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Metabolic syndrome: the dysmetabolic state of dysfunctional adipose tissue and insulin resistance

Jean-Pierre Despre´s and H. Bryan Brewer

The current world epidemic of obesity represents atremendous medical and public health challenge. Amajor consequence of obesity has been a rapid accelera-tion in the prevalence of type 2 diabetes;

however, it isnow recognized that even before the development of dia-betes, many individuals have the constellation of athero-thrombotic inﬂammatory abnormalities characteristic of type 2 diabetes.

Thus, the cluster of metabolic abnorm-alities is not the consequence of the hyperglycaemicstate of type 2 diabetes but is rather pathophysiologicallyrelated to insulin resistance, the most prevalent form of insulin resistance being present in individuals with excessvisceral as well as ectopic fat.

Thus, even in the absenceof hyperglycaemia, abdominally obese patients with anexcess of visceral and ectopic fat deposition are likelyto have the clustering of risk factors associated withinsulin resistance. In this regard, the pivotal role of insulin resistance in the pathophysiology of the clusterof risk factors was ﬁrst reported by Reaven

and desig-nated syndrome X. Since his seminal paper, numerousgroups have utilized the term insulin resistance syndromein the description of this cluster of athero-thromboticinﬂammatory abnormalities.

5,6

In 2001, the guidelinesdeveloped by the National Cholesterol EducationProgram-Adult Treatment Panel III (NCEP-ATP III) commit-tee considered abdominal obesity as central in the patho-physiological development of the insulin resistancesyndrome.

Since the measurement of insulin resistancewas not practical in the context of primary care clinicalpractice, the guidelines provided clinicians with simplediagnostic criteria, including waist circumference, trigly-cerides, high-density lipoprotein (HDL) cholesterol, bloodglucose, and blood pressure to identify patients with thecluster of risk factors, resulting in an increased risk of diabetes and cardiovascular disease (CVD). The clusterof athero-thrombotic inflammatory risk factors wasdesignated as the metabolic syndrome. Many groupshave confused the NCEP-ATP III five criteria to diagnosethe metabolic syndrome in the context of clinical prac-tice with the conceptual definition of the syndrome.The definition of the metabolic syndrome has a pathophy-siological basis

3,8

and places insulin resistance andabdominal obesity at the core of the cluster of abnormal-ities. The NCEP-ATP III five criteria should not be con-sidered as the definition of the metabolic syndrome butrather as simple screening tools. Refining the dis-criminating capabilities of these tools is work in progress.For instance, the International Diabetes Federation (IDF)

hasplacedmoreemphasisthanNCEP-ATPIIIontheimport-ance of abdominal obesity and recognized the importantethnic differences in susceptibility to visceral adiposityand related metabolic abnormalities.

Diagnosis of the metabolic syndromein clinical practice: does it matter?

Although many studies have shown that patients meetingthe NCEP-ATP III criteria for the metabolic syndrome areat increased risk of cardiovascular events,

10,11

the jointposition paper published by the American DiabetesAssociation-European Association for the Study of Dia-betes (ADA

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EASD)

has appropriately pointed out thata clinical diagnosis of the metabolic syndrome is notsufficient to assess CVD risk and that attention shouldbe first paid to classical risk factors such as age, malegender, blood pressure, smoking, low-density lipoprotein(LDL) cholesterol and HDL-cholesterol, and diabetes.These two organizations have even questioned the rel-evance of a clinical diagnosis of the metabolic syndromeand emphasized that attention should be first given toassessment and management of classical risk factors.Therefore, although our toxic lifestyle characterizedby lack of physical activity and an energy-dense diethas led to an epidemic of abdominal obesity and of themetabolic syndrome,

whether its diagnosis in clinical

The opinions expressed in this article are not necessarily those of theEditors of the

Eurpean Heart Journal Supplement

or of the EuropeanSociety of Cardiology.

European Heart Journal Supplements (2008)

(Supplement B), B1

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B3doi:10.1093/eurheartj/sum051

b y g u e s t onM a y 2 4 ,2 0 1 0 e ur h e ar t j s u p p. ox f or d j o ur n al s . or gD ownl o a d e d f r om

practice would lead to different therapeutic manage-ment is a question frequently raised.

To address thisissue, additional prospective data with hard CVD endpoints and a comprehensive set of morphometric andmetabolic markers are needed to sort the key predictorsof risk beyond what is currently assessed by physicians.At present, there is evidence

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that markers of inﬂammation (e.g. C-reactive protein), insulin resistance(insulin), an atherogenic dyslipidaemia (apolipoprotein Band LDL particle size), and possibly select cytokinesderived from adipose tissue (e.g. adiponectin andinterleukin-6) may be useful in risk assessment but theiradded value in global risk assessment, is frequentlydebated due to the lack of adequate data. Furthermore,

Figure 1

The building blocks of global cardiometabolic risk. In this model, the metabolic syndrome as its most prevalent form (visceral obesity/ectopicfat) is one more modiﬁable risk factor affecting global risk of cardiovascular disease. From Despre´s and Lemieux.

Figure 2

Assessment and management of global cardiometabolic risk. This illustration emphasizes the notion that in addition to assessing and managing‘traditional’ risk factors, targeting excess visceral adiposity/ectopic fat could lower the risk of CVD through its effects on several determinants of cardiometabolic risk.

EditorialB2