Metabolic Syndrome: A Comprehensive Update with New Insights E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Lebensstil
- Sprache: Englisch
The book focuses on a new interdisciplinary understanding of the metabolic syndrome (MetS) for better health maintenance. It provides an updated understanding of the underlying principles, possible targets, implementation approaches and the effectiveness of various avoidance strategies in MetS. The chapters cover a wide range of topics, including major advances in general aspects of metabolic syndrome, functional changes, new diagnostic methods, genotype-phenotype associations, the effect of exercise and multitarget pharmacotherapeutic strategies for MetS and perspectives on personalized medicine. It also discusses epigenetic mechanisms underlying MetS-related processes and epigenetic strategies to prevent related diseases. The book also presents summarized information about the associated factors and mechanisms linking cancer and MetS and to identify potential targets for the treatment of these patients. A better understanding of the various linkages will provide greater insight into the management of cancer patients by preventing MetS and related alterations.
Key Features
- Comprehensive information focused on the biological factors and physiological changes associated with metabolic syndrome
- Updates on metabolic syndrome diagnosis and management
- Summarized information on clinical implications for cancer therapy
- Thoroughly referenced chapters with summaries and discussions for quick understanding
The book is an informative resource for interdisciplinary scientists and researchers in life sciences and medicine. Furthermore, it, including the insulin-like growth factor (IGF-1) pathway, estrogen signaling, visceral adiposity, hyperinsulinemia, hyperglycemia, aromatase activity, adipokinase production, angiogenesis, oxidative stress, DNA damage and pro-inflammatory cytokines, and their clinical implications in cancer therapy.
Readership
General readers, microbiology and biotechnology enthusiasts, science students and industrial trainees
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Seitenzahl: 858
Veröffentlichungsjahr: 2025
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FOREWORD
Metabolic syndrome is an intricate condition characterized by a set of risk factors, including hyperglycemia, insulin resistance, hypertension, and obesity, which significantly elevate the risk of cardiovascular disease, stroke, and type 2 diabetes. Its growing prevalence worldwide poses a significant challenge to public health, necessitating a thorough understanding and innovative strategies for management. This book offers an in-depth exploration of metabolic syndrome, shielding a range of issues from functional changes and novel diagnostic methods to the interplay between metabolic syndrome and other health conditions like cancer, gastrointestinal disorders, and COVID-19. This complete text, featuring chapters on cutting-edge research and practical diagnosing and management strategies, is a valuable resource for healthcare professionals, researchers, and policymakers dedicated to addressing the multifaceted challenges of this syndrome.
PREFACE
Nowadays, metabolic syndrome (MetS) is a major health problem worldwide. MetS is characterized by high blood pressure, obesity, insulin resistance, and diabetes mellitus. Of these factors, insulin resistance is the main cause of MetS. It is very important for patients with MetS to change their lifestyle. Exercise, changes in dietary habits, and weight loss are necessary in the treatment of patients with MetS. As discussed in the light of current information about MetS in Chapter 13, exercise plays a very crucial role in controlling insulin activity, reducing the risk of cardiovascular disease, and maintaining weight control and Chapter 11 (Neutrogenomic strategies in metabolic syndrome) provides an update on our current understanding of the impact of neutrogenomic strategies on MetS. In the last few decades, many studies on the genetic and epigenetic screening of MetS in various populations have been published in the literature. The role of genetic and epigenetic mechanisms is discussed in Chapter 9.
Another important aspect is that MetS has been associated with psychiatric disorders. In those diagnosed with major depressive disorder and bipolar disorder in adulthood, the disruption of biological rhythms (sleep, social activities, and eating habits) has been associated with key components of MetS. MetS and its components have also been linked to a higher risk of suicide. It is clear that the relationship between behavior and MetS is bidirectional and that each component can influence the other. Awareness of factors related to MetS can help identify high-risk individuals and implement disease prevention and control strategies as well as lifestyle modifications. It is discussed in Chapter 10 (The Interplay between Metabolic Syndrome and Behavior) that lifestyle modification can help improve MetS status and behavior.
If patients with MetS fail to be treated with lifestyle changes, they should use certain medications. First, insulin resistance needs to be treated. Metformin, thiazolidinediones or glitazones should be used to treat insulin resistance and diabetes mellitus. Secondly, dyslipidemia and obesity need to be treated with statins and fibrates. Treatment of components of the MetS, such as cardiovascular disease, hypertension, and polycystic ovary syndrome, is often associated with the treatment of insulin resistance, obesity, and dyslipidemia. The MetS should be treated early because delayed treatment is ineffective and very expensive. In MetS and related diseases, rationalized and evidence-based pharmacotherapeutic strategies are cornerstones in reducing polypharmacy. The pharmacology network approach and advanced bioinformatics tools related to epigenetics, genomics, transcriptomics, proteomics, and metabolomics are recognized as useful bench-top tools for the search for molecular preventive and therapeutic multiple targets. Molecular multi-target therapy is recognized as a new pharmacological strategy underpinning personalized and precision medicine. This in turn will reduce socioeconomic burdens and improve health-related quality of life. In this context, Chapter 12 discusses perspectives on personalized medicine using a pharmacology network approach.
