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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0293
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4335-4340
Copyright © 2005 by The Endocrine Society

Increased Serum Resistin in Adults with Prader-Willi Syndrome Is Related to Obesity and Not to Insulin Resistance

Claudio Pagano, Oriano Marin, Alessandra Calcagno, Patrizia Schiappelli, Catia Pilon, Gabriella Milan, Matteo Bertelli, Erica Fanin, Gilberto Andrighetto, Giovanni Federspil and Roberto Vettor

Endocrine-Metabolic Laboratory (C.Pa., A.C., C.Pi., G.M., G.F., R.V.), Department of Medical and Surgical Sciences, Department of Biological Chemistry (O.M., P.S.), and Centro Ricerche Interdipartimentale Biotecnologie Innovative (O.M.), Biotechnology Centre, University of Padua, 35100 Padua, Italy; and Laboratory of Medical Genetics (M.B., E.F., G.A.), Baschirotto Institute for Rare Diseases, Costozza di Longare, 36023 Vicenza, Italy

Address all correspondence and requests for reprints to: Dr. Claudio Pagano, Department of Medical and Surgical Sciences, Via Ospedale 105, 35100 Padova, Italy. E-mail: claudio.pagano{at}unipd.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Determinants of insulin resistance in Prader-Willi syndrome (PWS) are not completely understood. The discovery of several adipokines with relevant effects on insulin resistance and cardiovascular complications of metabolic syndrome offered new tools of investigation of insulin resistance in PWS.

Objective: The purpose of this study was to measure serum resistin and mRNA in adipose tissue of patients with PWS, those with simple obesity, and healthy controls and correlate resistin levels with anthropometric and biochemical features.

Design: Twenty-eight adult PWS patients, 29 obese patients, and 25 healthy controls were studied. Anthropometric variables were measured and fasting serum and plasma were collected for measurement of resistin, adiponectin, leptin, lipid profile, glucose, and insulin.

Results: Serum resistin and resistin mRNA expression in adipose tissue was significantly higher in PWS patients, compared with both healthy lean controls and obese patients. Moreover, on regression analysis resistin was significantly correlated with body mass index, whereas no significant association was found between resistin and homeostasis model assessment index. A weak association between resistin and adiponectin was found in the PWS group only. However, on multivariate analysis only the correlation between resistin and body mass index remained significant.

Conclusions: These results support a link between circulating resistin and obesity in humans but do not support a role for resistin in human insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRADER-WILLI SYNDROME (PWS) is a genetic disorder whose clinical picture includes short stature, mild mental retardation, hyperphagia, and development of massive obesity during childhood and adult age and peculiar behavior abnormalities (1). Individuals with PWS have reduced life expectancy, compared with healthy controls, due to comorbidities that include diabetes and cardiovascular disease (2, 3). PWS results from genetic loss of one or more normally active paternal genes in the region 15q11-q13 (4, 5). Genetic damage is responsible for a major defect of hypothalamic centers leading to hyperphagia, hypogonadotropic hypogonadism, and deficient GH secretion. Excessive adiposity is due to both an increase of adipose tissue and to reduced lean body mass, compared with weight-matched obese non-PWS patients (6). Insulin resistance is a common feature of PWS, and type 2 diabetes often develops during childhood and adulthood.

Determinants of insulin resistance in PWS are not completely clear. High free fatty acids levels and hyperinsulinemia have been proposed to produce insulin resistance, but more recently a number of adipokines have been identified that are produced by adipose tissue and are involved in the pathogenesis of insulin resistance. Adiponectin was reported to be reduced in PWS, and this could explain the link between excessive fat deposition and insulin resistance and obesity complications (7, 8, 9).

Resistin was cloned in 2001 as a thiazolidinedione-regulated cytokine expressed in adipose tissue (10). Its effects on insulin action has been extensively investigated in mice (11, 12, 13, 14, 15, 16), whereas in humans its role in insulin resistance and obesity complications is still controversial (17). In mice resistin has relevant effects on hepatic glucose and lipid metabolism (13, 18) and seems to be a major determinant of hepatic insulin resistance induced by a high-fat diet (19). However, data on humans are conflicting because resistin levels have been reported to be elevated in obesity and diabetes (20, 21, 22), whereas other authors reported no changes of resistin levels in these conditions (23, 24, 25, 26).

