J. Clin. Endocrinol. Metab. 2006 91:5002-5007 originally published online Sep 26, 2006; , doi: 10.1210/jc.2006-0419
Peter D. Reaven Fahim Abbasi, Helke M. F. Farin, Cindy Lamendola, Tracey McLaughlin, Eric A. Schwartz, Gerald M. Reaven and
Resistance Is Altered in Smokers
The Relationship between Plasma Adiponectin Concentration and Insulin
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The Relationship between Plasma AdiponectinConcentration and Insulin Resistance Is Alteredin Smokers
Fahim Abbasi, Helke M. F. Farin, Cindy Lamendola, Tracey McLaughlin, Eric A. Schwartz,Gerald M. Reaven, and Peter D. Reaven
Department of Medicine (F.A., H.M.F.F., C.L., T.M., G.M.R.), Stanford University School of Medicine, Stanford, California94305; and Medical Research Service (E.A.S., P.D.R.), Division of Endocrinology and Metabolism, Department of Medicine,Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona 85012
Context: Low plasma adiponectin concentrations in smokers maycontribute to the adverse consequences that occur in theseindividuals.
Objective: The objective of the study was to define the relationshipamong smoking, plasma adiponectin concentrations, insulin resis-tance, and inflammation.
Design: This was a cross-sectional, observational study with a 2 � 2factorial design and a prospective longitudinal arm.
Setting: The study was conducted at a general clinical researchcenter.
Participants: Apparently healthy smokers (n � 30) and nonsmokers(n � 30), subdivided into insulin resistant (IR) (n � 15) and insulinsensitive (IS) (n � 15) subgroups participated in the study.
Intervention: Intervention included pioglitazone administration for3 months to 12 IR smokers and eight IS smokers.
Main Outcome Measures: Measures included fasting plasma adi-ponectin and C-reactive protein (CRP) concentrations and changes inadiponectin after pioglitazone treatment in IR and IS smokers.
Results: Being either a smoker or having insulin resistance was indepen-dently associated with lower adiponectin concentrations (P � 0.046 and0.001, respectively). The difference in mean adiponectin concentration be-tween smokers and nonsmokers did not depend on the insulin resistancestatus of the subjects. No difference was detected in average CRP concen-trations between smokers and nonsmokers (P � 0.18) and between IR andIS subjects (P � 0.13). CRP concentrations were unrelated to adiponectinin smokers (r � �0.05, P � 0.78) and nonsmokers (r � 0.03, P � 0.86).Finally, pioglitazone treatment increased adiponectin concentrations inboth IR (P � 0.001) and IS smokers (P � 0.001).
Conclusions: Plasma adiponectin concentrations are lower in smokersand IR subjects and are unrelated to CRP concentrations. These findingssuggest that low levels of adiponectin in smokers may be independent ofboth insulin resistance and a generalized inflammatory response.(J Clin Endocrinol Metab 91: 5002–5007, 2006)
ADIPONECTIN, AN ADIPOCYTE gene product, is se-creted in large amounts from adipose tissue and is
present in relatively high concentration in the blood. Lowcirculating concentrations of adiponectin have been associ-ated with obesity, dyslipidemia, essential hypertension, type2 diabetes, and cardiovascular disease (1–5). It is apparentthat the clinical syndromes in which hypoadiponectinemiaoccurs are all associated with peripheral resistance to insulin-mediated glucose uptake (6). In addition, variations inplasma adiponectin concentration and/or molecular formshave been suggested to modulate insulin sensitivity (2, 7–9).
More recently, plasma adiponectin concentrations havebeen reported to be low in smokers (10–13). Because resultsof in vitro studies have indicated that addition of proinflam-matory cytokines, such as TNF-� and IL-6, to isolated adi-pocytes can reduce adiponectin expression (14–16), it is pos-
sible that the association between smoking and loweradiponectin concentrations results from inflammation-me-diated down-regulation of adiponectin expression in adiposetissue. In support of this notion is evidence of an inverserelationship between markers of inflammation such as C-re-active protein (CRP) with adiponectin (17, 18). In addition,smoking has been identified as a source of reactive oxygenspecies (19, 20) and is associated with increased levels ofinflammatory markers (21–23), further suggesting that smok-ing-induced inflammation may contribute to lower adi-ponectin levels in smokers.