MetS is a cluster leading to increased cardiovascular morbidity and mortality as well as increased predisposition to other non-communicable diseases such as certain cancers. Although individual components of MetS have been linked to cancer, studies demonstrating a direct link between MetS and cancer are limited. Understanding this link will shed light on the process of oncogenesis in patients with MetS. Chapter 15 addresses the need to summarize the associated factors and mechanisms linking these two pathologies and to identify potential targets for treatment in patients with cancer and MetS. Furthermore, Chapter 15 focuses on the biological and physiological changes and specific factors associated with this process, including the insulin-like growth factor (IGF-1) pathway, estrogen signaling, visceral adiposity, hyperinsulinemia, hyperglycemia, aromatase activity, adipokinase production, angiogenesis, oxidative stress, DNA damage and pro-inflammatory cytokines, and their clinical implications in cancer therapy. A better understanding of this link will provide greater insight into the management of cancer patients by preventing MetS and related changes.
We would like to sincerely thank our team of authors from different countries who contributed excellent chapters that made the compilation of this book possible.
List of Contributors
General Aspects of Metabolic Syndrome: An Update on Diagnostic Criteria, Pathophysiology, and Management
Abdulhalim Senyigit1,*Abstract
Metabolic syndrome (MetS) is generally defined as a cluster/complex of factors that are risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM), including hyperglycemia, insulin resistance, hypertension, hypertriglyceridemia, decreased HDL-cholesterol concentration and central obesity. MetS is a health problem whose prevalence is increasing worldwide and negatively affects people's lives. Although MetS is essentially insulin resistance (IR), is not considered a disease, it consists of a combination of many risk factors that force the body metabolism to work abnormally. In addition to factors such as sedentary lifestyle and nutrition, hereditary factors are also important in the formation of MetS. The main components of MetS can be listed as hyperglycemia, hypertension, obesity and dyslipidemia. MetS has different definitions for different organizations. The basic components of these definitions are waist circumference, IR, high blood pressure and dyslipidemia (high triglyceride, low HDL cholesterol). The most recently agreed upon diagnostic criteria for MetS are increased waist circumference (society and country specific), high triglycerides, low HDL cholesterol, high blood pressure and high fasting blood glucose. For diagnosis, the presence of at least 3 of these parameters is required. When countries are examined in terms of the prevalence of MetS, different results are obtained from each country. The most important factor affecting the incidence of MetS in a country is the percentage of obesity and abdominal obesity in that country. Although obesity and physical activity factors have an impact on the incidence of MetS, it is an undeniable fact that genetic factors also have a significant impact. Lifestyle changes are at the core of MetS treatment. People with this syndrome need to change their diet, increase their physical activity and lose weight. Determining MetS risk levels and predisposing risk factors, determining whether they meet diagnostic criteria, and raising awareness through education and consultancy activities will be effective in combating the prevalence of MetS and cardiovascular risk factors.
INTRODUCTION
Metabolic syndrome (MetS) is generally defined as a cluster/complex of factors, such as hyperglycaemia, insulin resistance (IR), hypertension (HT), hypertriglyceridemia, decreased HDL-cholesterol concentration and central obesity, which are risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM) [1]. The association of MetS risk factors with T2DM and CVD began to be discussed in the 1970s and was first defined by Reaven in 1988 as a syndrome of metabolic abnormalities and named Syndrome X [2]. For the first time in 1988, Reaven defined “Syndrome X” as this complex disease in which various metabolic abnormalities (HT, hyperglycaemia, and hyperuricemia) coexist [1, 2]. MetS is also described by different terms such as IR syndrome, polymetabolic syndrome, deadly quartet, and civilisation syndrome [3]. MetS has also been given various names such as metabolic cardiovascular syndrome, dysmetabolic syndrome, plurimetabolic syndrome, and cardiometabolic risk syndrome. MetS is a major cause of morbidity, affecting an increasing number of people worldwide [4-6]. It is estimated that 3.2 million people die each year worldwide due to diabetes-related complications, and in countries with a high incidence of diabetes, such as the Pacific and the Middle East, diabetes accounts for a quarter of all causes of death in adults aged 35-64 years. CVD and its complications, a major component of the MetS, are also on the rise and have a major impact on global health systems. The estimated incidence of diabetes is projected to double by 2025 and cardiovascular diseases are expected to increase in parallel [7].
The National Cholesterol Education Program Adult Treatment Panel Working Group (NCEP-ATP III) introduced a new definition in 2001 and added abdominal obesity and waist circumference to the definition [8]. Today, the definition of MetS is widely used by various authorities such as the World Health Organization (WHO), American Heart Association (AHA), International Diabetes Federation (IDF), National Heart, Lung and Blood Institute (NHLBI), NCEP-ATP III).
