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The Relationship between Plasma Adiponectin Concentration and Insulin Resistance Is Altered in Smokers

Department of Medicine (F.A., H.M.F.F., C.L., T.M., G.M.R.), Stanford University School of Medicine, Stanford, California 94305; 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

Address all correspondence and requests for reprints to: Peter Reaven, M.D., Division of Endocrinology and Metabolism, Department of Medicine (CS-111E), Carl T. Hayden Veterans Affairs Medical Center, 650 East Indian School Road, Phoenix, Arizona 85012. E-mail: peter.reaven{at}med.va.gov.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Low plasma adiponectin concentrations in smokers may contribute to the adverse consequences that occur in these individuals.

Objective: The objective of the study was to define the relationship among smoking, plasma adiponectin concentrations, insulin resistance, and inflammation.

Design: This was a cross-sectional, observational study with a 2 x 2 factorial design and a prospective longitudinal arm.

Setting: The study was conducted at a general clinical research center.

Participants: Apparently healthy smokers (n = 30) and nonsmokers (n = 30), subdivided into insulin resistant (IR) (n = 15) and insulin sensitive (IS) (n = 15) subgroups participated in the study.

Intervention: Intervention included pioglitazone administration for 3 months to 12 IR smokers and eight IS smokers.

Main Outcome Measures: Measures included fasting plasma adiponectin and C-reactive protein (CRP) concentrations and changes in adiponectin after pioglitazone treatment in IR and IS smokers.

Results: Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (P = 0.046 and 0.001, respectively). The difference in mean adiponectin concentration between smokers and nonsmokers did not depend on the insulin resistance status of the subjects. No difference was detected in average CRP concentrations between smokers and nonsmokers (P = 0.18) and between IR and IS subjects (P = 0.13). CRP concentrations were unrelated to adiponectin in smokers (r = –0.05, P = 0.78) and nonsmokers (r = 0.03, P = 0.86). Finally, pioglitazone treatment increased adiponectin concentrations in both IR (P < 0.001) and IS smokers (P = 0.001).

Conclusions: Plasma adiponectin concentrations are lower in smokers and IR subjects and are unrelated to CRP concentrations. These findings suggest that low levels of adiponectin in smokers may be independent of both insulin resistance and a generalized inflammatory response.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ADIPONECTIN, AN ADIPOCYTE gene product, is secreted in large amounts from adipose tissue and is present in relatively high concentration in the blood. Low circulating concentrations of adiponectin have been associated with obesity, dyslipidemia, essential hypertension, type 2 diabetes, and cardiovascular disease (1, 2, 3, 4, 5). It is apparent that the clinical syndromes in which hypoadiponectinemia occurs are all associated with peripheral resistance to insulin-mediated glucose uptake (6). In addition, variations in plasma adiponectin concentration and/or molecular forms have been suggested to modulate insulin sensitivity (2, 7, 8, 9).

More recently, plasma adiponectin concentrations have been reported to be low in smokers (10, 11, 12, 13). Because results of in vitro studies have indicated that addition of proinflammatory cytokines, such as TNF- and IL-6, to isolated adipocytes can reduce adiponectin expression (14, 15, 16), it is possible that the association between smoking and lower adiponectin concentrations results from inflammation-mediated down-regulation of adiponectin expression in adipose tissue. In support of this notion is evidence of an inverse relationship between markers of inflammation such as C-reactive protein (CRP) with adiponectin (17, 18). In addition, smoking has been identified as a source of reactive oxygen species (19, 20) and is associated with increased levels of inflammatory markers (21, 22, 23), further suggesting that smoking-induced inflammation may contribute to lower adiponectin levels in smokers.

