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1.  Efficacy of Antioxidant Treatment in Reducing Resistin Serum Levels: A Randomized Study 
PLoS Clinical Trials  2007;2(5):e17.
Few in vitro studies have examined the participation of resistin, a recently discovered adipokine, in oxidative processes. We investigated whether in vivo treatment with the antioxidant vitamin C might affect resistin serum levels.
Randomized prospective open trial.
San Giovanni Battista Hospital, Turin, Italy.
Eighty healthy individuals.
Administration of 2 g of ascorbic acid orally for 2 wk (n = 40; experimental group) or no supplementation (n = 40; control group).
Outcome measures:
The primary end point was the between-group difference in the before–after change in resistin serum level after vitamin C supplementation. Secondary endpoints were the within- and between-group changes in glucose, insulin, lipid parameters, C-reactive protein fasting values, and markers of oxidative stress.
In the experimental group, vitamin C supplementation was significantly associated with both resistin concentration reduction (from 4.3 ± 1.5 to 2.9 ± 0.8 ng/ml; 95% confidence interval [CI] −1.87, −1.03) and ascorbic acid level increase (from 9.4 ± 2.9 to 19.0 ± 5.2 mg/l; 95% CI 7.9, 11.2). In the control group, resistin levels did not change significantly (from 4.2 ± 1.0 to 4.3 ± 0.9 ng/ml; 95% CI −0.07, 0.37). The between-group differences were highly significant (p < 0.001). Vitamin C supplementation was also associated with a statistically significant reduction in nitrotyrosine level and incremental increase in reduced glutathione. In a linear regression model, within-individual changes in vitamin C concentrations were inversely correlated with changes in resistin levels in both groups (each unit increase of vitamin C corresponded to a decrease of about 0.10 units of resistin levels (95% CI 0.13, 0.08; p < 0.001).
This is to our knowledge the first randomized trial in humans that has demonstrated that short-term vitamin C supplementation could significantly reduce resistin levels, independent of changes in inflammatory or metabolic variables. Future investigations of resistin participation in oxidative processes are warranted.
Editorial Commentary
Background: Resistin is a hormone that is produced by fat cells. Much of the work on resistin has been done in mice, and as a result of this research the hormone was thought to explain the link between obesity and development of diabetes. In obese mice, higher levels of resistin are seen, and this hormone seems to interfere with the normal role of insulin in reducing blood sugar levels. However, the exact biochemical pathways in mice and humans seem to be very different, and it is not obvious whether resistin plays the same role in the development of diabetes in humans as it does in mice. At the same time, some researchers have suggested links between resistin and oxidative stress, which is thought to be involved in the development of certain diseases, particularly cardiovascular disease. The researchers here wanted to more fully explore these links by finding out whether an antioxidant, vitamin C, affected levels of resistin in blood. The researchers carried out a trial in healthy human participants, who were randomized to receive 2 g of vitamin C daily for two weeks, or no treatment. The primary outcome of the trial was the change in resistin levels in blood, and the researchers also looked at the levels of other biochemical variables in blood, such as fasting glucose, insulin, cholesterol, fatty acids, and nitrotyrosine.
What the trial shows: The researchers recruited 80 participants into the trial, and 40 were randomized to receive 2 g of vitamin C supplementation for two weeks. Forty individuals acted as “controls” and received no intervention over the two weeks of the trial. Outcomes were assessed for all but two individuals in the control group. Overall, levels of resistin in blood fell substantially over the course of the trial among the individuals in the vitamin C supplementation group, but not in the control arm of the trial, and this difference between groups was statistically significant. The levels of many other biochemical markers in blood, such as glucose, cholesterol, fatty acids, and insulin, did not show statistically significant changes between the randomized groups. However, levels of two markers of oxidative stress did change: levels of nitrotyrosine, which is associated with cell damage and inflammation, seemed to drop in the vitamin C group relative to the control group, and levels of reduced glutathione (an antioxidant) seemed to increase in the vitamin C group relative to the control group.
Strengths and limitations: In this trial, all individuals were randomized at once to the two study groups. While this is unconventional (normally, participants are randomized one by one, as they are screened and deemed eligible for a study), the process would be likely to prevent bias in allocation of individuals to the study groups. Although participants were not blinded to which study group they were assigned to, the laboratory staff measuring biochemical marker levels in blood were blinded to the study groups. A key limitation of this study is that the participants in the control arm did not receive placebo tablets, but rather received no treatment. A placebo control group would have enabled the researchers to blind participants as to whether they received vitamin C or no active intervention. Participants' knowledge of their group assignment (e.g., to receive vitamin C or no intervention) may have affected their response in the trial. Finally, the trial was conducted on a small group of healthy individuals, and no clinical outcomes were examined. Therefore, although the findings are intriguing, their clinical meaning is not clear.
Contribution to the evidence: There are few other studies that have been carried out in humans examining the possibility of a link between resistin levels and oxidative stress. This study suggests that vitamin C administration reduces blood levels of resistin in humans. This finding does not yet clearly point to a specific role for resistin in disease processes or human disease, but raises questions for further study.
