type  2 diabetes results from the deterioration of both insulin secretion and insulin action , but the contribution of these factors to glucose intolerance varies among various ethnic groups . in japan , reduced insulinsecreting capacity is considered to play a more important role than impaired insulin resistance during the transition from normal glucose tolerance ( ngt ) to impaired glucose tolerance ( igt ) , and then to overt type  2 diabetes . the insulinogenic index ( i.i . ) is calculated by dividing the increment in serum insulin from 0 to 30  min during an oral glucose tolerance test ( ogtt ) by the increment in plasma glucose during the same period . the i.i . is a marker of earlyphase insulinsecretion capacity in response to a rise in blood glucose level . a low i.i . has been described in japanese patients , even in those with ngt or igt , compared with caucasian patients . the low i.i . in japanese patients we previously reported the positive association between body mass index ( bmi ) and i.i . in diabetic patients , and that bmi was an independent determinant of i.i .. because the average bmi is much lower in the japanese than in caucasians , it is possible that the earlyphase decrease in insulin secretion in the japanese patients is partly a result of the lower bmi . to clarify the insulinsecretion capacity in obese and nonobese japanese patients , we analyzed the insulinsecretion capacity measured by ogtt in subjects with ngt , igt or dm , who were divided into those with and without obesity ( bmi    25 or bmi  <  25 ) , and also estimated visceral fat area ( evfa )    100  cm or evfa  <  100  cm . the study group comprised employees of amagasaki city office , hyogo , japan , an urban area , who had completed the governmentfunded annual health checkup from 2004 to 2008 . among the tests carried out during the annual examination , ogtt was carried out in those participants with one or more risk factor(s ) based on the recommendation of the team physician . the risk factors included the following : ( i ) hypertension : systolic blood pressure ( sbp ) of 130  mmhg and/or diastolic blood pressure ( dbp ) of 85  mmhg ; ( ii ) high plasma glucose level : fasting plasma glucose ( fpg ) level of 110  mg / dl and/or hemoglobin a1c ( hba1c ) level of 5.9% ; ( iii ) dyslipidemia : serum triglyceride level of 150  mg / dl and/or a serum highdensity lipoprotein ( hdl)cholesterol level of < 40  mg / dl , and/or a serum lowdensity lipoprotein ( ldl)cholesterol level of 140  mg / dl ; ( iv ) hyperuricemia : serum uric acid level of 7.0  mg / dl ; and ( v ) abdominal obesity : waist circumference equal to or > 85  cm in men and 90  cm in women ; these are the essential criteria of metabolic syndrome in japan . these patients were provided with health guidance to improve their lifestyle . among the patients who underwent ogtt , 1848 patients were identified as having ngt from 2004 to 2007 , 321 patients were identified as having igt from 2004 to 2007 , and 69 patients developed dm after ifg and/or igt during the period from 2005 to 2008 . anthropometric variables ( height , weight and waist circumference [ wc ] ) were measured in a standing position . bmi was calculated as weight ( kg ) divided by the square of height in meters ( m ) . wc was measured at the umbilical level in cm with a nonstretchable tape in the late exhalation phase at standing position . plasma glucose was measured by the glucose oxidase method ( quickauto ii gluhks ; shinotest , tokyo , japan ) . hba1c was determined by highperformance liquid chromatography ( rapidia auto hba1cl ; tfb , tokyo , japan ) . the value of hba1c ( % ) was estimated as the national glycohemoglobin standardization program ( ngsp ) equivalent value ( % ) calculated by the formula : hba1c ( % )  =  hba1c ( jds )  ( % )  +  0.4% , considering the relational expression of hba1c ( jds ) ( % ) , measured by the previous japanese standard substance and measurement methods , and hba1c ( ngsp ) . serum insulin concentration was measured by doubleantibody radioimmunoassay ( access insulin ; beckman coulter , brea , ca , usa ) and was reported as immunoreactive insulin ( iri ) . serum uric acid ( ua ) , total cholesterol and triglyceride concentrations were measured by enzymatic methods . ldl and hdl cholesterol were also measured by enzymatic