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Total and High Molecular Weight But Not Trimeric or Hexameric Forms of Adiponectin Correlate with Markers of the Metabolic Syndrome and Liver Injury in Thai Subjects

Division of Endocrinology (R.R., A.H.) and Department of Nutritional Sciences (A.H.), University of Toronto, Toronto, Ontario, Canada M5S 2E4; Leadership Sinai Centre for Diabetes (R.R.), Mount Sinai Hospital, Toronto, Canada M5G 1X5; Department of Tropical Nutrition and Food Science (R.T.), Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; American Laboratory Products Company (ALPCO Diagnostics) (C.S.), Salem, New Hampshire 03079; and Department of Biology (Y.L., G.S.), York University, Toronto, Ontario, Canada M3J 1P3

Address all correspondence and requests for reprints to: Gary Sweeney, Department of Biology, York University Toronto, M3J 1P3, Ontario, Canada. E-mail: gsweeney{at}yorku.ca.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context/Objective: Decreased total adiponectin has been associated with metabolic disorders, including obesity, diabetes, fatty liver, and the metabolic syndrome. Although circulating adiponectin is composed of trimers, hexamers, and high molecular weight (HMW) multimers, there has been limited study of the specific metabolic correlates of these isoforms in humans. Thus, our objective was to evaluate the associations of these adiponectin isoforms with metabolic and anthropometric parameters.

Design/Participants/Setting: A total of 53 diabetic and 68 nondiabetic subjects attending outpatient clinics underwent cross-sectional metabolic characterization. Circulating levels of HMW, hexameric, and trimeric adiponectin were measured using a multimeric adiponectin ELISA based upon selective protease-mediated digestion.

Results: On Spearman univariate analysis, both total and HMW adiponectin levels were inversely associated with body mass index, fasting glucose, homeostasis model of assessment of insulin resistance, triglycerides, and alanine aminotransferase (ALT) (all |r| 0.22; P < 0.05), with the HMW isoform also positively correlated with high-density lipoprotein cholesterol (r = 0.19; P = 0.036). In contrast, hexameric and trimeric adiponectin were significantly associated with only body mass index (r = –0.23; P = 0.0102) and mid-upper arm circumference (r = 0.21; P = 0.039), respectively. On separate forward stepwise multiple linear regression analyses, fasting glucose and ALT emerged as independent, negative covariates of both total and HMW adiponectin, whereas no independent covariates of hexameric and trimeric adiponectin were identified. Furthermore, after adjustment for age, gender, and diabetes, mean ALT was highest in subjects in the lowest tertile of HMW adiponectin, followed in turn by the middle and highest tertiles, respectively (trend P = 0.028).

Conclusions: HMW adiponectin, but not hexameric or trimeric, tracks with the metabolic correlates of total adiponectin. Furthermore, an independent inverse association exists between ALT and HMW adiponectin.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ADIPONECTIN IS ONE of the most abundant plasma proteins and possesses antidiabetic properties due to insulin-mimetic and insulin-sensitizing actions (1, 2, 3). Whereas circulating levels of adipokines typically show a positive correlation with body mass index (BMI), decreased total adiponectin levels are observed in obesity and in metabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease, and the metabolic syndrome. Indeed, there is currently intense interest in the role of adiponectin in the pathophysiology of the metabolic syndrome and as a useful biomarker in this respect (3, 4). However, analysis of adiponectin function and regulation is complicated by the fact that the monomeric gene product is not found in the circulation. Instead, adiponectin undergoes extensive posttranslational modification (5, 6) and circulates in trimeric, hexameric, and oligomeric (18-mer) forms (5). Furthermore, basic research studies have shown that the various multimeric forms of adiponectin may mediate distinct physiological effects (1, 2, 3).

The vast majority of clinical studies published to date have evaluated correlations between total adiponectin levels and various markers of the metabolic syndrome. However, in the context of recent advances in our understanding of adiponectin structure and function, it has been suggested that assessment of total adiponectin may be insufficient and that analysis of the relative levels of the multimeric forms should be undertaken in relation to physiological parameters (7). However, to date, the metabolic correlates of oligomeric, hexameric, and trimeric adiponectin have not been extensively studied in humans. Indeed, establishing the specific clinical correlates of each multimer may be of particular value given the current need for more accurate risk assessment markers in the metabolic syndrome (8). Therefore, a particular strength of our current study is the detailed analysis of adiponectin multimer levels in circulation, and their correlation with metabolic and anthropometric measures.