Prevalence of Metabolic Syndrome
The prevalence of MS is steadily increasing worldwide and has recently been identified as one of the major global public health problems. Although the prevalence of MetS varies according to different geographical and ethnic characteristics of societies (lifestyle), definitions used, population age and gender characteristics, it is considered a pandemic in the adult population in many countries. When countries are analysed in terms of the prevalence of MetS, different results are obtained from each country. The most important factor affecting the prevalence of MetS in a country is the percentage of obesity and abdominal obesity in that country. Although obesity and physical activity have an effect on the incidence of MetS, it is an undeniable fact that genetic factors also have an important effect. Prevalence is reported to increase with body mass index (BMI) and age. According to the National Health and Nutrition Examination Survey (NHANES), the prevalence of MetS was 34-35% in the period 1999-2012, and this rate was found to be 50% over the age of 60 years [9]. About a quarter of adults in the US, India and Europe have MetS [10]. It has been reported that the risk of death is 2 times higher and the risk of major cardiovascular events is 3-5 times higher in individuals with MetS. It is also reported that the risk of developing T2DM is 2-5 times higher in these individuals and that more than 80% of the world's 230 million people with T2DM are at risk of CVD-related death [8-10]. There is also an increased risk of other preventable chronic diseases such as cancer, neurodegenerative diseases, non-alcoholic fatty liver disease, circulatory disorders, dyslipidemia, and infertility [9].
The prevalence of MetS increases with age and is difficult to prevent as the ageing population expands [11]. Studies indicate that by 2050, approximately 83.7 million people in the US will be over 65 years of age, double the 2012 population of 43.1 million [12]. Although there is no consensus on age and gender studies in MetS, in 2023 Rus et al. [13] reported that both genders displayed a higher risk of developing MetS related to age. The most affected age groups were aged between 60-69 years old and the 70-79-year-old group, categories where women had a higher risk of developing the disease. For the rest of the age categories, the incidence and prevalence continued to be higher among men [13].
The MetS global prevalence varied from 12.5% to 31.4% depending on the diagnostic criteria in the meta-analysis prevalence of MetS. Despite the publication of numerous primary studies on MetS in various populations across the globe, little effort has been dedicated to summarizing data on the epidemiology of MetS at the global level. In this study, we aimed to determine the prevalence rates of MetS and its individual components according to different diagnostic criteria and cutoffs and to compare these rates across geographic regions and socioeconomic levels [14].
Significance of Metabolic Syndrome
MS is an important public health problem seen in the adult population worldwide [15]. It is a risk factor for cardiovascular diseases and T2DM. MetS is associated with CVDs and increases the risk of cardiovascular morbidity 3-fold, mortality 2-fold, and type 2 diabetes 5-fold [16]. The onset of MetS in children is a result of the increase in the prevalence of obesity and is defined as a comorbid condition [17, 18]. It has been reported that obesity and overweight in young people play an important role in MetS. MetS seen in children increases the risk of early death due to coronary heart disease in adults. It has been reported that atherosclerosis seen at an early age is associated with MetS and obesity seen in childhood [19]. With the spread of obesity, it is predicted that 10% of school children are obese and 60% of obese children older than 10 years will become obese adults [20].
The high correlation between obesity and T2DM has changed the approach to childhood obesity. Insulin resistance has been detected in some obese children and adolescents. Some of these children will develop MetS and T2DM, while others will not. However, it is reported that 60% of obese children and adolescents have at least one cardiovascular risk factor [21].
There is no consensus between the WHO and the National Cholesterol Education Program regarding the diagnosis of MetS in children. Accurate diagnosis in children is important for reducing or preventing the high morbidity related to chronic diseases seen in young adults [21].
Pathogenesis of Metabolic Syndrome
The pathophysiology of MetS involves many complex mechanisms that have not yet been fully clarified. No single genetic, infectious, or environmental factor has yet been identified to explain the etiopathogenesis of all components of the MetS. However, the etiology of MetS can be divided into three categories: Obesity/adipose tissue disorders, insulin resistance, and independent factors (such as molecules of vascular, hepatic, and immunologic origin). Although MetS is thought to develop as a result of a complex relationship between many environmental and genetic factors, the latest data suggest that obesity and insulin resistance are at the center of the development of the syndrome and play a key role in the development of chronic inflammatory and prothrombotic processes that accompany the syndrome.
Since insulin resistance is thought to be the main culprit in the development of the syndrome, subsequent studies have focused on revealing the common relationship between insulin resistance, obesity, and CVD development. As a result of these studies, it has been agreed that insulin resistance is insufficient as the only etiopathogenetic factor to explain the clustering of CVD risk factors in an individual - in this sense, the development of MetS - but it is the main underlying mechanism [1, 22-24].
Diagnostic Criteria of Metabolic Syndrome
Since 1998, many definitions have been made for MetS by many expert groups, and organizations, including WHO, have tried to improve these definitions [25, 26]. The definitions made by WHO in 1999, the European Group for the Study of Insulin Resistance (EGIR) in 1999, the American Association of Clinical Endocrinology (AACE) in 2003, NCEP-ATP III in 2001-2005, and IDF in 2005 are guiding in diagnosis and treatment. The most widely accepted definitions are those made by WHO, EGIR, and NCEP-ATP III [8].