PMCID: PMC1865087  PMID: 17479165
2.  Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum 
Annals of the Rheumatic Diseases  2006;66(4):458-463.
Resistin is a newly identified adipocytokine which has demonstrated links between obesity and insulin resistance in rodents. In humans, proinflammatory properties of resistin are superior to its insulin resistance‐inducing effects.
To assess resistin expression in synovial tissues, serum and synovial fluid from patients with rheumatoid arthritis, osteoarthritis and spondylarthropathies (SpA), and to study its relationship with inflammatory status and rheumatoid arthritis disease activity.
Resistin expression and localisation in synovial tissue was determined by immunohistochemistry and confocal microscopy. Serum and synovial fluid resistin, leptin, interleukin (IL)1β, IL6, IL8, tumour necrosis factor α, and monocyte chemoattractant protein‐1 levels were measured. The clinical activity of patients with rheumatoid arthritis was assessed according to the 28 joint count Disease Activity Score (DAS28).
Resistin was detected in the synovium in both rheumatoid arthritis and osteoarthritis. Staining in the sublining layer was more intensive in patients with rheumatoid arthritis compared with those with osteoarthritis. In rheumatoid arthritis, macrophages (CD68), B lymphocytes (CD20) and plasma cells (CD138) but not T lymphocytes (CD3) showed colocalisation with resistin. Synovial fluid resistin was higher in patients with rheumatoid arthritis than in those with SpA or osteoarthritis (both p<0.001). In patients with rheumatoid arthritis and SpA, serum resistin levels were higher than those with osteoarthritis (p<0.01). Increased serum resistin in patients with rheumatoid arthritis correlated with both CRP (r = 0.53, p<0.02), and DAS28 (r = 0.44, p<0.05), but not with selected (adipo) cytokines.
The upregulated resistin at local sites of inflammation and the link between serum resistin, inflammation and disease activity suggest a role for resistin in the pathogenesis of rheumatoid arthritis.
PMCID: PMC1856051  PMID: 17040961
3.  Serum resistin levels in critically ill patients are associated with inflammation, organ dysfunction and metabolism and may predict survival of non-septic patients 
Critical Care  2009;13(3):R95.
Blood glucose levels and insulin resistance in critically ill patients on admission to intensive care units (ICUs) have been identified as factors influencing mortality. The pathogenesis of insulin resistance (IR) in critically ill patients is complex and not fully understood. Resistin is a hormone mainly derived from macrophages in humans and from adipose tissue in rodents, which regulates glucose metabolism and insulin sensitivity. In non-critically ill patients, resistin was found to be related to impaired glucose tolerance, insulin resistance, metabolic syndrome, obesity and type 2 diabetes. Therefore, resistin might represent a link between inflammation, acute phase response and insulin resistance in critically ill patients. We aimed to examine the correlation of serum resistin concentrations to parameters of inflammation, organ function, metabolism, disease severity and survival in critically ill patients.
On admission to the Medical ICU, 170 patients (122 with sepsis, 48 without sepsis) were studied prospectively and compared with 60 healthy non-diabetic controls. Clinical data, various laboratory parameters, metabolic and endocrine functions as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately three years.
Resistin serum concentrations were significantly elevated in all critical care patients compared with healthy controls, and significantly higher in sepsis than in non-sepsis patients. Serum resistin concentrations were not associated with pre-existing type 2 diabetes or obesity. For all critically ill patients, a correlation to the homeostasis model assessment index of insulin resistance (HOMA-IR) was shown. Serum resistin concentrations were closely correlated to inflammatory parameters such as C-reactive protein, leukocytes, procalcitonin, and cytokines such as IL6 and TNF-α, as well as associated with renal failure and liver synthesis capacity. High resistin levels (> 10 ng/ml) were associated with an unfavourable outcome in non-sepsis patients on ICU and the overall survival.
Serum resistin concentrations are elevated in acute inflammation due to sepsis or systemic inflammatory response syndrome (SIRS). The close correlation with other acute phase proteins suggests a predominant, clinically relevant resistin release from macrophages in ICU patients. Moreover, resistin could potentially serve as a prognostic biomarker in non-sepsis critically ill patients.
PMCID: PMC2717467  PMID: 19545363
4.  The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis 
BMC Gastroenterology  2014;14:39.
The relationship between resistin and non-alcoholic steatohepatitis (NASH) is not clear, some studies claimed that serum resistin levels were associated with neither the presence of NASH nor its severity, others declared that serum resistin was related with inflammation and fibrosis in NASH. Our animal study verified that the distribution of resistin in the liver is correlated with inflammation in NASH. However, there is no pertinent study in humans.
Thirty patients with NASH, 28 simple steatosis, and 43 controls were recruited. Blood was collected for resistin, liver chemistries, fasting insulin and some metabolic parameters. Liver histology was scored according to NAFLD activity scoring system. Hepatic resistin expression was examined by real-time polymerase chain reaction, immunohistochemistry. Resistin protein expression was confirmed by western blotting in 13 patients with concomitant NAFLD and gallstone.
