in 2002 , a baseline survey for this study was performed in the town of hisayama , japan .
briefly , of the total of 3,896 residents aged 40 to 79 years , 3,000 consented to participate in the survey ( participation rate , 77.0% ) . among them , 178 participants were not administered a 75-g oral glucose tolerance test ( ogtt ) : 100 refused the test , 46 had already eaten breakfast , and the other 32 were receiving insulin therapy for diabetes . consequently
after further excluding 485 participants who had newly diagnosed or known diabetes and 8 for whom there was no measurement of angptl2 , the remaining 2,329 ( 953 men and 1,376 women ) were enrolled in the baseline examination .
the baseline participants were followed up prospectively , from 2002 to 2009 , by yearly health examinations during which an ogtt was administered . of the baseline participants , 2,164
( 865 men and 1,299 women ) who underwent reexaminations during the follow - up period were finally selected for this study ( follow - up rate , 92.9% ; mean follow - up period , 6.0 years ) . these participants completed the follow - up examinations an average of 4.9 times , and among them , 861 ( 39.8% of the follow - up population ) underwent all 7 annual ogtts .
during the follow - up , t2 dm occurred in 221 participants ( 115 men and 106 women ) . in the baseline and follow - up examinations
, the study participants underwent the ogtt after an overnight fast of at least 12 h. diabetes was defined by the 2003 american diabetes association criteria ( 7 ) .
serum angptl2 concentrations were measured with the human angptl2 sandwich enzyme - linked immunosorbent assay using two mouse monoclonal antibodies that were confirmed to recognize only angptl2 and not to react with other angptls or angiopoietins ( 4 ) .
angptl2 levels were divided into quartile categories : 2.15 , 2.162.71 , 2.723.40 , and 3.41
the incidence of t2 dm was calculated by the person - year method and adjusted for age and sex by the direct method using 10-year age groupings . the adjusted hazard ratios ( hrs ) and their 95% cis
in 2002 , a baseline survey for this study was performed in the town of hisayama , japan .
briefly , of the total of 3,896 residents aged 40 to 79 years , 3,000 consented to participate in the survey ( participation rate , 77.0% ) . among them , 178 participants were not administered a 75-g oral glucose tolerance test ( ogtt ) : 100 refused the test , 46 had already eaten breakfast , and the other 32 were receiving insulin therapy for diabetes . consequently
after further excluding 485 participants who had newly diagnosed or known diabetes and 8 for whom there was no measurement of angptl2 , the remaining 2,329 ( 953 men and 1,376 women ) were enrolled in the baseline examination .
the baseline participants were followed up prospectively , from 2002 to 2009 , by yearly health examinations during which an ogtt was administered . of the baseline participants , 2,164
( 865 men and 1,299 women ) who underwent reexaminations during the follow - up period were finally selected for this study ( follow - up rate , 92.9% ; mean follow - up period , 6.0 years ) . these participants completed the follow - up examinations an average of 4.9 times , and among them , 861 ( 39.8% of the follow - up population ) underwent all 7 annual ogtts .
during the follow - up , t2 dm occurred in 221 participants ( 115 men and 106 women ) .
in the baseline and follow - up examinations , the study participants underwent the ogtt after an overnight fast of at least 12 h. diabetes was defined by the 2003 american diabetes association criteria ( 7 ) .
serum angptl2 concentrations were measured with the human angptl2 sandwich enzyme - linked immunosorbent assay using two mouse monoclonal antibodies that were confirmed to recognize only angptl2 and not to react with other angptls or angiopoietins ( 4 ) .
angptl2 levels were divided into quartile categories : 2.15 , 2.162.71 , 2.723.40 , and 3.41
the incidence of t2 dm was calculated by the person - year method and adjusted for age and sex by the direct method using 10-year age groupings . the adjusted hazard ratios ( hrs ) and their 95% cis
at baseline , the mean age of participants was 58.6 years , and the proportion of men was 40.9% .
the age- and sex - adjusted incidences of t2 dm increased significantly with elevating quartiles of angptl2 concentrations , and the risk was significantly higher in the second , third , and fourth quartiles than in the first quartile ( table 1 , model 1 ) . in the multivariate analysis ,
this association remained substantially unchanged even after adjustment for age , sex , family history of diabetes , fasting insulin , high - molecular - weight adiponectin , bmi , triglycerides , hdl cholesterol , hypertension , alcohol intake , smoking habits , and regular exercise ( model 2 ) .
as shown in model 3 , after further adjustment for high - sensitivity c - reactive protein ( hs - crp ) values , the risk of developing t2 dm was significantly higher in the highest angptl2 quartile than in the lowest quartile ( hr , 1.80 ; 95% ci , 1.142.85 ; p = 0.01 ) .
these findings remained substantially unchanged when waist circumference was used instead of bmi in the adjusted models .
in a prospective study of a cohort of the general japanese population , we clearly demonstrated that the risk for the development of t2 dm increased with increasing serum angptl2 levels .
this association remained robust even after controlling for other confounding factors , including hs - crp levels . to our knowledge , this is the first report to indicate that serum angptl2 levels are an independent risk factor for developing t2 dm in a general population .
the concept that heightened inflammation is important in the pathogenesis of t2 dm ( 8) is supported by the evidence that inflammation in islets , adipose tissue , liver , and muscle may provoke insulin resistance and -cell dysfunction ( 9,10 ) and may therefore antedate the diagnosis of t2 dm .
prospective observational studies have demonstrated that several nonspecific indicators of inflammation were found to be predictive of incident t2 dm ( 1114 ) . among them , c - reactive protein is a nonspecific inflammatory marker and the most commonly measured circulating marker for subclinical inflammation ( 13,15 ) .
the standardized assays for its measurement are widely available ( 13,15 ) . in this study ,
the association between serum baseline angptl2 levels and incident t2 dm was found to be independent of the hs - crp levels .
nevertheless , further studies would be required to reveal whether the association is truly independent of other established inflammatory markers .
this analysis clearly showed that elevated serum angptl2 levels were independently associated with incident t2 dm .
further studies are needed to reveal the role of angptl2 in inflammation in human adipose tissue and the development of t2 dm .
 objectiveto examine , for the first time , the association between a novel inflammatory cytokine , angiopoietin - like protein ( angptl ) 2 , and the development of type 2 diabetes ( t2dm).research design and methodsa total of 2,164 community - dwelling japanese individuals aged 40 to 79 years without diabetes were followed up for 7 years . 
 serum angptl2 levels were divided into quartile categories at baseline : < 2.15 , 2.162.71 , 2.723.40 , and 3.41 ng / ml . during follow - up , 221 participants developed t2dm.resultsin multivariate analyses , after adjusting for comprehensive risk factors and high - sensitivity c - reactive protein ( hs - crp ) levels , the risk of developing t2 dm was significantly higher in the highest angptl2 quartile than in the lowest quartile ( hazard ratio , 1.80 ; 95% ci , 1.142.85 ; p = 0.01).conclusionselevated serum angptl2 levels were positively associated with the development of t2 dm in a general population , independent of other risk factors including hs - crp levels . 
RESEARCH DESIGN AND METHODS
Study population and follow-up survey
Clinical evaluation and laboratory measurements
Statistical analysis
RESULTS
CONCLUSIONS