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 .