The Operative Risk Factors In The Metabolic Syndrome: Is .
The Operative Risk Factors in theMetabolic Syndrome: Is It Lipidsand High BP or Are There DirectVascular Effects of Insulin Resistanceand Obesity?Fabrice M.A.C. Martens, MD, PhD, and Frank L.J. Visseren, MD, PhDCorresponding authorFabrice M.A.C. Martens, MD, PhDDepartment of Cardiology, St. Antonius Hospital, Koekoekslaan 1,PO Box 2500, 3430 EM, The Netherlands.E-mail: f.martens@antonius.netCurrent Diabetes Reports 2007, 7:74 – 81Current Medicine Group LLC ISSN 1534-4827Copyright 2007 by Current Medicine Group LLCIncrease in patients with central obesity and insulin resistance is an important cause for the worldwide increasedincidence of type 2 diabetes. Several risk factors such asglucose intolerance, hyperinsulinemia, obesity, dyslipidemia, and hypertension, but also endothelial dysfunctionand inflammation, have been found to cluster and oftenprecede type 2 diabetes mellitus. Seeing the importanceof early identification, the US National Cholesterol Education Program created a readily applicable definition ofthe metabolic syndrome for daily clinical practice. It isassumed that the cardiovascular risk for patients belonging to the metabolic syndrome can just be calculatedout of the sum of the separate cardiovascular risk factorsdyslipidemia and hypertension. However, there are alsodata pointing toward a higher risk than expected fromthese separate cardiovascular risk factors because ofpossible direct vascular effects of insulin resistance andobesity. Awareness of the underlying disorders of insulinresistance and its associated (non-) traditional risk factors such as endothelial dysfunction and inflammationis important for understanding the pathophysiology andthus coherent treatment.IntroductionThe metabolic syndrome has received increasing attention over the past few years and is a subject of debate. Themetabolic syndrome is conceptualized as a constellation ofinterrelated cardiovascular risk factors of metabolic originthat appear to directly promote the development of atherosclerotic cardiovascular disease (CVD) and increase therisk for developing type 2 diabetes mellitus. The prevalenceof type 2 diabetes has soared in the past decades becauseof changing lifestyle and eating habits; there are currentlyapproximately 200 million people affected worldwide.Insulin resistance as a consequence of (abdominal) obesity(with approximately 400 million people affected worldwide right now) is one of the main underlying causes of theincreased incidence of type 2 diabetes.The major long-term complications of type 2 diabetesare an increased risk of myocardial infarction, stroke, andperipheral vascular disease. Although microvascular complications cause considerable morbidity in patients withtype 2 diabetes, up to 80% of patients die from macrovascular pathology [1]. Treatment of individual risk factorshas been shown to reduce cardiovascular events in type2 diabetes. Dysglycemia does not appear to be the majordeterminant of CVD in type 2 diabetes, a concept supported by observations in the UKPDS (United KingdomProspective Diabetes Study) [2]. Individuals or patientswith impaired glucose tolerance and/or impaired fasting glucose are so-called prediabetic and are at risk fordeveloping type 2 diabetes [3]. Treatment (with lifestylerecommendations and medication) as primary preventionof these individuals or patients can substantially reducethe risk of diabetes or death [4 ]. Although in type 2 diabetes elevated plasma glucose concentrations may inducevascular damage, in prediabetic patients the increasedcardiovascular risk is most likely the result of the pathophysiologic phenomenon of insulin resistance, which leadsto the occurrence of classic risk factors (eg, elevated bloodpressure, low high-density lipoprotein [HDL] cholesterol,elevated triglycerides) and new risk factors such as inflammation, hypercoagulability, hypoadiponectinemia, andimpaired vasoreactivity [5].
