Correlation Between Resistin Level and Metabolic Syndrome Component: A Review

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1 Mostafazadeh Mostafa et al. Correlation Between Resistin Level Horm Metab Res 2018; 00: Correlation Between Resistin Level and Metabolic Syndrome Component: A Review Authors Mostafa Mostafazadeh 1, 2, Sanya Haiaty 2, 3, Ali Rastqar 4, 5, Mahtab Keshvari 6 Affiliations 1 Immunology Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 2 Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran 3 Infectious and Tropical Diseases Research Center, Department of Clinical Biochemistry, Tabriz University of Medical Sciences, Tabriz, Iran 4 Department de Psychiatry et Neuroscience, Université Laval, Québec, QC, Canada 5 Centre Hospitalier de l Université Laval (CHUL), Québec, QC, Canada 6 Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of medical Sciences, Isfahan, Iran Key words correlation, resistin, metabolic syndrome received accepted Bibliography DOI Horm Metab Res 2018; 50: Georg Thieme Verlag KG Stuttgart New York ISSN Correspondence Dr. Mahtab Keshvari Isfahan Cardiovascular Research Center Cardiovascular Research Institute Isfahan University of medical Sciences Isfahan Iran Tel.: + 98/311/ , Fax: + 98/311/ Mahtabkeshvari87@yahoo.com Abstract Metabolic syndrome (MetS) has a collection of some abnormal and pathological conditions that cause many critical diseases. Resistin is one of the possible candidates for these pathologies but there are not enough data to prove if resistin has positive, neutral, or negative effects on one or some components of MetS. This review summarizes data about comparing the effects and contribution of resistin in initiation and progression of MetS components and also its different actions between human and other mammalians. This summarized data about the relationship of resistin and MetS components have been obtained from clinical researches and in some cases even animal studies. To find the relevant studies, the search in PubMed, Science Direct, and Scopus were performed. Human and animal studies on relationships between resistin and MetS (initiation and progression of components) were included in our search. In experiments reported among different human genetic groups as well as the patients with various disease such as diabetes, no significant correlation is shown between FBG and resistin level. Furthermore, this review shows that the results of correlation between resistin and TG, HDL, and central or abdominal obesity were inconsistent. These inconsistencies can arise from different sample size or genetic groups, gender, and also from experimental studies. Therefore, to obtain precise results systematic review and meta-analyses are required. Introduction The term of metabolic syndrome (MetS) is applied for a major and escalating group of risk factors that raises risk for public health and clinical challenge worldwide. The term metabolic refers to the biochemical processes involved in the body s normal functioning. Risk factors are traits, conditions, or habits that increase the chance of developing a disease [1, 2]. There is a cluster of metabolic risk factors for cardiovascular diseases and type-2 diabetes mellitus (T2DM). In the major components of metabolic syndrome, excess abdominal fat, atherogenic dyslipidemia, hypertension, hyperglycemia, insulin resistance, proinflammatory and prothrombotic (thrombosis) states, and visceral adipose tissue play a key role in the initiation and future pathogenesis of it and also its complications [3]. Adipose tissue is an active endocrine organ capable of producing several regulatory mediators that is called adipokines. Adipokines have been shown to be involved in several biological processes. Several adipokines have been illustrated to exert regulatory roles on cardiovascular risk factors, for example, inflammation, adipogenesis, lipid metabolism, and oxidative stress [4, 5]. Resistin is an adipokine with 114 amino acids, belonging to the resistin-like family of proteins [6]. In humans, resistin is an adipo- 521

2 cyte- and monocyte-derived cytokine, which modulates insulin action, energy, glucose, and lipid homeostasis [7]. It has been proposed that resistin might serve as a molecular link between inflammation, metabolic parameters, and vascular dysfunction, and can thus contribute to the risk for MetS, T2DM, and cardiovascular disease (CVD) [8, 9]. However, studies show controversial role of resistin in regulating insulin sensitivity and obesity [10, 11]. Therefore, the present study was aimed to compare the effects and contribution of resistin in initiation and progression of MetS components and also its different actions among human and other mammalians. Methods for Review An extensive search was performed in PubMed, Science Direct, Scopus, and Google scholar to identify clinical and animal studies on the correlation between resistin level and MetS components published from inception up to November 15, Search terms were ( Resistin OR Adipokines ) AND ( Metabolic Syndrome OR metabolic ). The search was performed in titles and abstracts that were restricted to articles published in English and sometimes French languages. All titles, abstracts, and full texts of potentially relevant studies were assessed for eligibility. Papers were excluded if: 1) data on exposure (Resistin) or outcome (Metabolic Syndrome) were not reported and 2) no data were reported on the relationship between exposure and outcome. Resistin and its Secretion Resistin (or resistance to insulin ), also known as the adipose tissue-specific secretory factor, C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1), found in inflammatory zone 3, was discovered in 2001 by Lazar s group from the University of Pennsylvania, who named resistin for its ability to interfere with insulin action and is identified as a link between obesity and diabetes [6, 12]. Resistin, encoded by the RETN gene, is a secretory protein that belongs to the resistin like molecules family with a distinct expression patterns and biological functions [13]. The resistin expression is identified in several cell types including adipocytes [6, 14], intestinal epithelium, adrenal gland, stomach, skeletal muscle cells [15], testis [16], and possibly astrocytes [17]. The main source of rodent s resistin is the white adipose tissue. Resistin in mouse has an 11 kda cysteine-rich polypeptide, and its gene (RETN) is located on chromosome 8A1. It is synthesized as a 114 amino acid (aa) precursor, with a signal peptide of 20 aa and a 94 aa mature segment. Amino acid identity in the mature segment within mice and