the clustering of cardiovascular risk factors that includes central adiposity , hypertension , hyperglycemia , and high triglycerides ( tg ) with low high density lipoprotein cholesterol ( hdl - c ) levels is termed the metabolic syndrome ( ms ) .
ms is known to strongly predict the long - term risk of diabetes and cardiovascular disease ( cvd ) .
adipose tissue products are reported to affect systemic metabolism ; among these are adiponectin , leptin , plasminogen activator inhibitor-1 ( pai-1 ) , resistin , inflammatory cytokines , and angiotensinogen .
adiponectin has recently attracted much attention with particular emphasis on the role of adiponectin in the regulation of insulin sensitivity and the development of insulin resistance .
plasma levels of adiponectin have also been reported to be significantly reduced in obese humans .
moreover , plasma adiponectin levels have been shown to be decreased in patients with type-2 diabetes mellitus ( t2 dm ) , cvd , hypertension , and ms.[69 ] adiponectin activates adenosine mono - phosphate activated protein kinase and peroxisome proliferator activated receptor- in the liver and skeletal muscle , thereby stimulating phosphorylation of acetyl - coa carboxylase , fatty acid oxidation , thus decreasing tissue triglyceride ( tg ) content in muscle and liver .
the expression levels of adipor1/r2 are also decreased in obesity , which reduces adiponectin sensitivity and finally leads to insulin resistance , the so - called  vicious cycle . 
adiponectin was demonstrated to strongly inhibit the expression of adhesion molecules , including intracellular adhesion molecule-1 , vascular cellular adhesion molecule-1 , and e - selectin .
thus , various studies have highlighted the potential antidiabetic , antiatherosclerotic and anti - inflammatory properties of adiponectin . decreased levels of plasma adiponectin
are associated with increased body mass index ( bmi ) , decreased insulin sensitivity , less favorable plasma lipid profiles , increased levels of inflammatory markers and increased risk for the development of cvd .
therefore , adiponectin levels hold great promise for use in clinical application , serving as a potent indicator of underlying metabolic complications .
plasma pai-1 levels are elevated in obesity and insulin resistance , are positively correlated with features of the ms , and predict future risk for type 2 diabetes and cvd .
thus , pai-1 may contribute to the development of obesity and insulin resistance and may be a causal link between obesity and cvd.[1113 ] there are few studies which have evaluated adipokines in indian population.[1417 ] hence , we studied adiponectin and pai-1 levels and their correlation with various parameters in subjects with ms .
this study was carried out at the department of endocrinology of a tertiary care center and details are provided in our previous publication in this journal . subjects with age 30 years and 50 years ( to exclude all postmenopausal women ) were screened for the presence of ms according to international diabetes federation ( idf ) criteria as follows : central obesity ( waist circumference  males > 90 cm , females > 80 cm ) plus any two of the following : raised triglycerides ( > 150 mg / dl ) , reduced hdl - c ( < 40 mg / dl in men and < 50 mg / dl in women ) , raised blood pressure ( systolic 130 mm hg or diastolic 85 mm hg ) , raised fasting plasma glucose ( fpg ) ( 100 mg / dl ) .
age- and sex - matched healthy subjects were screened for the absence of ms . only those cases with waist circumference below the idf criteria and absence of at least three of the four parameters
a total of 50 drug - nave subjects with ms ( 25 males and 25 females ) and 24 controls ( 12 males and 12 females ) were included in the study .
subjects with hepatic disease , renal disease , other endocrine diseases , alcoholism , infectious diseases or receiving any medications were excluded from the study .
body fat measurement was done using inbody composition analyser - biospacer manufactured by m / s biodex medical systems inc .
it measured waist hip ratio ( whr ) , body fat mass ( bfm ) , percent body fat ( pbf ) and basal metabolic rate ( bmr ) .
fasting blood samples were drawn for the estimation of fpg , renal and hepatic parameters , a1c , lipid profile , highly sensitive c - reactive protein ( hscrp ) and fibrinogen .
one aliquot of the sample was frozen at 80c for the measurement of plasma insulin , adiponectin and pai-1 .
adiponectin was measured with avibion human adiponectin ( acrp30 ) elisa commercial kits supplied by orgenium laboratories business unit , finland , as per manufacturer 's instructions .
it had an assay range of 0.18515 ng / ml and a sensitivity of < 0.3 ng / ml . intra - assay precision was 10% and inter - assay precision was 12% .
