Many centuries ago ‘Charwaka’, an Indian philosopher of ancient times, quoted “one should eat oily, spicy things even on credits. Because once you have burnt to ashes or lay down deep in the earth, there will be no coming back.” This is one of the several streams of Indian philosophy. Now-a-days as a result of changes in lifestyles and eating habits, the chemistry of human body starts changing. Even if people don’t know Charwaka, might be due to various reasons, they have started adapting his principle. Junk foods, lack of exercise, psychosocial stress are the conspicuous ones among the various reasons that are leading to dreadful metabolic disorders. The metabolic syndrome is one of them.

The metabolic syndrome (MetS) is a constellation of interrelated risk factors of metabolic origin - metabolic risk factors - that appear to directly promote the development of atherosclerotic cardiovascular disease (CVDs) [1]. The metabolic syndrome has become one of the most important topics for this decade because of the marked increase in cardiovascular risk associated with a clustering of risk factors.

It consists of atherogenic dyslipidemia (elevated triglycerides and apolipoprotein B-containing lipoproteins and decreased high-density lipoproteins [HDL]), elevations of blood pressure (BP) and glucose, and prothrombotic and proinflammatory states [2]. The constellation of dyslipidemia (hypertriglyceridemia and low levels of high-density lipoprotein cholesterol), elevated blood pressure, impaired glucose tolerance, and central obesity is now classified as metabolic syndrome, also called syndrome X [3].

Several expert groups have attempted to set forth simple diagnostic criteria for use in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general, they include a combination of multiple and metabolic risk factors [3].

The definitions of metabolic syndrome include those proposed by the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the US National Cholesterol Education Program (ATPIII) and International Diabetes Federation (IDF) [4-7].

In 1998, the WHO criteria for diagnosing the metabolic syndrome put forth. It is based on the insulin resistance in the form of diabetes mellitus or impaired glucose tolerance (IGT). Other criteria are any two of central obesity [Waist hip ratio >0.90 (Male), more than 0.85 (Female) and/or BMI >30 kg/m²], lipidemia [TG >1.7 mmol/l, HDL-C <0.9 mmol/l (Male), <1.0 mmol/l (Female)], hypertension (>140/90 mm Hg) or microalbuminuria (urinary albumin 20 μg/min or greater, or albumin-to-creatinine ratio 30 mg/g or greater).

Immediately next year in 1999, the European Group for the Study of Insulin Resistance (EGIR) proposed new criteria. Microalbuminuria was excluded. Insulin resistance was defined as insulin level more than 75^th percentile of normal non-diabetic subjects. For central obesity, waist circumference was the only criteria. Glycemia assessment (Fasting glucose ≥ 6.1 mmol/l & <7 mmol/) was included. Reference values for lipidemia were modified.

Later in the year 2001, NCEP ATP III came in to being. Three or more of the glycemia, lipidemia, obesity and hypertension were necessary for diagnosis. Only difference made was modified reference waist circumference and blood pressure.

In the year 2005, IDF proposed diagnostic criteria for metabolic syndrome. This was based on Central obesity of more than 30 Kg/m2 with ethnic specificity plus 2 or more of hyperglycemia, hyperlipidemia and hypertension. Modifications were made in glycemia (more than 100 mg%) and HDL levels. In each of derangements a new assessment criteria of normal levels with treatment was included.

WHO, EGIR, NCEP ATP III were lacking any ethnic specificity, as found in IDF. Also the insulin measurement which is available only with higher centers is a main drawback for WHO and EGIR criteria. Depending upon hyperglycemia, IDF criteria is more stringent. One can conclude that WHO and EGIR criteria are insulinocentric while the obesity is central to the IDF (Table 1).

Table 1: Three or more of the glycemia, lipidemia, obesity and hypertension were necessary for diagnosis. Only difference made was modified reference waist circumference and blood pressure.

Obesity and physical inactivity are the driving forces behind the syndrome but another set of factors, metabolic susceptibility, usually is required for the MetS to become evident [8] Susceptibility factors include adipose tissue disorders (typically manifest as abdominal obesity), genetic and racial factors, aging, and endocrine disorders [9].

MetS is associated with many diseases. Two primarily clinical outcomes of MetS are CVD and NIDDM, which both are leading diseases in the structure of the morbidity and mortality worldwide. In fact, all individual components of MetS are risk factors for CVD [10,11]. MetS implies even higher risk for coronary heart diseases (CHD) and CVD [12,13] and death from them [14] than individual abnormalities. Indeed, MetS was shown to be the most important factor responsible for myocardial infarction in the population younger than 45 [15]. Similarly, individual components of MetS (obesity, hypertension, low levels of HDL cholesterol, elevated TAG levels, and impaired fasting glucose) and MetS per se are all significant predictors of NIDDM [3,13].