rats is 72 % [6, 18]. The human resistin gene, located on chromosome 19p13.3, encodes a 12.5 kda cysteine-rich polypeptide with a mature segment consisting of 108 aa and has 55 % aa identity between mice and humans [6, 19]. In humans, resistin is predominantly produced by peripheral blood mononuclear cells (PBMCs), macrophages, and bone marrow cells [20, 21]. The mature protein has a tendency to form dimers and oligomers, thus circulating resistin consists of low molecular weight and high molecular weight isoforms [22]. Normally, the serum resistin levels ranges from 7 to 22 and ng/ml in human and rats, respectively, and its concentrations are significantly higher in females versus males. It has been reported that in obese and diabetic patients, the serum level of resistin is significantly increased [6, 22]. Resistin expression in rodent adipocytes is stimulated by high levels of glucose but suppressed by tumor necrosis factor α (TNF-α) while human resistin is strongly induced by various inflammatory stimuli, including interleukin 6 (IL-6), IL-1β, lipopolysaccharide (LPS), TNF-α, and resistin itself in PBMCs and macrophages [23]. Resistin Receptors According to the data obtained from animal and human studies, the receptor or receptors of resistin especially in human is not fully understood. But, Toll-like receptor 4 (TLR4) and adenylyl cyclase-associated protein 1 (CAP1) are accepted as putative candidates for its receptors [24]. TRL family is expressed in various organisms including mammalians. Among the reported 13 TLR (TLR1 13), TLR1 to 9 are both in human and mice, TRL10 is not functional in mice but in human is active, and the other ones do not express in human but only in mice [25 27]. TLR1, 2, 4, 5, 6, and 10 are present on the cell surface, whereas the others are endosomal or lysosomal receptors [25, 26]. TLRs participate essentially in immunologic pathways and are divided in some groups while each group has own signaling pathway (for more details, see ref. [26]). Among TLRs, TLR4 is proposed to be the one of resistin membrane receptors that mediates its intracellular functions [28, 29]. In fact, TLR4 is considered as an immunoreceptor that promotes the production of inflammatory substances in macrophages but, for example, it can also mediate the effects of resistin in hypothalamus for activating proinflammatory pathways [25, 29]. TLRs are found in macrophages, neutrophils, dendritic cells, natural killer cells, and mast cells of the innate-immune system; in T- and B-lymphocytes of the adaptive-immune system, as well as in some non-immune cells, such as epithelial and endothelial cells [30]. According to some evidences, among TLRs, TLR4 is unique because after binding to appropriate ligand, this receptor can undergo endocytosis and follow its action as an internal receptor [31]. Up to now, it was found that many endogenous ligands can activate TLR4. These include HSP22, EDA fibronectin, low molecular weight fragments of hyaluronic acid, fibrinogen, and tenascin-c, whereas lipoteichoic acid, LPS, CpG motifs of bacterial DNA, and viral RNA are exogenous ligands [26, 32]. After binding the ligands, TLR4 usually exerts its effects via two classic models of signaling pathways. They are MyD88 (myeloid differentiation primary response gene 88) and Toll-interleukin 1 receptor domain-containing adaptor inducing interferon-beta (TRIFβ) pathways. Then, autophosphorylation of interleukin-1 receptor-associated kinases (IRAK) and oligomerization of TNF receptor-associated factor 6 (TRAF6) occurs and cause the activation of IKK and mitogen-activated protein kinase (MAPK). Finally, subsequent signal propagation results in the translocation of nuclear factor kappa B (NF-κB) to the nucleus and the activation of the activator protein-1 (AP-1) transcriptional program [25, 26, 30, 32]. On the other hand, downstream of TRIF, in addition to the delayed activation of NF-κB via an interaction with TRAF6, the ubiquitination of TNF receptor-associated factor 3 (TRAF3) induces 522

3 Fig. 1 Tool-Like Receptor 4 (TLR4). A possible mechanism for resistin cytoplasmic and nuclear signal transduction by TLR4 in vertebrates. TANK-binding kinase 1 (TBK1) binding to IκB (inhibitor of NF-κB) kinase epsilon (IKKε). Then, the TBK1-IKKε complex phosphorylates the transcription factor interferon regulatory factor 3 (IRF3), ultimately driving the expression of interferon beta (IFNβ) and interferon-inducible protein 10 (IP-10) [25, 27, 32]. Fig. 1 shows the summary of this process. The other receptor, which was proposed as a putative resistin receptor, is CAP1. Although TLR4 has been extensively studied and even there is a report that revealed that resistin in mice binds to tyrosine kinase-like orphan receptor 1 (ROR1) [33, 34], it can directly bind to CAP1 in human monocytes [34]. During the evolution, CAP1 is conserved from yeast to human. It is an action-binding protein that regulates actin cytoskeleton and cell adhesion [34, 35]. Fig. 2 shows the summary of this process. Resistin and Hypertension Several recent experimental and clinical studies have highlighted a relationship between resistin and hypertension. In an experimental study, daily intravenous injections of 400 ng of recombinant mouse resistin for 6 consecutive days induces hypertension in mice [36]. In another study, Kosari et al. have shown that blood pressure in rats is not significantly affected by intracerebroventricular and intravenous administration of resistin [37]. Furthermore, another study reported that there was no significant relationship between circulating resistin levels and blood pressure in obese women [38]. Some clinical studies have suggested a correlation between circulating resistin levels and hypertension in humans [39, 40]. A positive correlation between circulating resistin levels and blood pressure has been reported in subjects both with and without type 2 diabetes mellitus [40, 41]. Plasma resistin levels are significantly higher in the young healthy offspring of individuals with essential hypertension compared to the young healthy offspring of normotensives [42]. Moreover, it has been reported that higher blood resistin levels are correlated with a raised risk for incident hypertension among women without diabetes or hypertension, which represents the effects of resistin on blood pressure [43]. Furthermore, a recent meta-analysis, which was conducted to evaluate the significance of serum resistin levels in hypertensive patients, show that serum resistin level in hypertensive patients is significantly higher than normotensive individuals [44]. Although, the precise mechanisms by which