On the other hand, because the prevalence of insulin resistance may also be increased in smokers (24, 25), it is not clear whether hypoadiponectinemia in these individuals is due to smoking, and possibly the associated inflammation, or to the coexistence of insulin resistance. The possible contribution of insulin resistance, as estimated by a surrogate indicator, to reduced adiponectin concentrations in smokers was considered in one brief correspondence (12), and the results of multivariate analysis suggested that the relationship between smoking and adiponectin was independent of insulin action. However, we felt that the possible relationship among smoking, hypoadiponectemia, and insulin resistance was important enough to evaluate further, using a specific measure of insulin action, rather than a surrogate estimate. To address these issues, we have in the present study measured adiponectin and CRP concentrations in smokers and nonsmokers, with each group further stratified into insulin-resistant (IR) and insulin-sensitive (IS) subgroups.

If adiponectin is lower in smokers, and this is not simply related to the extent of insulin resistance, identification of therapies that correct this abnormality may be clinically important. In this context, thiazolidinedione compounds have been shown to increase plasma adiponectin concentrations (9, 26), and there is evidence that they can exert a beneficial antiinflammatory effect independent of their ability to enhance insulin sensitivity (27). The ability of such agents to increase adiponectin may be particularly useful to prevent cardiovascular disease in smokers in light of the observation that smokers with low adiponectin concentrations are at greater risk for coronary stenosis than smokers with high concentrations of adiponectin (28). Thus, irrespective of the reasons that adiponectin concentrations are lower in smokers, we thought it would be important to also evaluate the ability of pioglitazone treatment to increase plasma adiponectin concentrations in the two smoking groups.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The study population consisted of 30 smokers and 30 nonsmokers who responded to print advertisements describing our research interest in smoking-associated metabolic abnormalities. Screening inclusion criteria included: healthy individuals between ages 29 and 65 yr; body mass indices (BMIs) between 20 and 35 kg/m²; and no medications known to affect glucose, insulin, or lipoprotein metabolism. In addition, the smokers had to have a history of smoking a minimum of 10 cigarettes per day for at least the past 5 yr. Potential participants were further evaluated by medical history, physical examination, and routine clinical laboratory measurement to exclude individuals with apparent disease, laboratory evidence of type 2 diabetes, anemia, and abnormal liver or kidney function. Renal function was also evaluated by calculating the estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula (29). Volunteers meeting these eligibility criteria were scheduled for admission to the General Clinical Research Center of the Stanford University Medical Center. The Stanford Human Subjects Committee approved the study, and each subject gave informed consent.

Insulin-mediated glucose disposal was quantified by a modified version (30) of the insulin suppression test as described and validated by our research group (31, 32). After an overnight fast, an iv catheter was placed in each arm of the subject. One arm was used for the simultaneous infusion of octreotide (0.27 µg/m²·min), insulin (32 mU/m²·min), and glucose (267 mg/m²·min) for 180 min, and the other arm was used for collection of blood samples. During the last 30 min of the infusion, blood was sampled at 10-min intervals to measure plasma glucose and insulin concentrations, and the values obtained were averaged to determine the steady-state plasma glucose (SSPG) and insulin concentrations. Because the steady-state plasma insulin concentrations are comparable in all individuals and glucose infusion is identical, the resultant SSPG concentrations provide a direct measure of the ability of insulin to mediate the disposal of a given glucose load; i.e. the higher the SSPG concentration, the more insulin resistant the individual. For the purpose of this study, individuals with a SSPG concentration more than 145 mg/dl were considered IR, whereas those with a SSPG concentration less than 95 mg/dl were classified as IS; and both sets of individuals were included in the study. The cut point for defining IR was based on a prospective study showing that apparently healthy, nonobese individuals with SSPG concentrations greater than 140 mg/dl had a significant increase in the incidence of a number of age-related diseases (33). The cut point for the IS stems from evidence that approximately one third of a large, apparently healthy population had values below this level (34).

