 15]; 6. doi: 10.1186/1475-2891-6-29.

105. Di Renzo L, Rizzo M, Iacopino L, Sarlo F, Domino E, Jacoangeli F, Colica C, Sergi D, De Lorenzo A. Body composition phenotype: Italian Mediterranean Diet and C677T MTHFR gene polymorphism interaction. Eur Rev Med Pharmacol Sci. 2013; 17: 2555-65.

106. Kirke PN. Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ. 2004; 328: 1535-6. doi: 10.1136/bmj.38036.646030.EE.

107. Elhawary NA, Hewedi D, Arab A, Teama S, Shaibah H, Tayeb MT, Bogari N. The MTHFR 677T Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer's Disease in an Egyptian Population. Disease Markers. 2013; 35: 439-46. doi: 10.1155/2013/524106.

108. McLean RR, Karasik D, Selhub J, Tucker KL, Ordovas JM, Russo GT, Cupples LA, Jacques PF, Kiel DP. Association of a Common Polymorphism in the Methylenetetrahydrofolate Reductase (MTHFR) Gene With Bone Phenotypes Depends on Plasma Folate Status. Journal of Bone and Mineral Research. 2003; 19: 410-8. doi: 10.1359/JBMR.0301261.

109. Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005; 82: 806-12.

110. Pastore A. Effects of Folic Acid Before and After Vitamin B12 on Plasma Homocysteine Concentrations in Hemodialysis Patients with Known MTHFR Genotypes. Clinical Chemistry. 2006; 52: 145-8. doi: 10.1373/clinchem.2005.056119.

111. Alberti A, Fruttini D, Fidanza F. The Mediterranean Adequacy Index: Further confirming results of validity. Nutrition, Metabolism and Cardiovascular Diseases. 2009; 19: 61-6. doi: 10.1016/j.numecd.2007.11.008.

112. Alberti-Fidanza A, Fidanza F, Chiuchiù MP, Verducci G, Fruttini D. Dietary studies on two rural italian population groups of the Seven Countries Study. 3. Trend Of food and nutrient intake from 1960 to 1991. Eur J Clin Nutr. 1999; 53: 854-60.

113. Fidanza F, Alberti A, Lanti M, Menotti A. Mediterranean Adequacy Index: correlation with 25-year mortality from coronary heart disease in the Seven Countries Study. Nutr Metab Cardiovasc Dis. 2004; 14: 254-8.

114. Menotti A, Alberti-Fidanza A, Fidanza F. The association of the Mediterranean Adequacy Index with fatal coronary events in an Italian middle-aged male population followed for 40 years. Nutrition, Metabolism and Cardiovascular Diseases. 2012; 22: 369-75. doi: 10.1016/j.numecd.2010.08.002.

115. De Lorenzo A, Petroni ML, De Luca PP, Andreoli A, Morini P, Iacopino L, Innocente I, Perriello G. Use of quality control indices in moderately hypocaloric Mediterranean diet for treatment of obesity. Diabetes Nutr Metab. 2001; 14: 181-8.

116. Bilenko N, Fraser D, Vardi H, Shai I, Shahar D. Mediterranean diet and cardiovascular diseases in an Israeli population. Preventive Medicine. 2005; 40: 299-305. doi: 10.1016/j.ypmed.2004.06.004.

117. Trichopoulou A, Kouris-Blazos A, Wahlqvist ML, Gnardellis C, Lagiou P, Polychronopoulos E, Vassilakou T, Lipworth L, Trichopoulos D. Diet and overall survival in elderly people. BMJ. 1995; 311: 1457-60.

118. Tektonidis TG, Åkesson A, Gigante B, Wolk A, Larsson SC. Adherence to a Mediterranean diet is associated with reduced risk of heart failure in men. Eur J Heart Fail. 2016; 18: 253-9. doi: 10.1002/ejhf.481.

119. A. De Lorenzo, Fidanza, F. Dieta mediterranea Italiana di Riferimento, la Dieta di Nicotera, 1960. MSI-Edizioni Mediche Scientifiche Internazionali-Roma. Sezione di Alimentazione e Nutrizione Umana, Dipartimento di Neuroscienze, Università di Roma Tor Vergata; 2003.

120. Harmon BE, Boushey CJ, Shvetsov YB, Ettienne R, Reedy J, Wilkens LR, Le Marchand L, Henderson BE, Kolonel LN. Associations of key diet-quality indexes with mortality in the Multiethnic Cohort: the Dietary Patterns Methods Project. American Journal of Clinical Nutrition. 2015; 101: 587-97. doi: 10.3945/ajcn.114.090688.

121. Salas-Salvadó J, Fernández-Ballart J, Ros E, Martínez-González M-A, Fitó M, Estruch R, Corella D, Fiol M, Gómez-Gracia E, Arós F, Flores G, Lapetra J, Lamuela-Raventós R, et al. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med. 2008; 168: 2449-58. doi: 10.1001/archinte.168.22.2449.

122. Estruch R, Ros E, Salas-Salvadó J, Covas M-I, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. New England Journal of Medicine. 2013; 368: 1279-90. doi: 10.1056/NEJMoa1200303.

123. Babio N, Toledo E, Estruch R, Ros E, Martinez-Gonzalez MA, Castaner O, Bullo M, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, et al. Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial. Canadian Medical Association Journal. 2014; 186: E649-57. doi: 10.1503/cmaj.140764.

124. Grosso G, Marventano S, Yang J, Micek A, Pajak A, Scalfi L, Galvano F, Kales SN. A Comprehensive Meta-analysis on Evidence of Mediterranean Diet and Cardiovascular Disease: Are Individual Components Equal? Critical Reviews in Food Science and Nutrition. 2015. doi: 10.1080/10408398.2015.1107021.

125. Pitsavos C, Panagiotakos DB, Tzima N, Chrysohoou C, Economou M, Zampelas A, Stefanadis C. Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study. Am J Clin Nutr. 2005; 82: 694-9.

126. Sofi F, Cesari F, Abbate R, Gensini GF, Casini A. Adherence to Mediterranean diet and health status: meta-analysis. BMJ. 2008; 337: a1344-a1344. doi: 10.1136/bmj.a1344.

127. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults. Journal of the American College of Cardiology. 2004; 44: 152-8. doi: 10.1016/j.jacc.2004.03.039.

128. Psaltopoulou T, Naska A, Orfanos P, Trichopoulos D, Mountokalakis T, Trichopoulou A. Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr. 2004; 80: 1012-8.

129. Andreoli A, Lauro S, Di Daniele N, Sorge R, Celi M, Volpe SL. Effect of a moderately hypoenergetic Mediterranean diet and exercise program on body cell mass and cardiovascular risk factors in obese women. European Journal of Clinical Nutrition. 2008; 62: 892-7. doi: 10.1038/sj.ejcn.1602800.

130. Andreoli A, Melchiorri G, Brozzi M, Di Marco A, Volpe SL, Garofano P, Di Daniele N, De Lorenzo A. Effect of different sports on body cell mass in highly trained athletes. Acta Diabetologica. 2003; 40: s122-5. doi: 10.1007/s00592-003-0043-9.

131. De Lorenzo A, Noce A, Bigioni M, Calabrese V, Della Rocca DG, Di Daniele N, Tozzo C, Di Renzo L. The effects of Italian Mediterranean organic diet (IMOD) on health status. Curr Pharm Des. 2010; 16: 814-24.

132. Di Daniele N, Di Renzo L, Noce A, Iacopino L, Ferraro PM, Rizzo M, Sarlo F, Domino E, De Lorenzo A. Effects of Italian Mediterranean organic diet vs. low-protein diet in nephropathic patients according to MTHFR genotypes. Journal of Nephrology. 2014; 27: 529-36. doi: 10.1007/s40620-014-0067-y.

133. Noce A, Vidiri MF, Marrone G, Moriconi E, Bocedi A, Capria A, Rovella V, Ricci G, De Lorenzo A, Di Daniele N. Is low-protein diet a possible risk factor of malnutrition in chronic kidney disease patients? Cell Death Discovery. 2016; 2: 16026. doi: 10.1038/cddiscovery.2016.26.

134. Di Daniele N, Petramala L, Di Renzo L, Sarlo F, Della Rocca DG, Rizzo M, Fondacaro V, Iacopino L, Pepine CJ, De Lorenzo A. Body composition changes and cardiometabolic benefits of a balanced Italian Mediterranean Diet in obese patients with metabolic syndrome. Acta Diabetologica. 2013; 50: 409-16. doi: 10.1007/s00592-012-0445-7.

135. De Lorenzo A, Alberti A, Andreoli A, Iacopino L, Serranò P, Perriello G. Food habits in a southern Italian town (Nicotera) in 1960 and 1996: still a reference Italian Mediterranean diet? Diabetes Nutr Metab. 2001; 14: 121-5.

136. Menotti A, Kromhout D, Blackburn H, Fidanza F, Buzina R, Nissinen A. Food intake patterns and 25-year mortality from coronary heart disease: cross-cultural correlations in the Seven Countries Study. The Seven Countries Study Research Group. Eur J Epidemiol. 1999; 15: 507-15.

137. Tierney AC, McMonagle J, Shaw DI, Gulseth HL, Helal O, Saris WHM, Paniagua JA, Gołąbek-Leszczyñska I, Defoort C, Williams CM, Karsltröm B, Vessby B, Dembinska-Kiec A, 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. International Journal of Obesity. 2011; 35: 800-9. doi: 10.1038/ijo.2010.209.

138. 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. Am J Clin Nutr. 2008; 88: 1232-41.

139. Due A, Larsen TM, Hermansen K, Stender S, Holst JJ, Toubro S, Martinussen T, Astrup A. Comparison of the effects on insulin resistance and glucose tolerance of 6-mo high-monounsaturated-fat, low-fat, and control diets. Am J Clin Nutr. 2008; 87: 855-62.

140. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nälsén C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia. 2001; 44: 312-9.

141. Maehre H, Jensen I-J, Elvevoll E, Eilertsen K-E. ω-3 Fatty Acids and Cardiovascular Diseases: Effects, Mechanisms and Dietary Relevance. International Journal of Molecular Sciences. 2015; 16: 22636-61. doi: 10.3390/ijms160922636.

142. Li G-R, Sun H-Y, Zhang X-H, Cheng L-C, Chiu S-W, Tse H-F, Lau C-P. Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes. Cardiovascular Research. 2008; 81: 286-93. doi: 10.1093/cvr/cvn322.

143. Xiao Y-F, Sigg DC, Leaf A. The Antiarrhythmic Effect of n-3 Polyunsaturated Fatty Acids: Modulation of Cardiac Ion Channels as a Potential Mechanism. Journal of Membrane Biology. 2005; 206: 141-54. doi: 10.1007/s00232-005-0786-z.

144. Marventano S, Kolacz P, Castellano S, Galvano F, Buscemi S, Mistretta A, Grosso G. A review of recent evidence in human studies of n-3 and n-6 PUFA intake on cardiovascular disease, cancer, and depressive disorders: does the ratio really matter? International Journal of Food Sciences and Nutrition. 2015; 66: 611-22. doi: 10.3109/09637486.2015.1077790.

145. Angelico F, Loffredo L, Pignatelli P, Augelletti T, Carnevale R, Pacella A, Albanese F, Mancini I, Di Santo S, Del Ben M, Violi F. Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome. Internal and Emergency Medicine. 2012; 7: 219-27. doi: 10.1007/s11739-011-0591-x.

146. de Beer D, Joubert E, Marais J, Manley M. Unravelling the Total Antioxidant Capacity of Pinotage Wines: Contribution of Phenolic Compounds. Journal of Agricultural and Food Chemistry. 2006; 54: 2897-905. doi: 10.1021/jf052766u.

147. Di Renzo L, Carraro A, Valente R, Iacopino L, Colica C, De Lorenzo A. Intake of Red Wine in Different Meals Modulates Oxidized LDL Level, Oxidative and Inflammatory Gene Expression in Healthy People: A Randomized Crossover Trial. Oxidative Medicine and Cellular Longevity. 2014; 2014: 1-9. doi: 10.1155/2014/681318.

148. Dong Z. Molecular mechanism of the chemopreventive effect of resveratrol. Mutat Res. 2003; 523-524: 145-50.

149. Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin K-M, Fulda S, Wabitsch M. Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. American Journal of Clinical Nutrition. 2010; 92: 5-15. doi: 10.3945/ajcn.2009.28435.

150. Tresserra-Rimbau A, Medina-Remón A, Lamuela-Raventós RM, Bulló M, Salas-Salvadó J, Corella D, Fitó M, Gea A, Gómez-Gracia E, Lapetra J, Arós F, Fiol M, Ros E, et al. Moderate red wine consumption is associated with a lower prevalence of the metabolic syndrome in the PREDIMED population. British Journal of Nutrition. 2015; 113: S121-30. doi: 10.1017/S0007114514003262.

151. Feng D, Ling W-H, Duan R-D. Lycopene suppresses LPS-induced NO and IL-6 production by inhibiting the activation of ERK, p38MAPK, and NF-κB in macrophages. Inflammation Research. 2010; 59: 115-21. doi: 10.1007/s00011-009-0077-8.

152. Ghavipour M, Saedisomeolia A, Djalali M, Sotoudeh G, Eshraghyan MR, Moghadam AM, Wood LG. Tomato juice consumption reduces systemic inflammation in overweight and obese females. British Journal of Nutrition. 2013; 109: 2031-5. doi: 10.1017/S0007114512004278.

153. McEneny J, Wade L, Young IS, Masson L, Duthie G, McGinty A, McMaster C, Thies F. Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals. The Journal of Nutritional Biochemistry. 2013; 24: 163-8. doi: 10.1016/j.jnutbio.2012.03.015.

154. Li Y-F, Chang Y-Y, Huang H-C, Wu Y-C, Yang M-D, Chao P-M. Tomato juice supplementation in young women reduces inflammatory adipokine levels independently of body fat reduction. Nutrition. 2015; 31: 691-6. doi: 10.1016/j.nut.2014.11.008.

155. Fuentes E, Forero-Doria O, Carrasco G, Maricán A, Santos L, Alarcón M, Palomo I. Effect of Tomato Industrial Processing on Phenolic Profile and Antiplatelet Activity. Molecules. 2013; 18: 11526-36. doi: 10.3390/molecules180911526.

156. Moreno-Luna R, Muñoz-Hernandez R, Miranda ML, Costa AF, Jimenez-Jimenez L, Vallejo-Vaz AJ, Muriana FJG, Villar J, Stiefel P. Olive Oil Polyphenols Decrease Blood Pressure and Improve Endothelial Function in Young Women with Mild Hypertension. American Journal of Hypertension [Internet]. 2012 [cited 2016 Dec 15]; . doi: 10.1038/ajh.2012.128.

157. Christoph L, Hoffmann G, Christoph M. Effects of Olive Oil on Markers of Inflammation and Endothelial Function-A Systematic Review and Meta-Analysis. Nutrients. 2015; 7: 7651-75. doi: 10.3390/nu7095356.

158. Zern TL, Fernandez ML. Cardioprotective effects of dietary polyphenols. J Nutr. 2005; 135: 2291-4.

159. Sánchez-Fidalgo S, Sánchez de Ibargüen L, Cárdeno A, Alarcón de la Lastra C. Influence of extra virgin olive oil diet enriched with hydroxytyrosol in a chronic DSS colitis model. European Journal of Nutrition. 2012; 51: 497-506. doi: 10.1007/s00394-011-0235-y.

160. Ruano J, Lopez-Miranda J, Fuentes F, Moreno JA, Bellido C, Perez-Martinez P, Lozano A, Gómez P, Jiménez Y, Pérez Jiménez F. Phenolic Content of Virgin Olive Oil Improves Ischemic Reactive Hyperemia in Hypercholesterolemic Patients. Journal of the American College of Cardiology. 2005; 46: 1864-8. doi: 10.1016/j.jacc.2005.06.078.

161. Ramírez-Anaya J del P, Samaniego-Sánchez C, Castañeda-Saucedo MC, Villalón-Mir M, de la Serrana HL-G. Phenols and the antioxidant capacity of Mediterranean vegetables prepared with extra virgin olive oil using different domestic cooking techniques. Food Chemistry. 2015; 188: 430-8. doi: 10.1016/j.foodchem.2015.04.124.

162. Martínez-González MA, Sánchez-Villegas A. The emerging role of Mediterranean diets in cardiovascular epidemiology: monounsaturated fats, olive oil, red wine or the whole pattern? Eur J Epidemiol. 2004; 19: 9-13.