pai-1 was measured with human pai-1 elisa ( ea-0207 ) supplied by signosis biosignal capture ( sunnyvale , ca , usa ) , as per manufacturer 's instructions .
it had an assay range of 0.320 ng / ml and a sensitivity of < 0.79 ng / ml . intra - assay and inter - assay precision was 15% . the homa model was used to calculate insulin resistance and insulin insensitivity .
the formulae are as follows : where fi = fasting insulin in iu / ml and g = fasting glucose in mmol / l .
the study was approved by the ethics committee of army hospital ( research and referral ) , delhi cantt , and all subjects gave written informed consent .
statistical analysis was carried out using epi info 3.5.3 ( cdc ; atlanta ; usa ) .
if barlett 's chi - square test for equality of population variances was < 0.05 , then kruskal  wallis test was applied .
this study was carried out in 50 cases of ms and 24 normal healthy controls .
basal characteristics of the cases and controls are shown in table 1 ( also given in our previous publication ) .
there were 37 ( 74% ) cases with t2 dm and 13 ( 26% ) cases with impaired glucose tolerance .
tg total cholesterol ( tc) low density lipoprotein ( ldl) and very low density lipoprotein ( vldl ) were significantly higher and hdl was significantly lower among cases than in controls .
most of the cases ( 28.56% ) had four features of ms , followed by cases with all features ( 16.32% ) , and 6 ( 12% ) cases had three features of ms [ table 1 ] .
basic characteristics of cases and controls subjects with ms had significantly lower adiponectin levels than controls ( 4.01  2.24 vs. 8.7  1.77 g / ml ; p < 0.0001 ) [ table 1 ] .
there was no difference in adiponectin levels between sexes ( 5.23  3.12 vs. 5.71  2.65 g / ml ; p = 0.49 ) .
adiponectin levels according to the number of metabolic abnormalities in univariate regression analysis , adiponectin was negatively associated with age , bmi , bfm and pbf , and positively associated with bmr . among the various parameters of ms ,
adiponectin was negatively associated with all parameters , except hdl - c with which it was positively associated .
adiponectin showed strong negative association with inflammatory markers ( crp , fibrinogen ) and procoagulant marker ( pai-1 ) .
adiponectin was positively associated with insulin secretion ( homa - s ) and negatively associated with insulin resistance ( homa - ir ) [ table 2 ] .
univariate regression analysis of adipokines among all subjects multiple regression analysis showed that among the metabolic parameters , whr , fpg and tg maintained negative association with adiponectin even after adjustment for all metabolic variables .
however , hdl and hypertension lost significance during multiple regression analysis [ table 3 ] .
only bmi remained negatively associated with adiponectin when adjusted for anthropometric parameters , e.g. bmr , bfm , and percent body fat , in multiple regression analysis [ table 4 ] .
bmr showed positive association when adjusted with bmi , but lost significance when bfm was added .
similarly , pai-1 levels showed strong negative association with adiponectin [ figure 2 ] even after adjustment with other parameters like homa - ir , crp , and fibrinogen [ table 5 ] . multivariate regression analysis of adipokines with metabolic parameters among all subjects multivariate regression analysis of adipokines with anthropometric parameters among all subjects correlation between adiponectin and pai-1 among all subjects multivariate regression analysis of adipokines with other parameters among all subjects receiver operating characteristic ( roc ) curve analysis revealed best prediction value of adiponectin at 6.7 g / ml with a sensitivity of 83% , specificity of 86% , accuracy of 85% , positive predictive value of 74% , negative predictive value of 84% and positive and negative likelihood ratios of 5.95 and 0.19 , respectively ( roc 0.934 , se 0.0277 , 95% ci = 0.8790.988 ) . subjects with ms had significantly higher pai-1 levels than controls ( 53.85  16.45 vs. 17.35  4.45 ng / ml ; p < 0.0001 ) [ table 1 ] .
there was no difference in pai-1 levels between sexes ( 8.59  4.42 vs. 8.21  4.44 ng / ml ; p = 0.71 ) .
pai-1 according to the number of metabolic abnormalities in univariate regression analysis , pai-1 was positively associated with bmi , bfm and pbf , and negatively associated with bmr . among the various parameters of ms ,
pai-1 was positively associated with all parameters of ms , except hdl with which it was negatively associated .
pai-1 showed strong positive association with inflammatory markers ( crp , fibrinogen ) , insulin resistance ( fasting plasma insulin and homa - ir ) and total and ldl cholesterol , but had strong negative association with adiponectin [ table 2 ] .
