the jichi medical school ( jms ) cohort study is a prospective , population - based study aimed at exploring the risk factors for cvd in 12 communities in japan .
details regarding the jms cohort study design and additional descriptive data are available in the supplementary data or in our previous reports ( 1315 ) .
enrollment into the jms cohort study and baseline data collection were performed between april 1992 and november 1993 .
a total of 12,490 subjects ( 39.3% male [ n = 4,911 ] ) , who were a mean  sd age of 55.3  11.6 years , participated in the current study . of these , 12,393 ( 99.2% ) gave us written informed consent to be prospectively followed up for study purposes and complete follow - up was achieved for 12,388 ( 99.9% ) .
glucose parameters ( i.e. , plasma glucose levels and hemoglobin alc [ hba1c ] ) and responses to a self - administered questionnaire documenting their medical history of diabetes were available for 3,727 subjects ( 33.2% male [ n = 1,240 ] ) , who were a mean age of 53.8  12.0 years .
we excluded 86 participants who had insufficient data for at least one clinical parameter of age , sex , bmi , systolic or diastolic blood pressure ( bp ) , habitual smoking , information on medical history of hypertension , myocardial infarction , stroke , and cancer , or data of circulating lipid parameters .
ultimately , data from 3,641 subjects were analyzed in the current study ( supplementary fig .
the 3,641 subjects who were included in the present analysis were showed a younger age ( 53.7  12.1 vs. 55.9  11.4 years ; p < 0.001 ) and a lower prevalence of men ( 33.5% [ n = 1,220 ] vs. 41.7% [ n = 3,649 ] ; p < 0.001 ) compared with the 8,747 who were excluded from the analysis . to synchronize the methods of data collection , we established a central committee composed of the chief medical officers from the participating districts .
information about lifestyle and medical history was gathered by means of a written questionnaire . in some subjects , information about physical activity ( n = 3,615 [ 99% ] ) , educational level ( n = 3,601 [ 99% ] ) , and marital status ( n = 3,616 [ 99% ] ) were also obtained ( supplementary data ) .
systolic and diastolic bp were measured with a fully automated sphygmomanometer , bp203rv - ii ( nippon colin , komaki , japan ) , which was placed on the right arm of a subject who had rested in a sitting position for 5 min before measurement .
hypertension was defined as systolic bp / diastolic bp 140/90 mmhg or self - reported usage of antihypertensive medication .
blood samples were drawn from the antecubital vein of seated subjects , with minimal tourniquet use ( details are described in the supplementary data ) .
total cholesterol and triglycerides were measured using an enzymatic method ( wako ; interassay coefficient of variation [ cv ] , 1.5% for total cholesterol and 1.7% for triglyceride ) .
hdl cholesterol was measured using the phosphotungstate precipitation method ( wako ; interassay cv , 1.9% ) .
blood glucose was measured via an enzymatic method ( kanto chemistry ; interassay cv , 1.9% ) , and the value for hba1c was estimated as a national glycohemoglobin standardization program equivalent value calculated with the following formula ( 16 ) : hbalc ( % ) = hbalc ( japan diabetes society ) ( % ) + 0.4% .
the japan society for the study of obesity defines obesity as a bmi 25 kg / m and leanness as a bmi < 18.5 kg / m ( 2,17 ) therefore , in the current study , we defined obesity as bmi 25 kg / m ( mean 27.0  2.4
. however , if we had defined leanness as bmi < 18.5 kg / m , only 160 subjects ( 4% of total patients ) would qualify .
thus , in the current study , we defined leanness as the lowest quartile of bmi ( range 14.221.1 ; mean 19.5  1.2 kg / m ; n = 910 ) . as a consequence , we defined normal bmi as bmi ranging from the second quartile of bmi to 25 kg / m ( mean 22.7  1.0 kg / m ; n = 1,535 ) .
diabetes was defined in accordance with the american diabetes association guidelines ( 18 ) as a fasting glucose concentration of 126 mg / dl or higher , casual blood glucose concentration of 200 mg / dl or higher , hba1c of 6.5% or higher , or self - reported use of antihyperglycemic drugs . as described in previous reports ( 1315 ) , mortality data from the date of entry to 31 december 2002
were collected from the cause - of - death register at public health centers in each community with the permission of the agency of general affairs and the ministry of health , labor , and welfare .
the follow - up period was 10.2  2.1 years ( 37,278 person - years ) .
information on the cause of death was coded for participants who died using icd-10 codes .