163. Fitó M. Effect of a Traditional Mediterranean Diet on Lipoprotein Oxidation: A Randomized Controlled Trial. Archives of Internal Medicine. 2007; 167: 1195. doi: 10.1001/archinte.167.11.1195.

164. Babio N, Bulló M, Salas-Salvadó J. Mediterranean diet and metabolic syndrome: the evidence. Public Health Nutrition. 2009; 12: 1607. doi: 10.1017/S1368980009990449.

165. Cho SS, Qi L, Fahey GC, Klurfeld DM. Consumption of cereal fiber, mixtures of whole grains and bran, and whole grains and risk reduction in type 2 diabetes, obesity, and cardiovascular disease. American Journal of Clinical Nutrition. 2013; 98: 594-619. doi: 10.3945/ajcn.113.067629.

166. Cuenca-García M, Artero EG, Sui X, Lee D, Hebert JR, Blair SN. Dietary indices, cardiovascular risk factors and mortality in middle-aged adults: findings from the Aerobics Center Longitudinal Study. Annals of Epidemiology. 2014; 24: 297-303.e2. doi: 10.1016/j.annepidem.2014.01.007.

167. Grosso G, Marventano S, Galvano F, Pajak A, Mistretta A. Factors associated with metabolic syndrome in a mediterranean population: role of caffeinated beverages. J Epidemiol. 2014; 24: 327-33.

168. Shaughnessy KS, Boswall IA, Scanlan AP, Gottschall-Pass KT, Sweeney MI. Diets containing blueberry extract lower blood pressure in spontaneously hypertensive stroke-prone rats. Nutr Res. 2009; 29: 130-8. doi: 10.1016/j.nutres.2009.01.001.

169. Kalea AZ, Clark K, Schuschke DA, Klimis-Zacas DJ. Vascular reactivity is affected by dietary consumption of wild blueberries in the Sprague-Dawley rat. J Med Food. 2009; 12: 21-8. doi: 10.1089/jmf.2008.0078.

170. Basu A, Du M, Leyva MJ, Sanchez K, Betts NM, Wu M, Aston CE, Lyons TJ. Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome. J Nutr. 2010; 140: 1582-7. doi: 10.3945/jn.110.124701.

171. Kolehmainen M, Mykkänen O, Kirjavainen PV, Leppänen T, Moilanen E, Adriaens M, Laaksonen DE, Hallikainen M, Puupponen-Pimiä R, Pulkkinen L, Mykkänen H, Gylling H, Poutanen K, et al. Bilberries reduce low-grade inflammation in individuals with features of metabolic syndrome. Molecular Nutrition & Food Research. 2012; 56: 1501-10. doi: 10.1002/mnfr.201200195.

172. Basu A, Fu DX, Wilkinson M, Simmons B, Wu M, Betts NM, Du M, Lyons TJ. Strawberries decrease atherosclerotic markers in subjects with metabolic syndrome. Nutrition Research. 2010; 30: 462-9. doi: 10.1016/j.nutres.2010.06.016.

173. Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong C-P, Nettleton JA, Jacobs DR. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007; 85: 895-909.

174. Stewart BW, Wild C, International Agency for Research on Cancer, World Health Organization. World cancer report 2014 [Internet]. Lyon; Geneva: International Agency for Research on Cancer; Distributed by WHO Press; 2014 [cited 2016 Dec 15]. Available from http://search.ebscohost.com/login.aspx?direct=true&scope=site&db=nlebk&db=nlabk&AN=979458

175. Vitale G, Salvioli S, Franceschi C. Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol. 2013; 9: 228-40. doi: 10.1038/nrendo.2013.29.

176. Sozzani S, Bosisio D, Mantovani A, Ghezzi P. Linking stress, oxidation and the chemokine system. Eur J Immunol. 2005; 35: 3095-8. doi: 10.1002/eji.200535489.

177. Tieri P, Termanini A, Bellavista E, Salvioli S, Capri M, Franceschi C. Charting the NF-κB pathway interactome map. PLoS ONE. 2012; 7: e32678. doi: 10.1371/journal.pone.0032678.

178. Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Current Opinion in Pharmacology. 2009; 9: 351-69. doi: 10.1016/j.coph.2009.06.020.

179. Rotblat B, Grunewald TGP, Leprivier G, Melino G, Knight RA. Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers. Oncotarget. 2013; 4: 2577-90. doi: 10.18632/oncotarget.1658.

180. Park SY, Kim MJ, Park SA, Kim JS, Min KN, Kim DK, Lim W, Nam JS, Sheen YY. Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells. Oncotarget [Internet]. 2015;6:37526-43. doi: 10.18632/oncotarget.6063.

181. Ko H, Jeong M-H, Jeon H, Sung G-J, So Y, Kim I, Son J, Lee S, Yoon H-G, Choi K-C. Delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis, by inducing DR5 and causing caspase-mediated HDAC3 cleavage. Oncotarget. 2015; 6: 9970-84. doi: 10.18632/oncotarget.3667.

182. Itsumi M, Inoue S, Elia AJ, Murakami K, Sasaki M, Lind EF, Brenner D, Harris IS, Chio IIC, Afzal S, Cairns RA, Cescon DW, Elford AR, et al. Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Cell Death Differ. 2015; 22: 1837-45. doi: 10.1038/cdd.2015.38.

183. Agostini M, Annicchiarico-Petruzzelli M, Melino G, Rufini A. Metabolic pathways regulated by TAp73 in response to oxidative stress. Oncotarget. 2016; 7: 29881-900. doi: 10.18632/oncotarget.8935.

184. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014; 39: 191-8. doi: 10.1016/j.tibs.2014.02.004.

185. Chen P-M, Lin C-H, Li N-T, Wu Y-M, Lin M-T, Hung S-C, Yen M-L. c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells. Oncotarget. 2015; 6: 35404-18. doi: 10.18632/oncotarget.6178.

186. Li H-Y, Zhang J, Sun L-L, Li B-H, Gao H-L, Xie T, Zhang N, Ye Z-M. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study. Cell Death Dis. 2015; 6: e1604. doi: 10.1038/cddis.2014.543.

187. Calderon-Aparicio A, Strasberg-Rieber M, Rieber M. Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate. Oncotarget. 2015; 6: 29771-81. doi: 10.18632/oncotarget.4833.

188. Jacquemin G, Margiotta D, Kasahara A, Bassoy EY, Walch M, Thiery J, Lieberman J, Martinvalet D. Granzyme B-induced mitochondrial ROS are required for apoptosis. Cell Death Differ. 2015; 22: 862-74. doi: 10.1038/cdd.2014.180.

189. Rotblat B, Southwell AL, Ehrnhoefer DE, Skotte NH, Metzler M, Franciosi S, Leprivier G, Somasekharan SP, Barokas A, Deng Y, Tang T, Mathers J, Cetinbas N, et al. HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. Proc Natl Acad Sci USA. 2014; 111: 3032-7. doi: 10.1073/pnas.1314421111.

190. Zhang C, Liu K, Yao K, Reddy K, Zhang Y, Fu Y, Yang G, Zykova TA, Shin SH, Li H, Ryu J, Jiang Y-N, Yin X, et al. HOI-02 induces apoptosis and G2-M arrest in esophageal cancer mediated by ROS. Cell Death Dis. 2015; 6: e1912. doi: 10.1038/cddis.2015.227.

191. Qin W, Li C, Zheng W, Guo Q, Zhang Y, Kang M, Zhang B, Yang B, Li B, Yang H, Wu Y. Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. Oncotarget. 2015; 6: 39839-54. doi: 10.18632/oncotarget.5674.

192. Park M-T, Kim M-J, Suh Y, Kim R-K, Kim H, Lim E-J, Yoo K-C, Lee G-H, Kim Y-H, Hwang S-G, Yi J-M, Lee S-J. Novel signaling axis for ROS generation during K-Ras-induced cellular transformation. Cell Death Differ. 2014; 21: 1185-97. doi: 10.1038/cdd.2014.34.

193. Fitzgerald AL, Osman AA, Xie T-X, Patel A, Skinner H, Sandulache V, Myers JN. Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells. Cell Death Dis. 2015; 6: e1678. doi: 10.1038/cddis.2015.44.

194. Singer E, Judkins J, Salomonis N, Matlaf L, Soteropoulos P, McAllister S, Soroceanu L. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis. 2015; 6: e1601. doi: 10.1038/cddis.2014.566.

195. Lee S-J, Jung YH, Oh SY, Jang KK, Lee HS, Choi SH, Han HJ. Vibrio vulnificus VvpE inhibits mucin 2 expression by hypermethylation via lipid raft-mediated ROS signaling in intestinal epithelial cells. Cell Death Dis. 2015; 6: e1787. doi: 10.1038/cddis.2015.152.

196. Hasanain M, Bhattacharjee A, Pandey P, Ashraf R, Singh N, Sharma S, Vishwakarma AL, Datta D, Mitra K, Sarkar J. α-Solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/mTOR pathway. Cell Death Dis. 2015; 6: e1860. doi: 10.1038/cddis.2015.219.

197. Zou P, Chen M, Ji J, Chen W, Chen X, Ying S, Zhang J, Zhang Z, Liu Z, Yang S, Liang G. Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. Oncotarget. 2015; 6: 36505-21. doi: 10.18632/oncotarget.5364.

198. Palikaras K, Lionaki E, Tavernarakis N. Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ. 2015; 22: 1399-401. doi: 10.1038/cdd.2015.86.

199. Giordano L, Deceglie S, d'Adamo P, Valentino ML, La Morgia C, Fracasso F, Roberti M, Cappellari M, Petrosillo G, Ciaravolo S, Parente D, Giordano C, Maresca A, et al. Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways. Cell Death Dis. 2015; 6: e2021. doi: 10.1038/cddis.2015.364.

200. Managò A, Leanza L, Carraretto L, Sassi N, Grancara S, Quintana-Cabrera R, Trimarco V, Toninello A, Scorrano L, Trentin L, Semenzato G, Gulbins E, Zoratti M, et al. Early effects of the antineoplastic agent salinomycin on mitochondrial function. Cell Death Dis. 2015; 6: e1930. doi: 10.1038/cddis.2015.263.

201. Guzzo G, Sciacovelli M, Bernardi P, Rasola A. Inhibition of succinate dehydrogenase by the mitochondrial chaperone TRAP1 has anti-oxidant and anti-apoptotic effects on tumor cells. Oncotarget. 2014; 5: 11897-908. doi: 10.18632/oncotarget.2472.

202. Agostini M, Romeo F, Inoue S, Niklison-Chirou MV, Elia AJ, Dinsdale D, Morone N, Knight RA, Mak TW, Melino G. Metabolic reprogramming during neuronal differentiation. Cell Death Differ. 2016; 23: 1502-14. doi: 10.1038/cdd.2016.36.

203. Cho J, Seo J, Lim CH, Yang L, Shiratsuchi T, Lee M-H, Chowdhury RR, Kasahara H, Kim J-S, Oh SP, Lee YJ, Terada N. Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis. Cell Death Differ. 2015; 22: 1437-50. doi: 10.1038/cdd.2014.230.

204. Mei H, Sun S, Bai Y, Chen Y, Chai R, Li H. Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs. Cell Death Dis. 2015; 6: e1710. doi: 10.1038/cddis.2015.78.

205. Liu J, Masurekar A, Johnson S, Chakraborty S, Griffiths J, Smith D, Alexander S, Dempsey C, Parker C, Harrison S, Li Y, Miller C, Di Y, et al. Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia. Oncotarget. 2015; 6: 43048-64. doi: 10.18632/oncotarget.5528.

206. Marini ES, Giampietri C, Petrungaro S, Conti S, Filippini A, Scorrano L, Ziparo E. The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria. Cell Death Differ. 2015; 22: 1131-43. doi: 10.1038/cdd.2014.197.

207. Kluckova K, Sticha M, Cerny J, Mracek T, Dong L, Drahota Z, Gottlieb E, Neuzil J, Rohlena J. Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation. Cell Death Dis. 2015; 6: e1749. doi: 10.1038/cddis.2015.110.

208. Lee S-J, Jung YH, Oh SY, Song EJ, Choi SH, Han HJ. Vibrio vulnificus VvhA induces NF-κB-dependent mitochondrial cell death via lipid raft-mediated ROS production in intestinal epithelial cells. Cell Death Dis. 2015; 6: 1655. doi: 10.1038/cddis.2015.19.

209. Tian Y, Kuo C-F, Sir D, Wang L, Govindarajan S, Petrovic LM, Ou J-HJ. Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. Cell Death Differ. 2015; 22: 1025-34. doi: 10.1038/cdd.2014.201.

210. Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 2015; 22: 248-57. doi: 10.1038/cdd.2014.173.

211. Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015; 22: 377-88. doi: 10.1038/cdd.2014.150.

212. Gu Y, Barzegar M, Chen X, Wu Y, Shang C, Mahdavian E, Salvatore BA, Jiang S, Huang S. Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5. Oncotarget. 2015; 6: 42322-33. doi: 10.18632/oncotarget.5996.

213. Kostecka A, Sznarkowska A, Meller K, Acedo P, Shi Y, Mohammad Sakil HA, Kawiak A, Lion M, Królicka A, Wilhelm M, Inga A, Zawacka-Pankau J. JNK-NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress. Cell Death Dis. 2014; 5: e1484. doi: 10.1038/cddis.2014.408.

214. Maniam S, Coutts AS, Stratford MR, McGouran J, Kessler B, La Thangue NB. Cofactor Strap regulates oxidative phosphorylation and mitochondrial p53 activity through ATP synthase. Cell Death Differ. 2015; 22: 156-63. doi: 10.1038/cdd.2014.135.

215. Melino G, Memmi EM, Pelicci PG, Bernassola F. Maintaining epithelial stemness with p63. Sci Signal. 2015; 8: re9. doi: 10.1126/scisignal.aaa1033.

216. Candi E, Amelio I, Agostini M, Melino G. MicroRNAs and p63 in epithelial stemness. Cell Death Differ. 2015; 22: 12-21. doi: 10.1038/cdd.2014.113.

217. Viticchiè G, Agostini M, Lena AM, Mancini M, Zhou H, Zolla L, Dinsdale D, Saintigny G, Melino G, Candi E. p63 supports aerobic respiration through hexokinase II. Proc Natl Acad Sci USA. 2015; 112: 11577-82. doi: 10.1073/pnas.1508871112.

218. Memmi EM, Sanarico AG, Giacobbe A, Peschiaroli A, Frezza V, Cicalese A, Pisati F, Tosoni D, Zhou H, Tonon G, Antonov A, Melino G, Pelicci PG, et al. p63 Sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. Proc Natl Acad Sci USA. 2015; 112: 3499-504. doi: 10.1073/pnas.1500762112.

219. Rufini A, Niklison-Chirou MV, Inoue S, Tomasini R, Harris IS, Marino A, Federici M, Dinsdale D, Knight RA, Melino G, Mak TW. TAp73 depletion accelerates aging through metabolic dysregulation. Genes Dev. 2012; 26: 2009-14. doi: 10.1101/gad.197640.112.

220. Amelio I, Inoue S, Markert EK, Levine AJ, Knight RA, Mak TW, Melino G. TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. Proc Natl Acad Sci USA. 2015; 112: 226-31. doi: 10.1073/pnas.1410609111.

221. Amelio I, Melino G. The p53 family and the hypoxia-inducible factors (HIFs): determinants of cancer progression. Trends Biochem Sci. 2015; 40: 425-34. doi: 10.1016/j.tibs.2015.04.007.

222. Ikeda K, Posillico JT, Boyle MB, Webb AC, Brown EM, Broadus AE. Microinjected Xenopus oocytes secrete mature, biologically active parathyroid hormone. Mol Endocrinol. 1989; 3: 1084-9. doi: 10.1210/mend-3-7-1084.

223. Gomez L, Thiebaut P-A, Paillard M, Ducreux S, Abrial M, Crola Da Silva C, Durand A, Alam MR, Van Coppenolle F, Sheu S-S, Ovize M. The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury. Cell Death Differ. 2015; 22: 1890. doi: 10.1038/cdd.2015.118.

224. Lamb R, Fiorillo M, Chadwick A, Ozsvari B, Reeves KJ, Smith DL, Clarke RB, Howell SJ, Cappello AR, Martinez-Outschoorn UE, Peiris-Pagès M, Sotgia F, Lisanti MP. Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Oncotarget. 2015; 6: 14005-25. doi: 10.18632/oncotarget.4159.

225. Hugle M, Belz K, Fulda S. Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs. Cell Death Differ. 2015; 22: 1946-56. doi: 10.1038/cdd.2015.59.