methods after heparin and calcium precipitation . visceral fat area ( vfa ) was determined by the bioelectrical impedance analysis ( bia ) method , as reported previously . in ogtt , plasma glucose ( pg ) and serum insulin concentrations were determined at 0 , 30 , 60 and 120  min after ingestion of 75  g of glucose . the i.i . was calculated by dividing the increment in serum insulin by the increment in pg from 0 to 30  min of the ogtt . < 0 or 10 were excluded from the analysis , because they probably do not express the true earlyphase insulin secretion in response to rise in pg . the area under the insulin curve during ogtt ( auc[insulin0120 ] ) was calculated by the trapezoid rule . the diagnoses of diabetes , igt and ngt were based on the criteria of the american diabetes association ( ada ) . actually , ngt was defined as having fpg  <  100  mg / dl and 2h postload glucose  <  140  mg / dl . igt was defined as having fpg  <  126  mg / dl and 2h postload glucose 140199  mg / dl . dm was defined as having fpg    126  mg / dl and/or 2h postload glucose    200  mg / dl . the study group comprised employees of amagasaki city office , hyogo , japan , an urban area , who had completed the governmentfunded annual health checkup from 2004 to 2008 . among the tests carried out during the annual examination , ogtt was carried out in those participants with one or more risk factor(s ) based on the recommendation of the team physician . the risk factors included the following : ( i ) hypertension : systolic blood pressure ( sbp ) of 130  mmhg and/or diastolic blood pressure ( dbp ) of 85  mmhg ; ( ii ) high plasma glucose level : fasting plasma glucose ( fpg ) level of 110  mg / dl and/or hemoglobin a1c ( hba1c ) level of 5.9% ; ( iii ) dyslipidemia : serum triglyceride level of 150  mg / dl and/or a serum highdensity lipoprotein ( hdl)cholesterol level of < 40  mg / dl , and/or a serum lowdensity lipoprotein ( ldl)cholesterol level of 140  mg / dl ; ( iv ) hyperuricemia : serum uric acid level of 7.0  mg / dl ; and ( v ) abdominal obesity : waist circumference equal to or > 85  cm in men and 90  cm in women ; these are the essential criteria of metabolic syndrome in japan . these patients were provided with health guidance to improve their lifestyle . among the patients who underwent ogtt , 1848 patients were identified as having ngt from 2004 to 2007 , 321 patients were identified as having igt from 2004 to 2007 , and 69 patients developed dm after ifg and/or igt during the period from 2005 to 2008 . anthropometric variables ( height , weight and waist circumference [ wc ] ) were measured in a standing position . bmi was calculated as weight ( kg ) divided by the square of height in meters ( m ) . wc was measured at the umbilical level in cm with a nonstretchable tape in the late exhalation phase at standing position . plasma glucose was measured by the glucose oxidase method ( quickauto ii gluhks ; shinotest , tokyo , japan ) . hba1c was determined by highperformance liquid chromatography ( rapidia auto hba1cl ; tfb , tokyo , japan ) . the value of hba1c ( % ) was estimated as the national glycohemoglobin standardization program ( ngsp ) equivalent value ( % ) calculated by the formula : hba1c ( % )  =  hba1c ( jds )  ( % )  +  0.4% , considering the relational expression of hba1c ( jds ) ( % ) , measured by the previous japanese standard substance and measurement methods , and hba1c ( ngsp ) . serum insulin concentration was measured by doubleantibody radioimmunoassay ( access insulin ; beckman coulter , brea , ca , usa ) and was reported as immunoreactive insulin ( iri ) . serum uric acid ( ua ) , total cholesterol and triglyceride concentrations were measured by enzymatic methods . ldl and hdl cholesterol were also measured by enzymatic methods after heparin and calcium precipitation . visceral fat area ( vfa ) was determined by the bioelectrical impedance analysis ( bia ) method , as reported previously . in ogtt , plasma glucose ( pg ) and serum insulin concentrations were determined at 0 , 30 , 60 and 120  min after ingestion of 75  g of glucose . the i.i . was calculated by dividing the increment in serum insulin by the increment in pg from 0 to 30  min of the ogtt . < 0 or 10 were excluded from the analysis , because they probably do not express the true earlyphase insulin