Given evidence that administration of thiazolidinedione compounds increased plasma adiponectin concentrations in IR nonsmokers (26), we evaluated the possibility that this intervention would be equally effective in both IR and IS smokers. To accomplish this goal, we enrolled 20 smokers, 12 classified as being IR and eight IS by the criteria outlined above, and treated them for 3 months with pioglitazone. Treatment was initiated 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 aminotransferase levels were checked at the end of each month, and the daily dose of pioglitazone increased only in the presence of continued normal liver function. Liver function did not deteriorate in the 20 volunteers studied, and they all completed the treatment period on the full pioglitazone dose.

Plasma glucose and insulin levels were measured as described previously (26). Plasma adiponectin levels were measured with a RIA established by Linco Research, Inc. (St. Charles, MO). This assay has a sensitivity of 0.01 mg/dl and intra- and interassay coefficient of variation of less than 8%. Serum high-sensitivity CRP was measured with a chemiluminescent assay established for use on an Immulite automatic analyzer (Diagnostics Products Corp., Los Angeles, CA). This assay has a sensitivity of 0.01 mg/dl and intra-and interassay coefficients of variation of less than 8%.

Summary statistics are expressed as mean ± SD or number of subjects. Adiponectin and CRP values were log transformed for statistical analyses. Means and the 95% confidence intervals (CIs) of the log-transformed data were calculated, and these values were then back transformed to the original scale. The resultant adiponectin and CRP averages, known as geometric means, are reported along with their 95% CI. One-way ANOVA and Tukey’s post hoc comparison test were used to compare the mean clinical and metabolic variables among the IR smokers, IS smokers, IR nonsmokers, and IS nonsmokers. A ² test was used to assess the differences in gender distribution among these four subgroups. Two-factor ANOVA was performed to evaluate the main effects 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 influence adiponectin levels, an analysis of covariance (ANCOVA) was performed to explore the effects of gender and BMI as covariates on plasma adiponectin concentrations in addition to the main effects of smoking and insulin resistance and their interaction. Pearson correlation coefficients were calculated to assess the strength of association between adiponectin and estimated GFR and between adiponectin and CRP concentrations. For the longitudinal pioglitazone treatment study in smokers, differences in baseline characteristics of the IR and IS subjects were compared with unpaired t test, and gender distribution was compared with Fisher’s exact test. The effect of pioglitazone treatment in smokers was evaluated using paired t test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The study participants were primarily of Caucasian ancestry (n = 44) of whom four were of Hispanic ethnicity; the rest of the volunteers were of Asian (n = 11) and African (n = 5) ancestries. Clinical and metabolic characteristics of the smokers and nonsmokers further divided into IR and IS groups are given in Table 1. All four groups were similar in terms of age, gender distribution, and BMI. The creatinine levels were normal and 1.2 mg/dl or less in all subjects. The estimated GFR of the subjects was 107 ± 19 ml/min per 1.73 m², and there was no significant correlation between adiponectin and the estimated GFR (r = –0.19; P = 0.16). By design, IR individuals, both smokers and nonsmokers, had SSPG concentrations that were approximately three times higher than the values in the two IS groups.

View larger version (18K): [in this window] [in a new window]   FIG. 1. Plasma adiponectin (A) and CRP concentrations (B) in smokers (n = 30) and nonsmokers (n = 30). Individual (nontransformed) data for each subject are shown with IR smokers (•), IS smokers (), IR nonsmokers (), and IS nonsmokers () identified. Adiponectin and CRP values were log transformed for statistical analysis. The horizontal lines represent the geometric means of the IR (solid line) and IS (broken line) subgroups within the main groups of smokers and nonsmokers. a, P value indicates the significance of the effect of smoking on adiponectin (A) and CRP (B) concentrations after controlling for differences in insulin resistance status by two-factor ANOVA; b, P value indicates the significance of the effect of insulin resistance on adiponectin (A) and CRP (B) concentrations after adjustment for differences in smoking status by two-factor ANOVA. The following data are geometric means, and their 95% CIs are in parentheses. The adiponectin concentrations were 7.0 µg/ml (4.9–10.1) in IR smokers, 10.6 µg/ml (8.2–13.7) in IS smokers, 8.6 µg/ml (6.3–11.7) in IR nonsmokers, and 15.9 µg/ml (11.2–22.6) in IS nonsmokers; whereas the CRP concentrations were 1.90 µg/ml (1.16–3.10) in IR smokers, 1.37 µg/ml (1.01–1.84) in IS smokers, 1.43 µg/ml (0.80–2.56) in IR nonsmokers, and 0.99 µg/ml (0.59–1.65) in IS nonsmokers.