The aim of this study was to determine circulating resistin and adipose tissue resistin expression in patients affected by PWS and simple obesity and correlate resistin levels with insulin sensitivity and other biochemical and anthropometric variables.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We studied 28 patients with PWS whose diagnosis was based on the clinical picture and confirmed by genetic analysis according to Holm et al. (27). Mean age was 26.5 ± 1.3 yr. Genetic tests revealed that 18 patients were affected by a deletion of 15q11-q13 region, seven patients had a uniparental disomy and one patient had a mutation of the imprinting center. Eight PWS patients had type 2 diabetes (four were taking insulin, two oral antidiabetic drugs, and two patients were on diet only). Nineteen patients had GH deficiency (nine were taking GH replacement therapy), four had normal GH secretion, and five patients had no evaluation of GH secretion or a borderline GH response to GHRH + arginine stimulation test. Liver ultrasound scan was performed in 17 patients, and fatty liver was reported in all patients examined.

The protocol was approved by the Ethics Committee of Padua University Hospital, and written informed consent to participate to the study was obtained from patients and their parents. Anthropometric and biochemical characteristics of PWS patients and control groups are illustrated in Tables 1Go and 2Go. A group of lean subjects (n = 25) and a group of obese subjects (n = 29) with comparable age and sex were used as control. In all subjects anthropometric parameters were measured. Waist was measured in standing position halfway between costal edge and iliac crest whereas hip was measured as the greatest circumference around the buttocks. Body mass index (BMI) and waist to hip ratio were calculated. In all subjects a blood sample was collected between 0900 and 1000 h after overnight fasting for biochemical and hormonal determinations. Resistin was measured by ELISA using a commercially available kit (BioVendor, Heidelberg, Germany). Assay sensitivity was 1 ng/ml and interassay and intraassay coefficients of variation were less than 10% and less than 5%, respectively. The assay was linear between 1 and 20 ng/ml. All patients’ samples were within this range and no dilution of samples was needed. No cross-reactivity was detected against human resistin-like molecule-ß, leptin and leptin receptor, adiponectin, TNF{alpha}, IL-6, and agouti-related protein. Insulin and leptin were assayed by RIA (Linco Research, Inc., St. Charles, MO). Glucose was measured by the glucose oxidase method (glucose analyzer II, Beckmann, Inc., Palo Alto, CA). Lipids were measured by enzymatic automated methods.


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  		TABLE 1. Anthropometric and clinical characteristics of PWS patients, obese and lean control subjects

 

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  		TABLE 2. Biochemical and hormonal parameters of PWS patients and lean and obese controls

 
Antibodies production and immunohistochemistry

Two synthetic peptides corresponding to amino acids 22–37 (CSMEEAINERIQEVAG) and 51–62 (CQSVTSRGDLAT) of the human resistin protein were synthesized by automatic solid-phase method on 4-hydroxymethyl-copolystirene-1% divinylbenzene-resin (Applied Biosystems, Foster City, CA) and fast 9-fluorenilmethoxycarbonyl chemistry using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and 1-hydroxybenzotriazole as coupling reagents (28) with a 431 A peptide synthesizer (Applied Biosystems) as improved in our laboratories (29). Antiresistin antibodies were raised in New Zealand rabbits against the synthetic peptides. Antisera were purified using an immobilized peptide affinity resin (Sulfo Link Coupling Gel, Pierce, Northumberland, UK) according to manufacturer’s instructions.

Subcutaneous adipose tissue obtained by percutaneous biopsies from normal, obese, and PWS subjects were fixed in formalin and embedded in paraffin. Six micrometer sections were prepared for immunohistochemistry. Sections were washed three times with PBS, and endogenous peroxidase was blocked by a 10-min incubation with 3% H2O2. For resistin immunohistochemistry, sections were incubated for 30 min with purified antiresistin antibodies diluted 1:1000. The sections were then exposed to a secondary biotinylated IgG (ScyTek Laboratory, Logan, UT) and visualized by incubation for 20 sec with a peroxidase substrate solution containing 3,3'-diaminobenzidine tetrahydrochloride. Slides were then washed, counterstained with hematoxylin, shed in water and alcohol, and mounted in synthetic resin. All passages were performed at room temperature. Negative control studies were performed by adsorbing resistin antibodies (1:1000) by preincubation with the synthetic peptides at a final concentration of 0.3 mM for 60 min.