226. Javadov S, Jang S, Rodriguez-Reyes N, Rodriguez-Zayas AE, Soto Hernandez J, Krainz T, Wipf P, Frontera W. Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats. Oncotarget. 2015; 6: 39469-81. doi: 10.18632/oncotarget.5783.

227. Dho SH, Kim JY, Kwon E-S, Lim JC, Park SS, Kwon K-S. NOX5-L can stimulate proliferation and apoptosis depending on its levels and cellular context, determining cancer cell susceptibility to cisplatin. Oncotarget. 2015; 6: 39235-46. doi: 10.18632/oncotarget.5743.

228. Liu L, Zou P, Zheng L, Linarelli LE, Amarell S, Passaro A, Liu D, Cheng Z. Tamoxifen reduces fat mass by boosting reactive oxygen species. Cell Death Dis. 2015; 6: e1586. doi: 10.1038/cddis.2014.553.

229. Martinez BA, Kim H, Ray A, Caldwell GA, Caldwell KA. A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans. Cell Death Dis. 2015; 6: e1908. doi: 10.1038/cddis.2015.270.

230. Granato M, Gilardini Montani MS, Filardi M, Faggioni A, Cirone M. Capsaicin triggers immunogenic PEL cell death, stimulates DCs and reverts PEL-induced immune suppression. Oncotarget. 2015; 6: 29543-54. doi: 10.18632/oncotarget.4911.

231. Beker MC, Caglayan AB, Kelestemur T, Caglayan B, Yalcin E, Yulug B, Kilic U, Hermann DM, Kilic E. Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation. Oncotarget. 2015; 6: 30604-14. doi: 10.18632/oncotarget.5773.

232. Zhao H, Ning S, Scicinski J, Oronsky B, Knox SJ, Peehl DM. Epigenetic effects of RRx-001: a possible unifying mechanism of anticancer activity. Oncotarget. 2015; 6: 43172-81. doi: 10.18632/oncotarget.6526.

233. Yadav N, Kumar S, Marlowe T, Chaudhary AK, Kumar R, Wang J, O'Malley J, Boland PM, Jayanthi S, Kumar TKS, Yadava N, Chandra D. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. Cell Death Dis. 2015; 6: e1969. doi: 10.1038/cddis.2015.305.

234. Solaini G, Sgarbi G, Baracca A. Oxidative phosphorylation in cancer cells. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2011; 1807: 534-42. doi: 10.1016/j.bbabio.2010.09.003.

235. Li K, Gao B, Li J, Chen H, Li Y, Wei Y, Gong D, Gao J, Zhang J, Tan W, Wen T, Zhang L, Huang L, et al. ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription. Oncotarget. 2015; 6: 38107-26. doi: 10.18632/oncotarget.5646.

236. Pérez-López FR, Chedraui P, Haya J, Cuadros JL. Effects of the Mediterranean diet on longevity and age-related morbid conditions. Maturitas. 2009; 64: 67-79. doi: 10.1016/j.maturitas.2009.07.013.

237. Noto D, Cefalù AB, Barbagallo CM, Ganci A, Cavera G, Fayer F, Palesano O, Spina R, Valenti V, Altieri GI, Caldarella R, Giammanco A, Termini R, et al. Baseline metabolic disturbances and the twenty-five years risk of incident cancer in a Mediterranean population. Nutr Metab Cardiovasc Dis. 2016; 26: 1020-5. doi: 10.1016/j.numecd.2016.07.003.

238. Arnold M, Leitzmann M, Freisling H, Bray F, Romieu I, Renehan A, Soerjomataram I. Obesity and cancer: An update of the global impact. Cancer Epidemiol. 2016; 41: 8-15. doi: 10.1016/j.canep.2016.01.003.

239. Vainio H, International Agency for Research on Cancer, International Agency for Research on Cancer, editors. Weight control and physical activity. Lyon: IARC Press; 2002. 315 p.

240. Fader AN, Beavis A, Smith A. Lifestyle changes and the risk of developing endometrial and ovarian cancers: opportunities for prevention and management. International Journal of Women's Health. 2016; : 151. doi: 10.2147/IJWH.S88367.

241. Ma Y, Yang Y, Wang F, Zhang P, Shi C, Zou Y, Qin H. Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS ONE. 2013; 8: e53916. doi: 10.1371/journal.pone.0053916.

242. Chen Y, Liu L, Wang X, Wang J, Yan Z, Cheng J, Gong G, Li G. Body mass index and risk of gastric cancer: a meta-analysis of a population with more than ten million from 24 prospective studies. Cancer Epidemiol Biomarkers Prev. 2013; 22: 1395-408. doi: 10.1158/1055-9965.EPI-13-0042.

243. Rai A, Mohapatra SC, Shukla HS. A review of association of dietary factors in gallbladder cancer. Indian J Cancer. 2004; 41: 147-51.

244. Wang F, Xu Y. Body mass index and risk of renal cell cancer: a dose-response meta-analysis of published cohort studies. Int J Cancer. 2014; 135: 1673-86. doi: 10.1002/ijc.28813.

245. Grosso G, Buscemi S, Galvano F, Mistretta A, Marventano S, La Vela V, Drago F, Gangi S, Basile F, Biondi A. Mediterranean diet and cancer: epidemiological evidence and mechanism of selected aspects. BMC Surg. 2013; 13 Suppl 2: S14. doi: 10.1186/1471-2482-13-S2-S14.

246. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr. 2010; 92: 1189-96. doi: 10.3945/ajcn.2010.29673.

247. Couto E, Boffetta P, Lagiou P, Ferrari P, Buckland G, Overvad K, Dahm CC, Tjønneland A, Olsen A, Clavel-Chapelon F, Boutron-Ruault M-C, Cottet V, Trichopoulos D, et al. Mediterranean dietary pattern and cancer risk in the EPIC cohort. British Journal of Cancer. 2011; 104: 1493-9. doi: 10.1038/bjc.2011.106.

248. Carruba G, Granata OM, Pala V, Campisi I, Agostara B, Cusimano R, Ravazzolo B, Traina A. A traditional Mediterranean diet decreases endogenous estrogens in healthy postmenopausal women. Nutr Cancer. 2006; 56: 253-9. doi: 10.1207/s15327914nc5602_18.

249. Castagnetta LAM, Granata OM, Traina A, Ravazzolo B, Amoroso M, Miele M, Bellavia V, Agostara B, Carruba G. Tissue content of hydroxyestrogens in relation to survival of breast cancer patients. Clin Cancer Res. 2002; 8: 3146-55.

250. Steck SE, Guinter M, Zheng J, Thomson CA. Index-Based Dietary Patterns and Colorectal Cancer Risk: A Systematic Review. Advances in Nutrition: An International Review Journal. 2015; 6: 763-73. doi: 10.3945/an.115.009746.

251. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009; 30: 1073-81. doi: 10.1093/carcin/bgp127.

252. Barera A, Buscemi S, Monastero R, Caruso C, Caldarella R, Ciaccio M, Vasto S. β-glucans: ex vivo inflammatory and oxidative stress results after pasta intake. Immun Ageing. 2016; 13: 14. doi: 10.1186/s12979-016-0068-x.

253. Decarli A, La Vecchia C, Cislaghi C, Mezzanotte G, Marubini E. Descriptive epidemiology of gastric cancer in Italy. Cancer. 1986; 58: 2560-9.

254. La Vecchia C, D'Avanzo B, Negri E, Decarli A, Benichou J. Attributable risks for stomach cancer in northern Italy. Int J Cancer. 1995; 60: 748-52.

255. Praud D, Bertuccio P, Bosetti C, Turati F, Ferraroni M, La Vecchia C. Adherence to the Mediterranean diet and gastric cancer risk in Italy. Int J Cancer. 2014; 134: 2935-41. doi: 10.1002/ijc.28620.

256. Giraldi L, Panic N, Cadoni G, Boccia S, Leoncini E. Association between Mediterranean diet and head and neck cancer: results of a large case-control study in Italy. Eur J Cancer Prev. 2016; . doi: 10.1097/CEJ.0000000000000277.

257. Bosetti C, Gallus S, Trichopoulou A, Talamini R, Franceschi S, Negri E, La Vecchia C. Influence of the Mediterranean diet on the risk of cancers of the upper aerodigestive tract. Cancer Epidemiol Biomarkers Prev. 2003; 12: 1091-4.

258. Jacobs DR, Marquart L, Slavin J, Kushi LH. Whole-grain intake and cancer: an expanded review and meta-analysis. Nutr Cancer. 1998; 30: 85-96. doi: 10.1080/01635589809514647.

259. Norat T, Aune D, Chan D, Romaguera D. Fruits and vegetables: updating the epidemiologic evidence for the WCRF/AICR lifestyle recommendations for cancer prevention. Cancer Treat Res. 2014; 159: 35-50. doi: 10.1007/978-3-642-38007-5_3.

260. Chatenoud L, La Vecchia C, Franceschi S, Tavani A, Jacobs DR, Parpinel MT, Soler M, Negri E. Refined-cereal intake and risk of selected cancers in italy. Am J Clin Nutr. 1999; 70: 1107-10.

261. Mudryj AN, Yu N, Aukema HM. Nutritional and health benefits of pulses. Appl Physiol Nutr Metab. 2014; 39: 1197-204. doi: 10.1139/apnm-2013-0557.

262. Falasca M, Casari I, Maffucci T. Cancer chemoprevention with nuts. J Natl Cancer Inst. 2014; 106. doi: 10.1093/jnci/dju238.

263. Yeh C-C, You S-L, Chen C-J, Sung F-C. Peanut consumption and reduced risk of colorectal cancer in women: a prospective study in Taiwan. World J Gastroenterol. 2006; 12: 222-7.

264. American Institute for Cancer Research, World Cancer Research Fund, editors. Food, nutrition, physical activity and the prevention of cancer: a global perspective: a project of World Cancer Research Fund International. Washington, D.C: American Institute for Cancer Research; 2007. 517 p.

265. Shufelt C, Merz CNB, Yang Y, Kirschner J, Polk D, Stanczyk F, Paul-Labrador M, Braunstein GD. Red Versus White Wine as a Nutritional Aromatase Inhibitor in Premenopausal Women: A Pilot Study. Journal of Women's Health. 2012; 21: 281-4. doi: 10.1089/jwh.2011.3001.

266. Arranz S, Chiva-Blanch G, Valderas-Martínez P, Medina-Remón A, Lamuela-Raventós RM, Estruch R. Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer. Nutrients. 2012; 4: 759-81. doi: 10.3390/nu4070759.

267. D'Alessandro A, De Pergola G, Silvestris F. Mediterranean Diet and cancer risk: an open issue. International Journal of Food Sciences and Nutrition. 2016; 67: 593-605. doi: 10.1080/09637486.2016.1191444.

268. Schwingshackl L, Hoffmann G. Does a Mediterranean-Type Diet Reduce Cancer Risk? Curr Nutr Rep. 2016; 5: 9-17. doi: 10.1007/s13668-015-0141-7.

269. Ostan R, Lanzarini C, Pini E, Scurti M, Vianello D, Bertarelli C, Fabbri C, Izzi M, Palmas G, Biondi F, Martucci M, Bellavista E, Salvioli S, et al. Inflammaging and Cancer: A Challenge for the Mediterranean Diet. Nutrients. 2015; 7: 2589-621. doi: 10.3390/nu7042589.

270. Paul L. Diet, nutrition and telomere length. The Journal of Nutritional Biochemistry. 2011; 22: 895-901. doi: 10.1016/j.jnutbio.2010.12.001.

271. Rafie N, Golpour Hamedani S, Barak F, Safavi SM, Miraghajani M. Dietary patterns, food groups and telomere length: a systematic review of current studies. Eur J Clin Nutr. 2016; . doi: 10.1038/ejcn.2016.149.

272. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology. 2006; 31: 277-87. doi: 10.1016/j.psyneuen.2005.08.011.

273. Hu FB. Plant-based foods and prevention of cardiovascular disease: an overview. Am J Clin Nutr. 2003; 78: 544S-551S.

274. Anderson AL, Harris TB, Tylavsky FA, Perry SE, Houston DK, Hue TF, Strotmeyer ES, Sahyoun NR, Health ABC Study. Dietary patterns and survival of older adults. J Am Diet Assoc. 2011; 111: 84-91. doi: 10.1016/j.jada.2010.10.012.

275. Boccardi V, Esposito A, Rizzo MR, Marfella R, Barbieri M, Paolisso G. Mediterranean Diet, Telomere Maintenance and Health Status among Elderly. Vinciguerra M, editor. PLoS ONE. 2013; 8: e62781. doi: 10.1371/journal.pone.0062781.

276. Tiainen A-MK, Männistö S, Blomstedt PA, Moltchanova E, Perälä M-M, Kaartinen NE, Kajantie E, Kananen L, Hovatta I, Eriksson JG. Leukocyte telomere length and its relation to food and nutrient intake in an elderly population. Eur J Clin Nutr. 2012; 66: 1290-4. doi: 10.1038/ejcn.2012.143.

277. Knoops KTB, Groot de LC, Fidanza F, Alberti-Fidanza A, Kromhout D, van Staveren WA. Comparison of three different dietary scores in relation to 10-year mortality in elderly European subjects: the HALE project. European Journal of Clinical Nutrition. 2006; 60: 746-55. doi: 10.1038/sj.ejcn.1602378.

278. Crous-Bou M, Fung TT, Prescott J, Julin B, Du M, Sun Q, Rexrode KM, Hu FB, De Vivo I. Mediterranean diet and telomere length in Nurses' Health Study: population based cohort study. BMJ. 2014; 349: g6674.

279. Zbeida M, Goldsmith R, Shimony T, Vardi H, Naggan L, Shahar DR. Mediterranean diet and functional indicators among older adults in non-Mediterranean and Mediterranean countries. The journal of nutrition, health & aging. 2014; 18: 411-8. doi: 10.1007/s12603-014-0003-9.

280. Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, Martínez-Lapiscina EH, Fitó M, Pérez-Heras A, Salas-Salvadó J, Estruch R, Ros E. Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Internal Medicine. 2015; 175: 1094. doi: 10.1001/jamainternmed.2015.1668.

281. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003; 348: 2599-608. doi: 10.1056/NEJMoa025039.

282. Marin C, Delgado-Lista J, Ramirez R, Carracedo J, Caballero J, Perez-Martinez P, Gutierrez-Mariscal FM, Garcia-Rios A, Delgado-Casado N, Cruz-Teno C, Yubero-Serrano EM, Tinahones F, Malagon M del M, et al. Mediterranean diet reduces senescence-associated stress in endothelial cells. AGE. 2012; 34: 1309-16. doi: 10.1007/s11357-011-9305-6.

283. Iantorno M, Campia U, Di Daniele N, Nistico S, Forleo GB, Cardillo C, Tesauro M. Obesity, inflammation and endothelial dysfunction. J Biol Regul Homeost Agents. 2014; 28: 169-76.

284. Fernández del Río L, Gutiérrez-Casado E, Varela-López A, Villalba J. Olive Oil and the Hallmarks of Aging. Molecules. 2016; 21: 163. doi: 10.3390/molecules21020163.

285. Santiago-Mora R, Casado-Díaz A, De Castro MD, Quesada-Gómez JM. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: the effect on differentiation in stem cells derived from bone marrow. Osteoporos Int. 2011; 22: 675-84. doi: 10.1007/s00198-010-1270-x.

286. Beauchamp GK, Keast RSJ, Morel D, Lin J, Pika J, Han Q, Lee C-H, Smith AB, Breslin PAS. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature. 2005; 437: 45-6. doi: 10.1038/437045a.

287. Agudo A, Cabrera L, Amiano P, Ardanaz E, Barricarte A, Berenguer T, Chirlaque MD, Dorronsoro M, Jakszyn P, Larrañaga N, Martínez C, Navarro C, Quirós JR, et al. Fruit and vegetable intakes, dietary antioxidant nutrients, and total mortality in Spanish adults: findings from the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). Am J Clin Nutr. 2007; 85: 1634-42.

288. Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, et al. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell. 2015; 14: 497-510. doi: 10.1111/acel.12338.

289. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999; 99: 779-85.

290. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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. 2001; 285: 2486-97.

291. Alberti KGMM, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new worldwide definition. Lancet. 2005; 366: 1059-62. doi: 10.1016/S0140-6736(05)67402-8.

292. Hamer M, McNaughton SA, Bates CJ, Mishra GD. Dietary patterns, assessed from a weighed food record, and survival among elderly participants from the United Kingdom. Eur J Clin Nutr. 2010; 64: 853-61. doi: 10.1038/ejcn.2010.93.

