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Is There a Simple Way to Identify Insulin-Resistant Individuals atIncreased Risk of Cardiovascular Disease?

Tracey McLaughlin, MDa,*, Gerald Reaven, MDa, Fahim Abbasi, MDa,Cindy Lamendola, MSNa, Mohammed Saad, MDb, David Waters, MDc,

Joel Simon, MDc, and Ronald M. Krauss MDd

The goal of this study was to evaluate the ability of various routine measures of lipopro-tein metabolism to identify patients who were insulin resistant and dyslipidemic, andtherefore, at increased risk of cardiovascular disease. For this purpose, insulin resistancewas quantified by determining the steady-state plasma glucose concentration during theinsulin suppression test in 449 apparently healthy patients. The low-density lipoprotein(LDL) particle diameter and subclass phenotype were measured by gradient gel electro-phoresis in 1,135 patients. Pearson’s correlation coefficients and receiver-operating char-acteristic curves were used to evaluate measures of lipoprotein metabolism as potentialmarkers of insulin resistance and LDL phenotype. The results indicated that the ratio ofthe plasma concentrations of triglyceride to high-density lipoprotein cholesterol was thebest predictor of insulin resistance and LDL particle diameter. The optimal triglyceride/high-density lipoprotein cholesterol ratio for predicting insulin resistance and LDL phe-notype was 3.5 mg/dl; a value that identified insulin-resistant patients with a sensitivityand specificity comparable to the criteria currently proposed to diagnose the metabolicsyndrome. The sensitivity and specificity were even greater for identification of patientswith small, dense, LDL particles. In conlusion, a plasma triglyceride/high-density lipopro-tein cholesterol concentration ratio >3.5 provides a simple means of identifying insulin-resistant, dyslipidemic patients who are likely to be at increased risk of cardiovascular

disease. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96:399–404)

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nsulin resistance and a related lipid abnormality, small,ense, low-density lipoprotein (LDL) cholesterol, are asso-iated with an increased risk of cardiovascular disease.1–6

he triglyceride (TG)/high-density lipoprotein (HDL) cho-esterol ratio, which is often elevated in insulin-resistantatients, has also been shown to predict cardiovascularvents independently.7,8 The present analysis was initiatedo test the hypothesis that the TG/HDL cholesterol concen-ration ratio, in addition to its link to increased cardiovas-ular disease risk, would provide a simple and useful ap-roach to identify insulin-resistant patients, as well as theresence of small, dense LDL particles. To address this

aStanford University School of Medicine, Stanford, California; bUni-ersity of California, Los Angeles, Diabetes Center, Los Angeles, Califor-ia; cSan Francisco General Hospital, University of California, San Fran-isco, School of Medicine, San Francisco, California; and dChildren’sospital Oakland Research Institute, Oakland, California. Manuscript re-

eived December 28, 2004; revised manuscript received and acceptedarch 29, 2005.

Dr. Krauss was supported by a grant from the National Dairy Council,osemont, Illinois. Drs. Krauss, Waters, Saad, and Simon were supportedy Grant U01-HL6975, Drs. McLaughlin, Reaven, Abbasi, and Ms.amendola were supported by Grant RR000070, and Dr. McLaughlinas supported by Grant RR16071-01 from the National Institutes ofealth, Bethesda, Maryland. The funding sources had no role in theesign, conduct, or manuscript preparation for this study.

* Corresponding author: Tel: 650-723-3186; fax: 650-725-7085.

wE-mail address: tmclaugh@stanford.edu (T. McLaughlin).

002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2005.03.085

ssue, we combined data available to the investigators fromtanford University School of Medicine (insulin resistance),awrence Berkeley National Laboratory (LDL particle di-meter and phenotype), and the Universities of California atan Francisco and Los Angeles (LDL particle diameter andhenotype).

ethods

he experimental subjects were healthy patients who hadolunteered for a variety of clinical studies in response todvertisements in local newspapers. Three study popula-ions were included in the analyses. The Stanford popula-ion consisted of 449 healthy volunteers recruited fromommunities in the vicinity of Palo Alto, California, whoere on an ad-lib diet; the San Francisco/Los Angelesopulation consisted of 456 patients recruited by clinics athe University of California, San Francisco, and the Uni-ersity of California, Los Angeles, who were also on and-lib diet; and the Berkeley population included 689 sub-ects sampled after 3 to 6 weeks on a defined weight-stableiet containing (as a percentage of daily calories) 20% to4% fat, 15% to 16% protein, and 60% to 65% carbohy-rate. All 3 groups were primarily of white ancestry�75%). During the initial screening visit, blood samples

ere obtained from all volunteers after a 12-hour overnight

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ast. All participants were in good general health, withasting plasma glucose concentrations �126 mg/dl and nor-al liver and kidney function, who were not taking any drug

nown to affect carbohydrate or lipid metabolism. Thenstitutional review boards at all sites approved the respec-ive studies, and all subjects gave written, informed consent.

