the nurses health study cohort was established in 1976 when 121,700 female registered nurses aged 30 to 55 years returned a mailed questionnaire about medical history and various risk factors for chronic disease . follow - up questionnaires were sent every 2 years to update information on lifestyle factors and newly diagnosed diseases . deaths in the cohort were identified by reports from family members in response to the follow - up questionnaires and from the national death index . in this study , women who reported renal cell cancer or any other cancer ( except for nonmelanoma skin cancer ) before baseline were excluded from analyses . the nurses health study was approved by the institutional review board of brigham and women s hospital ( boston , ma ) . on the baseline and subsequent biennial questionnaires , we asked the participants if and when they had ever been diagnosed with diabetes by a physician . all women who reported a diagnosis were mailed a supplementary questionnaire requesting additional information on symptoms , diagnostic tests , and treatments . participants were considered to have type 2 diabetes if they met the national diabetes data group criteria ( 14 ) , were diagnosed at age 30 years or over , and did not meet the criteria for type 1 ( insulin - dependent and ketosis - prone ) diabetes . women whose dates of diagnosis were unknown ( n = 113 ) were excluded from analyses . we included women who had been diagnosed with type 2 diabetes either at baseline or during the follow - up period . the validity of self - reported diabetes was investigated in a random sample of 62 women in this cohort . the diagnoses of type 2 diabetes were confirmed by medical record review for 98.4% of the women ( 15 ) . in addition , another substudy assessing the prevalence of undiagnosed diabetes suggested a very low rate ( 0.5% ) of false - negative results ( 15 ) . self - reported information on newly diagnosed kidney cancer was obtained on each biennial questionnaire . participants ( or next of kin on behalf of decedents ) who reported a diagnosis of kidney cancer were asked for permission to access medical records . women whose diagnoses of kidney cancer were not confirmed by pathology reports were excluded from analyses ( n = 115 ) . based on the world health organization classification ( 16 ) , cases of renal cell cancer included clear cell , papillary , chromophobe , collecting duct carcinoma , and renal cell carcinoma unclassified . renal pelvis or ureter cancer was not included due to a limited number of cases in this cohort . information on body weight , smoking , history of hypertension , and parity has been updated every 2 years since 1976 . bmi ( in kg / m ) was calculated using height from 1976 and updated weight . self - reported and measured weights were highly correlated ( r = 0.97 ) in a validation study ( 17 ) . for past and current smokers , pack - years of smoking were calculated by multiplying the duration and dose of smoking . physician - diagnosed hypertension was self - reported , and its reliability was reported by a validation study ( 18 ) . information on alcohol consumption , fruit and vegetable intake , and physical activity was obtained from 1980 . participants were followed up prospectively for the diagnosis of type 2 diabetes and incident renal cell cancer from 1976 to 2008 . person - years of follow - up were calculated from the date of return of the 1976 questionnaire to the date of renal cell cancer diagnosis , the date of death from any cause , or the end of follow - up ( 31 may 2008 ) , whichever came first . we entered status of type 2 diabetes in the model as a time - dependent variable allowing the status to change during follow - up upon a new diagnosis . for women who had diabetes at baseline , person - years as diabetic were calculated from the beginning of the study ( 1976 ) ; women who developed diabetes during follow - up contributed person - years as nondiabetic while they were free of diabetes and as diabetic from the dates of diagnosis . cox proportional hazards regression models were used to calculate the hazard ratios ( hrs ) with 95% cis . the proportionality assumption of cox models was not violated . to control as finely as possible for confounding by age , calendar time , and any possible two - way interactions between these two time scales , we stratified the analysis jointly by age in months at start of follow - up and calendar year of the current questionnaire cycle . in the multivariate models , we additionally adjusted for potential confounders , including bmi ( continuous ) , smoking status ( never , past , current ) and pack - years ( continuous ) , history of hypertension ( yes , no ) , and parity ( nulliparous , 12 , 3 , 4 , 5 children ) . in a secondary analysis beginning at the follow - up from 1980 , we tested whether inclusion of additional covariates ( race [ white , nonwhite ] , alcohol consumption , fruit and vegetable intake , and physical activity ) would alter the results . because insulin levels may vary at different stages of diabetes , we evaluated the risk of renal cell cancer depending on time since diagnosis of diabetes . time since diagnosis was calculated from the date of diabetes diagnosis and categorized into 5-year intervals . linear trend of renal cell cancer risk was tested among diabetic women using time since diagnosis as a continuous term ( in month ) in the model . we conducted stratified analyses by levels of bmi ( < 30 , 30 kg / m ) , smoking