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1.  Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures 
Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.
We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.
Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.
Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.
PMCID: PMC3141565  PMID: 21736747
2.  Relationship Between Plasma Adiponectin, Retinol-Binding Protein 4 and Uric Acid in Hypertensive Patients With Metabolic Syndrome 
Korean Circulation Journal  2011;41(4):198-202.
Background and Objectives
Adipokines have been suggested for their potential use in tracking the clinical progress in the subjects with metabolic syndrome (MS). To investigate the relationship between the serum levels of adipokines {adiponectin and retinol-binding protein 4 (RBP4)} and the serum level of uric acid in hypertensive (HTN) patients with MS.
Subjects and Methods
In this study, 38 totally untreated HTN patients were enrolled. Anthropometric measurements, blood pressure (BP) were taken in the 12 HTN patients without MS and the 26 HTN patients with MS. Fasting blood samples were collected for measurement of adiponectin, RBP4, nitric oxide (NO), glucose, creatinine, uric acid, lipid profile and insulin.
The HTN with MS group had significant higher values of body mass index, waist length, serum uric acid and triglyceride levels than the HTN without MS group. Compared to the HTN without MS group, the HTN with MS group showed significantly lower adiponectin (p=0.030), NO (p=0.003) and high density lipoprotein levels (p<0.001). Serum adiponectin levels negatively correlated with insulin level (R=-0.453, p=0.026) and uric acid level (R=-0.413, p=0.036), and serum RBP4 levels positively correlated with uric acid level (R=0.527, p=0.006) in the HTN with MS group. Multiple linear regression analysis using RBP4 and adiponectin levels as the dependent variables showed that uric acid level correlated with serum RBP4 level (p=0.046) and adiponectin level (p=0.044).
The HTN with MS group showed a correlation with two types of adipokines (adiponectin, RBP4) and uric acid. Adiponectin, RBP4 and uric acid may be important components associated with MS, especially when associated with hypertension.
PMCID: PMC3098412  PMID: 21607170
Adiponectin; Retinol-binding protein 4; Uric acid; Hypertension; Metabolic syndrome
3.  The association of carotid intima media thickness with retinol binding protein-4 and total and high molecular weight adiponectin in type 2 diabetic patients 
The aim of this study was to investigate whether carotid intima media thickness (CIMT) is associated with serum level of retinol- binding protein-4 (RBP4) and total and high molecular weight (HMW) adiponectin in type 2 diabetes (T2DM) without clinical symptom of atherosclerotic disease.
101 type 2 diabetic patients (mean age, 53.63 ± 8.42 years) and 42 body mass index (BMI) matched control (mean age 50.1 ± 8.4) were recruited. The CIMT was assessed by using B-mode ultrasonography, while serum levels of RBP4 and total and HMW adiponectin were measured by using enzyme linked immunosorbant assay (ELISA). Linear regression analysis was performed with CIMT as dependent variable and adipokines and cardio metabolic risk factors as independent variables.
The CIMT was higher in diabetic group compared to control group (p <0.05). The mean concentration of RBP4 and total and HMW adiponectin did not differ between two groups.
Age (B = 0.44 P <0.05), blood pressure (B = 0.37 P = <0.05), waist circumference (B = −0.21 P <0.05) and TG (B = 0.1 P <0.05) were identified as independent predictors for CIMT in diabetic group, while RBP4 and adiponectin were not associated with CIMT neither in diabetic group nor in control group.
In conclusion, the present study showed that serum levels of RBP4 or total and HMW adiponectin were not potential predictors of CIMT in type 2 diabetic patients who exposed to this risk factor at least for nine years.
PMCID: PMC3581102  PMID: 23497488
Carotid intima media thickness; Adipokines; B mode ultrasonography; Enzyme linked immunosorbant assay (ELISA); Type 2 diabetes
4.  Plasma total and high molecular weight adiponectin levels and risk of coronary heart disease in women 
Atherosclerosis  2011;219(1):322-329.
To examine prospectively the association of total and high molecular weight (HMW) adiponectin, and HMW/total adiponectin ratio with risk of incident coronary heart disease (CHD) in women, and to examine to what extent adjustment for potentially intermediary variables would explain this association.
Methods and Results
Among 30,111 women from the Nurses’ Health Study, 468 women developed non-fatal myocardial infarction or fatal CHD during 14 years of follow-up. Using risk set sampling, controls were selected 2:1 matched on age, smoking, and date of blood draw. Adjusted for matching factors, parental history of myocardial infarction, hormone replacement therapy, alcohol consumption, physical activity, body mass index, hypertension, and low-density lipoprotein cholesterol levels, the relative risk in the highest versus lowest quintile was 0.50 (95%-CI 0.33-0.75; p trend=0.001) for total adiponectin, 0.53 (95%-CI 0.35-0.80; p trend=0.004) for HMW adiponectin, and 0.63 (95%-CI 0.43-0.93; p trend=0.03) for HMW/total adiponectin ratio. After adjustment for diabetes, HDL-cholesterol, HbA1c, and CRP these associations were attenuated and no longer significant (RRs, 0.84; 95%-CI 0.53-1.33; p trend=0.62; 0.95; 95%-CI 0.60-1.52; p trend=0.98; 0.97; 95%-CI 0.64-1.47; p trend=0.80).
