Metabolic Syndrome

1International Diabetes MonitorVolume 18, Number 5, 2006

Abstract

The metabolic syndrome is a cluster of meta-bolic abnormalities associated with increasedrisk for cardiovascular disease and type 2diabetes.The most commonly used criteria todefine the metabolic syndrome include the pres-ence of abdominal obesity, high blood pressure,elevated fasting plasma glucose and dyslipidemia(high triglyceride and/or decreased HDL choles-terol).There is great variation in the prevalenceof the metabolic syndrome worldwide, withincreasing trends related to the epidemic of obe-sity in most countries. Insulin resistance and astate of chronic inflammation are also underlyingfactors contributing to this syndrome. C-reactiveprotein is an emerging biomarker that may beuseful for risk stratification.The presence of themetabolic syndrome identifies those with higherlong-term cardiovascular risk and thus calls forintensified lifestyle therapy weight loss,increased physical activity and antiatherogenicdiet. In some patients, pharmacologic interven-tions may be indicated for the management ofspecific components of this syndrome, mostlydepending upon the severity of the abnormality.Further studies are needed to define treatmentalgorithms for patients diagnosed with the meta-bolic syndrome based on a particular combina-tion of its components.

Key words:Metabolic syndrome, cardiovascular disease, diabetes,insulin resistance, obesity, inflammation, mortality

Historical background to definition of themetabolic syndrome

Investigators in the late 1980s, studying the rela-tionships between dyslipidemia, obesity, insulinresistance, glucose intolerance and the procoagu-lant state, independently recognized that these

factors were associated with one another as wellas with cardiovascular disease (CVD) [15].Thiscluster of CVD risk factors began to be referredto as a syndrome using several different names:the metabolic syndrome [68], the insulin resis-tance syndrome [9], or syndrome X [3]. As evi-dence accumulated to indicate that these riskfactors played an important role in the develop-ment of CVD, the need to enhance awareness ofthem among health professionals increased.Accordingly the term metabolic syndrome wasformally adopted first by theWorld Health Orga-nization (WHO) in 1999 [10] and soon after bythe National Cholesterol Education Program(NCEP)/AdultTreatment Panel III (ATP III) in2001 [11] and then by others to describe a clus-ter of metabolic factors associated with increasedrisk of type 2 diabetes and CVD [12, 13].

Diagnostic criteria

The most commonly used diagnostic criteriahave been those of theWHO definition [10] andthe NCEP/ATP III definition [11], which wasupdated in 2005 [13]. Recently the InternationalDiabetes Federation (IDF) published its defini-tion of the metabolic syndrome (Table I) [14].The latter two definitions are the more easilyapplicable tools to assess the metabolic syndromein clinical practice.It has been speculated that the predictive value

of the NCEP andWHO definitions may dependon the prevalence of the core metabolic compo-nents (dyslipidemia, hypertension, obesity andglycemia) in the population under investigation[15].Thus the usefulness of the NCEP vs.WHOcriteria with a differing emphasis on the compo-nents of the metabolic syndrome may varyaccording to the background population towhich they are being applied. Prevalence esti-mates for the NCEP/ATP III definition of the

REVIEW ARTICLES

Metabolic syndrome revisitedHermes Florez1,2,3 and Ron Goldberg1

1University of Miami Miller School of Medicine;2Miami Veterans Affairs Medical, Miami, FL, USA;

3University of Zulia School of Medicine, Maracaibo, Venezuela([email protected]; [email protected])

metabolic syndrome have been reported for sev-eral countries (Fig. 1) [1631].These differ withrespect to the sample selection, the year in whichthey were conducted, the precise definition used,and the age and sex structure of the population.There is a wide variation of prevalence by genderand race/ethnicity [22].Two more criteria sets for the diagnosis of the

metabolic syndrome have been suggested by theAmerican Association of Clinical Endocrinolo-gists [32] and by the European Group for theStudy of Insulin Resistance [33].The key differ-ences from the NCEP and IDF criteria are thatboth of these criteria sets are totally foundedon insulin resistance and exclude patientswith diabetes.The IDF clinical definition requires abdomi-