Serum resistin was significantly elevated in both NASH and simple steatotic subjects compared with controls (all P < 0.05). Hepatic resistin was significantly increased in NASH patients in both mRNA and protein levels than those in simple steatosis and control subjects (all P < 0.05). Both serum and hepatic resistin had a correlation with obesity, but not with insulin resistance. The distribution of resistin positive cells was predominantly in perisinusoidal cells (such as Kupffer cells and hepatic stellate cells) in human NASH. Multivariate analysis revealed that waist-hip ratio, higher serum triglyceride, and hyperresistinemia were independent factors related to higher grade of steatosis; whereas hepatic resistin and serum cytokeratin predict NASH and severity of liver fibrosis.
Hepatic resistin overexpression in NASH patients is associated with the severity of liver inflammation and fibrosis. Liver-derived resistin may be involved in the pathogenesis of human NASH.
PMCID: PMC3942781  PMID: 24559185
Resistin; Nonalcoholic steatohepatitis; Nonalcoholic fatty liver disease; Inflammation; Adipokine
5.  Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden 
PLoS Pathogens  2015;11(1):e1004579.
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg− mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
Author Summary
Parasitic helminths, which infect an estimated two billion people worldwide, represent a significant global public health problem. Infection is associated with life-long morbidity including growth retardation and organ failure. Despite these debilitating conditions, there are currently no successful vaccines against helminths. Further, great variability in the host immune response to helminths exists, with the ability of some individuals to develop immunity, while others are susceptible when re-exposed or maintain life-long chronic infections. Identifying new factors that are differentially expressed in immune versus susceptible individuals could provide new targeting strategies for diagnosis or treatment of helminth infection. Here, we identify an important immunoregulatory function for human resistin in helminth infection. Employing transgenic mice in which the human resistin gene was inserted, we show that human resistin is induced by infection with the helminth Nippostrongylus brasiliensis, where it promotes excessive inflammation and impedes parasite killing. Moreover, analysis of clinical samples from two cohorts of individuals infected with filarial nematodes or soil-transmitted helminths revealed increased resistin and serum proinflammatory cytokines compared to putatively immune individuals. Together, these studies suggest that human resistin is a detrimental cytokine that is expressed in multiple helminth infections, mediates pathogenic inflammation, and delays parasite clearance.
PMCID: PMC4287580  PMID: 25568944
6.  Inflammatory Induction of Human Resistin Causes Insulin Resistance in Endotoxemic Mice 
Diabetes  2011;60(3):775-783.
Although adipocyte-derived murine resistin links insulin resistance to obesity, the role of human resistin, predominantly expressed in mononuclear cells and induced by inflammatory signals, remains unclear. Given the mounting evidence that obesity and type 2 diabetes are inflammatory diseases, we sought to determine the relationship between inflammatory increases in human resistin and insulin resistance.
To investigate the role of human resistin on glucose homeostasis in inflammatory states, we generated mice lacking murine resistin but transgenic for a bacterial artificial chromosome containing human resistin (BAC-Retn), whose expression was similar to that in humans. The metabolic and molecular phenotypes of BAC-Retn mice were assessed after acute and chronic endotoxemia (i.e., exposure to inflammatory lipopolysaccharide).
We found that BAC-Retn mice have circulating resistin levels within the normal human range, and similar to humans, lipopolysaccharide markedly increased serum resistin levels. Acute endotoxemia caused hypoglycemia in mice lacking murine resistin, and this was attenuated in BAC-Retn mice. In addition, BAC-Retn mice developed severe hepatic insulin resistance under chronic endotoxemia, accompanied by increased inflammatory responses in liver and skeletal muscle.
These results strongly support the role of human resistin in the development of insulin resistance in inflammation. Thus, human resistin may link insulin resistance to inflammatory diseases such as obesity, type 2 diabetes, and atherosclerosis.
PMCID: PMC3046838  PMID: 21282361
7.  Resistin is not an appropriate biochemical marker to predict severity of acute pancreatitis: A case-controlled study 
World Journal of Gastroenterology : WJG  2014;20(41):15351-15357.
AIM: To assess levels of serum resistin upon hospital admission as a predictor of acute pancreatitis (AP) severity.
METHODS: AP is both a common and serious disease, with severe cases resulting in a high mortality rate. Several predictive inflammatory markers have been used clinically to assess severity. This prospective study collected data from 102 patients who were diagnosed with an initial acute biliary pancreatitis between March 2010 and February 2013. Measurements of body mass index (BMI) and waist circumference (WC) were obtained and serum resistin levels were analyzed at the time of hospital admission using enzyme-linked immunosorbent assay. Additionally, resistin levels were measured from a control group after matching gender, BMI and age.