According to the 2022 definition of MetS, considering the progress in understanding individual components of MetS and the most current guidance on the management of each individual condition, the authors propose that the definition of MetS encompasses the presence of obesity and two of the three following criteria: high blood pressure, impaired glucose metabolism, elevated non-high-density lipoprotein (non-HDL) cholesterol level (atherogenic dyslipidemia) [27]. The comparison of MetS diagnostic criteria between organizations is presented in Table 1.
According to the WHO's 1998 Diagnostic Criteria for Metabolic Syndrome [28]
√ Having at least one of the diagnoses of insulin resistance, impaired glucose tolerance, and obvious diabetes mellitus.
√ High blood pressure (blood pressure above 140/90 mmHg or taking antihypertensive medication).
√ Abdominal obesity (Body Mass Index (BMI) over 30 kg/m2 or waist/hip ratio greater than 0.90 cm in men and greater than 0.85 cm in women).
√ Dyslipidemia (Triglyceride (TG) level above 150 mg/dL or High-Density Lipoprotein (HDL) level less than 40 mg/dL in men and less than 50 mg/dL in women).
√ Microalbuminuria (urinary albumin excretion more than 20 μg/min or albumin/creatinine ratio more than 30 mg/g) in combination with at least two of the findings.
According to the Diagnostic Criteria of NCEP-ATP III [8]
NCEP-ATP III is one of the most widely used definitions of MetS criteria in the world.
√ Abdominal obesity (waist circumference: >102 cm in men, >88 cm in women).
√ Hypertriglyceridemia (≥150 mg/dL).
√ Low HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women).
√ Hypertension (blood pressure ≥ 130/85 mmHg).
√ Presence of at least three of the findings of hyperglycemia (fasting blood glucose > 100 mg/dL) makes the diagnosis of MetS.
According to the IDF's 2005 Diagnostic Criteria for MetS [29]
√ Abdominal obesity (waist circumference of 94 cm and above in European men and 80 cm and above in women).
√ TG level≥150 mg/dL.
√ HDL level <40 mg/dL in men and <50 mg/dL in women.
√ Blood pressure≥130/85 mmHg.
√ A fasting blood glucose level of ≥100 mg/dL indicates the diagnosis of MetS.
Any patient diagnosed with MetS should at least be seen as a high cardiovascular-risk patient. A comprehensive assessment of the main and additional conditions of the MetS is advised, as well as implementing lifestyle modifications alongside appropriate medical treatment. Early intervention can prevent the development or slow the progression of individual components of the MetS [27].
Risk Factors of Metabolic Syndrome
Although there is no consensus on the definition and diagnostic criteria of the syndrome, MetS is characterized by the coexistence of risk factors such as abdominal obesity, atherogenic dyslipidemia, high blood pressure, insulin resistance and high glucose levels [34] (Fig. 1). Among these criteria, obesity is among the controllable risk factors as it is generally associated with excess calorie intake and insufficient physical activity [35].
There is currently significant research focusing on understanding the key pathways that control metabolism, which would be likely targets of risk factors (e.g, exposure to xenobiotics, genetics) and lifestyle factors (e.g, microbiome, nutrition, and exercise) that contribute to MetS [36]. In addition to genetic predisposition, environmental factors such as obesity, fat metabolism, high calorie intake, diet rich in cholesterol and atherogenic foods and low physical activity, aging and hormonal imbalances are separate risk factors affecting the development and progression of the syndrome. MetS is an important risk factor for CVD and T2DM and hepatosteatosis, steatohepatitis, and cirrhosis may develop in the same time period in patients with MetS. The frequency of MetS and its complications increases in proportion to the increase in the frequency of obesity in children and adolescents [24]. Cardiovascular risk factors associated with insulin resistance have been summarized in Table 2 [36].
Fig. (1)) Risk factors of metabolic syndrome.Instead of listing the causes of MetS one by one, it is more accurate to define all problems that increase the risk of heart attack as part of MetS.
COMPONENTS OF METABOLIC SYNDROME
The main components of MetS are obesity, insulin resistance, T2DM, hypertension, dyslipidemia, and and prothrombotic state.
Metabolic Syndrome and Obesity
Abdominal obesity is the most frequently occurring component of the MetS. The most important triggering factor in the development of insulin resistance is also abdominal obesity. Although obesity is caused by the intake of more food than the metabolism needs, it is estimated that obese people consume more energy than they need in addition to their sedentary life [27, 37].
