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A Novel View of Metabolic Syndrome

PARESH DANDONA, MBBS, D.PHIL., AHMAD ALJADA, Ph.D., AJAY CHAUDHURI, MBBS, MRCP, PRIYA MOHANTY, MBBS, and RAJESH GARG, M.D.

ABSTRACT

The metabolic syndrome, as described by Reaven, is a combination of obesity, insulin resis-tance, hypertension, hypertriglyceridemia, low HDL cholesterol, and hyperinsulinemia. Thesyndrome was recognized as a very high pro-atherogenic risk causing coronary heart disease.More recently, other features like an elevated plasma PAI-1 and CRP have been added to thesyndrome. In view of the recent data demonstrating that insulin exerts an anti-inflammatoryeffect while macronutrients exert a pro-inflammatory effect, we are in a better position to ex-plain not only why an insulin resistant state like the metabolic syndrome is pro-inflammatorybut also to explain how it develops. This review discusses the relevance of these recent obser-vations and puts into perspective the pathogenesis of various features of the metabolic syn-drome and also predicts some features which may get incorporated into it in the future.

METABOLIC SYNDROME AND RELATED DISORDERSVolume 2, Number 1, 2004© Mary Ann Liebert, Inc.

INTRODUCTION

THE ORIGINAL DESCRIPTION of the metabolicsyndrome by Reaven consisted of obesity,

insulin resistance, hypertension, impaired glu-cose tolerance or diabetes, hyperinsulinemiaand dyslipidemia characterized by elevatedtriglyceride and low HDL concentrations.1 Allof the features described above are risk factorsfor atherosclerosis and thus metabolic syn-drome constituted a significant risk for coro-nary heart disease.2–5 The features of obesity/overweight and insulin resistance also pro-vided a significant risk for developing type 2diabetes.5,6 The risks for CHD and diabeteswith metabolic syndrome are greater thanthose for simple obesity alone and thereforethe understanding of the pathogenesis and

through it, a rational approach to its therapyare of prime importance.

As our understanding of the action of insulinevolves to comprehensively include the recentdiscoveries,7 we can better see that insulinresistance is the basis of most if not all the fea-tures of this syndrome. The original conceptu-alization of this syndrome was on the basis ofresistance to the metabolic actions of insulin.Thus, hyperinsulinemia, glucose intolerance,type 2 diabetes, hypertriglyceridemia and lowHDL concentrations could be accounted for byresistance to the actions of insulin on carbohy-drate and lipid metabolism. While the featuresdescribed above would explain to some extentthe atherogenesis, Reaven has maintained thathyperinsulinemia itself contributes to athero-genicity and thus insulin is atherogenic, leading

Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, and Kaleida Health,Buffalo, New York.

Review

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to CHD and cerebrovascular disease associatedwith this syndrome.

Several new features have been added to thesyndrome over time. These include elevatedPAI-1 concentrations and now, elevated CRPconcentrations. These features were added onthe basis that they were frequently found inassociation with the metabolic syndrome.However, there has hitherto been no rationalexplanation about why they actually occur.Are they features related to insulin resistanceor are they a part of the obese state? If thelatter, how do we explain their presence inpatients with metabolic syndrome withoutobesity?

NOVEL NON-METABOLIC ACTIONS OF INSULIN

These issues are readily explained by therecent observations that insulin is an anti-inflammatory hormone and that macronutrientintake is pro-inflammatory. Insulin has beenshown to suppress several pro-inflammatorytranscription factors like NFkB, Egr-1 and AP-1 and the corresponding genes regulatedby them which mediate inflammation.8,9 Animpairment of the action of insulin due to in-sulin resistance would thus result in the acti-vation of these pro-inflammatory transcriptionfactors and an increase in the expression of thecorresponding genes.