On the other hand, because the prevalence of insulin re-sistance may also be increased in smokers (24, 25), it is notclear whether hypoadiponectinemia in these individuals isdue to smoking, and possibly the associated inflammation,or to the coexistence of insulin resistance. The possible con-tribution of insulin resistance, as estimated by a surrogateindicator, to reduced adiponectin concentrations in smokerswas considered in one brief correspondence (12), and theresults of multivariate analysis suggested that the relation-ship between smoking and adiponectin was independent ofinsulin action. However, we felt that the possible relationshipamong smoking, hypoadiponectemia, and insulin resistancewas important enough to evaluate further, using a specific
First Published Online September 26, 2006Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass
index; CI, confidence interval; CRP, C-reactive protein; GFR, glomerularfiltration rate; IR, insulin resistant; IS, insulin sensitive; SSPG, steady-state plasma glucose.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.
measure of insulin action, rather than a surrogate estimate.To address these issues, we have in the present study mea-sured adiponectin and CRP concentrations in smokers andnonsmokers, with each group further stratified into insulin-resistant (IR) and insulin-sensitive (IS) subgroups.
If adiponectin is lower in smokers, and this is not simplyrelated to the extent of insulin resistance, identification oftherapies that correct this abnormality may be clinically im-portant. In this context, thiazolidinedione compounds havebeen shown to increase plasma adiponectin concentrations(9, 26), and there is evidence that they can exert a beneficialantiinflammatory effect independent of their ability to en-hance insulin sensitivity (27). The ability of such agents toincrease adiponectin may be particularly useful to preventcardiovascular disease in smokers in light of the observationthat smokers with low adiponectin concentrations are atgreater risk for coronary stenosis than smokers with highconcentrations of adiponectin (28). Thus, irrespective of thereasons that adiponectin concentrations are lower in smok-ers, we thought it would be important to also evaluate theability of pioglitazone treatment to increase plasma adi-ponectin concentrations in the two smoking groups.
Subjects and Methods
The study population consisted of 30 smokers and 30 nonsmokerswho responded to print advertisements describing our research interestin smoking-associated metabolic abnormalities. Screening inclusion cri-teria included: healthy individuals between ages 29 and 65 yr; body massindices (BMIs) between 20 and 35 kg/m2; and no medications known toaffect glucose, insulin, or lipoprotein metabolism. In addition, the smok-ers had to have a history of smoking a minimum of 10 cigarettes per dayfor at least the past 5 yr. Potential participants were further evaluatedby medical history, physical examination, and routine clinical laboratorymeasurement to exclude individuals with apparent disease, laboratoryevidence of type 2 diabetes, anemia, and abnormal liver or kidneyfunction. Renal function was also evaluated by calculating the estimatedglomerular filtration rate (GFR) using the Cockcroft-Gault formula (29).Volunteers meeting these eligibility criteria were scheduled for admis-sion to the General Clinical Research Center of the Stanford UniversityMedical Center. The Stanford Human Subjects Committee approved thestudy, and each subject gave informed consent.
Insulin-mediated glucose disposal was quantified by a modified ver-sion (30) of the insulin suppression test as described and validated byour research group (31, 32). After an overnight fast, an iv catheter wasplaced in each arm of the subject. One arm was used for the simultaneousinfusion of octreotide (0.27 �g/m2�min), insulin (32 mU/m2�min), andglucose (267 mg/m2�min) for 180 min, and the other arm was used forcollection of blood samples. During the last 30 min of the infusion, bloodwas sampled at 10-min intervals to measure plasma glucose and insulinconcentrations, and the values obtained were averaged to determine thesteady-state plasma glucose (SSPG) and insulin concentrations. Becausethe steady-state plasma insulin concentrations are comparable in allindividuals and glucose infusion is identical, the resultant SSPG con-centrations provide a direct measure of the ability of insulin to mediatethe disposal of a given glucose load; i.e. the higher the SSPG concen-tration, the more insulin resistant the individual. For the purpose of thisstudy, individuals with a SSPG concentration more than 145 mg/dl wereconsidered IR, whereas those with a SSPG concentration less than 95mg/dl were classified as IS; and both sets of individuals were includedin the study. The cut point for defining IR was based on a prospectivestudy showing that apparently healthy, nonobese individuals with SSPGconcentrations greater than 140 mg/dl had a significant increase in theincidence of a number of age-related diseases (33). The cut point for theIS stems from evidence that approximately one third of a large, appar-ently healthy population had values below this level (34).