The most important factor in the development of insulin resistance is abdominal obesity, which may not be present in every case of MetS [38] (Fig. 2). Adipose tissue plays an active role in inflammation through hormones such as resistin, leptin, adiponectin and cytokines such as TNF-α, IL-6, IL-1 [39, 40]. Waist circumference measurement, which is an indicator of visceral adiposity, is used in the evaluation of MetS, and it is recommended to measure at the midpoint of the distance between the arcus costarium and spina iliaca anterior superior of the pelvis. for this measurement. The cut-off values for waist circumference defined by the WHO for the white race in overweight and obese people are 94 cm in overweight and 102 cm in obesity in men; 80 cm in overweight and 88 cm in obesity in women [38].
Fig. (2)) Components of metabolic syndrome.Free fatty acids (FFAs) formed by lipolysis from adipose tissues in the body increase according to the size of adipocytes. In visceral adipose tissue composed of large adipocytes, cytokine production increases with the intensity of lipolysis, while insulin sensitivity decreases. As a result, the excess in visceral adipose tissue leads to an increase in FFAs and thus insulin resistance [41]. Establishing the link between insulin resistance and obesity was made possible by the determination of the endocrine organ function of adipose tissues, where energy is stored, by adding peptide complement effector and cytokine secretion to the circulatory system [42]. It has been suggested that chronic inflammation is effective in the progression of insulin resistance. In studies, acute phase reactants and proinflammatory cytokines have been linked to MetS variables [43-45]. The inflammatory resilience phenotype of the overfed healthy males moved toward that of males diagnosed with MetS [44].
The IDF has accepted the inclusion of central obesity in the diagnostic criteria (it has been reported that it is unnecessary to measure insulin resistance because central obesity is strongly associated with insulin resistance) and the presence of at least two of the following: high triglycerides, low HDL, high blood pressure and high fasting glucose as the definition of MetS [46, 47]. While criteria for both ATP III and IDF consider central obesity (defined by waist circumference, with ethnicity- and gender-specific cut-off values), the IDF uses central obesity as a prerequisite for diagnosis, while the ATP III considers central obesity as one component out of several that could be present [48].
Studies have shown that individuals with predominant upper body obesity are more prone to MetS and that excess visceral adiposity is strongly associated with MetS [49, 50]. Obesity is known to promote the recruitment of excess fat to various organs or tissues, especially muscle and liver [51, 52]. Recent studies reveal that adipose tissue contributes adipokines that may influence metabolic risk factors [52-54]. These include adiponectin, interleukin-6, tumor necrosis factor alpha (TNF-α) resistin, leptin, angiotensinogen, and plasminogen activator inhibitor-1 [52, 55].
Normally, as fat cells expand, more leptin is released into the brain to signal the end of eating behavior. However, obese individuals can develop leptin resistance, similar to insulin resistance. In these individuals, even high leptin levels are not enough to induce satiety [56, 57]. Weight loss in patients with MetS can lead to improvements in multiple traits simultaneously, so a certain degree of adiposity seems to be necessary to reveal the abnormal pathophysiology. However, there are also patients who are obese but do not show any of the other components of the MetS, so both metabolic susceptibility to insulin resistance and obesity are necessary for the MetS phenotype to be observed [58, 59].
Ectopic adiposity resulting in adipocyte hypertrophy or adipose tissue enlargement and visceral obesity is the most important constituent of MetS. Ectopic adiposity is the accumulation of fat in visceral organs such as the omentum, liver, and muscle, in addition to subcutaneous adipose tissue. Today, visceral obesity, in other words, excessive fat in the intra-abdominal region, is known to increase the prevalence of MetS. It has been reported that there is a positive correlation between waist/hip ratio, which is used as a marker of visceral obesity, and plasma fasting glucose level and systolic-diastolic blood pressure, and that these factors are among the important risk factors for the development of CVD [60, 61]. This explains why obesity is a poorly identifiable CVD risk factor compared to others such as hypertension, smoking, and cholesterol (increased low-density lipoprotein (LDL)/decreased HDL). Although the accumulation of excess visceral fat is associated with various atherogenic and diabetogenic abnormalities, an important question is whether visceral fat is a causal factor or simply a marker of a dysmetabolic profile. Although obesity is not a major risk factor for insulin resistance, T2DM, and CVD, not all obese patients are insulin resistant or at high risk of diabetes and CVD [62].
Metabolic Syndrome and Insulin Resistance
Individuals with MetS have a biological response to endogenous and exogenous insulin, and many factors such as genetic predisposition, nutritional disorders starting in the womb, malnutrition, malnutrition, concomitant obesity, inactivity, sedentary life, decreased body repair capacity with aging can lead to the development of insulin resistance. Although insulin resistance is accompanied by hyperglycemia, it is not always present [63].
Insulin resistance defined as an inadequate response to the required amount of insulin in the circulatory system, is a pathophysiology for the body and can be seen in obese, non-diabetic individuals and individuals with T2DM [64].