multiple regression analysis of various metabolic parameters showed that whr and tg maintained positive association with pai-1 even after adjustment for all metabolic variables .
however , hdl , fpg and hypertension lost significance during multiple regression analysis [ table 3 ] .
only pbf remained positively associated with pai-1 when adjusted for anthropometric parameters , e.g. bmr , bfm , and bmi , in multiple regression analysis [ table 4 ] .
similarly , pai-1 levels showed strong positive association with fibrinogen even after adjustment with other parameters like homa - ir , crp , and fibrinogen [ table 5 ] .
roc curve analysis revealed best prediction value of pai-1 at 25.0 ng / ml , with a sensitivity of 92% , specificity of 96% , accuracy of 95% , positive predictive value of 92% , negative predictive value of 96% and positive and negative likelihood ratios of 22.9 and 0.08 , respectively ( roc 0.975 , se 0.0178 , 95% ci = 0.9421.009 ) .
subjects with ms had significantly lower adiponectin levels than controls ( 4.01  2.24 vs. 8.7  1.77 g / ml ; p < 0.0001 ) [ table 1 ] . adiponectin levels decreased with increasing number of metabolic abnormalities [ figure 1 ] .
there was no difference in adiponectin levels between sexes ( 5.23  3.12 vs. 5.71  2.65 g / ml ; p = 0.49 ) .
adiponectin levels according to the number of metabolic abnormalities in univariate regression analysis , adiponectin was negatively associated with age , bmi , bfm and pbf , and positively associated with bmr . among the various parameters of ms ,
adiponectin was negatively associated with all parameters , except hdl - c with which it was positively associated .
adiponectin showed strong negative association with inflammatory markers ( crp , fibrinogen ) and procoagulant marker ( pai-1 ) .
adiponectin was positively associated with insulin secretion ( homa - s ) and negatively associated with insulin resistance ( homa - ir ) [ table 2 ] .
univariate regression analysis of adipokines among all subjects multiple regression analysis showed that among the metabolic parameters , whr , fpg and tg maintained negative association with adiponectin even after adjustment for all metabolic variables .
however , hdl and hypertension lost significance during multiple regression analysis [ table 3 ] .
only bmi remained negatively associated with adiponectin when adjusted for anthropometric parameters , e.g. bmr , bfm , and percent body fat , in multiple regression analysis [ table 4 ] .
bmr showed positive association when adjusted with bmi , but lost significance when bfm was added .
similarly , pai-1 levels showed strong negative association with adiponectin [ figure 2 ] even after adjustment with other parameters like homa - ir , crp , and fibrinogen [ table 5 ] . multivariate regression analysis of adipokines with metabolic parameters among all subjects multivariate regression analysis of adipokines with anthropometric parameters among all subjects correlation between adiponectin and pai-1 among all subjects multivariate regression analysis of adipokines with other parameters among all subjects receiver operating characteristic ( roc ) curve analysis revealed best prediction value of adiponectin at 6.7 g / ml with a sensitivity of 83% , specificity of 86% , accuracy of 85% , positive predictive value of 74% , negative predictive value of 84% and positive and negative likelihood ratios of 5.95 and 0.19 , respectively ( roc 0.934 , se 0.0277 , 95% ci = 0.8790.988 ) .
subjects with ms had significantly higher pai-1 levels than controls ( 53.85  16.45 vs. 17.35  4.45 ng / ml ; p < 0.0001 ) [ table 1 ] . pai-1 levels increased with increasing number of metabolic abnormalities [ figure 3 ] .
there was no difference in pai-1 levels between sexes ( 8.59  4.42 vs. 8.21  4.44 ng / ml ; p = 0.71 ) .
pai-1 according to the number of metabolic abnormalities in univariate regression analysis , pai-1 was positively associated with bmi , bfm and pbf , and negatively associated with bmr . among the various parameters of ms ,
pai-1 was positively associated with all parameters of ms , except hdl with which it was negatively associated .
pai-1 showed strong positive association with inflammatory markers ( crp , fibrinogen ) , insulin resistance ( fasting plasma insulin and homa - ir ) and total and ldl cholesterol , but had strong negative association with adiponectin [ table 2 ] .
multiple regression analysis of various metabolic parameters showed that whr and tg maintained positive association with pai-1 even after adjustment for all metabolic variables . however , hdl , fpg and hypertension lost significance during multiple regression analysis [ table 3 ] .
only pbf remained positively associated with pai-1 when adjusted for anthropometric parameters , e.g. bmr , bfm , and bmi , in multiple regression analysis [ table 4 ] .