Insulin has been shown to suppress NFkBbinding activity, reactive oxygen species (ROS)generation, p47phox expression, to increase IkBexpression in MNC as well as to suppressplasma concentrations of ICAM-1and MCP-1.8In addition, insulin suppresses AP-1 and Egr-1,two pro-inflammatory transcription factorsand their respective genes, MMP-9, TF andPAI-1.9–11 Thus, insulin has a comprehensiveanti-inflammatory effect and in addition, hasan antioxidant effect as reflected in the sup-pression of ROS generation and p47phox

expression.Two further pieces of evidence demonstrat-

ing the anti-inflammatory action of insulinhave emerged recently. Firstly, the treatmentof type 2 diabetes with insulin for 2 weekscaused a reduction in CRP and MCP-1.12 Sec-

ondly, the treatment of severe hyperglycemiaassociated with marked increases in inflam-matory mediators with insulin resulted in amarked fall in the concentration of inflamma-tory mediators.13 Most recently, in a rat modelin which inflammation was induced with en-dotoxin, insulin suppressed the concentrationof these inflammatory mediators including IL-1b, IL-6, MIF, and TNFa.14

Another novel anti-apoptotic effect of in-sulin has recently been described. In experi-mental acute myocardial infarction in the ratheart, the addition of insulin to the reperfusionfluid leads to the reduction in infarct size by50%.15 More recently, a similar cardio-protec-tive effect of insulin has been shown in humanacute myocardial infarction when insulin at alow dose was infused with a thrombolyticagent and heparin.16 Conversely, insulin resis-tant states of obesity and type 2 diabetes havebeen shown to be associated with larger in-farcts than those observed in non-diabeticsubjects. Further work is required to establishthis feature as an integral feature of metabolicsyndrome. It should also be mentioned thatinsulin suppresses atherogenesis in the apo-lipoprotein E null mouse.17 Conversely, inter-ference with insulin signal transduction, as inIRS-2 null mouse results in atherosclerosis.18

Consistent with the anti-inflammatory ef-fects of insulin, insulin sensitizers of thethiazolidinediones class, troglitazone19,20 androsiglitazone21 have been shown to exert ananti-inflammatory effect in addition to theirglucose lowering effect in patients with dia-betes. Troglitazone has been shown to sup-press the development of diabetes in patientsat high risk of developing this condition.22

Trials are under way to determine whetherrosiglitazone and pioglitazone prevent athero-sclerotic complications.

OBESITY AND INFLAMMATION

The above data explain why an insulin resis-tant state may be pro-inflammatory. They donot, however, explain the origin of insulin re-sistance itself. Mutations of the genes involvedin insulin signal transduction provides one ap-proach to the study of this issue in humans

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and in mice with specific gene knockouts. Suchlesions are of interest, but they are too in-frequent to provide us with a basis for the un-derstanding of the pathogenesis of insulinresistance at large in humans. Thus, some ofthe recent observations on the interference ofinsulin signal transduction by inflammatorymechanisms are of great interest since obesityis a pro-inflammatory state.

Even if we accept that inflammatory mecha-nisms are involved in the pathogenesis of in-terference with insulin signal transduction andof insulin resistance itself, how does inflam-mation arise? Over the past decade, obesityhas been associated with inflammation. Thisassociation was first proposed in the landmarkpaper by Hotamisligil et al. in which TNFawas shown to be constitutively expressed byadipose tissue, to be hyper-expressed in obe-sity and to mediate insulin resistance in themajor animal models of obesity.23 This seminalpaper also demonstrated that the neutraliza-tion of TNFa with soluble TNFa receptors re-sulted in the restoration of insulin sensitivity.Thus, the pro-inflammatory cytokine TNFawas the mediator of insulin resistance. Al-though the infusion of soluble TNFa receptorsin the human has not reproduced the resultsobserved in mice,24 Hotamisligil’s paper laidthe foundation of the concept that inflamma-tory mechanisms may have a role to play inthe pathogenesis of insulin resistance. Moredata have now accumulated to reinforce theconcept that obesity is an inflammatory statein the human: plasma concentration of TNFa,IL-6, CRP and other inflammatory mediatorshas been shown to be increased in theobese.25–29 Adipose tissue has been shown toexpress most of these pro-inflammatory medi-ators. It has also been shown that macro-phages residing in the adipose tissue may alsobe a source of pro-inflammatory factors andthey may also modulate the secretory activityof adipocytes.30 Tissue macrophages are de-rived from monocytes in blood. Recently, themononuclear cells of the obese, of whichmonocytes are a fraction, have also beenshown to be in an inflammatory state express-ing increased amounts of pro-inflammatorycytokines and related factors.31 In addition,these cells have been shown to have a signifi-