MetS and its single components are tightly connected with the development of non-alcoholic fatty liver disease [16] which is one of the most distributed liver diseases in industrial countries [17]. MetS is more prevalent in patients with polycystic ovarian syndrome (PCOS) [18]. The correlation was found between PCOS and single components of MetS such as insulin resistance and obesity [19]. Linking factor for both syndromes is considered to be insulin resistance [20] Breast cancer is the main cause of death from cancer in women. It was shown, that individual components of MetS increase the risk for breast cancer [21]. MetS is also associated with schizophrenia [22] and sleep apnea syndrome [23]. The MetS is often associated with other medical conditions, notably, fatty liver, cholesterol gallstones, obstructive sleep apnea, gout, depression, musculosketal disease, and polycystic ovarian syndrome [24].

Depending upon the criteria used, the prevalence varies. Least with initial version of NCEP ATP III, maximum prevalence found to be with IDF criteria. This is because IDF adapted lower cut off for glycemia and waist circumference [25]. Series of studies showed the change in the trend of prevalence of MetS. There is always increasing trend with increasing age. Prevalence of glycemia, hypertension and triglyceridemia shows downward trend which corresponds to the increase in hypolipidemic, antihypertensive and hypolipidemic drugs respectively [26].

Obesity is a major determinant of the MetS. It is estimated that by 2030 the absolute number of obese individuals could rise to a total of 1.12 billion, accounting for 20% of the world’s adult population [27]. This will definitely contribute to the increasing global burden of MetS in near future. DECODE (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe) describes significant increase in death by all causes and cardiovascular complications in individuals with MS [28].

Insulin resistance and obesity

The most accepted hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance. That is why the metabolic syndrome is also known as the insulin resistance syndrome. Insulin resistance has been defined as a defect in insulin action that results in hyperinsulinaemia, necessary to maintain euglycaemia. The predominant underlying risk factors for the syndrome appear to be abdominal obesity and insulin resistance [29-31].

A major contributor to the development of insulin resistance is an overabundance of circulating fatty acids, released from an expanded adipose tissue mass. Free fatty acids (FFAs) reduce insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. Increased level of circulating glucose increases pancreatic insulin secretion resulting in hyperinsulinemia. In the liver, FFAs increase the production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). The consequences of this are the reduction in glucose transformation to glycogen and the increased lipid accumulation in triglycerides (TG) [32]. Insulin is an important antilipolytic hormone. In the case of insulin resistance, the increased amount of lipolysis of stored triacylglycerol molecules in adipose tissue produces more fatty acids, which could further inhibit the antilipolytic effect of insulin, creating additional lipolysis [33].

The adipose tissue of obesity exhibits abnormalities in the production of several adipokines that may separately affect insulin resistance These include increased production of inflammatory cytokines, plasminogen activator inhibitor-1 and other bioactive products; at the same time the potentially protective adipokine, adiponectin are reduced [34-36].

Obesity is involved in the onset of MetS through the alteration of oxidative status of organism. In fact, oxidative stress is tightly involved in the increase of blood pressure through the regulation of a variety of factors [37]. More importantly, it is associated with the development of insulin resistance, another essential component of MetS. In fact, oxidative stress induces insulin resistance in variety of cells which regulate systemic response to insulin: adipocytes, muscle and liver cells [38-40]. It has been proven recently, that oxidative stress has a causative role and is primarily in relation to the onset of insulin resistance [41]. Ultimately, oxidative stress has been shown to correlate with dislipidemia (high triacylglyceride concentration, low level of high-density lipoprotein cholesterol) and abdominal fat [42]. In patients with MetS and thus might be considered as a linking factor between the single components of MetS. A genetic predisposition to defective insulin secretion when combined with insulin resistance can raise plasma glucose to abnormal levels [43]. Pathophysiology and effects of proinflamatory state are shown in Figures 1 and 2.

Figure 1: Pathophysiology of metabolic syndrome.

Figure 2: Paracrine and endocrine effects of proinflamatory state.

Free fatty acids (FFA) are released in abundance from an expanded adipose tissue mass. In the liver, FFAs leads to an increased production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). Associated lipid/lipoprotein abnormalities include reductions in high density lipoprotein (HDL) cholesterol and an increased density of low density lipoproteins (LDL). FFAs also reduce insulin sensitivity in muscle by inhibiting insulin mediated glucose uptake. Increase in circulating glucose and to some extent FFAs increase pancreatic insulin secretion resulting in hyperinsulinemia. This may results in enhanced sodium reabsorption and increased sympathetic nervous system (SNS) activity and contributes to the hypertension as might increase levels of circulating FFAs.