We have used a recently developed ELISA, based upon selective protease-mediated digestion of adiponectin (9, 10), to undertake quantitative analysis of each multimeric form of adiponectin in human plasma. We determined the circulating levels of oligomeric [high molecular weight (HMW)], hexameric [middle molecular weight (MMW)], and trimeric [low molecular weight (LMW)] adiponectin in a cohort of Thai patients and evaluated the relationships among these isoforms and a variety of biochemical and anthropometric measures associated with the metabolic syndrome.

	Subjects and Methods

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A total of 121 individuals participated in this cross-sectional study. The participants were: 1) volunteers from a diabetes mellitus outpatient clinic of the Burapha University Health Center, Thailand; and 2) healthy volunteers from the villages around the health center, representing the same catchment area from which the diabetic subjects for this study were recruited. All diabetic participants had type 2 diabetes diagnosed by a physician, and confirmed at recruitment by biochemical testing and clinical examination by study physicians. Exclusion criteria included current use of insulin, thus excluding individuals with type 1 diabetes mellitus, and previous history of any chronic disease, including kidney, liver, and inflammatory disorders. None of the patients included in this study were being treated with a thiazolidinedione. The protocol was approved by the ethics committee of Burapha University, and all participants provided written informed consent.

Circulating total, HMW, MMW, and LMW adiponectin levels were determined using an ELISA from American Laboratory Products Company (ALPCO Diagnostics) (Salem, NH). This system is capable of quantifying HMW, MMW, LMW, and total adiponectin in a single ELISA, and is advantageous because previously, the various oligomeric forms of adiponectin were fractionated and quantified by laborious techniques, including velocity sedimentation in sucrose gradients, HPLC, fast protein liquid chromatography, and Western blot analyses. S_A was calculated as the ratio of HMW to total adiponectin, expressed as a percentage, as originally defined (7). RIA from LINCO Research (St. Charles, MO) was used to determine serum insulin and resistin levels. Plasma glucose was measured by the enzymatic colorimetric method by the method of Ware and Marbach (11). The homeostasis model of assessment of insulin resistance (HOMA-IR) score was calculated as fasting insulin (µU/ml) times fasting glucose (mM/liter) divided by 22.5. Fasting blood sugar and lipid profile determinations were done on the same day after blood collection, whereas plasma was stored at –70 C for insulin determination. Serum creatinine was determined by standard colorimetry, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined by enzymatic methods as previously described (12). Total cholesterol (TC) was determined by a colorimetric method. Triglyceride (TG) levels were determined by an enzymatic colorimetric test with lipid clearing factor (glycerol phosphate oxidase phenol 4-aminoantipyrine peroxidase method). Chylomicrons, very low-density lipoprotein cholesterol (LDL-C), and LDL-C were removed from blood plasma by a precipitation method in adding phosphotungstic acid and magnesium chloride to the plasma. After centrifugation of the remaining plasma, high-density lipoprotein cholesterol (HDL-C) concentrations in the supernatant fluid were measured. The determination was done in the same way as TC using the CHOD-PAP method. LDL-C was calculated according to the formula LDL-C = TC – HDL-C – (TG/5) mg/dl.

Weight, height, waist circumference, hip circumference, mid-upper arm circumference, and triceps skinfold thickness were assessed. The BMI and waist-hip ratio were graded and calculated according to the World Health Organization Expert Committee.