cantly increased binding of nuclear factor kB(NFkB), the key pro-inflammatory transcrip-tion factor and an increase in the intranuclearexpression of p65 (Rel A), the major proteincomponent of NFkB. These cells also expressdiminished amounts of IkBb, the inhibitor ofNFkB. Clearly, therefore, evidence of inflam-mation exist in various cells and in plasma inobesity.

INSULIN RESISTANCE: ANINFLAMMATORY HYPOTHESIS

So, what is it in the inflammatory statewhich results in the causation of insulin resis-tance? The first of these potential mechanismswas described by Hotamisligil et al. Theydemonstrated that TNFa induced serine phos-phorylation of IRS-1 which in turn caused theserine phosphorylation of the insulin receptor.This prevented the normal tyrosine phospho-rylation of the insulin receptor and thus inter-fered with insulin signal transduction.32 IL-6and TNFa have recently been shown to in-duce SOCS-3,33,34 a protein which was hithertothought to interfere with cytokine signal trans-duction but which is now also known to in-terfere with tyrosine phosphorylation of theinsulin receptor and IRS-1, and to cause ubiq-uitination and proteosomal degradation ofIRS-1.35 This in turn reduces the activation ofAkt (protein kinase B) which normally causesthe translocation of the insulin responsive glu-cose transporter, Glut-4, to the plasma mem-brane. It also induces the phosphorylation ofthe enzyme nitric oxide synthase (NOS) andits activation to generate NO.36 A newly de-scribed protein, TRB3 has also been shown tointerfere with the activation of Akt and thus tointerfere with insulin action.37 However, its as-sociation with inflammatory mechanisms hasnot hitherto been demonstrated.

MACRONUTRIENTS AND THE ORIGINOF INFLAMMATION

If indeed, obesity is a pro-inflammatorystate and inflammatory mechanisms interferewith insulin signal transduction, what is the

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origin of this pro-inflammatory state? Theanswer to this question comes mainly from re-cent observations demonstrating that macro-nutrient intake may induce oxidative stressand inflammatory responses. Thus, a 75-g glu-cose challenge has been shown to induce anincrease in superoxide generation by leuco-cytes by 140% over the basal in addition toincreasing p47phox expression, a subunit ofNADPH oxidase, the enzyme which convertsmolecular O2 to superoxide radical.38 Equi-caloric amounts of cream (fat) intake result insimilar amounts of oxidative stress.39 Glucoseintake also results in comprehensive inflamma-tion as reflected in an increase in intranuclearNFkB binding, a decrease in IkB expressionand an increase in IKKa and IKKb, the two ki-nases which phosphorylate IkBa and IkBb andresult in their ubiquitination and proteosomaldegradation.40 Similar effects of a combinedfast food meal have been observed.41 Glucoseintake also causes an increase in two other pro-inflammatory transcription factors: AP-1 andEgr-1.42 AP-1 regulates the transcription of ma-trix metalloproteinases, while Egr-1 modulatesthe transcription of tissue factor (TF) and PAI-1.Thus, glucose intake increases the expressionof matrix metalloproteinases 2 and 9 as well asthat of TF and PAI-1.