RESULTS: A total of 102 patients (60 females and 42 males) were diagnosed with acute gallstone-induced pancreatitis. The mean age was 45 years, and mean BMI value was 30.5 kg/m2 (Obese, class I). Twenty-two patients (21.6%) had severe AP, while eighty-eight patients had mild pancreatitis (78.4%). Our results showed that BMI significantly correlated with pancreatitis severity (P = 0.007). Serum resistin did not correlate with BMI, weight or WC. Furthermore, serum resistin was significantly higher in patients with AP compared to control subjects (P < 0.0001). The mean resistin values upon admission were 17.5 ng/mL in the severe acute biliary pancreatitis group and 16.82 ng/mL in the mild AP group (P = 0.188), indicating that resistin is not an appropriate predictive marker of clinical severity.
CONCLUSION: We demonstrate that obesity is a risk factor for developing severe AP. Further, although there is a correlation between serum resistin levels and AP at the time of hospital admission, resistin does not adequately serve as a predictive marker of clinical severity.
PMCID: PMC4223269  PMID: 25386084
Acute pancreatitis; Resistin; Body mass index; Waist circumference
8.  Increased Resistin Levels in Intra-abdominal Sepsis 
Resistin, a hormone secreted from adipocytes and considered to be a likely cause of insulin resistance, has recently been accepted as a proinflammatory cytokine. This study aimed to determine the correlation between resistin levels in patients with intra-abdominal sepsis and mortality.
Of 45 patients with intra-abdominal sepsis, a total of 35 adult patients were included in the study. This study was undertaken from December 2011 to December 2012 and included patients who had no history of diabetes mellitus and who were admitted to the general surgery intensive care units of Gazi University and Bülent Ecevit University School of Medicine, Turkey. Evaluations were performed on 12 patients with sepsis, 10 patients with severe sepsis, 13 patients with septic shock and 15 healthy controls. The patients’ plasma resistin, interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), procalcitonin, lactate and glucose levels and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were studied daily for the first five days after admission. A correlation analysis of serum resistin levels with cytokine levels and APACHE II scores was performed.
Serum resistin levels in patients with sepsis were significantly higher than in the healthy controls (P <0.001). A significant correlation was found between serum resistin levels and APACHE II scores, serum IL-6, IL-1β, TNF-α, procalcitonin, lactate and glucose levels. Furthermore, a significant correlation was found between serum resistin levels and all-cause mortality (P = 0.02).
The levels of resistin were significantly positively correlated with the severity of disease and were a possible mediator of a prolonged inflammatory state in patients with intra-abdominal sepsis.
PMCID: PMC4205063  PMID: 25364554
Resistin; Systemic Inflammatory Response Syndrome; Sepsis; Shock; Cytokines; APACHE II; Intra-Abdominal Infections
9.  Relationship between resistin level in serum and acute coronary syndrome or stable angina pectoris*  
Objective: To investigate the relationship between serum resistin level and acute coronary syndrome (ACS) or stable angina pectoris (SAP). Methods: Sixty-five patients, with coronary artery disease, were enrolled and divided into three subgroups: acute myocardial infarction (AMI), unstable angina pectoris (UAP) and SAP, and 26 healthy people were recruited as controls in the cross-sectional study. Serum resistin levels were determined by ELISA (enzyme-linked immunosorbent assay), and WBC (white blood cell count), hsCRP (high sensitive C-reaction protein), CKmax (maximum of creatinkinase), CK-MBmax (maximum of isozyme of creatinkinase) and cTnImax (maximum of troponin) were measured by standard laboratory methods. Results: The serum resistin levels were 4 folds higher in AMI patients, 2.43 folds in UAP patients and 1.12 folds in SAP patients than in the healthy controls (P<0.05). The resistin levels were also significantly different between AMI [(8.16±0.79) ng/ml], UAP [(5.59±0.75) ng/ml] and SAP [(3.45±0.56) ng/ml] groups (P<0.01); WBC, hsCRP, CKmax, CK-MBmax and cTnImax were significantly increased in AMI patients over UAP and SAP patients. Spearman analysis showed that serum resistin levels were positively correlated with WBC (r=0.412, P=0.046), hsCRP (r=0.427, P=0.037), CKmax, CK-MBmax and cTnImax (r=0.731, 0.678, 0.656; P<0.01). Conclusion: Serum resistin levels increased with inflammatory factors and myocardial impairment. The results suggest that human resistin might play an important role in the pathogenesis of atherosclerosis and AMI as an inflammatory factor.
PMCID: PMC2100158  PMID: 18257120
Resistin; Acute coronary syndrome (ACS); Stable angina pectoris (SAP)
10.  Serum resistin is associated with C-reactive protein and LDL- cholesterol in type 2 diabetes and coronary artery disease in a Saudi population 
Resistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease.
One hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean ± SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean ± SD) 8.1 Kgm2 median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD).
Serum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R2 0.045).
The findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.