nal obesity for metabolic syndrome diagnosis, asa good surrogate for the more cumbersome mea-surement of insulin resistance and to reduce theamount of laboratory testing necessary for iden-tification.When abdominal obesity is present,two additional factors originally listed in theNCEP definition and now somewhat modifiedare sufficient for diagnosis.The IDF emphasizedthe presence of ethnic and national differences inthe abdominal obesity threshold [14, 34]. Recentanalyses in the US population (19992002)showed that the IDF definition leads to a higherprevalence estimate of the metabolic syndrome(39%) than that based on the updated NCEPdefinition (34.5%) [25], particularly in MexicanAmerican men.

Underlying mechanisms: insulin resistanceand obesity

The predominant underlying risk factors for themetabolic syndrome are thought to be insulinresistance [3, 35, 36] and abdominal obesity [13,3739]. Reaven [3] postulated that insulin resis-tance and its compensatory hyperinsulinemiapredispose patients to hypertension, hyperlipid-emia and type 2 diabetes and are thus the under-lying cause of much CVD.This constellation ofinterrelated metabolic risk factors appears topromote the development of atheroscleroticCVD (Fig. 2). Although obesity was not includedin Reavens primary list of disorders caused byinsulin resistance, he acknowledged that it, too,was correlated with insulin resistance or hyper-insulinemia, and that the obvious treatment forwhat he termed syndrome X was weight main-tenance (or weight loss) and physical activity. Astate of mild chronic inflammation has also beenrelated to features of the metabolic syndrome,particularly obesity and insulin resistance [40],as discussed below.

Insulin resistance

The metabolic syndrome is associated withinsulin resistance but is not a consequence ofinsulin resistance alone nor of the lack of insulinaction alone [41].Three mechanisms have beenproposed to explain how insulin resistance mightgenerate other features of the metabolic syn-

2 International Diabetes Monitor Volume 18, Number 5, 2006

Review articles

Table I: Criteria for clinical diagnosis of the metabolic syndrome.

Clinical measurea WHOb (1999) [10] ATP III (2005) [13] IDFc (2005) [14]

Abdominal obesity WHR >0.90 (M) Waist 102 cm (Asians 90 cm)(M)Waist 94 cm (Asians 90 cm)

(M)WHR >0.85 (F) Waist 88 cm (Asians 80 cm) (F) Waist 80 cm (Asians 80 cm) (F)or BMI

drome: the effects of mild to moderate hyper-glycemia, the effects of compensatory hyperinsu-linemia, and the effects of unbalanced pathwaysof insulin action. In insulin resistance condi-tions, the ability of insulin to augment glucoseuptake and inhibit hepatic glucose production isimpaired.The resultant hyperglycemia presentsa stimulus to the -cells, which secrete largeamounts of insulin after meals. In individualsin whom -cell dysfunction occurs, glucoseintolerance and type 2 diabetes may develop,and the development of hyperglycemia is associ-ated with an increasing prevalence of the meta-bolic syndrome.The two major pathways for insulin signaling

are the phosphatidylinositol 3-kinase (PI3K) andthe mitogen-activated protein (MAP) kinasepathways [42]. In the metabolic syndrome thepathways leading to activation of PI3K areimpaired, whereas the MAP kinase pathway,which mediates the mitogenic and proinflamma-tory responses of insulin signaling, may be over-stimulated [43], leading to unbalanced combina-tions of both reduced as well as excessive

activation of metabolic targets via these twopathways of insulin action.

