Metabolic Syndrome

**93**

**Chapter 6**

**Abstract**

syndrome.

**1. Introduction**

on PubMed and Google.

and 20% in the female sex.

syndrome [2].

costs [3].

Metabolic Syndrome

**Keywords:** diabetes, hypertension, dyslipidemia

*Armindo Miguel de Jesus Sousa de Araújo Ribeiro*

Metabolic syndrome (MS) is recognized by a set of cardiovascular risk factors (CVRF) that usually coincide with insulin resistance and hyperglycemia. These risk factors include hyperglycemia (fasting glucose > 100 mg/dl), high blood pressure (SAD ≥ 130 mmHg and TAD ≥ 85 mmHg), triglyceride increase (≥150 mg/dl), decreased HDL levels <40 mg/dl, and central obesity (waist circumference ≥102 cm in men and ≥88 cm in women). The purpose of this chapter is to review the natural history of metabolic syndrome and epidemiology and to review risk factors for the appearance of metabolic syndrome, pathophysiology, and biochemistry among the various cardiovascular risk factors and their importance within the metabolic

The purpose of this chapter is to provide a review of the pathophysiology of metabolic syndrome (MS) and the relationship between its different components. Because this is a very broad subject, not all aspects will be discussed. Throughout the chapter, a bibliographic reference is left for each topic so that this can be looked into more deeply. This is a non-systematic review of the literature through research

At an epidemiologic study conducted by Armindo Sousa Ribeiro et al, in a Portuguese population, was found that 23.8% of the population has MS more prevalent in 24 males, no smoking, no significant alcohol consumption, sedentary life style, with a high body mass index (BMI) and its prevalence increases with age [1]. Each CVRF has different importance in the metabolic

In Western societies, cardiovascular diseases (CVD) are the main cause of mortality and morbidity for both sexes. This fact entails very high social and economic

CVDs are the biggest cause of mortality worldwide. In the 2010 Global Burden of Disease Study, CVD is estimated to cause 15.6 million deaths per year worldwide, corresponding to 29.6% of all deaths [4]. Although the tendency is to reduce the number of deaths in Europe due to CVD, this remains the main cause of death, corresponding to more than 4 million deaths per year, that is to say 45% of all deaths recorded in Europe [4]. Of the CVD, coronary heart disease remains the most important cause of death in both genders, which corresponds to 19% in the male sex

### **Chapter 6** Metabolic Syndrome

*Armindo Miguel de Jesus Sousa de Araújo Ribeiro*

### **Abstract**

Metabolic syndrome (MS) is recognized by a set of cardiovascular risk factors (CVRF) that usually coincide with insulin resistance and hyperglycemia. These risk factors include hyperglycemia (fasting glucose > 100 mg/dl), high blood pressure (SAD ≥ 130 mmHg and TAD ≥ 85 mmHg), triglyceride increase (≥150 mg/dl), decreased HDL levels <40 mg/dl, and central obesity (waist circumference ≥102 cm in men and ≥88 cm in women). The purpose of this chapter is to review the natural history of metabolic syndrome and epidemiology and to review risk factors for the appearance of metabolic syndrome, pathophysiology, and biochemistry among the various cardiovascular risk factors and their importance within the metabolic syndrome.

**Keywords:** diabetes, hypertension, dyslipidemia

### **1. Introduction**

The purpose of this chapter is to provide a review of the pathophysiology of metabolic syndrome (MS) and the relationship between its different components. Because this is a very broad subject, not all aspects will be discussed. Throughout the chapter, a bibliographic reference is left for each topic so that this can be looked into more deeply. This is a non-systematic review of the literature through research on PubMed and Google.

At an epidemiologic study conducted by Armindo Sousa Ribeiro et al, in a Portuguese population, was found that 23.8% of the population has MS more prevalent in 24 males, no smoking, no significant alcohol consumption, sedentary life style, with a high body mass index (BMI) and its prevalence increases with age [1]. Each CVRF has different importance in the metabolic syndrome [2].

In Western societies, cardiovascular diseases (CVD) are the main cause of mortality and morbidity for both sexes. This fact entails very high social and economic costs [3].

CVDs are the biggest cause of mortality worldwide. In the 2010 Global Burden of Disease Study, CVD is estimated to cause 15.6 million deaths per year worldwide, corresponding to 29.6% of all deaths [4]. Although the tendency is to reduce the number of deaths in Europe due to CVD, this remains the main cause of death, corresponding to more than 4 million deaths per year, that is to say 45% of all deaths recorded in Europe [4]. Of the CVD, coronary heart disease remains the most important cause of death in both genders, which corresponds to 19% in the male sex and 20% in the female sex.

### **2. Metabolic syndrome and cardiovascular risk factors (CVRF)**

#### **2.1 Definition**

There are several definitions of MS. MS groups a constellation of pathophysiological factors that increase the risk of developing diabetes mellitus (DM) type 2 and CVD [5–10]. At present, attempts have been made to unify criteria to have a consensus on its diagnosis [11].

The World Health Organization (WHO), International Diabetes Federation (IDF), National Cholesterol Education Program Adult Treatment Panel III


**Figure 1.**

*Components of the metabolic syndrome considering its definition: according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III), World Health Organization (WHO), American Association of Clinical Endocrinologists (AACE), and International Diabetes Federation (IDF).*

**95**

*Metabolic Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.89193*

presence of three of the following five criteria:

or <50 mg/dl (women)

or non-pharmacological measures.

factors with atherosclerosis [15].

gynoid obesity [15].

risk factor for CVD [15, 16].

**2.2 Historical evolution**

over the years.

agents

treatment with insulin or oral antidiabetics

(NCEP-ATP III), and the American Association of Clinical Endocrinologists (AACE)

In 2009, representatives of the IDF and the American Heart Association/National

have proposed their diagnostic criteria or components of MS (**Figure 1**) [11].

Heart, Lung, and Blood Institute (AHA/NHLBI)-ATP III Guidelines discussed resolving differences between definitions of MS, unifying criteria [6, 11]. The definition of MS according to the unification of criteria (harmonizing the metabolic syndrome) is used for many international works and publications and requires the

1.Elevation of fasting blood glucose (≥100 mg/dl) or receiving antidiabetic

2.Elevation of systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (PAD) ≥ 85 mmHg or receiving antihypertensive drug treatment

3.High-density lipoprotein (HDL) cholesterol values <40 mg/dl (men)

5.Abdominal perimeter ≥102 cm (men) or ≥88 cm (women) [6, 12]

4.Triglycerides ≥150 mg/dl or under treatment with specific lipid lowering

The concept of MS was carried out in a progressive manner. Its clinical importance is enormous due to the fact that it can identify patients with high risk of suffering some CVD and/or DM, allowing a preventive intervention [6, 13, 14]. The notion that CVRF has a tendency to aggregation allows an earlier diagnosis of MS, thus also leading to the early introduction of therapeutic, pharmacological,

The interest in the MS is not something recent. Its nomenclature has evolved

About 260 years ago, before the description of MS, the Italian anatomist and doctor, Morgagni, identified the association between visceral obesity, arterial hypertension (AHT), atherosclerosis, hyperuricemia, and frequent episodes of sleep apnea. In the mid-twentieth century, French physicist Vague first identified the relationship between android obesity and the increased prevalence of DM and CVD. In the 1960s Avogaro and Crepaldi attributed the name "plurimetabolic syndrome" to the simultaneous presence of obesity, AHT, and DM. They verified that all these abnormalities were frequent among the population and contributed to an increase in cardiovascular risk [15]. A decade later, Haller related this set of risk

In 1980, Vague suggested that adipose tissue alone had little effect on the onset of DM in obese individuals. It is currently known that central or android obesity is a predisposing factor for DM and atherosclerosis and affects insulin secretion unlike

In 1988, Reaven described this phenomenon as syndrome X, the set of hyperglycemia and insulin resistance, obesity, dyslipidemia, and hypertension. Reaven also suggested that insulin resistance and the consequent increase in blood insulin levels were the central pathophysiological features in syndrome X which in itself was a

#### *Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.89193*

*Cellular Metabolism and Related Disorders*

consensus on its diagnosis [11].

**2.1 Definition**

**2. Metabolic syndrome and cardiovascular risk factors (CVRF)**

There are several definitions of MS. MS groups a constellation of pathophysiological factors that increase the risk of developing diabetes mellitus (DM) type 2 and CVD [5–10]. At present, attempts have been made to unify criteria to have a

The World Health Organization (WHO), International Diabetes Federation

*Components of the metabolic syndrome considering its definition: according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III), World Health Organization (WHO), American Association of Clinical Endocrinologists (AACE), and International Diabetes Federation* 

(IDF), National Cholesterol Education Program Adult Treatment Panel III

**94**

**Figure 1.**

*(IDF).*

(NCEP-ATP III), and the American Association of Clinical Endocrinologists (AACE) have proposed their diagnostic criteria or components of MS (**Figure 1**) [11].

In 2009, representatives of the IDF and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI)-ATP III Guidelines discussed resolving differences between definitions of MS, unifying criteria [6, 11]. The definition of MS according to the unification of criteria (harmonizing the metabolic syndrome) is used for many international works and publications and requires the presence of three of the following five criteria:


The concept of MS was carried out in a progressive manner. Its clinical importance is enormous due to the fact that it can identify patients with high risk of suffering some CVD and/or DM, allowing a preventive intervention [6, 13, 14].

The notion that CVRF has a tendency to aggregation allows an earlier diagnosis of MS, thus also leading to the early introduction of therapeutic, pharmacological, or non-pharmacological measures.

#### **2.2 Historical evolution**

The interest in the MS is not something recent. Its nomenclature has evolved over the years.

About 260 years ago, before the description of MS, the Italian anatomist and doctor, Morgagni, identified the association between visceral obesity, arterial hypertension (AHT), atherosclerosis, hyperuricemia, and frequent episodes of sleep apnea. In the mid-twentieth century, French physicist Vague first identified the relationship between android obesity and the increased prevalence of DM and CVD. In the 1960s Avogaro and Crepaldi attributed the name "plurimetabolic syndrome" to the simultaneous presence of obesity, AHT, and DM. They verified that all these abnormalities were frequent among the population and contributed to an increase in cardiovascular risk [15]. A decade later, Haller related this set of risk factors with atherosclerosis [15].

In 1980, Vague suggested that adipose tissue alone had little effect on the onset of DM in obese individuals. It is currently known that central or android obesity is a predisposing factor for DM and atherosclerosis and affects insulin secretion unlike gynoid obesity [15].

In 1988, Reaven described this phenomenon as syndrome X, the set of hyperglycemia and insulin resistance, obesity, dyslipidemia, and hypertension. Reaven also suggested that insulin resistance and the consequent increase in blood insulin levels were the central pathophysiological features in syndrome X which in itself was a risk factor for CVD [15, 16].

In 1991, Ferrannini and his colleagues referred to this as insulin resistance syndrome [15, 17].

In 1993, Van Gaal attributed for the first time the name MS to all comorbidities associated with visceral obesity and currently this nomenclature is being used [15].

The concept of MS has evolved significantly in the last decade, which resulted in the presentation of multiple clinical definitions by different scientific societies. In general terms as it was widely treated, MS is defined as an aggregation of several CVRF in the same individual. The nuclear elements for the classification and diagnosis of MS are basically obesity, abnormal glycemic metabolism, iatrogenic dyslipidemia, and hypertension.

The metabolic syndrome was defined by the World Health Organization (WHO) in 1998 [13, 15]. In 2001, there was a new revision of the definition through the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III), where glycemia is not considered an essential factor; in this way it only becomes one of the diagnostic components of MS [18].

With the verification of evidence of the relationship between central obesity and cardiovascular risk, there was a tendency to value this diagnostic component for MS more. Thus, in 2004, the International Diabetes Federation (IDF) created a new definition of MS, where central obesity, defined by the value of the abdominal circumference, would be essential for diagnosis [7, 19]. With the adoption of this definition, an increase in the prevalence of MS was observed in a large part of the populations studied, particularly in the elderly [20].

In 2005, a new review of the criteria by the American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI) maintained the criteria of the NCEP-ATP III [21]. The justification was the fact that in that criterion a single etiology for MS does not stand out and is of simpler application. They modified only the cutoff point of fasting blood glucose from 110 to 100 mg/dl, an adjustment promoted by the American Diabetes Association (ADA) in the diagnosis of DM. However, the first Brazilian Guideline for the Diagnosis of Treatment of MS, of 2005, uses the criteria of the NCEP-ATP III, of 2001, for diagnosis [22, 23]. In the criteria of the IDF, the component of the abdominal circumference becomes essential, using a smaller waist circumference, and categorized more people as having the MS than the ATP III definition. However, higher values of abdominal circumference in older people have been related to lower values of body mass index (BMI), in relation to younger adults [24–28].

#### **2.3 Prevalence of metabolic syndrome**

The prevalence of MS varies according to geographic area, with age, race, sex, and classification used for diagnosis [29].

The DARIOS study performs a pooled analysis of 11 studies in 24,670 Spanish individuals aged 35–74, using the criteria of the IDF/NHLBI/AHA-2009, and shows a prevalence of 32% in men and 29% in women [12, 30].

The West of Scotland Coronary Prevention Study (WOSCOPS), one of the largest in Europe, reports a general prevalence of 26.2% [31].

The Third National Health and Nutrition Examination Survey (NHANES III), in the USA showed that 7% of individuals between the ages of 20 and 29, 42% of individuals with ages between 60 and 69 years, and 44% of individuals with ages over 70 years presented MS. The overall prevalence was 23.7% in the 8814 adults who entered the study. This study showed that the incidence increased with age, mainly after 40 years, with significant variations consistent with ethnicity, being the most frequent MS in Hispanics (31.9%) compared with Caucasians (23.8%) and African-Americans (21.6%). A similar prevalence was recorded in both sexes,

**97**

(VLDL).

*Metabolic Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.89193*

Americans and Hispanics [32].