PMCID: PMC1183229  PMID: 15998471
type 2 diabetes; Coronary Artery disease; resistin; C-reactive protein
11.  Serum resistin levels may be new prognostic factor of crimean-congo hemorrhagic fever 
Crimean-Congo hemorrhagic fever (CCHF) virus can cause potentially fatal infections in humans. During this disease, cytokines are intensive released. Resistin which is a good marker of inflammation is an adipocytokine released from adipose tissue. We aimed to investigate whether serum resistin level in patients with CCHF has a prognostic value in predicting recovery time. Twenty men and 22 women (a total of 42 CCHF patients) and a similar age group of 40 healthy individuals (16 men and 24 women) were included in the study. Hematologic tests, serum resistin level, C-reactive protein (CRP) and others biochemical values of all the two group subjects were evaluated. Multivariate logistic regression analysis was performed. Resistin level of patients with CCHF was higher than the controls (1252.6±864.7 ng/ml vs. 824.1±224.6 ng/ml, p=0.003). There was strongly association among recovery time, increased resistin level (p < 0.001), prothrombin time (PT) (p < 0.001), INR (p < 0.001), decreased white blood cell count (WBC) (p=0.012) and lower platelet counts (p=0.007). Serum resistin level is significantly elevated in CCHF patients. Resistin level may be a good prognostic factor to predict recovery time in patients with CCHF.
PMCID: PMC4238463  PMID: 25419394
Crimean-Congo hemorrhagic fever; resistin; cytokines; C-reactive protein
12.  Role of resistin as a marker of inflammation in systemic lupus erythematosus 
Resistin is a cystein-rich secretory adipokine. It is proposed to have proinflammatory properties in humans. The aim of this study was to determine associations between serum levels of resistin and markers of inflammation and bone mineral density (BMD) in female patients with systemic lupus erythematosus (SLE).
One hundred sixty-three female patients with SLE (20 to 82 years old) were examined in a cross-sectional study. Venous blood samples were analyzed for resistin, erythrocyte sedimentation rate (ESR), C-reactive protein, creatinine, fasting lipids, complements, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, sIL-6R (soluble IL-6 receptor), ICTP (C-terminal telopeptide of type I collagen), and PINP (N-terminal propeptide of type I procollagen). Simple and multiple regression analyses as well as logistic regression analyses were performed. Resistin in serum was compared with 42 healthy female controls with respect to age.
Serum resistin levels in controls were similar to those of patients with SLE. Markers of inflammation and current dose of glucocorticosteroids correlated positively to resistin in serum. Markers of renal function, number of prevalent vertebral fractures, and BMD were also significantly associated with resistin. In a multiple regression model, ESR, creatinine, C3, current glucocorticosteroid dose, high-density lipoprotein, and BMD radius remained significantly associated with resistin. In logistic regression analyses with resistin as the independent variable, a significant association was found with ESR (normal or elevated) but not with S-creatinine or z score for hip and radius total.
Although resistin measurements did not differ between patients and controls, resistin was clearly associated with general inflammation, renal disease, treatment with glucocorticosteroids, and bone loss. We hypothesize that resistin has proinflammatory and disease-promoting properties in SLE. Further studies are needed to elucidate the mechanism behind these associations.
PMCID: PMC2374439  PMID: 18234104
13.  Putative Roles of Circulating Resistin in Patients with Asthma, COPD and Cigarette Smokers 
Disease markers  2011;31(1):1-7.
Aims: To investigate the hypothesis that circulating resistin reflects the degree of pulmonary inflammation, this study explores putative roles of resistin in patients with acute and stable inflammatory obstructive airway diseases and cigarette smokers.
Methods: We determined complements C3, C4, fasting resistin, insulin, glucose and lipid profile; calculated insulin resistance (homeostasis model assessment (HOMA-IR) in patients with acute asthma exacerbation (n = 34); stable asthma (n = 26) and stable chronic obstructive pulmonary disease (COPD; n = 26), cigarette smokers (n = 81), and healthy control subjects (n = 42). We determined the associations between these variables and pulmonary function tests.
Results: Patients with COPD, acute and stable asthma had significantly higher resistin and insulin than control subjects. Resistin, insulin, HOMA-IR, FEV1% and FEV1/FVC were significantly (p < 0.05) different between patients with acute asthma compared with stable asthma and COPD; smokers had similar levels of resistin, C3 and C4 as patients with asthma and COPD. In smokers, patientswith asthma or COPD, resistin showed significant inverse correlations with FEV1%; FEV1/FVC% and positive significant correlations with BMI and HOMA-IR. Logistic regression showed that resistin is associated (p < 0.05) with inflammatory obstructive airways disease − odds ratio (OR) = 1.22 and smoking OR = 1.18.
Conclusion: Resistin may be a disease activity marker and may contribute to insulin resistance in smokers, asthma and COPD.
PMCID: PMC3826866  PMID: 21846943
Asthma; chronic obstructive pulmonary diseases; insulin resistance; resistin; smokers
14.  Measurement of Salivary Resistin Level in Patients with Type 2 Diabetes 
Serum resistin was initially hypothesized as a link between obesity and insulin resistance in mice. The latest evidence suggests that serum resistin is proinflammatory cytokines. Inflammation plays a key role in the pathogenesis of type 2 diabetes mellitus (T2DM). Many reports have previously identified changed serum resistin levels in patients with T2DM, but little is known of the levels of resistin in saliva. In our study, saliva and serum samples were collected from 38 patients with newly diagnosed T2DM at each time point of OGTT and 35 nondiabetic controls at fasting state. Resistin concentrations were measured using ELISA. We have demonstrated the presence of resistin in saliva of T2DM and nondiabetic subjects. Saliva resistin levels of T2DM are significantly higher than those of nondiabetic controls. Resistin levels in saliva are not affected by eating activity and correlated with serum resistin levels at any time points of OGTT. A positive correlation of serum and salivary resistin with BMI and HOMA-IR existed in T2DM. Measurement of resistin in saliva is a simple, noninvasive and may be an acceptable alternative to blood sampling for evaluatinginflammation/obesity/insulin resistance state.