IDF tries to classify age related developmental changes. It age groups as 6-10, 10-16 and more than 16 years. There is lack of data available for the age group less than 6 years. Different cutoff values are assigned to the parameters for children and adolescents. Infants born to the diabetic mother or born to those having gestational diabetes mellitus are more susceptible for the development of MetS. Large for Gestational Age (LGA) babies born to diabetic mothers are more susceptible to development of MetS in childhood [44].

Recent epidemiological and environmental studies suggest relationship between antenatal environment and risk of developing insulin resistance with metabolic syndrome in middle age. This may caused by prenatal and postnatal environmental mismatch. Epigenetically if such changes are passed to further generations, may develop the disease even at low exposure [45].

Different methods are implemented for genetic studies in MetS. Inheritance patterns are studied using linkage analysis. Traits coinherited with disease causing mutation are used to detect mutations. The results of genome wide association studies (GWAS) are available where single nucleotide polymorphism (SNPs) is searched to study the disorder. Deviation in expression of gene activity without DNA changes is studied in epigenetic studies. Proteomics is one more tool for genomic analysis of MetS.

Many genes are studied for possible contribution to the development of MetS. They include lipoprotein lipase (LPL), apolipoprotein E (APOE) gene, [46]. Many SNPs are discovered in relation to the hypertension and body mass index [47,48]. Melanocortin receptor 4 (MC4R) gene and fat mass and obesity associated (FTO) gene are the important genes studied well with respect to obesity. Monogenic forms of obesity are related to the MC4R gene though some forms of polygenic obesity are also associated with it [49]. A particular form of SNP in FTO gene is associated with increased hunger, reduced satiety finally to raise BMI. As compared to the normal population, FTO gene is more prevalent in those with MetS [50].

Metabolic syndrome is associated with various cancers. The risk differs depending upon sex, ethnicity and criteria used for defining MetS. According to some meta-analytical studies, risk ratios for hepatic, colorectal, pancreatic carcinomas are higher in males while that in females prevalent are endometrium, pancreatic and breast cancer. In both males and females, gastric, lung and bladder cancers are rare [51]. Mechanisms for the link between metabolic syndrome and cancer risk are not fully understood.

Metabolic syndrome may be harbinger of cancer risk in future through decreased physical activity, consumption of high dietary fat and energy dense foods, low fiber intake, and damage by oxidative stress [52]. Inflammatory state is produced due to secretion of the inflammatory cytokines by adipocytes and immune cells which is fertile ground for tumors. Cytokines are link between the inflammation and cancer. Loss of function of tumor suppression, increase frequency of cell cycle, increase oncogenic expression are results of cytokines and other mediators of inflammation like tumor necrotic factor (TNF), reactive oxygen species (ROS) [53].

Peroxisome proliferator activated receptors (PPAR) are the receptor involved in glucose metabolism through action over insulin sensitivity and is one of the target diabetes treatment. This is a ligand-activated transcription factor belong to nuclear hormone receptor superfamily. PPARγ interaction with cytokines has key role to play in carcinogenesis [54]. Insulin resistance through insulin like growth factor-1 (IGF1) stimulates carcinogenesis. IGF1 has proliferative and antiapoptotic action over tumors. Important components of carcinogenesis cellular proliferation and angiogenesis are stimulated by IGF1 [55]. Adiponectine which is reduced with increase in adipocyte cell mass has tumor preventive action. In MetS adiponectin secretion is reduced. Antineoplastic activity is by the virtue of antiproliferative and anti-inflammtory effect with insulin antagonist action [56].

There are various styles for diagnosis of metabolic syndrome depending upon the criteria and cut off values used for them by the authorities. Depending on these styles, prevalence of metabolic syndrome change. Some criteria are modified for different ethnic groups. Some are more stringent as compared to others.

Developmental aspects play important role in metabolic syndrome. Along with environmental factors genetic makeup of person decides expression of MetS. Various tests are there to study the genomics of MetS. Genomic analysis provides information about SNPs or other genetic changes leading to MetS. Metabolic syndrome is not only limited to its components but also some dreadful diseases like cancers found their origin in MetS.

Thus metabolic syndrome is not the single entity but the orchestra of many disorders. Proper knowledge of diagnosing criteria, epidemiology, developmental aspects and genomics can help in timely diagnosis as well as finding the new avenues for treatment.