High levels of total and HMW adiponectin, and HMW/total adiponectin ratio are associated with a lower risk of CHD among women. HMW adiponectin and HMW/total adiponectin ratio are not more closely related to risk than total adiponectin. These associations are largely mediated by parameters related to glucose and lipid metabolism and inflammation, especially HDL-cholesterol levels.
PMCID: PMC3206156  PMID: 21813129
adiponectin; cohort study; coronary disease; epidemiology; risk factors
5.  Distribution of Adiponectin Multimeric Forms In Chinese Women With Polycystic Ovary Syndrome and Their Relation To Insulin Resistance 
Adiponectin, an abundant adipokine with insulin sensitizing properties, exists different multimeric forms, including low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) species. Alterations in the distribution of adiponectin multimers and the relationship between adiponectin multimers and insulin resistance (IR) in women with the polycystic ovary syndrome (PCOS) remain unclear. To compare adiponectin multimerization status and estimate of insulin sensitivity in Chinese women with PCOS compared with age and body mass index (BMI)-matched controls.
Cross-sectional study involving 64 Chinese women with PCOS and 59 normal women. Circulating total adiponectin and its multimeric forms were determined by ELISA and insulin resistance was estimated using the homeostasis assessment insulin resistance index (HOMA-IR).
After controlling for BMI status, levels of both total and HMW adiponectin were significantly lower in women with PCOS compared with normal women (P<0.05). Furthermore, HMW adiponectin provided a stronger contribution to models predicting insulin resistance than total adiponectin. Lastly, decreased HMW adiponectin was associated with increased HOMA-IR in both normal and PCOS women, and this association was independent of both overall adiposity and visceral adiposity.
Levels of both total and HMW adiponectin are decreased in Chinese women with PCOS compared with normal control women and the differences in HMW adiponectin persists after controlling for BMI. Furthermore, HMW adiponectin is a stronger predictor of insulin resistance in both women with PCOS and normal women than total adiponectin.
PMCID: PMC3683393  PMID: 20530094
Polycystic ovary syndrome; adiponectin; insulin resistance; HMW-adiponectin
6.  Relationships between lipid profiles and metabolic syndrome, insulin resistance and serum high molecular adiponectin in Japanese community-dwelling adults 
There are few studies to demonstrate the associations between newly addressed lipid profiles and metabolic syndrome (MetS)-associated variables.
Study participants without medications for hypertension, diabetes, or dyslipidemia {614 men aged 58 ± 14 (mean ± standard deviation; range, 20-89) years and 779 women aged 60 ± 12 (range, 21-88) years} were randomly recruited from a single community at the time of their annual health examination. The association between lipid profiles (total cholesterol (T-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, T-C/HDL-C, TG/HDL-C, LDL-C/HDL-C ratio and MetS, Insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR), and serum HMW adiponectin were analyzed.
In multiple linear regression analysis, TG/HDL-C and T-C/HDL-C ratios as well as TG showed significantly strong associations with all three MetS-associated variables in both men and women. In men, the ROC curve analyses showed that the best marker for these variables was TG/HDL-C ratio, with the AUC for presence of MetS (AUC, 0.82; 95% CI, 0.77-0.87), HOMA-IR (AUC, 0.75; 95% CI, 0.70-0.80), and serum HMW adiponectin (AUC, 0.67; 95% CI, 0.63-0.71), respectively. The T-C/HDL-C ratio, TG, HDL-C, LDL-C/HDL-C ratio, and non-HDL-C also discriminated these markers; however all their AUC estimates were lower than TG/HDL-C ratio. These results were similar in women.
In Japanese community-dwelling adults, lipid ratios of TG/HDL-C, T-C/HDL-C, LDL-C/HDL-C as well as TG and HDL-C were consistently associated with MetS, insulin resistance and serum HMW adiponectin. Lipid ratios may be used as reliable markers.
PMCID: PMC3118370  PMID: 21586120
7.  Association of Adiponectin Gene Polymorphism with Adiponectin Levels And Risk for Insulin Resistance Syndrome 
Adiponectin is an abundant adipose tissue–derived protein with anti-atherogenic, anti-inflammatory and antidiabetic properties. Plasma adiponectin levels are decreased in obesity, type 2 diabetes, and coronary artery disease and low adiponectin levels also predict insulin resistance (IR).