resistin affects blood pressure is unclear, but several mechanisms have been proposed for this effect. As a potential mechanism linking resistin to hypertension, resistin has vasoconstrictor property [45] and also promotes smooth muscle cell proliferation [46]. In other mechanism, resistin via affecting on renin-angiotensin system (RAS) causes hypertension. Angiotensinogen (a precursor of angiotensin II or ANG II) is released from the liver and converted to angiotensin I (ANG I) by renin. Then, ANG I is converted to ANG II (a major RAS effector) through the action of angiotensin converting enzyme (ACE) [47]. In an experimental study, treatment of mice with resistin significantly upregulates the expression of angiotensinogen in the liver. An increase in expression of angiotensinogen could cause an increase in ANG II and activation of RAS, leading to an elevation in blood pressure [36]. However, further studies are needed to determine the exact mechanisms linking resistin to hypertension (see Table 1). Resistin and Triglycerides The relationship between resistin and hypertriglyceridemia has been demonstrated in several studies. Over-expression of resistin in rat, by intramuscular injection of a recombinant eukaryotic expression vector pcdna3.1-retn, not altered significantly serum triglyceride (TG) levels compared to control group [48]. In contrast, adenovirus-mediated over-expression of resistin causes a significantly higher levels of triglyceride in mice [49]. Furthermore, a recent experimental study indicated that the treatment of human hepatocytes with resistin strongly stimulated the secretion of VLDL (apolipoprotein B) and increased hepatocyte lipid content and elimination of plasma resistin by reducing immunoprecipitation hepatocyte apob production [50]. In studies conducted on human populations, there are conflicting results regarding the relationship between circulating levels of resistin and triglycerides. In a study, which was conducted in Taiwan on 124 hypertensive patients, no correlation was found between plasma levels of resistin and triglycerides [51]. Moreover, among Iranian population, also no significant correlation between resistin serum levels and TG was observed [11]. As well as it has 523

4 Fig. 2 Adenylyl cyclase-associated protein 1 (CAP1). Intracellular signaling of resistin via CAP1 in human monocytes. been shown that resistin did not correlate significantly with TG circulating levels in Chinese type 2 diabetes mellitus (T2DM) patients [52]. In another study on 551 obese Spanish women, it has been shown that there is no significant relationship between serum levels of resistin and TG [38]. Unlike the above studies, in a large population-based study, it was found that circulating resistin levels have a strong positive correlation with fasting levels of plasma TG [53]. In Indian men, serum resistin levels are positively correlated with TG and very low density lipoprotein (VLDL) [54]. Osawa et al. showed a positive correlation between serum resistin and TG levels in levels in Japanese T2DM patients [55]. Luis et al. showed a significant correlation among resistin levels and TG in patients with morbid obesity [56]. Furthermore, a study on general population (6637 normal subjects) in Spain, between 2000 and 2005, showed a strong positive correlation between serum levels of resistin and triglyceride [57] (see Table 2). Although reports are contradictory in this regard, taken together, these results indicate that circulating concentration of resistin is positively correlated with increased levels of triglycerides. Resistin and HDL Cholesterol In the experimental studies, a significantly negative correlation between the plasma levels of resistin and high density lipoprotein cholesterol (HDL-C) has been demonstrated. Upregulation of resistin expression, by intramuscular injection of a recombinant eukaryotic expression vector pcdna3.1-retn, significantly decreased serum HDL levels compared to control group [48]. Aligning with this result, adenovirus-mediated over-expression of resistin causes a significantly lower levels of HDL in mice [49]. Human population studies have shown a conflicting relationship between circulating levels of resistin and HDL. In a study, which was conducted in China on first-de- 524

5 Table 1 Studies on correlation between resistin and hypertension. Article title Correlation Subjects Ref. Effects of antihypertensive treatment on plasma apelin, resistin, and visfatin concentrations Mean daily plasma resistin concentrations were significantly lower after 6 weeks treatment with amlodipine, bisoprolol, or indapamide compared with the baseline values Human [96] Resistin induces hypertension and insulin resistance in mice via a TLR4-dependent pathway Lack of association of serum resistin levels with metabolic syndrome criteria in obese female patient. Hyperresistinemia is associated with coexistence of hypertension and type 2 diabetes Plasma resistin levels associate with risk for hypertension among nondiabetic women Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue Association of resistin and adiponectin with different clinical blood pressure phenotypes Plasma resistin levels associate with risk for hypertension among nondiabetic women Masked hypertension and atherogenesis: the impact on adiponectin and resistin plasma levels Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes Adiponectin, insulin, and resistin plasma levels in young healthy offspring of patients with essential hypertension Adiponectin and resistin plasma levels in healthy individuals with prehypertension The relationship between human serum resistin level and body fat content, plasma glucose as well as blood pressure Serum resistin levels in patients of hypertension and coronary artery disease Resistin, blood pressure, and cardiovascular events Evaluation of resistin in obese patients with hypertension Association between serum resistin concentration and hypertension: A systematic review and meta-analysis Relation of resistin with obesity and some cardiovascular risk factors in hypertensive women Both systolic blood pressure (BP) and diastolic BP were markedly higher in WT mice treated with resistin for 6 days There was no significant relationship between circulating resistin levels and blood pressure in obese women A positive correlation between circulating resistin levels and blood pressure has been reported in subjects both with and without type 2 diabetes mellitus Higher blood resistin levels are correlated with a raised risk for incident hypertension among women without diabetes or hypertension, which represents the effects