Azores (26.05%) [34].

although it was more prevalent in males in Caucasians and in females in African-

Based on the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study of Europe in 2004, the prevalence of MS was 15.7% in male and 14.2% in the female [33]. Epidemiological studies on MS have suggested that the prevalence of MS in Western societies is high and is increasing

In Portugal there are few studies on the prevalence of MS. In 2004, an epidemiological study was carried out in Porto where the prevalence of MS was 23.9%, being

In 2008, the first study was conducted on the prevalence of MS and its cardiovascular complications in the Portuguese adult population at the primary care level in continental Portugal, Azores, and Madeira—VALSIM study (epidemiological study of the prevalence of metabolic syndrome in the Portuguese population). In this study, 719 family doctors participated. The study was carried out between April 2006 and November 2007. A total of 16,856 individuals were evaluated between the ages of 18 and 96, with averages of 58.1 ± 15.1 years. This study showed a high prevalence of MS in adults affecting 27.5% of the population analyzed, being more prevalent in females (28.7%) compared with males (26%). This study revealed an increase in the prevalence of MS related to age, body mass index, and abdominal perimeter. This study also demonstrated the association between metabolic risk factors, including MS and the occurrence of cardiac events, stroke, and DM [34]. The prevalence of MS exhibited a regional variation, being more prevalent in Alentejo (30.99%), Madeira (29.38%), Central Region (28.79%), and North Region (28.17%) and less prevalent in Algarve (24.42%), Lisbon and Tagus Valley (25.71%), and

The pathophysiology of MS is not yet fully understood, but the most accepted hypothesis is insulin resistance, so MS is also known as insulin resistance syndrome. Insulin resistance is defined as a defect in its action at the peripheral level that results in hyperinsulinemia, required to maintain normal blood glucose [36, 37]. Predisposing factors for insulin resistance are central obesity and the release of large concentrations of free fatty acids from adipose tissue. Free fatty acids in the liver will determine the increase in glycogenesis and gluconeogenesis, increased

triglyceride production, and the secretion of very low-density lipoproteins

Insulin is a hormone with anti-lipolytic action that is produced in pancreatic beta cells and is released into the bloodstream starting its metabolic effects after binding to its receptor. The insulin receptor is a transmembrane glycoprotein composed of four subunits linked by disulfide bridges, that is, two extracellular alpha subunits that contain the insulin binding domain and two β subunits, which contain an extracellular domain, a transmembrane domain, and a intracellular domain insulin binding to the α subunit and β subunit, and tyrosine kinase activation in the β subunit is the first stage of insulin action on glucose metabolism [38, 39]. The activation of tyrosine kinase, and phosphorylation of the β subunit of the insulin receptor, catalyzes the phosphorylation reaction of several tyrosine residues in a family of proteins called insulin receptor substrate (IRS), which include IRS-1, IRS-2, IRS-3, and IRS-4, which are the most specific in the insulin signaling cascade. Other isoforms are growth factor receptor-bound protein 2 (GRB2)-associated

due to the increase in obesity, especially in younger individuals [34].

more prevalent in females (27%) than in males (19.1%) [35].

**3. Insulin resistance and metabolic syndrome**

binding protein 1 (Gab-1), Shc, and p62 [40, 41].

#### *Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.89193*

*Cellular Metabolism and Related Disorders*

dyslipidemia, and hypertension.

becomes one of the diagnostic components of MS [18].

populations studied, particularly in the elderly [20].

(BMI), in relation to younger adults [24–28].

**2.3 Prevalence of metabolic syndrome**

and classification used for diagnosis [29].

a prevalence of 32% in men and 29% in women [12, 30].

est in Europe, reports a general prevalence of 26.2% [31].

syndrome [15, 17].

In 1991, Ferrannini and his colleagues referred to this as insulin resistance

In 1993, Van Gaal attributed for the first time the name MS to all comorbidities associated with visceral obesity and currently this nomenclature is being used [15]. The concept of MS has evolved significantly in the last decade, which resulted in the presentation of multiple clinical definitions by different scientific societies. In general terms as it was widely treated, MS is defined as an aggregation of several CVRF in the same individual. The nuclear elements for the classification and diagnosis of MS are basically obesity, abnormal glycemic metabolism, iatrogenic

The metabolic syndrome was defined by the World Health Organization (WHO)

in 1998 [13, 15]. In 2001, there was a new revision of the definition through the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III), where glycemia is not considered an essential factor; in this way it only

With the verification of evidence of the relationship between central obesity and cardiovascular risk, there was a tendency to value this diagnostic component for MS more. Thus, in 2004, the International Diabetes Federation (IDF) created a new definition of MS, where central obesity, defined by the value of the abdominal circumference, would be essential for diagnosis [7, 19]. With the adoption of this definition, an increase in the prevalence of MS was observed in a large part of the

In 2005, a new review of the criteria by the American Heart Association/ National Heart, Lung, and Blood Institute (AHA/NHLBI) maintained the criteria of the NCEP-ATP III [21]. The justification was the fact that in that criterion a single etiology for MS does not stand out and is of simpler application. They modified only the cutoff point of fasting blood glucose from 110 to 100 mg/dl, an adjustment promoted by the American Diabetes Association (ADA) in the diagnosis of DM. However, the first Brazilian Guideline for the Diagnosis of Treatment of MS, of 2005, uses the criteria of the NCEP-ATP III, of 2001, for diagnosis [22, 23]. In the criteria of the IDF, the component of the abdominal circumference becomes essential, using a smaller waist circumference, and categorized more people as having the MS than the ATP III definition. However, higher values of abdominal circumference in older people have been related to lower values of body mass index

The prevalence of MS varies according to geographic area, with age, race, sex,

The DARIOS study performs a pooled analysis of 11 studies in 24,670 Spanish individuals aged 35–74, using the criteria of the IDF/NHLBI/AHA-2009, and shows

The West of Scotland Coronary Prevention Study (WOSCOPS), one of the larg-

The Third National Health and Nutrition Examination Survey (NHANES III), in the USA showed that 7% of individuals between the ages of 20 and 29, 42% of individuals with ages between 60 and 69 years, and 44% of individuals with ages over 70 years presented MS. The overall prevalence was 23.7% in the 8814 adults who entered the study. This study showed that the incidence increased with age, mainly after 40 years, with significant variations consistent with ethnicity, being the most frequent MS in Hispanics (31.9%) compared with Caucasians (23.8%) and African-Americans (21.6%). A similar prevalence was recorded in both sexes,

**96**

although it was more prevalent in males in Caucasians and in females in African-Americans and Hispanics [32].

Based on the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study of Europe in 2004, the prevalence of MS was 15.7% in male and 14.2% in the female [33]. Epidemiological studies on MS have suggested that the prevalence of MS in Western societies is high and is increasing due to the increase in obesity, especially in younger individuals [34].

In Portugal there are few studies on the prevalence of MS. In 2004, an epidemiological study was carried out in Porto where the prevalence of MS was 23.9%, being more prevalent in females (27%) than in males (19.1%) [35].

In 2008, the first study was conducted on the prevalence of MS and its cardiovascular complications in the Portuguese adult population at the primary care level in continental Portugal, Azores, and Madeira—VALSIM study (epidemiological study of the prevalence of metabolic syndrome in the Portuguese population). In this study, 719 family doctors participated. The study was carried out between April 2006 and November 2007. A total of 16,856 individuals were evaluated between the ages of 18 and 96, with averages of 58.1 ± 15.1 years. This study showed a high prevalence of MS in adults affecting 27.5% of the population analyzed, being more prevalent in females (28.7%) compared with males (26%). This study revealed an increase in the prevalence of MS related to age, body mass index, and abdominal perimeter. This study also demonstrated the association between metabolic risk factors, including MS and the occurrence of cardiac events, stroke, and DM [34]. The prevalence of MS exhibited a regional variation, being more prevalent in Alentejo (30.99%), Madeira (29.38%), Central Region (28.79%), and North Region (28.17%) and less prevalent in Algarve (24.42%), Lisbon and Tagus Valley (25.71%), and Azores (26.05%) [34].

#### **3. Insulin resistance and metabolic syndrome**

The pathophysiology of MS is not yet fully understood, but the most accepted hypothesis is insulin resistance, so MS is also known as insulin resistance syndrome. Insulin resistance is defined as a defect in its action at the peripheral level that results in hyperinsulinemia, required to maintain normal blood glucose [36, 37]. Predisposing factors for insulin resistance are central obesity and the release of large concentrations of free fatty acids from adipose tissue. Free fatty acids in the liver will determine the increase in glycogenesis and gluconeogenesis, increased triglyceride production, and the secretion of very low-density lipoproteins (VLDL).

Insulin is a hormone with anti-lipolytic action that is produced in pancreatic beta cells and is released into the bloodstream starting its metabolic effects after binding to its receptor. The insulin receptor is a transmembrane glycoprotein composed of four subunits linked by disulfide bridges, that is, two extracellular alpha subunits that contain the insulin binding domain and two β subunits, which contain an extracellular domain, a transmembrane domain, and a intracellular domain insulin binding to the α subunit and β subunit, and tyrosine kinase activation in the β subunit is the first stage of insulin action on glucose metabolism [38, 39]. The activation of tyrosine kinase, and phosphorylation of the β subunit of the insulin receptor, catalyzes the phosphorylation reaction of several tyrosine residues in a family of proteins called insulin receptor substrate (IRS), which include IRS-1, IRS-2, IRS-3, and IRS-4, which are the most specific in the insulin signaling cascade. Other isoforms are growth factor receptor-bound protein 2 (GRB2)-associated binding protein 1 (Gab-1), Shc, and p62 [40, 41].

Structurally, the four IRS proteins have many similarities, in particular, the phosphotyrosine-binding domain (PTB), whose function is the recognition sequence of asparagine-proline glutamic phosphotyrosine acid (NPEpY) located in the juxta membrane region of the β receptor of insulin. It is involved in the interaction of IRS proteins with the insulin receptor and with the COOH-terminal domain of the proteins, capable of binding to the SH2 domains [39]. In addition to their similarities, the four IRS proteins differ in tissue distribution [39]. The SH2 domain consists of 100 amino acids, and it is the phosphotyrosine binding site [41]. The activation of proteins that contain the SH2 domain is important for the transmission of the insulin signal and thus carry out its functions [39].

The IRS-1 gene located on chromosome 2q36–37 was the first substrate that was identified. IRS-1 is involved in many of the actions of insulin, in the activation of nitric oxide (NO) synthetase, in the activation of the activity of the iN + pump, and in vascular relaxation through activated protein kinases by mitogens (MAP kinase) [39, 42].

The IRS-2 gene is found on chromosome 13q34 [43]. The IRS-2 protein and the IRS-1 are very similar in structure and functions, and the main difference lies in the region between amino acids 591 and 789 of the IRS-2. IRS-2, unlike IRS-1, is more in the cellular cytosol [44].

IRS-3 does not appear to be expressed in human cells [39].

IRS-4 is a protein that consists of 1257 amino acids located in the cell membrane of various organs in which it is expressed. It was discovered initially in embryonic kidney cells. The IRS-4 gene is found on the X chromosome [39].

Insulin causes vascular relaxation through stimulation of NO production in the endothelial cells of blood vessels and by reducing the concentration of intracellular calcium in muscle and smooth muscle cells by decreasing sensitization of the light chains of calcium (Ca2+)-myosin. These effects are mediated by the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, as well as the stimulation of glucose transport in skeletal muscle and vascular adipose tissue [45]. In the case of insulin resistance, the increase in lipolysis produces greater amounts of fatty acids, promoting greater inhibition of the lipolytic effect of insulin, causing an increase in lipolysis [46, 47].

Insulin resistance is defined as the inability of glucose uptake by skeletal muscle and adipose tissue and the inability of the liver to inhibit gluconeogenesis in response to an increase in insulin [38, 43].

The evidence of the causal relationships between insulin resistance and hypertension is increasing [48]. There are still many uncertainties about the mechanisms that link the two conditions, but in addition to the common genetic predisposition between insulin resistance and AHT, there are several other possible mechanisms that can explain it [48, 49].

The renin-angiotensin-aldosterone system (RAAS) is a therapeutic target for AHT. Changes in the RAAS are also important in insulin resistance, and the common molecular mechanisms of insulin resistance and AHT are not well understood [50, 51].

The RAAS thus plays an important role in MS. Angiotensinogen is a 58 kDa protein produced primarily in the liver under physiological conditions, but it can be produced in smaller amounts in adipocytes, mesangial cells, and epithelial cells of the proximal contoured tubule and in the brain (neurons and glial cells). Angiotensinogen by the action of the renin enzyme produced in the glomerular juxta cells in the kidney is subjected to cleavage in the amino-terminal acid of 10 NH2 to form angiotensin I. Angiotensin I is an inactive peptide that is hydroxylated by the enzyme angiotensin converter, forming an octapeptide designated angiotensin II [50].

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*Metabolic Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.89193*

The RAAS has autocrine/paracrine activity in various tissues, especially in the skeletal muscle, smooth muscle of blood vessels, kidneys, heart, and pancreas [52]. The angiotensin (AT) II receptor is a transmembrane protein that belongs to the family of receptors coupled to the G protein which is divided into type I (AT1) and type II (AT2) [40, 42, 53]. The genes encoding the AT1 receptor were cloned in 1992, and the genes encoding the AT2 receptor were cloned in 1994 [54]. The binding of angiotensin II to the AT1 receptor leads to the phosphorylation of various proteins such as IRS-1 and IRS-2, making the P110/PI3K subunit the common activation mechanism for the insulin signaling pathway. Resistance to insulin is caused by the inhibition of insulin through the inhibition of the mechanisms involved in glucose transport and vasodilation [42, 45]. Skeletal muscle is important in the development of insulin resistance, which is responsible for 75–95% glucose metabolism [55, 56]. Skeletal muscle constitutes the largest insulin-sensitive tissue in the body and is the primary site for insulin-stimulated glucose utilization [55]. Skeletal muscle resistance to insulin is fundamental to the metabolic dysregulation associated with obesity and physical inactivity and contributes to the development of the MS [55]. Potential mechanisms contributing to reduced insulin signaling and action in skeletal muscle include adipose tissue expansion and increased inflammatory adipokines, increased RAAS activity, decreases in muscle mitochondrial oxidative capacity, increased intramuscular lipid

accumulation, and increased reactive oxygen species (ROS) [55].

**3.1 Relationship between inflammation and insulin resistance**

can cause cardiovascular disease development [50].

Angiotensin II has prooxidant and pro-inflammatory effects that regulate apopto-

Obesity is a worldwide epidemic that has generated many scientific publications in recent years. Thus, new paradigms were emerging, while the old challenges are still to be unraveled [58]. Obesity is a chronic disease and has become a major problem in most industrialized countries due to its increased prevalence and association with various diseases and due to its great economic impact [59]. To preserve the energy reserves of body fat during periods of negative energy balance, the body has developed various regulatory mechanisms [60]. This control is achieved by balancing the intestinal absorption of glucose, the production of glucose by the liver, and the absorption and metabolism of glucose by peripheral tissues [61]. Insulin regulates blood glucose due to its action in stimulating glucose uptake in the muscle and liver and inhibiting hepatic gluconeogenesis [61]. Despite the change in tolerance to the action of insulin initially, blood glucose is normal because pancreatic β cells have the ability to increase the ability of insulin secretion to overcome existing insulin resistance [9]. Excess nutrients induce hypertrophy of adipocytes that promote the development of various chronic morbidities such as type 2 DM and insulin resistance, glucose intolerance, and dyslipidemia with the consequent development of cardiovascular diseases [60]. There is also strong evidence to suggest that cell hypoxia may be an important factor in the pathophysiology of adipocytes and may be one of the causes of this dysfunction contributing to the metabolic alteration associated with obesity [62].

sis, inflammation, cell growth, fibrosis, and insulin sensitivity by inducing the formation of oxygen free radicals through the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [56]. ROS are formed by the electron transport chain in the mitochondria, and it increases in situations that require the oxidation of substrates such as glucose [56]. Multiple ROS activate transcription factors such as factor nuclear kappa B (NF-KB) protein-1 and hypoxia-inducible factor-1 HIF-1, which are involved in the mechanism of insulin resistance in skeletal muscle [57]. Hyperinsulinemia can alter some of the components of the RAAS such as profibrotic stimulants and pro-inflammatory actions mediated by angiotensin II and

#### *Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.89193*

*Cellular Metabolism and Related Disorders*

signal and thus carry out its functions [39].