causes of death were classified as follows : 1 ) cvd death : heart disease including sudden death ( i21i23 , i46 , i48i50 , q20q28 ) , cvd ( i60 , i61 , i63 , i69 ) , and other cvd ( i71 ) ; 2 ) cancer death ( c02 , c10 , c14c20 , c22c26 , c30 , c34 , c41 , c50 , c53 , c54 , c61 , c64 , c65 , c71 , c74 , c76 , c81c85 , c90c93 ) ; and 3 ) other causes , such as infection and suicide ( a41 , b1519 , d65 , g12 , g21 , g93 , j10j18 , j43 , j84 , j96 , k72 , m62 , n00n08 , r57 , r54 , r64 , s06 , t58 , x60x84 , y85y87 , w75w84 ) .
all statistical analyses were performed with spss 18.0j software ( spss inc , chicago , il ) .
clinical parameters in subjects with or without death were compared using the unpaired t test , and categorical parameters were compared with the  test .
next , we used cox regression analysis to examine the independent effects of diabetes or bmi on the risk of all - cause death . after adjusting for significant covariates , such as age , sex , current smoking status , and systolic bp values , the hazard ratios ( hr ) and
95% cis were calculated for all - cause death , cvd death , or cancer death in subjects with diabetes or leanness ( obesity ) .
finally , our population was subdivided into six categories according to bmi ( leanness , normal bmi , and obesity ) and the presence of diabetes , and the hr ( 95% ci ) of all - cause deaths in each of the six categories was calculated . in that analysis , to examine whether the association among the six categories and all - cause death differed between middle - aged / younger individuals and older individuals , we used a cox regression analysis separately in subjects aged < 65 and 65 years .
this analysis included significant covariates for adjusted variables , such as sex , current smoking status , systolic bp values , and pre - existing myocardial infarction , stroke , or cancer .
we then performed additional adjustments for each of the following possible confounders : physical activity ( n = 3,615 ) , educational level ( n = 3,601 ) , and marital status ( n = 3,616 ) .
finally , using a cox regression analysis , we examined whether there were any interactions between diabetes and bmi in the risk of all - cause death separately in those aged < 65 years and those 65 years .
to synchronize the methods of data collection , we established a central committee composed of the chief medical officers from the participating districts .
information about lifestyle and medical history was gathered by means of a written questionnaire . in some subjects , information about physical activity ( n = 3,615 [ 99% ] ) , educational level ( n = 3,601 [ 99% ] ) , and marital status ( n = 3,616 [ 99% ] ) were also obtained ( supplementary data ) .
systolic and diastolic bp were measured with a fully automated sphygmomanometer , bp203rv - ii ( nippon colin , komaki , japan ) , which was placed on the right arm of a subject who had rested in a sitting position for 5 min before measurement .
hypertension was defined as systolic bp / diastolic bp 140/90 mmhg or self - reported usage of antihypertensive medication .
blood samples were drawn from the antecubital vein of seated subjects , with minimal tourniquet use ( details are described in the supplementary data ) .
total cholesterol and triglycerides were measured using an enzymatic method ( wako ; interassay coefficient of variation [ cv ] , 1.5% for total cholesterol and 1.7% for triglyceride ) .
hdl cholesterol was measured using the phosphotungstate precipitation method ( wako ; interassay cv , 1.9% ) .
blood glucose was measured via an enzymatic method ( kanto chemistry ; interassay cv , 1.9% ) , and the value for hba1c was estimated as a national glycohemoglobin standardization program equivalent value calculated with the following formula ( 16 ) : hbalc ( % ) = hbalc ( japan diabetes society ) ( % ) + 0.4% .
the japan society for the study of obesity defines obesity as a bmi 25 kg / m and leanness as a bmi < 18.5 kg / m ( 2,17 ) therefore , in the current study , we defined obesity as bmi 25 kg / m ( mean 27.0  2.4
however , if we had defined leanness as bmi < 18.5 kg / m , only 160 subjects ( 4% of total patients ) would qualify .
thus , in the current study , we defined leanness as the lowest quartile of bmi ( range 14.221.1 ; mean 19.5  1.2 kg / m ; n = 910 ) . as a consequence , we defined normal bmi as bmi ranging from the second quartile of bmi to 25 kg / m ( mean 22.7  1.0 kg / m ; n = 1,535 ) .