of resistin on blood pressure Blood pressure in rats is not significantly affected by intracerebroventricular and intravenous administration of resistin Mice [36] Human [38] Human [41] Human [43] Human [37] Increased resistin levels are associated without of clinic hypertension Human [40] Higher plasma resistin levels independently associated with an increased risk for incident hypertension among women without diabetes Human [44] Patients with masked hypertension have higher resistin levels compared Human [39] with normotensive individuals Serum resistin was positively correlated with hypertension Human [55] Plasma resistin levels are significantly higher in the young healthy offspring of individuals with essential hypertension compared to the young healthy offspring of normotensives Healthy individuals with prehypertension have significantly higher resistin plasma levels compared to healthy normotensives Fasting serum resistin concentrations not correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) Serum resistin levels were significantly raised in patients with hypertension and coronary artery disease as compared to normotensives Systolic and diastolic blood pressures showed an inverse correlation with resistin. Individuals above the 80 percentile of resistin had an inverse association with hypertension 1. Plasma resistin levels in hypertensive patients with obesity significantly exceeded those observed in the group without hypertension 2. Significantly higher resistin concentrations were found in non-dipper hypertensives as compared to dipper hypertensives 3. Positive correlation between resistin levels and systolic blood pressure was found Serum resistin level in hypertensive patients is higher than normotensive controls, indicating resistin might be a risk factor for hypertension In obese hypertensive female patients resistin levels were higher than the nonobese patients Human [42] Human [97] Human [98] Human [99] Human [100] Human [101] Meta-analysis [44] Human [102] gree relatives of type-2 diabetes patients, serum levels of resistin did not correlate significantly with HDL-C [52]. Luis et al. have also shown that there is no significant relationship between serum levels of resistin and cholesterol in obese female patients [38]. Moreover, among Iranian population, serum levels of resistin were not found to be correlated with levels of HDL-C [11]. It was also shown that the increased serum levels of resistin did not correlate significantly with HDL-C circulating levels in nonalcoholic fatty liver 525

6 Table 2 Studies on correlation between resistin and triglycerides. Article title Correlation Subjects Ref. Effects of over-expressing resistin on glucose and lipid metabolism in mice Over-expression of resistin in rat, by intramuscular injection of a recombinant eukaryotic expression vector pcd- NA3.1-Retn, not altered significantly serum triglyceride (TG) levels compared to control group Rat [48] Adenovirus-mediated high expression of resistin causes dyslipidemia in mice Lack of association of serum resistin levels with metabolic syndrome criteria in obese female patients Resistin levels and inflammatory markers in patients with morbid obesity Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling High serum resistin levels are associated with peripheral artery disease in the hypertensive patients Relationship between serum resistin concentrations with metabolic syndrome and its components in an Iranian population Serum resistin positively correlates with serum lipids, but not with insulin resistance, in first-degree relatives of type-2 diabetes patients: an observational study in China Plasma resistin levels correlate with determinants of the metabolic syndrome Association of resistin with insulin resistance and factors of metabolic syndrome in north Indians Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis Association of resistin with metabolic syndrome in Indian subjects Resistin - 420C/G polymorphism and serum resistin level in Iranian patients with gestational diabetes mellitus Resistin - 420C/G gene polymorphism on circulating resistin, metabolic risk factors and insulin resistance in adult women Increased serum leptin and resistin levels and increased carotid intima-media wall thickness in patients with psoriasis: Is psoriasis associated with atherosclerosis? Effect of six-month lifestyle intervention on adiponectin, resistin and soluble tumor necrosis factor-α receptors in obese adolescent The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis Assessment of serum leptin and resistin levels in association with the metabolic risk factors of pre- and post-menopausal rural women in south India Relationship of adipokines (adiponectin, resistin and RBP4) with metabolic syndrome components in pubertal obese children Correlates of resistin in children with chronic kidney disease: the chronic kidney disease in children cohort Association of circulating resistin with metabolic risk factors in Indianfemales having metabolic syndrome Adenovirus-mediated over-expression of resistin causes a significantly higher levels of triglyceride in mice There is no significant relationship between serum levels of resistin and TG There is a significant correlation among resistin levels and TG in patients with morbid obesity Treatment of human hepatocytes with resistin strongly stimulated the secretion of VLDL (apolipoprotein B) and increased hepatocyte lipid content and elimination of plasma resistin via immunoprecipitation reduces hepatocyte apob production Mouse [49] Human [38] Human [56] Cell culture Plasma levels of resistin was not correlated with triglyceride Human [51] Serum levels of resistin were not significantly correlated with triglycerides concentration Serum resistin did not correlate significantly with TG circulating levels [50] Human [11] Human [52] Circulating resistin levels have a strong positive correlation Human [53] with fasting levels of plasm TG Plasma resistin levels were well correlated with triglycerides Human [54] Positive correlation between serum resistin and TG levels observed in Japanese T2DM patients Human [55] Serum levels of resistin have a strong positive correlation Human [57] with triglycerides Resistin was positively and significantly associated with Human [60] serum triglycerides Serum resistin level was correlated with serum triglycerides Human [103] 420C/G polymorphism of resistin gene directly correlated with high circulating level triglycerides Positive correlations were found between serum resistin levels and serum TG concentration in both study groups Changes in resistin positively correlated with changes in triglycerides Serum resistin level in NAFLD patients had a positive correlation with triglycerides Resistin has no significant relationship with triglycerides in pre- and post-menopausal women Resistin concentrations were significantly inversely correlated with triglyceride Resistin level was positively correlated with serum triglycerides Triglyceride levels were positively correlated with resistin serum levels Human [104] Human [105] Human [106] Human [107] Human [108] Human [109] Human [110] Human [61] 526