Insulin-mediated glucose disposal was quantified by aodification9 of the insulin suppression test.10,11 In brief,

fter an overnight fast, octreotide was administered at 25g/hour in a solution containing 2.5% (weight/volume)uman serum albumin by an infusion pump to suppressndogenous insulin secretion. Simultaneously, insulin andlucose were infused at 25 mU/m2/min and at 240 mg/m2/in, respectively. Blood was sampled at 10-minute inter-

als from 150 to 180 minutes, and then averaged to obtainhe steady-state plasma glucose and insulin concentrationschieved during the infusion. Because the steady-statelasma insulin concentrations were comparable in all pa-ients qualitatively and quantitatively, and the glucose infu-ion rate was identical, the magnitude of the resultantteady-state plasma glucose concentration provided a spe-ific and quantitative measure of insulin-mediated glucoseisposal; the greater the concentration, the more insulinesistant the patient. Subjects were considered insulin resis-ant or insulin sensitive if their steady-state plasma glucoseoncentrations were in the top or bottom tertile, respec-ively, of the distribution of these values as described in a

able 1emographic and lipoprotein characteristics of three study populations

ariable Stanford;Ad-Lib Diet (n � 449)

ge (yrs) 48 � 13en/women 47%/53%ody mass index (kg/m2) 26.3 � 4.3otal cholesterol (mg/dl) 189 � 35riglyceride (mg/dl) 120 � 71DL cholesterol (mg/dl) 50 � 13DL cholesterol (mg/dl) 115 � 30on–HDL cholesterol (mg/dl) 139 � 37

Data presented as mean � SD.* Eucaloric diet with 20% to 24% fat, 15% to 16% protein, and 60% to

able 2orrelation with steady-state plasma glucose concentration: fasting

nsulin and lipoprotein concentrations

ariable r p Value

nsulin* 0.60 �0.001riglyceride/HDL cholesterol* 0.60 �0.001riglyceride* 0.57 �0.001holesterol/HDL cholesterol 0.43 �0.001DL cholesterol* �0.40 �0.001on–HDL cholesterol 0.35 �0.001DL cholesterol 0.18 �0.001

* Log transformed.

opulation of 490 healthy patients.12 S

Fasting plasma insulin concentrations were measured byadioimmunoassay.13 Lipid and lipoprotein concentrationsere measured by previously described methods.6,14–19 TheDL peak particle diameter was determined by nondenatur-

ng gradient gel electrophoresis, and the LDL subclass phe-otype B was determined from gradient gel electrophoresisy previously published criteria.17–19

Because of non-normal distributions, insulin, TG, HDLholesterol, and the TG/HDL cholesterol ratio were logransformed for tests of statistical significance. The resultsre presented as the mean (of the non–log-transformed val-es) � SD. Pearson’s correlations were performed on po-ential markers (lipid and lipoprotein concentrations) ofnsulin resistance and LDL particle diameter. Stepwise mul-iple linear regression analysis was conducted with all lipidnd lipoprotein markers, as well as age and body massndex, as predictors of insulin resistance and LDL particleiameter. Comparison of the predictive ability was donesing receiver-operating characteristic curves for eacharker with respect to (1) identification of insulin resistance

nd (2) LDL-phenotype B. The optimal cutpoint was deter-ined for the TG/HDL cholesterol ratio with respect to

redicting insulin resistance or LDL phenotype B usingaximization of M,20 with the following formula: M � ws

(1 � w) � p, where w is the prevalence of diseaseinsulin resistance or LDL phenotype B) in the study sam-le, s is the sensitivity, and p is the specificity. For purposesf comparison, we also determined the ability of the criteriaroposed by the Adult Treatment Panel III for the diagnosisf the metabolic syndrome21 to identify insulin resistance,s defined above. Because we did not have waist circum-erence measurements for most of our subjects, we substi-uted a body mass index of �25.0 kg/m2 for women and

29.0 kg/m2 for men, values that provided the same prev-lence of the metabolic syndrome in the Third Nationalealth and Nutrition Examination Survey population as did

he use of the waist circumference.4 Analyses were per-ormed using Statistical Analysis Systems, version 8.0 (SASnstitute, Cary, North Carolina) and, for comparison of therea under the receiver-operating characteristic curves,

San Francisco/Los Angeles;Ad-Lib Diet (n � 456)

Berkeley; DefinedDiet* (n � 689)

56 � 13 42 � 1149%/51% 89%/11%27.5 � 5.9 25 � 3.1213 � 36 178 � 36118 � 64 135 � 10255 � 16 41 � 10

134 � 34 111 � 31160 � 40 137 � 36

arbohydrate.