diabetes was defined in accordance with the american diabetes association guidelines ( 18 ) as a fasting glucose concentration of 126 mg / dl or higher , casual blood glucose concentration of 200 mg / dl or higher , hba1c of 6.5% or higher , or self - reported use of antihyperglycemic drugs .
as described in previous reports ( 1315 ) , mortality data from the date of entry to 31 december 2002 were collected from the cause - of - death register at public health centers in each community with the permission of the agency of general affairs and the ministry of health , labor , and welfare .
the follow - up period was 10.2  2.1 years ( 37,278 person - years ) .
information on the cause of death was coded for participants who died using icd-10 codes .
causes of death were classified as follows : 1 ) cvd death : heart disease including sudden death ( i21i23 , i46 , i48i50 , q20q28 ) , cvd ( i60 , i61 , i63 , i69 ) , and other cvd ( i71 ) ; 2 ) cancer death ( c02 , c10 , c14c20 , c22c26 , c30 , c34 , c41 , c50 , c53 , c54 , c61 , c64 , c65 , c71 , c74 , c76 , c81c85 , c90c93 ) ; and 3 ) other causes , such as infection and suicide ( a41 , b1519 , d65 , g12 , g21 , g93 , j10j18 , j43 , j84 , j96 , k72 , m62 , n00n08 , r57 , r54 , r64 , s06 , t58 , x60x84 , y85y87 , w75w84 ) .
all statistical analyses were performed with spss 18.0j software ( spss inc , chicago , il ) .
clinical parameters in subjects with or without death were compared using the unpaired t test , and categorical parameters were compared with the  test .
next , we used cox regression analysis to examine the independent effects of diabetes or bmi on the risk of all - cause death . after adjusting for significant covariates , such as age , sex , current smoking status , and systolic bp values , the hazard ratios ( hr ) and
95% cis were calculated for all - cause death , cvd death , or cancer death in subjects with diabetes or leanness ( obesity ) .
finally , our population was subdivided into six categories according to bmi ( leanness , normal bmi , and obesity ) and the presence of diabetes , and the hr ( 95% ci ) of all - cause deaths in each of the six categories was calculated . in that analysis , to examine whether the association among the six categories and all - cause death differed between middle - aged / younger individuals and older individuals , we used a cox regression analysis separately in subjects aged < 65 and 65 years .
this analysis included significant covariates for adjusted variables , such as sex , current smoking status , systolic bp values , and pre - existing myocardial infarction , stroke , or cancer .
we then performed additional adjustments for each of the following possible confounders : physical activity ( n = 3,615 ) , educational level ( n = 3,601 ) , and marital status ( n = 3,616 ) .
finally , using a cox regression analysis , we examined whether there were any interactions between diabetes and bmi in the risk of all - cause death separately in those aged < 65 years and those 65 years .
the mean  sd age of the 3,641 subjects was 53.7  12.1 years , and 1,220 ( 33.5% ) were men . at the time of study recruitment
, there were 507 patients ( 13.9% ) defined as having diabetes , 1,277 ( 35.1% ) with hypertension , 58 ( 1.6% ) with a pre - existing myocardial infarction or stroke , and 43 ( 1.2% ) with a pre - existing cancer . during an average duration of 10.2  2.1 years ( 37,278 person - years )
, 240 deaths occurred ( 6.4 events/1,000 person - years ) , including 54 cvd deaths , 101 cancer deaths , and 85 other - cause deaths ( e.g. , infection , suicide , accident ) .
the baseline clinical characteristics according to the incidence of all - cause death are reported in table 1 .
the prevalence of leanness or diabetes was higher in subjects with death than in those without death .
the crude incidence rate of all - cause death was 13.0 events/1,000 person - years for diabetes and 5.4 events/1,000 person - years for nondiabetes . by comparison , the crude incidence rate per 1,000 person - years of all - cause death was 8.4 events in lean subjects , 5.2 events in subjects with normal bmi , and 6.5 events in obese subjects .
the prevalence of cause - specific death subdivided by the presence of diabetes or bmi is reported in supplementary tables 1 and 2 .
kaplan - meier curves showing cumulative all - cause death according to the presence of diabetes or the classification of bmi are shown in fig .