7 Table 3 Studies on correlation between resistin and HDL-cholesterol. Article title Correlation Subjects Ref. Association of adiponectin, leptin and resistin with inflammatory markers and obesity in dementia A negative correlation between the levels of resistin with HDL-cholesterol was stated in patients with all-cause dementia Human [62] Relationships between serum resistin and fat intake, serum lipid concentrations and adiposity in the general population Inverse association of resistin with physical activity in the general population Resistin as an inflammatory marker in patients with schizophrenia treated with clozapine Circulating resistin protein and mrna concentrations and clinical severity of coronary artery disease Serum resistin is related to plasma HDL cholesterol and inversely correlated with LDL cholesterol in diabetic and obese humans Patients with nonalcoholic fatty liver disease display increased serum resistin levels and decreased adiponectin levels Associations of resistin with inflammatory and fibrinolytic markers, insulin resistance, and metabolic syndrome in middle-aged and older Chinese Relationship of serum resistin level to traits of metabolic syndrome and serum paraoxonase 1 activity in a population with a broad range of body mass index Lack of association of serum resistin levels with metabolic syndrome criteria in obese female patients Resistin increases with obesity and atherosclerotic risk factors in patients with myocardial infarction Effects of over-expressing resistin on glucose and lipid metabolism in mice 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 Serum resistin level among healthy subjects: relationship to anthropometric and metabolic parameters Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes Adenovirus-mediated high expression of resistin causes dyslipidemia in mice Relationship between serum resistin concentrations with metabolic syndrome and its components in an Iranian population Serum resistin positively correlates with serum lipids, but not with insulin resistance, in first-degree relatives of type-2 diabetes patients: an observational study in China Plasma resistin levels correlate with determinants of the metabolic syndrome Association of resistin with insulin resistance and factors of metabolic syndrome in north Indians Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type-2 diabetes An elevated resistin concentration (fifth quintile) was associated with a low HDL cholesterol level Mean resistin level was correlated inversely with HDL cholesterol Levels of resistin among male patients was associated with low levels of HDL-cholesterol Both plasma resistin and peripheral blood mononuclear cells resistin mrna were negatively associated with plasma HDL-C In diabetic and nondiabetic subjects the protective anti-atherosclerotic HDL cholesterol is positively correlated with resistin No correlation was found between resistin levels and serum HDL levels Resistin was negatively correlated weakly with high-density lipoprotein (HDL) cholesterol No association was detected between the serum concentrations of resistin and HDL-C There is no significant relationship between serum levels of resistin and cholesterol in obese female patients Negative relation was observed between resistin and high-density lipoprotein cholesterol Over-expression of resistin in rat, by intramuscular injection of a recombinant eukaryotic expression vector pcdna3.1-retn decreased significantly serum HDL levels compared to control group Simple regression analysis revealed that low HDL cholesterol were positively correlated with plasma resistin Serum resistin level only negatively correlated with high-density lipoprotein cholesterol (HDL-C) level in men; there was no correlation between serum resistin level and lipid profiles in women The G allele was associated with lower HDL cholesterol in both type-2 diabetes patients and controls A negative correlation was found between serum levels of resistin and HDL Adenovirus-mediated over-expression of resistin caused a significantly lower levels of HDL in mice Serum levels of resistin were not found to be correlated with levels of HDL-C Serum resistin did not correlate significantly with high-density lipoprotein cholesterol (HDL) Human [57] Human [63] Human [111] Human [112] Human [59] Human [58] Human [113] Human [85] Human [38] Human [74] Rat [48] Human [114] Human [83] Human [115] Human [116] Mouse [49] Human [11] Human [52] Plasma resistin levels were inversely correlated with high density lipoprotein (HDL) levels Human [53] Plasma resistin levels were well correlated with high density Human [54] lipoprotein (HDL) levels Serum resistin was correlated with lower HDL Human [55] 527

8 Table 3 Studies Continued. correlation between resistin and HDL-cholesterol. Article title Correlation Subjects Ref. Association of resistin with metabolic syndrome in Indian subjects Correlates of resistin in children with chronic kidney disease: the chronic kidney disease in children cohort Association of circulating resistin with metabolic risk factors in Indian females having metabolic syndrome Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population Resistin was negatively and significantly associated with serum high-density lipoprotein (HDL) levels Resistin level was negatively correlated with high-density lipoprotein cholesterol Resistin levels was negatively associated with high-density lipoprotein Multiple linear regression analysis showed that the plasma resistin level was significantly associated with serum concentrations of HDL-cholesterol Human [60] Human [110] Human [61] Human [90] disease (NAFLD) patients [58]. In a study, which was conducted on diabetic and obese humans, a positive correlation between circulating levels of resistin and HDL-C has been reported [59]. Unlike the mentioned studies, the negative correlations between circulating levels of resistin and HDL-C have been demonstrated in several other studies. In a large population-based study, it was found that plasma levels of resistin have a strong negative correlation with circulating