293. L.J. Dominguez. Healthy aging and Mediterranean diet. 2014; 62: 157-60.

# data[].attributes.attachment_link.title
Impact of Mediterranean diet on metabolic syndrome, cancer and longevity | Oncotarget

# data[].attributes.attachment_link.description
Obesity and metabolic syndrome (MetS) showed a significant increase in the last decades, becoming a public health problem due to high hospitalization rates, treatment costs and impaired quality of life. Both obesity that MetS are characterized by insulin resistance that expose the patients to an increased risk of cardiovascular disease and cancer, despite the healthy nutritional habits [ 1].

# data[].attributes.headline
Research Article Avocado Oil Supplementation Modifies Cardiovascular Risk Profile Markers in a Rat Model of Sucrose-Induced Metabolic Changes

# data[].attributes.subject
Research Article Avocado Oil Supplementation Modifies Cardiovascular Risk Profile Markers in a Rat Model of Sucrose-Induced Metabolic Changes

# data[].attributes.body
-Clarisa Williams

The researchers aimed to evaluate the use of avocado oil and its effects in rats with metabolic changes. This study utilized rats to evaluate the effects of avocado oil and olive oil for the animals on increased sucrose consumption. The researchers had found that the use of avocado oil resulted in a lower levels of triglycerides. TG levels were higher in the rat groups that received higher sucrose in the diet compared to the group that did not. Avocado is commonly recommended as a nutritional adaptation to help reduce the risk of diabetes, normalize blood cholesterol, and is a good source of antioxidants. Since the use of avocado oil has been associated with the reduction of triglycerides, nutritionists and those involved in creating a management plan can consider utilizing avocado oil as a supplement. The use of avocado oil can be a supplement for those at elevated risk for metabolic syndrome and who potential have elevated blood sugar levels.

Carvajal-Zarrabal, O., Nolasco-Hipolito, C., Aguilar-Uscanga, M. G., Melo-Santiesteban, G., Hayward-Jones, P. M., & Barradas-Dermitz, D. M. (2014). Avocado oil supplementation modifies cardiovascular risk profile markers in a rat model of sucrose-induced metabolic changes. Disease markers, 2014.

# data[].attributes.headline
Potassium Intake and the Prevalence of Metabolic Syndrome: The Korean National Health and Nutrition Examination Survey 2008–2010 (Richard Adefioye)

# data[].attributes.subject
Potassium Intake and the Prevalence of Metabolic Syndrome: The Korean National Health and Nutrition Examination Survey 2008–2010 (Richard Adefioye)

# data[].attributes.body
Positive dietary choices are one of the lifestyle changes that can be made in an attempt to manage metabolic syndrome, and one of those changes is to reduce sodium and/or increase potassium intake.

I found this paper that looked at the correlation between potassium intake and metabolic syndrome. The study was based on a survey by the Korean National Health Council that ran from 2008 to 2010. Over 16,000 participants including men and women were involved in this study.

The key finding that stood out for me in this study was that potassium intake was inversely associated with an increased risk of metabolic syndrome, as there was an 11% increase in metabolic syndrome risk for every 1 g reduction in daily potassium intake in women that consumed less than adequate potassium levels.

Another interesting result of this study is that this effect was more pronounced in post-menopausal women, but not observed in men.

Reference:

Lee H, Lee J, Hwang SS, et al. Potassium intake and the prevalence of metabolic syndrome: the Korean National Health and Nutrition Examination Survey 2008-2010. PLoS One. 2013;8(1):e55106. doi:10.1371/journal.pone.0055106

# data[].attributes.headline
Metabolic syndrome and clinical outcomes in patients infected with COVID‐19 - Dierra Doaks 

# data[].attributes.subject
Metabolic syndrome and clinical outcomes in patients infected with COVID‐19 - Dierra Doaks 

# data[].attributes.body
The paper that I am discussing is about the association between metabolic syndrome and mortality, need for ventilation, and need for the intensive care unit among patients with covid-19. The study done was important because data for the on metabolic syndrome and covid-19 is scarce right now. A cohort study was done on close to two thousand subjects with covid-19. All of the subjects were over 18 years old. Data was collected on the subjects demographics including BMI, smoking, what happened during their hospital stays with covid-19, and their comorbidities. The results of the study were interesting. Patients with metabolic syndrome had increased mortality rates, increased need for mechanical ventilation, and higher admission into the intensive care unit in the hospital. These rates were regardless of their age, sex, and or race. This paper was important because it showed that metabolic syndrome is a good prognostic indicator for the outcomes in patients with covid-19.

Lohia, Prateek et al. “Metabolic Syndrome and Clinical Outcomes in Patients Infected with COVID‐19: Does Age, Sex, and Race of the Patient with Metabolic Syndrome Matter?” Journal of diabetes 13.5 (2021): 420–429. Web.

# data[].attributes.headline
Cassie Craig: The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice

# data[].attributes.subject
Cassie Craig: The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice

# data[].attributes.body
This study is important because it shows potential impacts of a major green tea polyphenol (EGCG) in metabolic syndrome (MetS). The mice used in this experiment were fed a diet with a high fat content with the intention of mimicking MetS symptoms. It was found that the EGCG treatment lowered obesity levels as well as symptoms of MetS. The treatment was long term which is a consideration that scientists should take moving forward, as patients would have to include green tea in their diet long term to see possible results. This applies to nutritional sciences because in humans, EGCG treatment is a nutrient supplement that can impact this disease. Although this study was done in mice, it has the potential to be applied to the clinical setting. Scientists can take this information and start doing studies in humans with MetS and see if the same effects occur. More specifically, patients could possibly combat symptoms of MetS by consuming green tea in their diet as a supplement.

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 Sep;138(9):1677-83. doi: 10.1093/jn/138.9.1677. PMID: 18716169; PMCID: PMC2586893.

# data[].attributes.headline
Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness: posted by Jaida Garrett

# data[].attributes.subject
Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness: posted by Jaida Garrett

# data[].attributes.body
This study brings forth important information useful for countries who may be increasing in numbers for metabolic syndrome. Developing Western countries and Asian countries have been rising in metabolic syndrome so researchers are trying to find a way to detect metabolic disorders with individuals who have metabolic syndrome. Specifically the study looks at how metabolic syndrome can be used as a predictor for type 2diabetes. If this is ossicle, it will be good for the health of the patient and overall public health of the effected population. They found that IFG was the strongest predictor for type 2 development, other factors are such as RR is a better implication for CVD. Clinically the hope is for patients to become motivated to make a lifestyle change when diagnosed with metabolic syndrome. It’s important because the earlier one can detect symptoms with metabolic syndrome, they can catch the developing disease before it develops. This results in lowered cardiovascular complications and prevention of diabetes. Overall the study came to the conclusion that using metabolic syndrome is a great way to diagnose or predict diabetes and CVD.

Shin, J.-A., Lee, J.-H., Lim, S.-Y., Ha, H.-S., Kwon, H.-S., Park, Y.-M., Lee, W.-C., Kang, M.-I., Yim, H.-W., Yoon, K.-H., & Son, H.-Y. (2013, May 28). Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness. Wiley Online Library. Retrieved February 23, 2022, from https://onlinelibrary.wiley.com/doi/full/10.1111/jdi.12075

# data[].attributes.headline
A perspective on vegetarian dietary patterns and risk of metabolic syndrome- Lydia Duncan

# data[].attributes.subject
A perspective on vegetarian dietary patterns and risk of metabolic syndrome- Lydia Duncan

# data[].attributes.body
For this week’s topic, I picked an article review of the vegetarian diet and its connections to Metabolic Syndrome (MetS). The purpose of this article was to present the known research on vegetarian dietary patterns and the risk of developing MetS from said diet. This review is important because it helps us compile and evaluate the already existing research, which then allows us to see what areas might need more research. This article was also interesting because it included some research on the Mediterranean diet in association to MetS, which we know is closer to a vegetarian diet that the typical Western diet is (less of a focus on meat and more of a focus on fruits, veggies, etc.).

There were a few key points from this article that I would like to highlight. Three large studies (the Isle of Ely, Malmo Diet and Cancer Project and the CARDIA study) were combined, and found that dietary patterns with a high meat intake were associated with the criteria of MetS. On the other hand, they found that dietary patterns that were high in vegetables, fruit, and dairy were associated with a lower prevalence of MetS. Another study cross-sectionally evaluated 773 individuals, and found that the individuals with a vegetarian dietary pattern had a 56% lower risk of developing MetS than their non-vegetarian counterparts.

This review relates to nutritional sciences because the studying of different dietary patterns has become very common. While it focused heavily on a vegetarian dietary pattern, it also included an article that assessed the consumption of fruits and vegetables among children and their associated risks for MetS later on in life (27 year study). They found that children with a high vegetable consumption had a 14% lower risk of developing MetS, and children with a lower vegetable consumption were found to have a higher risk of high blood pressure.

A clinical implication from this study is that getting less of your food intake from meats and more from fruits and vegetables can potentially lower a patients risk of developing MetS (along with a few other conditions). While this review did help show the benefits of a vegetarian diet, we must remember that no dietary pattern is perfect for every individual in preventing conditions like MetS.
Sabaté, J., & Wien, M. (2015). A perspective on vegetarian dietary patterns and risk of metabolic syndrome. British Journal of Nutrition, 113(S2), S136-S143. doi:10.1017/S0007114514004139

# data[].attributes.attachment_link.title
A perspective on vegetarian dietary patterns and risk of metabolic syndrome | British Journal of Nutrition | Cambridge Core

# data[].attributes.attachment_link.description
A perspective on vegetarian dietary patterns and risk of metabolic syndrome - Volume 113 Issue S2

# data[].attributes.headline
Julie Rees: Clinical study finds eating within 10-hour window may help stave off diabetes, heart disease

# data[].attributes.subject
Julie Rees: Clinical study finds eating within 10-hour window may help stave off diabetes, heart disease

# data[].attributes.body
In this section we looked a couple diets for metabolic syndrome including the Mediterranean and DASH diets.  Time-restricted eating (TRE) has been studied in animals for years and has recently caught on as a weight loss option for humans.  A group in California did a small study (n=19) on patients with metabolic syndrome who were taking medications for cholesterol and/or hypertension.  The goal was to determine if TRE could enhance the effects of the medications.  After 12 weeks of only eating inside a 10 hour window each day, patients had improved numbers and reduced belly fat.  TRE is a simple diet for patients to follow since calories are not counted and the only restriction is when you can eat.  Patient compliance is an issue that should be considered when making recommendation so TRE may be a good option along with medications if other lifestyles changes do not appear to be working or being followed.  It would be interesting to see the results of a similar study with a large group of participants.  I could not find the full study paper outside of libraries.uky.edu so I have attached an article discussing the findings.

# data[].attributes.attachment_link.readable_text
Metabolic syndrome affects nearly 30 percent of the U.S. population, and increases the risk for type 2 diabetes, heart disease and stroke. But lifestyle interventions such as adopting a healthy diet and increasing physical exercise are difficult to maintain and, even when combined with medication, are often insufficient to fully manage the disease.

Now, in a collaborative effort, researchers from the Salk Institute and the UC San Diego School of Medicine found that a 10-hour time-restricted eating intervention, when combined with traditional medications, resulted in weight loss, reduced abdominal fat, lower blood pressure and cholesterol, and more stable blood sugar and insulin levels for participants. The pilot study, published in Cell Metabolism on December 5, 2019, could lead to a new treatment option for metabolic syndrome patients who are at risk for developing life-altering and costly medical conditions such as diabetes.

"We have found that combining time-restricted eating with medications can give metabolic syndrome patients the ability to better manage their disease," says Satchidananda Panda, co-corresponding author and professor in Salk's Regulatory Biology Laboratory. "Unlike counting calories, time-restricted eating is a simple dietary intervention to incorporate, and we found that participants were able to keep the eating schedule."

Time-restricted eating (eating all calories within a consistent 10-hour window) supports an individual's circadian rhythms and can maximize health benefits, as evidenced by previous research published by the Salk team. Circadian rhythms are the 24-hour cycles of biological processes that affect nearly every cell in the body. Increasingly, scientists are finding that erratic eating patterns can disrupt this system and increase the risk for metabolic syndrome and other metabolic disorders with such symptoms as increased abdominal fat, abnormal cholesterol or triglycerides, and high blood pressure and blood sugar levels.

"Eating and drinking everything (except water) within a consistent 10-hour window allows your body to rest and restore for 14 hours at night. Your body can also anticipate when you will eat so it can prepare to optimize metabolism," says Emily Manoogian, the paper's co-first author and a postdoctoral fellow in the Panda lab. "We wanted to know if controlling the timing of food intake to support circadian rhythms would improve the health of individuals that were already being treated for cardiometabolic diseases."

"We suspected a 10-hour eating intervention might be beneficial because of Satchidananda Panda's pioneering work in animals, which showed that time-restricted eating led to dramatic health benefits, including a healthier metabolism," adds Michael Wilkinson, co-first author, assistant clinical professor of medicine at UC San Diego School of Medicine and a cardiologist at UC San Diego Health.

The pilot study included 19 participants (13 men and 6 women) diagnosed with metabolic syndrome who self-reported eating during a time window of more than 14 hours per day. Additionally, 84 percent of participants were taking at least one medication such as a statin or an antihypertensive therapy. Study participants used the Panda lab's myCircadianClock app to log when and what they ate during an initial 2-week baseline period followed by the three-month, 10-hour time-restricted eating intervention. Nearly 86 percent of participants correctly logged their food using the app, indicating high compliance throughout the study.

Participants did not report any adverse effects during the intervention. To reduce food intake to the 10-hour window, most participants delayed their first meal and advanced their last meal each day, so meals were not skipped. Although calories were not recommended to be reduced for the intervention, some participants did report eating less, likely due to the shorter eating window.

Overall, participants experienced improved sleep as well as a 3-4 percent reduction in body weight, body mass index, abdominal fat and waist circumference. Major risk factors for heart disease were diminished as participants showed reduced blood pressure and total cholesterol. Blood sugar levels and insulin levels also showed a trend toward improvement.

"Metabolism is closely linked with circadian rhythms, and knowing this, we were able to develop an intervention to help patients with metabolic syndrome without decreasing calories or increasing physical exercise," says Pam Taub, co-corresponding author and associate professor of medicine at the UC San Diego School of Medicine and a cardiologist at UC San Diego Health. "If we can optimize circadian rhythms then we might be able to optimize the metabolic system."

"Adapting this 10-hour time-restricted eating is an easy and cost-effective method for reducing symptoms of metabolic syndrome and improving health," adds Panda. "By delaying the onset of diabetes by even one year in a million people with prediabetes, the intervention could save roughly 9.6 billion dollars in healthcare costs."

The scientists are currently conducting a clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases to examine the benefits of time-restricted eating in a larger group of more than 100 participants with metabolic syndrome. The study includes additional measures that will help the researchers investigate changes in body composition and muscle function.

# data[].attributes.attachment_link.keywords[]
diet and weight loss; fitness; obesity; diseases and conditions; eating disorder research; heart disease; cholesterol; diabetes

# data[].attributes.attachment_link.title
Clinical study finds eating within 10-hour window may help stave off diabetes, heart disease

# data[].attributes.attachment_link.description
Researchers have found that a 10-hour time-restricted eating intervention, when combined with traditional medications, resulted in weight loss, reduced abdominal fat, lower blood pressure and cholesterol for participants. The pilot study could lead to a new treatment option for metabolic syndrome patients who are at risk for developing life-altering and costly medical conditions such as diabetes.

# data[].attributes.headline
Sidney Harm: Effects of cumin (Cuminum cyminum L.) essential oil supplementation on metabolic syndrome components: A randomized, triple‐blind, placebo‐controlled clinical trial

# data[].attributes.subject
Sidney Harm: Effects of cumin (Cuminum cyminum L.) essential oil supplementation on metabolic syndrome components: A randomized, triple‐blind, placebo‐controlled clinical trial

# data[].attributes.body
Metabolic Syndrome  is a diagnosis that an individual will have when meeting three out of five of the criteria. The criteria includes; waist circumference, triglycerides > or = 150 mg/dL, HDL-C <40 mg/dL (men) or <50 mg/dL (women), blood pressure > or = 130/> or = 85, and a fasting glucose > or = 100 mg/dL. This diagnosis of Metabolic Syndrome increases an individuals chance for Type 2 diabetes as well as cardiovascular disease¹. This study looks at the impact of a cumin essential oil supplement on the metabolic syndrome parameters. One reason this study interested me out of the others while researching was the look at some kind of supplement or treatment that isn’t necessarily a “drug” and more of a natural alternative. Overall the study didn’t have very positive outcomes for the cumin essential oil supplement none of the parameters showed significant improvements expect for individuals diastolic blood pressure, which I found out and wonder why it would’ve caused a different in diastolic blood pressure but no other parameter measured.