Quantification of resistin mRNA expression by real-time RT-PCR in adipose tissue

Resistin mRNA expression was assessed by quantitative RT-PCR in sc adipose tissue obtained by percutaneous needle biopsies of the gluteal region in lean (n = 8), obese (n = 13), and PWS (n = 8) subjects. Total RNA was extracted with RNEasy lipid tissue mini kit (QIAGEN GmbH, Hilden, Germany) following the supplier instructions. Five hundred nanograms of RNA was treated with DNase treatment and removal reagents (Ambion, Inc., Austin, TX) and reverse transcribed for 1 h at 37 C in a 50-µl reaction containing 1x reverse transcription buffer, 150 ng random hexamers, 0.5 mM deoxynucleotide triphosphates, 20 U RNAsin ribonuclease inhibitor, and 200 U Muloney murine leukemia virus reverse transcription (Promega Corp., Madison, WI). Oligonucleotide primers and probe for human resistin were designed using Omiga TM 2.0 program (Oxford Molecular Ltd., San Diego, CA) (30). PCR was carried out on DNA Engine Opticon TM 2 continuous fluorescence detection system (MJ Research, Waltham, MA), and all reactions were performed on at least two occasions. Standard curve for resistin amplification was constructed using 50 ng of RNA reverse-transcribed from peripheral blood mononuclear cells of healthy subject serially diluted (1:3) and for reference with 50 ng of RNA reverse transcribed from adipose tissue of normal subject serially diluted (1:10) by plotting values for log cDNA quantity (in arbitrary units) vs. cycle threshold (Ct). For each sample, results were normalized by rRNA18S content. Each sample was assayed in triplicate and a no template control was included in every reaction.

Statistical analysis

Results are expressed as mean ± SE. Different groups were compared by ANOVA. Correlations between different variables were analyzed by linear regression analysis and multivariate analysis using the MDAS 2.0 (medical data analysis system) software package (EsKay Software, Pittsburgh, PA). P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patients with PWS were compared with a lean control group and an obese group with similar age and gender distribution (Table 1Go).

Serum resistin was significantly increased in PWS compared with both the lean and obese groups, whereas no difference was found between the lean and obese groups (Fig. 1Go). Circulating adiponectin was significantly reduced in the obese group, compared with lean controls (Table 2Go). Serum adiponectin in PWS was comparable with the lean group and was higher than the obese patients (Table 2Go). Adiponectin was significantly lower in the subgroup of diabetic PWS, compared with nondiabetic PWS (13.80 ± 1.25 vs. 17.52 ± 0.90 ng/ml, P < 0.05). Serum leptin was similar in PWS and obese subjects, whereas both groups had circulating leptin significantly higher than lean subjects. When subgroups of PWS were analyzed, serum resistin was found to be similar in diabetic and nondiabetic PWS patients (7.02 ± 1.25 vs. 5.92 ± 0.58 ng/ml, P = NS) and patients with and without GH deficiency (5.67 ± 0.57 vs. 7.39 ± 1.13 ng/ml, P = NS). When GH-deficient patients were divided according to GH replacement therapy, serum resistin was slightly lower in the patients taking GH replacement (4.57 ± 0.42 vs. 6.55 ± 0.89 ng/ml, P = 0.08), but the difference failed to reach statistical significance.



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  		FIG. 1. Serum resistin (upper panel) and resistin mRNA quantification in sc adipose tissue (lower panel) of lean controls, simple obese patients, and PWS patients. Data are expressed as mean ± SEM. *, P = 0.01 or less vs. lean controls; #, P ≤ 0.003 vs. obese group.

 
Immunohistochemistry of sc adipose tissue showed that all adipocytes were resistin positive in PWS and lean and obese patients (Fig. 2Go). Quantitative PCR revealed that resistin expression in sc adipose tissue was significantly increased in PWS, compared with both the lean controls (6.98 ± 1.39 vs. 2.44 ± 0.85 AU; P = 0.01) and obese patients (6.98 ± 1.39 vs. 2.48 ± 0.74 AU; P = 0.005). No differences were found between lean and obese subjects (Fig. 1Go).