Given evidence that administration of thiazolidinedione compoundsincreased plasma adiponectin concentrations in IR nonsmokers (26), we
evaluated the possibility that this intervention would be equally effec-tive in both IR and IS smokers. To accomplish this goal, we enrolled 20smokers, 12 classified as being IR and eight IS by the criteria outlinedabove, and treated them for 3 months with pioglitazone. Treatment wasinitiated with 15 mg/d for 2 wk, increased to 30 mg/d for the next 2 wk,and followed by 45 mg/d for 8 wk. Plasma alanine aminotransferaselevels were checked at the end of each month, and the daily dose ofpioglitazone increased only in the presence of continued normal liverfunction. Liver function did not deteriorate in the 20 volunteers studied,and they all completed the treatment period on the full pioglitazonedose.
Plasma glucose and insulin levels were measured as described pre-viously (26). Plasma adiponectin levels were measured with a RIAestablished by Linco Research, Inc. (St. Charles, MO). This assay has asensitivity of 0.01 mg/dl and intra- and interassay coefficient of variationof less than 8%. Serum high-sensitivity CRP was measured with a chemi-luminescent assay established for use on an Immulite automatic ana-lyzer (Diagnostics Products Corp., Los Angeles, CA). This assay has asensitivity of 0.01 mg/dl and intra-and interassay coefficients of vari-ation of less than 8%.
Summary statistics are expressed as mean � sd or number of subjects.Adiponectin and CRP values were log transformed for statistical anal-yses. Means and the 95% confidence intervals (CIs) of the log-trans-formed data were calculated, and these values were then back trans-formed to the original scale. The resultant adiponectin and CRPaverages, known as geometric means, are reported along with their 95%CI. One-way ANOVA and Tukey’s post hoc comparison test were usedto compare the mean clinical and metabolic variables among the IRsmokers, IS smokers, IR nonsmokers, and IS nonsmokers. A �2 test wasused to assess the differences in gender distribution among these foursubgroups. Two-factor ANOVA was performed to evaluate the maineffects of smoking (smoker vs. nonsmoker) and insulin resistance (IR vs.IS) and their interaction on plasma adiponectin and CRP concentrations.Because differences in gender and body fat have been shown to influenceadiponectin levels, an analysis of covariance (ANCOVA) was performedto explore the effects of gender and BMI as covariates on plasma adi-ponectin concentrations in addition to the main effects of smoking andinsulin resistance and their interaction. Pearson correlation coefficientswere calculated to assess the strength of association between adiponec-tin and estimated GFR and between adiponectin and CRP concentra-tions. For the longitudinal pioglitazone treatment study in smokers,differences in baseline characteristics of the IR and IS subjects werecompared with unpaired t test, and gender distribution was comparedwith Fisher’s exact test. The effect of pioglitazone treatment in smokerswas evaluated using paired t test.
Results
The study participants were primarily of Caucasian an-cestry (n � 44) of whom four were of Hispanic ethnicity; therest of the volunteers were of Asian (n � 11) and African (n �5) ancestries. Clinical and metabolic characteristics of thesmokers and nonsmokers further divided into IR and ISgroups are given in Table 1. All four groups were similar interms of age, gender distribution, and BMI. The creatininelevels were normal and 1.2 mg/dl or less in all subjects. Theestimated GFR of the subjects was 107 � 19 ml/min per 1.73m2, and there was no significant correlation between adi-ponectin and the estimated GFR (r � �0.19; P � 0.16). Bydesign, IR individuals, both smokers and nonsmokers, hadSSPG concentrations that were approximately three timeshigher than the values in the two IS groups.
Figure 1A shows adiponectin concentrations in the 30smokers and the 30 nonsmokers, with the IR and IS indi-viduals in each group identified. The most obvious findingis that the variability of plasma adiponectin concentrationswas much greater in the nonsmokers. For example, adi-ponectin concentrations were 20.9 �g/ml or less in all smok-ers, whereas that value was exceeded in 20% of nonsmokers.