The contribution of inflammation toward adiponectin levels was evaluated by examining the correlation coefficients between CRP and adiponectin concentrations. The results of this analysis showed there was no significant relationship between adiponectin and CRP levels among smokers (r = –0.05, P = 0.78), nonsmokers (r = 0.03, P = 0.86), or the whole group (r = –0.04, P = 0.74) of subjects.

The results in Fig. 2 display the effects of administering pioglitazone to the two groups of smokers. By selection, pretreatment SSPG concentrations in the IR and IS smokers were 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, 4/8 vs. 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, SSPG significantly decreased to 142 ± 70 mg/dl (P = 0.001) in the IR 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 µg/ml (5.5–16.2, P < 0.001) in IR smokers and 10.0 µg/ml (4.0–25.0, P = 0.001) in IS smokers. It should also be noted that the average posttreatment adiponectin concentrations in both IR smokers [14.7 µg/ml (8.9–24.3)] and IS smokers [22.7 µg/ml (13.7–37.6)] were similar to or greater than the value in IS nonsmokers [15.9 µg/ml (11.2–22.6)].

View larger version (21K): [in this window] [in a new window]   FIG. 2. Plasma adiponectin concentrations before and after administration of pioglitazone for 3 months to IR and IS smokers. Individual (nontransformed) data for each subject are shown, as are the arithmetic means (bars) for the IR smokers (A) and IS smokers (B). The change in adiponectin concentrations was log transformed and evaluated using paired t test in both groups.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

At the simplest level, our results are consistent with previous reports that plasma adiponectin concentrations are lower in cigarette smokers, compared with nonsmokers (10, 11, 12, 13). In contrast to these earlier studies, we quantified insulin-mediated glucose disposal with the insulin suppression test (30, 31, 32), a method shown to provide essentially identical values for insulin action as the euglycemic, hyperinsulinemic clamp technique (32), thus allowing us to account more precisely for the effect of insulin resistance when assessing the role of cigarette smoking. The fact that mean adiponectin concentrations in smokers were lower by 26% in the present study, a decrease similar to the 20% decrement in adiponectin concentrations in the 311 smokers studied by Iwashima et al. (11), lends further support for the notion that plasma adiponcentin concentrations are lower in smokers.

Our data provide substantial evidence that differences in the degree of insulin sensitivity have a powerful impact on plasma adiponectin concentrations with the levels in IS individuals essentially 1.5-fold higher than those in IR subjects. Smoking also appears to have a distinct negative effect on plasma adiponectin concentrations because these levels were lower in smokers than nonsmokers. Furthermore, the lower plasma adiponectin concentrations in smokers were not dependent on the insulin resistance status of the subjects. This indicates that the effect of smoking independently attenuates the differences in plasma adiponectin concentrations normally present between IR and IS individuals. Finally, when we evaluated the effects of gender and BMI on adiponectin in ANCOVA, the mean adiponectin levels continued to be significantly lower in smokers, compared with nonsmokers, even after controlling for differences in gender, BMI, and insulin resistance status.