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  		FIG. 2. Localization of immunoreactive-resistin in sections of sc adipose tissue of lean (A), obese (B), and PWS (C) as assessed by immunohistochemistry. Negative controls were carried out by adsorbing antibodies with specific peptides before the assay in lean (D), obese (E), and PWS (F) subjects. Magnification, x20.

 
Simple correlation analyses showed a significant positive correlation between resistin and BMI in PWS, whereas no association was found among resistin and insulin, homeostasis model assessment (HOMA), and age (Table 3Go and Fig. 3Go). However, a significant correlation also was found between resistin and adiponectin in PWS only. However, when multiple regression analysis was performed in all subjects, only BMI retained a significant correlation with resistin when age, HOMA, BMI, and adiponectin were included in the statistical model (Table 4Go).


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  		TABLE 3. Simple regression analysis between serum resistin and different parameters in adult PWS patients, in the obese group, and in normal-weight controls

 


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  		FIG. 3. Linear regression between serum resistin and BMI (upper panel) and between serum resistin and HOMA index (lower panel). Solid circles, PWS; open circles, lean subjects; triangles, obese subjects. y = 0.0797x + 2.2345; r2 = 0.19; P = 0.001.

 

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  		TABLE 4. Overall multiple regression analysis between resistin (dependent variable) and BMI, age, adiponectin, and HOMA (independent variables)

 
Finally, a significant negative correlation between adiponectin and BMI was found in both the PWS group (r2 = 0.16, P = 0.03) and lean and obese populations (r2 = 0.20; P = 0.002) (Fig. 4Go).



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  		FIG. 4. Linear regression between serum adiponectin and BMI. Solid circles, PWS; open circles, obese subjects; triangles, lean subjects. y = –0.1074x + 19,637; r = 0.30; P = 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is, to our knowledge, the first study to analyze serum resistin and adipose tissue expression in adult PWS patients. Resistin levels were found to be significantly higher in PWS patients, compared with lean controls and an obese group with similar degree of adiposity. The increase of resistin levels was not associated to increased insulin or HOMA index and were significantly associated to the degree of obesity.

Factors that determine the evolution to diabetes and cardiovascular disease in these patients are not fully clear. The discovery in recent years of several proteins selectively produced in adipose tissue, the so-called adipokines, have provided new clues to the understanding of the mechanisms of insulin resistance and cardiovascular disease.

In our study higher circulating resistin levels were found in PWS, compared with both the lean and obese groups. Moreover, resistin was positively correlated to BMI and not to insulin resistance as assessed by the HOMA index. The relationship among resistin, BMI, and insulin resistance in humans is still controversial (26). Several studies have reported an association among these factors, whereas other authors failed to find any significant correlation.

Serum resistin was found by some authors to be increased in obesity and positively correlated with BMI or body fat (20, 22, 31, 32, 33), whereas this observation was not confirmed by other studies (21, 23, 24, 34, 35). On the other hand, resistin was found to be related to insulin resistance and increased in type 2 diabetes (20, 21, 34, 35), but these data were not confirmed by other studies (23, 24, 31, 32, 36, 37). Our results support an association between resistin and BMI in the PWS patients, whereas no association was found with the HOMA index of insulin resistance. Moreover, no difference was found between diabetic and nondiabetic PWS patients. It is noteworthy that Bajaj et al. (36) recently reported that pioglitazone treatment in type 2 diabetic patients causes a reduction of circulating resistin and that plasma resistin was associated with hepatic fat content and hepatic insulin resistance and not to peripheral insulin resistance measured by the euglycemic hyperinsulinemic clamp. Most of the PWS patients in our study have a fatty liver at ultrasound scans, and therefore, one could speculate that higher resistin levels in these patients may be related to increased hepatic fat and hepatic insulin resistance. This is in agreement with experiments in rodents that clearly showed a major role of resistin in hepatic glucose metabolism and the pathogenesis of diet-induced hepatic insulin resistance (13, 19). However, the hypothesis of a link between resistin and hepatic glucose metabolism needs further confirmations in humans. The inconstant link among serum resistin, obesity, and insulin resistance could also be explained by genetic factors. In fact, it has been reported that genetic polymorphisms in the promoter region of resistin gene may be independent predictors of circulating resistin concentrations in humans (38, 39). However, it is unlikely that these polymorphisms may be responsible for resistin levels in PWS.

