Epidemiology of Metabolic Syndrome: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Marko Kumric.

Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities that includes hypertension, central obesity, insulin resistance, and atherogenic dyslipidemia. Due to the high prevalence (around 1/3 of the world population) economic burden of MetS, there is a need for new dietary, lifestyle, and therapeutic options. 

  • metabolic syndrome

1. The Definition of Metabolic Syndrome

In 1988, during his Banting lecture, Reaven characterized a cluster of conditions related to insulin resistance. He called the cluster “Syndrome X” or “the deadly quartet”, and it consisted of obesity, non-insulin-dependent diabetes mellitus, hypertension, and dyslipidemia [26,33][1][2]. Since then, multiple definitions have been brought forward to better encompass this clustering of cardiometabolic risk factors. These include the WHO definition from 1998, the NCEP (National Cholesterol Education Program) definition from 2003, and the IDF (International Diabetes Federation) definition from 2006 [20][3]. To avoid further discrepancies and to standardize the diagnostic criteria, several major health organizations jointly produced the harmonized definition of MetS that is currently in use [34][4].
According to the harmonized definition, MetS is defined by the following criteria:
(1) The presence of insulin resistance/prediabetes (glucose level > 100 mg/dL (5.6 mmol/L)), or diagnosed type 2 DM.
(2) Enlarged waist circumference (the exact values of which are adjusted according to population-specific and country-specific criteria).
(3) HDL-C < 40 mg/dL (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women or triglycerides ≥ 150 mg/dL (1.69 mmol/L) (with the inclusion of those taking medicine to treat dyslipidemia).
(4) Systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg (including patients on anti-hypertensive therapy).

2. Epidemiology of Metabolic Syndrome

The central type of obesity is the most common characteristic found in MetS; therefore, the incidence and prevalence of MetS closely follow that of obesity [35,36][5][6]. Every two years, the US conducts the National Health and Nutrition Examination Survey (NHANES), in which they obtain obesity rates among people aged two or older. The latest data for 2017–2018 show that obesity prevalence among adults was 42.4% [37][7]. By contrast, the obesity rates for adults at the start of the decade were 35.7%, with a rising trend of approximately 2% every two years. The rising trend is slower for the pediatric population, with the 2009–2010 obesity rate at 16.9% and the 2017–2018 obesity rate at 19.3% [37][7]. In a study by Hirode et al., where the authors examined NHANES data form 2011 to 2016, among 17048 participants, the MetS weighted prevalence was 34.7% (95% CI, 33.1–36.3% [n = 5885]) [11][8]. In other words, as much as one-third of the US adult population suffers from MetS.
The large prevalence is not restricted to the US, as comparable data were found in Brazil, where the latest MetS prevalence was 38.4% [13][9]. High waist circumference (65.5%) and low HDL cholesterol (49.4%) were the most prevalent MetS components among the Brazilian population. In addition, MetS was more frequent among women (41.8%), individuals with less education (47.5%), and older adults (66.1%) [13][9]. Similarly, in Mexico, investigators performed a systematic meta-analysis on 15 studies in which the pooled prevalence of MetS was 41% (95% CI 0.34–0.47) [12][10].
In Asia, a metanalysis in which investigators pooled MetS prevalence data from the Chinese population from 2008–2015 found that the pooled prevalence for subjects aged 15 years and older was 24.5% (95% CI: 22.0–26.9%). This metanalysis on the Chinese population also saw a similar trend, according to which the MetS prevalence was higher in females 27.0% (95% CI: 23.5–30.5%) vs. males 19.2% (95% CI: 16.9–21.6%) [38][11]. However, another study on the Chinese population showed marked differences in MetS prevalence between various ethnic groups. The Korean population featured the highest MetS prevalence (35.42%), the Hui population the second highest (22.82%), while the Mongolian and Tibetan populations featured the lowest (11.61%) and (6.17%) respectively [39][12].
Furthermore, in a European study examining data from two cohorts, one from Russia and the other from Italy, the MetS prevalence was 37% for the former and 21% for the latter [40][13]. In addition, another study examined the data from 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA. MetS prevalence was 24.3% (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001), with an age-related increase in prevalence across all cohorts [15][14]. Furthermore, in a study on the Portuguese population, in which data were gathered from 2007 to 2009, MetS prevalence was 36.5%, 49.6%, and 43.1%, using the Adult Treatment Panel III, International Diabetes Federation, and Joint Interim Statement definitions, respectively [14][15]. MetS prevalence was significantly higher in women and the older population in Portugal, as shown in the aforementioned studies. At the same time, it was also more frequent in non-urban areas than in urban areas (p = 0.001) [14][15]. Interestingly, in contrast to these findings, a study on the Czech population found that MetS is less common in females 25.5%, then in males 37.6% [41][16]. Akin to these findings, MetS prevalence was also higher in Slovakian males (30.2%), than in females (26.6%), with an increasing trend from 2003 to 2012 [42][17].
When examining the data we mentioned, we can see large differences in MetS prevalence among various populations, from the low of 11.61% in the Tibetan population, to the high of 41% in the Mexican population [12,39]. The reasons behind the observed discrepancies are probably a result of different lifestyles, with Western dietary habits making people more susceptible to MetS. If we take a closer look at migrant populations (from countries with low to countries with high rates of obesity) we observe a rather interesting twist. Namely, although migrants arrive with a health advantage, including generally healthier body weight, intrinsic and environmental factors combine to cause unhealthy weight gain, often to beyond the levels seen in native populations [43]. According to Neel et al., this observation may be explained from an evolutionary standpoint. Although the loss of uricase may have provided a survival advantage by amplifying the effects of fructose to enhance fat stores, and by increasing blood pressure in response to salt, the absence of the “thrifty” uricase gene may have caused a range of detrimental metabolic effects on modern humans (characterized by excessive caloric intake), thus explaining the current epidemic of obesity and diabetes [44]. The putative mechanism associating fructose and loss of uricase lies in the observation that uric acid may regulate fructose metabolism by affecting fructose transporters in the intestines and fructokinase in the liver [45]. Nevertheless, with the Western lifestyle prevailing in most of the world, there is an increasing global trend of MetS prevalence, with approximately one-quarter of the world’s population currently suffering from MetS [11,20,46].