In contrast to the impact of smoking on plasma adiponectin concentrations, we could not discern an adverse effect of smoking on CRP concentration. Thus, although the CRP concentrations in smokers were somewhat higher than in nonsmokers, the differences were not statistically significant, even after controlling for differences in their insulin resistance status. Moreover, there was no relationship between concentrations of CRP and adiponectin in smokers. Although these data suggest that lower adiponectin concentrations in IR and IS smokers are not a consequence of greater systemic inflammation, we cannot rule out the possibility that a relationship between CRP and adiponectin concentrations might have emerged if our study population had been larger. Furthermore, we recognize that other inflammatory factors such as TNF- and IL-6 have been associated with lower adiponectin levels (37, 38) and may directly reduce adiponectin secretion (14, 15, 16); however, our data would appear to indicate that if these factors are indeed relevant, they may be operating not through systemic inflammation but via local induction of adipose tissue inflammation.

Because cigarette smoke contains thousands of potentially bioactive constituents, including free radicals, it is quite possible that one or more of these factors may lower adiponectin production or release from adipocytes. For example, several studies demonstrated that nicotine, a major component of cigarette smoke, promotes inflammation and appears to have direct effects on adipose tissue, inducing adipose tissue lipolysis via enhanced release of catecholamines (39, 40, 41, 42). Consistent with this, addition of nicotine (as well as hydrogen peroxide) to 3T3-L1 adipocytes reduced expression of adiponectin in a dose-dependent fashion (11).

Finally, the result of administrating pioglitazone to smokers once again shows that thiazolidinedione compounds will enhance insulin sensitivity when given to nondiabetic, insulin-resistant individuals (26, 27), even if, as in this instance, they continue to smoke. Not surprisingly, there was no significant change in SSPG concentrations in the IS smokers. In contrast, plasma adiponectin concentrations increased significantly in both IS and IR smokers, indicating that this therapy, whether by antiinflammatory effects on adipose tissue or direct regulation of adiponectin gene expression (43), can overcome the detrimental effects of smoking on adiponectin concentrations.

In summary, at a pathophysiological level, the data presented support the concept that adiponectin concentrations are lower in smokers (10, 11, 12, 13), and this phenomenon does not seem to be due to the concomitant presence of insulin resistance. These data, and other examples of discordance between adiponectin concentrations and extent of IR (26, 44, 45, 46, 47), must be kept in mind when considering adiponectin as a marker of IR. At a clinical level, it is obvious that smoking cessation is the most effective way to overcome the harmful effects of smoking. On the other hand, there are individuals who are either unwilling or unable to stop smoking, and our findings raise the possibility that thiazolidinedione administration may be of some clinical benefit in these situations. This may be particularly important if future studies confirm recent findings indicating that individuals who smoke and have low adiponectin levels are at a substantially greater risk for cardiovascular disease than individuals with either of these risk factors alone (28).

	Footnotes

 
This work was supported by the Tobacco-Related Disease Research Program (12RT-0159), the National Insitutes of Health/Stanford Vascular Biology and Medicine Training Grant (5 T32 HL07708), Grant RR-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 interest to disclose.

First Published Online September 26, 2006

Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; GFR, glomerular filtration rate; IR, insulin resistant; IS, insulin sensitive; SSPG, steady-state plasma glucose.

Received February 23, 2006.