Statistical analysis

All statistical analyses were conducted using the Statistical Analysis System (version 9.1; SAS Institute Inc., Cary, NC). In Table 1 continuous variables are presented as mean followed by SD, and categorical variables are presented as percentages. The distributions of AST, ALT, TGs, fasting glucose, HOMA-IR, resistin, and total, HMW, MMW, and LMW adiponectin were skewed, and, thus, medians and interquartile ranges are presented for these variables in Table 1. The natural logarithmic transformations of these skewed variables (AST, ALT, TGs, fasting glucose, HOMA-IR, resistin, and total, HMW, MMW, and LMW adiponectin) were used in subsequent multivariate analyses, with back-transformed values presented where applicable. In Table 1, differences between the diabetic and nondiabetic groups were determined by the t and ² tests for continuous and categorical variables, respectively. Spearman correlation analysis was used to assess the univariate associations of clinical and metabolic variables with total, HMW, MMW, and LMW adiponectin, respectively, in the full data set (Table 2). This approach enabled the assessment of associations of adiponectin multimeric forms across the spectrum of glucose tolerance, and provided maximum statistical power for subsequent multivariate adjustment. Forward stepwise multiple linear regression analysis was used to determine factors independently associated with total, HMW, MMW, and LMW adiponectin, respectively (Table 3). Covariates considered for selection in this analysis were chosen on the basis of either: 1) significant association with adiponectin (total, HMW, MMW, or LMW) in the univariate analysis (BMI, mid-upper arm circumference, fasting glucose, HOMA-IR, HDL, TGs, ALT); or 2) known/suspected clinical or biological relevance (age, gender). Analysis of covariance was used to assess differences in mean ALT between study participants stratified by tertiles of HMW adiponectin, after adjustment for age, gender, and diabetes (Fig. 1).

View larger version (14K): [in this window] [in a new window]   FIG. 1. Plot of mean ALT by tertile of HMW adiponectin, adjusted for age, gender, and diabetes.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

On Spearman univariate correlation analysis (Table 2), total adiponectin was inversely and significantly associated with BMI, fasting glucose, HOMA-IR, TGs, and ALT. HMW adiponectin showed similar inverse associations with each of these five variables, in addition to a positive correlation with HDL-C. In contrast, MMW adiponectin was only significantly associated with BMI, whereas LMW adiponectin was only related to mid-upper arm circumference. Similar relationships were generally noted upon adjustment for age, gender, and diabetes (data not shown).

Forward stepwise multiple linear regression analysis was performed to determine independent correlates of total, HMW, MMW, and LMW adiponectin. Covariates considered for selection in these models included age, gender, and the univariate correlates identified in Table 2 (BMI, mid-upper arm circumference, fasting glucose, HOMA-IR, HDL, TGs, and ALT). On this analysis, fasting glucose and ALT emerged as independent, negative covariates of dependent variable total adiponectin, whereas age was a positive determinant (Table 3). The same three covariates were identified as independently associated with HMW adiponectin. In contrast, no independent correlates were found for MMW and LMW adiponectin (data not shown).

Having noted that ALT was the strongest univariate correlate of HMW adiponectin (Table 2; r = –0.33; P = 0.0002) and an independent covariate of this multimeric form on multiple linear regression analysis (Table 3), we sought to evaluate further this relationship. Indeed, after adjustment for age, gender, and diabetes status, mean ALT was highest in subjects in the lowest tertile of HMW adiponectin (28), followed in turn by the middle tertile (24), and highest tertile (21), respectively (trend P = 0.0283) (Fig. 1).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A multitude of previous studies have consistently characterized hypoadiponectinemia as an independent biomarker of the metabolic syndrome (13, 14, 15, 16, 17, 18, 19, 20, 21, 22). These studies have exclusively measured total circulating adiponectin levels, yet it has become apparent that the multimeric forms of adiponectin in circulation require independent analysis (1). Accordingly, within the last year or so, several studies have begun to address the clinical significance of adiponectin multimers. A recent study based upon calculation of S_A values from Western blot analysis of serum has suggested that HMW is the active form (23). In a study of 298 Japanese patients, the ratio of plasma HMW to total adiponectin was found to be a stronger predictor of insulin resistance than total adiponectin (9). More recently, it was suggested that the quantity of HMW, rather than total adiponectin or S_A, correlated best with lipoprotein alterations characteristic of the metabolic syndrome (24). The current study is among the first to use accurate quantitative analysis of adiponectin multimers to determine specifically how the HMW, hexameric, and trimeric forms of adiponectin correlate with a wide array of anthropometric and clinical variables in obese and diabetic individuals.

Adiponectin is known to mediate insulin-mimetic effects on liver to suppress glucose production and on skeletal muscle to enhance glucose uptake (2). However, studies to date have not clearly addressed the significance of each multimeric form of the protein, and with the discovery of adiponectin receptor isoforms exhibiting different affinities for adiponectin multimers and tissue-specific distributions, it is clear that the physiological regulation of adiponectin bioactivity is complex and highly dependent on multimeric composition. Indeed, there is currently great interest in determining the intracellular mechanisms controlling the oligomerization and secretion of adiponectin in adipocytes (25).

