Management of Metabolic Syndrome: Comparison
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Metabolic syndrome (MS) is a growing disorder affecting thousands of people worldwide, especially in industrialised countries, increasing mortality. Oxidative stress, hyperglycaemia, insulin resistance, inflammation, dysbiosis, abdominal obesity, atherogenic dyslipidaemia and hypertension are important factors linked to MS clusters of different pathologies, such as diabesity, cardiovascular diseases and neurological disorders. All biochemical changes observed in MS, such as dysregulation in the glucose and lipid metabolism, immune response, endothelial cell function and intestinal microbiota, promote pathological bridges between metabolic syndrome, diabesity and cardiovascular and neurodegenerative disorders. 

  • metabolic syndrome
  • diabesity
  • gut microbiota
  • dysbiosis
  • cardiovascular diseases
  • neurodegeneration

1. Introduction

Metabolic syndrome (MS) is one of the most common health problems today, affecting almost 30% of the world’s population. It is considered one of the major issues of industrialisation in developing countries and will affect more than half of the population in the next 20 years [1]. The increase in MS is linked to many factors, such as sedentary lifestyle, environmental factors and diet as the Food Away from Home (FAFH), constituting an important public health problem [2]. It has been estimated that MS [3], especially among women [4,5][4][5]. Approximately 24% of adults in the USA, 12–37% of the Asian population and 12–26% of the European population suffer from this disease [6], and about 44% of people are in the age group ≥ 50 years. The concept of MS was introduced in the 1920s [7]. MS has been described as a cluster of cardiometabolic risk factors, including hyperglycaemia [8[8][9],9], central obesity (waist circumference), hyperinsulinemia and insulin resistance (IR) [10], hypertension, hypertriglyceridaemia, low plasma high-density lipoprotein (HDL) and high cholesterol levels. Moreover, ageing and hormonal changes have been associated with the development of MS [11,12,13,14,15][11][12][13][14][15]. Other pathological disorders closely correlated to MS include liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) [16], neurological diseases [17] and cancer [18].
Different clinical criteria have been adopted for the definition of MS by international organisations (Table 1).
Table 1.
Diagnostic clinical criteria of metabolic syndrome by different health organizations.
Clinical Parameters Criteria
Central Obesity Fasting Blood Sugar ↑ Triglycerides ↓ HDL-Cholesterol ↑ Blood Pressure Diagnosed as MS
IDF (2005)

[19]		 Waist circumference defined in terms of ethnicity-specific values ≥100 mg/dL or on medication ≥150 mg/dL or on medication Male: <40 mg/dL

Female: <50 mg/dL		 Diastolic ≥130 and/or systolic ≥85 mmHg or on medication Absolutely required central obesity plus ≥2 criteria
AHA/NHLBI

(2005) [20]		 Waist circumference

Male: ≥102 cm

Female: ≥88 cm		 ≥100 mg/dL or on medication ≥150 mg/dL or on medication Male: <40 mg/dL

Female: <50 mg/dL		 Diastolic ≥130 and/or systolic ≥85 mmHg or on medication ≥3 criteria
AHA/NHLBI

and IDF:2009

[21]		 Waist circumference defined in terms of population- and country-based-specific definition ≥100 mg/dL or on medication ≥150 mg/dL or on medication Male: <40 mg/dL

Female: <50 mg/dL		 Diastolic ≥130 and/or systolic ≥85 mmHg or on medication ≥3 criteria
Note: IDF, International Diabetes Federation. AHA/NHLBI, American Heart Association/National Heart, Lung and Blood Institute.
According to a joint agreement between international organisations, individuals suffering from MS must show three clinical signs on the following five criteria: central obesity (specific definition in relation to the population and country), TG ≥ 150 mg/dL and/or on pharmacological treatment; HDL-C < 40 mg/dL in males and <50 mg/dL in females; diastolic BP ≥ 130 and systolic ≥ 85 mmHg and/or under pharmacological treatment; and FBS ≥ 100 mg/dL and/or drug treatment [20].

2. Free Radicals, Oxidative Stress and Metabolic Syndrome

Free radicals are produced during cell metabolism and redox processes. They include reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulphur species (RSS) [22,23][22][23]. All free radicals are involved in body pathophysiological processes [24]. Superoxide can damage molecules (DNA, proteins and lipids) [25]. The hydroxyl radical reacts strongly with most organic and inorganic molecules (DNA, proteins, lipids, amino acids, sugars, vitamins and metals) faster than its speed of generation [26]. It is estimated that OH• is responsible for 60–70% of the tissue damage caused by ionising radiation [27]. Hydroxyl radicals are involved in several disorders, such as cardiovascular diseases [28] and cancer [29]. Nitric oxide is also involved in many physiological processes, such as neurotransmission, relaxation of smooth muscle, vasodilation and regulation of blood pressure, gene expression, defence mechanisms, cell function and regulation of inflammatory and immune mechanisms, as well as in pathological processes such as neurodegenerative disorders and heart diseases [30]. Cells and the body can protect themselves from free radicals through antioxidants to lower the concentration of free radicals and maintain redox homeostasis in the body [31]. The antioxidant defence systems consist of endogenous (generated in situ) and exogenous antioxidants (supplied through foods). They play the role of neutralising excess free radicals and protecting cells from their toxic effects, helping to prevent diseases. When body defence mechanisms are reduced, free radicals, generated by endogenous and exogenous sources, can cause direct oxidative damage to biological molecules and organs, with consequent oxidative stress and metabolic disorders [24]. Oxidative stress concerns intracellular damage as well as secondary damage due to the cytotoxic and mutagenic characteristics of the metabolites produced [24,32,33][24][32][33]. In particular, carbon reactive compounds, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which are formed during lipid oxidation and carbohydrate glycoxidation, reacting with cell tissues and proteins generate the advanced lipid peroxidation end-product (ALE) and the advanced glycation end-products (AGE), which cause protein-level dysfunction, such as loss of activity and increased sensitivity to proteases [34] and in inflammatory responses and apoptosis [35]. As a result, oxidative stress contributes significantly to the pathogenesis of different diseases [31]. Carbon reactive compounds, such as MDA, 4-HNE or oxidised LDL, have been found in cardiovascular disease [36], atherosclerosis [37], diabetes [38], obesity and IR [39]. The role of oxidative stress in MS is rapidly evolving as a result of evidence and related manifestations, including atherosclerosis, hypertension and T2D [40], low-grade inflammation [41], adiposity and IR [42[42][43],43], cardiovascular diseases and neurological disorders [17].