3. Pathophysiological Background of Metabolic Syndrome

As is the case with other chronic non-communicable diseases, MetS also results from a complex interplay between genetic and environmental factors. Currently, central obesity/visceral adipose tissue (VAT) is considered to play one of the main roles in initiating the deadly quartet of MetS. VAT exerts its influence on glucose and lipid metabolism via multiple mechanisms. Firstly, VAT is a major source of free fatty acids (FFA), which are directly connected to the liver via splanchnic circulation [4][18]. In the liver, FFAs lead to increased gluconeogenesis, as well as increased triglycerides and very low-density lipoprotein (VLDL) production [6][19]. The increase in liver FFA oxidation induces a decrease in xylulose 5-phosphate, which results in the activation of gluconeogenesis (by inhibiting phosphofructokinase 1 and activating fructose-1,6-bisphosphatase) [47][20]. Furthermore, the ectopic accumulation of lipid metabolites (ceramides, diacylglycerol, acetyl-CoA and fatty acids) decreases insulin sensitivity [48][21]. These lipid metabolites, in turn, activate serine/threonine kinases (protein kinase C (PKC), nuclear factor-kB (NFkB), inhibitory kB kinase b (IKKb)), which then phosphorylate insulin receptor substrate (IRS) and protein kinase B/Akt, and therefore inhibit insulin signaling [47,48][20][21].
Moreover, adipose tissue is a source of many cytokines and hormones, called adipokines. Studies have shown that central obesity/VAT is related to dysregulated adipokine secretion, with increased levels of plasminogen activator inhibitor (PAI-1), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), angiotensinogen, and interleukin 6 (IL-6). In addition, leptin, a hormone that regulates satiety, energy expenditure, and appropriate glucose homeostasis, is directly correlated to the amount of white adipose tissue. Even though, in physiological conditions, leptin promotes satiety and signals the amount of fat storage to the hypothalamus, it seems that in MetS, there is a leptin resistance or a certain ceiling on the possible effect of leptin, beyond which new leptin stimulates little effect [49][22].
On the other hand, in central obesity, there are decreased levels of adiponectin, which is considered the “good” adipokine. The primary action of adiponectin is phosphorylation and the activation of key intermediates in the insulin signaling pathway, increasing insulin sensitivity [50][23]. Therefore, a lack of adiponectin in MetS promotes insulin resistance and disrupts glucose homeostasis.
The aforementioned TNF-α, IL-6, and MCP-1 are pro-inflammatory cytokines, which contribute to the systemic low-grade inflammation found in MetS. At the same time, PAI-1 increases the risk of thrombosis and accelerates the development of atherosclerosis [4,51][18][24]. This low-grade inflammation leads to further insulin resistance in muscles, as well as to disruption of o β-cells [52,53][25][26].
As recently reviewed, there is also essential gut–adipose tissue crosstalk, which is disrupted in the setting of MetS. Postprandial incretins, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP), which regulate glucose homeostasis and exert anorexigenic effects, are significantly decreased in obese or T2DM patients [54][27]. Furthermore, in patients with obesity and MetS, the levels of appetite-inducing hormone ghrelin fail to progressively decline after meal ingestion [54][27]. This disruption in anorexigenic/orexigenic hormone homeostasis induces a positive loop that ultimately ends in obesity/MetS.
Finally, the pathogenesis of hypertension in MetS is multifactorial as well. Hyperinsulinemia exerts an anabolic effect on the heart muscle and the media of the blood vessel wall. It also promotes sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) activity, leading to vasoconstriction, sodium retention, and endothelial dysfunction [55][28]. Interestingly, recent studies have also elucidated leptin’s role in obesity-related hypertension. Acting on its receptors in the hypothalamus, leptin initiates a downstream signal transduction that ends in the preganglionic autonomic neurons of the spinal cord, leading to increased sympathetic activity in the kidneys and, therefore, increased blood pressure [56][29]. Nevertheless, each presented mechanism’s relative contribution to hypertension development remains elusive.
Moreover, the presence of obstructive sleep apnea and baroreflex dysfunction in MetS further increase SNS activity [57,58,59][30][31][32].
While the current understanding of MetS pathophysiology is discussed above, it is a continuously improving subject with new research that will help us better understand the puzzle of MetS.