1a and b. there was no significant difference in the rate of all - cause death among the subjects subdivided by the presence of diabetes or bmi in the first 5-year period , whereas the differences were significant for the second 5-year period ( both p < 0.05 by log - rank test ) .
baseline clinical characteristics of the study population according to the occurrence of death kaplan - meier curves show the cumulative incidence of all - cause death by the presence of diabetes vs. nondiabetes ( a ) , or the classification of bmi by leanness or obesity vs. normal bmi ( b ) .
next , the hr ( 95% ci ) of all - cause death associated with leanness ( obesity ) or diabetes was calculated using cox regression analysis ( table 2 ) .
the hr ( 95% ci ) of all - cause death in subjects with leanness , but not obesity , and diabetes were significant , even after adjustment for significant covariates .
stratification with cause - specific deaths showed that leanness and obesity were both associated with an increased risk of cvd death , whereas diabetes was associated with an increased risk of cancer death . when we defined obesity as the highest quartile of bmi ( 25.3 kg / m ; mean 27.7 kg / m , n = 910 ) instead of bmi 25 kg / m , the risk of cvd death in obesity remained unchanged ( data not shown ) .
furthermore , when we examined the male - to - female differences in the risk of all - cause death as well as cancer death in diabetes , we found that this conclusion remained unchanged ( supplementary tables 3 and 4 ) .
cox regression analysis for all - cause death , cvd death , and cancer death in the total population ( n = 3,641 ) the increased risk of all - cause death in leanness or diabetes ( table 2 ) did not change when the 66 subjects who died within 2 years of follow - up were excluded ( data not shown ) .
after exclusion of 58 subjects with a pre - existing myocardial infarction or stroke and 43 with cancer at baseline , associations of leanness or diabetes with all - cause death remained significant ( data not shown ) .
when we adjusted for various confounding factors , such as physical activity , educational level , and marital status in the associations between diabetes or leanness and all - cause death , the risk of diabetes or leanness remained unchanged ( data not shown ) . among 2,866 subjects aged < 65 years
, the risk of all - cause death conferred by diabetes , compared with nondiabetes with normal bmi ( reference ) , increased when diabetes was accompanied by leanness or obesity ( fig .
in contrast , among the 775 subjects aged 65 years , the risk of all - cause death conferred by diabetes , compared with nondiabetes with normal bmi , increased when the diabetes was accompanied by leanness but not by obesity ( fig .
we repeated the analysis after excluding subjects who died within the initial 2 years of follow - up or those who had a pre - existing myocardial infarction , stroke , or cancer at baseline , and the conclusions remained unchanged ( data not shown ) .
furthermore , we performed additional adjustments for each of the following possible confounders in fig .
the hr ( 95% ci ) of all - cause deaths according to the presence of diabetes and bmi are shown separately in those aged < 65 years ( a ) and those 65 years ( b ) .
the analysis was adjusted for sex , current smoking status , systolic bp values , and pre - existing myocardial infarction , stroke , or cancer .
p < 0.05 vs. reference group , p < 0.01 vs. reference group , and p < 0.001 vs. reference group .
finally , using a cox regression analysis ( including sex , current smoking status , systolic bp values , and pre - existing myocardial infarction , stroke , or cancer ) , we examined whether there was an interaction between diabetes and bmi in the risk of all - cause death separately in those aged < 65 years and those 65 years . as a result , we found a significant interaction between diabetes and leanness only in subjects aged < 65 years ( p = 0.047 ) .
the mean  sd age of the 3,641 subjects was 53.7  12.1 years , and 1,220 ( 33.5% ) were men . at the time of study recruitment
, there were 507 patients ( 13.9% ) defined as having diabetes , 1,277 ( 35.1% ) with hypertension , 58 ( 1.6% ) with a pre - existing myocardial infarction or stroke , and 43 ( 1.2% ) with a pre - existing cancer .
during an average duration of 10.2  2.1 years ( 37,278 person - years ) , 240 deaths occurred ( 6.4 events/1,000 person - years ) , including 54 cvd deaths , 101 cancer deaths , and 85 other - cause deaths ( e.g. , infection , suicide , accident ) .
the baseline clinical characteristics according to the incidence of all - cause death are reported in table 1 .
the prevalence of leanness or diabetes was higher in subjects with death than in those without death .
the crude incidence rate of all - cause death was 13.0 events/1,000 person - years for diabetes and 5.4 events/1,000 person - years for nondiabetes . by comparison ,
the crude incidence rate per 1,000 person - years of all - cause death was 8.4 events in lean subjects , 5.2 events in subjects with normal bmi , and 6.5 events in obese subjects .
the prevalence of cause - specific death subdivided by the presence of diabetes or bmi is reported in supplementary tables 1 and 2 .
kaplan - meier curves showing cumulative all - cause death according to the presence of diabetes or the classification of bmi are shown in fig .