[39, 42].

the cellular cytosol [44].

Structurally, the four IRS proteins have many similarities, in particular, the phosphotyrosine-binding domain (PTB), whose function is the recognition sequence of asparagine-proline glutamic phosphotyrosine acid (NPEpY) located in the juxta membrane region of the β receptor of insulin. It is involved in the interaction of IRS proteins with the insulin receptor and with the COOH-terminal domain of the proteins, capable of binding to the SH2 domains [39]. In addition to their similarities, the four IRS proteins differ in tissue distribution [39]. The SH2 domain consists of 100 amino acids, and it is the phosphotyrosine binding site [41]. The activation of proteins that contain the SH2 domain is important for the transmission of the insulin

The IRS-1 gene located on chromosome 2q36–37 was the first substrate that was identified. IRS-1 is involved in many of the actions of insulin, in the activation of nitric oxide (NO) synthetase, in the activation of the activity of the iN + pump, and in vascular relaxation through activated protein kinases by mitogens (MAP kinase)

The IRS-2 gene is found on chromosome 13q34 [43]. The IRS-2 protein and the IRS-1 are very similar in structure and functions, and the main difference lies in the region between amino acids 591 and 789 of the IRS-2. IRS-2, unlike IRS-1, is more in

IRS-4 is a protein that consists of 1257 amino acids located in the cell membrane of various organs in which it is expressed. It was discovered initially in embryonic

Insulin causes vascular relaxation through stimulation of NO production in the endothelial cells of blood vessels and by reducing the concentration of intracellular calcium in muscle and smooth muscle cells by decreasing sensitization of the light chains of calcium (Ca2+)-myosin. These effects are mediated by the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, as well as the stimulation of glucose transport in skeletal muscle and vascular adipose tissue [45]. In the case of insulin resistance, the increase in lipolysis produces greater amounts of fatty acids, promoting greater inhibition of the lipolytic effect

Insulin resistance is defined as the inability of glucose uptake by skeletal muscle

The evidence of the causal relationships between insulin resistance and hypertension is increasing [48]. There are still many uncertainties about the mechanisms that link the two conditions, but in addition to the common genetic predisposition between insulin resistance and AHT, there are several other possible mechanisms

The renin-angiotensin-aldosterone system (RAAS) is a therapeutic target for AHT. Changes in the RAAS are also important in insulin resistance, and the common molecular mechanisms of insulin resistance and AHT are not well

The RAAS thus plays an important role in MS. Angiotensinogen is a 58 kDa protein produced primarily in the liver under physiological conditions, but it can be produced in smaller amounts in adipocytes, mesangial cells, and epithelial cells of the proximal contoured tubule and in the brain (neurons and glial cells). Angiotensinogen by the action of the renin enzyme produced in the glomerular juxta cells in the kidney is subjected to cleavage in the amino-terminal acid of 10 NH2 to form angiotensin I. Angiotensin I is an inactive peptide that is hydroxylated by the enzyme angiotensin converter, forming an octapeptide designated angioten-

and adipose tissue and the inability of the liver to inhibit gluconeogenesis in

IRS-3 does not appear to be expressed in human cells [39].

kidney cells. The IRS-4 gene is found on the X chromosome [39].

of insulin, causing an increase in lipolysis [46, 47].

response to an increase in insulin [38, 43].

that can explain it [48, 49].

understood [50, 51].

**98**

sin II [50].

The RAAS has autocrine/paracrine activity in various tissues, especially in the skeletal muscle, smooth muscle of blood vessels, kidneys, heart, and pancreas [52]. The angiotensin (AT) II receptor is a transmembrane protein that belongs to the family of receptors coupled to the G protein which is divided into type I (AT1) and type II (AT2) [40, 42, 53]. The genes encoding the AT1 receptor were cloned in 1992, and the genes encoding the AT2 receptor were cloned in 1994 [54]. The binding of angiotensin II to the AT1 receptor leads to the phosphorylation of various proteins such as IRS-1 and IRS-2, making the P110/PI3K subunit the common activation mechanism for the insulin signaling pathway. Resistance to insulin is caused by the inhibition of insulin through the inhibition of the mechanisms involved in glucose transport and vasodilation [42, 45].

Skeletal muscle is important in the development of insulin resistance, which is responsible for 75–95% glucose metabolism [55, 56]. Skeletal muscle constitutes the largest insulin-sensitive tissue in the body and is the primary site for insulin-stimulated glucose utilization [55]. Skeletal muscle resistance to insulin is fundamental to the metabolic dysregulation associated with obesity and physical inactivity and contributes to the development of the MS [55]. Potential mechanisms contributing to reduced insulin signaling and action in skeletal muscle include adipose tissue expansion and increased inflammatory adipokines, increased RAAS activity, decreases in muscle mitochondrial oxidative capacity, increased intramuscular lipid accumulation, and increased reactive oxygen species (ROS) [55].

Angiotensin II has prooxidant and pro-inflammatory effects that regulate apoptosis, inflammation, cell growth, fibrosis, and insulin sensitivity by inducing the formation of oxygen free radicals through the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [56]. ROS are formed by the electron transport chain in the mitochondria, and it increases in situations that require the oxidation of substrates such as glucose [56]. Multiple ROS activate transcription factors such as factor nuclear kappa B (NF-KB) protein-1 and hypoxia-inducible factor-1 HIF-1, which are involved in the mechanism of insulin resistance in skeletal muscle [57].

Hyperinsulinemia can alter some of the components of the RAAS such as profibrotic stimulants and pro-inflammatory actions mediated by angiotensin II and can cause cardiovascular disease development [50].

#### **3.1 Relationship between inflammation and insulin resistance**

Obesity is a worldwide epidemic that has generated many scientific publications in recent years. Thus, new paradigms were emerging, while the old challenges are still to be unraveled [58]. Obesity is a chronic disease and has become a major problem in most industrialized countries due to its increased prevalence and association with various diseases and due to its great economic impact [59]. To preserve the energy reserves of body fat during periods of negative energy balance, the body has developed various regulatory mechanisms [60]. This control is achieved by balancing the intestinal absorption of glucose, the production of glucose by the liver, and the absorption and metabolism of glucose by peripheral tissues [61]. Insulin regulates blood glucose due to its action in stimulating glucose uptake in the muscle and liver and inhibiting hepatic gluconeogenesis [61]. Despite the change in tolerance to the action of insulin initially, blood glucose is normal because pancreatic β cells have the ability to increase the ability of insulin secretion to overcome existing insulin resistance [9]. Excess nutrients induce hypertrophy of adipocytes that promote the development of various chronic morbidities such as type 2 DM and insulin resistance, glucose intolerance, and dyslipidemia with the consequent development of cardiovascular diseases [60]. There is also strong evidence to suggest that cell hypoxia may be an important factor in the pathophysiology of adipocytes and may be one of the causes of this dysfunction contributing to the metabolic alteration associated with obesity [62].

Obesity is defined according to the WHO, as an abnormal or excessive accumulation of fat that can cause imbalances in the health of an individual [63]. Males are more likely to accumulate intra-abdominal adipose tissue compared with females [32, 64]. On average, men have twice the amount of visceral fat than women and have a higher prevalence of metabolic diseases associated with obesity and MS [65].

Obesity is associated with a higher incidence of type 2 DM, insulin resistance, AHT, dyslipidemia, some types of cancer, and CVD [66]. Fat tissue is deposited in two main compartments, subcutaneous and central or visceral [63]. Based on this, obesity can be divided into central and peripheral obesity. Central obesity is characterized by hyperplasia and hypertrophy of adipocytes around the intra-abdominal organs and is associated with greater development of MS [65].

Adipocyte hypertrophy is the main consequence of excess nutrient intake, promoting the development of insulin resistance and glucose intolerance [63]. Triglycerides present in fatty tissue are the body's largest energy reserve, so adipose tissue is a very effective energy storage mechanism that allows survival of living beings in times of famine [59].

Recent studies have shown that hypoxia in adipose tissue can play an important role in the cellular mechanisms of chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte apoptosis, and reticulum endoplasmic and mitochondrial dysfunction in white adipose tissue in obese [67].

Hypoxia inhibits pre-adipocyte differentiation and stimulates the secretion of leptin and vascular epithelial growth factor (VEGF) of mature adipocytes [68].

There are several genes that regulate the action of hypoxia, such as HIF-1α (hypoxia-inducible factor 1α), vascular endothelial growth factor VEGF, glucose transporter-1 (GLUT-1), heme oxygenase-1, and pyruvate dehydrogenase kinase 1 [67]. It was found that, under conditions of hypoxia in adipose tissue, all genes increased their expression except for VEGF messenger ribonucleic acid (mRNA) [67].

Adipose tissue is thus divided into white adipose tissue and brown adipose tissue, which have different functions. Brown adipose tissue has the function of producing heat. The understanding and vision we currently have in white adipose tissue have changed significantly in the last 15 years [69]. Currently, white adipose tissue is considered, not only as a tissue in which energy is stored in the form of triglycerides but also as the main secretory and endocrine organ of the organism [70]. White adipose tissue produces and secretes various proteins. Initially, these proteins were designated adipocytokines [71]. Currently, it is universally adopted the name of adipokines to the set of proteins synthesized and secreted by adipose tissue, since not all proteins are cytokines [71].

In addition to adipokines and fatty acids, adipose tissue produces other lipid substances such as steroid hormones, prostaglandins and prostanoids, cholesterol, and retinol (cholesterol and retinol are not synthesized by adipocytes but are stored and released from them) [71].

In 1994, Friedman and his colleagues discovered leptin, a hormone produced by white adipose tissue. Leptin, also called OB protein, is a hormone composed of 16 kDa and is produced from a protein with molecular weight of 18 kDa. It is cleaved leading to the production of leptin protein. Leptin is expressed in many tissues including the white and brown adipose tissue, stomach, placenta, mammary gland, ovarian follicles, and others [72]. It is expressed primarily in adipose tissue, but it is also expressed in smaller amounts in the brain and in the cerebrospinal fluid [70].

Leptin acts both in the central nervous system (hypothalamus) and in the peripheral organs. This discovery allowed us to realize that adipose tissue is not only a tissue in which energy storage occurs but also an endocrine organ [73].

**101**

*Metabolic Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.89193*

vascular epidermal growth factor) [62, 71].

pathway insulin signaling [61, 75].

insulin resistance [63].

**3.2 Relationship between hypoxia and insulin resistance**

concomitant sensitivity decrease in insulin [79, 80].

**4. Obesity and metabolic syndrome**

White adipose tissue produces various adipokines, many of which are inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-β, and IL-6. The production of inflammatory interleukins increases with obesity and is involved in the development of insulin resistance and in the metabolic syndrome [62, 74]. Adipokines have various functions, in particular in the energy balance (e.g., leptin) on insulin sensitivity and glucose metabolism (e.g., adiponectin), inflammation (e.g., TNF-α), immunity (e.g., adipsin), lipid metabolism (e.g., cholesterol ester transfer protein), blood pressure control (e.g., angiotensinogen) hemostasis (e.g., plasminogen activation inhibitor-1), and angiogenesis (e.g.,

Inflammation is an important process in obesity and in type 2 DM, as it promotes insulin resistance by inhibiting the function of IRS-1 and IRS-2 in the

Obesity is characterized by a state of chronic inflammation with increased inflammatory parameters, for example, haptoglobin, IL-6, C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), and TNF-α [69]. Large concentrations of cytokines produced by adipose tissue, such as TNF-α, IL-6, and IL-1β, and low concentrations of certain adiponectins cause chronic hyperinsulinemia and

**3.3 Relationship between endothelial dysfunction and insulin resistance**

During periods of positive energy balance, there is an increase in white adipose tissue in order to be able to store excess triglycerides. Consequently, adipose tissue becomes hypoxic due to the decrease in vascularization of the same [62]. The role of hypoxia in adipose tissue in obesity and insulin resistance is still unclear [76]. Regulatory responses mediated by HIF-1 depend on its degree and duration [76]. HIF-1 is a heterodimeric transcription factor induced by hypoxia and composed of two subunits, the α subunit consisting of 120 kDa and the β subunit, consisting of 91 to 94 kDa [77]. The α subunit (HIF-1α) determines the transcriptional activity of HIF-1, and its increase occurs in response to hypoxia. The β (HIF-1β) subunit is constitutively expressed and may also be referred to as an aryl hydrocarbon receptor nuclear translocator (tRNA) [78]. Under normoxia conditions, HIF-1α is hydroxylated in proline and asparaginyl residues, catalyzed by the enzyme prolylhydroxylase (PHD), which promotes binding to an ubiquitin ligase complex. This process leads to proteosomal degradation mediated by HIF-1 [76, 78]. Under conditions of hypoxia, hydroxylation and activation of HIF-1 target genes are inhibited [76]. HIF-1α activates fibrosis of adipose tissue, causing an increase in macrophage infiltration into adipose tissue that mediates a greater increase in inflammation and

VEGF is a target gene of HIF-1. VEGF promotes angiogenesis, a necessary process for the differentiation of adipocytes and the growth of adipose tissue [81].

The endothelium is a layer of cells that lines the inner surface of the blood vessel [82]. Endothelial dysfunction is defined as the interruption of the release of vasodilator factors such as NO and prostacyclin (PGI2) and vasoconstrictor factors such as endothelin-1 (ET-1) and angiotensin II [74]. Alterations in vascular endothelial

#### *Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.89193*

*Cellular Metabolism and Related Disorders*

beings in times of famine [59].

not all proteins are cytokines [71].

and released from them) [71].

(mRNA) [67].