The Operative Risk Factors in the Metabolic SyndromeTable 1. Most used definition of themetabolic syndromeCombination of 3 or more of the following parameters:Fasting glucose 6.1 mmol/L and/or medicationCentral obesity in terms of a waist 102 cm for malesand 88 cm for femalesTriglycerides 1.7 mmol/L; or specific treatmentHDL 1.04 mmol/L for males and 1.29 mmol/L forfemales; or specific treatmentBlood pressure 130/85 mm Hg and/or medicationHDL—high-density lipoprotein.(From the National Cholesterol Education Program AdultTreatment Panel III [8].)Martens and Visseren 75glucose, type 2 diabetes mellitus, or impaired disposalof glucose as measured by hyperinsulinemic-euglycemic clamping. The other risk factors used for diagnosisincluded obesity, hypertension, high triglycerides, reducedHDL cholesterol level, or microalbuminuria [6].EGIRIn 1999, the EGIR proposed a modification of the WHOdefinition by assuming that insulin resistance is the majorcause and required evidence of hyperinsulinemia. Nextto an elevated plasma insulin, microalbuminuria wasreplaced by an elevated plasma glucose to diagnose theinsulin resistance syndrome. Patients with type 2 diabeteswere excluded because insulin resistance was viewed primarily as a risk factor for diabetes [7].The Term “Metabolic Syndrome”Many studies confirm that multiple cardiovascular riskfactors of endogenous origin commonly aggregate in oneindividual. Several terms have been proposed to describethis clustering, but the term “metabolic syndrome” ismost commonly used in the cardiovascular field. It isimportant to recognize that the metabolic syndrome isnot a defined uniform entity. No clear pathogenesis hasbeen elucidated and may not exist. The concept of thesyndrome could range from a cluster of (un-) related riskfactors to a constellation of risk factors linked through acommon underlying mechanism.New definition by NCEPFor practical reasons, a new definition was introduced in2001 by the NCEP: the Adult Treatment Panel III (ATPIII) criteria [8]. According to this definition, the metabolicsyndrome can be diagnosed if at least three out of the following five (metabolic) abnormalities are present: elevatedfasting glucose levels, elevated blood pressure, low plasmaHDL cholesterol levels, elevated plasma triglycerides, andcentral obesity. Because the obligatory presence of insulinresistance is abandoned, this definition is easy to use fordaily clinical practice.AACEDefinitions of the Metabolic SyndromeThat the pathogenesis is not clear yet is shown in the different definitions several organizations have attemptedto formulate in the effort to introduce the metabolicsyndrome into clinical practice. All definitions include ameasure of blood pressure, triglycerides, HDL cholesterol,and fasting glucose. They differ with respect to the selection of cutoff points and a measure of obesity.NCEPIn contrast to the World Health Organization (WHO) andthe European Group for Study of Insulin Resistance (EGIR)definitions, in which the presence of hyperinsulinemia asan indicator of insulin resistance is the starting point, theNational Cholesterol Education Program (NCEP) definitionis based on the number of abnormalities only, whereas theAmerican Association of Clinical Endocrinologists (AACE)definition considers the number of abnormalities in selectedsubjects with high risk of insulin resistance. The latestInternational Diabetes Federation (IDF) definition considersabdominal obesity as the pathogenetic starting point.WHOIn 1998, the WHO proposed the first definition, whichemphasized that insulin resistance is the major underlyingrisk factor and required evidence of insulin resistance fordiagnosis: impaired glucose tolerance, impaired fastingIn 2003, the AACE modified the ATP III criteria to refocus on insulin resistance as the primary cause of metabolicrisk factors [9]. Major criteria were impaired glucose tolerance, elevated triglycerides, reduced HDL cholesterol,elevated blood pressure, and obesity.IDFIn 2005, a new definition for the metabolic syndrome wasintroduced by the IDF. Based on the obligatory presenceof an increased waist circumference, it paid attention tothe elementary role of abdominal obesity in the development of the metabolic syndrome (Table 1) [10].Prevalence of the Metabolic Syndrome andRisk for Cardiovascular EventsIt is estimated that approximately one fifth of the USpopulation has the metabolic syndrome, and prevalenceincreases with age. The prevalence of the metabolicsyndrome in a healthy American population is approximately 24% [11]. In Europe, the prevalence seems similar,approximately 20%, with a difference between women(12%) and men (23%) [12,13]. In patients with clinicalmanifestations of vascular disease, the prevalence is 45%;and in patients with type 2 diabetes mellitus the prevalence is 80% [14]. Alternative definitions of the metabolicsyndrome highly predict type 2 diabetes mellitus [15].