Accepted September 19, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599[Abstract/Free Full Text]
2. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935[Abstract/Free Full Text]
3. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y 2003 Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23:85–89[Abstract/Free Full Text]
4. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y 2003 Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 16:72–75[CrossRef][Medline]
5. Baratta R, Amato S, Degano C, Farina MG, Patane G, Vigneri R, Frittitta L 2004 Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies. J Clin Endocrinol Metab 89:2665–2671[Abstract/Free Full Text]
6. Reaven G 2004 The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 33:283–303[CrossRef][Medline]
7. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y 2001 Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50:1126–1133[Abstract/Free Full Text]
8. Chandran M, Phillips SA, Ciaraldi T, Henry RR 2003 Adiponectin: more than just another fat cell hormone? Diabetes Care 26:2442–2450[Free Full Text]
9. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE 2004 Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152–12162[Abstract/Free Full Text]
10. Miyazaki T, Shimada K, Mokuno H, Daida H 2003 Adipocyte derived plasma protein, adiponectin, is associated with smoking status in patients with coronary artery disease. Heart 89:663
11. Iwashima Y, Katsuya T, Ishikawa K, Kida I, Ohishi M, Horio T, Ouchi N, Ohashi K, Kihara S, Funahashi T, Rakugi H, Ogihara T 2005 Association of hypoadiponectinemia with smoking habit in men. Hypertension 45:1094–1100[Abstract/Free Full Text]
12. Thamer C, Stefan N, Stumvoll M, Haring H, Fritsche A 2005 Reduced adiponectin serum levels in smokers. Atherosclerosis 179:421–422[CrossRef][Medline]
13. Tsukinoki R, Morimoto K, Nakayama K 2005 Association between lifestyle factors and plasma adiponectin levels in Japanese men. Lipids Health Dis 4:27
14. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R 2002 Hormonal regulation of adiponectin gene expression in 3T3–L1 adipocytes. Biochem Biophys Res Commun 290:1084–1089[CrossRef][Medline]
15. Suganami T, Nishida J, Ogawa Y 2005 A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25:2062–2068[Abstract/Free Full Text]
16. Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R 2003 Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3–L1 adipocytes. Biochem Biophys Res Commun 301:1045–1050[CrossRef][Medline]
17. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y 2003 Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 107:671–674
18. Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke J, Mohlig M, Pfeiffer AF, Luft FC, Sharma AM 2003 Association between adiponectin and mediators of inflammation in obese women. Diabetes 52:942–947[Abstract/Free Full Text]
19. Traber MG, van der Vliet A, Reznick AZ, Cross CE 2000 Tobacco-related diseases. Is there a role for antioxidant micronutrient supplementation? Clin Chest Med 21:173–187, x[CrossRef][Medline]
20. Moller P, Wallin H, Knudsen LE 1996 Oxidative stress associated with exercise, psychological stress and life-style factors. Chem Biol Interact 102:17–36[CrossRef][Medline]
21. Wannamethee SG, Lowe GD, Shaper AG, Rumley A, Lennon L, Whincup PH 2005 Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J 26:1765–1773[Abstract/Free Full Text]
22. Ikonomidis I, Lekakis J, Vamvakou G, Andreotti F, Nihoyannopoulos P 2005 Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease: effects of aspirin treatment. Am Heart J 149:832–839[CrossRef][Medline]
23. Miller EA, Pankow JS, Millikan RC, Bray MS, Ballantyne CM, Bell DA, Heiss G, Li R 2003 Glutathione-S-transferase genotypes, smoking, and their association with markers of inflammation, hemostasis, and endothelial function: the atherosclerosis risk in communities (ARIC) study. Atherosclerosis 171:265–272[CrossRef][Medline]
24. Facchini FS, Hollenbeck CB, Jeppesen J, Chen YD, Reaven GM 1992 Insulin resistance and cigarette smoking. Lancet 339:1128–1130[CrossRef][Medline]
25. Attvall S, Fowelin J, Lager I, Von Schenck H, Smith U 1993 Smoking induces insulin resistance—a potential link with the insulin resistance syndrome. J Intern Med 233:327–332[Medline]