Although insulin-resistant individualsneed not be clinically obese, theynevertheless commonly have an

abnormal fat distribution characterizedby predominant upper body

fat accompanied by an expandedvisceral fat depot

Obesity

During the last decade, newly discovered adipo-kinetic pathways have suggested novel patho-physiologic mechanisms linking increased adi-pose tissue mass with the development of insulinresistance and other components of the meta-bolic syndrome [44]. In the Insulin ResistanceAtherosclerosis Study [45], the strongest predic-tor of the metabolic syndrome was waist circum-ference; thus, abdominal obesity may precede


Review articles

Mexico (19971999)

Saudi Arabia (19952000)

Iran (19992001)

Turkey (2000)

USA (19992002)

Venezuela (19992001)

Portugal (2000)

USA (19881994)

Oman (2001)

Greece (2003)

Spain (20002003)

Italy (2000)

South Korea (1998)

India (2003)

Australia (19992000)

France (1996)

0 10 20 30 40 50 60

Prevalence (%)

WomenMen

Fig. 1: Prevalence of the metabolic syndrome in several countries according to NCEP/ATP III criteria. Data from a recent analysisof a national survey showed a prevalence of 34% in Mexico (personal communication from Simon Barquera,MD, PhD).

the development of components of the metabolicsyndrome. Likewise, in the San Antonio HeartStudy [46], one-third of subjects with both alarge waist circumference and high BMI devel-oped the metabolic syndrome during the 8-yearfollow-up. Adjusting for fasting insulin concen-trations had only a minor effect on the predictivevalue of the anthropometric indices.It is recognized that some people who are not

obese or even overweight by traditional measuresare nevertheless insulin-resistant and haveabnormal levels of metabolic risk factors (nor-mal weight, metabolically obese) [47].This wasalso observed in lean individuals with twodiabetic parents or one parent and a first- orsecond-degree relative [48]. Although insulin-resistant individuals need not be clinically obese,they nevertheless commonly have an abnormalfat distribution characterized by predominantupper body fat which is accompanied by anexpanded visceral fat depot (or visceral adipos-ity) and which is associated with increasedrelease of non-esterified fatty acids from adiposetissue [49, 50]; this contributes to ectopic lipidaccumulation in muscle and liver, which isthought to predispose to insulin resistance [51]and dyslipidemia [52].The tendency to increasevisceral fat with only modest increases in subcu-taneous fat and body weight is especially true inpopulations from Asia [34].This has led to therecommendation in the IDF and the AmericanHeart Association update on the NCEP defini-tion of the metabolic syndrome that cut-pointsfor increased waist circumference be set lowerfor these populations.Therefore some investiga-tors regard insulin resistance as a mediating fac-tor in the metabolic syndrome, but not as theprimary cause, and consider dysfunctionalenergy storage to be a fundamental step [41].Abnormalities in the processing and storage offatty acids and triglycerides, the molecules that

account for most of the bodys energy utilizationand storage, are observed when there is toomuch triglyceride or body fat (i.e. obesity).When the capacity of adipocytes to store triglyc-eride is exceeded, fat accumulates in hepato-cytes, skeletal myocytes and other tissues. Exces-sive maldistribution of fat in visceral tissuesappears to be a marker or perhaps a determinantof insulin resistance.Visceral adiposity correlateswell with insulin resistance and most features ofthe metabolic syndrome.The adipose tissue of obesity exhibits abnor-

malities in the production of adipokines, whichmay separately affect insulin resistance and/ormodify the risk of atherosclerotic CVD.Theseinclude increased production of inflammatorycytokines [53, 54], plasminogen activatorinhibitor-1 [55] and other bioactive products[44]; at the same time the potentially protectiveadipokine, adiponectin, is reduced [56]. All ofthese changes have been implicated in the gen-esis of metabolic risk factors. Indeed, as men-tioned above, some individuals exhibit the meta-bolic syndrome with only a moderate degree oftotal body obesity [47].