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401Preventive Cardiology/TG/HDL Cholesterol, Insulin Resistance, and LDL Phenotype

esults

able 1 lists the demographic and metabolic characteristicsf the 3 study populations; age, gender, and body massndex were relatively comparable, with the exception thathe Berkeley group on the defined diet was predominantlyen.The fasting plasma insulin concentration is considered a

seful surrogate estimate of insulin action.12,22 Table 2 com-ares the relation between a specific measure of insulin-ediated glucose disposal (steady-state plasma glucose

oncentration) and fasting plasma insulin concentration, asell as between the steady-state plasma glucose concentra-

ion and various aspects of lipoprotein metabolism. The ralues are ranked in order of the magnitude of the relation.t was clear that the correlation between the degree ofnsulin resistance and the TG/HDL cholesterol concentra-ion ratio was equal to that between the degree of insulinesistance and the fasting insulin concentrations. The cor-elation between TG and insulin resistance was nearly astrong. Furthermore, the relations between these 2 markers

igure 1. Receiver-operating characteristic curves of the TG/HDL choleholesterol concentrations for prediction of insulin resistance in the (A) Staopulation, and (C) Berkeley defined diet population.

able 3elation between lipoprotein variables and low-density lipoprotein peak p

ipoprotein Variable San Francisco/Los Angeles

Particle Diameter

G/HDL cholesterol* �0.77riglyceride* �0.73DL cholesterol* 0.59holesterol/HDL cholesterol �0.58on–HDL cholesterol �0.30DL cholesterol �0.06

* Log transformed.

nd the steady-state plasma glucose concentration were sub- p

tantially closer than any of the other measures of lipopro-ein metabolism.

Table 3 presents the relation between lipoprotein vari-bles and LDL peak particle diameter. As in Table 2, theipoprotein variables are listed in order of the magnitude ofheir relation with the LDL peak particle diameter. Theseata are similar to those seen in Table 2, in that the TG/HDLholesterol concentration ratio was most closely related tohe LDL peak particle diameter, followed by the relationetween the plasma TG concentration and the LDL particleeak diameter. As with the measure of insulin resistance,he LDL particle peak diameter and HDL cholesterol andhe cholesterol/HDL cholesterol concentration ratio wereoderately related, and the non–HDL cholesterol and LDL

holesterol concentrations were most weakly related to theDL peak particle diameter.

Stepwise linear regression analysis was performed tourther evaluate the relation between the various mea-ures of lipoprotein metabolism and insulin resistancend LDL particle diameter. The TG/HDL cholesterolatio entered the model first when applied to all 3 study

HDL-C) ratio, triglyceride, cholesterol/HDL cholesterol ratio, and HDLopulation, LDL phenotype B in (B) San Francisco/Los Angeles ad-lib diet

diameter

b Diet Berkeley Defined Diet

p Value Particle Diameter p Value

�0.0001 �0.77 �0.0001�0.0001 �0.72 �0.0001�0.0001 0.60 �0.0001�0.0001 �0.63 �0.0001�0.0001 �0.34 �0.0001NS �0.01 NS

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402 The American Journal of Cardiology (www.AJConline.org)

ndependent predictor of insulin resistance and the LDLarticle diameter.

The ability of the 4 lipoprotein variables that were mostlosely related to the steady-state plasma glucose concen-ration and LDL peak particle diameter to predict insulinesistance and LDL phenotype B were evaluated byeceiver-operating characteristic curve analysis. These re-ults are shown in Figure 1, and the c values for these 4ariables are shown in Table 4. In line with the Pearsonorrelations shown in Tables 2 and 3, the areas (c) under theeceiver-operating characteristic curves were greatest forhe TG/HDL cholesterol concentration ratio and TG con-entration in the Stanford population, and the c values forhe markers were significantly greater statistically thanhose for the cholesterol/HDL cholesterol concentration ra-io and HDL cholesterol. The receiver-operating character-stic curves were essentially identical in the San Francisco/os Angeles and Berkeley populations, with the TG/HDLholesterol ratio a significantly better predictor statisticallyhan the next best marker, plasma TG, in these 2 groups (p

0.04 and p � 0.009, respectively). The areas under theeceiver-operating characteristic curves were significantlyower statistically for the cholesterol/HDL cholesterol andDL cholesterol concentration in the San Francisco/Losngeles and Berkeley populations. For all 3 populations

nd for all markers, the comparison of the area under theeceiver-operating characteristic curves by gender revealedo statistically significant differences.

