Association of Resistin with Metabolic Syndrome in Indian Subjects

Abstract

Background:

The role of resistin in insulin sensitivity and metabolic syndrome has been controversial until now. Increased plasma/serum resistin levels are associated with metabolic syndrome and insulin resistance. The aim of this study was to investigate the relationship between serum resistin levels with markers of metabolic syndrome in males.

Methods:

A total of 386 male volunteers were enrolled in a case–control study. All of the enrolled volunteers were analyzed to confirm metabolic syndrome following the guidelines of National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) of 2001. Of the 386 volunteers, 192 were categorized as cases of metabolic syndrome, whereas 194 were registered as controls without metabolic syndrome. Volunteers enrolled in the study were analyzed for anthropometrical parameters, lipid profile status, insulin, insulin resistance, and resistin.

Results:

Higher levels of resistin were observed in cases when compared to controls (12.49±4.73 ng/mL vs. 6.99±1.98 ng/mL). Resistin was positively and significantly associated with serum triglyceride, cholesterol, and very-low-density lipoprotein, whereas it was negatively and significantly associated with serum high-density lipoprotein (HDL) levels. Multiple regression analysis of the data observed indicated that the triglyceride level was the major determinant for the development of metabolic syndrome in male samples.

Conclusion:

This study demonstrates a positive correlation between resistin and factors of metabolic syndrome, except for HDL cholesterol (HDL-C), which was found to be negatively correlated in Indian male subjects. The study also found resistin to be a suitable peripheral blood marker.

Introduction

R esistin is a circulating 12.5-kD protein of 114 amino acids that belongs to the resistin-like family.^1,2 Resistin is regulated by insulin, glucose, growth hormone, and thiazolidinediones.^3,4 The main function of resistin in humans is still unclear. Studies in rodents have suggested resistin as a link between obesity, insulin resistance, and diabetes.^5
–7 In humans, data on the role of this adipokine in insulin sensitivity and obesity are controversial.⁸

Resistin is increased in mice with diet-induced obesity and in ob/ob mice.¹ Studies have also suggested that mice injected with recombinant resistin or overexpressing resistin had impaired glucose tolerance and insulin action.⁹ In addition, resistin is found to be an in vitro antagonist of insulin in human preadipocytes.¹⁰ It has been seen that human hepatic cells overexpressing resistin had impaired glucose uptake and glycogen synthesis.¹¹ Resistin, also identified as found in inflammatory zone 3 (FIZZ 3), has also been reported to be linked with inflammation.¹² In some studies, resistin is positively correlated with proinflammatory factors in adults with pathophysiological conditions, such as atherosclerosis, renal disease, and inflammation of respiratory tracts.^13

–16

Proinflammatory molecules, such as tumor necrosis factor-α, interleukin-6, and lipopolysaccharide, regulate resistin gene expression in various cell models, and reciprocal modulation has been hypothesized.¹⁷ Resistin is clearly involved in inflammation, but its specific function in that situation remains to be clarified. Because of its link with obesity and inflammation and its potential link with insulin resistance, resistin has been tagged as a potential metabolic syndrome marker. In support of this theory, adults with metabolic syndrome tend to have higher resistin levels than their healthy counterparts.¹⁷ However, the correlation between insulin resistance and serum resistin in adult humans remains controversial. This correlation is supported by some studies^18,19 and not by some others,^20,21 therefore weakening the relationship between resistin and metabolic syndrome. Some authors have indicated that increased serum resistin levels are associated with markers of metabolic syndrome, increased obesity, visceral fat,^1,22
–24 insulin resistance, and type 2 diabetes,¹² whereas other groups have failed to observe such correlations.^25
–27 Furthermore, the contribution of resistin to the metabolic syndrome is still under investigation.²⁸ The aim of the present study is to investigate the relation of serum resistin levels with markers of the metabolic syndrome in a case—control study.

Methods

Study design

We conducted a case–control study in north Indian adult men between 20 and 40 years of age. A total of 386 adult men were enrolled for the study. A structured proforma was filled to collect the information regarding their medical, personal, family, as well as dietary history. The study was approved by the institutional ethical committee and by the Indian Council of Medical Research (ICMR), New Delhi, and “we certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research.” Written informed consent was obtained from all of the participants. This study was conducted under the principles of the Declaration of Helsinki.

