Of the Following, Which Group Would Not Fit the Definition of a Public Family?

Abstruse

The metabolic syndrome refers to the co-occurrence of several known cardiovascular risk factors, including insulin resistance, obesity, atherogenic dyslipidemia and hypertension. These conditions are interrelated and share underlying mediators, mechanisms and pathways. In that location has been recent controversy near its definition and its utility. In this article, I review the electric current definitions for the metabolic syndrome and why the concept is important. It identifies a subgroup of patients with shared pathophysiology who are at high hazard of developing cardiovascular disease and blazon 2 diabetes. By because the central features of the metabolic syndrome and how they are related, we may amend empathize the underlying pathophysiology and illness pathogenesis. A comprehensive definition for the metabolic syndrome and its cardinal features would facilitate research into its causes and hopefully lead to new insights into pharmacologic and lifestyle treatment approaches.

Physicians and scientists have long known that sure conditions increase a person's risk of developing atherosclerotic cardiovascular disease (CVD). These risk factors include a family history of premature coronary illness, hypertension, hyperlipidemia, diabetes and smoking. Historic period increases the hazard of CVD, as does male gender and post-menopausal hormonal status. Of these risks, some can exist modified – for example, cessation of smoking – whereas others, like genetic predisposition, cannot. The hazard of CVD can be decreased by addressing these individual take chances factors, both by lifestyle modifications and, if appropriate, pharmacologic treatment (National Cholesterol Teaching Program, 2002).

It has go increasingly articulate that sure CVD risks tend to cluster, or occur together. Furthermore, the lifestyle modifications of dietary modify and increased concrete activity can significantly touch on several risk factors simultaneously and, in so doing, reduce the risk of CVD. This clustering of some hazard factors and their shared responsiveness to lifestyle modifications suggests that they are not contained of i another and that they share underlying causes, mechanisms and features (Grundy et al., 2005; Kahn et al., 2005).

The metabolic syndrome is a clustering of hyperglycemia/insulin resistance, obesity and dyslipidemia. It is of import for several reasons. First, it identifies patients who are at high adventure of developing atherosclerotic CVD and blazon two diabetes (T2D). 2d, by considering the relationships between the components of metabolic syndrome, nosotros may be able to better sympathize the pathophysiology that links them with each other and with the increased risk of CVD. Third, it facilitates epidemiological and clinical studies of pharmacological, lifestyle and preventive treatment approaches.

Current definitions of metabolic syndrome

Table one summarizes four of the about commonly used definitions of metabolic syndrome. The World Health Organization (WHO) get-go developed its definition in 1998 (Alberti and Zimmet, 1998). Because insulin resistance was felt to be central to the pathophysiology of metabolic syndrome, bear witness for insulin resistance is an accented requirement in the WHO definition. This could exist dumb fasting glucose [IFG, defined as a fasting glucose level above a predetermined cutoff, unremarkably 100 milligrams per deciliter (mg/dl)] or impaired glucose tolerance (IGT, defined equally a glucose level above a predetermined cutoff, commonly 140 mg/dl, for 120 minutes afterward ingestion of 75 grams of glucose load during an oral glucose tolerance test). Alternatively, other measures could serve as testify of insulin resistance, such as an elevated homeostatic model cess of insulin resistance (HOMA-IR) value, which is proportional to the product of the fasting insulin and fasting glucose level. Finally, euglycemic hyperinsulinemic clamp studies could be used as show of insulin resistance. In addition to this absolute requirement for insulin resistance, two additional criteria have to exist met. These include obesity, dyslipidemia, hypertension and microalbuminuria.

Table one.

Definitions of metabolic syndrome

The WHO definition was the get-go to tie together the primal components of insulin resistance, obesity, dyslipidemia and hypertension. The definition mandates that insulin resistance be present; without information technology, even if all the other criteria were met, the patient would non take metabolic syndrome. The WHO definition also allows patients with T2D to be diagnosed with metabolic syndrome if they meet the other criteria. Because some of the measurements are not performed routinely, for instance, euglycemic clench studies, this definition is non easily applied clinically and does not lend itself besides to big epidemiologic studies, where rapid and simple assessment is important.