Case-control study in which 642 male and female subjects were participated from the North Indian population. Lipid, insulin, leptin and adiponectin level were estimated using standard protocols by commercially available test kits. Single nucleotide polymorphisms +45T>G and +276G>T of the AMP1 (adiponectin) gene was genotyped by polymerase chain reaction restriction fragment length polymorphism method.
Levels of adiponectin, insulin, homeostasis model assessment-IR index (HOMA-IR index), systolic blood pressure and fat mass showed significant differences between male and female subjects. Serum adiponectin level showed highly significant association with both the +45 and the +276 genotypes. The common haplotype triglyceride (TG) showed a significantly lower adiponectin value than other haplotypes (P = 0.0001). A clear trend of decreasing adiponectin levels per copy of the common haplotype was observed. Nonobese insulin sensitive subjects showed a higher adiponectin value (P = 0.0006) than nonobese insulin resistant subjects. The values of blood pressure, adiponectin, insulin, HOMA-IR, total-cholesterol, and low-density lipoprotein-cholesterol significantly associated with TG haplotype.
We observed the very strong association of the adiponectin 45-276 genotypes and haplotypes with adiponectin levels in healthy north Indian population and TG haplotypes also associated with metabolic parameters of the IR syndrome.
PMCID: PMC4410438  PMID: 25949781
Adiponectin; AMP1; haplotype; insulin resistance; polymorphism
8.  C-Reactive Protein, High-Molecular-Weight Adiponectin and Development of Metabolic Syndrome in the Japanese General Population: A Longitudinal Cohort Study 
PLoS ONE  2013;8(9):e73430.
To clarify predictive values of C-reactive protein (CRP) and high-molecular-weight (HMW) adiponectin for development of metabolic syndrome.
Research Design and Methods
We conducted a prospective cohort study of Japanese workers who had participated in an annual health checkup in 2007 and 2011. A total of 750 subjects (558 men and 192 women, age 46±8 years) who had not met the criteria of metabolic syndrome and whose CRP and HMW-adiponectin levels had been measured in 2007 were enrolled in this study. Associations between CRP, HMW-adiponectin and development of metabolic syndrome after 4 years were assessed by logistic regression analysis and their predictive values were compared by receiver operating characteristic analysis.
Among 750 subjects, 61 (8.1%) developed metabolic syndrome defined by modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria and 53 (7.1%) developed metabolic syndrome defined by Japan Society for the Study of Obesity (JASSO) in 2011. Although CRP and HMW-adiponectin were both significantly correlated with development of metabolic syndrome, multivariate logistic regression analysis revealed that HMW-adiponectin but not CRP was associated with metabolic syndrome independently of BMI or waist circumference. Adding these biomarkers to BMI or waist circumference did not improve the predictive value for metabolic syndrome.
Our findings indicate that the traditional markers of adiposity such as BMI or waist circumference remain superior markers for predicting metabolic syndrome compared to CRP, HMW-adiponectin, or the combination of both among the Japanese population.
PMCID: PMC3772031  PMID: 24069195
9.  Circulating HMW adiponectin isoform is heritable and shares a common genetic background with insulin resistance in non diabetic White Caucasians from Italy: evidence from a family-based study 
Journal of internal medicine  2009;267(3):287-294.
Reduced circulating adiponectin levels contribute to the etiology of insulin-resistance. Adiponectin circulates in three different isoforms: high (HMW), medium (MMW), and low (LMW) molecular weight. The genetics of adiponectin isoforms is mostly unknown. Our aim was to investigate whether and to which extent circulating adiponectin isoforms are heritable and whether they share common genetic backgrounds with insulin resistance-related traits.
In a family based sample of 640 non diabetic White Caucasians from Italy, serum adiponectin isoforms concentrations were measured by ELISA. Three SNPs in the ADIPOQ gene previously reported to affect total adiponectin levels (rs17300539, rs1501299 and rs677395) were genotyped. The heritability of adiponectin isoform levels was assessed by variance component analysis. A linear mixed effects model was used to test association between SNPs and adiponectin isoforms. Bivariate analyses were conducted to study genetic correlations between adiponectin isoforms levels and other insulin resistance-related traits.
All isoforms were highly heritable (h2=0.60−0.80, p=1×10−13–1×10−23). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2–9%, p=1×10−3–1×10−5). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (p=3×10−4 and 2.0×10−2). Significant genetic correlations (p=1×10−2–1×10−5) were observed between HMW adiponectin and fasting insulin, HOMAIR, HDL-cholesterol and the metabolic syndrome score. Only rs1501299 partly accounted for these genetic correlations.
Circulating levels of adiponectin isoforms are highly heritable. The genetic control of HMW adiponectin is shared in part with insulin resistance-related traits and involves, but is not limited to the ADIPOQ locus.