All of the cases were diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome.²⁹ Subjects were divided into case and control groups. The case group was comprised of 192 male subjects with proven metabolic syndrome [mean age 32.03±4.06, waist circumference (WC) 105.46±10.72, body mass index (BMI) 29.2±3.85] and the control group was comprised of 194 age-matched, healthy, male subject without metabolic syndrome (mean age 31.67±5.09, WC 82.48±9.21, BMI 22.66±2.78) who were nonalcoholic as well as nondiabetic and without any kind of cardiac, respiratory, or inflammatory diseases. All samples were collected from Lucknow and nearby areas.

Anthropometric measurements

All of the cases and controls were evaluated, in addition to the waist-to-hip ratio (WHR; a good marker for measuring central/visceral obesity), using the following anthropometric parameters: BMI, height, weight, WC, blood pressure, and pulse rate. BMI was calculated as weight (in kilograms) divided by height (in meters) squared.

Biochemical measurements

Blood samples (for measuring the serum/plasma biochemical parameters) were obtained in the morning after 12 h of fasting. Serum and plasma were separated from 3.0 mL of blood. Estimation of plasma glucose was performed by the glucose oxidase–peroxidase (GOD-POD) method (Randox Laboratories Ltd., Antrim, UK), and the serum lipid profile was done by enzymatic method (Randox Laboratories Ltd., Antrim, UK). Plasma insulin was estimated by the immunoradiometric assay method (Immunotech Radiova, Prague). Subsequently, insulin resistance was calculated by homeostatic model assessment (HOMA) index,³⁰ using the equation:

HOMA index=[fasting Insulin (μU/I)×fasting glucose (mmol/L)/ 22.5].

Determination of serum resistin levels

The serum concentration of resistin was measured with a sandwich enzyme-linked immunosorbent assay (ELISA) kit (Biovendor Research and Diagnostic Products, Czech Republic), according to the manufacturer's instructions. Serum samples were diluted 1:3 with dilution buffer. The lowest level of human resistin detectable by the assay was 0.1 ng/mL. The interassay variability was 5.1% and the intraassay variability was 2.8%. For this analysis, an aliquot of serum kept at −20°C was thawed for the first time and processed.

Statistical analysis

Results are expressed as the mean±standard deviation (SD). Groups were compared by the Student t-test. Simple linear correlation and multiple regression analysis were used to assess the association of circulating resistin level with demographic characteristics and biochemical parameters in controls, cases, and both (control+cases). A two-tailed (α=2) P≤0.05 was considered statistically significant.

Results

Various physiological and biochemical parameters of control and cases are shown in Table 1. The mean levels of all five characteristics of metabolic syndrome [WC, blood pressure, glucose, triglyceride, and high-density lipoprotein cholesterol (HDL-C)] in cases were found to be significantly higher as compared to controls. Similarly, the serum resistin levels (mean±SD) were significantly higher in cases (with metabolic syndrome) compared to controls (without metabolic syndrome) (12.49±4.73 ng/mL vs. 6.99±1.98 ng/mL; p≤0.001; Fig. 1). We observed a significant difference in levels of biochemical parameters of cases compared to controls. Factors of metabolic syndrome were significantly different in cases compared to controls (Table 1), namely WC 105.46±10.72 vs. 82.48±9.21, p≤0.001); systolic (SBP) and diastolic blood pressure (DBP) (128.79±7.41 vs. 121.96±7.99, p≤0.001, and 87.01±6.84 vs. 82.61±5.07, p≤0.001); triglyceride levels (171.17±25.49 vs.113.89 mg/dL±22.30 mg/dL, p≤0.001); HDL level (38.88±6.72 mg/dL vs. 43.87±6.68, p≤0.001); and glucose concentration (107.58±14.88 vs. 90.82±15.38 mg/dL, p≤0.001). Anthropometric measurements like BMI, WHR, and hip circumference (HC) were also significantly higher in cases as compared to the controls (BMI 29.2±3.85 vs. 22.66±2.78 kg/m², p≤0.001; WHR 1.04±0.07 vs. 0.92±0.05, p≤0.001; HC (cm) 101.43±7.76 vs. 90.01±7.21, p≤0.001). Fasting plasma insulin (FPI) and calculated HOMA index were also found to be significantly higher in cases when compared with the controls [FPI (μU/mL) 8.590±2.63 vs. 7.02±1.45, P≤0.01; HOMA-IR 2.27±0.75 vs. 1.58±0.44, p≤0.001) (Table 1).