PMCID: PMC3437284  PMID: 22969799
15.  An Inflammatory Cascade Leading to Hyperresistinemia in Humans 
PLoS Medicine  2004;1(2):e45.
Obesity, the most common cause of insulin resistance, is increasingly recognized as a low-grade inflammatory state. Adipocyte-derived resistin is a circulating protein implicated in insulin resistance in rodents, but the role of human resistin is uncertain because it is produced largely by macrophages.
Methods and Findings
The effect of endotoxin and cytokines on resistin gene and protein expression was studied in human primary blood monocytes differentiated into macrophages and in healthy human participants.
Inflammatory endotoxin induced resistin in primary human macrophages via a cascade involving the secretion of inflammatory cytokines that circulate at increased levels in individuals with obesity. Induction of resistin was attenuated by drugs with dual insulin-sensitizing and anti-inflammatory properties that converge on NF-κB. In human study participants, experimental endotoxemia, which produces an insulin-resistant state, causes a dramatic rise in circulating resistin levels. Moreover, in patients with type 2 diabetes, serum resistin levels are correlated with levels of soluble tumor necrosis factor α receptor, an inflammatory marker linked to obesity, insulin resistance, and atherosclerosis.
Inflammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inflammatory states.
Inflammatory stimuli affect resistin expression in human macrophages and raise serum resistin levels in healthy volunteers
PMCID: PMC529430  PMID: 15578112
16.  Peripheral Mononuclear Cell Resistin mRNA Expression Is Increased in Type 2 Diabetic Women 
Mediators of Inflammation  2008;2008:892864.
Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were all significantly higher in DM2 compared to control women (P < .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1β, TNF-α, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients.
PMCID: PMC2606019  PMID: 19125180
17.  Resistin in Rodents and Humans 
Diabetes & Metabolism Journal  2013;37(6):404-414.
Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease.
PMCID: PMC3881324  PMID: 24404511
Adipocytes; Atherosclerosis; Cardiovascular diseases; Diabetes mellitus, type 2; Inflammation; Insulin resistance; Macrophages; Obesity; Polymorphism, genetic; Resistin
18.  Resistin mediates the hepatic stellate cell phenotype 
AIM: To describe the role of resistin in liver fibrosis.
METHODS: For the in vivo animal study, Sprague Dawley rats were subjected to bile duct ligation (BDL) for 4 wk. Rat liver, adipose tissue (epididymal fat) and serum were analyzed for resistin expression. For the in vitro experiment, rat primary hepatic stellate cells (HSCs) and Kupffer cells (KCs) were used. HSCs were exposed to recombinant resistin, and collagen I, transforming growth factor β1, α smooth muscle actin, tissue inhibitor of metalloproteinase 1 and connective tissue growth factor expression were analyzed. Resistin gene and protein expression was quantified as was the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1). The effects of resistin on HSC proliferation, migration and apoptosis were determined. The effects of resistin on KCs were also investigated.
RESULTS: Following BDL, rat epididymal fat and serum rather than liver showed higher resistin expression compared to control rats. In liver, resistin was expressed in quiescent HSCs and KCs. Resistin treatment resulted in enhancement of TNFα, IL-6, IL-8 and MCP-1 gene expression and increased IL-6 and MCP-1 protein in HSCs. Resistin activated HSC phospho-MAPK/p38, and p38 inhibition diminished IL-6 and MCP-1 expression. Furthermore, resistin facilitated HSC proliferation and migration, but decreased apoptosis which was via an IL-6 and MCP-1 mechanism. Finally, resistin-induced transforming growth factor β1 from KCs enhanced HSC collagen Iexpression.
CONCLUSION: Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.
PMCID: PMC3725371  PMID: 23901222
Resistin; Hepatic stellate cell; Kupffer cell; Liver fibrosis; Monocyte chemotactic protein-1
19.  Increased resistin in brain dead organ donors is associated with delayed graft function after kidney transplantation 
Resistin increases during several inflammatory diseases and after intracerebral bleeding or head trauma. Resistin activates the endothelium and may initiate an inflammatory response. No data are available on resistin in brain dead donors (DBD) that regularly manifest a pronounced inflammatory state.
We analyzed plasma resistin in 63 DBDs and correlated results with donor variables and the postoperative course following kidney transplantation using organs from these donors. Endocan and monocyte chemotactic protein (MCP)-1 were also studied. Twenty-six live kidney donors (LD) and the corresponding kidney transplantations were used as controls.
