we ascertained subjects with lada and type 2 diabetes from the lada china multicenter study ( 46 hospitals throughout china contributed ) ; type 1 diabetes , defined by who criteria ( 4 ) , from the type 1 diabetes collaboration net ( 18 hospitals in hunan province ) ; and normal subjects were screened by 75-g oral glucose tolerance test from 5,000 chinese in a population - based study .
definition of lada ( 57 ) was 1 ) gad antibody ( gada ) positive , 2 ) age > 30 years at diagnosis , 3 ) independence from insulin treatment 6 months postdiagnosis , and 4 ) without ketoacidosis .
subjects with hs - crp > 10 mg / l or taking anti - inflammatory drugs within 3 months were excluded .
metabolic syndrome was defined by national cholesterol education program - adult treatment panel iii criteria ( 8) .
this study was approved by ethics committees at second xiangya hospital of central south university and at each center and conducted according to the declaration of helsinki .
height , weight , waist circumference , hip circumference , and blood pressure were recorded locally , and fasting sera samples were processed centrally .
elisa determined high - sensitivity il-6 ( il-6 hs ; r&d systems , minneapolis , mn ) , 7% intraassay and 5% interassay coefficient of variation ( cv ) ; lcn2 ( 10 ) , 3.86.0% intraassay and 3.15.2% interassay cv ; adiponectin ( 11 ) 56% intraassay and 68% interassay cv .
hs - crp was measured by immunoturbidometric assay ( orine diagnostica ) with 2.13.3% intraassay and 3.44.6% interassay cv .
we used spss ( version 13 ; spss , chicago , il ) for statistical analysis .
data are expressed when normally distributed as means  sd and when skewed as median ( 25th75th percentiles ) .
we used a general linear model of univariate analysis adjusted for age , sex , and bmi ; log - transformed cytokine value was the dependent variable , different diabetes groups were fixed , and age , sex , and bmi were covariates ( fig .
multivariate regression models investigated differences in log - transformed cytokine concentrations ( dependent variables ) , with increasing number of variables ( model 1 : unadjusted ; model 2 : sex and age adjusted ; model 3 : age , sex , and bmi [ independent variables ] adjusted ) ( supplementary table 2 ) .
linear relationships were evaluated by partial correlations test adjusted age , sex , and bmi .
data were not corrected for multiple comparisons and are descriptive ; p < 0.01 was considered significant .
univariate of general linear model adjusted according to age , sex , and bmi between groups . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 .
ngt , normal glucose tolerance subjects ; t1d , type 1 diabetic subjects ; t2d , type 2 diabetic subjects .
we used spss ( version 13 ; spss , chicago , il ) for statistical analysis .
data are expressed when normally distributed as means  sd and when skewed as median ( 25th75th percentiles ) .
we used a general linear model of univariate analysis adjusted for age , sex , and bmi ; log - transformed cytokine value was the dependent variable , different diabetes groups were fixed , and age , sex , and bmi were covariates ( fig .
multivariate regression models investigated differences in log - transformed cytokine concentrations ( dependent variables ) , with increasing number of variables ( model 1 : unadjusted ; model 2 : sex and age adjusted ; model 3 : age , sex , and bmi [ independent variables ] adjusted ) ( supplementary table 2 ) .
linear relationships were evaluated by partial correlations test adjusted age , sex , and bmi .
data were not corrected for multiple comparisons and are descriptive ; p < 0.01 was considered significant .
univariate of general linear model adjusted according to age , sex , and bmi between groups . * p < 0.05 , * * p < 0.01 , * * * p < 0.001 .
ngt , normal glucose tolerance subjects ; t1d , type 1 diabetic subjects ; t2d , type 2 diabetic subjects .
of 784 subjects , patients with both lada and type 2 diabetes were significantly older than subjects with normal glucose tolerance or type 1 diabetic patients . as expected , lada patients had lower insulin secretion than type 2 diabetic patients , while in type 1 diabetic patients , insulin secretion was lower than in both lada and type 2 diabetic patients .