A mixed meal from a fast food chain wasalso shown to induce the activation of NFkB, areduction in IkBa, an increase in IKKa andIKKb along with an increase in superoxideradical generation by MNC.41 It is also of inter-est that the intravenous infusion of triglyc-eride with heparin in normal subjects withelevation of FFA concentration to a level com-parable to that found in the obese results in aninflammatory response.43 All genes which arestimulated by acute nutritional intake havealso been shown to be activated in the basalstate of obese subjects such that the concentra-tions of these gene products are elevated in theobese. Consistent with this, a reduction inmacronutrient intake in the obese (1000 kcaldaily for 4 weeks) has been shown to reduceboth oxidative stress and inflammatory media-tors.44 Similarly, a 48-h fast has been shown toreduce ROS generation by over 50% in normalsubjects; the expression of p47phox was also re-duced.45 Clearly, macronutrient intake is a

major regulator of oxidative stress. It is rele-vant that the superoxide radical generated dur-ing oxidative stress is an activator of at leasttwo major pro-inflammatory transcription fac-tors, NFkB and AP-1. NFkB regulates the tran-scriptional activity of at least 125 genes, most ofwhich are pro-inflammatory.46–49 Thus, it is notsurprising that obesity is a pro-inflammatorycondition. Indeed, the MNC in the obese is in apro-inflammatory state, expressing an excessof a series of pro-inflammatory genes in addi-tion to having increased NFkB binding, p65expression and decreased IkBb protein.31 In ad-dition to obesity and increased macronutrientintake, there may also be genetic and other en-vironmental factors which may induce the acti-vation of inflammatory mechanisms and theinduction of oxidative stress. These genetic andother environmental factors may be relevant inthose ethnic groups in whom metabolic syn-drome has been shown to occur in the absenceof obesity.

The increase in superoxide radical genera-tion also results in diminished bioavailabilityof NO since NO binds to superoxide radical toform peroxynitrate.50 In addition to the factthat Akt is inhibited due to insulin resistance,and thus NOS also inhibited, the reduction inNO availability can result in a marked reduc-tion in NO. This results in abnormalities inendothelium mediated vasodilatation and vas-cular reactivity.51 Interestingly, the abnormali-ties in vascular reactivity in the obese insulinresistant population can be reproduced acutelyby a 900-kcal fast food meal, just as the pro-inflammatory changes in obesity can be repro-duced by a similar meal.41 It is noteworthy, thatin obesity the plasma concentrations of asym-metric dimethylarginine (ADMA) are elevatedand that it inhibits NOS activity thus reducingthe synthesis and secretion of NO.52

CONCLUSION

In conclusion, the pro-inflammatory state ofobesity and metabolic syndrome originateswith excessive caloric intake and is probablydue to over nutrition in a majority of patients inthe United States. The pro-inflammatory stateinduces insulin resistance leading to clinical

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and biochemical manifestations of the meta-bolic syndrome. This resistance to insulin actionpromotes inflammation further through an in-crease in FFA concentration and interferencewith the anti-inflammatory effect of insulin.While these factors may be the most importantfactor in a majority of patients with metabolicsyndrome, it is possible that other factors likegenetic factors may also contribute to theinflammatory stress in metabolic syndrome.These factors may be important in ethnicgroups like Asian Indians who may have in-creased amounts of upper abdominal fat inspite of a normal BMI.53 Since excessive nutri-tional intake probably accounts for the inflam-mation at least in obesity associated metabolicsyndrome, the most rational way to suppresssuch inflammation is through caloric restric-tion. The other lifestyle change which affects in-flammation is exercise. Exercise results in a fallin the indices of inflammation like plasma CRPconcentration.54 The mechanism underlyingthis effect of exercise is not known. However, itis noteworthy that life style change is a very ef-fective way to reduce the rate of developmentof diabetes in a pre-diabetic population asshown by the diabetes prevention study.55 Botha reduction in macronutrient intake and exer-cise cause a reduction in inflammation.

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Address reprint requests to:Paresh Dandona

Diabetes-Endocrinology Center of Western New YorkSUNY at Buffalo

Kaleida Health3 Gates Circle

Buffalo, NY 14209

E-mail: pdandona@kaleidahealth.com

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