HDL-C [53]. A study on Indian MetS patients showed that resistin was negatively and significantly associated with serum HDL-C levels [60]. Moreover, in Indian females with MetS, serum resistin levels was negatively correlated with HDL-C [61]. In Japanese T2DM patients, serum resistin was correlated with lower HDL [55]. Furthermore, a study on general population showed a negative correlation between serum levels of HDL-C and resistin [57]. A negative correlation between the levels of resistin with HDL-cholesterol was stated in patients with all-cause dementia [62]. Also, in another general population based study, it has been shown that resistin level was correlated inversely with HDL cholesterol [63] (see Table 3). Although reports are contradictory in this regard, taken together, these results indicate that circulating resistin levels circulating concentration of resistin is negatively correlated with of HDL-C. Resistin and Fasting Blood Glucose It has been postulated that resistin is involved in the regulation of glucose metabolism since its administration to rodents increased blood glucose levels, while injection of anti-resistin antibodies into rodent ameliorated insulin action [6]. Experimental studies have shown that resistin impairs glucose-induced insulin release from pancreatic islets of rats [64], and decreases insulin signaling and glucose uptake in rat skeletal muscle cells [65]. Consistent with these evidence, transiently resistin-expressing mice exhibit an impaired insulin secretory response to glucose resulting in insulin resistance (IR) [64]. Transgenic mice that have high plasma levels of resistin showed higher fasting blood glucose (FBG) levels [66]. Against this, adenovirus-mediated high expression of resistin caused an elevation in basal insulin concentration, but did not change FBG levels [49]. Another study on obese T2DM Rhesus monkey showed serum resistin levels was positively correlated with FBG, fasting insulin, and HbA1c insulin resistance index, but had a negative correlation with islet β-cell function [67]. The relationship between resistin and FBG levels in human has been investigated in several studies. A study on north Indians indicated that plasma resistin levels were well correlated with FBG, insulin, and IR [54]. Increased serum resistin levels in patients with coronary slow-flow phenomenon was correlated positively with the plasma levels of glucose [68]. Another study, which aimed to investigate the relationship between plasma levels of resistin with MetS factors among Indian females with MetS, showed circulating levels of resistin were positively associated with plasma glucose [61]. Another study demonstrated that the fasting plasma resistin level was positively correlated with FBG in obstructive sleep apnea hypopnea syndrome [69]. A significant correlation of plasma resistin with fasting blood glucose, and HOMA-IR score in nondiabetic and diabetic, overweight/obese Thai had been observed [70]. Furthermore, the serum resistin concentration was positively correlated with FBG in obese children [71]. Also, another study showed that in type 2 diabetic patients, plasma levels of resistin had a significant positive correlation with FBG [72]. In the studies on Saudi women with type 2 diabetes mellitus, it was shown that resistin correlated significantly and positively with FBG in diabetic women but in nondiabetic subjects, no correlation was observed between resistin and blood glucose levels [73]. A significant positive correlation has been shown between blood resistin concentration and fasting glucose levels in patients with myocardial infarction [74]. Unlike the above mentioned reports, many studies have shown that there is no significant relationship between plasma levels of resistin and fasting blood glucose. The Pearson analysis indicated that serum levels of resistin did not correlate significantly with blood glucose, insulin level, and HbA1c in first-degree relatives of type-2 diabetes Chinese patients [52]. Another assessment on obese Chinese children revealed resistin levels were not related to fasting blood glucose [75]. In another study, also, circulating levels of resistin were not significantly correlated with FBG in obese subjects [22]. Among diabetic patients with acute ST segment elevation myocardial infarction, serum resistin was not correlated with fasting blood glucose [76]. Another study, which aimed to investigate the relationship between serum resistin concentration and 528

9 Table 4 Studies on correlation between resistin and fasting blood glucose. Article title Correlation Subjects Ref. Adenovirus-mediated high expression of resistin causes dyslipidemia in mice Fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice Mouse [49] Relevance and clinical significance of serum resistin level in obese T2DM rhesus monkey models Association of resistin with insulin resistance and factors of metabolic syndrome in north Indians Increased serum resistin levels in patients with coronary slow-flow phenomenon Association of circulating resistin with metabolic risk factors in Indian females having metabolic syndrome Plasma resistin level in obstructive sleep apnea hypopnea syndrome Plasma resistin and insulin concentration in nondiabetic and diabetic overweight/obese Thai Serum resistin concentration and insulin resistance in obese children Roles of adipocyte derived hormone adiponectin and resistin in insulin resistance of type 2 diabetes Serum resistin, adiposity and insulin resistance in Saudi women with type-2 diabetes mellitus Resistin increases with obesity and atherosclerotic risk factors in patients with myocardial infarction Serum resistin positively correlates with serum lipids, but not with insulin resistance, in first-degree relatives of type-2 diabetes patients: an observational study in China Association of serum resistin levels with metabolic syndrome and early atherosclerosis in obese Chinese children Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance Serum resistin in acute myocardial infarction patients with and without diabetes mellitus Relationship between serum resistin concentration and proinflammatory cytokines in obese women with impaired and normal glucose tolerance Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients Circulating resistin levels are not associated with fat redistribution, insulin resistance, or metabolic profile in patients with the highly active antiretroviral therapy-induced metabolic syndrome High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians Serum resistin levels in women with polycystic ovary syndrome Increased resistin blood levels