26. Abbasi F, Chang SA, Chu JW, Ciaraldi TP, Lamendola C, McLaughlin T, Reaven GM, Reaven PD 2006 Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin or adiponectin multimeric complexes. Am J Physiol Regul Integr Comp Physiol 290:R139–R144
27. Chu JW, Abbasi F, Lamendola C, McLaughlin T, Reaven GM, Tsao PS 2005 Effect of rosiglitazone treatment on circulating vascular and inflammatory markers in insulin-resistant subjects. Diab Vasc Dis Res 2:37–41[Abstract/Free Full Text]
28. Imatoh T, Miyazaki M, Kadowaki K, Babazono A, Sato M, Une H 2006 Interaction of low serum adiponectin levels and smoking on coronary stenosis in Japanese men. Int J Cardiol 110:251–255[CrossRef][Medline]
29. Cockcroft DW, Gault MH 1976 Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41[Medline]
30. Pei D, Jones CN, Bhargava R, Chen YD, Reaven GM 1994 Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test. Diabetologia 37:843–845[CrossRef][Medline]
31. Shen SW, Reaven GM, Farquhar JW 1970 Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Invest 49:2151–2160[Medline]
32. Greenfield MS, Doberne L, Kraemer F, Tobey T, Reaven G 1981 Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes 30:387–392[Abstract]
33. Facchini FS, Hua N, Abbasi F, Reaven GM 2001 Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 86:3574–3578[Abstract/Free Full Text]
34. Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM 2000 Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Diabetes Care 23:171–175[Abstract]
35. Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, Matsuda M, Kondo H, Furuyama N, Kihara S, Nakamura T, Tochino Y, Funahashi T, Matsuzawa Y 2002 Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein. Diabetes 51:2734–2741[Abstract/Free Full Text]
36. Abbasi F, Chu JW, Lamendola C, McLaughlin T, Hayden J, Reaven GM, Reaven PD 2004 Discrimination between obesity and insulin resistance in the relationship with adiponectin. Diabetes 53:585–590[Abstract/Free Full Text]
37. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G 2003 Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor- expression. Diabetes 52:1779–1785[Abstract/Free Full Text]
38. Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, Richelsen B 2003 Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 285:E527–E533
39. Lau PP, Li L, Merched AJ, Zhang AL, Ko KW, Chan L 2006 Nicotine induces proinflammatory responses in macrophages and the aorta leading to acceleration of atherosclerosis in low-density lipoprotein receptor(–/–) mice. Arterioscler Thromb Vasc Biol 26:143–149[Abstract/Free Full Text]
40. Kershbaum A, Khorsandian R, Caplan RF, Bellet S, Feinberg LJ 1963 The role of catecholamines in the free fatty acid response to cigarette smoking. Circulation 28:52–57[Medline]
41. Chajek-Shaul T, Scherer G, Barash V, Shiloni E, Caine Y, Stein O, Stein Y 1994 Metabolic effects of nicotine on human adipose tissue in organ culture. Clin Invest 72:94–99[Medline]
42. Andersson K, Arner P 2001 Systemic nicotine stimulates human adipose tissue lipolysis through local cholinergic and catecholaminergic receptors. Int J Obes Relat Metab Disord 25:1225–1232[CrossRef][Medline]
43. Gustafson B, Jack MM, Cushman SW, Smith U 2003 Adiponectin gene activation by thiazolidinediones requires PPAR2, but not C/EBP —evidence for differential regulation of the aP2 and adiponectin genes. Biochem Biophys Res Commun 308:933–939[CrossRef][Medline]
44. Ryan AS, Nicklas BJ, Berman DM, Elahi D 2003 Adiponectin levels do not change with moderate dietary induced weight loss and exercise in obese postmenopausal women. Int J Obes Relat Metab Disord 27:1066–1071[CrossRef][Medline]
45. Abbasi F, Lamendola C, McLaughlin T, Hayden J, Reaven GM, Reaven PD 2004 Plasma adiponectin concentrations do not increase in association with moderate weight loss in insulin-resistant, obese women. Metabolism 53:280–283[CrossRef][Medline]
46. Marcell TJ, McAuley KA, Traustadottir T, Reaven PD 2005 Exercise training is not associated with improved levels of C-reactive protein or adiponectin. Metabolism 54:533–541[CrossRef][Medline]
47. Nassis GP, Papantakou K, Skenderi K, Triandafillopoulou M, Kavouras SA, Yannakoulia M, Chrousos GP, Sidossis LS 2005 Aerobic exercise training improves insulin sensitivity without changes in body weight, body fat, adiponectin, and inflammatory markers in overweight and obese girls. Metabolism 54:1472–1479[CrossRef][Medline]

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