In 1999, the European Group for the Report of Insulin Resistance (EGIR) proposed a modification to the WHO definition (Balkau and Charles, 1999). Similar the WHO, the EGIR felt that insulin resistance is primal to the pathophysiology of the metabolic syndrome, so it also requires it for the definition. In this case, insulin resistance is defined by a fasting plasma insulin value that is greater than the 75th percentile. The use of elevated fasting insulin alone equally a reflection of insulin resistance simplifies the definition, but information technology also ways that patients with T2D cannot be diagnosed as having metabolic syndrome, since fasting insulin may not be a useful measure of insulin resistance in such patients. Also, similar to the WHO definition, the EGIR definition requires two additional criteria, which tin can be selected from obesity, hypertension and dyslipidemia. The obesity criteria were simplified to waist circumference, whereas the WHO definition used a choice of waist-to-hip ratio or body-mass index. Microalbuminuria was eliminated as a diagnostic benchmark.

In 2001, the National Cholesterol Pedagogy Programme (NCEP) Adult Treatment Panel III (ATP III) devised a definition for the metabolic syndrome (National Cholesterol Education Program, 2002), which was updated by the American Heart Clan and the National Heart Lung and Blood Constitute in 2005 (Grundy et al., 2005). According to the NCEP ATP Three definition, metabolic syndrome is present if iii or more of the following five criteria are met: waist circumference over twoscore inches (men) or 35 inches (women), blood force per unit area over 130/85 mmHg, fasting triglyceride (TG) level over 150 mg/dl, fasting loftier-density lipoprotein (HDL) cholesterol level less than 40 mg/dl (men) or 50 mg/dl (women) and fasting claret saccharide over 100 mg/dl.

The NCEP ATP III definition is one of the almost widely used criteria of metabolic syndrome. Information technology incorporates the central features of hyperglycemia/insulin resistance, visceral obesity, atherogenic dyslipidemia and hypertension. It uses measurements and laboratory results that are readily bachelor to physicians, facilitating its clinical and epidemiological application. It is also simple and easy to remember. Importantly, it does non require that any specific criterion be met; only that at least three of five criteria are met. Thus, the definition does not build in any preconceived notion of the underlying crusade of metabolic syndrome, whether it is insulin resistance or obesity.

In 2005, the International Diabetes Foundation (IDF) published new criteria for metabolic syndrome (Zimmet et al., 2005). Although it includes the same general criteria every bit the other definitions, it requires that obesity, only not necessarily insulin resistance, exist present. The obesity requirement is met past population-specific cutpoints. This accounts for the fact that different populations, ethnicities and nationalities have different distributions of norms for torso weight and waist circumference. Information technology likewise recognizes that the relationship betwixt these values and the take chances for T2D or CVD differs in different populations. For example, Southward Asian populations accept an increased risk for T2D and CVD at smaller waist circumferences that would not be considered to see the criteria in a Western population. Although visceral obesity is now recognized as an important factor, the IDF definition has been criticized for its accent on obesity, rather than insulin resistance, in the pathophysiology (Reaven, 2006).

Utility of the concept of metabolic syndrome

Patients at risk of CVD and T2D

The concept of metabolic syndrome has several practical uses. I important employ is in the everyday clinical assessment of patients, to identify patients at higher take chances of T2D or CVD. Withal, the metabolic syndrome should not be considered but as a way to identify patients at increased adventure, every bit other established run a risk cess methods accept other of import factors into consideration (Meigs, 2004). For example, none of the definitions of metabolic syndrome take into account family history of diabetes, which is 1 of the most potent known T2D risk factors. Thus, conclusion of metabolic syndrome would exist inferior to the use of a specific gamble assessment method such as the diabetes predicting model, which takes family history into account. Similarly, the metabolic syndrome definitions do non consider age, gender (although some of the cutpoints are gender specific), smoking, low-density lipoprotein (LDL) or full cholesterol levels, all known to be important CVD run a risk factors. Thus, metabolic syndrome would be inferior to a risk assessment tool, such as the Framingham risk score, for the prediction of CVD hazard. The major use of metabolic syndrome is not and then much in identifying patients at general hazard of CVD and T2D, but that it identifies a specific subgroup of patients with a shared pathophysiology. Thus, the term serves as autograph for clinicians for the common underlying biological processes.