secretion in response to rise in pg . the area under the insulin curve during ogtt ( auc[insulin0120 ] ) was calculated by the trapezoid rule . the diagnoses of diabetes , igt and ngt were based on the criteria of the american diabetes association ( ada ) . actually , ngt was defined as having fpg  <  100  mg / dl and 2h postload glucose  <  140  mg / dl . igt was defined as having fpg  <  126  mg / dl and 2h postload glucose 140199  mg / dl . dm was defined as having fpg    126  mg / dl and/or 2h postload glucose    200  mg / dl . table  1 lists the clinical characteristics of the bmi    25 and bmi  <  25 groups with ngt , igt and dm . the mean bmi of the entire bmi  <  25 group was 22.9    1.6  kg / m , and that of the entire bmi    25 group was 27.6    2.4  kg / m . none of the patients in this study were receiving treatment for hypertension , diabetes mellitus or dyslipidemia . auc , area under the curve ; bmi , body mass index ; dm , diabetes mellitus ; fpg , fasting plasma glucose ; igt , impaired glucose tolerance ; i.i . , insulinogenic index ; iri , immunoreactive insulin ; ngt , normal glucose tolerance . the insulinsecreting patterns during ogtt for the bmi    25 and bmi  <  25 groups with ngt , igt and dm are presented in figure  1a  c , respectively . the iri values at 0 , 30 , 60 and 120  min , and the auc(insulin0120 ) were all significantly higher in the bmi    25 group than in the bmi  <  25 group , including those with ngt , igt and dm ( table  1 ) . the insulinsecreting patterns between the bmi    25 and bmi  <  25 groups with ngt , igt or dm were also different ; the peak iri in ngt was noted at 60  min and that in igt was recorded at 120  min in both groups , but the peak iri in dm was observed at 120  min in the bmi    25 group , whereas at 60  min in the bmi  <  25 group ( figure  1a  c ) . figure  2 shows data of the patients divided according to the vfa value ( evfa    100 and evfa the iri at 0 , 30 , 60 and 120  min were significantly higher in ngt and igt subjects with evfa    100 than those with evfa  <  100 . however , in the evfa    100 group with dm , only the iri at 120  min was significantly higher than that of the evfa  <  100 group ( figure  2c ) . insulin secretion patterns during oral glucose tolerance test ( ogtt ) in obese ( body mass index [ bmi ]    25 ) and nonobese ( bmi  <  25 ) patients with ( a ) normal glucose tolerance ( ngt ) , ( b ) impaired glucose tolerance ( igt ) and ( c ) diabetes mellitus ( dm ) . * p  <  0.0001 vs bmi  <  25 ; * * p  <  0.05 vs bmi  <  25 . insulin secretion patterns during oral glucose tolerance test ( ogtt ) in patients with abdominal obesity ( estimated visceral fat area [ evfa ]    100 ) and nonabdominal obesity ( evfa  <  100 ) with ( a ) normal glucose tolerance ( ngt ) , ( b ) impaired glucose tolerance ( igt ) and ( c ) diabetes mellitus ( dm ) . * p  <  0.0001 vs vfa  <  100 ; * * p  <  0.05 vs vfa  <  100 . next , we examined i.i . and homeostasis model of insulin resistance ( homair ) in the bmi    25 and bmi  <  25 groups with ngt , igt and dm . the i.i . decreased from ngt to igt and to dm in both the bmi    25 and bmi values of the bmi    25 groups were significantly higher than those of the bmi  <  25 groups in each stage of glucose tolerance ( table  1 ) . the homair increased from ngt to igt and to dm in both the bmi    25 and bmi <  25 groups ( figure  3b ) . furthermore , homair values of the bmi    25 groups with ngt , igt and dm were significantly higher than those of the bmi  <  25 groups ( table  1 ) . ( a ) insulinogenic index ( i.i . ) and ( b ) homeostasis model of insulin resistance ( homair ) of obese ( body mass index [ bmi ]    25 ) and nonobese ( bmi  <  25 ) patients with normal glucose tolerance ( ngt ) , impaired glucose tolerance ( igt ) and diabetes mellitus ( dm ) . * p  <  0.0001 vs bmi  <  25 ; * * p  <  0.05 vs bmi  <  25 . values also decreased from ngt to igt and to dm in both the evfa    100 and evfa  <  100 groups ( figure  4a ) . values of the evfa    100 group were significantly higher than those of the evfa  <  100 with ngt and igt ( ngt : 0.76    0.70 vs 0.58    0.64 , p  <  0.0001 ; igt : 0.36 0.33 vs 0.20    0.16 , p  =  0.0016 ) . the homair values increased from ngt to igt and to dm in both the evfa    100 and evfa  <  100 groups ( figure  4b ) . furthermore , the homair values of the evfa    100 group were significantly higher than those of the evfa  <  100 group with ngt and igt ( ngt : 1.33    0.77 vs 0.87    0.46 , p  < 0.0001 ; igt : 1.98    1.58 vs 1.29    0.86 , p  =  0.0035 ) . in patients with dm , the i.i . and homair values of the evfa    100 group tended to be higher than those of the evfa  <  100 group , albeit insignificantly ( i.i . : 0.24    0.26 vs 0.16    0.13 , p  =  0.3270 ; homair : 2.42    1.11 vs 1.94    1.03 , p  =  0.2054 ) . ( a ) insulinogenic index ( i.i . ) and ( b ) homeostasis model of insulin resistance ( homair ) of patients with abdominal obesity ( estimated visceral fat area [ evfa ]    100 ) and nonabdominal obesity ( evfa  <  100 ) according to glucose tolerance ( normal glucose tolerance [ ngt ] , impaired glucose tolerance [ igt ] and diabetes mellitus [ dm ] ) . * p  <  0.0001 vs vfa  <  100 ; * * p  <  0.005 vs vfa  <  100 . we also analyzed 230 isolated igt in our patients in order to compare them with those in the botnia study , because that study showed only the data in isolated igt , not in total igt . isolated igt was defined as having fpg  <  110  mg / dl and 2h postload glucose of 140199  mg / dl according to the diagnostic criteria of the ada guideline 1997 . the insulinsecreting patterns were similar in all igt subjects ; that is , the peak iri was recorded at 120  min in both the bmi    25 and bmi  <  25 groups ( 57.4    47.8  mu / ml vs 39.1    23.4  mu / ml , p  =  0.0017 ) . the i.i . values of the bmi    25 and the bmi  <  25 groups in our isolated igt were 0.39    0.37 and 0.29    0.28 ( bmi    25 vs bmi  <  25 , p  =  0.0374 ) , respectively . value in obese japanese patients with isolated igt was lower than that in the caucasian patients with isolated igt from the literature ( 0.39    0.37 vs 0.77    0.21 , p  <  0.01 ) , although the mean bmi were not significantly different ( 28.0    2.6 vs 27.4    4.5 ) . the homair values of the bmi    25 and the bmi  <  25 groups in our isolated igt were 1.85    1.71 and 1.25    0.70 ( bmi    25 vs bmi the homair value in obese japanese with isolated igt was significantly lower than that in the caucasian patients with isolated igt ( 1.85    1.71 vs 2.36    2.00 , p  <  0.01 ) . reduction in insulinsecretion capacity is considered to play a more important role than insulin resistance in the development to dm in japanese patients . first , serum insulin levels during ogtt are lower in patients with igt than those with ngt , and even lower in dm patients . values are low throughout the development of glucose tolerance from ngt to igt and to dm compared with caucasians . in the present study , we analyzed these issues in patients divided according to their bmi , and also according to the vfa value . our results showed significantly higher iri values at 0 , 30 , 60 and 120 min , i.i . and auc(insulin0120 ) in obese ( bmi    25 ) than in nonobese ( bmi  <  25 ) patients with all stages of glucose tolerance . as shown in table  1 , in the bmi    25 group , the auc(insulin0120 ) of igt was 1.22fold higher than that of the ngt patients ( 5155    3973 vs 4232    2375 ) and that of the dm patients was almost 1.17fold ( 4944    2563 ) that of the ngt subjects . in addition , the peak level of iri during ogtt in dm was noted at 120  min in the bmi    25 patients and 60  min in the bmi  <  25 group . these observations show that the total and late insulin secretion during ogtt in obese patients does not decrease as much as in nonobese patients with ngt to igt and to dm , and it is similar to the pattern in caucasians . the previous report that insulin concentrations during ogtt are lower in japanese patients with igt than those with ngt , and even lower in dm patients , does not match our obese group . it is not clear what causes the differences of insulinsecretion patterns between the obese and nonobese groups , but we believe they are cell capacity and visceral fat volume . individuals who have a larger cell capacity could easily be developing visceral fat by overeating , leading to insulin resistance , deterioration of glucose tolerance and delayed hyperinsulin secretion in ogtt . in contrast , individuals who have a smaller cell capacity might not be developing so much visceral fat , but easily developing a deterioration of glucose