are not associated with insulin resistance in patients with renal disease Serum resistin levels was positively correlated with fasting plasma glucose, fasting insulin and HbA1c, insulin resistance index, but had a negative correlation with islet β-cell function Monkey [67] Plasma resistin levels were well correlated with fasting glucose, Human [54] insulin and insulin resistance The resistin levels correlated positively with the plasma levels of Human [68] glucose Resistin levels were positively associated with plasma glucose Human [61] Correlation analysis demonstrated that the fasting plasma resistin level was positively correlated with fasting blood glucose A significant correlation of plasma resistin with fasting blood sugar, and HOMA score had been observed The serum resistin concentration was positively correlated with fasting glucose Plasma resistin concentration correlated positively with fasting blood glucose levels Resistin correlated significantly and positively with fasting blood glucose in diabetic women but in non-diabetic subjects, no correlation was observed between resistin and blood glucose levels Significant positive correlation was revealed between blood resistin concentration and fasting glucose levels The Pearson analysis showed that serum levels of resistin did not correlate significantly with HOMA indexes, blood glucose, insulin, and HbA1c in Chinese T2DM patients The resistin levels positively correlated with fasting insulin, HOMA-IR, but not related to fasting blood glucose No significant correlation was found between resistin levels and glucose concentrations in obese subjects Among diabetic patients with acute ST segment elevation myocardial infarction, serum resistin was not correlated with fasting blood glucose The results showed that serum resistin concentrations did not correlate with fasting plasma glucose level, or fasting plasma insulin level No significant correlation was observed between serum resistin levels with insulin and glucose levels Resistin levels were not correlated with fasting glucose, insulin, and homeostasis model assessment of insulin resistance index Serum resistin levels were not associated with fasting blood glucose and insulin levels Multiple regression analysis showed that resistin levels do not correlate with fasting blood glucose concentrations Plasma resistin levels were not significantly correlated with insulin and fasting blood glucose levels Human [69] Human [70] Human [71] Human [72] Human [73] Human [74] Human [52] Human [75] Human [22] Human [76] Human [77] Human [78] Human [79] Human [80] Human [81] Human [82] 529

10 Table 4 Studies Continued. correlation between resistin and fasting blood glucose. Article title Correlation Subjects Ref. Relationship between serum resistin concentrations with metabolic syndrome and its components in an Iranian population Serum resistin level among healthy subjects: relationship to anthropometric and metabolic parameters Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance Relationship of serum resistin level to traits of metabolic syndrome and serum paraoxonase 1 activity in a population with a broad range of body mass index High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes Association of plasma levels of resistin with subcutaneous fat mass and markers of inflammation but not with metabolic determinants or insulin resistance Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance proinflammatory cytokines in obese women with impaired and normal glucose tolerance, showed that serum resistin concentrations did not correlate with fasting plasma glucose level, or fasting plasma insulin level [77]. Furthermore, no significant correlation was observed between serum resistin levels with insulin and glucose levels in chronic hemodialysis patients [78]. However, in patients with the highly active antiretroviral therapy-induced metabolic syndrome, resistin levels were not correlated with FBG and insulin levels [79]. Serum resistin levels were not associated with FBG and insulin levels in Pima Indians [80]. In addition, serum resistin levels in women with polycystic ovary syndrome was not correlated with FBG concentrations [81]. Increased resistin blood levels are not associated with insulin resistance, and insulin and FBG levels in patients with renal disease [82]. Another study conducted to investigate the relationship between plasma levels of resistin and MetS and its components among Iranian population revealed that serum levels of resistin were not correlated with FBG levels [11]. Furthermore, a study on healthy subjects revealed that serum resistin level did not correlate with fasting plasma levels [83]. In nonalcoholic fatty liver disease (NAFLD), increased serum resistin was not related to insulin resistance and glucose values [84]. In addition, the lack of correlation between plasma levels of resistin and fasting glucose has also been shown in several other studies [85 87] (see Table 4). Resistin and Central or Abdominal Obesity The relationship between circulating levels of resistin and abdominal obesity (measured by waist circumference) in human has been investigated in several studies. A study on north Indians indicated that plasma resistin levels were well correlated with waist circumference and waist/hip ratio (WHR) [54]. Another study, which aimed Serum levels of resistin were not correlated with levels of FBS Human [11] The results revealed that serum resistin level did not correlate with fasting plasma levels in women No correlation was found between resistin and insulin and glucose values No association was detected between the serum concentrations of resistin and glucose, insulin, or insulin resistance (HOMA-IR) Plasma resistin concentration was not associated with plasma insulin or glucose levels The plasma resistin levels were not correlated with the HOMA-IR, fasting plasma glucose or insulin levels Plasma resistin in cirrhosis was negatively associated with hepatic glucose production Human [83] Human [84] Human [85] Human [86] Human [87] Human [93] to investigate the relationship between plasma levels of resistin with MetS factors among Indian females with MetS, showed circulating levels of resistin were positively associated with waist circumference [61]. Also it has been demonstrated that the fasting plasma resistin level was positively correlated with waist circumference and WHR in obstructive sleep apnea hypopnea syndrome [69]. A significant correlation of plasma resistin with body mass index (BMI), waist circumference, and WHR in nondiabetic and diabetic overweight/obese Thai had been observed [70]. Furthermore, the