Obesity is defined according to the WHO, as an abnormal or excessive accumulation of fat that can cause imbalances in the health of an individual [63]. Males are more likely to accumulate intra-abdominal adipose tissue compared with females [32, 64]. On average, men have twice the amount of visceral fat than women and have a higher prevalence of metabolic diseases associated with obesity and MS [65]. Obesity is associated with a higher incidence of type 2 DM, insulin resistance, AHT, dyslipidemia, some types of cancer, and CVD [66]. Fat tissue is deposited in two main compartments, subcutaneous and central or visceral [63]. Based on this, obesity can be divided into central and peripheral obesity. Central obesity is characterized by hyperplasia and hypertrophy of adipocytes around the intra-abdominal

Adipocyte hypertrophy is the main consequence of excess nutrient intake, promoting the development of insulin resistance and glucose intolerance [63]. Triglycerides present in fatty tissue are the body's largest energy reserve, so adipose tissue is a very effective energy storage mechanism that allows survival of living

Recent studies have shown that hypoxia in adipose tissue can play an important

role in the cellular mechanisms of chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte apoptosis, and reticulum endoplasmic and mitochondrial dysfunction in white adipose tissue in obese [67]. Hypoxia inhibits pre-adipocyte differentiation and stimulates the secretion of leptin and vascular epithelial growth factor (VEGF) of mature adipocytes [68]. There are several genes that regulate the action of hypoxia, such as HIF-1α (hypoxia-inducible factor 1α), vascular endothelial growth factor VEGF, glucose transporter-1 (GLUT-1), heme oxygenase-1, and pyruvate dehydrogenase kinase 1

[67]. It was found that, under conditions of hypoxia in adipose tissue, all genes increased their expression except for VEGF messenger ribonucleic acid

Adipose tissue is thus divided into white adipose tissue and brown adipose tissue, which have different functions. Brown adipose tissue has the function of producing heat. The understanding and vision we currently have in white adipose tissue have changed significantly in the last 15 years [69]. Currently, white adipose tissue is considered, not only as a tissue in which energy is stored in the form of triglycerides but also as the main secretory and endocrine organ of the organism [70]. White adipose tissue produces and secretes various proteins. Initially, these proteins were designated adipocytokines [71]. Currently, it is universally adopted the name of adipokines to the set of proteins synthesized and secreted by adipose tissue, since

In addition to adipokines and fatty acids, adipose tissue produces other lipid substances such as steroid hormones, prostaglandins and prostanoids, cholesterol, and retinol (cholesterol and retinol are not synthesized by adipocytes but are stored

In 1994, Friedman and his colleagues discovered leptin, a hormone produced by white adipose tissue. Leptin, also called OB protein, is a hormone composed of 16 kDa and is produced from a protein with molecular weight of 18 kDa. It is cleaved leading to the production of leptin protein. Leptin is expressed in many tissues including the white and brown adipose tissue, stomach, placenta, mammary gland, ovarian follicles, and others [72]. It is expressed primarily in adipose tissue, but it is also expressed in smaller amounts in the brain and in the cerebrospinal

Leptin acts both in the central nervous system (hypothalamus) and in the peripheral organs. This discovery allowed us to realize that adipose tissue is not only

a tissue in which energy storage occurs but also an endocrine organ [73].

organs and is associated with greater development of MS [65].

**100**

fluid [70].

White adipose tissue produces various adipokines, many of which are inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-β, and IL-6. The production of inflammatory interleukins increases with obesity and is involved in the development of insulin resistance and in the metabolic syndrome [62, 74]. Adipokines have various functions, in particular in the energy balance (e.g., leptin) on insulin sensitivity and glucose metabolism (e.g., adiponectin), inflammation (e.g., TNF-α), immunity (e.g., adipsin), lipid metabolism (e.g., cholesterol ester transfer protein), blood pressure control (e.g., angiotensinogen) hemostasis (e.g., plasminogen activation inhibitor-1), and angiogenesis (e.g., vascular epidermal growth factor) [62, 71].

#### **3.2 Relationship between hypoxia and insulin resistance**

Inflammation is an important process in obesity and in type 2 DM, as it promotes insulin resistance by inhibiting the function of IRS-1 and IRS-2 in the pathway insulin signaling [61, 75].

Obesity is characterized by a state of chronic inflammation with increased inflammatory parameters, for example, haptoglobin, IL-6, C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), and TNF-α [69]. Large concentrations of cytokines produced by adipose tissue, such as TNF-α, IL-6, and IL-1β, and low concentrations of certain adiponectins cause chronic hyperinsulinemia and insulin resistance [63].

#### **3.3 Relationship between endothelial dysfunction and insulin resistance**

During periods of positive energy balance, there is an increase in white adipose tissue in order to be able to store excess triglycerides. Consequently, adipose tissue becomes hypoxic due to the decrease in vascularization of the same [62]. The role of hypoxia in adipose tissue in obesity and insulin resistance is still unclear [76]. Regulatory responses mediated by HIF-1 depend on its degree and duration [76].

HIF-1 is a heterodimeric transcription factor induced by hypoxia and composed of two subunits, the α subunit consisting of 120 kDa and the β subunit, consisting of 91 to 94 kDa [77]. The α subunit (HIF-1α) determines the transcriptional activity of HIF-1, and its increase occurs in response to hypoxia. The β (HIF-1β) subunit is constitutively expressed and may also be referred to as an aryl hydrocarbon receptor nuclear translocator (tRNA) [78]. Under normoxia conditions, HIF-1α is hydroxylated in proline and asparaginyl residues, catalyzed by the enzyme prolylhydroxylase (PHD), which promotes binding to an ubiquitin ligase complex. This process leads to proteosomal degradation mediated by HIF-1 [76, 78]. Under conditions of hypoxia, hydroxylation and activation of HIF-1 target genes are inhibited [76].

HIF-1α activates fibrosis of adipose tissue, causing an increase in macrophage infiltration into adipose tissue that mediates a greater increase in inflammation and concomitant sensitivity decrease in insulin [79, 80].

VEGF is a target gene of HIF-1. VEGF promotes angiogenesis, a necessary process for the differentiation of adipocytes and the growth of adipose tissue [81].

#### **4. Obesity and metabolic syndrome**

The endothelium is a layer of cells that lines the inner surface of the blood vessel [82]. Endothelial dysfunction is defined as the interruption of the release of vasodilator factors such as NO and prostacyclin (PGI2) and vasoconstrictor factors such as endothelin-1 (ET-1) and angiotensin II [74]. Alterations in vascular endothelial

function at the level of adipose tissue can cause insulin resistance [81]. In insulin resistance, the release rate of free fatty acids from the adipose tissue, which contribute to diabetic dyslipidemia, increased. HDL-cholesterol decreased, increasing low-density lipoprotein (LDL) cholesterol and free fatty acids. This stimulates the inflammatory response, causing the adhesion of monocytes and lymphocytes to the endothelial cells, and increases the flow of glucose and free fatty acids to the cells, causing excessive formation of oxygen free radicals, with an increase in metabolic and hemodynamic degradation. There is an increase in free radicals and nitrites by intramitochondrial enzymatic oxy-reduction which promotes apoptosis and impaired vascular endothelial function [82]. This alteration causes insulin metabolic dysfunction, promoting greater resistance to insulin [74, 82].

#### **4.1 Relationship between insulin resistance and hypertension in obesity**

Obesity alone is the cause of AHT in 78% of men and 65% of women [83]. Evidence of the causal relationship between insulin resistance and AHT is increasing [40]. Under physiological circumstances, insulin and insulin growth factor-1 (IGF-1) increase vasodilation by stimulating the production of NO and reducing the concentration of intravascular calcium in vascular smooth muscle cells. It also increases the sensitization of myosin-Ca2+ light chains. These actions are mediated through the activation of the PI3K enzyme and the Akt protein. Vascular relaxation in response to activation of PI3K/Akt pathway is mediated by endothelial cells producing NO, which involves phosphorylation of endothelial NO synthetase [41].

Patients with AHT have an increase in fasting and postprandial insulin levels in relation to non-hypertensive patients with the same body mass index [41]. It does not occur with secondary AHT but with essential AHT. This is related in part to the action of insulin that changes at the level of muscle tissue, which is the predominant site of glucose use stimulated by insulin [40].

There is an association between blood pressure and the proportion of type II fibers in skeletal muscle, which are less sensitive to insulin than type I fibers [40]. Under normal physiological conditions, there is a relationship between glucosemediated insulin availability and increased blood flow in response to insulin. This response decreases in obese people with insulin resistance, which suggests resistance to insulin action in reference to vascular NO production [41]. Due to the difficulty of assimilating the rapid growth of adipose tissue in a hypoxia at an early stage, conditions are created for an increase in the expression of HIF-1α [84–87].

There is evidence that insulin resistance and hyperinsulinemia predispose patients to the development of AHT due to cellular abnormalities in insulin signaling pathways and are associated with metabolic and hemodynamic alterations [84]. Metabolic abnormalities are linked to hypertension caused by pathophysiological processes that involve the sympathetic-adrenergic system, the imbalance of cell cations, the increase in inflammation, the oxidative stress, and the RAAS [40].

RAAS plays an important role in insulin resistance by being more active in visceral adipose tissue compared to peripheral adipose tissue [83]. Insulin resistance in obese individuals is also associated, in part, with an antagonism to the action of angiotensin II (AT II) [83]. This produces a decrease in NO production with an increase in vasoconstriction and a decrease in GLUT-4 in skeletal muscle. It also reduces glucose uptake and decreases vasodilation in tissues [83]. Under normal conditions, the RAAS system is a mechanism for regulating blood pressure [88]. With the increase in the activity of the RAAS, there is a greater production of ATII, which leads to stimulation of the sympathetic nervous system, insulin resistance, sodium retention, and increased intravascular volume. It also contributes to kidney disease, hypertension, insulin resistance, and left ventricular hypertrophy [83].

**103**

*Metabolic Syndrome*

**5. Conclusion**

**Author details**

Santiago do Cacém, Portugal

*DOI: http://dx.doi.org/10.5772/intechopen.89193*

There is a common genetic predisposition to insulin resistance and hypertension. Genetic defects have been described in people who had insulin resistance and AHT and mutations found on chromosome 7q, where other genes important for

Hyperinsulinemia can directly stimulate the reabsorption of sodium and water in the kidney, which increases the volume in the extracellular space, causing AHT. Another mechanism by which insulin can cause hypertension involves stimulation of the sympathetic nervous system (SNS) by increasing the concentration of norepinephrine. This increase is directly related to the increase in pulse and blood pressure by direct effect on the reabsorption of sodium in the kidney, peripheral

The correlation of CVRF with the metabolic syndrome differs from one another. The notion that CVRF has a tendency to aggregation allows an earlier diagnosis of MS, thus also leading to the early introduction of therapeutic, pharmacological, or non-pharmacological measures. The prevalence of MS increases with age and is present in people of working age, increasing the risk of cardiovascular diseases, work-related absences, and socioeconomic costs. The concept of MS was carried out in a progressive manner. Its clinical importance is enormous due to the fact that it can identify patients with high risk of suffering some CVD and/or DM, allowing a preventive intervention. This may explain the importance of understanding the pathophysiology of the MS, and the author hopes that at the end of the chapter, the reader can understand it. This chapter is the beginning of an explanation of meta-

bolic syndrome that should be complemented by reading other articles.

1 Unidade Local de Saúde do Litoral Alentejano, Hospital Litoral Alentejano,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

glycemic control, blood pressure, and obesity are also found [49].

vasoconstriction, and increased cardiac output [9].

Armindo Miguel de Jesus Sousa de Araújo Ribeiro1,2

2 Universidad de Extremadura, Badajoz, Spain

provided the original work is properly cited.

\*Address all correspondence to: amsr29@gmail.com

#### *Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.89193*

There is a common genetic predisposition to insulin resistance and hypertension. Genetic defects have been described in people who had insulin resistance and AHT and mutations found on chromosome 7q, where other genes important for glycemic control, blood pressure, and obesity are also found [49].

Hyperinsulinemia can directly stimulate the reabsorption of sodium and water in the kidney, which increases the volume in the extracellular space, causing AHT. Another mechanism by which insulin can cause hypertension involves stimulation of the sympathetic nervous system (SNS) by increasing the concentration of norepinephrine. This increase is directly related to the increase in pulse and blood pressure by direct effect on the reabsorption of sodium in the kidney, peripheral vasoconstriction, and increased cardiac output [9].

#### **5. Conclusion**

*Cellular Metabolism and Related Disorders*

function at the level of adipose tissue can cause insulin resistance [81]. In insulin resistance, the release rate of free fatty acids from the adipose tissue, which contribute to diabetic dyslipidemia, increased. HDL-cholesterol decreased, increasing low-density lipoprotein (LDL) cholesterol and free fatty acids. This stimulates the inflammatory response, causing the adhesion of monocytes and lymphocytes to the endothelial cells, and increases the flow of glucose and free fatty acids to the cells, causing excessive formation of oxygen free radicals, with an increase in metabolic and hemodynamic degradation. There is an increase in free radicals and nitrites by intramitochondrial enzymatic oxy-reduction which promotes apoptosis and impaired vascular endothelial function [82]. This alteration causes insulin meta-

bolic dysfunction, promoting greater resistance to insulin [74, 82].

site of glucose use stimulated by insulin [40].

**4.1 Relationship between insulin resistance and hypertension in obesity**

Obesity alone is the cause of AHT in 78% of men and 65% of women [83]. Evidence of the causal relationship between insulin resistance and AHT is increasing [40]. Under physiological circumstances, insulin and insulin growth factor-1 (IGF-1) increase vasodilation by stimulating the production of NO and reducing the concentration of intravascular calcium in vascular smooth muscle cells. It also increases the sensitization of myosin-Ca2+ light chains. These actions are mediated through the activation of the PI3K enzyme and the Akt protein. Vascular relaxation in response to activation of PI3K/Akt pathway is mediated by endothelial cells producing NO, which involves phosphorylation of endothelial NO synthetase [41]. Patients with AHT have an increase in fasting and postprandial insulin levels in relation to non-hypertensive patients with the same body mass index [41]. It does not occur with secondary AHT but with essential AHT. This is related in part to the action of insulin that changes at the level of muscle tissue, which is the predominant

There is an association between blood pressure and the proportion of type II fibers in skeletal muscle, which are less sensitive to insulin than type I fibers [40]. Under normal physiological conditions, there is a relationship between glucosemediated insulin availability and increased blood flow in response to insulin. This response decreases in obese people with insulin resistance, which suggests resistance to insulin action in reference to vascular NO production [41]. Due to the difficulty of assimilating the rapid growth of adipose tissue in a hypoxia at an early stage, conditions are created for an increase in the expression of HIF-1α [84–87]. There is evidence that insulin resistance and hyperinsulinemia predispose patients to the development of AHT due to cellular abnormalities in insulin signaling pathways and are associated with metabolic and hemodynamic alterations [84]. Metabolic abnormalities are linked to hypertension caused by pathophysiological processes that involve the sympathetic-adrenergic system, the imbalance of cell cations, the increase in inflammation, the oxidative stress, and the RAAS [40]. RAAS plays an important role in insulin resistance by being more active in visceral adipose tissue compared to peripheral adipose tissue [83]. Insulin resistance in obese individuals is also associated, in part, with an antagonism to the action of angiotensin II (AT II) [83]. This produces a decrease in NO production with an increase in vasoconstriction and a decrease in GLUT-4 in skeletal muscle. It also reduces glucose uptake and decreases vasodilation in tissues [83]. Under normal conditions, the RAAS system is a mechanism for regulating blood pressure [88]. With the increase in the activity of the RAAS, there is a greater production of ATII, which leads to stimulation of the sympathetic nervous system, insulin resistance, sodium retention, and increased intravascular volume. It also contributes to kidney disease, hypertension, insulin resistance, and left ventricular hypertrophy [83].