1a and b. there was no significant difference in the rate of all - cause death among the subjects subdivided by the presence of diabetes or bmi in the first 5-year period , whereas the differences were significant for the second 5-year period ( both p < 0.05 by log - rank test ) .
baseline clinical characteristics of the study population according to the occurrence of death kaplan - meier curves show the cumulative incidence of all - cause death by the presence of diabetes vs. nondiabetes ( a ) , or the classification of bmi by leanness or obesity vs. normal bmi ( b ) .
next , the hr ( 95% ci ) of all - cause death associated with leanness ( obesity ) or diabetes was calculated using cox regression analysis ( table 2 ) .
the hr ( 95% ci ) of all - cause death in subjects with leanness , but not obesity , and diabetes were significant , even after adjustment for significant covariates .
stratification with cause - specific deaths showed that leanness and obesity were both associated with an increased risk of cvd death , whereas diabetes was associated with an increased risk of cancer death .
when we defined obesity as the highest quartile of bmi ( 25.3 kg / m ; mean 27.7 kg / m , n = 910 ) instead of bmi 25 kg / m , the risk of cvd death in obesity remained unchanged ( data not shown ) .
furthermore , when we examined the male - to - female differences in the risk of all - cause death as well as cancer death in diabetes , we found that this conclusion remained unchanged ( supplementary tables 3 and 4 ) .
cox regression analysis for all - cause death , cvd death , and cancer death in the total population ( n = 3,641 ) the increased risk of all - cause death in leanness or diabetes ( table 2 ) did not change when the 66 subjects who died within 2 years of follow - up were excluded ( data not shown ) .
after exclusion of 58 subjects with a pre - existing myocardial infarction or stroke and 43 with cancer at baseline , associations of leanness or diabetes with all - cause death remained significant ( data not shown ) .
when we adjusted for various confounding factors , such as physical activity , educational level , and marital status in the associations between diabetes or leanness and all - cause death , the risk of diabetes or leanness remained unchanged ( data not shown ) .
among 2,866 subjects aged < 65 years , the risk of all - cause death conferred by diabetes , compared with nondiabetes with normal bmi ( reference ) , increased when diabetes was accompanied by leanness or obesity ( fig .
in contrast , among the 775 subjects aged 65 years , the risk of all - cause death conferred by diabetes , compared with nondiabetes with normal bmi , increased when the diabetes was accompanied by leanness but not by obesity ( fig .
we repeated the analysis after excluding subjects who died within the initial 2 years of follow - up or those who had a pre - existing myocardial infarction , stroke , or cancer at baseline , and the conclusions remained unchanged ( data not shown ) .
furthermore , we performed additional adjustments for each of the following possible confounders in fig .
the hr ( 95% ci ) of all - cause deaths according to the presence of diabetes and bmi are shown separately in those aged < 65 years ( a ) and those 65 years ( b ) .
the analysis was adjusted for sex , current smoking status , systolic bp values , and pre - existing myocardial infarction , stroke , or cancer .
* p < 0.05 vs. reference group , p < 0.01 vs. reference group , and p < 0.001 vs. reference group .
finally , using a cox regression analysis ( including sex , current smoking status , systolic bp values , and pre - existing myocardial infarction , stroke , or cancer ) , we examined whether there was an interaction between diabetes and bmi in the risk of all - cause death separately in those aged < 65 years and those 65 years . as a result
, we found a significant interaction between diabetes and leanness only in subjects aged < 65 years ( p = 0.047 ) .
in the present 10-year prospective study in a rural japanese general population , we have demonstrated for the first time the associations between diabetes , bmi , and the risk of death .
the main findings of the current study are that 1 ) leanness , but not obesity , and diabetes were independently associated with an increased risk of all - cause death ; 2 ) leanness and obesity were both associated with an increased risk of cvd death , whereas diabetes was associated with cancer death ; and 3 ) lean diabetic subjects had a substantially high risk of all - cause death regardless of age , whereas obese diabetic subjects showed increased risk only in those aged < 65 years .
these findings provide opportunities for a careful evaluation of the risks accompanying diabetes that can be modified by bmi or age .
most of the literature regarding diabetes and excess mortality has been derived from western populations ( 19,20 ) , and there are few prospective studies on mortality and cause of death from diabetes in japan .