DBDs had higher resistin (median/range 30.75 ng/ml, 5.41–173.6) than LD (7.71 ng/ml, 2.41–15.74, p < 0.0001). Resistin in DBD correlated with delayed graft function (DGF) in the kidney recipients (r = 0.321, p < 0.01); receiver operating characteristic curve revealed an area under the curve of 0.765 (95% confidence interval [CI] 0.648–0.881, p < 0.01) and a cut-off value for resistin of 25 ng/ml; MCP-1 and endocan were higher in DBDs (p < 0.0001) but did not correlate with DGF or acute rejection. No relationship was found between the studied molecules and the postoperative course of LD kidney transplants.
High resistin levels in the DBD before organ retrieval are associated with DGF after kidney transplantation. The resistin increase seems related to the inflammatory state after brain death but not to the cause of death.
PMCID: PMC3849100  PMID: 24070260
20.  Sirt1 Inhibits Resistin Expression in Aortic Stenosis 
PLoS ONE  2012;7(4):e35110.
The development of human calcified aortic stenosis (AS) includes age-dependent processes that have been involved in atherosclerosis, such as infiltration of macrophages in aortic valves, which then promote production of many pro-inflammatory cytokines, including resistin. However, the molecular mechanisms contributing to these processes are not established. Since Sirt1 has been shown to modulate macrophage biology and inflammation, we examined its levels in human AS and tested its impact on resistin expression. Sirt1 mRNA (p = 0.01) and protein (p<0.05) levels were reduced in explanted valves from AS patients (n = 51) compared to those from control (n = 11) patients. Sirt1 mRNA levels were negatively associated with resistin mRNA levels quantified in AS valves (p = 0.02). Stimulation of Sirt1 by resveratrol or virus-driven overexpression robustly diminished resistin mRNA and protein expression in macrophages, whereas down-regulation of Sirt1 triggered a large increase in resistin expression. These effects were direct, as chromatin immunoprecipitation assays showed that Sirt1 physically interacted with the resistin promoter region at an AP-1 response element. Moreover, Sirt1 blocked c-jun-induced resistin transactivation in gene reporter assays. These findings demonstrate that, in calcified AS, levels of Sirt1 are reduced whereas those of resistin are increased within aortic valve leaflets. Our results also suggest that this loss of Sirt1 expression alleviates its inhibition of resistin transcription in macrophages. Although the overall contribution of this process to the underlying mechanisms for AS disease development remains unresolved, these observations suggest that modification of Sirt1 expression and/or activity could represent a novel approach against inflammation in AS.
PMCID: PMC3320872  PMID: 22493735
21.  Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease 
Inflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood.
For these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation.
The expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 ± 1.57 μg/mL vs CABG: 9.11 ± 15.7 μg/mL; p < 0.001) and resistin (control: 10.53 ± 0.81 ng/mL vs CABG: 16.8 ± 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 ± 14.8 μg/mL vs CABG: 11.9 ± 6.0 μg/mL; p < 0.05) when compared to BMI matched controls.
Epicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease.
PMCID: PMC1352345  PMID: 16412224
Clinical endocrinology  2011;74(3):294-299.
Both resistin and vitamin D have been associated with the renin-angiotensin-aldosterone system (RAAS). We investigated the association between resistin and the RAAS, and resistin and vitamin D under controlled dietary sodium conditions.
Retrospective cross-sectional study of subjects from the HyperPATH Consortium, who were maintained in high dietary sodium (HS) and low dietary sodium (LS) balance for one week each.
Caucasian subjects with hypertension (n=177).
25-hydroxyvitamin D (25[OH]D) levels were used to assess vitamin D status. Plasma resistin and RAAS measures were evaluated on each dietary intervention.
Resistin levels were significantly higher in LS, where RAAS activity was high, when compared to HS balance, where RAAS activity was suppressed (6.36 vs. 5.86 µg/L, p<0.0001); however, resistin concentrations were not associated with plasma renin activity or serum aldosterone on either diet. 25(OH)D levels were positively and independently associated with resistin in both dietary conditions (HS: β=0.400, p-trend=0.027; LS: β=0.540, p-trend=0.014).
Dietary sodium loading reduced resistin levels, possibly by suppressing the RAAS; however, circulating RAAS components were not related to resistin concentrations within each specific dietary sodium condition. 25(OH)D was positively associated with resistin and may be involved in resistin regulation through an unknown mechanism. Further studies to better understand resistin regulation in human hypertension are warranted.
PMCID: PMC3059847  PMID: 21050256
resistin; renin; angiotensin; sodium; vitamin D
23.  Association of resistin polymorphism, its serum levels and prevalence of stroke in Japanese type 2 diabetic patients 
Aims/Introduction:  Resistin, an inflammatory cytokine, might be involved in the development of atherosclerosis. In a recent paper, we showed that resistin polymorphism might be a risk marker for stroke susceptibility in Japanese type 2 diabetic patients. We tested whether the serum resistin levels might be also a risk marker of stroke independently from RETN polymorphism.