The NCEP ATP III definition is practical easily in the clinical setting. Physicians tin can easily score patients (and, indeed, motivated patients can score themselves) on the five criteria using hands measured end points and come upwardly with a 'yes' or 'no' answer equally to whether metabolic syndrome is present. This differs from some of the more complicated adventure calculation methods, which may crave complicated algorithms or computation to come upwardly with an respond. Although it has not been proven, the promise is that realization of a diagnosis of metabolic syndrome will motivate people and their physicians to accept appropriate steps to reduce their adventure of CVD and T2D. This may involve lifestyle modifications such as improved food choices and increased physical activities, and appropriate pharmacological management for the component criteria.

Understanding common pathophysiological processes

The metabolic syndrome ties together insulin resistance, visceral adiposity, dyslipidemia and hypertension, which are known to be interrelated. In so doing, the concept may assistance usa to better understand the mutual pathophysiological processes; to develop useful animal models for the disorder; and to devise and test new therapies.

The metabolic syndrome has been assigned its own ICD-9 diagnostic code: 277.7. Despite this, in that location is ongoing controversy about whether metabolic syndrome is a homogeneous disorder or disease, and whether it claim recognition as a syndrome (Meigs, 2004; Grundy et al., 2005; Kahn et al., 2005; Reaven, 2006; Grundy, 2007). When considering the pathophysiology, information technology is important to recognize that people with isolated components, but who exercise not fit the definition of metabolic syndrome, are not at as high a take a chance for T2D or CVD. For case, people with isolated hypertension or isolated hyperlipidemia are at take a chance of CVD, merely less then than people who see multiple criteria. People with isolated obesity are at adventure for T2D, merely less so than people with metabolic syndrome. Although diabetes is considered by NCEP ATP III to be a CVD risk equivalent, boosted risk factors that lead to the diagnosis of metabolic syndrome further increase the risk of CVD in these patients. The argument has been fabricated that hypothetical patients with some, but not other, features may be miscategorized past one or another definition (Reaven, 2006). However, as discussed beneath, the structure of the definitions make this unlikely, and patients who truly reflect the common pathophysiological processes that underlie metabolic syndrome should, in fact, be captured past most of the definitions.

Epidemiological studies

There have been many epidemiological studies on metabolic syndrome, focusing on the prevalence of metabolic syndrome in various populations and the magnitude of risks for T2D, CVD and other related medical problems, including fatty liver, cholesterol gallstones, polycystic ovary syndrome, obstructive sleep apnea and gout. Such epidemiologic studies crave a simple, readily practical definition. These studies may add to our understanding not merely of the pathophysiology of the status, but also its genetic footing, using genome-wide association approaches. They may also lead to the development of treatment approaches that target the blended physiological abnormalities, rather than the private component criteria.

Central features

The expression, 'get in equally uncomplicated every bit possible, just not simpler' has been attributed to Albert Einstein. Post-obit this principle, the current definitions of metabolic syndrome may be distilled into four fundamental features: insulin resistance, visceral obesity, atherogenic dyslipidemia and endothelial dysfunction. Of these, the starting time two appear to be absolutely required for metabolic syndrome. In patients with metabolic syndrome, weight loss can atomic number 82 to improvements in multiple features at the same time, so a sure degree of adiposity appears to be required to manifest the abnormal pathophysiology. Conversely, in that location are patients who are obese just who practise not manifest any of the other components of metabolic syndrome, so both metabolic predisposition to insulin resistance and obesity appear to be necessary for expression of the metabolic syndrome phenotype. Atherogenic dyslipidemia follows from insulin resistance and visceral obesity, and can exist captured in the definition by including separate criteria for high serum TG levels and low HDL levels. Endothelial dysfunction too follows from insulin resistance and from adipokines and free fatty acids (FFAs) that are released from visceral adipose tissue. Endothelial dysfunction is captured past the requirement for hypertension in the definition. Both atherogenic dyslipidemia and endothelial dysfunction contribute mechanistically to the evolution of atherosclerosis and CVD.

Thus, the iv central features – insulin resistance, visceral adiposity, atherogenic dyslipidemia and endothelial dysfunction –would make up the simplest comprehensive definition for the metabolic syndrome, which cannot be simplified further. Even if other associated findings such as systemic inflammation, hypercoagulability or microalbuminuria are important to the pathophysiology, they would not be necessary as role of the definition because these findings would not be required independently. We volition discuss each of these primal features in the post-obit section. Their interrelationships are shown in the accompanying affiche.