FIG. 1.

Comparison of serum resistin levels in controls and cases. CONC, concentration.

Table 1.

Comparison of Demographic, Biochemical, Factors of Metabolic Syndrome and Serum Resistin in Controls and Cases Enrolled in the Study

	Control	Cases
Variables	(n=194)	(n=192)	p value
Age (years)	31.67±5.09	32.03±4.06	NS
BMI (kg m⁻²)	22.66±2.78	29.2±3.85	0.001^a
HC (cm)	90.01±7.21	101.43±7.76	0.001^a
WHR	0.92±0.05	1.04±0.07	0.001^a
WC (cm)	82.48±9.21	105.46±10.72	0.001^a
SBP (mmHg)	121.96±7.99	128.79±7.41	0.001^a
DBP (mmHg)	82.61±5.07	87.01±6.84	0.001^a
FPG (mmHg)	90.82±15.38	107.58±14.88	0.001^a
TG (mg/dL)	113.89±22.30	171.17±25.49	0.001^a
HDL (mg/dL)	43.87±6.68	38.88±6.72	0.001^a
Resistin (ng/mL)	6.99±1.98	12.498±4.73	0.001^a
FPI (μU/mL)	7.02±1.45	8.59±2.63	0.01^a
HOMA-IR	1.58±0.44	2.27±0.75	0.001^a
TC (mg/dL)	148.95±25.04	180.58±34.81	0.001^a
VLDL (mg/dL)	22.88±4.68	34.14±5.13	0.001^a
LDL (mg/dL)	91.21±33.08	117.18±44.18	0.001^a
TC/HDL	3.48±0.87	4.79±1.24	0.001^a

Values are presented as mean±standard deviation (SD) and significance was calculated between control versus cases.

Data are expressed as mean±SD.

Insignificant p values are p≥0.05.

Significant p values (p≤0.05).

BMI, body mass index; HC, hip circumference; WHR, waist-to-hip ratio; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TG, triglyceride; HDL, high-density lipoprotein; FPI, fasting plasma insulin; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein;TC/HDL, total cholesterol/high-density lipoprotein.

Correlation (Pearson correlation) of serum resistin was carried out with factors of metabolic syndrome and other biochemical variables in cases and controls. In the cases, resistin was positively and significantly correlated with serum levels of triglycerides (r=0.258, p=0.0003), total cholesterol (r=0.227, p=0.001), and very-low-density lipoprotein (VLDL) (r=0.244, p=0.0006). It was also correlated positively, but not significantly, with BMI, SBP, HDL, homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.048, p=0.505), low-density lipoprotein (LDL), and total cholesterol (TC)/HDL, whereas it was negatively correlated with HC, WHR, DBP, WC, fasting plasma glucose (FPG), and serum HDL levels, thus suggesting the correlation of resistin with the determinants of the metabolic syndrome; it was not correlated strongly in controls (Table 2). We performed multiple regression analyses, including all of the parameters in the statistical model that revealed significant correlation of serum resistin levels with serum triglyceride levels and VLDL (Table 3). Finally, we observed that serum resistin levels were very strongly correlated with serum triglyceride, a factor of metabolic syndrome in Indian males.

Table 2.

Pearson Correlation (r) of Serum Resistin Levels with Phenotypic and Biochemical Variables in Controls (194) and Cases (192)

	Controls (194)		Cases (192)
Variables	Correlation coefficient (r)	p value	Correlation coefficient (r)	p value
BMI	0.010	0.887	0.005	0.942
HC	−0.027	0.712	−0.028	0.695
WHR	0.026	0.710	−0.075	0.295
WC	0.005	0.940	−0.070	0.329
SBP	−0.070	0.326	0.054	0.456
DBP	−0.032	0.651	−0.018	0.795
GLU	−0.026	0.716	−0.047	0.515
TG	0.086	0.228	0.258	0.0003^a
HDL	0.048	0.505	−0.211	0.003^a
HOMA	−0.091	0.202	0.048	0.505
TC	0.109	0.129	0.227	0.001^a
VLDL	0.069	0.339	0.244	0.0006^a
LDL	0.232	0.086	0.119	0.098
TC/HDL	0.013	0.853	0.132	0.067

Data are expressed as mean±standard deviation (SD).