**102**

The correlation of CVRF with the metabolic syndrome differs from one another. The notion that CVRF has a tendency to aggregation allows an earlier diagnosis of MS, thus also leading to the early introduction of therapeutic, pharmacological, or non-pharmacological measures. The prevalence of MS increases with age and is present in people of working age, increasing the risk of cardiovascular diseases, work-related absences, and socioeconomic costs. The concept of MS was carried out in a progressive manner. Its clinical importance is enormous due to the fact that it can identify patients with high risk of suffering some CVD and/or DM, allowing a preventive intervention. This may explain the importance of understanding the pathophysiology of the MS, and the author hopes that at the end of the chapter, the reader can understand it. This chapter is the beginning of an explanation of metabolic syndrome that should be complemented by reading other articles.

#### **Author details**

Armindo Miguel de Jesus Sousa de Araújo Ribeiro1,2

1 Unidade Local de Saúde do Litoral Alentejano, Hospital Litoral Alentejano, Santiago do Cacém, Portugal

2 Universidad de Extremadura, Badajoz, Spain

\*Address all correspondence to: amsr29@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[79] Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Molecular and Cellular Biology.

[80] Michailidou Z, Turban S, Miller E, Zou X, Schrader J, Ratcliffe P, et al. Increased angiogenesis protects against adipose hypoxia and fibrosis in metabolic disease-resistant 11β-hydroxysteroid dehydrogenase type 1 (HSD-1)-deficient mice. Journal of Biological Chemistry. 3 Feb

[81] Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nature Reviews. Drug Discovery. 2010;**9**:107-115

[82] Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction:

diseases. Diabetes/Metabolism Reviews.

[83] El-Atat FA, Stas SN, Mcfarlane SI, Sowers JR. The relationship between hyperinsulinemia, hypertension and progressive renal disease. Journal of the American Society of Nephrology.

[84] Kalidas K, Wasson J, Glaser B, Meyer JM, Duprat LJ, White MF, et al. Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with type II diabetes: No evidence for a major susceptibility role. Diabetologia.

The road map to cardiovascular

2006;**22**:423-436

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[70] Rajala MW, Scheerer PE. Minireview: The adipocyte-at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology.

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Physiological role of adipose tissue: White adipose tissue as an endocrine and secretory organ. Proceedings

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[67] Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. International Journal of

[68] Ye J, Gao Z, Yin J, He H. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. American Journal of Physiology. Endocrinology and Metabolism.

[69] Trayhurn P, Wang B, Wood SI. Hypoxia in adipose tissue: A basis for the dysregulation of tissue function in obesity? British Journal of Nutrition.

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[80] Michailidou Z, Turban S, Miller E, Zou X, Schrader J, Ratcliffe P, et al. Increased angiogenesis protects against adipose hypoxia and fibrosis in metabolic disease-resistant 11β-hydroxysteroid dehydrogenase type 1 (HSD-1)-deficient mice. Journal of Biological Chemistry. 3 Feb 2012;**287**(6):4188-4197

[81] Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nature Reviews. Drug Discovery. 2010;**9**:107-115

[82] Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: The road map to cardiovascular diseases. Diabetes/Metabolism Reviews. 2006;**22**:423-436

[83] El-Atat FA, Stas SN, Mcfarlane SI, Sowers JR. The relationship between hyperinsulinemia, hypertension and progressive renal disease. Journal of the American Society of Nephrology. 2004;**15**:2816-2827

[84] Kalidas K, Wasson J, Glaser B, Meyer JM, Duprat LJ, White MF, et al. Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with type II diabetes: No evidence for a major susceptibility role. Diabetologia. 1998;**41**:1389-1391

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**111**

**Chapter 7**

**Abstract**

approaches.

**1. Introduction**

the increase in stress [4].

hypertension [5, 6].

Dietary Therapy

*Suzanne Fouad Soliman*

Metabolic Syndrome: Impact of

Metabolic syndrome refers to the coexistence of insulin resistance (IR) with several risk factors, including abdominal obesity, atherogenic dyslipidemia, and hypertension, which is usually complicated by cardiovascular and/or cerebrovascular diseases. This clustering of risk factors suggests that they are interrelated and not independent of one another and that they share underlying mechanisms, mediators, and pathways. Its prevalence exceeds 40% of those over 40, and it has recently been diagnosed in adolescents and even children. Metabolic syndrome is a pro-inflammatory prothrombotic state with determination of elevated level of cytokines, acute phase reactants, fibrinogen, and plasminogen activator inhibitor-1. A comprehensive definition of metabolic syndrome and its pathogenesis would facilitate research into its causes and disease pathophysiology linking the components of metabolic syndrome with the increased risk of cardiovascular diseases. The management to mitigate these underlying risk factors constitutes a first-line intervention; dietary therapy of metabolic syndrome includes lifestyle modification, hypocaloric diet, and consumption of functional food. Healthy food quantity and time of consumption help restore the normal metabolic profiles. Hopefully, this will lead to new insights into facilitating epidemiological and clinical studies of pharmacological, lifestyle, and preventive treatment

**Keywords:** metabolic syndrome, circadian rhythm, insulin resistance, sleep,

The prevalence of metabolic syndrome (MetS) worldwide varies between 10 and 84% depending on the age, gender, and race of the population [1]. The International Diabetes Federation estimates that one-quarter of the world's population has MetS [2]. Although the prevalence of MetS varies throughout the world and depends on the particular health organization used for its definition, it is clear that the number of people complaining about this syndrome has globally risen [3], due to a more sedentary life, the increase in the number of smokers, unhealthy dietary habits, and

MetS is a cluster of metabolic disturbances that tend to coexist. Different health organizations have suggested diverse definitions for MetS. However, it is clear that MetS is a clinical entity of substantial heterogeneity, commonly represented by the combination of central abdominal obesity, hyperglycemia, dyslipidemia, and/or

functional foods, lifestyle modification, hypocaloric diets

#### **Chapter 7**

## Metabolic Syndrome: Impact of Dietary Therapy

*Suzanne Fouad Soliman*

#### **Abstract**

Metabolic syndrome refers to the coexistence of insulin resistance (IR) with several risk factors, including abdominal obesity, atherogenic dyslipidemia, and hypertension, which is usually complicated by cardiovascular and/or cerebrovascular diseases. This clustering of risk factors suggests that they are interrelated and not independent of one another and that they share underlying mechanisms, mediators, and pathways. Its prevalence exceeds 40% of those over 40, and it has recently been diagnosed in adolescents and even children. Metabolic syndrome is a pro-inflammatory prothrombotic state with determination of elevated level of cytokines, acute phase reactants, fibrinogen, and plasminogen activator inhibitor-1. A comprehensive definition of metabolic syndrome and its pathogenesis would facilitate research into its causes and disease pathophysiology linking the components of metabolic syndrome with the increased risk of cardiovascular diseases. The management to mitigate these underlying risk factors constitutes a first-line intervention; dietary therapy of metabolic syndrome includes lifestyle modification, hypocaloric diet, and consumption of functional food. Healthy food quantity and time of consumption help restore the normal metabolic profiles. Hopefully, this will lead to new insights into facilitating epidemiological and clinical studies of pharmacological, lifestyle, and preventive treatment approaches.

**Keywords:** metabolic syndrome, circadian rhythm, insulin resistance, sleep, functional foods, lifestyle modification, hypocaloric diets

#### **1. Introduction**

The prevalence of metabolic syndrome (MetS) worldwide varies between 10 and 84% depending on the age, gender, and race of the population [1]. The International Diabetes Federation estimates that one-quarter of the world's population has MetS [2]. Although the prevalence of MetS varies throughout the world and depends on the particular health organization used for its definition, it is clear that the number of people complaining about this syndrome has globally risen [3], due to a more sedentary life, the increase in the number of smokers, unhealthy dietary habits, and the increase in stress [4].

MetS is a cluster of metabolic disturbances that tend to coexist. Different health organizations have suggested diverse definitions for MetS. However, it is clear that MetS is a clinical entity of substantial heterogeneity, commonly represented by the combination of central abdominal obesity, hyperglycemia, dyslipidemia, and/or hypertension [5, 6].

In 1994, the World Health Organization [7] defined MetS as the presence of one of the following: type II diabetes mellitus, insulin resistance, or impaired glucose tolerance, plus at least two of the following—triglycerides (TG) ≥150 mg/ dL (≥1.7 mmol/L) and/or HDL cholesterol <40 mg/dL (≤0.9 mmol/L) (males) and <50 mg/dL (≤1.0 mmol/L) (females); urine albumin excretion >20 g/min or albumin/creatinine ratio >30 mg/g; systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or a prescription of hypertension; and central obesity, waist circumference (WC) ≥102 cm (males) and ≥ 88 cm (females), waist/hip ratio > 0.90 (males) and >0.85 (females), and/or body mass index (BMI) >30 kg/m2 [8].

The International Diabetes Federation defined MetS as encompassing at least three of the following five conditions: (1) male waist circumference ≥ 94 cm and female waist circumference ≥ 80 cm; (2) fasting glucose level ≥ 100 mg/dL; (3) SBP ≥130 and/or DBP ≥85 mmHg or under medical treatment for hypertension; (4) TG ≥150 mg/dL or ≥ 1.7 mmol/L or prescribed pharmacological treatment for hypertriglyceridemia; or (5) male HDL cholesterol <40 mg/dL and female HDL cholesterol <50 mg/dL [9].

Other markers used for diagnosis of metabolic syndrome include high-sensitivity C-reactive protein concentrations (hs-CRP) ≥3 mg/dL [10], uric acid [11], fibrinogen [12], plasminogen activator inhibitor-1 [13, 14], increased homocysteine [15, 16], and decreased adiponectin [17]. Fibrinogen, plasminogen activator inhibitor-1, cytokines, and hs-CRP protein are often elevated in patients with MetS, resulting in a prothrombotic and pro-inflammatory state. These biomarkers are not routinely evaluated in clinical practice. hs-CRP ≥3 mg/dL indicates a state of inflammation and a higher risk of atherosclerotic cardiovascular disease (ASCVD).

#### **2. Characterization and risk assessment**

MetS is a link between visceral adiposity, insulin resistance, inflammation, and endothelial dysfunctions [18, 19].

#### **2.1 Visceral adiposity**

Visceral adiposity (abdominal fats close to the visceral organs) leads to an imbalance in the secretion of pro-inflammatory and anti-inflammatory factors. Adipocytes produce pro-inflammatory factors in excess, such as IL-6, IL-10, TNF-ɑ, and hs-CRP. These cytokines block the intracellular insulin signaling pathways. Moreover, the adipose tissue inhibits adiponectin [20, 21].

#### **2.2 Insulin resistance**

Insulin resistance (IR) rises with increased waist circumference or body fat and is not related to the body mass index. IR results in the diversion of excess nonestrified fatty acids from lipid-overloaded IR muscles to the hepatic cells, resulting in nonalcoholic fatty liver disease and atherogenic dyslipidemia. IR predisposes to glucose intolerance, which may be aggravated by increased hepatic gluconeogenesis with an IR liver [22].

#### **2.3 Pro-inflammatory condition**

Inflammation is a response of the immune system to injury. It is a mechanism in the pathogenesis and progression of obesity-related medical disorders and the link between adiposity, IR, MetS, and cardiovascular disease [23]. Oxidative stress is a

**113**

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

impairment of HDL-c functions [26].

**2.5 Circadian rhythm disruption**

**2.4 High blood pressure**

diseases [28].

in synchrony [32].

condition in which there is an imbalance between the prooxidants and antioxidants in the body [24]. It plays a key role in the pathogenesis of atherosclerosis through different mechanisms such as the oxidation of LDL-c particles [24, 25] or the

Hypertension is defined as a resting SBP ≥140 mmHg and/or DBP ≥90 mmHg or the use of medical prescription to lower blood pressure [27]. Activation of the sympathetic nervous system together with the activation of the renin-angiotensin system by the hyperglycemia and antinatriuretic effect of insulin, in addition to some obese people being salt sensitive, contributes to the development of hypertension. It is identified as a major cardiovascular and renal risk factor related to heart disease, myocardial infarction, cerebrovascular stroke, and vascular

Over the last two decades, a deeper comprehension of the molecular mechanisms that control the biological clock and circadian rhythm has been achieved. The 2017 Nobel Prize in Physiology was awarded to Jeffrey C. Hall, Michael Rosbash, and Michael Young for their work on circadian rhythms [29, 30]. There are interconnections between the circadian rhythm and endocrine homeostasis. Biological clock disruption was in fact associated to an increased incidence of metabolic and endocrine diseases. Irregular rhythms have been linked to various chronic health conditions, such as sleep disorders, obesity, type II diabetes mellitus, hypertension, gastrointestinal motility diseases, depression, cardiac diseases, cognitive dysfunction, bipolar disorder, and seasonal affective disorder [31]. The master clock in mammals that controls circadian rhythms consists of a group of nerve cells in the brain called the suprachiasmatic nucleus (SCN) which contains about 20,000 nerve cells. It is located in the hypothalamus superior to the optic chiasm and receives direct light information from the retina via the retinohypothalamic tract. The master clock in the brain coordinates all of the body's peripheral clocks through different neural and humoral signals, so they are

The nonstop 24/7 lifestyle has given rise to human clock gene mutation, for which the human biological clock does not have a suitable design for physiological adaptation; this leads to an imbalance of autonomic nervous system function toward the parasympathetic predominance in the abdominal compartment and the sympathetic predominance in the muscular and thoracic compartments, resulting in the impairment of insulin secretion, glucose uptake by the muscle, and increase

The timing and nutritional composition of meals can regulate circadian rhythms, particularly in the peripheral tissue. The translation of these findings to human physiology now represents an important goal. In healthy humans, glucose tolerance lowers throughout the day, leading to the term "afternoon diabetes"; a daily rhythm in pancreatic insulin production is observed, with increased insulin production in the morning compared to the evening. Moreover, lipid metabolism exhibits circadian regulation, with elevated plasma concentrations of triacylglycerol during the biological night and an elevated postprandial response following a nighttime meal compared with the same meal consumed during the day [34]. In 2006, Staels stated "When the clock stops ticking, metabolic syndrome explodes"

in blood pressure, intra-abdominal fat, and fatty liver [33].