serum resistin concentration was positively correlated with BMI, percent of body fat (BF %), and WHR in obese children [71]. Also, another study showed that in type 2 diabetic patients, plasma levels of resistin had a significant positive correlation with BMI [72]. A study on Saudi women with type 2 diabetes mellitus showed that resistin correlated significantly and positively with hip circumferences in diabetic women, but no correlation was observed with hip, waist, and WHR in overweight and obese nondiabetic subjects [73]. A significant positive correlation has been reported between blood resistin concentration against waist and hip circumferences in patients with myocardial infarction [74]. Correlation of serum resistin with waist circumference, fat-mass percentage, WHR, and BMI was positive in both genders among Chinese children and adolescents [88]. In addition, the concentration of serum resistin was positively correlated with waist circumference in patients with nonalcoholic fatty liver disease [58]. In another cross-sectional study, visceral adipose tissue, subcutaneous adipose tissue, pericardial fat, and intrathoracic fat were positively correlated with plasma levels of resistin [89]. A study conducted on Spanish female obese patients showed that serum resistin was correlated with weight, fat mass, waist circumference of obese subjects, although, serum resistin was not associated with the presence of metabolic syndrome [38]. In addi- 530

11 Table 5 Studies on correlation between resistin and central or abdominal obesity. Article title Correlation Subjects Ref. Association of resistin with insulin resistance and factors of metabolic syndrome in north Indians Plasma resistin levels were well correlated with waistt circumference and waist/hip ratio Human [54] Association of circulating resistin with metabolic risk factors in Indian females having metabolic syndrome Lack of association of serum resistin levels with metabolic syndrome criteria in obese female patients Resistin levels were positively associated with waist circumference and waist/hip ratio There was a significant relationship between serum levels of resistin and waist circumference and waist/hip ratio in obese female patients There was a significant correlation among resistin levels and weight, BMI, and fat mass Correlation analysis demonstrated that the fasting plasma resistin level was positively correlated with waist circumference and waist/hip ratio A significant correlation of plasma resistin with BMI, waist circumference, and waist-to-hip ratio The serum resistin concentration was positively correlated with BMI, percent of body fat (BF %), and waist-hip ratio Plasma resistin concentration was positively correlated with body mass index. Resistin correlated significantly and positively with hip circumferences in diabetic women, but no correlation was observed with hip, waist, and waist/hip ratio (WHR) in overweight and obese nondiabetic subjects Significant positive correlation was revealed between blood resistin concentration and waist and hip circumferences The Pearson analysis showed that serum levels of resistin did not significantly correlate with BMI and waist or hip circumference in Chinese T2DM patients No significant correlation was observed between serum resistin levels with BMI and body fat content Resistin levels were weak positively correlated with percent of total body fat, total extremity fat, and abdominal sub cutaneous fat, but not abdominal visceral fat or waist/hip ratio Plasma resistin levels not correlated significantly with body mass index, and waist/hip ratio Serum levels of resistin were not correlated with waist circumference and body mass index Human [61] Human [38] Resistin levels and inflammatory markers in patients with morbid obesity Plasma resistin level in obstructive sleep apnea hypopnea syndrome Human [56] Plasma resistin and insulin concentration in non-diabetic and diabetic overweight/obese Thai Serum resistin concentration and insulin resistance in obese children Roles of adipocyte derived hormone adiponectin and resistin in insulin resistance of type 2 diabetes Serum resistin, adiposity and insulin resistance in Saudi women with type 2 diabetes mellitus Resistin increases with obesity and atherosclerotic risk factors in patients with myocardial infarction Serum resistin positively correlates with serum lipids, but not with insulin resistance, in first-degree relatives of type-2 diabetes patients: an observational study in China Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients Circulating resistin levels are not associated with fat redistribution, insulin resistance, or metabolic profile in patients with the highly active antiretroviral therapy-induced metabolic syndrome Increased resistin blood levels are not associated with insulin resistance in patients with renal disease Relationship between serum resistin concentrations with metabolic syndrome and its components in an Iranian population Serum resistin level among healthy subjects: relationship to anthropometric and metabolic parameters The results revealed that serum resistin level did not correlate with body mass index, waist and hip circumferences, and waist/hip ratio in women The plasma resistin levels were positively correlated with the abdominal subcutaneous fat Human [69] Human [70] Human [71] Human [72] Human [73] Human [74] Human [52] Human [78] Human [79] Human [82] Human [11] Human [83] Association of plasma levels of resistin with subcutaneous fat mass and markers of inflammation but not with metabolic determinants or insulin resistance Elevated resistin levels in cirrhosis are associated with the proinflammatory state and altered hepatic glucose metabolism but not with insulin resistance Serum resistin correlates with central obesity but weakly with insulin resistance in Chinese children and adolescents Human [87] No correlation was observed between resistin and body fat mass Human [93] Waist circumference, fat-mass percentage, waist/height ratio and body mass index are (BMI) positively correlated with resistin in both genders Serum resistin concentration was positively correlated with waist circumference Cross-sectional visceral adipose tissue, subcutaneous adipose tissue, pericardial fat, and intrathoracic fat were positively correlated with resistin Human [88] Patients with nonalcoholic fatty liver disease display increased serum resistin levels and decreased adiponectin levels Cross-sectional associations between abdominal and thoracic adipose tissue compartments and adiponectin and resistin in the Framingham heart study Human [58] Human [89] 531