PMCID: PMC2833228  PMID: 19761474
ADIPOQ gene; Adiponectin isoforms; insulin resistance
10.  High Molecular Weight (HMW): total adiponectin ratio is low in hiv-infected women receiving protease inhibitors 
At the time of the study, the HIV-treatment policy in South Africa included highly active antiretroviral therapy (HAART) regimens 1 (nucleotide reverse transcriptase inhibitors (NRTIs) only), and 2 (protease inhibitors (PI) and NRTIs). HAART is associated with the lipodystrophy syndrome, insulin resistance and reduced total adiponectin (TA) levels. The high molecular weight (HMW):TA ratio is a superior marker of insulin resistance. The aim of this study was to establish whether HMW:TA ratios are low in patients on PIs and whether they correlate with insulin resistance.
This was a cross-sectional study undertaken in an antiretroviral clinic at a tertiary hospital. The participants were 66 HIV-infected females: 22 were on regimen 2 (PI group), 22 on regimen 1 (non-PI) and 22 treatment naïve (TN), matched for BMI and age. Patients with a history of diabetes or impaired glucose tolerance were excluded. Serum adiponectin multimers were analysed using the AlpcoTM Adiponectin (Multimeric) enzyme immunoassay. Waist hip ratios (WHR), glucose and insulin levels were assessed, and HOMA-IR and QUICKI calculated. Data were analysed non-parametrically and multivariate analysis was performed.
TA and HMW levels were lower in the treatment groups than in the TN group. HMW:TA was lower in the PI than in the non-PI and TN groups, and in the non-PI than in the TN groups. HMW:TA correlated negatively with waist, insulin and HOMA-IR, independently of BMI and duration of therapy. HOMA-IR and QUICKI did not differ among the groups.
HMW:TA is significantly decreased with HAART (particularly with PIs, but also with non-PIs) and may be a more sensitive marker of insulin resistance in these patients than conventional markers or HMW and total adiponectin individually.
PMCID: PMC4289558  PMID: 25580091
HMW adiponectin; Lipodystrophy syndrome; HMW: adiponectin ratio; Protease inhibitors; Insulin resistance
11.  Ovarian HMW adiponectin is associated with folliculogenesis in women with polycystic ovary syndrome 
Adiponectin may regulate ovarian steroidogenesis, folliculogenesis and ovulation. The alterations in the distribution of adiponectin multimers in follicular fluid (FF) and the relationship between adiponectin multimers and folliculogenesis in women with polycystic ovary syndrome (PCOS) remain unclear. In this study, we aimed to investigate the association between the levels of total and high molecular weight (HMW) adiponectin in serum and FF and folliculogenesis in women undergoing in vitro fertilisation (IVF).
This prospective study included ten Chinese women with PCOS and ten controls undergoing IVF. The levels of the total and HMW adiponectin in serum and FF were determined by ELISA. Insulin resistance (IR) was estimated using the homeostasis model assessment insulin resistance index (HOMA-IR).
After controlling for the body mass index (BMI), the levels of the total, and the HMW adiponectin in the serum and FF were significantly lower in the women with PCOS compared with the normovulatory women undergoing IVF (P < 0.05). The levels of the HMW adiponectin were significantly lower in the FF than in the serum (P < 0.01). No significant differences were found in the total adiponectin levels in the serum and in the FF (P > 0.05). Decreased HMW adiponectin in the FF was associated with an increased number of follicles and decreased follicular diameters in the normovulatory and PCOS women, and this association was independent of the overall adiposity. A strong positive linear correlation was observed between the number of the follicles and the IR estimated by HOMA-IR (r = 0.784, P < 0.0001). We found that the larger follicular diameters had a negative relationship with the IR estimated by HOMA-IR (r = −0.445, P < 0.05). A strong negative linear correlation was observed between HOMA-IR and the HMW adiponectin levels (r = −0.726, P < 0.001) and the total adiponectin levels (r = −0.759, P < 0.001) in the FF.
The levels of the total adiponectin and the HMW adiponectin in the FF and serum were decreased in the Chinese women with PCOS compared with the normovulatory women undergoing IVF, and the differences persisted after controlling for the BMI. Ovarian HMW adiponectin is negatively correlated to folliculogenesis.
PMCID: PMC4015744  PMID: 24144083
Polycystic ovary syndrome; Adiponectin multimers; Follicular fluid; In vitro fertilisation; Folliculogenesis
12.  Total and High-Molecular-Weight Adiponectin and Risk of Incident Diabetes in Older People 
Diabetes Care  2012;35(2):415-423.
To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.
Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.
Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.
In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.
PMCID: PMC3263897  PMID: 22148099
13.  High Molecular Weight Adiponectin and Incident Ischemic Stroke in Postmenopausal Women: A Women’s Health Initiative Study 
Background and Purpose
While low levels of adiponectin are associated with coronary heart disease and cardiovascular disease (CVD) risk factors, it is unclear whether adiponectin levels are related to the risk of developing ischemic stroke.