[35]. When to eat is as important as what to eat.

condition in which there is an imbalance between the prooxidants and antioxidants in the body [24]. It plays a key role in the pathogenesis of atherosclerosis through different mechanisms such as the oxidation of LDL-c particles [24, 25] or the impairment of HDL-c functions [26].

#### **2.4 High blood pressure**

*Cellular Metabolism and Related Disorders*

**2. Characterization and risk assessment**

Moreover, the adipose tissue inhibits adiponectin [20, 21].

endothelial dysfunctions [18, 19].

**2.1 Visceral adiposity**

**2.2 Insulin resistance**

with an IR liver [22].

**2.3 Pro-inflammatory condition**

<50 mg/dL [9].

In 1994, the World Health Organization [7] defined MetS as the presence of one of the following: type II diabetes mellitus, insulin resistance, or impaired glucose tolerance, plus at least two of the following—triglycerides (TG) ≥150 mg/ dL (≥1.7 mmol/L) and/or HDL cholesterol <40 mg/dL (≤0.9 mmol/L) (males) and <50 mg/dL (≤1.0 mmol/L) (females); urine albumin excretion >20 g/min or albumin/creatinine ratio >30 mg/g; systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or a prescription of hypertension; and central obesity, waist circumference (WC) ≥102 cm (males) and ≥ 88 cm (females), waist/hip ratio > 0.90

The International Diabetes Federation defined MetS as encompassing at least three of the following five conditions: (1) male waist circumference ≥ 94 cm and female waist circumference ≥ 80 cm; (2) fasting glucose level ≥ 100 mg/dL; (3) SBP ≥130 and/or DBP ≥85 mmHg or under medical treatment for hypertension; (4) TG ≥150 mg/dL or ≥ 1.7 mmol/L or prescribed pharmacological treatment for hypertriglyceridemia; or (5) male HDL cholesterol <40 mg/dL and female HDL cholesterol

Other markers used for diagnosis of metabolic syndrome include high-sensitivity C-reactive protein concentrations (hs-CRP) ≥3 mg/dL [10], uric acid [11], fibrinogen [12], plasminogen activator inhibitor-1 [13, 14], increased homocysteine [15, 16], and decreased adiponectin [17]. Fibrinogen, plasminogen activator inhibitor-1, cytokines, and hs-CRP protein are often elevated in patients with MetS, resulting in a prothrombotic and pro-inflammatory state. These biomarkers are not routinely evaluated in clinical practice. hs-CRP ≥3 mg/dL indicates a state of inflammation and a higher risk of atherosclerotic cardiovascular disease (ASCVD).

MetS is a link between visceral adiposity, insulin resistance, inflammation, and

Visceral adiposity (abdominal fats close to the visceral organs) leads to an imbalance in the secretion of pro-inflammatory and anti-inflammatory factors. Adipocytes produce pro-inflammatory factors in excess, such as IL-6, IL-10, TNF-ɑ, and hs-CRP. These cytokines block the intracellular insulin signaling pathways.

Insulin resistance (IR) rises with increased waist circumference or body fat and

Inflammation is a response of the immune system to injury. It is a mechanism in the pathogenesis and progression of obesity-related medical disorders and the link between adiposity, IR, MetS, and cardiovascular disease [23]. Oxidative stress is a

is not related to the body mass index. IR results in the diversion of excess nonestrified fatty acids from lipid-overloaded IR muscles to the hepatic cells, resulting in nonalcoholic fatty liver disease and atherogenic dyslipidemia. IR predisposes to glucose intolerance, which may be aggravated by increased hepatic gluconeogenesis

[8].

(males) and >0.85 (females), and/or body mass index (BMI) >30 kg/m2

**112**

Hypertension is defined as a resting SBP ≥140 mmHg and/or DBP ≥90 mmHg or the use of medical prescription to lower blood pressure [27]. Activation of the sympathetic nervous system together with the activation of the renin-angiotensin system by the hyperglycemia and antinatriuretic effect of insulin, in addition to some obese people being salt sensitive, contributes to the development of hypertension. It is identified as a major cardiovascular and renal risk factor related to heart disease, myocardial infarction, cerebrovascular stroke, and vascular diseases [28].

#### **2.5 Circadian rhythm disruption**

Over the last two decades, a deeper comprehension of the molecular mechanisms that control the biological clock and circadian rhythm has been achieved. The 2017 Nobel Prize in Physiology was awarded to Jeffrey C. Hall, Michael Rosbash, and Michael Young for their work on circadian rhythms [29, 30]. There are interconnections between the circadian rhythm and endocrine homeostasis. Biological clock disruption was in fact associated to an increased incidence of metabolic and endocrine diseases. Irregular rhythms have been linked to various chronic health conditions, such as sleep disorders, obesity, type II diabetes mellitus, hypertension, gastrointestinal motility diseases, depression, cardiac diseases, cognitive dysfunction, bipolar disorder, and seasonal affective disorder [31]. The master clock in mammals that controls circadian rhythms consists of a group of nerve cells in the brain called the suprachiasmatic nucleus (SCN) which contains about 20,000 nerve cells. It is located in the hypothalamus superior to the optic chiasm and receives direct light information from the retina via the retinohypothalamic tract. The master clock in the brain coordinates all of the body's peripheral clocks through different neural and humoral signals, so they are in synchrony [32].

The nonstop 24/7 lifestyle has given rise to human clock gene mutation, for which the human biological clock does not have a suitable design for physiological adaptation; this leads to an imbalance of autonomic nervous system function toward the parasympathetic predominance in the abdominal compartment and the sympathetic predominance in the muscular and thoracic compartments, resulting in the impairment of insulin secretion, glucose uptake by the muscle, and increase in blood pressure, intra-abdominal fat, and fatty liver [33].

The timing and nutritional composition of meals can regulate circadian rhythms, particularly in the peripheral tissue. The translation of these findings to human physiology now represents an important goal. In healthy humans, glucose tolerance lowers throughout the day, leading to the term "afternoon diabetes"; a daily rhythm in pancreatic insulin production is observed, with increased insulin production in the morning compared to the evening. Moreover, lipid metabolism exhibits circadian regulation, with elevated plasma concentrations of triacylglycerol during the biological night and an elevated postprandial response following a nighttime meal compared with the same meal consumed during the day [34]. In 2006, Staels stated "When the clock stops ticking, metabolic syndrome explodes" [35]. When to eat is as important as what to eat.

#### *2.5.1 Sleep in relation to melatonin and growth hormone secretions*

Melatonin is synthesized by multiple tissues in the body, but the pineal gland is the major contributor to circulating melatonin concentration. The rhythmic activity of the SCN determines the release of melatonin, which directly correlates with day length, and it may in turn modulate other physiological functions through paracrine signaling. Pancreatic hormone insulin, gastric hormone ghrelin, growth hormone (GH) from the pituitary gland, and leptin hormone represent as key factors in metabolic regulation, and now several circadian factors are recognized as regulators of their secretion and activity. Sleep deprivation results in circadian misalignment and increases markers of inflammation and IR. A better understanding of such relationships might prove useful and supportive in designing new therapeutic approaches for metabolic syndrome [36].

Growth hormone is a peptide hormone secreted by the anterior pituitary under control of the hypothalamic-pituitary axis. Actions of GH depend on the age of the individual. The primary role of GH in children and adolescents is to promote growth until the final adult height is achieved, while in adults, the role of GH is the regulation of protein, carbohydrate, and lipid metabolism, insulin resistance, and metabolic homeostasis. Sleep restriction and disturbance have also been shown to negatively impact hormone secretion. In sleep deprivation cases, GH secretion decreases, the appetite-suppressing hormone leptin decreases, and the appetitestimulating hormone ghrelin increases. The end result is the consumption of additional food and calories. Plasma GH peak appeared with the onset of deep sleep and did not correlate with the changes in plasma glucose and insulin. GH secretion decreased if the onset of sleep was delayed [37].

#### **2.6 Risk assessment**

Metabolic syndrome directly promotes the development of atherosclerotic cardiovascular disease (ASCVD) [38] and type II diabetes mellitus [39]. Atherogenic dyslipidemia, high circulating levels of prothrombotic factors, and the increase of inflammatory markers carry a higher risk for acute cardiovascular syndromes [40]. Previous studies on middle-aged persons with metabolic syndrome had concluded that many middle-aged people are at increased absolute risk for cardiovascular diseases in the 10-year risk. Furthermore, in young adults who develop the syndrome, long-term risk for ASCVD is increased even when the 10-year risk is not high. The Framingham risk scoring is used to classify metabolic syndrome patients into three risk categories based on a 10-year risk for coronary heart disease, cerebrovascular disease, peripheral artery disease, and heart failure risk: *low-risk* (10-year risk <10%), *moderate-risk* (10-year risk 10–20%), and *high-risk patients* (10-year risk >20%) [41, 42].

#### **3. Metabolic syndrome, mental and cognitive functions**

Obesity and dementia frequently coexist. They share many common pathways such as insulin resistance as well as inflammation and oxidative stress. Midlife obesity is directly related to the risk of developing dementia later in life. Dementia is a syndrome characterized by gradual decline in cognitive functions (memory, attention, behavior, language, mood, and learning). In 2008, Dr. Suzanne de la Monte and Dr. Jack Wands proposed that Alzheimer's disease could be termed type III diabetes, based on the fact that IR within the brain revealed to be a characteristic of Alzheimer's disease [43]. There is no definite cure for dementia, and prevention

**115**

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

**3.1 Cognitive and mental evaluations**

and history of exercising were recorded.

diabetic patients using exogenous insulin [46]:

future.

is the only option. Prevention may be achieved by early treatment of the risk factors resulting in cognitive impairments (obesity, DM, HTN, smoking, dyslipidemia, anxiety, and depression). Several biomarkers could be involved in the pathogenesis of mild cognitive impairment or early neurodegenerative diseases. Assessment of these biomarkers in obese middle-aged persons could serve as a basis for early management to alleviate the burden of cognitive impairment and dementia in the

The Mini-Mental State Examination (MMSE) was performed for clinical evaluation of mental and cognitive status. The 30-point questionnaires take between 5 and 10 minutes and examination functions including registration, attention, calculation, recall, language, commands, and orientation [44]. It is a sensitive, valid, and reliable method that is used extensively in clinical and research settings to measure cognitive impairment and to estimate the severity and progression of cognitive impairment. It is also used to follow the course of cognitive changes in an individual over time, thus making it an effective way to document an individual's response to treatment. Sleep quality and the number of sleep hours and their pattern were evaluated. Exposure to sun and length of time, duration, and clothing were recorded. General subjective life stresses, life pattern to evaluate general activity,

C-peptide was detected by C-peptide enzyme immunoassay [45]. Modified homeostatic model assessment of insulin resistance (M.HOMA-IR) was calculated by Eq. (1), in which insulin was replaced by C-peptide so as to be applied on

M.HOMA − IR = 1.5 + Fasting blood glucose × Fasting c − peptide/2800 (1)

Ceramides are agents involved in the pathogenesis of mild cognitive impairment or early neurodegenerative diseases. They are mediated by insulin resistance and inflammatory states. Ceramides are lipid soluble and therefore likely to readily cross the blood-brain barrier resulting in cytotoxic effects in the central nervous system with various dementia-associated diseases, including Alzheimer's disease. It is important to prevent its elevation in the human body via increasing the activity of the ceramide kinase enzyme (CERK enzyme) that converts the ceramide to ceramide-1-phosphate (C1P) via its phosphorylation. C1P is a sphingolipid metabolite that has been implicated in the membrane fusion of brain synaptic vesicles and neutrophil phagolysosome formation. C1P is a key regulator of cell growth and survival, it stimulates DNA synthesis and cell division, and it is a potent inhibitor of apoptosis. Many studies have shown that C1P is important for membrane biology and for the regulation of membrane-bound proteins and the CERK enzyme has appeared to be tightly regulated in order to control both ceramide levels and production of C1P [47]. Improvement of the metabolic profiles including C-peptide concentration and the M.HOMA-IR values was associated with the improvement of

Blood sampling and biochemical markers of cognitive function impairments were performed as ceramide kinase enzyme, alpha-synuclein, serum clusterin,

amyloid beta, and inflammatory markers (hs-CRP, IL-6, and TNF-α).

the serum level of the enzyme CERK and of cognitive functions [48].

Alpha-synuclein (α-Syn) protein was originally isolated from Alzheimer's disease plaques and was thought to be a presynaptic nerve terminal protein. The α-Syn is a member of the synuclein's family of cytoplasmic, predominantly neuronspecific proteins. Synucleins are small, prone to aggregate proteins associated

*Cellular Metabolism and Related Disorders*

approaches for metabolic syndrome [36].

decreased if the onset of sleep was delayed [37].

**3. Metabolic syndrome, mental and cognitive functions**

**2.6 Risk assessment**

>20%) [41, 42].