Insulin resistance

Insulin is produced by the pancreas in response to hyperglycemia and stimulates glucose employ differently in various tissues. The tissues that remove glucose from the circulation and impact glucose utilise the most are skeletal muscle, liver and adipose tissue. In the skeletal muscle and adipose tissue, insulin stimulates glucose uptake by translocation of the GLUT4 glucose transporter to the cell surface. In the skeletal musculus and liver, insulin stimulates the synthesis of glycogen from glucose and inhibits glycogenolysis. In the liver, insulin as well decreases hepatic gluconeogenesis, preventing an influx of more glucose into the bloodstream. In adipose tissue, insulin inhibits fat breakdown, or lipolysis, and stimulates glucose uptake. The net effect of all of these changes is to increment glucose uptake, reduce circulating glucose levels and increase the conversion of glucose into the storage molecules, glycogen or fatty (Kim et al., 2006). In insulin resistance, adipose, muscle and liver cells do not reply appropriately to insulin, and circulating glucose levels remain high, which leads to pathology. This is exacerbated by the deregulation of feedback mechanisms.

Insulin-mediated glucose disposal rates vary in the population by over six-fold. Some of this variation is because of adiposity and fitness, and some is the result of genetic origin. Insulin resistance occurs when in that location is a subtract in the responsiveness of peripheral tissues (skeletal muscle, fatty and liver) to the furnishings of insulin. Insulin resistance is a powerful predictor of T2D, and hyperinsulinemia is a surrogate mark for insulin resistance.

Physiological insulin signaling occurs post-obit the binding of insulin to the insulin receptor, a ligand-activated tyrosine kinase. Binding of insulin results in tyrosine phosphorylation of downstream substrates and activation of ii parallel pathways: the phosphoinositide 3-kinase (PI3K) pathway and the mitogen-activated poly peptide (MAP) kinase pathway. Tyrosine phosphorylation of insulin receptor substrates (IRS) activates PI3K, leading to activation of the 3-phosphoinositide-dependent protein kinase 1 (PDK1) kinase and Akt kinase. The PI3K-Akt pathway is responsible for many of the downstream metabolic effects of insulin. In vascular endothelial cells, Akt kinase phosphorylates and activates endothelial nitric oxide synthase (eNOS). In skeletal muscle and adipose tissue, Akt kinase stimulates translocation of the insulin-responsive glucose transporter GLUT4 to the cell surface, leading to increased glucose uptake.

In parallel, tyrosine phosphorylation of the Shc protein activates the GTP exchange factor Sos. This results in activation of the MAP kinase pathway involving Ras, Raf, MAP kinase kinase (MEK) and extracellular regulated kinase (ERK). The MAP kinase pathway mediates endothelin-1 (ET-1) production, leading to vasoconstriction; expression of the vascular jail cell adhesion molecules VCAM-1 and E-selectin, leading to more leukocyte-endothelial interactions; and growth and mitogenesis effects on vascular smoothen muscle cells.

In insulin resistance, the PI3K-Akt pathway is afflicted, whereas the MAP kinase pathway is not. This leads to a change in the residue between these two parallel pathways. Inhibition of the PI3K-Akt pathway leads to a reduction in endothelial nitric oxide (NO) production, resulting in endothelial dysfunction, and a reduction in GLUT4 translocation, leading to decreased skeletal muscle and fatty glucose uptake. By contrast, the MAP kinase pathway is unaffected, so there is connected ET-1 production, expression of vascular cell adhesion molecules and mitogenic stimulus to vascular smooth muscle cells. In these ways, insulin resistance leads to vascular abnormalities that predispose to atherosclerosis.

Insulin increases local blood catamenia in tissues through the activation of eNOS, leading to two separable effects (Kim et al., 2006; Jonk et al., 2007). Capillary recruitment occurs within minutes, whereas dilation of the larger-resistance vessels increases overall perfusion between thirty minutes and 2 hours. Both of these effects contribute to vasodilation and increased delivery of glucose and insulin to tissues. The vascular effects of insulin couple glucose homeostasis with blood flow and contribute to glucose metabolism at physiological concentrations of insulin. Pharmacologic inhibition of NO production reduces glucose disposal by 40%.