metabolic syndrome in type 1 diabetic and control subjects was less frequent than in both lada and type 2 diabetic subjects .
we used univariate and multivariate regression models to adjust age , sex , and bmi differences ( fig . 1 and supplementary table 2 ) .
after adjustment , all three types of diabetes ( type 1 diabetes , lada , and type 2 diabetes ) showed increased il-6 and lcn2 .
all four cytokines were increased in lada . in type 1 diabetes , adiponectin but not hs - crp was increased . in type 2 diabetes , hs - crp but not adiponectin was increased , and adiponectin was decreased after adjustment .
gada titer was positively correlated with adiponectin ( r = 0.14 , p < 0.01 ) and negatively correlated with hs - crp ( r = 0.15 , p < 0.001 ) ( supplementary tables 3 and 4 ) . in lada subjects , hs - crp was strongly related to bmi ( r = 0.363 , p < 0.001 ) .
some inflammatory markers were increased in diabetes ( i.e. , il-6 and lcn2 ) irrespective of diabetes type , implying that cytokine changes are secondary features of the disease independent of obesity , and consistent with a proinflammatory effect in diabetes in general .
nevertheless , obesity ( waist - to - hip ratio ) was associated with all four cytokines assayed , and the pattern of cytokine changes differed according to diabetes type .
cytokines ( il-6 , tnf , and il-1 receptor antagonist ) in europeans with these same major diabetes types were also positively associated with bmi , which was higher in diabetic patients than in control subjects and highest in type 2 diabetes but similar in lada and type 1 diabetes ; after correction , only tnf in lada and type 1 diabetes was no longer different from that in control subjects ( 5 ) . in both the european study and this chinese study ,
il-6 showed remarkably similar increases in major diabetes types ; il-6 , as well as lcn2 , levels were higher than in control subjects and highest in type 2 diabetes ( 5 ) .
however , hs - crp was increased in both lada and type 2 diabetes , but not type 1 diabetes , while adiponectin was only increased in lada and type 1 diabetes . despite adiponectin
being positively correlated with gada titer , it has no established role in autoimmune diabetes and certainly can not predict it ( 12 ) .
however , low - grade inflammation could be important in autoimmunity , potentially explaining any benefit of rosiglitazone ( 13 ) .
indeed , each cytokine ( il-6 , lcn2 , hs - crp , and adiponectin ) was increased in chinese lada , though probably for different reasons ( 14 ) .
given the relative lack of obesity in china , comparative chinese and european studies could delineate the relative roles of obesity , diabetes , and autoimmunity on cytokines .
surprisingly , therefore , metabolic syndrome was prevalent in this large lada cohort , in contrast to european studies ( 5,6 ) . these results point toward a complex relationship between diabetes types and altered cytokine levels .
 objectiveto determine the relationship between selected cytokines and diabetes in chinese subjects.research design and methodsadult patients with recent - onset type 1 diabetes ( n = 53 ) , latent autoimmune diabetes in adults ( lada ) ( n = 250 ) , and type 2 diabetes ( n = 285 ) from multiple centers were compared with normal subjects ( n = 196 ) . 
 we centrally tested serum gad antibodies ( gadas ) , interleukin-6 ( il-6 ) , lipocalin 2 ( lcn2 ) , high - sensitivity c - reactive protein ( hs - crp ) , and adiponectin.resultsafter adjustment for age , sex , and bmi , all diabetes types had increased il-6 and lcn2 ( p < 0.01 ) , and all four cytokines were increased in lada ( p < 0.01 ) . in type 1 diabetes , adiponectin but not hs - crp was increased ( p < 0.01 ) , whereas in type 2 diabetes , hs - crp but not adiponectin was increased ( p < 0.01 ) . 
 adiponectin was correlated positively with gada titer and negatively with hs - crp ( p < 0.01 for both).conclusionsin china , inflammatory markers are increased in all three major types of diabetes , but probably for different reasons , even in autoimmune diabetes . 
RESEARCH DESIGN AND METHODS
Statistical analysis
RESULTS
CONCLUSIONS
Supplementary Material