Abbasi et al. • Smoking, Adiponectin, and Insulin Resistance J Clin Endocrinol Metab, December 2006, 91(12):5002–5007 5003
Consistent with prior reports (10–13), the plasma adiponec-tin concentrations [mean (95% CI)] were lower in smokers[8.6 �g/ml (6.9–10.8)] than nonsmokers [11.7 �g/ml (9.2–15.0)]. Adiponectin levels were also lower in IR individuals[7.8 �g/ml (6.2–9.7)], compared with those who were IS [13.0�g/ml (10.5–16.2)]. Differences in means among thesegroups were compared using two-factor ANOVA with in-teraction. The results showed that smokers had significantlylower (F � 4.2, P � 0.046) average adiponectin concentra-tions, compared with nonsmokers, after taking into accountdifferences in their insulin resistance status (significant maineffect of smoking). IR subjects on average also had signifi-cantly lower (F � 11.7, P � 0.001) adiponectin concentrations,compared with IS subjects, after controlling for differences intheir smoking status (significant main effect of insulin resis-tance). Moreover, the differences in mean adiponectin con-centrations between smokers and nonsmokers did not de-pend on the insulin resistance status (F � 0.46, P � 0.50) ofthe subjects (nonsignificant smoking and insulin resistanceinteraction effect). When gender and BMI were included ascovariates in the ANCOVA, the main effects of smoking andinsulin resistance on adiponectin levels remained significant(P � 0.037 and 0.008, respectively), whereas the effects of BMIand the interaction between insulin resistance and smokingwere not. This finding indicated that after adjustment fordifferences in gender, BMI, and insulin resistance status, themean adiponectin levels continued to be significantly lowerin smokers. Furthermore, this analysis confirmed that on
average women had higher adiponectin levels, comparedwith men (P � 0.002), as previously reported (35).
Figure 1B displays the CRP concentrations in smokers andnonsmokers, again subdivided based on their classificationas IR or IS. In contrast to the data shown in Fig. 1A, thevariability in the individual values seemed comparable innonsmokers and smokers. The CRP values [mean (95% CI)]were somewhat higher in the smokers [1.61 �g/ml (1.22–2.12)] than nonsmokers [1.19 �g/ml (0.82–1.72)], and therewas also a trend toward higher values among the IR subjects[1.65 �g/ml (1.15–2.36)], compared with those who were IS[(1.16 �g/ml (0.87–1.54)]. Two-factor ANOVA showed thatthe average CRP concentrations were not significantly dif-ferent between the smokers and nonsmokers (F � 1.8, P �0.18), even after controlling for differences in their insulinresistance status. There were also no significant differencesin average CRP concentrations between the IR and IS subjectsdespite dissimilarity in their smoking status (F � 2.4, P �0.13). Finally, there was no significant effect (F � 0.01, P �0.92) of an interaction between smoking and insulin resis-tance on CRP levels.
The contribution of inflammation toward adiponectin lev-els was evaluated by examining the correlation coefficientsbetween CRP and adiponectin concentrations. The results ofthis analysis showed there was no significant relationshipbetween adiponectin and CRP levels among smokers (r ��0.05, P � 0.78), nonsmokers (r � 0.03, P � 0.86), or thewhole group (r � �0.04, P � 0.74) of subjects.
FIG. 1. Plasma adiponectin (A) and CRP concentrations (B) insmokers (n � 30) and nonsmokers (n � 30). Individual (nontrans-formed) data for each subject are shown with IR smokers (F), ISsmokers (E), IR nonsmokers (Œ), and IS nonsmokers (‚) identified.Adiponectin and CRP values were log transformed for statisticalanalysis. The horizontal lines represent the geometric means of theIR(solidline)andIS(brokenline)subgroupswithinthemaingroupsof smokers and nonsmokers. a, P value indicates the significance oftheeffectof smokingonadiponectin (A)andCRP(B)concentrationsafter controlling for differences in insulin resistance status by two-factor ANOVA; b, P value indicates the significance of the effect ofinsulin resistance on adiponectin (A) and CRP (B) concentrationsafter adjustment for differences in smoking status by two-factorANOVA. The following data are geometric means, and their 95%CIs are in parentheses. The adiponectin concentrations were 7.0�g/ml(4.9–10.1) inIRsmokers,10.6�g/ml(8.2–13.7) inISsmokers,8.6 �g/ml (6.3–11.7) in IR nonsmokers, and 15.9 �g/ml (11.2–22.6)inISnonsmokers;whereastheCRPconcentrationswere1.90�g/ml(1.16–3.10) in IR smokers, 1.37 �g/ml (1.01–1.84) in IS smokers,1.43 �g/ml (0.80–2.56) in IR nonsmokers, and 0.99 �g/ml (0.59–1.65) in IS nonsmokers.