*2.5.1 Sleep in relation to melatonin and growth hormone secretions*

Melatonin is synthesized by multiple tissues in the body, but the pineal gland is the major contributor to circulating melatonin concentration. The rhythmic activity of the SCN determines the release of melatonin, which directly correlates with day length, and it may in turn modulate other physiological functions through paracrine signaling. Pancreatic hormone insulin, gastric hormone ghrelin, growth hormone (GH) from the pituitary gland, and leptin hormone represent as key factors in metabolic regulation, and now several circadian factors are recognized as regulators of their secretion and activity. Sleep deprivation results in circadian misalignment and increases markers of inflammation and IR. A better understanding of such relationships might prove useful and supportive in designing new therapeutic

Growth hormone is a peptide hormone secreted by the anterior pituitary under control of the hypothalamic-pituitary axis. Actions of GH depend on the age of the individual. The primary role of GH in children and adolescents is to promote growth until the final adult height is achieved, while in adults, the role of GH is the regulation of protein, carbohydrate, and lipid metabolism, insulin resistance, and metabolic homeostasis. Sleep restriction and disturbance have also been shown to negatively impact hormone secretion. In sleep deprivation cases, GH secretion decreases, the appetite-suppressing hormone leptin decreases, and the appetitestimulating hormone ghrelin increases. The end result is the consumption of additional food and calories. Plasma GH peak appeared with the onset of deep sleep and did not correlate with the changes in plasma glucose and insulin. GH secretion

Metabolic syndrome directly promotes the development of atherosclerotic cardiovascular disease (ASCVD) [38] and type II diabetes mellitus [39]. Atherogenic dyslipidemia, high circulating levels of prothrombotic factors, and the increase of inflammatory markers carry a higher risk for acute cardiovascular syndromes [40]. Previous studies on middle-aged persons with metabolic syndrome had concluded that many middle-aged people are at increased absolute risk for cardiovascular diseases in the 10-year risk. Furthermore, in young adults who develop the syndrome, long-term risk for ASCVD is increased even when the 10-year risk is not high. The Framingham risk scoring is used to classify metabolic syndrome patients into three risk categories based on a 10-year risk for coronary heart disease, cerebrovascular disease, peripheral artery disease, and heart failure risk: *low-risk* (10-year risk <10%), *moderate-risk* (10-year risk 10–20%), and *high-risk patients* (10-year risk

Obesity and dementia frequently coexist. They share many common pathways such as insulin resistance as well as inflammation and oxidative stress. Midlife obesity is directly related to the risk of developing dementia later in life. Dementia is a syndrome characterized by gradual decline in cognitive functions (memory, attention, behavior, language, mood, and learning). In 2008, Dr. Suzanne de la Monte and Dr. Jack Wands proposed that Alzheimer's disease could be termed type III diabetes, based on the fact that IR within the brain revealed to be a characteristic of Alzheimer's disease [43]. There is no definite cure for dementia, and prevention

**114**

is the only option. Prevention may be achieved by early treatment of the risk factors resulting in cognitive impairments (obesity, DM, HTN, smoking, dyslipidemia, anxiety, and depression). Several biomarkers could be involved in the pathogenesis of mild cognitive impairment or early neurodegenerative diseases. Assessment of these biomarkers in obese middle-aged persons could serve as a basis for early management to alleviate the burden of cognitive impairment and dementia in the future.

#### **3.1 Cognitive and mental evaluations**

The Mini-Mental State Examination (MMSE) was performed for clinical evaluation of mental and cognitive status. The 30-point questionnaires take between 5 and 10 minutes and examination functions including registration, attention, calculation, recall, language, commands, and orientation [44]. It is a sensitive, valid, and reliable method that is used extensively in clinical and research settings to measure cognitive impairment and to estimate the severity and progression of cognitive impairment. It is also used to follow the course of cognitive changes in an individual over time, thus making it an effective way to document an individual's response to treatment. Sleep quality and the number of sleep hours and their pattern were evaluated. Exposure to sun and length of time, duration, and clothing were recorded. General subjective life stresses, life pattern to evaluate general activity, and history of exercising were recorded.

C-peptide was detected by C-peptide enzyme immunoassay [45]. Modified homeostatic model assessment of insulin resistance (M.HOMA-IR) was calculated by Eq. (1), in which insulin was replaced by C-peptide so as to be applied on diabetic patients using exogenous insulin [46]:

M.HOMA − IR = 1.5 + Fasting blood glucose × Fasting c − peptide/2800 (1)

Blood sampling and biochemical markers of cognitive function impairments were performed as ceramide kinase enzyme, alpha-synuclein, serum clusterin, amyloid beta, and inflammatory markers (hs-CRP, IL-6, and TNF-α).

Ceramides are agents involved in the pathogenesis of mild cognitive impairment or early neurodegenerative diseases. They are mediated by insulin resistance and inflammatory states. Ceramides are lipid soluble and therefore likely to readily cross the blood-brain barrier resulting in cytotoxic effects in the central nervous system with various dementia-associated diseases, including Alzheimer's disease. It is important to prevent its elevation in the human body via increasing the activity of the ceramide kinase enzyme (CERK enzyme) that converts the ceramide to ceramide-1-phosphate (C1P) via its phosphorylation. C1P is a sphingolipid metabolite that has been implicated in the membrane fusion of brain synaptic vesicles and neutrophil phagolysosome formation. C1P is a key regulator of cell growth and survival, it stimulates DNA synthesis and cell division, and it is a potent inhibitor of apoptosis. Many studies have shown that C1P is important for membrane biology and for the regulation of membrane-bound proteins and the CERK enzyme has appeared to be tightly regulated in order to control both ceramide levels and production of C1P [47]. Improvement of the metabolic profiles including C-peptide concentration and the M.HOMA-IR values was associated with the improvement of the serum level of the enzyme CERK and of cognitive functions [48].

Alpha-synuclein (α-Syn) protein was originally isolated from Alzheimer's disease plaques and was thought to be a presynaptic nerve terminal protein. The α-Syn is a member of the synuclein's family of cytoplasmic, predominantly neuronspecific proteins. Synucleins are small, prone to aggregate proteins associated

with several neurodegenerative diseases. The α-Syn has been found in body fluids, including blood and cerebrospinal fluid, peripheral tissues, and the central nervous system. Previous reports suggest that α-Syn is widely expressed peripherally, including the macrophages. The expression of α-Syn is enhanced in activated macrophages, suggesting that α-Syn may modulate macrophage function and thereby inflammatory processes. Diet-induced obesity may be an environmental risk factor for the development alpha-synucleinopathies [49]. There was a significant positive correlation between serum IL-6 and serum α-Syn. Fighting obesity, dyslipidemia, and the associated complications especially the inflammatory processes improved the deleterious effects on the cognitive functions in obese persons [50].

Clusterin (apolipoprotein J) is a heterodimeric glycoprotein in which α and β chains are interconnected via five disulfide bonds. There is a strong association between the single-nucleotide polymorphisms in the clusterin gene and Alzheimer's disease. Moreover, plasma clusterin is considered a potential peripheral biomarker of cognitive dysfunction and AD. Clusterin may be related to AD pathogenesis through various mechanisms. It could bind amyloid extracellularly and inhibit the aggregation of amyloid beta monomers into toxic oligomers. In addition, the neurotoxicity of the amyloid might be reduced by the interaction of clusterin with the molecules involved in signal transduction, DNA repair, cell cycle, and apoptosis. Brain apolipoprotein clusterin plays an important role in cholesterol transport and neuronal lipid metabolism. Furthermore, it has a role in the inhibition of neuroinflammation which is thought to be a major factor in AD pathogenesis and identified as a key component in cerebrovascular diseases. In addition, it is known that neuroinflammation plays an important role in dementia pathogenesis and neurodegenerative diseases [51, 52]. The improvement of the C-peptide concentration and the M.HOMA values were parallel with improvement of oral cognitive tests and clusterin value; clusterin was presented as a cognitive function parameter [52].

Plasma amyloid beta (Aβ) can be applied as trait, risk, or state biomarker for AD and denote a neuropathologic condition. A previous study has reported the presence of a stronger correlation between plasma Aβ and positron emission tomography or Pittsburgh Compound-B-C11 as radiotracers illustrate fibrillar brain amyloid deposits which is a reliable method to measure brain amyloid plaque accumulation. Reduction of body weight and improving the metabolic profile reduced the level of serum Aβ protein, an effective role in improving the cognitive function. At the same time, previous studies stated that plasma Aβ measures possibly aid in clinical investigations as markers for the pharmacological impacts of medications that influence amyloid protein transformation [53].

Serum hs-CRP level may be used as a marker for cognitive functions in obese middle-aged persons. Peripheral inflammatory markers are elevated in obese patients. Improvement in cognitive functions is recorded after dietary therapy, with decrease in hs-CRP serum levels. Significant inverse correlation is found between cognitive functions and hs-CRP levels, insulin resistance, minimal waist circumference, and BMI [54].

#### **4. Management of metabolic syndrome**

As the presence of MetS carries a risk for cardiovascular diseases and diabetes mellitus, the primary goal of clinical management to individuals with metabolic syndrome is directed towards decreasing the major metabolic risk factors: high LDL-C, hypertension, obesity by losing fat percentage and not muscle mass, decreasing insulin resistance, blood glucose, and maintaining normal HDL and

**117**

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

studied and encouraged [55, 56].

**4.1 Therapeutic lifestyle modifications**

body [57].

water is the best [7].

**4.2 Energy-restricted diets**

triglyceride levels through lifestyle changes. Moreover, medical drug therapy might be considered in high-risk patients to modify cardiovascular disease risk factors [7]. Bariatric surgery has been indicated to treat morbidly obese persons. The safety and effectiveness of bariatric surgery in patients with metabolic syndrome have been

Chronotherapy means the timing of drug and dietary treatment to obtain maximum therapeutic effect. It can be achieved through the timing of light exposure, exercise, food consumption, medication uptake, and sleep, with the goal of optimizing any treatment by taking into account the circadian rhythms of the

Physical exercise, diet, and adequate sleep are the way to reach the target. Gradual permanent change in the patient's lifestyle can lead to better and easily maintain normal parameters than major food deprivation introduced all at once. Implementing the following changes increases the chances of success: changing a sedentary life through regular sustained physical exercise and eating several small portions of different foods varieties; consuming complex carbohydrates such as barley, oat, corn, quinoa, and brown rice while decreasing the consumption of simple carbohydrates such as white sugar and sweets; eating fresh seasonal fruit and vegetables daily as they are good sources of fiber, vitamins, and minerals noting that dietary fiber helps prevent gastrointestinal problems such as flatulence and constipation; eating foods rich in unsaturated fatty acids such as salmon, mackerel, sardines, tuna, raw nuts, and flaxseed oil; increasing the consumption of black beans, kidney beans, green peas, and lentils; avoiding processed and red meats; limiting the intake of sugar, salt, and carbonated drinks; replacing salt with spices; boiling, baking, or steaming food instead of frying; paying attention to portion size by utilizing smaller plates; and drinking plenty of fluids, of which 30 ml/kg/day

Avoid light exposure in late evening or at night as artificial light disrupts the circadian rhythm and the production of melatonin and therefore has a negative effect on sleep quality, mood, cognition, and hormonal functions [58, 59]. Sleep early and

For our patients, the Harris-Benedict equation (Eq. (2)) was used to calculate the caloric requirements for each individual in order to estimate the caloric needs or

 Males: BEE = 66.5 + 13.8 (weight in Kg) + 5 (height in cm)–6.8 (age). Females: BEE = 65.5 + 9.6 (weight in Kg) + 1.7 (height in cm)–4.7 (age).

by various activities and/or stress factors to generate the patient's estimated resting energy expenditure, and then we subtracted 500 calories per week from the calculated energy requirement, to produce weight loss of 0.5–1 kg per week. A hypocaloric diet goal is to reduce body weight by about 10% over the first 6 months. The menu varied according to the participant's age and eating habits. It was low in fat (20–25%), high in complex carbohydrate (50–60%), and sufficient in protein (25–30%) from both animal and vegetarian sources [54]. Carbohydrates in the

These equations yield basal energy expenditure that is frequently multiplied

(2)

get at least 6 hours of sleep per night [60], and stop smoking.

basal energy expenditure (BEE) as follows [61]:

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

*Cellular Metabolism and Related Disorders*

function parameter [52].

ence, and BMI [54].

influence amyloid protein transformation [53].

**4. Management of metabolic syndrome**

with several neurodegenerative diseases. The α-Syn has been found in body fluids, including blood and cerebrospinal fluid, peripheral tissues, and the central nervous system. Previous reports suggest that α-Syn is widely expressed peripherally, including the macrophages. The expression of α-Syn is enhanced in activated macrophages, suggesting that α-Syn may modulate macrophage function and thereby inflammatory processes. Diet-induced obesity may be an environmental risk factor for the development alpha-synucleinopathies [49]. There was a significant positive correlation between serum IL-6 and serum α-Syn. Fighting obesity, dyslipidemia, and the associated complications especially the inflammatory processes improved

Clusterin (apolipoprotein J) is a heterodimeric glycoprotein in which α and β chains are interconnected via five disulfide bonds. There is a strong association between the single-nucleotide polymorphisms in the clusterin gene and Alzheimer's disease. Moreover, plasma clusterin is considered a potential peripheral biomarker of cognitive dysfunction and AD. Clusterin may be related to AD pathogenesis through various mechanisms. It could bind amyloid extracellularly and inhibit the aggregation of amyloid beta monomers into toxic oligomers. In addition, the neurotoxicity of the amyloid might be reduced by the interaction of clusterin with the molecules involved in signal transduction, DNA repair, cell cycle, and apoptosis. Brain apolipoprotein clusterin plays an important role in cholesterol transport and neuronal lipid metabolism. Furthermore, it has a role in the inhibition of neuroinflammation which is thought to be a major factor in AD pathogenesis and identified as a key component in cerebrovascular diseases. In addition, it is known that neuroinflammation plays an important role in dementia pathogenesis and neurodegenerative diseases [51, 52]. The improvement of the C-peptide concentration and the M.HOMA values were parallel with improvement of oral cognitive tests and clusterin value; clusterin was presented as a cognitive

Plasma amyloid beta (Aβ) can be applied as trait, risk, or state biomarker for AD and denote a neuropathologic condition. A previous study has reported the presence of a stronger correlation between plasma Aβ and positron emission tomography or Pittsburgh Compound-B-C11 as radiotracers illustrate fibrillar brain amyloid deposits which is a reliable method to measure brain amyloid plaque accumulation. Reduction of body weight and improving the metabolic profile reduced the level of serum Aβ protein, an effective role in improving the cognitive function. At the same time, previous studies stated that plasma Aβ measures possibly aid in clinical investigations as markers for the pharmacological impacts of medications that

Serum hs-CRP level may be used as a marker for cognitive functions in obese middle-aged persons. Peripheral inflammatory markers are elevated in obese patients. Improvement in cognitive functions is recorded after dietary therapy, with decrease in hs-CRP serum levels. Significant inverse correlation is found between cognitive functions and hs-CRP levels, insulin resistance, minimal waist circumfer-

As the presence of MetS carries a risk for cardiovascular diseases and diabetes mellitus, the primary goal of clinical management to individuals with metabolic syndrome is directed towards decreasing the major metabolic risk factors: high LDL-C, hypertension, obesity by losing fat percentage and not muscle mass, decreasing insulin resistance, blood glucose, and maintaining normal HDL and

the deleterious effects on the cognitive functions in obese persons [50].

**116**

triglyceride levels through lifestyle changes. Moreover, medical drug therapy might be considered in high-risk patients to modify cardiovascular disease risk factors [7]. Bariatric surgery has been indicated to treat morbidly obese persons. The safety and effectiveness of bariatric surgery in patients with metabolic syndrome have been studied and encouraged [55, 56].

Chronotherapy means the timing of drug and dietary treatment to obtain maximum therapeutic effect. It can be achieved through the timing of light exposure, exercise, food consumption, medication uptake, and sleep, with the goal of optimizing any treatment by taking into account the circadian rhythms of the body [57].