76Insulin Resistance Syndrome, Including Polycystic Ovary SyndromeAlthough different definitions have been used in various studies, in most studies a similar increased risk ofCVD of approximately twofold is found in patients withthe metabolic syndrome compared to those without themetabolic syndrome [16–22,23 ]. Associations betweenmetabolic syndrome definitions and the risk of CVDranged between 1.5 for fatal and nonfatal myocardialinfarction or stroke for the NCEP definition in high-risksubjects with elevated cholesterol [20], and 3.7 for fataland nonfatal coronary disease for the WHO definitionin the general Italian population [24]. In addition, themetabolic syndrome is associated with advanced vasculardamage in patients with coronary heart disease, stroke,peripheral arterial disease or abdominal aortic aneurysm[25], and untreated essential hypertension [26]. However,the ATP III but not the IDF criteria of the metabolic syndrome predict clinical cardiovascular events in subjectswho underwent coronary angiography [27 ].The enormous number of people at risk for CVD andtype 2 diabetes is about to increase dramatically becauseof the global increase in abdominal obesity [28].Is It Dyslipidemia and High BP That Causethe Elevated Risk for Cardiovascular Eventsin the Metabolic Syndrome or Are ThereDirect Vascular Effects of Insulin Resistanceand Obesity?It is assumed that the cardiovascular risk for patients withthe metabolic syndrome can be explained by the sum ofthe separate cardiovascular risk factors. However, thereare also suggestions that the risk for developing CVD ismore than just the sum of the separate cardiovascularrisk factors [29 ]. Moreover, the increased cardiovascular risk for patients with the metabolic syndrome cannotbe completely explained by the traditional models forrisk scoring, such as the Framingham score [20,30].This increased cardiovascular risk may be due to thecombination of nontraditional markers, which all havea relation with insulin resistance, together with theseparate traditional components of the metabolic syndrome (hyperglycemia, hypertension, low plasma HDLcholesterol, high plasma triglyceride levels, and obesity).The nontraditional markers are endothelial dysfunction, inflammation, hyperinsulinemia, oxidative stress,hypercoagulability together with decreased fibrinolysis,decreased adiponectin levels, and increased small-denselow-density lipoprotein (LDL) [31–34].Insulin Resistance and the PathophysiologyBehind the Clustered Risk Factors inAssociation with Central ObesityInsulin is the most important regulator for the plasma glucose level. It works by stimulating the disposal of glucosein skeletal muscle and adipose tissue and decreasing thehepatic glucose production. Furthermore, insulin stimulates the lipogenesis and glycogen- and protein-synthaseactivity in adipocytes, liver, and skeletal muscle, andinhibits glycogenolysis, lipolysis, and protein breakdown(Fig. 1). In addition, insulin plays a role in the regulationof cell growth and differentiation.Insulin resistance means that when insulin binds to theinsulin receptor on the cell surface, this stimulation is notstrong enough to induce the normal intracellular signaltransduction with the consequence of insufficient reactionof target organs on insulin binding to the insulin receptor.In case of a sufficient pancreatic C-cell function, insulinresistance will lead to a compensatory hyperinsulinemia tomaintain normoglycemia. Hyperglycemia follows by furtherincreasing insulin resistance and after failure of the pancreatic C-cell function. Hyperinsulinemia has several importantconsequences as to cardiovascular risk, as described next.Adipose tissueAdipose tissue, especially intra-abdominal obesity, plays animportant role in insulin resistance. In the INTERHEARTstudy, abdominal obesity accounted for 44% of the risk ofa first myocardial infarction [35 ]. Adipose tissue is nolonger only a depot, but can be seen as an endocrine organ[36]. Several products of adipose tissue may influence development of insulin resistance. Important adipocyte-derivedfactors are free fatty acids (FFAs), tumor necrosis factor-B(TNF-B), adiponectin, and leptin. High levels of FFAs havebeen linked to (the induction of) insulin resistance becauseincreased FFA production in the liver leads to increasedgluconeogenesis and decreased glucose metabolism inskeletal muscle [37]. Furthermore, high levels of FFAs willlead to an increase of very low density lipoprotein (VLDL),together with an increase of plasma triglycerides [38]. Inan insulin-resistant state there is an attenuated lipoproteinlipase activity. Lipoprotein lipase is involved in the lipolysisof VLDL. Decreased breakdown of VLDL particles leadsto reduced availability of small VLDL fragments and anincrease in triglyceride-rich HDL particles via cholesterolester transfer protein. Triglyceride-rich HDL particles arecleared faster by the liver, resulting in a decreased HDLplasma concentration and an increased triglyceride concentration [39]. The expression of TNF-B by adipose tissue isupregulated in obesity and TNF-B levels are increased inpatients with features of the insulin resistance syndrome (ie,endothelial dysfunction), inducing a higher risk of recurrentcoronary events [40–42]. Adiponectin is an adipocytederived hormone that decreases insulin resistance. A lowadiponectin plasma concentration precedes a decrease inwhole-body insulin sensitivity in humans [34,43,44]. Therole of leptin in insulin resistance is controversial, but leptinmight interfere with insulin signaling in certain cell types.HypertensionHyperinsulinemia also causes hypertension. Normallyinsulin has a vasodilating effect; however, in an insulin-