Insignificant p values are p≥0.05.

Significant p values (p≥0.05).

BMI, body mass index; HC, hip circumference; WHR, waist-to-hip ratio; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; GLU, glucose; TG, triglyceride; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; TC, total cholesterol; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein; TC/HDL, total cholesterol/high-density lipoprotein.

Table 3.

Multiple Regression Analysis for the Relationship between Resistin and Different Phenotypic and Metabolic Variables

					95% CI
Predictors	Coef.	SE coefficient	t ratio	P value	Lower	Upper
BMI	−0.335	0.481	0.696	0.486	−1.27	0.60
WC	0.115	0.281	0.410	0.681	−0.43	0.66
SBP	0.036	0.029	1.221	0.222	−0.02	0.09
DBP	−0.047	0.039	1.181	0.238	−0.12	0.03
GLU	0.056	0.044	1.271	0.204	−0.03	0.14
TG	0.127	0.044	2.870	0.004^a	0.04	0.21
HDL	0.076	0.101	0.751	0.452	−0.12	0.27
TC	0.005	0.045	0.113	0.910	−0.08	0.09
VLDL	−0.414	0.216	1.914	0.050^a	−0.83	0.009
LDL	0.005	0.043	0.136	0.891	−0.07	0.09
TC/HDL	1.133	1.767	0.641	0.521	−2.33	4.59
HOMA-IR	−2.318	2.106	1.101	0.271	−6.44	1.80

Data are expressed as mean±standard deviation (SD).

Insignificant p values are p≥0.05.

Significant p values (p≤0.05).

BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; GLU, glucose; TG, triglyceride; HDL, high-density lipoprotein; TC, total cholesterol; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein; TC/HDL, total cholesterol/high-density lipoprotein. HOMA-IR, homeostasis model assessment of insulin resistance.

Discussion

In this study, we observed that metabolic risk factors, namely, glucose, triglycerides, HDL, blood pressure, and WC along with serum resistin levels differ significantly between controls (without metabolic syndrome) and cases (with metabolic syndrome). The major finding of this study is that serum resistin levels correlate with factors of metabolic syndrome and various biochemical and physiological parameters in control and cases with different magnitudes (Table 2). We also observed that triglycerides are the major determinant of metabolic syndrome, and a significant association between resistin and triglycerides is observed in this study.

Resistin is a protein related to glucose homeostasis, lipid metabolism, and insulin action. In mice, it is expressed mainly in adipose tissue,^31,32 whereas it is produced by adipocytes and inflammatory cells in humans.^13,26 Reilly and colleagues have found that plasma resistin levels are associated with inflammatory markers in a large, nondiabetic cohort as well as in type 2 diabetes.¹³ Apart from these findings, the role of resistin in the metabolic syndrome is controversial. Most studies have reported that resistin levels in humans correlated positively with obesity, insulin resistance, and type 2 diabetes,^1,2,22,33,34 whereas other authors have failed to observe such correlations. No significant difference was observed in resistin levels in cases compared to controls.^26,35,36