A possible confounding factor in evaluating adipokines in PWS may be represented by hormonal defects that are present in these patients. However, GH treatment was found not to modify circulating resistin in GH-deficient adults and circulating resistin is normal in acromegalic patients (40, 41). In the PWS group of this study, we found no difference in GH-deficient patients, compared with those with normal GH secretion. Moreover, GH treatment did not modify significantly resistin levels. It is therefore unlikely that GH deficiency could play a role in altered resistin levels in PWS.

Because resistin is produced in not only adipose tissue but also inflammatory and immune cells (42), we evaluated resistin expression in sc adipose tissue by immunohistochemistry and quantitative RT-PCR. Our results confirmed that resistin protein is present in adipocytes of PWS patients as well as lean and obese subjects and that resistin mRNA is higher in sc adipose tissue of PWS, thus confirming that adipose tissue overproduction is responsible for increased serum resistin. However, it cannot be excluded that infiltration of inflammatory cells in adipose tissue could be responsible for the increased resistin levels in PWS (43). In fact, it has been reported that macrophage accumulation in adipose tissue is increased in obesity (44), and then one could put forward the hypothesis that activation of macrophages could directly or indirectly be responsible for the increased resistin expression in adipose tissue.

Adiponectin, another adipokine that was proposed to be protective in the evolution of atherosclerosis, probably because of its antiinflammatory action (45, 46, 47, 48, 49), has received attention also in PWS as a possible clue to understanding cardiovascular complication. Adiponectin has also been related to insulin resistance, and in particular, its effect was demonstrated, in rodents, on hepatic glucose production (18, 19). In our study serum adiponectin was significantly higher in PWS patients, compared with the obese group. These is in agreement with a previous report by Hoybye et al. (7). However, in contrast to their data, a weak but significant negative correlation was found between adiponectin and BMI. This discrepancy probably could be explained by the greater number of PWS patients enrolled in our study. Our data support that the negative correlation between increasing BMI and circulating adiponectin is present in not only the lean and obese population but also PWS patients. Therefore, it is not possible to rule out the hypothesis that lower serum adiponectin may be involved in cardiovascular complications of obese PWS patients. Moreover, recently Goldstone et al. (50) demonstrated that adult women with PWS are more insulin sensitive and have lower amounts of visceral adipose tissue, compared with women with nongenetic obesity. This fact could explain why we found insulin and HOMA values similar in PWS and lean controls that were significantly lower than in simple obese controls. However, when the diabetic PWS subjects were considered, a lower adiponectin concentration was found, thus suggesting that the role of adiponectin in insulin resistance in diabetic PWS patient cannot be definitively ruled out.

In conclusion, we report that circulating resistin is increased in PWS and its concentration is related to the degree of obesity. The lack of correlation between resistin and insulin resistance does not support a role for resistin in the pathogenesis of insulin resistance in obesity associated with PWS.


   Footnotes
 
This work was supported by a grant from the University of Padova (ex-60% 2003; to C.Pa.), grants from the Italian Ministero dell’Istruzione, dell’Università e della Ricerca, COFIN Grant 2003061834-006 (to R.V.), and FIRB 2002 Grant RBHE01 KDX4_009 (to M.B., G.A., and E.F.).

First Published Online May 3, 2005

Abbreviations: BMI, Body mass index; HOMA, homeostasis model assessment; PWS, Prader-Willi syndrome.

Received February 10, 2005.