The Operative Risk Factors in the Metabolic SyndromeMartens and Visseren 77Figure 1. Pathophysiology of insulinresistance. FFA—free fatty acids;VLDL—very low density lipoprotein.Increased glucose productionIncreased VLDL production– IncreasedFFA fluxInsulinDecreasedglucose uptake–Increasedlipolysis Decreasedglucose uptakeresistant state, insulin can cause sympathetic activation,production of the vasoconstrictor endothelin-1, andincrease of renal salt retention. Together with, or leadingto, endothelial dysfunction, leading to increased arterialresistance in the peripheral vasculature, these mechanisms can result in elevated blood pressure [45]. Severalstudies showed a relation between hyperinsulinemia,increased plasma FFA levels, and more oxidized smalldense LDL with endothelial dysfunction [46–48]. TheFramingham study showed that abdominal obesity is themain hypertensinogenic factor [49]. A direct associationbetween hypertension and body mass index has beenobserved in cross-sectional and longitudinal populationstudies from early childhood to old age [50]. The mechanism by which obesity raises blood pressure is not fullyunderstood, but increased body mass index is associatedwith an increase in plasma volume and cardiac output.These alterations and blood pressure can be decreased byweight loss in both normotensive and hypertensive subjects. Furthermore, blood pressure in obese adolescents issodium-sensitive, and fasting insulin is the best predictorof this sensitivity; after weight loss the blood pressuredecreases and the salt sensitivity is reduced [51]. Thevariables that best predict sodium sensitivity are fastingplasma insulin, plasma aldosterone, and plasma norepinephrine, supporting the hypothesis that blood pressureis sensitive to dietary sodium and that this sensitivity maybe due to the combined effect of hyperinsulinemia, hyperaldosteronism, and increased activity of the sympatheticnervous system [52]. Hyperinsulinemia increases bothsympathetic nerve activity and sodium and water retention. The expected vasodilation, upon binding of insulinto the endothelial insulin receptor and causing activationof endothelial nitric oxide synthase, is impaired in insulin-resistant states [53]. It is also the heterogeneous effectof endogenous nitric oxide on proliferation along the vascular tree that relates to the two different phenomenonsof insulin-resistant vascular dysfunction. Endothelialdysfunction exists in conduit arteries, whereas elevatedvascular resistance of resistance arteries is observed inessential hypertension [54,55].Enhanced low-grade inflammationEnhanced low-grade inflammation induces endothelialdysfunction by increased production of cytokines such as Creactive protein (CRP), TNF-B, and interleukin-6 [56–58].In addition, increased high-sensitivity CRP is associatedwith obesity, insulin resistance, and endothelial dysfunction. The more components of the metabolic syndromethat are present in the same person, the higher the plasmaCRP concentration [59]. It is noteworthy that CRP not onlyseems to function as an indicator for CVD, but CRP mayalso play a role as a risk factor in atherogenesis [60].DiscussionThe metabolic syndrome as an independentcardiovascular risk factorCurrently, a critical discussion is ongoing concerning therole of the metabolic syndrome in (cardiovascular) riskprediction [61]. The additive value of using the metabolicsyndrome in the prediction of future cardiovascular riskcompared with various alternative risk-score algorithms isnot fully clear yet. From a clinical standpoint, presence ofthe metabolic syndrome identifies a person at increasedrisk of CVD and/or type 2 diabetes. Eventually, a better
78Insulin Resistance Syndrome, Including Polycystic Ovary Syndromeunderstanding of the specific cause(s) of the syndromemay contribute to improved risk estimation for the development of CVD and/or type 2 diabetes. For now, thepresence of the syndrome is a more general indicator ofhigher risk for developing CVD and/or type 2 diabetesand may also give insight into the pathophysiology behindthe occurrence of individual risk factors. This knowledgemay lead to better treatment of risk factors.The observation that cardiovascular risk factors tendto cluster in individual patients is intriguing and has triggered basic and clinical researchers trying to understandand unravel the underlying pathophysiologic mechanismsbehind this clustering. It is now generally accepted thatinsulin resistance plays an important and central role. Theabdominal adipose tissue can be regarded as an organ withimportant endocrinologic functions, by the production ofadipokines and cytokines, involved in energy homeostasis, inflammation, and fibrinolysis. In case of adiposity,the production of several inflammatory cytokines such asTNF-B, leptin, and interleukin-6 is increased, whereasthe production of adiponectin is diminished. This alteration of adipokines is not only due to the excess of adiposetissue. Also, adipocyte dysfunction by itself contributes tothe metabolic changes, which can be seen as a cause or aconsequence of insulin resistance.Treatment of the metabolic syndromeTreatment of the metabolic syndrome has also been a topicof debate. It is assumed that the cardiovascular risk forpatients with the metabolic syndrome can be calculatedout of the sum of the separate cardiovascular risk factors.In the
ment of the metabolic syndrome (Table 1) [10]. Prevalence of the Metabolic Syndrome and Risk for Cardiovascular Events It is estimated that approximately one fifth of the US population has the metabolic syndrome, and prevalence increases with age. The prevalence of the metabolic syndrome in a healthy American population is approxi-mately 24% [11].
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