Thus, insulin signaling coordinately affects peripheral glucose use, vascular tone and blood menses. Common mechanisms that contribute to insulin resistance can, therefore, as well affect vascular function, including hyperglycemia, advanced glycation products, toxicity from FFAs, obesity, dyslipidemia and other proinflammatory conditions.

Visceral adiposity

Visceral obesity causes a subtract in insulin-mediated glucose uptake, and is clearly related to insulin resistance. The mechanisms for this probably involve adipokines, which are made by adipose tissue, that modulate crosstalk betwixt metabolism and vascular function (Kershaw and Flier, 2004). These include tumor necrosis factor α (TNFα) and interleukin-half-dozen (IL-six), which are proinflammatory and contribute to insulin resistance and vascular dysfunction. The renin angiotensin organisation is also activated in adipose tissue, leading to hypertension and insulin resistance. By contrast, adiponectin is a protective adipokine that couples insulin sensitivity with energy metabolism. Adiponectin levels are decreased in obesity, T2D and metabolic syndrome. In add-on to these adipokines, FFAs, which are released from visceral fat, and bioactive lipid intermediates act together to impair the PI3K-Akt pathway and increase oxidative stress.

Atherogenic dyslipidemia

The cardinal features of atherogenic dyslipidemia are high plasma TG levels, low HDL cholesterol levels and an increment in small dense LDL. Insulin resistance and visceral obesity are associated with atherogenic dyslipidemia (Semenkovich, 2006).

Insulin resistance leads to atherogenic dyslipidemia in several means. First, insulin usually suppresses lipolysis in adipocytes, so dumb insulin signaling increases lipolysis, resulting in increased FFA levels. In the liver, FFAs serve as a substrate for synthesis of TGs. FFAs also stabilize the production of apoB, the major lipoprotein of very-low-density lipoprotein (VLDL) particles, resulting in more VLDL product. Second, insulin normally degrades apoB through PI3K-dependent pathways, and so insulin resistance directly increases VLDL production. Third, insulin regulates the activity of lipoprotein lipase, the rate-limiting and major mediator of VLDL clearance.

Thus, hypertriglyceridemia in insulin resistance is the result of both an increase in VLDL production and a subtract in VLDL clearance. VLDL is metabolized to remnant lipoproteins and small dense LDL, both of which can promote atheroma formation. The TGs in VLDL are transferred to HDL by the cholesterol ester transport protein (CETP) in exchange for cholesteryl esters, resulting in TG-enriched HDL and cholesteryl ester-enriched VLDL particles. The TG-enriched HDL is a better substrate for hepatic lipase, so it is cleared speedily from the circulation, leaving fewer HDL particles to participate in reverse cholesterol send from the vasculature.

Endothelial dysfunction

Endothelial dysfunction is the final common pathway between many cardiovascular gamble factors and the development of atherosclerosis (Gimbrone et al., 2000; Huang, 2005; Kim et al., 2006). Endothelial cells line the inner surface of claret vessels and serve important mechanical, as well as biological, functions. The endothelium senses and responds to physiological and pathological stimuli, and produces vasoactive substances, including NO, prostacyclin and endothelins. Endothelial expression of cell adhesion molecules governs interactions with circulating leukocytes and monocytes, affecting inflammation, and with circulating platelets, affecting hemostasis and thrombosis. The endothelium also modulates the response of the vascular smooth muscle layer, which may contribute to intimal formation during the development of atherosclerotic plaques. Normal endothelial office protects confronting these processes, and endothelial dysfunction is central to the pathogenesis of atherosclerotic lesion development.

Endothelial dysfunction, broadly defined, occurs when the endothelium fails to serve its normal physiological and protective mechanisms. This might exist because the endothelium is damaged or missing, as in the case of denuded endothelium in coronary arteries that have been subjected to angioplasty. It may occur when the normal responses of the endothelium are affected, for example by oxidative stress, hyperglycemia, advanced glycation products, FFAs, inflammatory cytokines or adipokines. A mutual feature of endothelial dysfunction is the reduced bioavailability of NO in the vasculature.