the recent substantial increase in rates of diabetes in asian countries ( 2,3 ) highlights the need to better understand the mortality related to diabetes and to identify high - risk subjects in order to prevent excess mortality from diabetes within each asian country . in the current study
, diabetes almost doubled the incidence of all - cause death compared with nondiabetes , and diabetes increased the risk of all - cause deaths by 65% , even after adjustment for significant covariates ( table 2 ) .
contrary to previous reports from western populations ( 21,22 ) , we observed that cvd mortality was not significantly greater in diabetes than nondiabetes . because the number of cvd death was small , this issue merits further analysis .
nevertheless , a direct comparison between diabetes in japanese in caucasians showed that the cvd mortality is threefold higher in caucasians ( 23 ) .
moreover , a world health organization multinational study demonstrated that japanese cohorts showed a very low excess mortality from cvd death compared with western populations ( 24 ) .
these findings indicate that the association of diabetes with cvd mortality may differ between japanese and western populations ; further studies on a large cohort from a japanese general population will be required to clarify that issue . diabetes and cancer are common conditions , and their codiagnosis in the same individual is not infrequent ( 25 ) . in a previous japanese cohort study ,
diabetes was associated with an increase in the risk of total cancer incidence of 27% in men and 21% in women ( 26 ) .
we also demonstrated that cancer death was higher in diabetes compared with nondiabetes without sex differences ( supplementary tables 3 and 4 ) .
it is not easy to differentiate whether diabetes causes cancer or whether risk factors for diabetes , such as obesity and physical inactivity , are associated with cancer .
however , our data showed that an increased risk of cancer mortality in diabetes remained unchanged even after adjustment for significant covariates , including obesity or physical activity . by site ,
emerging data support higher risks of death from cancers of the liver , pancreas , and colon among adults with diabetes , whereas the evidence with other malignancies is equivocal ( 2527 ) .
there were not enough cancer deaths in the current study to analyze the association between diabetes and cancer death by tumor site ( supplementary tables 1 and 2 ) .
the biological plausibility of the associations between diabetes and cancer has tended to be site - specific but may partly be the result of diabetic metabolic and hormonal alternations as well as their underlying common biological mechanisms such as hyperinsulinemia , abnormal production of adipocytokines and growth factors , and epigenetic changes ( 25 ) . because our data showed only cancer deaths , but not cancer incidences , we can not exclude the possibility that a diagnosis of diabetes or poor glycemic control can lead to poor outcomes among subjects who developed cancer during the follow - up period ( 28 ) .
further studies are warranted to quantify the specific impact of diabetes on cancer incidence versus cancer survival .
we demonstrated that , compared with nondiabetes with normal bmi , lean diabetes showed a substantially higher risk of all - cause death in subjects aged < 65 years and also those aged 65 years . especially in subjects aged
< 65 years , a significant interaction was found between diabetes and leanness in the risk of all - cause death .
obese diabetes , by contrast , showed an elevated risk only in subjects aged < 65 years ( fig .
2 ) , a finding similar to the previous findings of nilsson et al . ( 29 ) that obese diabetes in older persons ( all subjects were 75 years old ) presented no mortality risk .
this may be partly explained by a survival bias ; that is , the detrimental effects of obesity - related metabolic abnormalities are generally less prominent among older subjects than they are in middle - aged individuals ( 30,31 ) .
the reasons for pronounced mortality in lean diabetes in the current study are not clear .
the pathophysiology of lean diabetes is heterogeneous , including impaired insulin secretion , increased endogenous glucose production , high inflammatory state , and higher perceived stress hormones ( 32,33 ) .
the contrasting general clinical phenotypes of lean diabetes compared with obese diabetes have recently been discussed ( 32,33 ) , although we can not contribute to that discussion . incomplete control for confounding or reverse causation bias
in an effort to control for reverse causation , we repeated the analysis after excluding subjects who died within the initial 2 years of follow - up and those who had a pre - existing myocardial infarction , stroke , or cancer at baseline ; the conclusions remained unchanged .
however , that the leanness associated with higher mortality during the follow - up period was a result of occult diseases involving muscle or fat wasting can not be excluded .
the strengths of the current study include 1 ) this is a population - based study in an asian ( japanese ) population where there are limited data available addressing the association between diabetes , leanness , and mortality ; and 2 ) complete follow - up was achieved in almost the entire cohort .
a number of people from the original cohort ( 1315 ) were excluded ( 71% ) ; thus , there is a potential bias in the study participants chosen for the study analysis .