We examined the relationship between baseline high molecular weight (HMW) adiponectin levels and incident ischemic stroke in postmenopausal women, using data and specimens from the Hormones and Biomarkers Predicting Stroke Study, a case-control study nested within the Women’s Health Initiative Observational Study. Included were 855 incident ischemic stroke cases and 855 controls, matched for age, race-ethnicity, date of entry into the cohort, and follow-up time. Odds ratios of incident ischemic stroke associated with baseline HMW adiponectin levels were calculated using conditional logistic regression modeling, adjusting for body mass index (BMI), type 2 diabetes, hypertension, smoking, LDL-C, HDL-C, physical activity, C-reactive protein, and aspirin use.
Lower levels of HMW adiponectin were significantly associated with type 2 diabetes, hypertension, higher BMI, waist, glucose, and insulin levels, and lower HDL-C levels. The distribution of incident stroke cases by HMW adiponectin quartiles was 49.9%, 50.5%, 50.7%, and 48.9%, respectively (p =0.96). Multivariable-adjusted odds ratios of stroke associated with the top three quartiles of HMW adiponectin versus the first quartile were 0.99 (95%CI 0.71 to 1.37), 1.37 (0.99 to 1.91), and 1.25 (0.88 to 1.79), respectively (p-trend =0.14).
Despite moderate associations between HMW adiponectin and CVD risk factors, we found no evidence of an association between HMW adiponectin levels and incident ischemic stroke in these postmenopausal women.
PMCID: PMC2907159  PMID: 20508194
high molecular weight adiponectin; postmenopausal women; ischemic stroke
14.  Adipokines, Insulin Resistance and Coronary Artery Calcification 
We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, the metabolic syndrome and plasma C-reactive protein (CRP).
Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.
We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA).
Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjusting for age, gender, traditional risk factors and Framingham Risk Scores (FRS) [tobit regression ratio 2.42 (95% CI 1.48–3.95, p=0.002)] and further adjusting for metabolic syndrome and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
In SIRCA, while both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.
Condensed Abstract
Adipokines are fat-secreted biomolecules with pleiotropic actions and represent novel markers for cardiovascular risk. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic Caucasians. Leptin was positively (top vs. bottom quartile) associated with higher CAC even after adjustment for age, gender, traditional risk factors, Framingham Risk Score, metabolic syndrome, and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. Adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
PMCID: PMC2853595  PMID: 18617073
Adiponectin; Leptin; Coronary Artery Calcification; Atherosclerosis; Inflammation
15.  Younger age, higher body mass index and lower adiponectin concentration predict higher serum thromboxane B2 level in aspirin-treated patients with type 2 diabetes: an observational study 
Evidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High on-aspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2.
A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median.
Significant trends in age, body mass index (BMI), HOMA-IR, HMW adiponectin concentration, C-reactive protein concentration and the frequency of achieving target triglyceride levels were observed across increasing quartiles of TXB2. In a multivariate analysis, only younger age and higher BMI were independent predictors of TXB2 concentration above the upper quartile, while younger age and lower HMW adiponectin concentration were predictors of TXB2 concentration above the median.
These results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA.
PMCID: PMC4149275  PMID: 25123549
Aspirin; Platelet aggregation; Diabetes mellitus; Insulin resistance; Adipokines
16.  Gestational Diabetes Mellitus Causes Changes in the Concentrations of Adipocyte Fatty Acid–Binding Protein and Other Adipocytokines in Cord Blood 
Diabetes Care  2011;34(9):2061-2066.
To determine the concentrations of adipocyte fatty acid–binding protein (AFABP) and other adipocytokines in maternal and cord serum of pregnant women with gestational diabetes mellitus (GDM) and of control subjects and to relate them to indexes of insulin sensitivity.
In 86 control and 98 GDM pregnant women, venous blood was collected before vaginal delivery and arterial blood from cord immediately after delivery. Serum insulin and adipocytokines were measured by enzyme-linked immunosorbent assay (ELISA).
GDM women had higher prepregnancy BMI, and data were adjusted for it. Maternal serum insulin, insulin-to-glucose ratio, homeostasis model assessment (HOMA), AFABP, and retinol-binding protein 4 (RBP4) were higher and adiponectin was lower in GDM than in control subjects, whereas serum glucose, insulin, insulin-to-glucose ratio, HOMA, nonesterified fatty acids, and RBP4 were higher and glycerol, AFABP, and adiponectin were lower in cord blood serum of GDM than of control subjects. AFABP and adiponectin in cord serum of control subjects were higher than in maternal serum; in GDM women no difference was found for AFABP in cord versus maternal serum, although adiponectin remained higher in cord. Values of leptin in both groups were lower in cord than in maternal serum, and those of RBP4 were lower in only GDM women.