One of the hypotheses accepted to explain the pathophysiology of MetS is insulin resistance. MetS is, therefore, also known as insulin resistance syndrome. Insulin resistance is defined as a defect in the action of insulin, which is required to maintain euglycemia leading to hyperinsulinemia. Considering the main tissues targeted by insulin, it appears that insulin resistance in skeletal muscle leads to a reduction in glycogen synthesis and glucose transport, while insulin resistance in the liver leads to a reduction in the efficiency of insulin signaling. The exact mechanisms have not been fully confirmed and research in this area is ongoing [65, 66]. Hyperinsulinemia occurs to counteract this resistance and maintain euglycemia. While insulin resistance is usually associated with hyperinsulinemia, hyperglycemia may not always accompany insulin resistance. Hyperglycemia occurs in advanced stages of insulin resistance [67-69]. Abdominal obesity (visceral adiposity) is thought to be the main cause of insulin resistance. On the other hand, the increase in circulating FFA is thought to play an important role in the pathogenesis of MetS. With abdominal obesity, insulin-stimulated glucose uptake by cells is reduced, the non-esterified fatty acid is abnormally released from adipose tissue, muscle cells, and liver adiposity are formed, and these effects facilitate the development of insulin resistance and dyslipidemia [70, 71]. The increase in circulating FFAs has multiple effects on metabolism; FFAs reduce glucose uptake into muscles. They promote gluconeogenesis and lipogenesis in the liver. Acute skeletal muscle exposure to high FFA levels induces insulin resistance by inhibiting insulin-induced glucose uptake. Chronic exposure of the pancreas to high FFAs impairs pancreatic beta cell function. FFAs are also lipotoxic to pancreatic beta cells and cause impaired insulin secretion. As a result, insulin secretion is reduced [72, 73].
Metabolic Syndrome and Prediabetes
Although the definitions of prediabetes, MetS and insulin resistance syndrome are closely related, they are recognized as separate entities that overlap each other. Different criteria for MetS developed by different groups are still widely used. Among these, the NCEP-ATP III criteria is one of the most widely used [74, 75].
The different definitions, interpretations and diagnostic criteria provided by each organization not only confuse clinicians but are also not similar in terms of determining cardiovascular risk. For example, in a survival analysis, it was found that NCEP diagnostic criteria were more in line with the risk of CVD than IDF diagnostic criteria [76]. In another study, it was shown that IDF diagnostic criteria were more sensitive than ATP III, WHO diagnostic criteria, impaired glucose tolerance, and impaired fasting glucose in predicting future diabetes development, but the false positive rate increased similarly with increasing sensitivity [77]. The fact that metformin treatment of patients with MetS in the diabetes prevention program has been shown to have little effect on the improvement of MetS compared to lifestyle changes is another indirect evidence that prediabetes and MetS are different entities. In conclusion, insulin resistance is a starting point for the presence of both prediabetes and MetS, approximately 75% of prediabetics may be associated with MetS, both insulin resistance, prediabetes and MetS are individually associated with increased cardiovascular risk, and prediabetes determines the future development of diabetes [77]. Accordingly, prediabetes and MetS are intertwined but separate concepts.
Beyond the fact that prediabetes is a condition that must be diagnosed correctly and closely monitored and treated in terms of both its conversion to diabetes and the many health problems it may cause, it is possible to prevent prediabetes by taking precautions to be taken by addressing risky individuals individually in order to prevent the aforementioned health problems from occurring, and today, it has been adopted by guidelines that prevention of prediabetes is the most accurate approach to reduce future health risks and expenditures [78].
Metabolic Syndrome and Diabetes Mellitus
T2DM is becoming one of the most common chronic diseases after cancer and cardiovascular diseases. In recent years, the prevalence of this disease has been increasing significantly worldwide and is becoming one of the major societal social problems in the 21st century [79]. Although not all patients with T2DM have insulin resistance, the presence of overt DM or impaired glucose tolerance fulfills the first step of the diagnostic criteria for MetS and insulin resistance is not required. Insulin resistance increases the risk of atherosclerosis and cardiovascular disease independent of other risk factors [80]. In addition to fasting glucose levels, high postprandial glucose levels are risk factors for insulin resistance, prediabetes and overt diabetes, and this risk is present from the preclinical period [81-83].
DM is a metabolic disease characterized by hyperglycemia due to impaired insulin secretion/effectiveness. Long-term damage, dysfunction and failure of end organs such as kidneys, heart, and eyes may occur as a result of chronic hyperglycemia. Symptoms such as polyuria, polydipsia, polyphagia, nocturia, weight loss, numbness in hands and feet, burning, itching, and dry skin may be observed. Complications such as hyperglycemic hyperosmolar state or ketoacidosis may occur. Fasting plasma glucose, glycosylated hemoglobin A1c (HbA1c), or an oral glucose tolerance test (OGTT) may be used in the diagnosis [84].