References:

1.     Morovati, Pourghassem Gargari, B., & Sarbakhsh, P. (2019). Effects of cumin (Cuminum cyminum L.) essential oil supplementation on metabolic syndrome components: A randomized, triple‐blind, placebo‐controlled clinical trial. Phytotherapy Research, 33(12), 3261–3269. https://doi.org/10.1002/ptr.6500

# data[].attributes.headline
Rhoda Inimgba: Supplementation Effect of a Combination of Olive(Olea europea L.) Leaf and Fruit Extracts in theClinical Management of Hypertension and Metabolic Syndrome.

# data[].attributes.subject
Rhoda Inimgba: Supplementation Effect of a Combination of Olive(Olea europea L.) Leaf and Fruit Extracts in theClinical Management of Hypertension and Metabolic Syndrome.

# data[].attributes.body
The purpose of this study was to analyze how effective supplementation could be in clinically managing hypertension and metabolic syndrome. This is important because most times after taking the drugs prescribed by physicians, that might not be enough for better health. This is because our diet plays a huge role when it comes to our health. Knowing different kinds of food we can put in place to manage a disease or just live healthy generally is important. This study focuses on a combination of olive leaf and fruit extracts as a supplement to be able to manage hypertension and metabolic syndrome. One key finding of the study was that they found out that a combination of olive leaf extract and fruit extract could most likely be a non-pharmacological solution to people who have hypertension and metabolic syndrome. This is great because most of the side effects associated with this extracts were just headache, nausea, diarrhea which can easily be managed. This related to nutritional sciences as this study shows that making supplements to our diet can be important in helping with giving individuals a better health without having to take drugs which could be more expensive. The clinical implications of this study is that it gives patients with hypertension and metabolic syndrome more options to be able to deal with their illness. They could either go the pharmacological route or herbal route or maybe even both.

Hermans, M. P., Lempereur, P., Salembier, J.-P., Maes, N., Albert, A., Jansen, O., & Pincemail, J. (2020). Supplementation effect of a combination of olive (olea Europea L.) leaf and fruit extracts in the clinical management of hypertension and metabolic syndrome. Antioxidants, 9(9), 872.https://doi.org/10.3390/antiox9090872

# data[].attributes.headline
Tamunoerenomie Inimgba: Cardiac Health in Women With Metabolic Syndrome.

# data[].attributes.subject
Tamunoerenomie Inimgba: Cardiac Health in Women With Metabolic Syndrome.

# data[].attributes.body
The article focuses on identifying the gender disparity that may be present in patients with metabolic syndrome. Metabolic syndrome is known to affect both men and women of all races and increases heart diseases in both genders, however there seems to be an increased prevalence in women, especially women aged 45-64 years.  Previous studies have e shown that without metabolic syndrome, women experience a significantly lower risk of heart disease before menopause when compared to age-matched males, and the incidence and severity of cardiovascular disease increases post menopause. It has been suggested that the interaction between female sex hormones such as estrogen and specific risk factors for metabolic syndrome may be responsible for this gender bias that is seen in the disease. A key finding in the article was that the gender difference in the prevalence of cardiovascular disease in patients with metabolic syndrome may be highlighted by numerous factors including intrinsic electromechanical properties myocardial structure , adipokine and inflammatory status, which female sex hormones such as estrogen definitely play a role in regulation of some of these factors during the progression of metabolic syndrome. The clinical implications of the study would be to provide a better understanding of the gender difference , which would help to offer new ideas that could reduce the prevalence of metabolic syndrome and the different co-morbidities that come alongside it.
Ren, & Kelley, R. O. (2009). Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology. Obesity (Silver Spring, Md.), 17(6), 1114–1123. https://doi.org/10.1038/oby.2009.8

# data[].attributes.headline
Joe Devine: Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle

# data[].attributes.subject
Joe Devine: Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle

# data[].attributes.body
The purpose of this study is to highlight the molecular mechanistic changes the body undergoes during exercise and how that translates to treatment for type 2 diabetes. The study shows that people can prevent insulin resistance and reduce the risk of type 2 diabetes by 58% through diet and regular exercise (~150 min/week). The article also highlights a study that showed ~11% of patents that had a remission of type 2 diabetes diagnosis through an interventional diet and exercise regiment. The clinical implication that this article highlights is that there is improvement at the molecular level that can be utilized through simple means in order to aid in the treatment of patients suffering from type 2 diabetes. These “means” not only lead to healthy lifestyle choices but to a higher quality of life and in many cases have a longitudinal benefit in terms of mortality outcome.

Stanford, K. I., & Goodyear, L. J. (2014). Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle. Advances in physiology education, 38(4), 308–314. https://doi.org/10.1152/advan.00080.2014

# data[].attributes.headline
Effect of low-carbohydrate diets on cardiometabolic risk, insulin resistance, and metabolic syndrome

# data[].attributes.subject
Effect of low-carbohydrate diets on cardiometabolic risk, insulin resistance, and metabolic syndrome

# data[].attributes.body
Posted by Mitchell Watts

This review discussed findings on the comparison between a low-carbohydrate, specifically a ketogenic diet, versus a standard low-fat diet in the treatment of dyslipidemia, insulin resistance, hyperinsulinemia, and systemic inflammation seen in metabolic syndrome. A very low carb diet (VCLD) or ‘ketogenic’ diet requires carb intake to ideally be less than 20 grams per day or at most 50 grams per day. Nutritional ketosis results from a severe restriction of carbs, and this metabolic effect has been found to stabilize serum glucose and minimize insulin release seen in hyperinsulinemia.

The author mentions one clinical trial that involved 262 patients with T2DM, and separated them into a control group diet based on typical ADA diet guidelines and a VLCD group. The researchers confirmed diet adherence and nutritional ketosis over 1 year. The VLCD group compared to control had greater reductions in weight loss and improvement in triglycerides, HDL, LDL, HbA1c, and 10-year atherosclerotic CVD risk. In another meta-analysis that compared standard low-carb (not a VLCD) with a low-fat diet for patients with overweight/obesity. The low-carb diet participants had statistically significant greater improvement in weight loss and reduced CVD risk. Lastly, a VLCD compared to a low-fat diet showed greater reduction in inflammatory markers.

Clinically, these findings warrant continued research and randomized control trials of a ketogenic diet to improve outcomes with markers of metabolic syndrome, particularly with hyperglycemia and insulin resistance. In my opinion though, this diet is not feasible for everyone and could lead to nutritional deficiencies. Therefore, I would only recommend it if standard diet recommendations, such as a Mediterranean or ADA diet guidelines, were not effective and the patient would have good compliance with a ketogenic diet. Though I imagine this could also be useful for short term treatment. This could be helpful for a patient to become more metabolically healthy, but then focus on a standard healthy diet long term.

O'Neill B. J. (2020). Effect of low-carbohydrate diets on cardiometabolic risk, insulin resistance, and metabolic syndrome. Current opinion in endocrinology, diabetes, and obesity, 27(5), 301–307. https://doi.org/10.1097/MED.0000000000000569

# data[].attributes.attachment_link.readable_text
Abstract

Purpose of review: An obesity epidemic has resulted in increasing prevalence of insulin resistance, hyperinsulinemia, metabolic syndrome (MetS), and cardiovascular disease (CVD). The Diet-Heart Hypothesis posited that dietary fat is the culprit. Yet dietary fat reduction has contributed to the problem, not resolved it. The role of hyperinsulinemia, the genesis of its atherogenic dyslipidemia and systemic inflammation in CVD and its reversal is reviewed.

Recent findings: Overnutrition leads to weight gain and carbohydrate intolerance creating a vicious cycle of insulin resistance/hyperinsulinemia inhibiting fat utilization and encouraging fat storage leading to an atherogenic dyslipidemia characterized by hypertriglyceridemia, low HDL, and small dense LDL. The carbohydrate-insulin model better accounts for the pathogenesis of obesity, MetS, and ultimately type 2 diabetes (T2DM) and CVD. Ketogenic Diets reduce visceral obesity, increase insulin sensitivity, reverse the atherogenic dyslipidemia and the inflammatory biomarkers of overnutrition. Recent trials show very high adherence to ketogenic diet for up to 2 years in individuals with T2DM, reversing their metabolic, inflammatory and dysglycemic biomarkers as well as the 10-year estimated atherosclerotic risk. Diabetes reversal occurred in over 50% and complete remission in nearly 8%.

Summary: Therapeutic carbohydrate-restricted can prevent or reverse the components of MetS and T2DM.

Beneficial Diets and Pancreatic Cancer: Molecular Mechanisms and Clinical Practice.

Zhang Y, Zhang T, Yang W, Chen H, Geng X, Li G, Chen H, Wang Y, Li L, Sun B. Zhang Y, et al. Front Oncol. 2021 May 28;11:630972. doi: 10.3389/fonc.2021.630972. eCollection 2021. Front Oncol. 2021. PMID: 34123787 Free PMC article. Review.

Therapeutic Use of the Ketogenic Diet in Refractory Epilepsy: What We Know and What Still Needs to Be Learned.

Zarnowska IM. Zarnowska IM. Nutrients. 2020 Aug 27;12(9):2616. doi: 10.3390/nu12092616. Nutrients. 2020. PMID: 32867258 Free PMC article. Review.

References

Obesity is a common, serious, and costly disease. Centers for Disease Control and Prevention. https://www.cdc.gov/obesity/data/adult.html. [Accessed 28 April 2020].

Flegal KM, Kruszon-Moran D, Carroll MD, et al. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016; 315:22842291.

Ladabaum U, Mannalithara A, Myer PA, Singh G. Obesity, abdominal obesity, physical activity, and caloric intake in US adults: 1988 to 2010. Am J Med 2014; 127:717727.e712.

https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-stat.... [Accessed by 29 April 2020].

Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980-2012. JAMA 2014; 312:12181226.

# data[].attributes.attachment_link.keywords[]
cardiovascular diseases / prevention & control*

# data[].attributes.attachment_link.keywords[]
metabolic syndrome / prevention & control*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Effect of low-carbohydrate diets on cardiometabolic risk, insulin resistance, and metabolic syndrome - PubMed

# data[].attributes.attachment_link.description
Purpose of review: An obesity epidemic has resulted in increasing prevalence of insulin resistance, hyperinsulinemia, metabolic syndrome (MetS), and cardiovascular disease (CVD). The Diet-Heart Hypothesis posited that dietary fat is the culprit. Yet dietary fat reduction has contributed to the problem, not resolved it.

# data[].attributes.headline
Seonwook Kim: Hypolipidemic Effect of Tomato Juice in Hamsters in High Cholesterol Diet-Induced Hyperlipidemia

# data[].attributes.subject
Seonwook Kim: Hypolipidemic Effect of Tomato Juice in Hamsters in High Cholesterol Diet-Induced Hyperlipidemia

# data[].attributes.body
My selected article is how tomato juice ameliorates hyperlipidemia in high cholesterol diet hamster model. This study is important because the key point of diet management is how easy to access foods. Tomato is a globally famous food and easy to access. And their phytonutrients including lycopene and beta-carotene are well known for antioxidants. In this study, this research group investigated the beneficial effects of processed tomato juice. The experimental hamster group had high-cholesterol diet for inducing hyperlipidemia condition and were consumed tomato juice for six weeks. Then they investigated the lipid profile of serum, liver, and feces. High cholesterol diet significantly increased serum total cholesterol (TC), triglyceride (TG), LDL/HDL ratio, hepatic and fetal TC and TG levels. The key finding of this study is that the tomato juice supplement group decreased serum TC, TG, LDL/HDL ratio, hepatic and fetal TC and TG levels. As a clinical implication, tomato may be useful in treating or preventing the onset of hyperlipidemia. As we learned in this week's module diet plan, tomato can be easily added to any type of diet plan in TLC III, DASH, Mediterranean.

Lee LC, Wei L, Huang WC, Hsu YJ, Chen YM, Huang CC. Hypolipidemic Effect of Tomato Juice in Hamsters in High Cholesterol Diet-Induced Hyperlipidemia. Nutrients. 2015 Dec 17;7(12):10525-37. doi: 10.3390/nu7125552. PMID: 26694461; PMCID: PMC4690101.

# data[].attributes.attachment_link.title
Hypolipidemic Effect of Tomato Juice in Hamsters in High Cholesterol Diet-Induced Hyperlipidemia - PubMed

# data[].attributes.attachment_link.description
Tomato is a globally famous food and contains several phytonutrients including lycopene, β-carotene, anthocyanin, and flavonoids. The increased temperature used to produce tomato juice, ketchup, tomato paste and canned tomato enhances the bioactive composition. We aimed to verify the beneficial effe…

# data[].attributes.headline
Leisure-Time Physical Activity, Sedentary Behavior and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study- Esraa Zamzami

# data[].attributes.subject
Leisure-Time Physical Activity, Sedentary Behavior and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study- Esraa Zamzami

# data[].attributes.body
The study I chose for this week’s wall is an observational study that included 5739 participants with metabolic syndrome features who were either obese or overweight. The study examined different lifestyle factors that may increase or decrease the likelihood of developing metabolic syndrome. The main key finding of this study is that participants who had higher levels of depression risk and a sedentary lifestyle had a higher metabolic syndrome severity score. These participants tended to consume a pro-inflammatory dietary pattern that was high in saturated fats, trans fat, protein, and processed meats. On the other hand, participants with lower levels of depression risk and a more active lifestyle had a lower metabolic syndrome severity score. These low-risk patients consumed an antioxidant dietary pattern and were more adherent to a Mediterranean diet. This study is strongly related to nutritional sciences because it directly examines different dietary patterns and their impact on the severity of the disease. It is a critical study because it sheds light on the harmful effect of a sedentary lifestyle and bad eating habits that many people have developed as their everyday lifestyle. The clinical implication of this study is that people should be more encouraged to develop a healthy lifestyle by being more physically active and developing antioxidant dietary patterns.

Gallardo-Alfaro, L., Bibiloni, M., Mascaró, C. M., Montemayor, S., Ruiz-Canela, M., Salas-Salvadó, J., Corella, D., Fitó, M., Romaguera, D., Vioque, J., Alonso-Gómez, Á. M., Wärnberg, J., Martínez, J. A., Serra-Majem, L., Estruch, R., Fernández-García, J. C., Lapetra, J., Pintó, X., García Ríos, A., Bueno-Cavanillas, A., … Tur, J. A. (2020). Leisure-Time Physical Activity, Sedentary Behaviour and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study. Nutrients, 12(4), 1013. https://doi.org/10.3390/nu12041013

# data[].attributes.attachment_link.readable_text
Open Access Feature Paper Article

Received: 10 March 2020 / Revised: 31 March 2020 / Accepted: 1 April 2020 / Published: 7 April 2020

Healthy lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease the likelihood of developing metabolic syndrome (MetS). The aim of this study was to report main lifestyle components and related factors according to the MetS severity. Cross-sectional analysis was done of baseline lifestyle factors from 5739 participants with overweight/obesity and MetS features (aged 55-75 years) included in the PREDIMED-PLUS primary cardiovascular prevention randomized trial. Participants were categorized in tertiles according to a validated MetS severity score (MetSSS). Anthropometrics, visceral adiposity index, dietary nutrient intake, biochemical marker levels, as well as a Dietary Inflammatory Index and depression symptoms (Beck Depression Inventory-II) were measured. Diet quality was assessed using a 17-item energy-restricted MD questionnaire. Duration and intensity of PA was self-reported using the Minnesota-REGICOR Short Physical Activity Questionnaire. Sedentary behaviours were measured using the Spanish version of the Nurses' Health Study questionnaire. The 30 s chair stand test was also assessed. Participants with highest MetSSS showed higher values of cardiovascular risk factors (except for total cholesterol and LDL cholesterol), depression risk, sedentary and TV viewing time, and lower moderate and vigorous leisure-time physical activity (LTPA). Highest MetSSS participants tended to a pro-inflammatory dietary pattern and tended to lower MD adherence. In addition, they showed lower carbohydrate and nut intake and higher intake of protein, saturated and trans fatty acids, cholesterol, iodine, sodium, red and processed meat products, other oils different from olive oil and spirit alcoholic drinks. The highest MetS severity score was associated with lower moderate and vigorous LTPA and higher sedentary time and depression risk, as they tended to a pro-inflammatory dietary pattern and lower MD adherence. View Full-Text