similarly , pai-1 levels showed strong positive association with fibrinogen even after adjustment with other parameters like homa - ir , crp , and fibrinogen [ table 5 ] .
roc curve analysis revealed best prediction value of pai-1 at 25.0 ng / ml , with a sensitivity of 92% , specificity of 96% , accuracy of 95% , positive predictive value of 92% , negative predictive value of 96% and positive and negative likelihood ratios of 22.9 and 0.08 , respectively ( roc 0.975 , se 0.0178 , 95% ci = 0.9421.009 ) .
ms is known to strongly predict long - term risk of diabetes and cvd , and has also been reported to be associated with increased morbidity and mortality .
it is becoming increasingly common in the united states and worldwide , and is emerging as the dominant risk factor for cvd in asia .
the ms represents a combination of risk determinants , which include atherogenic dyslipidemia , elevated blood pressure , elevated glucose , a prothrombotic state , and a proinflammatory state . in obese persons ,
adipose tissue products are reported to affect systemic metabolism ; among these are adiponectin , leptin , inflammatory cytokines , pai-1 , resistin , and angiotensinogen . in this study , we evaluated 50 subjects with ms ( 25 males and 25 females ) and 24 controls ( 12 males and 12 females ) .
we have used here idf criteria as it provides ethnic - specific criteria for central obesity .
all cases had significantly higher whr , bmi bfm and pbf than controls in both the sexes , which is similar to asian indian obesity phenotype .
low adiponectin levels have been reported in most of the studies on ms among people of various age groups , ethnicity and gender.[14152127 ] however , one study reported higher adiponectin levels in ms and another found low adiponectin level which was statistically not significant .
there was negative graded response of adiponectin levels with metabolic abnormalities [ figure 1 ] .
adiponectin was negatively related with age , bmi , bfm and pbf , whr , fpg , hypertension , tg , tc , hscrp , fibrinogen , homa - ir and pai-1 , and positively related with bmr , hdl and homa - s in the present study .
similar associations have been reported in the literature.[17263135 ] however , certain differences were observed between the present study and other studies . in this study ,
adiponectin showed no relation with fasting insulin levels , as also observed by one study from south india , whereas others have reported negative correlation .
we have observed negative correlation of cholesterol with adiponectin , similar to that reported by bilgili et al . but others found no relation of adiponectin with tc .
, did not observe any relation between adiponectin and hscrp in post - pubertal asian indian adolescents , as seen by us .
multiple regression analysis of the metabolic parameters showed whr , fpg and tg to have an independent negative association with adiponectin even after adjustment for all metabolic variables .
yang et al . , observed positive association of hdl with adiponectin in multiple regression analysis .
however , in our study , hdl and hypertension lost significance during multiple regression analysis .
ku et al . , reported correlation between serum adiponectin and bmi , triglyceride , hdl - c and fasting glucose in multiple regression analysis . in the present study ,
only bmi remained negatively associated with adiponectin when adjusted for anthropometric parameters , e.g. bmr , bfm , and pbf , in multiple regression analysis .
jung et al . , showed significant negative correlation of adiponectin levels with percent body fat , lipid profile and homa - ir .
bmr showed positive association when adjusted with bmi , but lost significance when bfm was added .
similarly , pai-1 levels showed strong negative association with adiponectin even after adjustment with other parameters like homa - ir , crp , and fibrinogen .
bilgili et al . , also found an inverse relationship between plasma adiponectin and pai-1 ( r = 0.653 , p < 0.001 ) .
roc curve analysis revealed best prediction value at 6.7 g / ml , with a sensitivity of 83% , specificity of 86% , and accuracy of 85% .
mohan et al . , also reported similar adiponectin levels ( 5.0 g / ml for males and 6.5 g / ml for females ) in a study from south india .
however , studies from japan have suggested lower cut - off point ( 4 g / ml ) of serum adiponectin level for the diagnosis of ms .
seino et al . , also suggested that measuring adiponectin may be effective for evaluating the presence of ms in nondiabetic subjects through analysis of area under the curve of roc curves .
subjects with ms had significantly higher pai-1 levels than controls , which is similar to that reported in many studies in the literature.[13263945 ] however , pai-1 level was higher in the present study than that reported from other ethnic populations .
indian population has higher pai-1 compared to african population , which is explained by the increased frequency of pai-1 4 g allele .
pai-1 was positively associated with bmi , bfm and pbf , and negatively associated with bmr . among the various parameters of ms ,
pai-1 was positively associated with all parameters of ms , except hdl with which it was negatively associated .
pai-1 showed a strong positive association with inflammatory markers ( hscrp , fibrinogen ) , insulin resistance ( fasting plasma insulin , homa - ir ) and total and ldl cholesterol , but had strong negative association with adiponectin .
tg and whr were independently associated with pai-1 even after adjustment for all metabolic variables in multiple regression analysis .