Metabolic Syndrome and Hypertension
Hypertension is common in individuals with T2DM, as it is often a component of the MetS. Other components of the MetS, such as central obesity and dyslipidemia (especially an atherogenic lipid profile) and associated oxidative stress, low-grade chronic inflammation, endothelial dysfunction, insulin resistance and hyperinsulinemia, are the most important underlying causes of hypertension in T2DM. Hypertension is one of the most influential components of MetS and is the sole risk factor for CVD. The strongest hypothesis about the causes of HT in MetS is the hyperinsulinemia-induced increase in sodium reabsorption. Although HT individuals do not have obesity, IR has been found to be present [85, 86]. Although insulin resistance is frequently found in the background of HT, insulin resistance is not only involved here but also in other vascular diseases. There may be an increase in sympathetic system activation and renal sodium retention through mediators such as nitric oxide (NO) [85]. There is a connection between hypertension, insulin resistance, hyperglycemia, and hyperinsulinemia [87].
High blood pressure is often associated with other CVD risk factors, including dyslipidemia and insulin resistance. Insulin resistance is one of the underlying causes of hypertension in individuals. The relationship between insulin resistance and hypertension is well known [88, 89]. Various mechanisms have been proposed to establish the relationship between hypertension and insulin resistance [88, 90]. For example, insulin is a vasodilator that has secondary effects in increasing sodium reabsorption by the kidney and can lead to hypertension. Insulin has a vasodilator effect, but in the case of insulin resistance, its vasodilator effect is reduced, while its effect on sodium reabsorption remains unchanged. Hyperinsulinemia activates the renin-angiotensin system (RAS) by increasing the expression of angiotensinogen, angiotensin II (AT-II), and angiotensin I (AT-I) receptors, which contribute to the development of vasoconstriction and hypertension [88, 91].
Metabolic Syndrome and Dyslipidemia (Hyperlipidemia)
Dyslipidemia is defined as raised triglycerides and decreased high-density lipoprotein (HDL) cholesterol levels. Dyslipidemia in MetS is characterized by high triglyceride values and is a common component in various diagnostic criteria made by international organizations [92, 93]. In addition, low levels of HDL cholesterol are another criterion associated with MetS. Low-Density Lipoprotein (LDL) levels, which have a potential atherogenic effect, are usually elevated. Similar to LDL cholesterol, Apolipoprotein B also has an atherogenic effect and increases the risk of cardiovascular disease. Apolipoprotein B measurement and monitoring are not yet widely used [94].
Muscle, fat, and other tissues may become less sensitive to insulin as we age, resulting in dysglycemia and dyslipidemia [95]. As a result of defects in lipoproteins, the amount of free fatty acids in circulation increases. Insulin resistance is caused by abdominal obesity and this increase in free fatty acids increases triglyceride synthesis in the liver. This dyslipidemia picture that emerges in MetS leads to cardiovascular disease predisposition and endothelial damage [96].
Dyslipidemia, which is the leading cause of young death in many countries, increases the likelihood of atherosclerotic CVDs [97, 98]. Among the factors that increase the likelihood of atherosclerotic CVD, dyslipidemia is the most likely to be prevented. In addition to directly affecting the pathogenesis of atherosclerosis, it is highly prevalent and asymptomatic in humans. In studies conducted on individuals living in North America and Europe, it has been reported that one in two adults has dyslipidemia [99, 100]. The rapid increase in T2DM and obesity today causes dyslipidemia to be seen frequently [101].
The claim that it is caused by lifestyle is not true for dyslipidemia. This is because the symptoms of familial hypercholesterolemia, which is an autosomal dominantly inherited single-gene disease and is very common worldwide, are associated with high cholesterol levels and early atherosclerotic CVDs, which do not occur due to lifestyle. Heterozygous familial hypercholesterolemia rates have been shown to range from 1/100 to 1/500 [102, 103].
There are many polygenic familial dyslipidemias with high lipid levels and the incidence in humans is 5-7%. Some of the polygenic familial dyslipidemias that are not related to lifestyle, such as familial hypercholesterolemia, are associated with TG alone, while others are associated with LDL and TG. Dyslipidemia is mostly investigated in association with the possibility of atherosclerotic CVD, and the increased risk of pancreatitis in case of excessive increase in TG levels should also be taken into consideration [104].
In many studies, it has been reported that the use of statins, a group of lipid-lowering drugs for primary and secondary prevention, reduces mortality from atherosclerotic CVDs [105, 106]. Research has shown that the magnitude of cardiovascular benefit is proportional to the reduction in LDL levels [107]. Based on this, several agents have been developed that provide strong reductions in LDL levels, and good results have been obtained [108].
Metabolic Syndrome and Endothelial Dysfunction
Risk factors for oxidative stress such as hypertension, diabetes, smoking, and dyslipidemia cause vascular inflammation and endothelial dysfunction. In addition, a decrease in the level of vasodilator nitric oxide (NO) affects the increase in oxidative stress, leading to pathobiological consequences that open the door to vascular complexities [109-111].
With hyperinsulinemia and insulin resistance, endothelial function deteriorates and vascular damage progresses. One of the harms of insulin resistance is the inhibition of NO-induced vasodilation. In the presence of diabetes and MetS, NO levels decrease in the presence of excess synthesis of superoxide-like reactive oxygen radicals (ROS). Insulin resistance and the level of endothelial dysfunction are proportional to each other [112].