As expected, we observed that total adiponectin, as well as HMW and MMW, decreased as BMI increased. The circulating level of trimeric adiponectin is known to be much lower than hexameric or HMW forms, and in our study we did not find a significant correlation between this LMW form of adiponectin and BMI. Indeed, multiple linear regression analyses failed to highlight a significant correlate with LMW or MMW adiponectin among those variables measured in our study. This does not exclude the possibility that these forms of adiponectin mediate important physiological effects, and further studies are likely to highlight these roles. Interestingly, a recent study supports our conclusion that the metabolic effects of adiponectin are mediated via the HMW form because after biliopancreatic diversion surgery, there was a significant increase in both total and HMW adiponectin, and improvement in metabolic profile (26). Another study of obese individuals found that circulating levels of all multimers were effectively increased via diet-induced weight loss (27).

Our findings indicate that both total and HMW adiponectin correlated inversely with insulin resistance, and further analysis by linear regression models showed that total and HMW were significantly inversely associated with increased fasting blood glucose levels. This is in agreement with previous work showing that the quantity of HMW adiponectin in serum is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation (24). However, in the same study, total adiponectin (r = 0.45), HMW (r = 0.47), LMW (r = 0.31), and HMW to total adiponectin ratio (r = 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. It has also been suggested that the improved insulin sensitivity occurring as a result of diet-induced weight loss was associated with an increased amount of HMW, MMW, and LMW adiponectin complexes in plasma (27).

We also observed that total and HMW adiponectin inversely correlated with TG levels and that HMW positively correlated with HDL levels. These findings are in agreement with a study by Bobbert et al. (28), demonstrating that total adiponectin, and especially HMW adiponectin, were closely related to circulating HDL-C (28). In a study of 182 Korean subjects, Kim et al. (29) recently showed that HDL-C, sex, and HOMA-IR were associated independently with plasma adiponectin levels. Finally, reduced quantities of HMW were shown to recapitulate independently the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI (24).

A particularly intriguing aspect of our analyses is that serum ALT was the strongest univariate correlate of HMW adiponectin, and an independent covariate of both total and HMW adiponectin on multiple linear regression analysis. Furthermore, after adjustment for age, gender, and diabetes status, mean ALT levels showed a progressive decrease as HMW adiponectin levels increased. It is well established that, in the absence of other causes, overweight and obesity increase the risk of nonalcoholic fatty liver disease (30), which is recognized as a leading cause of elevated serum ALT (31). In a recent study of patients with type 2 diabetes, it was observed that ALT levels were inversely correlated with total adiponectin, leading the authors to conclude that hypoadiponectinemia was linked with liver injury in these individuals (32). Even in juveniles, hepatic steatosis has been associated with hypoadiponectinemia (33). Several additional studies have demonstrated an inverse correlation between total adiponectin and ALT levels (34, 35, 36, 37, 38). Our findings extend these data by demonstrating that it is specifically the HMW form of adiponectin that is inversely and independently correlated with ALT, and suggest that deficiency of this isoform may be associated with liver injury. Further study of this novel relationship between HMW adiponectin and ALT is warranted.

This analysis must be interpreted in the context of certain limitations. First, the sample size is relatively modest (n = 121), which may limit the statistical power for detecting associations. Second, HOMA-IR has limitations as a measure of insulin resistance. However, in this context it is encouraging that the previously reported inverse associations between insulin resistance and total adiponectin and HMW adiponectin, respectively, were indeed observed using HOMA-IR in this analysis. Finally, the cross-sectional nature of this study precludes comment on causality in the relationships under study. Nevertheless, this study represents one of the first investigations of the specific relationships of each of HMW, hexameric, and trimeric adiponectin with metabolic parameters, and should subsequently lead to further studies.

In summary, we have demonstrated that HMW and total adiponectin share similar metabolic correlates, in contrast to the hexameric and trimeric forms. Furthermore, an independent inverse association was demonstrated between serum ALT and HMW adiponectin. Overall, these data support an emerging consensus that the HMW complex is the major physiological determinant of the metabolic effects of adiponectin.

	Acknowledgments

 
We thank the volunteers in the Faculty of Tropical Medicine, Mahidol University.