It is suggested that fetal tissues are the main source of cord arterial serum AFABP, and in GDM fetuses AFABP values correlate with adiposity markers. A downregulation of adiponectin and upregulation of RBP4 in GDM mothers and their fetuses may be related to their insulin-resistant condition, whereas changes in AFABP do not seem to be related.
PMCID: PMC3161255  PMID: 21775757
17.  Serum Adiponectin in Relation to Race–Ethnicity and Vascular Risk Factors in the Northern Manhattan Study 
Population-based data on serum adiponectin levels, an adipocytokine secreted from adipose tissue, are lacking, particularly across race–ethnic groups. Studies have suggested an inverse association between adiponectin and vascular risk factors, but data are limited and inconsistent. We examined the cross-sectional association between adiponectin, vascular risk factors and race–ethnicity in the population-based Northern Manhattan Study (NOMAS).
Blood samples, anthropomorphics, and vascular risk factors were collected at baseline. Multivariable linear regression analysis was conducted with log-transformed adiponectin as the dependent variable.
Adiponectin was measured among 2900 participants (age 69±10 years, body mass index (BMI) 28.0±5.6, 37% male, 21% white, 53% Hispanic, 24% black). The mean adiponectin was 11.4±6.2 μg/mL (median=9.8, range=2.1–53.3). After multivariable adjustment, adiponectin levels were greatest among whites, followed by Hispanics, and lowest among blacks. Lower adiponectin levels were observed in participants with the following characteristics: Male, former smoking, hypertension, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), metabolic syndrome, moderate alcohol use, elevated waist circumference, BMI, estimated glomerular filtration rate (eGFR), triglycerides, low-density lipoprotein cholesterol (LDL-C), lower high-density lipoprotein cholesterol (HDL-C), and younger age. Obesity was a stronger risk factor for decreased adiponectin among blacks than among whites or Hispanics. The associations for several vascular risk factors, including hypertension, triglycerides, and low HDL-C, with low adiponectin were stronger among individuals who were not obese than among those who were obese.
Adiponectin levels were lower among blacks and Hispanics and among those with various vascular risk factors, and greater with older age. The association between BMI and adiponectin varied across race–ethnic groups. Investigation of whether differences in body fat distribution may explain race–ethnic differences in adiponectin is needed.
PMCID: PMC3593695  PMID: 23127161
18.  Impact of Treatment with Rosiglitazone or Metformin on Biomarkers for Insulin Resistance and Metabolic Syndrome in Patients with Polycystic Ovary Syndrome 
There is increasing evidence that insulin resistance (IR) has an important implication in the pathogenesis of polycystic ovary syndrome (PCOS), a common endocrinopathy in women. This study was performed to investigate the impact of different treatments for IR on five currently discussed markers for insulin resistance: intact proinsulin, adiponectin, retinol-binding protein 4 (RBP4), resistin, and visfatin in patients with PCOS.
Thirty-five women with clinically confirmed PCOS diagnosis were included in the study [age (mean±SD): 24.7±4.8 years; body mass index: 27.4±6.0 kg/m2]. They were randomized to receive either metformin (850 mg twice a day) or rosiglitazone (4 mg once a day). Blood samples for measurement of the HOMAIR score, visfatin, RBP4, intact proinsulin, resisitin, and adiponectin were taken at baseline and after 6 months of treatment.
Both drugs improved ovulation, and an increase in insulin sensitivity was observed, especially in the rosiglitazone arm. Adiponectin levels increased in both treatment arms (metformin: 8.6±3.3 to 16.7±7.2 mg/liter, p < 0.001; rosiglitazone: 8.2±3.5 to 26.2±9.5 mg/liter, p < 0.001), but the increase was more pronounced with rosiglitazone (p < 0.001). While no changes of visfatin concentrations were observed during rosiglitazone therapy (15.4±6.9 ng/ml vs 17.4±4.8 ng/ml, n.s.), there was an increase in the metformin treatment arm (11.9±4.0 to 21.8±8.3 ng/ml, p < 0.001). Significant increases demonstrated for RBP4 in both treatment arms were more pronounced in the metformin group (metformin: +66%, rosiglitazone: +33%). All patients were in stage I or II of ß-cell dysfunction and none of them showed increased intact proinsulin levels or changes in resisitin at baseline or end point.
Both drugs slightly improved ovulation in our PCOS patient population during 6 months of therapy, which was accompanied by improved insulin sensitivity and an increase in adiponectin levels. Metformin increased visfatin concentrations. Despite improved insulin resistance, an increase in RBP4 concentration was seen for both drugs. Rosiglitazone seems to be the more favorable drug under these circumstances. However, our results regarding visfatin and RBP4 contradict other reports and further research is required to clarify their value as diagnostic markers for the metabolic syndrome. In this study, adiponectin appeared to be the most promising indicator of both metabolic status and therapeutic success.