4. Effects of Diet on Metabolic Syndrome

The Western diet, characterized by a high intake of red and processed meat, refined grains, sweets, and sugary beverages, is associated with an increased risk of developing MetS [60,61][33][34]. This diet is calorie-dense, rich in small-chain fatty acids (SFA), simple carbohydrates, and other nutrients that feature pro-inflammatory properties, disrupt the gut microbiota, and dampen insulin sensitivity [61,62,63][34][35][36]. A meta-analysis by Fabiani et al. has shown that the “Meat/Western” pattern leads to a 19% increase in MetS risk, while a “Healthy” dietary pattern (fruit, vegetables, whole grains, fish, no processed food/high content of vitamins, minerals, antioxidants, fiber, MUFA, and n-3 fatty acids) is associated with a 15% decrease in MetS risk [60][33]. Similar results were obtained in another meta-analysis that also studied the relationship between a posteriori dietary patterns and MetS: a healthy/prudent diet was associated with a lower prevalence of MetS, while an unhealthy/Western pattern was associated with an increased risk of developing MetS [64][37]. Another popular dietary pattern, the Mediterranean diet, has also shown benefits regarding MetS [65,66][38][39]. In a meta-analysis by Kastorini et al., the combined effect of prospective studies and clinical trials showed that the Mediterranean diet is associated with a reduced risk of MetS (log hazard ratio: −0.69, 95% confidence interval (CI): −1.24 to −1.16) [67][40]. Comparable results were achieved with the dietary approaches to stop hypertension (DASH), where multiple studies showed how the DASH diet led to a reduction in systolic and diastolic blood pressure, a reduction in BMI and waist circumference, an improvement in cardiometabolic profile, and a reduction in T2DM incidence [68,69,70,71,72][41][42][43][44][45].
Therefore, there is substantial evidence that diets such as the Mediterranean diet and DASH exert a beneficial effect on cardiometabolic risk factors, with a common theme in which foods such as vegetables, fruit, whole grains, and fish are associated with these benefits. Nevertheless, in addition to the diet itself, dietary regime adjustments may provide metabolic benefits regardless of the amount and type of food ingested.

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