Inflammation and the metabolic syndrome

In recent years extensive studies have uncoveredthe importance of systemic low-grade inflamma-tion in the initiation and development of athero-sclerosis as well as acute CVD events [5759].Several cytokines and acute-phase reactants havebeen shown to be associated with and predictCVD, including C-reactive protein, interleukin 6(IL-6), serum amyloid A, fibrinogen, whiteblood cell count, D-dimer, plasminogen activa-tor, tumor necrosis factor- (TNF), lipoproteinphospholipase A2, interleukin-18, metallopro-teinase PAPP-A and secretory non-pancreaticphospholipase A2 type IIA [6062]. In addition,systemic inflammation is also associated withatherogenic changes in lipoprotein metabolismincluding hypertriglyceridemia; elevated triglyc-eride-rich lipoprotein; small, dense LDL; anddecreased HDL cholesterol [63].C-reactive protein correlates with the severity

of the metabolic syndrome [64] and, eventhough several studies support the role ofinflammation in the development of the meta-bolic syndrome, the nature of the relationshipsamong these inflammatory markers, the pres-ence of dyslipidemia and the degree of insulinresistance remain unclear [6567].There is evidence that obesity and chronic

subclinical inflammation may play intermediary


Review articles

Dyslipidemia

Hypertriglyceridemia

Small, dense LDL

Low HDL

Hypertension

HyperglycemiaHypercoagulability

Underlyingfactors

Metabolicfactors

Clinicaloutcomes

Cardiovasculardisease

Insulinresistance

Inflammation

Abdominalobesity

Type 2diabetes

Fig. 2:Metabolic syndrome pathways.

roles in the pathogenesis of CVD and type 2 dia-betes [68].The levels of C-reactive protein andIL-6 increase with the degree of adiposity andmay lead to higher insulin resistance and the riskof developing type 2 diabetes [69].To the extentthat elevated IL-6 and C-reactive protein levelsreflect adipocyte activation, the availability ofthese markers represents an approach for earlyidentification of individuals at increased riskof the metabolic syndrome, type 2 diabetesand CVD.

The American Heart Associationrecommends the use of C-reactive

protein as the best inflammatory markerin the clinical assessment of CVD risk

Among a wide range of biomarkers, C-reactiveprotein is considered to be the most applicablefor clinical use. In several studies, C-reactiveprotein has actually predicted CVD better thanother inflammatory biomarkers including inter-cellular adhesion molecule-1 and vascular celladhesion molecule-1,TNF and IL-6, and inde-pendently of LDL cholesterol and other lipopro-tein levels [61]. In the general population, thelevel of C-reactive protein has been found toconsistently predict incident myocardial infarc-tion, stroke, peripheral arterial disease, suddencardiac death, and recurrent ischemia and deathin patients with angina and acute coronarysymptoms [70].The American Heart Associationrecommendations state that, although inconclu-sive, evidence supports the use of C-reactiveprotein as the best inflammatory marker in theclinical assessment of CVD risk [60].

Association of the metabolic syndrome withmortality and CVD

There is uncertainty about the clinical and pub-lic health importance of the metabolic syndrome[71, 72]. A recent report summarizing its predic-tive value [73] concluded that the population-attributable risk (PAR) associated with the meta-bolic syndrome, based on the NCEP andWHOdefinitions, is approximately 67% for all-causemortality and 1217% for CVD. A report fromthe Framingham Heart Offspring Study [74]recently showed that the PAR for the metabolicsyndrome as a predictor of CVD and coronaryheart disease was 34% and 29%, respectively, inmen and 16% and 8%, respectively, in women.The metabolic syndrome components that con-

tributed most to the cardiovascular outcomeswere elevated blood pressure and low HDL cho-lesterol, with PAR estimates of 33% and 25%,respectively.The metabolic syndrome varies in its predic-

tive capacity for CVD by ethnicity, gender andthe presence or absence of hyperglycemia [75,76]. In the Framingham Offspring database, themetabolic syndrome accounted for approxi-mately one-fourth of cardiovascular morbidity[74]. In the Botnia study, subjects with themetabolic syndrome had a threefold increasedrisk of coronary heart disease and stroke, a five-to sixfold increased risk of CVD death, andincreased all-cause mortality [77]. In Finnishmen, insulin resistance and the metabolic syn-drome predicted coronary heart disease eventsand both CVD and all-cause mortality [78].Therisk of death from all causes and CVD increasedwith growing numbers of abnormalities [79].The presence of the metabolic syndrome iden-

tifies those with relatively high long-term risk ofCVD and thus calls for intensified lifestyletherapy. It needs to be stressed that the meta-bolic syndrome itself is a relatively poor indicatorof absolute short-term risk [80], because it doesnot contain key determinants of short-term risksuch as age, serum cholesterol, gender andsmoking status. A more accurate predictor ofshort-term risk is Framingham scoring, whichincludes all of the major risk factors.