PMCID: PMC2771474  PMID: 19888409
adiponectin; insulin resistance; metformin; polycystic ovary syndrome; rosiglitazone
19.  Altered distribution of adiponectin isoforms in children with Prader–Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones 
Clinical endocrinology  2007;67(6):944-951.
Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones.
Design, patients and measurements
We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11.35 years, body mass index (BMI) Z-score 2.15] and 14 BMI-matched controls (median age 11.97 years, BMI Z-score 2.34).
Despite comparable BMI Z-scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA-IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z-score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0.05), HOMA-IR (P < 0.01), BMI Z-score (P < 0.05), insulin (P < 0.01) and leptin (P < 0.05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls.
Relative to controls of similar age and BMI Z-score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI-matched controls.
PMCID: PMC2605973  PMID: 17666087
20.  High adiponectin levels fail to protect against the risk of hypertension and, in women, against coronary disease: involvement in autoimmunity? 
World Journal of Diabetes  2013;4(5):219-225.
AIM: To investigate whether serum adiponectin protects against cardiometabolic risk in a population sample with prevailing metabolic syndrome.
METHODS: Middle-aged adults representative of a general population with baseline circulating adiponectin measurements (n = 1224) were analyzed prospectively at a mean of 3.8 years’ follow-up, using continuous values or sex-specific tertiles. Total adiponectin was assayed by an ELISA kit. Type-2 diabetes was identified by criteria of the American Diabetes Association. Hypertension was defined as a blood pressure ≥ 140 mmHg and/or ≥ 90 mmHg and/or use of antihypertensive medication. Outcomes were predicted using Cox proportional hazards regression analysis in models that were controlled for potential confounders.
RESULTS: In models of multiple linear regression, sex hormone-binding globulin, fasting insulin (inverse) and, in men, age were significant independent covariates of serum adiponectin which further tended in women to be positively associated with serum creatinine. Cox regression analyses for incident coronary heart disease (CHD), adjusted for sex, age, non-HDL cholesterol, waist circumference and C-reactive protein, revealed significant inverse association with adiponectin tertiles in men but not women (HR = 0.66; 95%CI: 0.32-1.38 for highest tertile). Cox regression for type-2 diabetes in a similar model (wherein glucose replaced non-HDL cholesterol), adiponectin tertiles appeared to protect in each gender. HR for incident hypertension roughly displayed unity in each of the adiponectin tertiles (P-trend = 0.67).
CONCLUSION: High adiponectin levels failed to protect against the development of hypertension and, in women, against CHD, presumably paralleling impairment in renal function as well. Involvement of adiponectin in autoimmune complex with loss of antioxidative-antiatherogenic properties may be underlying.
PMCID: PMC3797887  PMID: 24147206
Adiponectin; Antioxidative function; Coronary heart disease; Creatinine; Type-2 diabetes; Hypertension
21.  Adiponectin Multimers in Normal Pregnancy 
Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic adipokine that circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight.
Study design
In this cross-sectional study, serum concentrations of total, HMW, MMW and LMW adiponectin were determined in women included in three groups: 1) normal pregnant women of normal body mass index (BMI) (n=466); 2) overweight/obese pregnant women (BMI ≥25; n=257); and 3) non-pregnant women of normal weight (n=40). Blood samples were collected once from each pregnant woman between 11 and 42 weeks of gestation. Serum adiponectin multimers concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
1) The median HMW adiponectin concentration and the median HMW/Total adiponectin ratio were significantly higher and the median LMW adiponectin concentration was significantly lower in pregnant than in non-pregnant women; 2) among pregnant women, the median serum concentration of total, HMW and MMW adiponectin was significantly higher in normal weight women than in overweight/obese patients; 3) HMW adiponectin was the most prevalent multimer in maternal serum regardless of gestational age or BMI status; 4) there were no significant differences in the median concentration of total, MMW, LMW adiponectin, and their relative distribution with advancing gestation.
Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially of the most active isoform, HMW adiponectin.
PMCID: PMC2729195  PMID: 19031276
Adiponectin; Adipokines; Pregnancy; High molecular weight (HMW) adiponectin; Medium molecular weigh (MMW) adiponectin; Low molecular weight (LMW) adiponectin; BMI
22.  Total and High Molecular Weight Adiponectin Levels and Prediction of Cardiovascular Risk in Diabetic Patients 
The study aimed at assessing the potential use of lower total and HMW adiponectin levels for predicting cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). Concentrations of total adiponectin or high molecular weight (HMW) adiponectin decrease in association with the development of metabolic dysfunction such as obesity, insulin resistance, or T2DM. Increased adiponectin levels are associated with a lower risk for coronary heart disease. A total of 551 individuals were assessed. The first group comprised metabolically healthy participants (143 females, and 126 males) and the second group were T2DM patients (164 females, and 118 males). Both total adiponectin and HMW adiponectin in diabetic patients were significantly lower when compared with the group of metabolically healthy individuals. There was a weak monotonic correlation between HMW adiponectin levels and triglycerides levels. Binary logistic regression analysis, gender adjusted, showed a higher cardiovascular risk in diabetic persons when both total adiponectin (OR = 1.700) and HMW adiponectin (OR = 2.785) levels were decreased. A decrease in total adiponectin levels as well as a decrease in its HMW adiponectin is associated with a higher cardiovascular risk in individuals with T2DM. This association suggests that adiponectin levels may be potentially used as an epidemiological marker for cardiovascular risk in diabetic patients.