tolerance owing to the decompensation of earlyphase and then delayedphase insulin secretion when overeating . in order to examine whether it is also true in obese japanese patients that earlyphase insulin secretion is lower than caucasian patients , we compared the i.i . in japanese obese patients with isolated igt with that in caucasian patients with isolated igt . value in obese japanese patients with isolated igt was lower than that of the caucasian patients with isolated igt , although the mean bmi of them were not significantly different , suggesting decreased earlyphase insulin secretion in obese , as well as nonobese , japanese patients compared with caucasian patients . in addition , the homair value in obese japanese patients with isolated igt was lower than that in the caucasian patients with isolated igt . together , with the lower i.i . , these findings suggest that decreased earlyphase insulinsecretion capacity plays a more important role than insulin resistance in the transition of igt to dm , even in japanese obese patients . first , in screening patients , ogtt was carried out in subjects with one or more risk factor(s ) as mentioned in the methods section . therefore , individuals with metabolic syndrome showing insulin resistance might be over represented in the present study , even in ngt . actually , of the 1848 ngt patients in the present study , the number of individuals with bmi    25 was 1025 and the number of individuals with evfa    100 was 1324 . however , the mean homair of nonobese patients in the ngt group was 0.96 and they showed no insulin resistance . the second limitation was the comparison with the botnia study . in the botnia study , patients with known type  2 diabetes and their available family members were included . the study population was basically different from the present study population , including the male and female ratio . it might be that we can not say the population of the botnia study is an appropriate one as a comparative study with the present study . in addition , comparison of mean bmi with caucasian patients in the botnia study might not be reasonable , as they did not separate the subjects with and without obesity . a comparative study with caucasian patients in appropriate populations with matched bmi will be necessary in the future . in conclusion , the present study showed that earlyphase insulin secretion in obese japanese patients is higher than in nonobese patients in all stages of glucose tolerance and the delayed insulinsecretion capacity is also conserved in obese japanese patients , even in igt and dm , which is similar to caucasian patients .
abstractaims / introduction :   pronounced reduction of insulin secretion in response to a rise in glucose level has been reported in japanese patients compared with caucasian patients , but the mean body mass index ( bmi ) is also lower in japanese patients . as bmi is a determinant of insulin secretion , we examined insulinsecretion capacity in obese and nonobese japanese patients.materials and methods :   using the oral glucose tolerance test ( ogtt ) , we estimated the insulinsecreting capacity in obese ( bmi    25 ) and nonobese ( bmi  <  25 ) japanese patients , including 1848 patients with normal glucose tolerance ( ngt ) , 321 patients with impaired glucose tolerance ( igt ) and 69 diabetes ( dm ) patients.results :   the insulinogenic index ( i.i . ) , calculated by dividing the increment in serum insulin by the increment in plasma glucose from 0 to 30  min during ogtt , decreased from ngt to igt and to dm in patients with and without obesity . in patients with ngt , igt and dm , the i.i . 
 values of obese patients were higher than those of the nonobese patients . 
 the peak of insulin concentration in ogtt appeared at 60  min in ngt and at 120  min in igt in both obese and nonobese patients , but in dm it was observed at 120  min in obese patients and at 60  min in nonobese patients.conclusions :   these results show that earlyphase insulin secretion in obese japanese patients is higher than in nonobese patients in all stages of glucose tolerance , and delayed insulinsecretion capacity is also conserved in obese japanese patients , even in igt and dm , which is similar to caucasian patients . 
 ( j diabetes invest , doi:10.1111/j.20401124.2011.00180.x , 2011 )