On the basis of these data and the previous observation

able 4reas under receiver-operating characteristic curves (c values) and 95% c

ipoprotein Variable StanfordAd-Lib Diet

riglyceride/HDL cholesterol 0.84* (0.80–0.88)riglyceride 0.83* (0.79–0.87)holesterol/HDL cholesterol 0.76 (0.72–0.80)DL cholesterol 0.72 (0.67–0.77)

* p �0.001 compared with c value for cholesterol/HDL cholesterol and† p �0.001 compared with c value for triglycerides.

able 5ensitivity and specificity of triglyceride/HDL cholesterol concentration rDL phenotype (San Francisco/Los Angeles and Berkeley) compared wittanford population

ariable Predicted Sensitivity (%)

nsulin resistance (Stanford criteria) 47mall, dense LDL phenotype (SanFrancisco/Los Angeles ad-lib diet)

79

mall, dense LDL phenotype (Berkeleydefined diet)*

71

etabolic syndrome (Adult TreatmentPanel III criteria)

46

* No analysis by gender because small number of women in populationNPV � negative predictive value; PPV � positive predictive value.

hat the plasma TG and HDL cholesterol concentrations are

ndependently related to insulin resistance,16 the TG/HDLholesterol concentration ratio was deemed to be preferableo TG alone as the best predictor of insulin resistance andDL phenotype B, and a ratio of 3.5 was determined to be

he most useful cutpoint. The sensitivity, specificity, andositive and negative predictive power of the TG/HDLholesterol ratio as a predictor of insulin resistance and LDLhenotype B are shown in Table 5. For the sake of com-arison, the Adult Treatment Panel III criteria for the met-bolic syndrome were applied as a predictor of insulinesistance. The results in Table 5 showed that the TG/HDLholesterol ratio is comparable to the Adult Treatment PanelII criteria in predicting insulin resistance, and even better inredicting the LDL phenotype B in 2 separate populationsho were on different diets. The positive likelihood TG/DL cholesterol ratio for the Stanford, San Francisco/Losngeles, and Berkeley populations was 3.9, 9.3, and 8.1,

espectively.

iscussion

he present study was initiated in an effort to find a simplepproach to identify apparently healthy patients who werensulin resistant and at an increased risk of cardiovascularisease and other clinical syndromes related to this defect innsulin action. The results presented support the view that alasma TG/HDL cholesterol concentration ratio �3.5 mayell provide such information.

ce intervals

San Francisco/Los AngelesAd-Lib Diet

BerkeleyDefined Diet

0.94*† (0.92–0.96) 0.91*† (0.89–0.93)0.92* (0.90–0.95) 0.90* (0.88–0.92)0.82 (0.79–0.88) 0.87 (0.84–0.89)0.83 (0.78–0.87) 0.78 (0.74–0.81)

cholesterol.

.5 for identifying insulin resistance (Stanford) and small denseTreatment Panel III criteria for identifying insulin resistance in

Specificity (%) PPV (%) NPV (%)

88 66 7785 82 83

91 88 78

92 75 77

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403Preventive Cardiology/TG/HDL Cholesterol, Insulin Resistance, and LDL Phenotype

hat the TG/HDL cholesterol ratio was as closely associatedith the specific measure of insulin-mediated glucose dis-osal as was the fasting plasma insulin concentration—aurrogate estimate of insulin action that has been widelysed to study the relation between insulin resistance andarious clinical syndromes. Mathematic manipulations ofasting plasma glucose and insulin concentrations, aimed atroviding a better estimate of insulin sensitivity, such asomeostasis Model Assessment of Insulin Resistance