data on diabetes type , duration ( i.e. , no distinction between subjects with new - onset diabetes and those with longer - duration diabetes ) , disease severity , and the presence of diabetes complications at baseline would have been informative and would have extended the knowledge achieved in the current study .
second , we could not separate diabetes into type 1 or type 2 diabetes , although the incidence of type 1 diabetes is extremely low ( approximately 2 cases / year/100,000 individuals ) in japan ( 34 ) .
lastly , information regarding bmi and glucose values was available only at baseline , making it impossible to evaluate the effects of changes during the follow - up period in either or both of these factors .
in conclusion , among the japanese general population , a diagnosis of diabetes confers an increased risk of all - cause death .
particular attention must be paid to the pronounced high mortality for lean diabetes . taken together with the evidence of a rapidly increasing number of diabetes cases in asia
, the findings from the current study suggest that an integrated strategy combining preventive actions against diabetes , improvement of care for diabetes that includes early detection of diabetes complications as well as undiagnosed chronic disease , and multidisciplinary care programs is needed .
most of the literature regarding diabetes and excess mortality has been derived from western populations ( 19,20 ) , and there are few prospective studies on mortality and cause of death from diabetes in japan .
the recent substantial increase in rates of diabetes in asian countries ( 2,3 ) highlights the need to better understand the mortality related to diabetes and to identify high - risk subjects in order to prevent excess mortality from diabetes within each asian country . in the current study , diabetes almost doubled the incidence of all - cause death compared with nondiabetes , and diabetes increased the risk of all - cause deaths by 65% , even after adjustment for significant covariates ( table 2 ) .
contrary to previous reports from western populations ( 21,22 ) , we observed that cvd mortality was not significantly greater in diabetes than nondiabetes . because the number of cvd death was small , this issue merits further analysis .
nevertheless , a direct comparison between diabetes in japanese in caucasians showed that the cvd mortality is threefold higher in caucasians ( 23 ) .
moreover , a world health organization multinational study demonstrated that japanese cohorts showed a very low excess mortality from cvd death compared with western populations ( 24 ) .
these findings indicate that the association of diabetes with cvd mortality may differ between japanese and western populations ; further studies on a large cohort from a japanese general population will be required to clarify that issue . diabetes and cancer are common conditions , and their codiagnosis in the same individual is not infrequent ( 25 ) . in a previous japanese cohort study ,
diabetes was associated with an increase in the risk of total cancer incidence of 27% in men and 21% in women ( 26 ) .
we also demonstrated that cancer death was higher in diabetes compared with nondiabetes without sex differences ( supplementary tables 3 and 4 ) .
it is not easy to differentiate whether diabetes causes cancer or whether risk factors for diabetes , such as obesity and physical inactivity , are associated with cancer .
however , our data showed that an increased risk of cancer mortality in diabetes remained unchanged even after adjustment for significant covariates , including obesity or physical activity . by site ,
emerging data support higher risks of death from cancers of the liver , pancreas , and colon among adults with diabetes , whereas the evidence with other malignancies is equivocal ( 2527 ) .
there were not enough cancer deaths in the current study to analyze the association between diabetes and cancer death by tumor site ( supplementary tables 1 and 2 ) .
the biological plausibility of the associations between diabetes and cancer has tended to be site - specific but may partly be the result of diabetic metabolic and hormonal alternations as well as their underlying common biological mechanisms such as hyperinsulinemia , abnormal production of adipocytokines and growth factors , and epigenetic changes ( 25 ) . because our data showed only cancer deaths , but not cancer incidences , we can not exclude the possibility that a diagnosis of diabetes or poor glycemic control can lead to poor outcomes among subjects who developed cancer during the follow - up period ( 28 ) .
further studies are warranted to quantify the specific impact of diabetes on cancer incidence versus cancer survival .
a recent meta - analysis from western populations demonstrated the  obesity paradox  in diabetes and the importance of assessing nonobese ( bmi < 25 kg / m ) diabetes as being high - mortality cases ( 9 ) .
we demonstrated that , compared with nondiabetes with normal bmi , lean diabetes showed a substantially higher risk of all - cause death in subjects aged < 65 years and also those aged 65 years . especially in subjects aged < 65 years , a significant interaction was found between diabetes and leanness in the risk of all - cause death .
obese diabetes , by contrast , showed an elevated risk only in subjects aged < 65 years ( fig .