Most of the anthropometric measurements, metabolic syndrome factors, and biochemical parameters, as depicted in Table 1, have shown significant differences. Serum resistin levels were also significantly higher in cases compared with controls. There was also a significant correlation of serum resistin with BMI; however, to date, the relation between serum resistin and BMI has been controversial.^37
–39 It has been reported that resistin is associated with low HDL in a smaller number of healthy subjects and subjects with type 2 diabetes mellitus.^40,41 A study conducted by H. Asano and co-workers in Japan demonstrated that the plasma resistin level was associated with serum concentrations of HDL-C and triglycerides.⁴² Our study also showed the same result (Table 2). The serum resistin level was negatively, but significantly, associated with serum concentrations of HDL-C and positively associated with triglycerides,^40,41 and it was in agreement with the previous findings of Osawa et al., who reported an inverse correlation of resistin with HDL in the Japanese general population (Table 2).^43,44 Furuhashi and his colleagues reported that circulating resistin was neither correlated with blood pressure, nor different among controls and cases with essential HT with or without insulin resistance; however, our results suggest a positive correlation between serum resistin level and SBP and DBP. Some recent reports suggest that serum resistin levels are higher in subjects with metabolic syndrome in a population-based study including 1,090 cases.^45,46 Menzaghi and co-workers also reported significant genetic correlations between resistin and WC, HOMA-IR, and the metabolic syndrome score by analyzing 264 nondiabetic cases and their 473 adult family members.⁴⁷ In contrast, Utzschneider et al. reported that serum resistin was not correlated with the number of metabolic syndrome criteria or any of the individual factors in 177 cases.²⁶ Multiple regression analysis of the data observed indicated that triglycerides and VLDL levels are the major determinants for the development of metabolic syndrome in male samples (Table 3). Different explanations could account for these discrepancies, including the use of different assay methods and the definition used to select patients with the metabolic syndrome.

In conclusion, we found that resistin levels were associated with the factors of metabolic syndrome and anthropometric parameters in the general cases and controls. Resistin levels are also correlated with the biochemical and anthropometrical parameters of metabolic syndrome.

Footnotes

Acknowledgments

Financial support to this work was provided by the Indian Council of Medical Research, New Delhi (ICMR 45/11/06 BIC-BMS) and is duly acknowledged.

Author Disclosure Statement

No competing financial interests exist.

References

Steppan

, Bailey

, Bhat

et al. The hormone resistin links obesity to diabetes. Nature, 2001; 409:307–312.

Steppan

, Lazar

. Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab, 2002; 1:18–23.

Kawashima

, Tsuruzoe

, Motoshima

et al. Insulin down-regulates resistin mRNA through the synthesis of protein(s) that could accelerate the degradation of resistin mRNA in 3T3-L1 adipocytes. Diabetologia, 2003; 2:231–240.

Shojima

, Sakoda

, Ogihara

et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes, 2002; 6:1737–1744.

Juan

, Au

, Fang

et al. Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. Biochem Biophys Res Commun, 2001; 289:1328–1333.

Le Lay

, Boucher

, Rey

et al. Decreased resistin expression in mice with different sensitivities to a high-fat diet. Biochem Biophys Res Commun, 2001; 289:564–567.

Way

, Gorgun

, Tong

et al. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferators activated receptor gamma agonists. J Biol Chem, 2001; 276:25651–25653.

Ukkola

. Resistin—a mediator of obesity-associated insulin resistance or an innocent bystander? Eur J Endocrinol, 2002; 147:571–574.

Palanivel

, Maida

, Liu

et al. Regulation of insulin signaling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia, 2006; 1:183–190.

10.

Kim

, Lee

, Moon

et al. A cysteine-rich adipose tissue specific secretory factor inhibits adipocyte differentiation. J Biol Chem, 2001; 14:11252–11256.

11.

Sheng

, Di

, Jin

et al. Resistin is expressed in human hepatocytes and induces insulin resistance. Endocrine, 2008; 33:135–143.

12.

Holcomb

, Kabakoff

, Chan

et al. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J, 2000; 15:4046–4055.

13.

Reilly

, Lehrke

, Wolfe

et al. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation, 2005; 7:932–939.

14.

, Gambino

, Pagani

, Guidi

, Gentile

, Cassader

, Pagano

. 2005. Relationships between human plasma resistin, inflammatory markers, insulin resistance. Int J Obes, 11:1315–1320.

15.

Shetty

, Economides

, Horton

et al. Circulating adiponectin, resistin levels in relation to metabolic factors, inflammatory markers, vascular reactivity in diabetic patients, subjects at risk for diabetes. Diabetes Care, 2004; 10:2450–2457.

16.

Filippidis

, Liakopoulos

, Mertens

et al. Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purif, 2005; 6:421–428.

17.

Aquilante

, Kosmiski

, Knutsen

et al. Relationship between plasma resistin concentrations, inflammatory chemokines, components of the metabolic syndrome in adults. Metab Clin Exp, 2008; 4:494–501.

18.

Wasim

, Al-Daghri

, Chetty

et al. Relationship of serum adiponectin and resistin to glucose intolerance and fat topography in South-Asians. Cardiovasc Diabetol, 2006; 2:5–10.