TABLE 1. Clinical and metabolic characteristics of the 60 study subjects classified by smoking status and insulin resistance
CharacteristicSmokers Nonsmokers
P valueIR (n � 15) IS (n � 15) IR (n � 15) IS (n � 15)
Data are expressed as mean � SD or number of subjects.a P value denotes the significance of differences in means of the characteristic among the four subgroups by one-way ANOVA.b P value indicates the significance of differences in gender distribution among the four subgroups by �2 test.c P � 0.001 by Tukey’s post hoc test for the comparison of SSPG concentration between IR smokers and IS smokers and between IR nonsmokers
and IS nonsmokers.
5004 J Clin Endocrinol Metab, December 2006, 91(12):5002–5007 Abbasi et al. • Smoking, Adiponectin, and Insulin Resistance
The results in Fig. 2 display the effects of administeringpioglitazone to the two groups of smokers. By selection,pretreatment SSPG concentrations in the IR and IS smokerswere quite different (198 � 42 vs. 79 � 13 mg/dl, P � 0.001).However, there were no differences in the age (50 � 10 vs.51 � 5 yr, P � 0.90), gender distribution (female/male, 4/8vs. 6/2; P � 0.17), or BMI (29.3 � 3.6 vs. 26.7 � 4.1 kg/m2,P � 0.15) of the two groups. After pioglitazone therapy, SSPGsignificantly decreased to 142 � 70 mg/dl (P � 0.001) in theIR smokers but remained unchanged in the IS smokers (78 �30 mg/dl, P � 0.99). Plasma adiponectin levels [mean (95%CI)] increased by 9.5 �g/ml (5.5–16.2, P � 0.001) in IR smok-ers and 10.0 �g/ml (4.0–25.0, P � 0.001) in IS smokers. Itshould also be noted that the average posttreatment adi-ponectin concentrations in both IR smokers [14.7 �g/ml (8.9–24.3)] and IS smokers [22.7 �g/ml (13.7–37.6)] were similarto or greater than the value in IS nonsmokers [15.9 �g/ml(11.2–22.6)].
Discussion
Although not a major goal of this study, we demonstratedthat the IR individuals have significantly lower plasma adi-ponectin concentrations than their IS counterparts, a findingconsistent with previous publications (2, 7, 36). Because thereis evidence suggesting that the prevalence of insulin resis-tance is increased in smokers (24, 25), it was possible thatreports of lower adiponectin concentrations in smokers (10–13) was not related to smoking, per se, but to the concomitantpresence of insulin resistance in smokers. The results of thecurrent study argue against this possibility and provide ev-idence that plasma adiponectin levels are on the averagelower in smokers and demonstrate less interindividual vari-ability than in nonsmokers.
At the simplest level, our results are consistent with pre-vious reports that plasma adiponectin concentrations arelower in cigarette smokers, compared with nonsmokers (10–13). In contrast to these earlier studies, we quantified insulin-mediated glucose disposal with the insulin suppression test(30–32), a method shown to provide essentially identical
values for insulin action as the euglycemic, hyperinsulinemicclamp technique (32), thus allowing us to account more pre-cisely for the effect of insulin resistance when assessing therole of cigarette smoking. The fact that mean adiponectinconcentrations in smokers were lower by 26% in the presentstudy, a decrease similar to the 20% decrement in adiponec-tin concentrations in the 311 smokers studied by Iwashimaet al. (11), lends further support for the notion that plasmaadiponcentin concentrations are lower in smokers.
Our data provide substantial evidence that differences inthe degree of insulin sensitivity have a powerful impact onplasma adiponectin concentrations with the levels in IS in-dividuals essentially 1.5-fold higher than those in IR subjects.Smoking also appears to have a distinct negative effect onplasma adiponectin concentrations because these levels werelower in smokers than nonsmokers. Furthermore, the lowerplasma adiponectin concentrations in smokers were not de-pendent on the insulin resistance status of the subjects. Thisindicates that the effect of smoking independently attenuatesthe differences in plasma adiponectin concentrations nor-mally present between IR and IS individuals. Finally, whenwe evaluated the effects of gender and BMI on adiponectinin ANCOVA, the mean adiponectin levels continued to besignificantly lower in smokers, compared with nonsmokers,even after controlling for differences in gender, BMI, andinsulin resistance status.