Metabolic syndrome and diabetesdevelopment

The metabolic syndrome not only accompaniesbut also precedes and predicts type 2 diabetes[81, 82].The San Antonio Heart Study investi-gators compared OGTT results against theNCEP andWHO criteria for the metabolic syn-drome in predicting diabetes. Of the three,impaired glucose tolerance on the OGTT wasthe best with a predictive value of 43% vs. 31%by the NCEP criteria and 30% by the modifiedWHO criteria [83]. Furthermore, even in sub-jects with impaired glucose tolerance, the pres-ence of the metabolic syndrome increased therisk of progression of type 2 diabetes, althoughfurther studies are needed to confirm this obser-vation. Interestingly, in a study among non-diabetic American Indians, the homeostasismodel assessment for insulin resistance and themetabolic syndrome at baseline were associatedwith an increased risk of type 2 diabetes, butCVD was not predicted independently of othercardiovascular risk factors [84].


Review articles

In a recent review of prospective studies usingthe NCEP andWHO definitions of the meta-bolic syndrome, Ford [73] found that the PARfor type 2 diabetes was between 30% and 52%.

The primary goal of clinical managementin patients with the metabolic syndromeis to reduce their long-term risk of CVD

In the Framingham cohort, the presence of themetabolic syndrome at baseline was also foundto be a powerful predictor of new-onset diabetes.Using the revised NCEP definition for the meta-bolic syndrome, the PAR for type 2 diabetes was62% in men and 47% in women [74]. Asexpected, elevated blood glucose (100 mg/dl)was associated with the highest PAR of 62%for type 2 diabetes, while the combination ofelevated blood glucose, abdominal obesity andlow HDL cholesterol was associated with a large12-fold increased risk of incident type 2diabetes. However, trait combinations that didnot include elevated blood glucose also impartedan approximately fivefold increased risk of inci-dent type 2 diabetes.This is consistent with theconcept that the metabolic syndrome trait com-bination reflects an underlying insulin resistancepathophysiology.

Management of the metabolic syndrome

The primary goal of clinical management inpatients with the metabolic syndrome is toreduce their long-term risk of CVD.The primaryemphasis should be on the modification ofunderlying risk factors (obesity, physical inactiv-ity and atherogenic diet) through lifestylechanges. Not only do these interventionsimprove individual metabolic syndrome compo-nents, but they have been shown to amelioratethe underlying pathophysiologic determinants ofthe syndrome, such as obesity, insulin resistanceand inflammation [13, 85]. No studies haveexamined the value of tailoring the treatmentalgorithm to the particular combination of crite-ria that resulted in the diagnosis of the metabolicsyndrome [72], nor whether the presence of themetabolic syndrome justifies earlier applicationof pharmacologic interventions for preclinicalabnormalities in syndrome components, e.g. pre-hypertension, prediabetes or suboptimal lipidlevels. Specific pharmacologic interventions maybe indicated for the management of clinicallysignificant components of the syndrome, e.g.

hypertension, dyslipidemia, glucose intoleranceor the procoagulant state. It is unknown whetherinsulin sensitizers, as an approach to the treat-ment of insulin resistance itself, or the use ofagents that lower C-reactive protein levels such asstatins, fibrates, nicotinic acid and thiazolidine-diones would be of value in preventing CVD inall or a subset of patients with the metabolic syn-drome outside their current clinical indications.

Acknowledgments

Dr Florezs work is supported by grants from theDepartment ofVeterans Affairs MiamiGRECCand CSP#465, Pan American Health Organiza-tion RC/RG-T/VEN/3201, and UMHumanaHealth Service Research. Dr Goldbergs work issupported by grants from the National Institutesof Health NIDDK DK01 0500 and2RO1HL36588-16.

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