▼ Show Figures

Graphical abstract

Gallardo-Alfaro, L.; Bibiloni, M.d.M.; Mascaró, C.M.; Montemayor, S.; Ruiz-Canela, M.; Salas-Salvadó, J.; Corella, D.; Fitó, M.; Romaguera, D.; Vioque, J.; Alonso-Gómez, Á.M.; Wärnberg, J.; Martínez, J.A.; Serra-Majem, L.; Estruch, R.; Fernández-García, J.C.; Lapetra, J.; Pintó, X.; García Ríos, A.; Bueno-Cavanillas, A.; Gaforio, J.J.; Matía-Martín, P.; Daimiel, L.; Micó-Pérez, R.M.; Vidal, J.; Vázquez, C.; Ros, E.; Fernandez-Lázaro, C.I.; Becerra-Tomás, N.; Gimenez-Alba, I.M.; Zomeño, M.D.; Konieczna, J.; Compañ-Gabucio, L.; Tojal-Sierra, L.; Pérez-López, J.; Zulet, M.Á.; Casañas-Quintana, T.; Castro-Barquero, S.; Gómez-Pérez, A.M.; Santos-Lozano, J.M.; Galera, A.; Basterra-Gortari, F.J.; Basora, J.; Saiz, C.; Pérez-Vega, K.A.; Galmés-Panadés, A.M.; Tercero-Maciá, C.; Sorto-Sánchez, C.; Sayón-Orea, C.; García-Gavilán, J.; Muñoz-Martínez, J.; Tur, J.A., on behalf of the PREDIMED-Plus Investigators. Leisure-Time Physical Activity, Sedentary Behaviour and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study. Nutrients 2020, 12, 1013. https://doi.org/10.3390/nu12041013

AMA Style

Gallardo-Alfaro L, Bibiloni MdM, Mascaró CM, Montemayor S, Ruiz-Canela M, Salas-Salvadó J, Corella D, Fitó M, Romaguera D, Vioque J, Alonso-Gómez ÁM, Wärnberg J, Martínez JA, Serra-Majem L, Estruch R, Fernández-García JC, Lapetra J, Pintó X, García Ríos A, Bueno-Cavanillas A, Gaforio JJ, Matía-Martín P, Daimiel L, Micó-Pérez RM, Vidal J, Vázquez C, Ros E, Fernandez-Lázaro CI, Becerra-Tomás N, Gimenez-Alba IM, Zomeño MD, Konieczna J, Compañ-Gabucio L, Tojal-Sierra L, Pérez-López J, Zulet MÁ, Casañas-Quintana T, Castro-Barquero S, Gómez-Pérez AM, Santos-Lozano JM, Galera A, Basterra-Gortari FJ, Basora J, Saiz C, Pérez-Vega KA, Galmés-Panadés AM, Tercero-Maciá C, Sorto-Sánchez C, Sayón-Orea C, García-Gavilán J, Muñoz-Martínez J, Tur JA on behalf of the PREDIMED-Plus Investigators. Leisure-Time Physical Activity, Sedentary Behaviour and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study. Nutrients. 2020; 12(4):1013. https://doi.org/10.3390/nu12041013

Chicago/Turabian Style

Gallardo-Alfaro, Laura, Maria d.M. Bibiloni, Catalina M. Mascaró, Sofía Montemayor, Miguel Ruiz-Canela, Jordi Salas-Salvadó, Dolores Corella, Montserrat Fitó, Dora Romaguera, Jesús Vioque, Ángel M. Alonso-Gómez, Julia Wärnberg, J. A. Martínez, Lluís Serra-Majem, Ramon Estruch, José C. Fernández-García, José Lapetra, Xavier Pintó, Antonio García Ríos, Aurora Bueno-Cavanillas, José J. Gaforio, Pilar Matía-Martín, Lidia Daimiel, Rafael M. Micó-Pérez, Josep Vidal, Clotilde Vázquez, Emilio Ros, Cesar I. Fernandez-Lázaro, Nerea Becerra-Tomás, Ignacio M. Gimenez-Alba, María D. Zomeño, Jadwiga Konieczna, Laura Compañ-Gabucio, Lucas Tojal-Sierra, Jéssica Pérez-López, M. Á. Zulet, Tamara Casañas-Quintana, Sara Castro-Barquero, Ana M. Gómez-Pérez, José M. Santos-Lozano, Ana Galera, F. J. Basterra-Gortari, Josep Basora, Carmen Saiz, Karla A. Pérez-Vega, Aina M. Galmés-Panadés, Cristina Tercero-Maciá, Carolina Sorto-Sánchez, Carmen Sayón-Orea, Jesús García-Gavilán, Júlia Muñoz-Martínez, and Josep A. Tur on behalf of the PREDIMED-Plus Investigators. 2020. "Leisure-Time Physical Activity, Sedentary Behaviour and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study" Nutrients 12, no. 4: 1013. https://doi.org/10.3390/nu12041013

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

# data[].attributes.attachment_link.title
Leisure-Time Physical Activity, Sedentary Behaviour and Diet Quality are Associated with Metabolic Syndrome Severity: The PREDIMED-Plus Study

# data[].attributes.attachment_link.description
Healthy lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease the likelihood of developing metabolic syndrome (MetS). The aim of this study was to report main lifestyle components and related factors according to the MetS severity.

# data[].attributes.headline
Katelyn Spain: A High-Protein Diet With Resistance Exercise Training Improves Weight Loss and Body Composition in Overweight and Obese Patients With Type 2 Diabetes

# data[].attributes.subject
Katelyn Spain: A High-Protein Diet With Resistance Exercise Training Improves Weight Loss and Body Composition in Overweight and Obese Patients With Type 2 Diabetes

# data[].attributes.body
The purpose of this study was to evaluate the effects of two different low-fat hypocaloric diets, both differing in carbohydrate to protein ratios, with the addition of resistance exercise training or without, and the risk of cardiovascular disease in overweight patients diagnosed with type II diabetes. It was found that there was a significant reduction in body weight, fat mass, and waist circumference in patients that were given the treatment of a high protein diet and resistance exercise training.  A significant finding of this study was that there was no significant difference in the total energy intake of the different groups, but those patients consuming high protein diets with exercise, exhibited increasing training loads in exercise, opposed to those not on the high protein diet. This shows that an increase in protein can increase muscle strength and reduce body fat. The clinical implications of this study are they primary care physicians that have patients with type II diabetes, can recommend a high protein diet with resistance exercise training to help reduce body weight, fat mass, and waist circumference in these patients.

# data[].attributes.attachment_link.readable_text
Abstract

OBJECTIVE

To evaluate the effects of two low-fat hypocaloric diets differing in the carbohydrate-to-protein ratio, with and without resistance exercise training (RT), on weight loss, body composition, and cardiovascular disease (CVD) risk outcomes in overweight/obese patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 83 men and women with type 2 diabetes (aged 56.1 ± 7.5 years, BMI 35.4 ± 4.6 kg/m ²) were randomly assigned to an isocaloric, energy-restricted diet (female subjects 6 MJ/day, male subjects 7 MJ/day) of either standard carbohydrate (CON; carbohydrate:protein:fat 53:19:26) or high protein (HP; 43:33:22), with or without supervised RT (3 days/week) for 16 weeks. Body weight and composition, waist circumference (WC), and cardiometabolic risk markers were assessed.

RESULTS

Fifty-nine participants completed the study. There was a significant group effect ( P ≤ 0.04) for body weight, fat mass, and WC with the greatest reductions occuring in HP+RT (weight [CON: −8.6 ± 4.6 kg, HP: −9.0 ± 4.8 kg, CON+RT: −10.5 ± 5.1 kg, HP+RT: −13.8 ± 6.0 kg], fat mass [CON: −6.4 ± 3.4 kg, HP: −6.7 ± 4.0 kg, CON+RT: −7.9 ± 3.7 kg, HP+RT: −11.1 ± 3.7 kg], and WC [CON: −8.2 ± 4.6 cm, HP: −8.9 ± 3.9 cm, CON+RT: −11.3 ± 4.6 cm, HP+RT: −13.7 ± 4.6 cm]). There was an overall reduction ( P < 0.001) in fat-free mass (−2.0 ± 2.3 kg), blood pressure (−15/8 ± 10/6 mmHg), glucose (−2.1 ± 2.2 mmol/l), insulin (−4.7 ± 5.4 mU/l), A1C (−1.25 ± 0.94%), triglycerides (−0.47 ± 0.81 mmol/l), total cholesterol (−0.67 ± 0.69 mmol/l), and LDL cholesterol (−0.37 ± 0.53 mmol/l), with no difference between groups ( P ≥ 0.17).

CONCLUSIONS

An energy-restricted HP diet combined with RT achieved greater weight loss and more favorable changes in body composition. All treatments had similar improvements in glycemic control and CVD risk markers.

Caloric restriction and physical activity are cornerstones of obesity and type 2 diabetes management ( 1). The substitution of some dietary carbohydrate for protein in a low-fat (<30% total energy) diet may improve body composition and cardiovascular disease (CVD) risk factors including insulin sensitivity, glycemic control, and blood lipids in overweight/obese populations, including patients with type 2 diabetes ( 2- 5). However, these studies have almost invariably assessed modified macronutrient compositions without the inclusion of any exercise intervention.

Layman et al. ( 6) showed additive effects of a high-protein (HP) diet combined with exercise for improving body composition in healthy overweight/obese women with greater weight and fat loss following a lifestyle intervention of exercise plus an HP diet, compared with HP diet alone or a standard carbohydrate (CON) diet with or without exercise. A study by Meckling et al. ( 7) showed similar effects. In both these studies, the exercise programs used were primarily aerobic exercise based, whereas resistance exercise training (RT) may be more efficacious ( 8). During weight loss, RT can maintain and/or increase lean tissue and improve physical functioning ( 8), and its importance for improving glycemic control in patients with type 2 diabetes is well established ( 9). Recently, Kerksick et al. ( 10) showed greater improvements in body composition in obese women following a 14-week RT program when carbohydrate was substituted with protein. This suggests that an HP diet combined with RT may improve weight loss, body composition, and cardiometabolic risk factors. However, despite its importance, no studies have evaluated these effects in individuals with type 2 diabetes. This study compared the effects of an energy-restricted HP diet and an isocaloric "traditional" CON diet with and without RT on weight loss, body composition, CVD risk factors, and glycemic control in patients with type 2 diabetes. We hypothesized that HP+RT treatment would produce the greatest improvements on these outcomes.

RESEARCH DESIGN AND METHODS

A total of 83 overweight/obese sedentary men and women (BMI 35.3 ± 4.5 kg/m ²; aged 55.0 ± 8.4 years) with type 2 diabetes were recruited by public advertisement (). Participants were excluded if they had known proteinuria; had a malignancy; had a history of liver, kidney, cardiovascular, respiratory, or gastrointestinal disease; had uncontrolled hypertension; were pregnant or lactating; were a smoker; or were using insulin. Participants with any musculoskeletal injury or joint or peripheral vascular disease sufficient to impede exercise or who had participated in regular physical exercise (more than two 30-min sessions/week of moderate/vigorous aerobic exercise or one 30-min session/week of RT) during the 6 months prior to study were also excluded. Participants provided written informed consent. The study was approved by the human research ethics committees of the Commonwealth Scientific and Industrial Research Organisation (CSIRO) and the University of Adelaide.

In a parallel study, participants were blocked matched for age, sex, and weight, then randomized to one of four lifestyle interventions: an energy-restricted standard carbohydrate, low-protein, low-fat diet alone (CON) or with RT (CON+RT); or an isocaloric higher-protein, moderate-carbohydrate, low-fat diet alone (HP) or with RT (HP+RT) for 16 weeks. At baseline (week 0) and week 16, participants attended the CSIRO research clinic after an overnight fast for assessment. At the clinic testing visits, height (week 0 only), body weight, blood pressure, waist circumference (WC), and body composition were measured before a venous blood sample was drawn and muscle strength was assessed. Prior to the clinical assessments, a 24-h urine sample was collected.

Medications at baseline and changes throughout the study were documented. Lipid-lowering and antihypertensive medications were encouraged to remain constant throughout the intervention. Participants were asked not to modify their lifestyle patterns other than necessary during the intervention to comply with the study protocol.

Diet interventions

The diets were designed to be isocaloric with moderate energy restriction (∼6,000 kJ/day for women, ∼7,000 kJ/day for men). The planned macronutrient profile of the CON diet was 53% of total energy as carbohydrate, 19% (∼0.7 g · kg −1 · day −1) protein, and 26% fat. The target profile for the HP diet was 43% carbohydrate, 33% (∼1.2 g · kg −1 · day −1) protein, and 22% fat. To facilitate dietary compliance, detailed dietary advice, meal planning, and recipe information were provided at baseline and every 2 weeks by a qualified dietitian. Key foods representative of each diet's macronutrient profile (∼50% total energy) were supplied every 2 weeks. Diets were structured to include specific food quantities/weights to ensure correct macronutrient and energy profile were achieved. These foods were listed in a quantitative food record completed daily by participants. Participants were asked to weigh and measure their food using scales provided. Dietary composition was assessed by a qualified dietitian based on the analysis of 7 consecutive days from the semiquantitative food record of each 2-week period using a computerized database (Foodworks Professional Edition, version 4, 1998; Xyris Software, Highgate Hill, Australia). Participants who did not complete the food records were excluded as noncompliers.

Exercise intervention

The CON+RT and HP+RT group participants followed a progressive RT program. Eight separate exercises (leg press, knee extension, chest press, shoulder press, lat pull down, seated row, triceps press, and sit-ups) were performed using weight-stacked machines (Maxim Health Fitness, Adelaide, Australia), except sit-ups, on 3 nonconsecutive days/week. The weight loading was set at 70-85% one repetition maximum (1RM, protocol described below), determined for each exercise at Week 0. This allowed ∼8-12 reps to volitional fatigue with two sets per exercise and 1-2 min rest between sets to be performed. Once participants could successfully perform two sets of >12 repetitions, the weight load was increased to maintain the training load. Resistance exercise training sessions lasted ∼45 min and were conducted at the CSIRO gymnasium under professional supervision. Participants completed a training diary, and if a scheduled session was missed, they were encouraged to attend a make-up session as soon as possible.

Outcomes, body weight, composition, blood pressure, and muscle strength

Body mass was measured using calibrated electronic digital scales (Mercury; AMZ 14, Tokyo, Japan), and body composition was measured using dual-energy X-ray absorptiometry (DXA; Lunar Prodigy; General Electric, Madison, WI) to assess total body fat mass and total body fat-free mass (FFM). WC was measured on a horizontal plane 2 cm proximal to the uppermost lateral border of the right iliac crest. Seated blood pressure was measured using an automated sphygmomanometer (DYNAMAP 8100; Criticon, Tampa, FL).

Muscle strength (1RM) was assessed pre- and postintervention for chest press and lat pull down according to standard guidelines ( 11). 1RM of the other five weight-stacked exercises were also assessed in the participants in the exercise groups at baseline only to set initial training loads. To determine 1RM, following a low-intensity warm-up, participants performed four to five trials (separated by a 2-min resting interval) using varying moderate-heavy weights to determine the highest weight that could be lifted with only one repetition through the full range of motion with correct technique.

Biochemical analyses

Serum lipids and insulin, plasma glucose, C-reactive protein (CRP), and creatinine were measured using standard methods ( 12). A1C, measured using high-performance liquid chromatography, and 24-h urinary urea, creatinine, and albumin were assessed at a commercial laboratory (IMVS, Adelaide, Australia). Creatinine clearance was calculated as (urine creatinine [μmol/l] × urine volume [ml])/(plasma creatinine [μmol/l] × minutes) and corrected for body surface area ( 13).

Statistical analysis

Statistical analyses were performed using SPSS for Windows (version 17.0; SPSS, Chicago, IL). Prior to hypothesis testing, data were examined for normality. Non-normally distributed variables (insulin, CRP, and urinary albumin) were logarithmically transformed before analysis. Differences in baseline characteristics were compared by one-way ANOVA for continuous variables and χ ² tests for categorical variables. This investigation represents an efficacy trial to determine the physiological/metabolic effects of the treatments. Primary analysis was conducted on participants who completed the study per protocol. Secondary intention-to-treat (ITT) analysis was also conducted for the primary outcome measures (body weight and composition, cardiometabolic and glycemic control), including participants who completed the study irrespective to protocol adherence. Changes over time in the groups were assessed using repeated-measures ANOVA. The effects of the treatments on changes were assessed using one-way ANOVA, with group (CON, HP, CON+RT, and HP+RT) as a between-subject factor. Where there was a significant main effect, post hoc tests with Dunnett adjustment for multiple comparisons were performed to determine differences between group means compared with HP+RT; based on a prior hypothesis, the HP+RT group would achieve greater changes compared with the other treatments. Age and sex were included as covariates. No significant effect of sex or age was observed for any of the outcomes. To compare the magnitude of change between the two diets (CON and CON+RT versus HP and HP+RT) and exercise versus nonexercise (CON and HP versus CON+RT and HP+RT), planned contrasts were used in the statistical model. Pearson correlation coefficients were used to determine the relationships between variables. Statistical significance was set at P < 0.05. Data are means ± SD.