19.

Burnett

, Devaney

, Adenika

, Lindsay

, Howard

. 2006. Cross-sectional associations of resistin, coronary heart disease, and insulin resistance. J Clin Endocrinol Metab, 1:64–68.

20.

Degawa-Yamauchi

, Bovenkerk

et al. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab, 2003; 11:5452–5455.

21.

Heilbronn

, Rood

, Janderova

et al. Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab, 2004; 4:1844–1848.

22.

Malo

, Ukkola

, Jokela

et al. Resistin is an indicator of the metabolic syndrome according to five different definitions in the Finnish Health 2000 survey. Metab Syndr Relat Disord, 2011; 9:203–210.

23.

Pagano

, Marin

, Calcagno

et al. Increased plasma resistin in adults with prader-willi syndrome is related to obesity and not to insulin resistance. J Clin Endocrinol Metab, 2005; 90:4335–4340.

24.

Matsuda

, Kawasaki

, Yamada

et al. Impact of adiposity and plasma adipocytokines on diabetic angiopathies in Japanese type 2 diabetic subjects. Diabet Med, 2004; 21:881–888.

25.

Farvid

, Ng

, Chan

et al. Association of adiponectin and resistin with adipose tissue compartments, insulin resistance and dyslipidemia. Diabetes Obes Metab, 2005; 7:406–413.

26.

Utzschneider

, Carr

, Tong

et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Diabetologia, 2005; 48:2330–2333.

27.

Filippidis

, Liakopoulos

, Mertens

et al. Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purif, 2005; 23:421–428.

28.

Lakka

, Laaksonen

, Lakka

et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA, 2002; 288:2709–2716.

29.

Expert Panel on Detection Evaluation, Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) JAMA, 2001; 285:2486–2497.

30.

Keskin

, Kurtoglu

, Kendirci

et al. Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics, 2005; 115:e500–e503.

31.

Rajala

, Obici

, Scherer

et al. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest, 2003; 111:225–230.

32.

Rajala

, Scherer

. Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology, 2003; 144:3765–3773.

33.

Azuma

, Katsukawa

, Oguchi

et al. Correlation between serum resistin level and adiposity in obese individuals. Obes Res, 2003; 11:997–1001.

34.

Silha

, Krsek

, Skrha

et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol, 2003; 149:331–335.

35.

Pfutzner

, Langenfeld

, Kunt

et al. Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Clin Lab, 2003; 49:571–576.

36.

Iqbal

, Seshadri

, Stern

et al. Serum resistin is not associated with obesity or insulin resistance in humans. Eur Rev Med Pharmacol Sci, 2005; 9:161–165.

37.

Cho

, Youn

B-S

, Chung

et al. Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. Diabetologia, 2004; 47:559–565.

38.

Fujinami

, Obayashi

, Ohta

et al. Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta, 2004; 339:57–63.

39.

Lee

, Chan

, Yiannakouris

et al. 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. l Clin Endocrinol Metab, 2003; 88:4848–4856.

40.

Youn

B-S

, Yu

K-Y

, Park

et al. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. Clin Endocrinol Metab, 2004; 89:150–156.

41.

Chen

, Li

et al. Serum resistin level among healthy subjects: Relationship to anthropometric and metabolic parameters. Metabolism, 2005; 54:471–475.

42.

Shetty

, Economides

, Horton

et al. 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, 2004; 27:2450–2457.

43.

Asano

, Izawa

, Nagata

et al. Yokota. Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population. Diabetologia 10.1007/s00125-009-1517-2.

44.

Osawa

, Tabara

, Kawamoto

et al. Plasma resistin, associated with single nucleotide polymorphism – 420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population. Diabetes Care, 2007; 30:1501–1506.

45.

Furuhashi

, Ura

, Higashiura

et al. Circulating resistin levels in essential hypertension. Clin Endocrinol, 2003; 59:507–510.

46.

Norata

, Ongari

, Garlaschelli

et al. Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol, 2007; 156:279–284.

47.

Menzaghi

, Coco

, Salvemini

et al. Heritability of serum resistin and its genetic correlation with insulin resistance-related features in nondiabetic Caucasians. J Clin Endocrinol Metab, 2006; 7:2792–2795.