#### **4.1 Therapeutic lifestyle modifications**

Physical exercise, diet, and adequate sleep are the way to reach the target. Gradual permanent change in the patient's lifestyle can lead to better and easily maintain normal parameters than major food deprivation introduced all at once. Implementing the following changes increases the chances of success: changing a sedentary life through regular sustained physical exercise and eating several small portions of different foods varieties; consuming complex carbohydrates such as barley, oat, corn, quinoa, and brown rice while decreasing the consumption of simple carbohydrates such as white sugar and sweets; eating fresh seasonal fruit and vegetables daily as they are good sources of fiber, vitamins, and minerals noting that dietary fiber helps prevent gastrointestinal problems such as flatulence and constipation; eating foods rich in unsaturated fatty acids such as salmon, mackerel, sardines, tuna, raw nuts, and flaxseed oil; increasing the consumption of black beans, kidney beans, green peas, and lentils; avoiding processed and red meats; limiting the intake of sugar, salt, and carbonated drinks; replacing salt with spices; boiling, baking, or steaming food instead of frying; paying attention to portion size by utilizing smaller plates; and drinking plenty of fluids, of which 30 ml/kg/day water is the best [7].

Avoid light exposure in late evening or at night as artificial light disrupts the circadian rhythm and the production of melatonin and therefore has a negative effect on sleep quality, mood, cognition, and hormonal functions [58, 59]. Sleep early and get at least 6 hours of sleep per night [60], and stop smoking.

#### **4.2 Energy-restricted diets**

For our patients, the Harris-Benedict equation (Eq. (2)) was used to calculate the caloric requirements for each individual in order to estimate the caloric needs or basal energy expenditure (BEE) as follows [61]:

 Males: BEE = 66.5 + 13.8 (weight in Kg) + 5 (height in cm)–6.8 (age). Females: BEE = 65.5 + 9.6 (weight in Kg) + 1.7 (height in cm)–4.7 (age). (2)

These equations yield basal energy expenditure that is frequently multiplied by various activities and/or stress factors to generate the patient's estimated resting energy expenditure, and then we subtracted 500 calories per week from the calculated energy requirement, to produce weight loss of 0.5–1 kg per week. A hypocaloric diet goal is to reduce body weight by about 10% over the first 6 months. The menu varied according to the participant's age and eating habits. It was low in fat (20–25%), high in complex carbohydrate (50–60%), and sufficient in protein (25–30%) from both animal and vegetarian sources [54]. Carbohydrates in the

form of complex CHO, which have low glycemic loads and indexes such as whole grains, oats, fresh seasonal fruits, and vegetables, were consumed to increase high fiber content (eight servings of fresh vegetables and fruits/day). On the other hand, they were instructed to decrease foods rich in saturated fats such as fried foods and packaged meats [62].

#### **4.3 The Mediterranean diet**

The Mediterranean diet (MedDiet) is based on scientific evidence that inhabitants of Mediterranean countries (Greece, Italy, and Spain), around the Mediterranean Sea adhering to the principles of nutrition traditional for their region, have better health indicators than people in other areas. Originally, it was developed to prevent and treat the symptoms of hypertension and/or heart disease. In this MedDiet, the emphasis is on the use of plant-based foods as the main source of nourishment: fruits, vegetables, cereals, nuts, legumes, seeds, and whole grains. It is also recommended to replace butter and hydrogenated fats with extra-virgin olive oil and salts with spices and herbs. Red meat and sweets should be eaten once a week, and the main sources of protein should be eggs, yoghurt, fish, and poultry. Red wine could be taken in limited amounts (one glass per day for women; two glasses per day for men) [63–65].

#### **4.4 Role of functional foods**

There is no universal definition for functional foods, but the easiest one is from the International Food Information Council which described functional foods as "dietary or food components that provide a health benefit beyond providing basic nutrition" [55]. Functional foods have an important role in the management of metabolic syndrome. Functional foods can help in weight loss, regulation of blood pressure, and control of blood glucose and lipid profile levels. Previous studies supported the beneficial effects of using functional foods containing bioactive components in the management of metabolic syndrome. This includes the intake of foods which have a thermogenesis effect (process in which body heat production increases, e.g., ginger, caffeine, red pepper, and green tea); functional foods with anti-inflammatory properties such as curcumin; and foods with the ability to increase insulin sensitivity, e.g., cinnamon, and increase intake of foods rich in plant estrogens such as soymilk, soybeans, flaxseed, sesame, green beans, fennel, peanut, and pumpkin seeds. In addition, soy products are rich in amino acids and can preserve lean body mass, decrease body fat percentage, and increase basal metabolic rate [48, 50, 53, 66–70].

#### *4.4.1 Functional food classification*


**119**

**5. Conclusion**

**Financial support**

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

The use of functional and prepared designed food would help fight MetS. Three thousand years ago, Hippocrates announced the tenet "Let food be thy medicine and medicine be thy food." Dietary supplements proved to improve the MetS criteria which include Syrian bread prepared mainly from barley flour and wheat germ mixed with either turmeric or ginger; doum biscuits; barley biscuits; bread prepared with soybean flour and enriched with curcumin or ginger; and cookies prepared with whole wheat flour and fennel or chia seeds. The higher fiber content of these products has a satiety effect so as to decrease food consumption. Moreover, fibers decrease digestion and absorption of dietary carbohydrates. Soy flour is a very rich source of essential amino acids except methionine. Preparation of bakery products using bioactive ingredients has positive beneficial effects for obesity, diabetes, and dyslipidemia management. These compounds have different benefits such as anti-atherogenic, antioxidant, and anti-inflammatory effects [48, 50, 53, 67–70].

There are no specific recommendations regarding the pharmacological management of metabolic syndrome; instead, the focus is on the management of the risk factors which need to be aggressively treated in order to prevent cardiovascular disease and type II diabetes mellitus if lifestyle changes aren't enough to reduce the risks. The available evidence of the pharmacological prescriptions is related to their cardiovascular benefits in clinical practice. Pharmacological treatments include statins and/or fibrates for dyslipidemia, angiotensin-converting enzyme inhibitors or renin-angiotensin-aldosterone system inhibitors for hypertension, metformin or sodium/glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1RAs) for glucose intolerance, and low-dose aspirin for prevention of arterial thrombosis [73]. Melatonin provides an innovative approach in the management of MetS through its useful effects on circadian rhythmicity, insulin resistance, dyslipidemia, high blood pressure, weight loss, and improving the antioxidative status (melatonin tablet 1 mg/kg) [74, 75]. Melatonin reduces the toxicity of many

Prevention is the best form of treatment of metabolic syndrome, and it starts from childhood by following a healthy lifestyle based on proper nutrition, exercise, and adequate early night sleep. Timing of food consumption, food quality, food quantity, light exposure, medication intake, and sleep are likely to play an important role in human health. Eat small portion sizes of food, and follow the rhythm of the day to maintain the synchronicity of the biological clock. Consuming natural effective supplements rich in bioactive substances leads toward the optimization of biochemical parameters of patients with metabolic syndrome in favor of a healthy outcome. Bariatric surgery should be considered in individuals with morbid obesity

The practical part of the work was financially supported by the National

Research Centre, Egypt, but no fund supports for publication fees.

*4.4.2 Eat to beat metabolic syndrome*

**4.5 Pharmacological management**

pharmaceutical agents and has a high safety profile [76].

or obesity associated with comorbidity.

• Fermented products rich in probiotics or synbiotics [72]

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

#### *4.4.2 Eat to beat metabolic syndrome*

*Cellular Metabolism and Related Disorders*

packaged meats [62].

**4.3 The Mediterranean diet**

glasses per day for men) [63–65].

**4.4 Role of functional foods**

rate [48, 50, 53, 66–70].

*4.4.1 Functional food classification*

*sativum*), and fish (omega 3 fatty acids) [71]

• Fermented products rich in probiotics or synbiotics [72]

form of complex CHO, which have low glycemic loads and indexes such as whole grains, oats, fresh seasonal fruits, and vegetables, were consumed to increase high fiber content (eight servings of fresh vegetables and fruits/day). On the other hand, they were instructed to decrease foods rich in saturated fats such as fried foods and

The Mediterranean diet (MedDiet) is based on scientific evidence that inhabitants of Mediterranean countries (Greece, Italy, and Spain), around the Mediterranean Sea adhering to the principles of nutrition traditional for their region, have better health indicators than people in other areas. Originally, it was developed to prevent and treat the symptoms of hypertension and/or heart disease. In this MedDiet, the emphasis is on the use of plant-based foods as the main source of nourishment: fruits, vegetables, cereals, nuts, legumes, seeds, and whole grains. It is also recommended to replace butter and hydrogenated fats with extra-virgin olive oil and salts with spices and herbs. Red meat and sweets should be eaten once a week, and the main sources of protein should be eggs, yoghurt, fish, and poultry. Red wine could be taken in limited amounts (one glass per day for women; two

There is no universal definition for functional foods, but the easiest one is from the International Food Information Council which described functional foods as "dietary or food components that provide a health benefit beyond providing basic nutrition" [55]. Functional foods have an important role in the management of metabolic syndrome. Functional foods can help in weight loss, regulation of blood pressure, and control of blood glucose and lipid profile levels. Previous studies supported the beneficial effects of using functional foods containing bioactive components in the management of metabolic syndrome. This includes the intake of foods which have a thermogenesis effect (process in which body heat production increases, e.g., ginger, caffeine, red pepper, and green tea); functional foods with anti-inflammatory properties such as curcumin; and foods with the ability to increase insulin sensitivity, e.g., cinnamon, and increase intake of foods rich in plant estrogens such as soymilk, soybeans, flaxseed, sesame, green beans, fennel, peanut, and pumpkin seeds. In addition, soy products are rich in amino acids and can preserve lean body mass, decrease body fat percentage, and increase basal metabolic

• Natural functional foods: food products rich in biological active compounds (food rich in dietary fiber such as oat, barley, psyllium, vegetables, and fruits) [66]

• Foods with approved scientific heath nutrients: apple (pectin), garlic (*Allium* 

• Fortified foods with specific nutrients: iron fortified chocolate for iron deficiency anemia, calcium fortified juices, and zinc fortified products

**118**

The use of functional and prepared designed food would help fight MetS. Three thousand years ago, Hippocrates announced the tenet "Let food be thy medicine and medicine be thy food." Dietary supplements proved to improve the MetS criteria which include Syrian bread prepared mainly from barley flour and wheat germ mixed with either turmeric or ginger; doum biscuits; barley biscuits; bread prepared with soybean flour and enriched with curcumin or ginger; and cookies prepared with whole wheat flour and fennel or chia seeds. The higher fiber content of these products has a satiety effect so as to decrease food consumption. Moreover, fibers decrease digestion and absorption of dietary carbohydrates. Soy flour is a very rich source of essential amino acids except methionine. Preparation of bakery products using bioactive ingredients has positive beneficial effects for obesity, diabetes, and dyslipidemia management. These compounds have different benefits such as anti-atherogenic, antioxidant, and anti-inflammatory effects [48, 50, 53, 67–70].

#### **4.5 Pharmacological management**

There are no specific recommendations regarding the pharmacological management of metabolic syndrome; instead, the focus is on the management of the risk factors which need to be aggressively treated in order to prevent cardiovascular disease and type II diabetes mellitus if lifestyle changes aren't enough to reduce the risks. The available evidence of the pharmacological prescriptions is related to their cardiovascular benefits in clinical practice. Pharmacological treatments include statins and/or fibrates for dyslipidemia, angiotensin-converting enzyme inhibitors or renin-angiotensin-aldosterone system inhibitors for hypertension, metformin or sodium/glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1RAs) for glucose intolerance, and low-dose aspirin for prevention of arterial thrombosis [73]. Melatonin provides an innovative approach in the management of MetS through its useful effects on circadian rhythmicity, insulin resistance, dyslipidemia, high blood pressure, weight loss, and improving the antioxidative status (melatonin tablet 1 mg/kg) [74, 75]. Melatonin reduces the toxicity of many pharmaceutical agents and has a high safety profile [76].

#### **5. Conclusion**

Prevention is the best form of treatment of metabolic syndrome, and it starts from childhood by following a healthy lifestyle based on proper nutrition, exercise, and adequate early night sleep. Timing of food consumption, food quality, food quantity, light exposure, medication intake, and sleep are likely to play an important role in human health. Eat small portion sizes of food, and follow the rhythm of the day to maintain the synchronicity of the biological clock. Consuming natural effective supplements rich in bioactive substances leads toward the optimization of biochemical parameters of patients with metabolic syndrome in favor of a healthy outcome. Bariatric surgery should be considered in individuals with morbid obesity or obesity associated with comorbidity.

#### **Financial support**

The practical part of the work was financially supported by the National Research Centre, Egypt, but no fund supports for publication fees.

### **Abbreviations**


#### **Author details**

Suzanne Fouad Soliman1,2

1 Nutrition and Food Science Department, National Research Centre, Dokki, Giza, Egypt

2 Critical Care Medicine, Faculty of Medicine, Cairo University, Egypt

\*Address all correspondence to: suzannefouad6161@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**121**

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

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[12] Ding L, Zhang C, Zhang G, Zhang T, Zhao M, Ji X, et al. A new insight into the role of plasma fibrinogen in the development of metabolic syndrome from a prospective cohort study in urban Han Chinese population. Diabetology & Metabolic Syndrome.

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**References**

Springer; 2014

*Metabolic Syndrome: Impact of Dietary Therapy DOI: http://dx.doi.org/10.5772/intechopen.90835*

#### **References**

*Cellular Metabolism and Related Disorders*

α-Syn alpha-synuclein AD Alzheimer's disease Aβ amyloid beta

BMI body mass index C1P cermide-1-phosphate CERK ceramide kinase enzyme CRP C-reactive protein DBP diastolic blood pressure DM diabetes mellitus

GH growth hormone

MedDiet Mediterranean diet MetS metabolic syndrome

SBP systolic blood pressure SCN suprachiasmatic nucleus

TNF-ɑ tumor necrosis factor-ɑ WC waist circumference

provided the original work is properly cited.

IL-6 interleukin-6 IL-10 interleukin-10 IR insulin resistance

TG triglycerides

**Author details**

Egypt

Suzanne Fouad Soliman1,2

BEE basal energy expenditure

ASCVD atherosclerotic cardiovascular disease

GLP-1RAs glucagon-like peptide 1 receptor agonists

HDL-c high-density lipoprotein cholesterol hs-CRP high-sensitivity C-reactive protein

LDL-c low-density lipoprotein cholesterol

MMSE mini-mental state examination

M.HOMA-IR modified homeostatic model assessment of insulin resistance

1 Nutrition and Food Science Department, National Research Centre, Dokki, Giza,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Critical Care Medicine, Faculty of Medicine, Cairo University, Egypt

\*Address all correspondence to: suzannefouad6161@yahoo.com

**Abbreviations**

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Section 5

Hypothyroidism