PMCID: PMC4436467  PMID: 26074960
23.  Maternal Serum Adiponectin Multimers in Preeclampsia 
Journal of perinatal medicine  2009;37(4):349-363.
Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, “adipose tissue failure”, characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (SA) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers.
Study design
This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (p<0.001 and p=0.01, respectively); 2) patients with preeclampsia had a lower HMW/Total adiponectin ratio (p<0.001) and higher MMW/Total adiponectin and LMW/Total adiponectin ratios than those with a normal pregnancy (p<0.001 and p=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (p=0.001) and with a low HMW/Total adiponectin ratio (p<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia.
1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/Total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia.
PMCID: PMC3166229  PMID: 19348608
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; overweight; obesity
24.  Increased plasma levels of retinol‐binding protein 4 with visceral obesity is associated with cardiovascular risk factors 
Aims/Introduction:  Visceral obesity has been suggested to be an independent risk factor for cardiovascular disease (CVD); the role of adipokines in the risk for CVD is less clear. Aim of this study was to investigate the relationship between parameters of visceral obesity and index of CVD risk factors.
Materials and Methods:  A cross‐sectional analysis of healthy males (n = 116) and females (n = 175) for evaluation of clinical, laboratory and anthropometric parameters were undertaken. Abdominal subcutaneous (SAT) and visceral adipose tissues (VAT) were measured by computed tomography. Adipokines, including retinol‐binding protein 4 (RBP4) and adiponectin, were determined. The risk for CVD was estimated using the 10‐year Framingham Coronary Heart Disease Risk Point scale (Framingham score).
Results:  The Framingham score was increased in subjects with metabolic syndrome, and significantly increased with various indices of obesity, traditional risk factors of CVD, C‐reactive protein (CRP) and RBP4, but decreased with adiponectin. With multiple linear regression analysis, the Framingham score independently associated with age, smoking status, body mass index, triglyceride and RBP4. The magnitude of the Framingham score showed a linear trend of increase with CRP, VAT and RBP4 (all P < 0.001), but of decrease with SAT and adiponectin (all P < 0.05) at stratified levels of obesity.
Conclusions:  RBP4 is increased with visceral fat accumulation and associated with CVD risk factors independent of obesity or traditional risk factors. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00213.x, 2012)
PMCID: PMC4019246  PMID: 24843606
Visceral obesity; Adipokines; Retinol binding protein 4
25.  Association of plasma adiponectin levels with cellular hydration state measured using bioelectrical impedance analysis in patients with COPD 
It is widely recognized that chronic obstructive pulmonary disease (COPD) includes a variety of extra pulmonary complications and comorbidities. Recently, adiponectin was shown to regulate cellular metabolism in humans. Cellular hydration state is affected by a variety of hormonal factors and regulates cellular metabolic state. Therefore, this study was designed to determine whether adiponectin is a possible factor involved in cellular hydration state in COPD.
Thirty patients with COPD and 41 age-matched controls participated in the study. Plasma levels of total and high molecular weight (HMW) adiponectin were measured and anthropometry and pulmonary function tests were conducted. Intracellular water (ICW), extracellular water (ECW), and ECW/ICW ratio, which are parameters of cellular hydration state, were measured using bioelectrical impedance analysis.
Higher levels of total and HMW adiponectin in plasma were found in patients with COPD compared with levels in controls. A significant inverse correlation was observed between body mass index and plasma levels of total and HMW adiponectin in the control group. However, this significant correlation was not observed in patients with COPD. The plasma levels of total and HMW adiponectin were also not significantly correlated with any pulmonary function parameters in patients with COPD. Regarding the state of cellular hydration, the plasma levels of total adiponectin were inversely correlated with the ECW/ICW ratio and positively with ICW values in patients with COPD. Moreover, closer correlations were found between these parameters and plasma HMW adiponectin levels.
The results of the present study suggest a novel association of the plasma adiponectin with cellular hydration state in patients with COPD. Accordingly, lower adiponectin levels may result in cellular shrinkage, leading to metabolic malfunction at a cellular level. Thus, our findings provide new insights regarding the preventive roles of adiponectin in the progression of comorbidities in COPD.
PMCID: PMC3422121  PMID: 22927754
adiponectin; bioelectrical impedance analysis (BIA); cellular hydration; COPD; extra pulmonary phenotype

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