HOMA-IR) and Quantitative Insulin Sensitivity Check In-ex (QUICKI), provide values for insulin resistance that aressentially identical to the information gained by simplyeasuring the fasting plasma insulin concentration.12,23 The

onclusion that the TG/HDL cholesterol concentration ratiorovides an estimate of insulin sensitivity that is as useful asny other surrogate estimate used for this purpose dependsn the specificity of the method used to quantify insulin-ediated glucose disposal. The insulin suppression test has

een validated and used for 30 years,10–12 and it has pro-ided considerable information concerning the relation be-ween insulin resistance and human disease.23,24 It also isighly correlated (r �0.9) with measurements of insulin-ediated glucose disposal by the euglycemic, hyperinsu-

inemic clamp technique.12 Thus, it seems reasonable toonclude that the greater the TG/HDL cholesterol concen-ration ratio, the more insulin resistant the patient, and thathis value provides an estimate of insulin sensitivity that iss accurate as the fasting plasma insulin concentration andhe other surrogate estimates that use measures of fastinglasma glucose and insulin concentration to assess insulinction.

In addition to being as useful a surrogate estimate ofnsulin sensitivity as is the fasting plasma insulin concen-ration, the TG/HDL cholesterol concentration ratio hasther advantages. At the simplest level, measures of plasmaipid concentrations are standardized to a much greateregree than are assays of fasting plasma insulin concentra-ion, so the possibility of finding a specific numeric valuehat would have clinical utility throughout the country isuch greater in the case of the TG/HDL cholesterol ratio.f greater significance is the TG/HDL cholesterol concen-

ration ratio not only provides an estimate of insulin resis-ance, but also identifies patients who have an atherogenicipoprotein profile that puts them at increased cardiovascu-ar disease risk.

The lipoprotein phenotype that characterizes insulin-re-istant/hyperinsulinemic patients consists of a high plasmaG and low HDL cholesterol concentration, smaller andenser LDL particles, and an increase in the postprandialccumulation of remnant lipoproteins.24 In addition to beingssociated with insulin resistance, this lipoprotein pheno-ype is also associated with increased cardiovascular dis-ase. Although plasma TG and HDL cholesterol concentra-ions are routinely measured, this is not the case for the LDLarticle diameter or postprandial remnant concentrations.

owever, the results of the present study have confirmed a

revious report of the existence of a strong relation betweenhe TG/HDL cholesterol ratio and LDL peak diameter,25

nd the results in Table 5 indicate that a TG/HDL choles-erol concentration ratio �3.5 predicts the presence of themall dense LDL phenotype (LDL phenotype B) with highensitivity and specificity. Thus, by measuring plasma TGnd HDL cholesterol concentrations, and calculating theiratio, it is possible to gain insight into 3 of the 4 changes inipoprotein metabolism that increase cardiovascular diseaseisk in insulin-resistant patients.

Although the TG/HDL cholesterol ratio is a significantredictor of insulin resistance, the actual value of this ratiohat would be most useful to identify insulin-resistant pa-ients is not as straightforward as it is for the LDL pheno-ype. Specifically, values for insulin-mediated glucose dis-osal vary continuously throughout the population,12 so anbjective way to classify a patient as either insulin resistantr insulin sensitive is not available. However, we havehown in prospective studies that the tertile of the generalopulation with the greatest steady-state plasma glucoseoncentrations is at significantly greater risk of developing

variety of adverse outcomes, including cardiovascularisease.26,27 Using this operational definition of insulin re-istance, we found that a TG/HDL cholesterol concentrationatio �3.5 identified insulin-resistant patients with a reason-ble degree of sensitivity and specificity.

Finally, because the plasma TG concentration performslmost as well as does the TG/HDL cholesterol concentra-ion ratio in identifying insulin-resistant patients withmaller and denser LDL particles, it could be argued that itseasurement offers an even simpler way to identify patients

t increased cardiovascular risk. However, neither its rela-ion to insulin nor the LDL particle diameter was as strongs that of the TG/HDL cholesterol ratio, and, in the case ofhe LDL phenotype (Table 4), the difference was statisti-ally significant. Furthermore, when placed in the stepwiseinear regression model, with either the steady-state plasmalucose concentration or the LDL particle diameter, theG/HDL cholesterol ratio always entered first. Finally, be-ause TG and HDL cholesterol were independently relatedo insulin resistance,16 the TG/HDL cholesterol ratio alsoppears to offer a more physiologically relevant choice,ith a solitary high plasma TG convention more likely to

esult from abnormalities unrelated to insulin resistance.

cknowledgment: We acknowledge the assistance of Pa-ricia Blanche, BS, Laura Holl, BA, and Joseph Orr, BA, inerforming the lipid and lipoprotein analyses.

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