status ( never , ever ) , and history of hypertension ( no , yes ) because these are known risk factors of renal cell cancer and may be related to type 2 diabetes through insulin resistance and metabolic syndrome . using the likelihood ratio test , the model including the interaction term for variables of interest was compared with the model with the main effect only . in addition , the combined effects of obesity ( bmi 30 kg / m ) , hypertension , and type 2 diabetes on the risk of renal cell cancer were evaluated . according to the number of combined conditions , participants were categorized into four subgroups ( zero , one , two , or three conditions ) . linear trend was examined by treating the number of combined conditions as a continuous term . finally , we assessed public health burden of prevalent obesity , hypertension , and type 2 diabetes by calculating population - attributable risk proportions . statistical tests were performed using sas statistical software version 9.1 ( sas institute , cary , nc ) . all p values were two - tailed ; p < 0.05 was considered statistically significant . the nurses health study cohort was established in 1976 when 121,700 female registered nurses aged 30 to 55 years returned a mailed questionnaire about medical history and various risk factors for chronic disease . follow - up questionnaires were sent every 2 years to update information on lifestyle factors and newly diagnosed diseases . deaths in the cohort were identified by reports from family members in response to the follow - up questionnaires and from the national death index . in this study , women who reported renal cell cancer or any other cancer ( except for nonmelanoma skin cancer ) before baseline were excluded from analyses . the nurses health study was approved by the institutional review board of brigham and women s hospital ( boston , ma ) . on the baseline and subsequent biennial questionnaires , we asked the participants if and when they had ever been diagnosed with diabetes by a physician . all women who reported a diagnosis were mailed a supplementary questionnaire requesting additional information on symptoms , diagnostic tests , and treatments . participants were considered to have type 2 diabetes if they met the national diabetes data group criteria ( 14 ) , were diagnosed at age 30 years or over , and did not meet the criteria for type 1 ( insulin - dependent and ketosis - prone ) diabetes . women whose dates of diagnosis were unknown ( n = 113 ) were excluded from analyses . we included women who had been diagnosed with type 2 diabetes either at baseline or during the follow - up period . the validity of self - reported diabetes was investigated in a random sample of 62 women in this cohort . the diagnoses of type 2 diabetes were confirmed by medical record review for 98.4% of the women ( 15 ) . in addition , another substudy assessing the prevalence of undiagnosed diabetes suggested a very low rate ( 0.5% ) of false - negative results ( 15 ) . self - reported information on newly diagnosed kidney cancer was obtained on each biennial questionnaire . participants ( or next of kin on behalf of decedents ) who reported a diagnosis of kidney cancer were asked for permission to access medical records . women whose diagnoses of kidney cancer were not confirmed by pathology reports were excluded from analyses ( n = 115 ) . based on the world health organization classification ( 16 ) , cases of renal cell cancer included clear cell , papillary , chromophobe , collecting duct carcinoma , and renal cell carcinoma unclassified . renal pelvis or ureter cancer was not included due to a limited number of cases in this cohort . information on body weight , smoking , history of hypertension , and parity has been updated every 2 years since 1976 . bmi ( in kg / m ) was calculated using height from 1976 and updated weight . self - reported and measured weights were highly correlated ( r = 0.97 ) in a validation study ( 17 ) . for past and current smokers , pack - years of smoking were calculated by multiplying the duration and dose of smoking . physician - diagnosed hypertension was self - reported , and its reliability was reported by a validation study ( 18 ) . information on alcohol consumption , fruit and vegetable intake , and physical activity was obtained from 1980 . participants were followed up prospectively for the diagnosis of type 2 diabetes and incident renal cell cancer from 1976 to 2008 . person - years of follow - up were calculated from the date of return of the 1976 questionnaire to the date of renal cell cancer diagnosis , the date of death from any cause , or the end of follow - up ( 31 may 2008 ) , whichever came first . we entered status of type 2 diabetes in the model as a time - dependent variable allowing the status to change during follow - up upon a new diagnosis . for women who had diabetes at baseline , person - years as diabetic were calculated from the beginning of the study ( 1976 ) ; women who developed diabetes during follow - up contributed person - years as nondiabetic while they were free of diabetes and as diabetic from the dates of diagnosis . cox proportional hazards regression models were used to calculate the hazard ratios ( hrs ) with 95% cis . the proportionality assumption of cox models was not violated . to control as finely as possible for confounding by age , calendar time , and any possible two - way interactions between these two time scales , we stratified the analysis jointly by age