With the increase in insulin ratio in hyperinsulinemia, the nuclear effect caused by oxidative stress activates kappa B (NF-κB), leaving soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) in excess, which is recognized as the inflammatory phase of atherosclerosis. In addition, the regional concentration of C-reactive protein (CRP) leads to the production of interleukin-like pro-inflammatory cytokines [109]. In this way, hyperinsulinemia puts direct pressure on vascular smooth muscle and endothelial cells and supports the formation of atherosclerosis [113].
Vascular Inflammation and Prothrombotic Status in Metabolic Syndrome
In addition to inflammatory cytokines, many substances are produced from adipose tissue. Interleukin-6 (IL-6), which is the most potent cytokine involved in inflammatory activities, is one of the most important stimulators in CRP synthesis. Tumor necrosis alpha (TNF-α) can also be demonstrated from adipose tissue. TNF-α, which inhibits lipogenesis, prevents obesity formation by increasing apoptotic adipocyte formation and lipolysis. The best measures of the procoagulant or prothrombic pattern in these patients are the increase in plasminogen and plasminogen activator inhibitor-1 (PAI-1). As a result, it prepares the ground for the increase in atherogenesis and the formation of a thrombus that enables acute coronary progression [114, 115].
The variety of released adipokines includes hormones (e.g. leptin, adiponectin), peptides (e.g. angiotensinogen, apelin, resistin, and PAI-1, and inflammatory cytokines (IL-6, TNF-α, visfatin, omentin, and chemerin), all of which play a major role in the pathophysiology of insulin resistance and MetS [1, 115].
Metabolic Syndrome and Non-alcoholic Fatty Liver Disease
Non-alcoholic fatty liver disease (NAFLD) is a group of diseases characterized by marked macrovesicular steatosis in the liver without alcohol intake. Recent studies have shown that the relationship between NAFLD and MetS is reciprocal and bidirectional. For example, in the early 2000s, it became clear that surrogate indices of liver dysfunction predict T2DM and MetS [116, 117]. Taking these epidemiologic data further, it has been possible to conduct theoretical and meta-analytic studies showing that NAFLD is in fact a potential precursor of T2DM and MetS and that the fibrosis stage is a strong predictor of such a risk [118-120].
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the latest term for steatotic liver disease associated with MetS. In July 2023, with the consensus of the International Liver Societies, terminology, and diagnostic criteria were revised under the main heading of 'steatotic liver disease (SLD)', and the name NAFLD was changed to 'metabolic associated steatotic liver disease (MASLD)' because the terms 'non-alcoholic' and 'fatty' did not fully reflect the pathophysiology [121].
MASLD is closely linked to MetS, as both conditions involve disturbances in metabolic processes that can lead to liver complications. Individuals with MetS often have a higher risk of developing MASLD. The accumulation of fat in the liver (steatosis) is a common feature of both conditions. In MetS, insulin resistance and dyslipidemia contribute to the accumulation of fat in the liver, leading to MASLD. The presence of MetS, T2DM, hypertension, dyslipidemia/hyperlipidemia, and hyperuricemia increases the risk of developing more severe forms of liver disease, such as MAFLD and metabolic dysfunction-associated steatohepatitis (MASH, former name NASH) [122-125].
The presence of NASH increases the risk of T2DM 2-5 times and the risk of cardiovascular disease 2-3 times [123, 125]. Insulin resistance is the most important responsible mechanism in comorbidities and NAFLD. In the association of NASH and T2DM, the risk of developing cirrhosis and HCC increases 2-4-fold [123-125]. The risk of death due to chronic liver disease is approximately 3 times higher in T2DM patients compared to non-diabetic patients [126]. Therefore, guidelines recommend that patients with obesity, insulin resistance, and/or MetS should be screened for NAFLD, and patients with prediabetes or T2DM should be evaluated for NAFLD every 6-12 months [127].
TREATMENT
The primary treatment in MetS, which is a disease picture that emerges under the influence of genetic and environmental factors, should be a positive and permanent lifestyle modification. The general approach in treatment is to first establish lifestyle changes in the patient [128]. Lifestyle and dietary changes are encouraged to treat all of the components of MetS. Lifestyle and dietary changes are encouraged to treat all of the components of MetS. Since the majority of individuals with MetS are overweight, it is important to focus on dietary therapies that help individuals lose weight [129]. Weight loss provides many benefits. It is reported that a small decrease in body weight (5-10%) is sufficient to raise HDL-C and lower TG levels [130]. In addition, ideal weight loss has been shown to regulate blood pressure and reduce parameters associated with fasting blood glucose and insulin resistance [131]. Since the majority of individuals with MetS are overweight, it is important to focus on dietary therapies that help individuals lose weight [129]. Weight loss provides many benefits. It is reported that a small decrease in body weight (5-10%) is sufficient to raise HDL-C and lower TG levels [130]. In addition, ideal weight loss has been shown to regulate blood pressure and reduce parameters associated with fasting blood glucose and insulin resistance [131]. Baxheinrich et al. [132