3. Management of Metabolic Syndrome

The modern management of MS involves a multidisciplinary approach that combines lifestyle changes and pharmacological interventions. Pharmacotherapy and associated comorbidities necessitate the prolonged use of multiple medications, which is challenging for patients with poor compliance. Thus, there is a growing interest in lifestyle changes to the management of metabolic dysfunction, such as the control of body weight and healthy diets. Based on animal and human studies, anti-oxidative therapies have been found to be effective in the treatment of a common node, such as redox imbalance, between multifactorial disorders associated with MS [562,563][44][45]. The imbalance between free radicals/oxidants and antioxidant defences leads to oxidative stress, which promotes a wide range of clinical disorders, both as a source and as a result, and diseases [31]. Antioxidant systems include endogenous antioxidant defence mechanisms that act along with exogenous antioxidants, such as vitamins and derivatives of dietary polyphenols, to counteract stress and oxidative damage [564][46]. Antioxidants, such as vitamins (E, C, Q) and carotenoids or polyphenols (as phenolic acids and flavonoids), are derived from food [565,566,567][47][48][49]. Antioxidants act synergistically by trapping single electrons from free radicals or by reducing ROS enzymatically. There is a general trend toward the use of natural rather than synthetic antioxidants [568,569][50][51]. Plant antioxidant therapies have shown significant effects in various stress conditions [561,562,570,571][44][52][53][54] and in the protection of diseases associated with MS [572][55]. Many natural compounds derived from plant extracts, spices, herbs and essential oils have beneficial effects in patients with MS [573,574,575][56][57][58]. Polyphenols are the most prevalent antioxidants in plant-based diets, including fruits, vegetables and cereals [576][59], whose consumption reduces the risk of MS [337][60]. A high-quality plant-based diet is an effective intervention for weight management [577][61]. A higher consumption of fruits and vegetables reduces the risk of cognitive impairment and dementia [578][62]. The phytochemicals of fruits and vegetables have protective effects against PD [579][63]. Mediterranean diets rich in neuroprotective nutrients have a beneficial effect on developing Alzheimer’s disease [580][64]. However, many problems still remain elusive: most exogenously administrated antioxidants are not selective or uniformly distributed in the various parts of cells or tissues [581,582][65][66]; the threshold level of antioxidant nutrients needed for optimal nutrition is unclear [573[56][67],583], as well as the specificity of antioxidants and their possible interactions [573,584][56][68]. Therefore, it is suggested to focus on developing innovative targeted antioxidants to achieve precise therapeutic effects [581,585][65][69]. Lifestyle is important in the prevention and treatment of obesity, diabetes and diseases linked to MS [586][70]. Weight loss may prevent and reverse diabetes [587,588,589][71][72][73] and improve blood glucose, insulin sensitivity and comorbidities [590][74]. The decrease in weight can reduce cardiovascular risk associated with obesity and diabetes [591,592][75][76]. Dietary energy restriction promotes weight loss and reduces risks of metabolic disorders [593,594][77][78]. It also improves lipid and cytokine profiles, reduces cardiovascular risks [595][79] and improves blood sugar and insulin sensitivity in obese patients with T2D [596][80]. Johnston and coworkers [597][81] reported that low carbohydrate ketogenic diets were similarly effective in reducing body weight and IR in patients with diabesity. Dietary protein restriction has been associated with a reduction in diabetes [593][77] and can lead to the same clinical results as calorie restriction without reducing calorie intake [598][82]. Evidence indicates that intermittent fasting can replace the mechanisms of dietary or caloric restriction in weight loss [599,600][83][84]. Microbiota control can play an important role in the development of obesity and diabetes [601][85]. The Mediterranean diet is associated with a wide range of benefits in young and adult patients with diabesity and metabolic syndrome in the prevention of derived complications [602[86][87][88][89][90],603,604,605,606], partly due to the ability to regulate microbial populations, improving the growth of Lactobacillus spp., Bifidobacterium spp. and Prevotella spp. and limiting Clostridium spp. development [607][91]. Restoring intestinal microbiota composition and function can have a significant impact on improving cardiovascular disease [608][92] and neurodegenerative diseases [609][93].

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