	Footnotes

 
G.S. was supported by an operating grant and New Investigator Award from Canadian Institutes of Health Research. A.H. is a Scholar of the Canadian Diabetes Association. R.R. is supported by a Canadian Institutes of Health Research Clinical Research Initiative New Investigator Award.

Disclosure Statement: Y.L., R.R., A.H., R.T., and G.S have nothing to declare. C.S. is employed by the American Laboratory Products Company (ALPCO Diagnostics).

First Published Online August 14, 2007

¹ Y.L. and R.R. contributed equally.

Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model of assessment of insulin resistance; HMW, high molecular weight; LDL-C, low-density lipoprotein cholesterol; LMW, low molecular weight; MMW, middle molecular weight; TC, total cholesterol; TG, triglyceride.

Received April 18, 2007.

Accepted August 7, 2007.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Fang X, Sweeney G 2006 Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes. Biochem Soc Trans 34:798–801[CrossRef][Medline]
2. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K 2006 Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792[CrossRef][Medline]
3. Trujillo ME, Scherer PE 2005 Adiponectin–journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med 257:167–175[CrossRef][Medline]
4. Nawrocki AR, Scherer PE 2005 Keynote review: the adipocyte as a drug discovery target. Drug Discov Today 10:1219–1230[CrossRef][Medline]
5. Wang Y, Lam KS, Chan L, Chan KW, Lam JB, Lam MC, Hoo RC, Mak WW, Cooper GJ, Xu A 2006 Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem 281:16391–16400[Abstract/Free Full Text]
6. Wang Y, Lu G, Wong WP, Vliegenthart JF, Gerwig GJ, Lam KS, Cooper GJ, Xu A 2004 Proteomic and functional characterization of endogenous adiponectin purified from fetal bovine serum. Proteomics 4:3933–3942[CrossRef][Medline]
7. 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]
8. Despres JP, Lemieux I 2006 Abdominal obesity and metabolic syndrome. Nature 444:881–887[CrossRef][Medline]
9. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T 2006 Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 29:1357–1362[Abstract/Free Full Text]
10. Ebinuma H, Miyazaki O, Yago H, Hara K, Yamauchi T, Kadowaki T 2006 A novel ELISA system for selective measurement of human adiponectin multimers by using proteases. Clin Chim Acta 372:47–53[CrossRef][Medline]
11. Ware AG, Marbach EP 1968 Glucose in serum and cerebrospinal fluid by direct application of a glucose oxidase method. Clin Chem 14:548–554[Abstract]
12. Bauer JD 1982 Total lipids. In: Clinical laboratory methods. 9th ed. St. Louis: Mosby; 566–607
13. Shaibi GQ, Cruz ML, Weigensberg MJ, Toledo-Corral CM, Lane CJ, Kelly LA, Davis JN, Koebnick C, Ventura EE, Roberts CK, Goran MI 2007 Adiponectin independently predicts metabolic syndrome in overweight Latino youth. J Clin Endocrinol Metab 92:1809–1813[Abstract/Free Full Text]
14. Santaniemi M, Kesaniemi YA, Ukkola O 2006 Low plasma adiponectin concentration is an indicator of the metabolic syndrome. Eur J Endocrinol 155:745–750[Abstract/Free Full Text]
15. Tajtakova M, Petrasova D, Petrovicova J, Pytliak M, Semanova Z 2006 Adiponectin as a biomarker of clinical manifestation of metabolic syndrome. Endocr Regul 40:15–19[Medline]
16. Winer JC, Zern TL, Taksali SE, Dziura J, Cali AM, Wollschlager M, Seyal AA, Weiss R, Burgert TS, Caprio S 2006 Adiponectin in childhood and adolescent obesity and its association with inflammatory markers and components of the metabolic syndrome. J Clin Endocrinol Metab 91:4415–4423[Abstract/Free Full Text]
17. Choi KM, Ryu OH, Lee KW, Kim HY, Seo JA, Kim SG, Kim NH, Choi DS, Baik SH 2007 Serum adiponectin, interleukin-10 levels and inflammatory markers in the metabolic syndrome. Diabetes Res Clin Pract 75:235–240[CrossRef][Medline]
18. Mojiminiyi OA, Abdella NA, Al Arouj M, Ben Nakhi A 2007 Adiponectin, insulin resistance and clinical expression of the metabolic syndrome in patients with type 2 diabetes. Int J Obes (Lond) 31:213–220[CrossRef][Medline]