RESULTS

Participants

Of 83 randomized participants, 18 withdrew and 6 participants were excluded for dietary noncompliance (failure to complete food records); 59 participants completed the study per protocol (). There was no difference between treatment groups, diets, or exercise versus nonexercise groups in the number of participants who withdrew ( P ≥ 0.34) or who were excluded ( P ≥ 0.17). At baseline, there were no significant differences in age, weight, BMI, A1C, and sex distribution between groups ( P ≥ 0.12). These characteristics were also similar between participants who completed or did not complete the study ( P ≥ 0.09), except for age in which completers were on average 5 years younger (completers: aged 50.8 ± 10.4 years, dropouts: aged 56.1 ± 7.4 years; P = 0.02).

Dietary composition and exercise compliance

Based on the food records, participants showed good compliance with the prescribed diets (). Total energy intake was similar across treatment groups, while macronutrient composition was different between the diet groups; the HP and HP+RT groups consumed significantly more protein and less carbohydrate and fat compared with the CON and CON+RT groups. There was a significant diet effect for the urinary urea-to-creatinine excretion ratio ( P = 0.003), which decreased in the CON diet groups (CON: 30.8 ± 8.6 to 26.7 ± 3.8, CON+RT: 25.9 ± 5.1 to 24.2 ± 4.0) and increased in the HP diet groups (HP: 31.1 ± 9.8 to 33.6 ± 11.2, HP+RT: 28.3 ± 9.5 to 31.5 ± 7.7), indicating higher protein intakes in the HP diet groups.

Table 1

Compliance with RT was defined as the number of exercise sessions completed at the prescribed training loads per total number of prescribed sessions. All participants in the CON+RT and HP+RT groups achieved compliance with the prescription (defined as 75% of prescribed sessions), on average completing 93% (43.5 ± 4.0 of 47) of the prescribed sessions. There was a significant effect of exercise treatment for 1RM lat pull down and chest press ( P < 0.001) such that increases occurred in the diet+RT groups, with no change in the diet-only groups (), indicating compliance with the prescribed RT.

Table 2

Body weight and composition

Overall, body weight was reduced ( P < 0.001), with a significant group effect ( P = 0.04), such that HP+RT achieved greatest weight loss (CON: −8.9%, HP: −8.7%, CON+RT: −10.0%, HP+RT: −12.7%) (). Post hoc analysis showed that the greater weight loss in HP+RT was statistically significant compared with CON and HP groups ( P < 0.05), but compared with CON+RT statistical significance was not reached ( P = 0.20). Overall, weight loss was not different between the two diets ( P = 0.18); however, the exercise groups (HP+RT and CON+RT) lost more weight compared with the diet-only groups (CON and HP) (diet+RT: −12.0 ± 5.7 kg, diet only: −8.8 ± 4.6 kg; P = 0.02). ITT analysis showed a similar weight loss pattern, albeit the magnitude of effect was reduced (CON: −9.4 ± 6.5 kg, HP: −8.0 ± 4.8 kg, CON+RT: −10.5 ± 5.1 kg, HP+RT: −12.6 ± 6.5 kg; P = 0.16 group effect).

Similarly, fat mass and WC reduced in all groups ( P < 0.001) (), with a significant group effect ( P ≤ 0.006) such that HP+RT had greatest reductions. Post hoc analysis showed that HP+RT had significantly greater reductions compared with CON and HP ( P ≤ 0.02), but compared with CON+RT, statistical significance was not reached (fat mass: P = 0.06, WC: P = 0.32). Overall, compared with the diet-only groups, the exercising groups had greater reductions in fat mass (diet+RT: −9.6 ± 4.1 kg, diet only: −6.7 ± 3.8 kg; P < 0.01) and WC (diet+RT: −12.4 ± 4.7 cm, diet only: −8.5 ± 4.3 cm; P < 0.01). Overall, more fat mass loss occurred in participants consuming the HP diet (−9.4 ± 4.5 kg) compared with the CON diet (7.3 ± 3.8 kg; P = 0.06). There was an overall reduction in FFM (), with no effect of treatment group ( P = 0.91), diet composition ( P = 0.80), or exercise participation ( P = 0.51). ITT analysis confirmed these results, with a significant group effect evident for fat mass and WC ( P ≤ 0.02) but not for FFM ( P = 0.75).

Cardiometabolic outcomes and glycemic control

Overall, blood pressure, lipids, glucose, A1C, and CRP were reduced ( P ≤ 0.02) () with no difference between treatment groups ( P ≥ 0.37), diet composition ( P ≥ 0.27), or exercise participation ( P ≥ 0.21). Insulin concentrations also decreased ( P < 0.001) with a differential (nonsignificant) effect evident between treatment groups ( P = 0.11), such that HP+RT experienced approximately twofold greater reductions compared with the other groups. No differential insulin response between diet compositions ( P = 0.19) or exercise participation ( P = 0.29) were observed. Changes in insulin were significantly correlated with changes in weight ( r = 0.35, P < 0.01) and fat mass ( r = 0.36, P = 0.005). ITT analysis also showed no significant differences in the changes of these parameters between the groups.

Creatinine clearance and urinary albumin

Overall, creatinine clearance was reduced ( P < 0.001) (), with no differential effect between treatments ( P = 0.68), diet composition ( P = 0.55), or exercise participation ( P = 0.46). At week 0, 45 participants (CON diet: 27, HP diet: 18) had normoalbuminuria (urinary albumin excretion <20 μg/min), and values remained in the normoalbuminuria range at week 16, except in 1 participant in the CON group whose urinary albumin excretion increased (33.4 μg/min) to microalbuminuria classification (urinary albumin excretion 20-200 μg/min). At baseline, 14 participants (24%; CON diet: n = 6, HP diet: n = 8) had microalbuminuria; at week 16, 4 participants (CON: n = 2, HP: n = 2) remained in the microalbuminuria range and 10 participants decreased to normoalbuminuria classification (CON: n = 4, HP: n = 6).

Medication changes

A total of 33 participants were on hypoglycemic medication at baseline (CON: n = 11, HP: n = 7, CON+RT: n = 10, HP+RT: n = 5), and during the intervention, medication dose was reduced in 9 participants (CON: n = 2, HP: n = 1, CON+RT: n = 4, HP+RT: n = 2) and increased in 1 participant in the HP group. There were no significant differences between the treatment groups. At baseline, 36 and 29 participants were on antihypertensive medication (CON: n = 9, HP: n = 4, CON+RT: n = 14, HP+RT: n = 9) and lipid-lowering medication (CON: n = 9, HP: n = 5, CON+RT: n = 9, HP+RT: n = 6), respectively. Following the intervention, antihypertensives were reduced in six participants (CON+RT: n = 4, HP+RT: n = 2) and increased in 1 participant in the CON+RT group, and 1 participant in the HP+RT group ceased lipid-lowering medication.

CONCLUSIONS

This study showed substantial improvements in CVD risk factors and glycemic control following lifestyle intervention incorporating a structured, energy-restricted diet that occurred independent of macronutrient composition or participation in a RT program in sedentary obese patients with type 2 diabetes. The addition of RT increased weight and fat mass loss, which was further magnified by replacing some dietary carbohydrate with protein.

The HP+RT group exhibited at least a 3.3-kg greater weight and fat loss and 21% greater reduction in WC compared with the other treatment groups. Previous studies in healthy, overweight/obese individuals without type 2 diabetes show greater reductions in weight and fat mass of similar magnitude when exercise training is combined with a hypocaloric HP diet compared with an isocaloric CON diet ( 6, 7). The CON diet was designed to reflect standard dietary recommendations (15-20% of total energy as protein) ( 1). The HP diet was designed to achieve protein intake of >25%, corresponding with typically prescribed HP diets; it provided an average protein intake of 1.12 g · kg −1 · day −1. Previous studies show that an HP diet compared with a CON diet is associated with greater reductions in fat mass ( 5, 6). RT also reduces fat mass in obese individuals, independent of caloric restriction ( 14), suggesting that the separate interventional components of an HP diet and RT may have contributed to the greater weight and fat mass losses following the HP+RT treatment.

Although a significant main group effect was observed, post hoc analysis showed that greater weight, fat mass, and WC reductions in the HP+RT group only reached statistical significance compared with the CON and HP groups but not the CON+RT group ( P ≥ 0.06), despite large absolute differences. Nevertheless, the additional weight and fat losses that occurred when RT was combined with an HP diet compared with a CON diet represent moderate to large effect sizes (0.67-0.85) and are considered clinically relevant and shown to produce important health outcomes ( 15). Furthermore, clinical and experimental evidence shows that WC is an independent predictor of CVD ( 16), and the 21% greater reductions following the HP+RT group would represent a significant health improvement. Power analysis estimates that a sample size of 24 subjects per group would have been needed for the observed 3.3-kg weight loss difference between the groups to have been statistically significant (80%, P = 0.05). Further larger studies are required to confirm these findings. In contrast, Layman et al. ( 6), who observed similar absolute weight and fat loss differences between treatment groups comparing CON and HP diets with and without exercise, achieved statistically significant diet and exercise effects with smaller sample sizes ( n = 12 per group). However, this study only examined women, and sex differences in body composition responses to dieting have been previously observed ( 5). Although no sex effects were observed in our study, inclusion of men and women may have increased the data variability, subsequently lowering the statistical power.

Mechanisms underlying the greater weight and fat changes in HP+RT are not clear. Given that both diets were isocaloric and participants undertook the same RT program under controlled conditions, it suggests these changes reflect metabolic differences. The HP+RT group experienced approximately twofold greater reductions in fasting insulin compared with the other treatments, although, again, power was not sufficient to reveal significant differences. Nevertheless, there was a significant correlation between the changes in weight and fat mass and insulin levels. Insulin has fat-sparing effects and promotes adipose tissue accumulation ( 17). Hence, greater insulin reductions in the HP+RT group may explain the greater fat mass reductions; however, causation cannot be determined. Other evidence suggests that fat mass accumulation drives insulin resistance ( 17). Alternately, fat has more positive effects on energy balance compared with other macronutrients ( 18). Therefore, although unlikely, the possibility that lower fat intakes in the HP diet contributed greater fat reductions in the HP+exercise group cannot be dismissed.

In the exercising groups, high compliance with the RT program achieved substantial strength gains, which is associated with metabolic disease reductions ( 19). Nevertheless, FFM reduced similarly across treatment groups. Although previous studies have observed protective effects of RT ( 20) and HP diets ( 3) on FFM during caloric restriction, these effects have not been consistently shown ( 5), and perhaps even higher relative protein intakes are required. Compared with this study, experiments demonstrating FFM preservation following a hypocaloric HP diet with RT ( 6, 21) administered higher relative protein intakes (1.12 vs. ≥1.4 g · kg −1 · day −1). A meta-analysis showed that the degree of FFM retention during weight loss increases with increasing quartiles of protein intake ( 2), suggesting that relative protein intakes may be an important weight loss program design consideration.

Substantial reductions in CVD risk markers and glycemic control occurred during the intervention with no observable differences between the groups. Previous studies report that RT ( 14) and HP diets ( 22) improve A1C independent of weight loss in type 2 diabetic patients. The lack of any difference in glycemic control between the treatment groups in the present study may therefore be due to the hypoglycemic effects of energy restriction ( 23), masking any potential effects of exercise or diet composition. Under milder energy restriction, RT has been shown to provide additional reductions in A1C ( 9). Longer-term studies are required to separate out these effects. Nevertheless, the overall A1C reductions observed is clinically relevant and associated with a 21% reduction in diabetes-related mortality ( 24).

HP diets having potentially adverse effects on renal function remains a concern ( 25). However, no differences in creatinine clearance or presence of microalbuminuria between the diets groups were observed. Other short-term, interventional studies also report no differences in renal function in obese individuals with type 2 diabetes following either an HP or low-protein diet ( 5, 22). This suggests that a hypocaloric HP diet does not adversely affect renal function, at least over the short term, in subjects without overt renal impairment. Nevertheless, diabetes is associated with impaired renal function, and the longer-term effects in this patient population warrants further investigation.

Although not statistically significant, higher participant withdrawals/exclusions in the HP diet groups are noteworthy. The exact reason/s are not entirely clear, but this is not consistent with previous studies comparing HP versus CON diets that report similar dropouts with both dietary treatments and in some studies lower dropouts following the HP diet ( 5, 7).

In conclusion, participation in RT produced greater weight and fat loss and increases in muscular strength compared with energy restriction alone. Additionally, replacement of some carbohydrate for protein further magnified these effects, resulting in greatest reductions in weight, fat mass, WC, and insulin. All treatments had similar improvements in glycemic control and CVD risk. A lifestyle modification program combining an energy-restricted HP diet and RT appears to be a preferred treatment strategy in overweight/obese individuals with type 2 diabetes. Further studies should evaluate the longer-term effects.

Acknowledgments

This work was supported with project grants from the National Heart Foundation of Australia, the Diabetes Australia Research Trust, and the Pork Cooperative Research Centre. George Weston Foods donated foods for this study. None of the funding agencies played a role in the conception, design or conduct of the study, collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript.

No potential conflicts of interest relevant to this article were reported.

We thank the volunteers who made the study possible through their participation. We gratefully acknowledge Anne McGuffin for coordinating this trial; Penelope Taylor and Heidi Sulda for assisting in delivering of the dietary intervention; Rosemary McArthur and Lindy Lawson for nursing expertise; and Candita Sullivan, Robb Muirhead, Cathryn Seccafien, Vanessa Russell, and Mark Mano for assisting with the biochemical assays. We thank Kylie Lange for assisting with the statistical analysis and David Jesudason for assisting with the medical supervision of the participants.

The authors' responsibilities were as follows: T.P.W. and G.D.B. were responsible for the conception and design of the study, coordinated the study, performed data analyses, interpreted the data, and coordinated and contributed to the writing of the manuscript. M.N. contributed to the conception and design of the study and data interpretation and the writing of the manuscript and designed the experimental diets. P.M.C. was responsible for the medical monitoring of the research participants and contributed to the data interpretation and writing of the manuscript. X.C. designed the experimental diets, coordinated the implementation of the dietary protocols, and contributed to the writing of the manuscript. J.B.K. assisted in the design of the experimental diets, contributed to the conception and design of the study, and contributed to the manuscript. All authors agreed on the final version of the manuscript.

Footnotes

Australian New Zealand clinical trials reg. ACTR no. 12608000206325, anzctr.org.au.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

References

1. Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, Franz MJ, Hoogwerf BJ, Lichtenstein AH, Mayer-Davis E, Mooradian AD, Wheeler ML: Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care 2008; 31( Suppl. 1): S61- S78 [[ PubMed] Google Scholar]

10. Kerksick C, Thomas A, Campbell B, Taylor L, Wilborn C, Marcello B, Roberts M, Pfau E, Grimstvedt M, Opusunju J, Magrans-Courtney T, Rasmussen C, Wilson R, Kreider RB: Effects of a popular exercise and weight loss program on weight loss, body composition, energy expenditure and health in obese women. Nutr Metab (Lond) 2009; 6: 23. [[ PubMed] PMC free article] [ Google Scholar]

11. American College of Sports Medicine. ACSM's Guidelines for Exercise Testing and Prescription 6th ed.Philadelphia, Lippincott Williams and Wilkins, 2000 [ Google Scholar]

18. 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- S50 [[ PubMed] Google Scholar]

24. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405- 412 [[ PubMed] PMC free article] [ Google Scholar]

# data[].attributes.attachment_link.title
A High-Protein Diet With Resistance Exercise Training Improves Weight Loss and Body Composition in Overweight and Obese Patients With Type 2 Diabetes

# data[].attributes.attachment_link.description
To evaluate the effects of two low-fat hypocaloric diets differing in the carbohydrate-to-protein ratio, with and without resistance exercise training (RT), on weight loss, body composition, and cardiovascular disease (CVD) risk outcomes in overweight/obese patients with type 2 diabetes.