, also found waist circumference as the strongest independent predictor of pai-1 . however , hdl , fpg and hypertension lost significance during multiple regression analysis .
only pbf remained positively associated with pai-1 when adjusted for anthropometric parameters , e.g. bmr , bfm , and bmi , in multiple regression analysis .
similarly , pai-1 levels showed a strong positive association with fibrinogen even after adjustment with other parameters like homa - ir , crp , and adiponectin .
roc curve analysis revealed the best prediction value at 25.0 ng / ml , with a sensitivity of 92% , specificity of 96% , accuracy of 95% , and positive predictive value of 92% .
other studies have also made similar observation that pai-1 is an independent determinant of ms in multivariate logistic regression analysis .
surprisingly , we have found higher cut - off value for adiponectin and lower cut - off value for pai-1 for diagnosis of ms .
the primary limitation of the present study is its cross - sectional design and the inherent possibility that genetic and/or lifestyle factors may have influenced the results of our group comparisons .
however , in an effort to minimize the influence of lifestyle behaviors , we studied subjects of similar age who were non - smokers , who were not currently taking medication that could influence inflammatory and oxidative markers ( i.e. statins ) , and who did not differ in habitual physical activity .
in addition , we used strict inclusion criteria to eliminate the confounding effects of underlying cardiovascular and metabolic disease .
in the present study , subjects with ms had higher bmi , bfm and percent body fat , which is reflected in lower level of adiponectin and higher level of pai-1 . also , they had increased insulin resistance and decreased insulin secretion compared to healthy controls .
subjects with ms were associated with higher hscrp level , emphasizing low - grade systemic inflammatory state .
all these factors were interdependent and associated with other cardiovascular risk factors . although the knowledge on pathogenesis and its association with metabolic risk factors such as obesity , hypertension , and cardiovascular risk is increasing day by day , the challenge is to translate research findings into substantial clinical improvements for patients . demographic and epidemiological evidence indicates that unless an effective preventive strategy is developed , there will be a sharp increase in the global prevalence of cardiometabolic risk factors including diabetes and ms .
lifestyle measures have been shown to improve insulin resistance , insulin secretion and various components and effects of ms,[14951 ] and hence there is an urgent need for public health measures to prevent the ongoing epidemic of diabetes and cvd .
 background : the clustering of cardiovascular risk factors is termed the metabolic syndrome ( ms ) , which strongly predicts the risk of diabetes and cardiovascular disease ( cvd ) . 
 adipokines may contribute to the development of obesity and insulin resistance and may be a causal link between ms , diabetes and cvd . 
 hence , we studied the adipokines  adiponectin and plasminogen activator inhibitor-1 ( pai-1 )  in subjects with ms.materials and methods : we studied 50 subjects with ms diagnosed by international diabetes federation ( idf ) criteria and 24 healthy age- and sex - matched controls . 
 clinical evaluation included anthropometry , body fat analysis by bioimpedance , highly sensitive c - reactive protein , insulin , adiponectin , and pai-1 measurement.results:subjects with ms had lower adiponectin ( 4.01  2.24 vs. 8.7  1.77 g / ml ; p < 0.0001 ) and higher pai-1 ( 53.85  16.45 vs. 17.35 
  4.45 ng / ml ; p < 0.0001 ) levels than controls . 
 both were related with the number of metabolic abnormalities . 
 adiponectin was negatively and pai-1 was positively associated with body mass index , waist hip ratio ( whr ) , body fat mass , percent body fat , and all the parameters of ms , except hdl where the pattern reversed . 
 whr and triglycerides were independent predictors of adipokines in multiple regression analysis . 
 receiver operating characteristic curve analysis showed that adiponectin ( 6.7 g / ml ) and pai-1 ( 25.0 ng / ml ) levels predicted the ms with high sensitivity , specificity and accuracy in indian population.conclusions:subjects with ms have lower adiponectin and higher pai-1 levels compared to healthy controls . 
 lifestyle measures have been shown to improve the various components of ms , and hence there is an urgent need for public health measures to prevent the ongoing epidemic of diabetes and cvd . 