2 ) , a finding similar to the previous findings of nilsson et al . ( 29 ) that obese diabetes in older persons ( all subjects were 75 years old ) presented no mortality risk .
this may be partly explained by a survival bias ; that is , the detrimental effects of obesity - related metabolic abnormalities are generally less prominent among older subjects than they are in middle - aged individuals ( 30,31 ) .
the reasons for pronounced mortality in lean diabetes in the current study are not clear .
the pathophysiology of lean diabetes is heterogeneous , including impaired insulin secretion , increased endogenous glucose production , high inflammatory state , and higher perceived stress hormones ( 32,33 ) .
the contrasting general clinical phenotypes of lean diabetes compared with obese diabetes have recently been discussed ( 32,33 ) , although we can not contribute to that discussion . incomplete control for confounding or reverse causation bias
in an effort to control for reverse causation , we repeated the analysis after excluding subjects who died within the initial 2 years of follow - up and those who had a pre - existing myocardial infarction , stroke , or cancer at baseline ; the conclusions remained unchanged .
however , that the leanness associated with higher mortality during the follow - up period was a result of occult diseases involving muscle or fat wasting can not be excluded .
the strengths of the current study include 1 ) this is a population - based study in an asian ( japanese ) population where there are limited data available addressing the association between diabetes , leanness , and mortality ; and 2 ) complete follow - up was achieved in almost the entire cohort .
a number of people from the original cohort ( 1315 ) were excluded ( 71% ) ; thus , there is a potential bias in the study participants chosen for the study analysis .
data on diabetes type , duration ( i.e. , no distinction between subjects with new - onset diabetes and those with longer - duration diabetes ) , disease severity , and the presence of diabetes complications at baseline would have been informative and would have extended the knowledge achieved in the current study .
second , we could not separate diabetes into type 1 or type 2 diabetes , although the incidence of type 1 diabetes is extremely low ( approximately 2 cases / year/100,000 individuals ) in japan ( 34 ) .
lastly , information regarding bmi and glucose values was available only at baseline , making it impossible to evaluate the effects of changes during the follow - up period in either or both of these factors . in conclusion , among the japanese general population
particular attention must be paid to the pronounced high mortality for lean diabetes . taken together with the evidence of a rapidly increasing number of diabetes cases in asia
, the findings from the current study suggest that an integrated strategy combining preventive actions against diabetes , improvement of care for diabetes that includes early detection of diabetes complications as well as undiagnosed chronic disease , and multidisciplinary care programs is needed .
 objectiveto examine the bmi - stratified associations between diabetes and the risks of all - cause death , cardiovascular disease ( cvd ) death , and cancer death.research design and methodsusing a prospective study with 12 rural japanese general populations ( n = 3,641 , mean age , 53.7 years ; 33.5% men ) , we examined the associations between diabetes and the risk of all - cause death , cvd death , and cancer death . 
 we also examined the effects of bmi and age on such associations.resultsduring an average duration of 10.2 years ( 37,278 person - years ) , 240 deaths occurred ( 54 deaths from cvd , 101 from cancer , and 85 from other causes ) . 
 cox regression analysis showed leanness ( defined as the lowest quartile of entire bmi ; mean , 19.5 kg / m2 ) , but not obesity ( bmi 25 kg / m2 ) , and diabetes were independently associated with an increased risk of all - cause death ( hazard ratio [ hr ] 1.70 and 1.65 , respectively ; both p < 0.01 . ) . 
 stratification with cause - specific deaths showed that leanness and obesity were associated with cvd death ( hr 3.77 and 2.94 , respectively ) , whereas diabetes was associated with cancer death ( hr 1.87 ; all p < 0.05 ) . 
 the increased risk of all - cause death in diabetes was substantially higher in lean subjects aged < 65 years ( hr 3.4 ) or those aged 65 years ( hr 4.2 ) , whereas the risk in obese diabetes patients was significant only in subjects aged < 65 years ( hr 2.32 ; all p < 0.05).conclusionsamong the japanese general population , diabetes confers an increased risk of all - cause death . 
 particular attention must be paid to the pronounced high mortality in diabetes accompanied with leanness , regardless of age . 
RESEARCH DESIGN AND METHODS
Measurements of baseline variables
Definition of leanness, obesity, and diabetes
End point
Statistical analysis
RESULTS
Baseline clinical characteristics
Leanness, diabetes, and all-cause deaths
Effects of BMI or age on the associations between diabetes and all-cause death
CONCLUSIONS
Excess mortality in diabetes
Effects of age and BMI on the association between diabetes and all-cause death