Accepted April 22, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Prader A, Labhart A, Willi H 1956 Ein syndrom von adipositas, kleinwuchs, kryptorchismus und oligophrenie nach myatonieartigem zustand in neugeborenenalter. Schweiz Med Wochenschr 86:1260
  2. Burman P, Ritzen EM, Lindgren AC 2001 Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev 22:787–799[Abstract/Free Full Text]
  3. Rosen T, Eden S, Larson G, Wilhelmsen L, Bengtsson BA 1993 Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol 129:195–200
  4. Ledbetter DH, Riccardi VM, Airhart SD, Strovel RJ, Kunan BS, Crawford JD 1981 Deletion of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med 304:325–329[Medline]
  5. Butler MG, Palmar CG 1983 Parental origin of chromosome 15 deletion in Prader-Willi syndrome. Lancet 1:285–286
  6. Hoybye C, Hilding A, Jacobsson H, Thoren M 2002 Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity. J Clin Endocrinol Metab 87:3590–3597[Abstract/Free Full Text]
  7. Hoybye C, Bruun JM, Richelsen B, Flyvbjerg A, Frystyk J 2004 Serum adiponectin levels in adults with Prader-Willi syndrome are independent of anthropometrical parameters and do not change with GH treatment. Eur J Endocrinol 151:457–461[Abstract]
  8. Tsao TS, Lodish HF, Fruebis J 2002 ACRP30, a new hormone controlling fat and glucose metabolism. Eur J Pharmacol 440:213–221[CrossRef][Medline]
  9. Diez JJ, Iglesias P 2003 The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol 148:293–300[Abstract]
  10. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409:307–312[CrossRef][Medline]
  11. Satoh H, Nguyen MT, Miles PD, Imamura T, Usui I, Olefsky JM 2004 Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats. J Clin Invest 114:224–231[CrossRef][Medline]
  12. Steppan CM, Lazar MA 2004 The current biology of resistin. J Intern Med 255:439–447[CrossRef][Medline]
  13. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE, Steppan CM, Ahima RS, Obici S, Rossetti L, Lazar MA 2004 Regulation of fasted blood glucose by resistin. Science 303:1195–1198[Abstract/Free Full Text]
  14. Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, Rossetti L, Lazar MA 2004 Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes 53:1937–1941[Abstract/Free Full Text]
  15. Nogueiras R, Gallego R, Gualillo O, Caminos JE, Garcia-Caballero T, Casanueva FF, Dieguez C 2003 Resistin is expressed in different rat tissues and is regulated in a tissue- and gender-specific manner. FEBS Lett 548:21–27[CrossRef][Medline]
  16. Sato N, Kobayashi K, Inoguchi T, Sonoda N, Imamura M, Sekiguchi N, Nakashima N, Nawata H 2004 Adenovirus-mediated high expression of resistin causes dyslipidemia in mice. Endocrinology 146:273–279
  17. Ukkola O 2002 Resistin—a mediator of obesity-associated insulin resistance or an innocent bystander? Eur J Endocrinol 147:571–574[Abstract]
  18. Rajala MW, Obici S, Scherer PE, Rossetti L 2003 Adipose-derived resistin and gut-derived resistin-like molecule-ß selectively impair insulin action on glucose production. J Clin Invest 111:225–230[CrossRef][Medline]
  19. Muse ED, Obici S, Bhanot S, Monia BP, McKay RA, Rajala MW, Scherer PE, Rossetti L 2004 Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest 114:232–239[CrossRef][Medline]
  20. Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M 2004 Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta 339:57–63[CrossRef][Medline]
  21. Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY, Cho YM, Park YJ, Kim SY, Lee HK, Park KS 2004 Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab 89:150–156[Abstract/Free Full Text]
  22. Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV 2003 Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab 88:5452–5455[Abstract/Free Full Text]
  23. Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR 2004 Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab 89:1844–1848[Abstract/Free Full Text]
  24. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS 2003 Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 88:4848–4856[Abstract/Free Full Text]
  25. Shetty GK, Economides PA, Horton ES, Mantzoros CS, Veves A 2004 Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 27:2450–2457[Abstract/Free Full Text]
  26. Rea R, Donnelly R 2004 Resistin: an adipocyte-derived hormone. Has it a role in diabetes and obesity? Diabetes Obes Metab 6:163–170[CrossRef][Medline]
  27. Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F 1993 Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 91:398–402[Abstract/Free Full Text]