In contrast to the impact of smoking on plasma adiponec-tin concentrations, we could not discern an adverse effect ofsmoking on CRP concentration. Thus, although the CRPconcentrations in smokers were somewhat higher than innonsmokers, the differences were not statistically significant,even after controlling for differences in their insulin resis-tance status. Moreover, there was no relationship betweenconcentrations of CRP and adiponectin in smokers. Althoughthese data suggest that lower adiponectin concentrations inIR and IS smokers are not a consequence of greater systemicinflammation, we cannot rule out the possibility that a re-lationship between CRP and adiponectin concentrationsmight have emerged if our study population had been larger.
FIG. 2. Plasma adiponectin concentrations before and afteradministration of pioglitazone for 3 months to IR and ISsmokers. Individual (nontransformed) data for each subjectare shown, as are the arithmetic means (bars) for the IRsmokers (A) and IS smokers (B). The change in adiponectinconcentrations was log transformed and evaluated usingpaired t test in both groups.
Abbasi et al. • Smoking, Adiponectin, and Insulin Resistance J Clin Endocrinol Metab, December 2006, 91(12):5002–5007 5005
Furthermore, we recognize that other inflammatory factorssuch as TNF-� and IL-6 have been associated with loweradiponectin levels (37, 38) and may directly reduce adiponec-tin secretion (14–16); however, our data would appear toindicate that if these factors are indeed relevant, they may beoperating not through systemic inflammation but via localinduction of adipose tissue inflammation.
Because cigarette smoke contains thousands of potentiallybioactive constituents, including free radicals, it is quite pos-sible that one or more of these factors may lower adiponectinproduction or release from adipocytes. For example, severalstudies demonstrated that nicotine, a major component ofcigarette smoke, promotes inflammation and appears to havedirect effects on adipose tissue, inducing adipose tissue li-polysis via enhanced release of catecholamines (39–42). Con-sistent with this, addition of nicotine (as well as hydrogenperoxide) to 3T3-L1 adipocytes reduced expression of adi-ponectin in a dose-dependent fashion (11).
Finally, the result of administrating pioglitazone to smok-ers once again shows that thiazolidinedione compounds willenhance insulin sensitivity when given to nondiabetic, in-sulin-resistant individuals (26, 27), even if, as in this instance,they continue to smoke. Not surprisingly, there was no sig-nificant change in SSPG concentrations in the IS smokers. Incontrast, plasma adiponectin concentrations increased sig-nificantly in both IS and IR smokers, indicating that thistherapy, whether by antiinflammatory effects on adiposetissue or direct regulation of adiponectin gene expression(43), can overcome the detrimental effects of smoking onadiponectin concentrations.
In summary, at a pathophysiological level, the data pre-sented support the concept that adiponectin concentrationsare lower in smokers (10–13), and this phenomenon does notseem to be due to the concomitant presence of insulin resis-tance. These data, and other examples of discordance be-tween adiponectin concentrations and extent of IR (26, 44–47), must be kept in mind when considering adiponectin asa marker of IR. At a clinical level, it is obvious that smokingcessation is the most effective way to overcome the harmfuleffects of smoking. On the other hand, there are individualswho are either unwilling or unable to stop smoking, and ourfindings raise the possibility that thiazolidinedione admin-istration may be of some clinical benefit in these situations.This may be particularly important if future studies confirmrecent findings indicating that individuals who smoke andhave low adiponectin levels are at a substantially greater riskfor cardiovascular disease than individuals with either ofthese risk factors alone (28).
Acknowledgments
Received February 23, 2006. Accepted September 19, 2006.Address all correspondence and requests for reprints to: Peter
Reaven, M.D., Division of Endocrinology and Metabolism, Departmentof Medicine (CS-111E), Carl T. Hayden Veterans Affairs Medical Center,650 East Indian School Road, Phoenix, Arizona 85012. E-mail:[email protected].
This work was supported by the Tobacco-Related Disease ResearchProgram (12RT-0159), the National Insitutes of Health/Stanford Vas-cular Biology and Medicine Training Grant (5 T32 HL07708), GrantRR-00070 from the National Institutes of Health, and resources and use
of the facilities at the Carl T. Hayden Veterans Affairs Medical Center(Phoenix, Arizona).
Disclosure statement: The authors have no potential conflicts of in-terest to disclose.
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