Materials and Methods:  Type 2 diabetic outpatients from our hospitals were enrolled. Patients (n = 89) with a history of coronary heart disease and stroke, and randomly selected controls (n = 178) matched for sex and age, but without a history of coronary heart disease and stroke, were examined for polymorphism ‐420 (C>G) and cytokines levels.
Results:  Serum resistin levels were significantly higher in patients with cardiovascular diseases (CVD) than in those without CVD (P = 0.024), and were highest in patients with stroke among the CVD. In multiple logistic regression analysis, serum resistin levels was an independent risk marker of stroke even after adjusted by RETN polymorphism, age, sex, body mass index, HbA1c, systolic and diastolic blood pressure, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, creatinine, history of coronary heart disease, treatment of insulin, sulfonylurea and aspirin (odds ratio 1.33, 95% confidence interval [CI] 1.02–1.73, P = 0.039). The enrolled patients were divided by their serum resistin levels (high or low group) and their genotypes (CC, CG, GG at ‐420) into six groups. Patients with the GG genotype and high resistin levels showed the highest odds ratio, 5.69 (95% CI 1.24–26.1), compared with the group with CC and low levels.
Conclusions:  The results suggest that serum resistin levels might be a good marker of susceptibility to stroke as well as RETN polymorphism. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.00040.x, 2010)
PMCID: PMC4008008  PMID: 24843425
Resistin; Type 2 diabetes; Stroke
24.  Resistin in serum and gingival crevicular fluid as a marker of periodontal inflammation and its correlation with single-nucleotide polymorphism in human resistin gene at −420 
Contemporary Clinical Dentistry  2013;4(2):192-197.
Resistin is an adipocytokine, which have been studied for its role in insulin resistance and recently in inflammation. The aim of the present study is to assess the concentration of resistin in serum and gingival crevicular fluid (GCF) and to compare the levels between subjects with and without periodontitis and type 2 diabetes mellitus (T2DM) and to further correlate the resistin levels with the single-nucleotide polymorphism (SNP) at −420.
Setting and Designs:
A total of 96 subjects (48 males and 48 females) were divided on the basis of gingival index (GI), probing pocket depth (PD), clinical attachment level (CAL) and hemoglobin A1c levels into healthy (group 1, n = 24), uncontrolled-diabetes related periodontitis (group 2, n = 24), controlled-diabetes related periodontitis (group 3, n = 24) and chronic periodontitis without T2DM (group 4, n = 24).
Materials and Methods:
The GCF and serum levels of resistin were quantified using the enzyme-linked immunosorbent assay and compared among the study groups. Further, the association of the resistin levels with periodontal inflammation and SNP at −420 was studied.
Results and Conclusion:
The resistin levels in GCF and serum from patients with periodontitis or diabetes mellitus related periodontitis (controlled or uncontrolled) were higher than that of healthy subjects and correlated positively with GI. Further, subjects with GG genotype at −420 showed significantly higher GI, PD, CAL as compared with genotype group CC. Resistin was detected in all serum and GCF samples and was significantly higher in periodontitis. Further, GG genotype at −420 was associated significantly with periodontal inflammation and resistin levels.
PMCID: PMC3757881  PMID: 24015008
Biomarker; diabetes mellitus; periodontitis; resistin
25.  Adipokine resistin predicts anti-inflammatory effect of glucocorticoids in asthma 
Adipokines are protein mediators secreted by adipose tissue. Recently, adipokines have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma especially in obese female patients. We assessed if adipokines predict responsiveness to glucocorticoids and if plasma adipokine levels are associated with lung function or inflammatory activity also in non-obese (body mass index (BMI) ≤ 30 kg/m2) women with newly-diagnosed steroid-naïve asthma.
Lung function, exhaled NO, plasma levels of adipokines leptin, resistin, adiponectin and adipsin, and inflammatory markers were measured in 35 steroid-naïve female asthmatics and in healthy controls. The measurements were repeated in a subgroup of asthmatics after 8 weeks of treatment with inhaled fluticasone. Adipokine concentrations in plasma were adjusted for BMI.
High baseline resistin concentrations were associated with a more pronounced decrease in serum levels of eosinophil cationic protein (ECP) (r = -0.745, p = 0.013), eosinophil protein X (EPX) (r = -0.733, p = 0.016) and myeloperoxidase (MPO) (r = -0.721, p = 0.019) during fluticasone treatment. In asthmatics, leptin correlated positively with asthma symptom score and negatively with lung function. However, no significant differences in plasma adipokine levels between non-obese asthmatics and healthy controls were found. The effects of resistin were also investigated in human macrophages in cell culture. Interestingly, resistin increased the production of proinflammatory factors IL-6 and TNF-α and that was inhibited by fluticasone.
High resistin levels predicted favourable anti-inflammatory effect of inhaled glucocorticoids suggesting that resistin may be a marker of steroid-sensitive phenotype in asthma. High leptin levels were associated with a more severe disease suggesting that the link between leptin and asthma is not restricted to obesity.
PMCID: PMC3117675  PMID: 21615949

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