  28. Fields GB, Noble RL 1990 Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res 35:161–214[Medline]
  29. Marin O, Meggio F, Sarno S, Pinna LA 1997 Physical dissection of the structural elements responsible for regulatory properties and intersubunit interactions of protein kinase CK2 ß-subunit. Biochemistry 36:7192–7198[CrossRef][Medline]
  30. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S 2001 Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-{gamma} action in humans. Diabetes 50:2199–2202[Abstract/Free Full Text]
  31. Volarova de Courten B, Degawa-Yamauchi M, Considine RV, Tataranni PA 2004 High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes 53:1279–1284[Abstract/Free Full Text]
  32. Panidis D, Koliakos G, Kourtis A, Farmakiotis D, Mouslech T, Rousso D 2004 Serum resistin levels in women with polycystic ovary syndrome. Fertil Steril 81:361–366[CrossRef][Medline]
  33. Silha JV, Murphy LJ 2004 Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab 89:1977–1978[Free Full Text]
  34. Zhang JL, Qin YW, Zheng X, Qiu JL, Zou DJ 2003 Serum resistin level in essential hypertension patients with different glucose tolerance. Diabet Med 20:828–831[CrossRef][Medline]
  35. Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ 2003 Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 149:331–335[Abstract]
  36. Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T, DeFronzo RA 2004 Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Int J Obes Relat Metab Disord 28:783–789[CrossRef][Medline]
  37. Stejskal D, Adamovska S, Bartek J, Jurakova R, Proskova J 2003 Resistin-concentrations in persons with type 2 diabetes mellitus and in individuals with acute inflammatory disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 147:63–69[Medline]
  38. Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G 2003 A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 52:1611–1618[Abstract/Free Full Text]
  39. Cho YM, Youn BS, Chung SS, Kim KW, Lee HK, Yu KY, Park HJ, Shin HD, Park KS 2004 Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. Diabetologia 47:1337–1338
  40. Hana V, Silha JV, Justova V, Lacinova Z, Stepan JJ, Murphy LJ 2004 The effects of GH replacement in adult GH-deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance. Clin Endocrinol (Oxf) 60:442–450[CrossRef][Medline]
  41. Silha JV, Krsek M, Hana V, Marek J, Jezkova J, Weiss V, Murphy LJ 2003 Perturbations in adiponectin, leptin and resistin levels in acromegaly: lack of correlation with insulin resistance. Clin Endocrinol (Oxf) 58:736–742[CrossRef][Medline]
  42. Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R 2002 Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes Res 10:1095–1103[Medline]
  43. Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR 2003 Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 309:286–290[CrossRef][Medline]
  44. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW 2003 Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808[CrossRef][Medline]
  45. Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K, Okazaki Y, Ishii T, Nishikai K, Saruta T 2002 Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin Sci 103:137–142[Medline]
  46. Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara S, Nagai R, Funahashi T, Matsuzawa Y 2002 Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 277:37487–37491[Abstract/Free Full Text]
  47. Costacou T, Zgibor JC, Evans RW, Otvos J, Lopes-Virella MF, Tracy RP, Orchard TJ 2005 The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 48:41–48[CrossRef][Medline]
  48. Higashiura K, Ura N, Ohata J, Togashi N, Takagi S, Saitoh S, Murakami H, Takagawa Y, Shimamoto K 2004 Correlations of adiponectin level with insulin resistance and atherosclerosis in Japanese male populations. Clin Endocrinol (Oxf) 61:753–759[CrossRef][Medline]
  49. Dzielinska Z, Januszewicz A, Wiecek A, Demkow M, Makowiecka-Ciesla M, Prejbisz A, Kadziela J, Mielniczuk R, Florczak E, Janas J, Januszewicz M, Ruzyllo W 2003 Decreased plasma concentration of a novel anti-inflammatory protein—adiponectin—in hypertensive men with coronary artery disease. Thromb Res 110:365–369[CrossRef][Medline]
  50. Goldstone AP, Thomas EL, Brynes AE, Bell JD, Frost G, Saeed N, Hajnal JV, Howard JK, Holland A, Bloom SR 2001 Visceral adipose tissue and metabolic complications of obesity are reduced in Prader-Willi syndrome female adults: evidence for novel influences on body fat distribution. J Clin Endocrinol Metab 86:4330–4338[Abstract/Free Full Text]



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