19. Matsushita K, Yatsuya H, Tamakoshi K, Wada K, Otsuka R, Takefuji S, Sugiura K, Kondo T, Murohara T, Toyoshima H 2006 Comparison of circulating adiponectin and proinflammatory markers regarding their association with metabolic syndrome in Japanese men. Arterioscler Thromb Vasc Biol 26:871–876[Abstract/Free Full Text]
20. Gilardini L, McTernan PG, Girola A, da Silva NF, Alberti L, Kumar S, Invitti C 2006 Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents. Atherosclerosis 189:401–407[CrossRef][Medline]
21. Salmenniemi U, Ruotsalainen E, Pihlajamaki J, Vauhkonen I, Kainulainen S, Punnonen K, Vanninen E, Laakso M 2004 Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome. Circulation 110:3842–3848[Abstract/Free Full Text]
22. Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T 2004 Adiponectin as a biomarker of the metabolic syndrome. Circ J 68:975–981[CrossRef][Medline]
23. Fisher FF, Trujillo ME, Hanif W, Barnett AH, McTernan PG, Scherer PE, Kumar S 2005 Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia 48:1084–1087[CrossRef][Medline]
24. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT 2006 Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 55:249–259[Abstract/Free Full Text]
25. Wang ZV, Schraw TD, Kim JY, Khan T, Rajala MW, Follenzi A, Scherer PE 2007 Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention. Mol Cell Biol 27:3716–3731[Abstract/Free Full Text]
26. Salani B, Briatore L, Andraghetti G, Adami GF, Maggi D, Cordera R 2006 High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects. Obesity (Silver Spring) 14:1511–1514[Medline]
27. Polak J, Kovacova Z, Jacek M, Klimcakova E, Kovacikova M, Vitkova M, Kuda O, Sebela M, Samcova E, Stich V 2007 An increase in plasma adiponectin multimeric complexes follows hypocaloric diet-induced weight loss in obese and overweight pre-menopausal women. Clin Sci (Lond) 112:557–565[Medline]
28. Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert MO, Mohlig M, Pfeiffer AF, Spranger J 2005 Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes 54:2712–2719[Abstract/Free Full Text]
29. Kim SM, Cho KH, Park HS 2006 Relationship between plasma adiponectin levels and the metabolic syndrome among Korean people. Endocr J 53:247–254[CrossRef][Medline]
30. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N 2001 Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850[Abstract/Free Full Text]
31. Clark JM, Brancati FL, Diehl AM 2003 The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98:960–967[CrossRef][Medline]
32. Hickman IJ, Whitehead JP, Prins JB, Macdonald GA 2007 Raised alanine transaminase and decreased adiponectin are features of the metabolic syndrome in patients with type 2 diabetes. Diabetes Obes Metab 9:438–440[CrossRef][Medline]
33. Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, Constable RT, Weiss R, Tamborlane WV, Savoye M, Seyal AA, Caprio S 2006 Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 91:4287–4294[Abstract/Free Full Text]
34. Kazumi T, Kawaguchi A, Hirano T, Yoshino G 2006 Serum alanine aminotransferase is associated with serum adiponectin, C-reactive protein and apolipoprotein B in young healthy men. Horm Metab Res 38:119–124[CrossRef][Medline]
35. Louthan MV, Barve S, McClain CJ, Joshi-Barve S 2005 Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease. J Pediatr 147:835–838[CrossRef][Medline]
36. Sargin H, Sargin M, Gozu H, Orcun A, Baloglu G, Ozisik M, Seker M, Uygur-Bayramicli O 2005 Is adiponectin level a predictor of nonalcoholic fatty liver disease in nondiabetic male patients? World J Gastroenterol 11:5874–5877[Medline]
37. Kim SG, Kim HY, Seo JA, Lee KW, Oh JH, Kim NH, Choi KM, Baik SH, Choi DS 2005 Relationship between serum adiponectin concentration, pulse wave velocity and nonalcoholic fatty liver disease. Eur J Endocrinol 152:225–231[Abstract/Free Full Text]
38. Targher G, Bertolini L, Scala L, Poli F, Zenari L, Falezza G 2004 Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals. Clin Endocrinol (Oxf) 61:700–703[CrossRef][Medline]

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