There are several mechanisms for endothelial dysfunction (Huang, 2005). The about important ones are a reduction in eNOS phosphorylation at S1177 (Dimmeler et al., 1999; Fulton et al., 1999) and the rapid reaction of NO with superoxide to grade peroxynitrite anion (Beckman and Koppenol, 1996). In addition, asymmetric dimethylarginine (ADMA) may compete with arginine to reduce endothelial NO production. eNOS requires enzymatic cofactors, including flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), NADPH and tetrahydrobiopterin (BH₄). In the absence of BH₄, electron send through eNOS tin can get 'uncoupled', resulting in the generation of superoxide by eNOS. Superoxide, whether formed past NADPH oxidase or by uncoupled eNOS, reacts with NO in an extremely rapid, improvidence-limited reaction to form peroxynitrite anion, which has its own toxic furnishings.

eNOS phosphorylation at S1177 appears to be a crucial regulator of its enzymatic activity. S1177 phosphorylation results in an increased electron flux through the reductase domain and reduced calmodulin dissociation. Every bit a result, eNOS becomes more active and produces more NO, even at resting levels of intracellular calcium. eNOS phosphorylation is diminished in diabetes, hypercholesterolemia and atherosclerosis. Physiological insulin signaling increases eNOS phosphorylation through the PI3K-Akt pathway. Estrogens, statins, VEGF and leptin all increase eNOS phosphorylation by Akt kinase. Adiponectin, the protective adipokine, increases eNOS phosphorylation by AMP kinase. The fact that diverse signaling pathways bear on multiple kinases that converge to attune eNOS activity by phosphorylation suggests that this is a common integration point that underlies endothelial dysfunction from various causes. Thus, the phosphorylation of eNOS at S1177 appears to be a crucial step in the regulation of eNOS activity and an of import target for intervention to care for endothelial dysfunction (Huang, 2005; Atochin et al., 2007).

Insulin resistance causes endothelial dysfunction past decreasing Akt kinase action, resulting in diminished eNOS phosphorylation and activity. Considering the phosphorylation of eNOS at S1177 is required for the hemodynamic deportment of insulin, this results in diminished blood period to skeletal muscle, creating a vicious cycle where endothelial dysfunction then worsens insulin resistance. In improver, insulin-mediated ET-1 expression and vascular shine muscle mitogenic effects are not affected by insulin resistance, further contributing to endothelial dysfunction.

Visceral adiposity causes endothelial dysfunction through the effects of resistin, IL-half-dozen and TNFα on eNOS phosphorylation. In add-on to blocking IRS-1 activation, TNFα directly activates NADPH oxidase, increasing superoxide generation; TNFα also stimulates lipolysis, resulting in FFA release. By contrast, adiponectin, which stimulates eNOS phosphorylation, is diminished in metabolic syndrome. In visceral fat, leptin resistance also increases the generation of reactive oxygen species. FFAs contribute to endothelial dysfunction by a combination of diminished PI3K-Akt signaling, increased reactive oxygen species and increased ET-1 production.

Conclusions

In summary, the central features of the metabolic syndrome are insulin resistance, visceral adiposity, atherogenic dyslipidemia and endothelial dysfunction. These conditions are interrelated and share common mediators, pathways and pathophysiological mechanisms. A comprehensive definition of the metabolic syndrome, expressed as simply as possible, would comprise only these features. The requirement of multiple criteria would ensure the exclusion of people with individual components (e.grand. isolated hypertension or isolated hyperlipidemia), as opposed to the composite pathophysiology discussed above. Inclusion of both TG and HDL criteria increases the specificity for atherogenic dyslipidemia, and inclusion of the blood pressure criterion ensures that the physiologic derangements are astringent plenty to take resulted in endothelial dysfunction.

Of the various definitions for the metabolic syndrome, the NCEP ATP Iii definition is the easiest to apply clinically and epidemiologically, because information technology uses straightforward criteria that are measured readily. Despite the ongoing controversy about whether the concept of metabolic syndrome is useful, it conspicuously defines specific pathophysiological mechanisms that link the primal features. Consideration of metabolic syndrome equally a specific entity allows for inquiry on the genetic basis for susceptibility to this syndrome, a improve agreement of its underlying pathophysiology and the evolution of treatment approaches.

Footnotes

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675814/

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