# data[].attributes.headline
Andrea Ballinger: Nut Consumption and Decreased Risk for Cardiovascular Disease and Metabolic Syndrome

# data[].attributes.subject
Andrea Ballinger: Nut Consumption and Decreased Risk for Cardiovascular Disease and Metabolic Syndrome

# data[].attributes.body
The paper I chose for this week shows a correlation between lower risk factors for cardiovascular disease and metabolic syndrome with increased nut consumption. It is a longitudinal study conducted over a 5 year period between nut/tree nut consumers and non consumers. Nuts are low in saturated fatty acids, high in dietary fiber, vitamin E, and other bioactive compounds that work as antioxidants and are anti-inflammatory. There is also some data to show that nut consumption can help improve insulin resistance, but this particular paper was inconclusive. The nutritional benefits of nut consumption is particularly important with MetS and potential risk prevention because increasing soluble fiber helps with hyperlipidemia, as well as limiting saturated fats and increasing monounsaturated fats (like nuts). Limiting saturated fats, and increasing monounsaturated fats also helps with hyperglycemia, hypertension, and low HDL. The results of the study showed that nut consumption was correlated with high levels of HDL, lower BMI and weight circumference versus non-nut consumers. These results are important because it provides additional information on the role nutrition plays in the development of MetS. Although pistachios and walnuts are not entire meals, they do offer an alternative to other quick on the go food sources that may be more harmful to someone with a MetS comorbidity.

Carol E O'Neil, Debra R Keast, Theresa A Nicklas & Victor L Fulgoni III (2011) Nut Consumption Is Associated with Decreased Health Risk Factors for Cardiovascular Disease and Metabolic Syndrome in U.S. Adults: NHANES 1999–2004, Journal of the American College of Nutrition, 30:6, 502-510, DOI: 10.1080/07315724.2011.10719996

# data[].attributes.attachment_link.readable_text
Background: Few recent epidemiologic studies have assessed the effect that nut consumption (including tree nuts and peanuts) has on health risks, including metabolic syndrome (MetS).

Objective: This study compared the health risk for cardiovascular disease, type 2 diabetes, and MetS of nut consumers with that of nonconsumers.

Design: Adults 19+ years (n = 13,292) participating in the 1999-2004 National Health and Nutrition Examination Survey were used. Intake from 24-hour recalls was used to determine intake. Nut/tree nut consumers consumed ≥¼ ounce per day. Covariate-adjusted means, standard errors, and prevalence rates were determined for the nut consumption groups.

Results: The prevalence of nut consumers was 18.6% ± 0.7% and 21.0% ± 0.9% in those 19-50 years and 51 years and older, respectively. Nut consumption was associated with a decreased body mass index (27.7 kg/m ² ± 0.2 vs 28.1 ± 0.1 kg/m ², p < 0.05), waist circumference (95.6 ± 0.4 cm vs 96.4 ± 0.3 cm, p < 0.05), and systolic blood pressure (121.9 ± 0.4 mmHg vs 123.20 ± 0.3 mmHg, p < 0.01) compared with nonconsumers. Tree nut consumers also had a lower weight (78.8 ± 0.7 kg vs 80.7 ± 0.3 kg, p < 0.05). Nut consumers had a lower percentage of two risk factors for MetS: hypertension (31.5% ± 1.0% vs 34.2% ± 0.8%, p < 0.05) and low high density lipoprotein-cholesterol (HDL-C) (29.6% ± 1.0% vs 34.8% ± 0.8%, p < 0.01). Tree nut consumers had a lower prevalence of four risk factors for MetS: abdominal obesity (43.6% ± 1.6% vs 49.5% ± 0.8%, p < 0.05), hypertension (31.4% ± 1.2% vs 33.9% ± 0.8%, p < 0.05), low HDL-C (27.9% ± 1.7% vs 34.5% ± 0.8%, p < 0.01), high fasting glucose (11.4% ± 1.4% vs 15.0% ± 0.7%, p < 0.05), and a lower prevalence of MetS (21.2% ± 2.1% vs 26.6% ± 0.7%, p < 0.05).

Conclusion: Nut/tree nut consumption was associated with a decreased prevalence of selected risk factors for cardiovascular disease, type 2 diabetes, and MetS.

# data[].attributes.attachment_link.title
Nut Consumption Is Associated with Decreased Health Risk Factors for Cardiovascular Disease and Metabolic Syndrome in U.S. Adults: NHANES 1999-2004

# data[].attributes.attachment_link.description
Background: Few recent epidemiologic studies have assessed the effect that nut consumption (including tree nuts and peanuts) has on health risks, including metabolic syndrome (MetS). Objective: This study compared the health risk for cardiovascular disease, type 2 diabetes, and MetS of nut consumers with that of nonconsumers.

# data[].attributes.headline
Dietary Fiber and Diseases Associated with Metabolic Syndrome- Cole Cincinelli

# data[].attributes.subject
Dietary Fiber and Diseases Associated with Metabolic Syndrome- Cole Cincinelli

# data[].attributes.body
Metabolic syndrome is characterized by 3 out of 5 of the following factors: waist circumference, triglycerides, blood sugar, blood pressure and HDL level. Low levels of HDL can be associated with high levels of bad cholesterol or LDL. High levels of bad cholesterol can then lead to disease of the heart and circulatory system leading to other risk factors. One study documented a protective effect of dietary fiber on the reduction of heart disease by lowering LDL levels[1]. This study found significant results with at least 7g fiber/ day to lower LDL cholesterol and Mayo Clinic says “5 to 10 grams or more of soluble fiber a day decreases your LDL cholesterol.” Three major biological mechanisms have been proposed to explain the cholesterol-reducing effects of soluble fiber diet: prevention of bile salt reabsorption from the small intestine leading to an excess fecal bile salt excretion; reduced glycemic response leading to lower insulin stimulation of hepatic cholesterol synthesis; and physiological effects of soluble fiber diet[2]. Soluble fiber can also slow the absorption of sugar and help improve blood sugar levels which is helpful to metabolic syndrome patients[3]. The abundance of dietary fiber in whole grain, fruits, and vegetables, makes diet an attractive target for disease prevention and reduction of risk of atherosclerosis, cardiovascular disease and metabolic syndrome.

[1] Soliman GA. Dietary Fiber, Atherosclerosis, and Cardiovascular Disease. Nutrients. 2019; 11(5):1155. https://doi.org/10.3390/nu11051155

[2] Gunness, P., & Gidley, M. J. (2010). Mechanisms underlying the cholesterol-lowering properties of soluble dietary fibre polysaccharides. Food & function, 1(2), 149–155. https://doi.org/10.1039/c0fo00080a

[3]“How to Add More Fiber to Your Diet.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 6 Jan. 2021, https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/fiber/art-20043983#:~:text=Soluble%20fiber%20found%20in%20beans,reducing%20blood%20pressure%20and%20inflammation.

# data[].attributes.body
Hatori, Megumi et al. “Time-Restricted Feeding Without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet.” Cell metabolism 15.6 (2012): 848–860. Web.

One of the reasons this study is important is that almost all of the time when we think of nutrition, we think of what we eat and not when we eat it. As a former night shift worker, I was intrigued by this article because it tries to elucidate the effects that eating rhythms, or the disruption of, have on metabolic health. Could regulating eating/fasting times modulate the onset of metabolic disease? This study fed standard or high-fat diets to mice and divided them into 2 groups for each category: ad lib (could eat any time, day or night) and time-restricted feeding (tRF) (restricted the amount of time the mice had to eat).

While there are a couple of interesting findings, I think a key one is that tRF prevented enlarged liver and liver damage (measured via ALT) for mice on a high-fat diet. For results in the murine model for liver weight (measure for enlarged liver), mice that were fed a time-restricted high fat diet had a significantly lower weight and it was actually comparable to the mice that were fed a normal chow diet—ad lib (Figure 4). It relates to nutritional sciences because it is another tool when planning dietary recommendations for a patient at high risk of metabolic syndrome. Not only asking what the patient is eating, but establishing a regimen of when they can eat so that eating patterns synergize with the complex relationship between circadian oscillators and metabolic regulators.

Clinically, tRF could be used to prevent obesity and the metabolic diseases associated with it. Incorporating it in a clinical plan gives providers more avenues to help patients understand the importance nutrition plays in their health. Given the potential of overlapping conditions and drug-drug interactions for the complex treatment of metabolic diseases, it could potentially be a viable nonpharmaceutical alternative.

# data[].attributes.headline
Green Tea and Metabolic Syndrome: A 10-year Research Update Review. -Ashley Wahlman

# data[].attributes.subject
Green Tea and Metabolic Syndrome: A 10-year Research Update Review. -Ashley Wahlman

# data[].attributes.body
This study is important because it points out that it can be quite taxing on the healthcare system to treat MetS. Therefore, they decided to look into the therapeutic properties associated with green tea, which could be a possible novel mechanism in aiding to combat the symptoms associated with MetS. I thought this was interesting because green tea is something that is accessible to so many people and easily found, which would make it a great solution for this condition. In a study using green tea to look at blood pressure and blood glucose levels they found that green tea diminished blood glucose and insulin levels. This occurred restoring AKT activity and GLUT4 transporter activity. This resulted in very interesting data. It relates to nutritional science because it comes back to a diet modification of adding in green tea. This has great clinical implications because it allows physicians to recommend something that isn't completely overpriced or another pill that a patient must take. Instead, it is a simple and affordable solution for patients that it is pretty simple to add into someone's lifestyle. However, I would be cautious still moving forward with this remedy. There were a couple of studies that negated the results achieved as well. So, I believe this may be a potential solution for metabolic syndrome, but more research would need to be done on the efficacy of this potential treatment.

Reference
Esmaeelpanah, E., Razavi, B. M., & Hosseinzadeh, H. (2021). Green tea and metabolic syndrome: A 10-year research update review. Iranian Journal of Basic Medical Sciences, 24(9), 1159–1172. https://doi-org.ezproxy.uky.edu/10.22038/IJBMS.2021.52980.11943

# data[].attributes.headline
T2DM put in remission by personalized diet.

# data[].attributes.subject
T2DM put in remission by personalized diet.

# data[].attributes.body
Posted by Richard Proudfoot

The research paper selected for this week is titled: “Effects of personalized diets by prediction of glycemic responses on glycemic control and metabolic health in newly diagnosed T2DM: a randomized dietary intervention pilot trial

This research paper is a pilot randomized crossover trial of 23 newly diagnosed T2DM patients of 2-week-long dietary intervention, followed by an additional 6-month studied diet intervention.  The studied personalized postprandial targeting (PPT) diet was based on a machine learning algorithm that integrates clinical and microbiome features to predict personal postprandial glucose responses (PPGR). (This was determined by a previous dietary study by the same group: “Personalized Nutrition by Prediction of Glycemic Responses.,” DOI: https://doi.org/10.1016/j.cell.2015.11.001) The control diet was the commonly proscribed Mediterranean diet. Participants were connected to continuous glucose monitoring (CGM) throughout the study and self-recorded dietary intake using a smartphone application. The study comes from Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 7610001, Rehovot, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001, Rehovot, Israel; School of Public Health, University of Haifa, 3498838, Haifa, Israel,

This study is important because out of 16 participants in the long-term intervention, 13 had HbA1c levels > 6.5% (threshold for diabetes diagnosis) at baseline, and 8 of them (61%) reached HbA1c levels < 6.5% at 6 months, indicating diabetes remission.

The key findings from this study in this short-term crossover dietary intervention in adults with newly diagnosed T2DM and naive to glucose-lowering medications, an algorithm-based personalized postprandial targeting (PPT) diet, successfully improved CGM-based measures of average PPGR, glucose fluctuations, and daily time with glucose levels > 140 mg/dl, as compared to a commonly recommended Mediterranean-style (MED) diet. Additional 6-month PPT intervention resulted in significant improvements in multiple metabolic parameters, including HbA1c, fasting glucose, HOMA-IR, daily time with glucose levels > 140 mg/dl, and blood triglycerides.

Clinical implication from of this study is that non-calorie-restricted interventions directly targeting reductions in PPGRs may be more effective than standard medical and nutritional care for improving glycemic control in newly diagnosed T2DM. 1 My personal observations is that patients have CGMs but no instructions in how to use the data to determine a personalized health promoting diet. This study shows we need to target postprandial glucose control.

Rein, M., Ben-Yacov, O., Godneva, A. et al. Effects of personalized diets by prediction of glycemic responses on glycemic control and metabolic health in newly diagnosed T2DM: a randomized dietary intervention pilot trial. BMC Med 20, 56 (2022). https://doi.org/10.1186/s12916-022-02254-y

Posted by Richard Proudfoot

# data[].attributes.headline
Effects of probiotic yogurt on glycemic indexes and endothelial dysfunction markers in patients with metabolic syndrome - post by COLE ZETTER

# data[].attributes.subject
Effects of probiotic yogurt on glycemic indexes and endothelial dysfunction markers in patients with metabolic syndrome - post by COLE ZETTER

# data[].attributes.body
For this week's weekly wall, I read an article related to MetS titled Effects of pobiotic yogurt on glycemic indexes and endothelial dysfunction markers in patients with metabolic syndrome. I found this study to be important first and foremost because it broke down what MetS is by explaining that MetS is a syndrome which can be characterized by patients being diagnosed with interrelated cardiovascular risk factors. These risk factors greatly increases the risk of cardiovascular disease and type 2 diabetes mellitus. The components of MetS are found to include  abdominal obesity, impaired glucose metabolism, dyslipidemia, and hypertension. Within this study, the actual aim was to assess the effects of probiotic yogurt on glycemic indexes and endothelial dysfunction markers in patients with metabolic syndrome. One key finding that I found in this study was that consumption of probiotic yogurt resulted in a significant reduction in the level of blood glucose. This is a positive outcome for patients with metabolic syndrome. I found that to be very remarkable for on a nutrition/metabolism level. I would say that the clinical implications of this study would be that if I were a clinician and I were dealing with a patient diagnosed with MetS that has high blood glucose, I would recommend that they include probiotic yogurt in their daily diet while at the same time excluding excess unnecessary sugars like sodas, candy, etc.

# data[].attributes.headline
Dietary Fiber and Metabolic Syndrome: A Meta-Analysis and Review of Related Mechanisms

# data[].attributes.subject
Dietary Fiber and Metabolic Syndrome: A Meta-Analysis and Review of Related Mechanisms

# data[].attributes.body
Ellen Reusch

For this week's topic, we learned about metabolic syndrome and some of the nutritional approaches that patients might enlist in order to treat some of the aspects of MetS. One of those approaches included increasing their fiber intake in order to manage hyperlipidemia. In relation to that concept, I found this article documenting a meta-analysis that was conducted in 2017 on several observational studies in order to evaluate whether dietary fiber intake was actually beneficial at reducing MetS risk. Prior to this review, the data was inconsistent. However, after compiling all the data together in a larger view, these researchers determined that increased dietary fiber intake was indeed inversely associated with MetS risk. In addition to decreasing lipid content, some of the mechanisms by which fiber could affect MetS risk include: promoting weight loss, improving glucose homeostasis, and decreasing blood pressure.  This could be an important finding for physicians as they may be able to recommend patients increase their daily fiber intake if they feel that the patient is at risk of developing MetS.

Chen, Jia-Ping, et. al. Dietary Fiber and Metabolic Syndrome: A Meta-Analysis and Review of Related Mechanisms. nutrients. 26 December 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793252/pdf/nutrients-10-00024.pdf

# data[].attributes.headline
A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses.

# data[].attributes.subject
A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses.

# data[].attributes.body
A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses - PubMed (nih.gov)

Emalee Haynes

This study looked at glycemic control, cardiovascular risk factors as a result of a patient’s diet choice for those with or at risk of developing type 2 diabetes. The main object was to decide specifically if the Mediterranean diet was effective for these components as compared to other fad diets. The study did find that the Mediterranean diet was found to be associated with a better glycemic control and cardiovascular risk factor control versus other fad diets (NIH).  The clinical implications for this finding are more solid supports for recommending this diet choice for patients with diabetes, heart conditions, etc. Additionally, this study found an improvement in cholesterol levels and reduction in body weight for patients following the Mediterranean diet. Having more evidence from actual patients will make patients being counseling on it by healthcare providers feel likely more confident because they know other people like them have tried it. Knowing that this is more of a tested diet that worked would likely improving willingness to try and confidence in being successful.

Esposito K, Maiorino MI, Bellastella G, Chiodini P, Panagiotakos D, Giugliano D. A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses. BMJ Open. 2015 Aug 10;5(8):e008222. doi: 10.1136/bmjopen-2015-008222. PMID: 26260349; PMCID: PMC4538272.