in months at start of follow - up and calendar year of the current questionnaire cycle . in the multivariate models , we additionally adjusted for potential confounders , including bmi ( continuous ) , smoking status ( never , past , current ) and pack - years ( continuous ) , history of hypertension ( yes , no ) , and parity ( nulliparous , 12 , 3 , 4 , 5 children ) . in a secondary analysis beginning at the follow - up from 1980 , we tested whether inclusion of additional covariates ( race [ white , nonwhite ] , alcohol consumption , fruit and vegetable intake , and physical activity ) would alter the results . because insulin levels may vary at different stages of diabetes , we evaluated the risk of renal cell cancer depending on time since diagnosis of diabetes . time since diagnosis was calculated from the date of diabetes diagnosis and categorized into 5-year intervals . linear trend of renal cell cancer risk was tested among diabetic women using time since diagnosis as a continuous term ( in month ) in the model . we conducted stratified analyses by levels of bmi ( < 30 , 30 kg / m ) , smoking status ( never , ever ) , and history of hypertension ( no , yes ) because these are known risk factors of renal cell cancer and may be related to type 2 diabetes through insulin resistance and metabolic syndrome . using the likelihood ratio test , the model including the interaction term for variables of interest was compared with the model with the main effect only . in addition , the combined effects of obesity ( bmi 30 kg / m ) , hypertension , and type 2 diabetes on the risk of renal cell cancer were evaluated . according to the number of combined conditions , participants were categorized into four subgroups ( zero , one , two , or three conditions ) . linear trend was examined by treating the number of combined conditions as a continuous term . finally , we assessed public health burden of prevalent obesity , hypertension , and type 2 diabetes by calculating population - attributable risk proportions . statistical tests were performed using sas statistical software version 9.1 ( sas institute , cary , nc ) . all p values were two - tailed ; p < 0.05 was considered statistically significant . during 32 years of follow - up of 118,177 women ( 3,531,170 person - years ) , we documented 16,819 cases of type 2 diabetes ( 1,638 at baseline and 15,181 during follow - up ) and 330 cases of incident renal cell cancer . table 1 presents characteristics of the study population in 1990 ( the midpoint of the follow - up period was chosen to best represent the overall follow - up ) . women who reported type 2 diabetes had a substantially higher bmi and history of hypertension compared with nondiabetic women . age - standardized characteristics of study participants in 1990 * * except for the data on mean of age , all data shown are age - standardized to the age distribution of study population ; among current or past smokers only ; among parous women only . type 2 diabetes was associated with a significantly increased risk of renal cell cancer ( table 2 ) . the age - adjusted hr was 2.22 ( 95% ci 1.672.95 ) for diabetic women compared with nondiabetic women . after additional adjustment for bmi and hypertension , the hr was attenuated to 1.61 ( 1.192.18 ) . further adjustment for smoking status , pack - years of smoking , and parity did not materially change the hr ( 1.60 [ 1.192.17 ] ) . secondary analyses with additional adjustment for race , alcohol consumption , fruit and vegetable intake , and physical activity showed a similar hr of 1.61 ( 1.192.19 ) . in all of the multivariate models , bmi and history of hypertension as well as type 2 diabetes the results for either clear cell ( n = 224 ) or nonclear cell ( n = 106 ) were similar to the results for overall renal cell cancer ( 1.84 [ 1.302.60 ] for clear cell ; 1.72 [ 1.012.96 ] for nonclear cell ) . when compared with nondiabetic women , diabetic women on any diabetic medication status ( none , oral medications only , and insulin with or without oral medications ) experienced higher hrs for renal cell cancer ( 1.81 [ 1.202.75 ] , 1.51 [ 1.002.28 ] , 1.29 [ 0.572.95 ] , respectively ) . to exclude the possible cases of renal cell cancer preceding diabetes , we dropped five cases of cancer occurring within 2 years of diabetes diagnoses , and the increased risk was still significant ( 1.48 [ 1.082.02 ] ) . history of type 2 diabetes and hrs of renal cell cancer among participants in the nurses health study , 19762008 rcc , renal cell cancer . * adjusted for age in months , bmi ( kg / m , continuous ) , and hypertension ( yes , no ) ; adjusted for everything in * , and smoking status ( never , past , current ) , pack - years of smoking ( continuous ) , and parity ( nulliparous , 12 , 3 , 4 , 5 children ) . the increased hrs of renal cell cancer were observed up to 15 years of duration of diabetes , and then the hr diminished ( ptrend = 0.01 ; table 3 ) . diabetic women whose duration of diabetes was 510 years had the strongest hr of 2.07 ( 95% ci 1.283.36 ) . when the analysis was confined to the incident diabetes during follow - up with 256 cases of renal cell cancer , similar association was observed ( data not shown ) . diabetic women had consistently higher cumulative incidence of renal cell cancer than nondiabetic women , and the cumulative incidence curves did not cross over the follow - up period ( supplementary fig . 1 ) . duration of type 2 diabetes and hrs of renal cell cancer rcc , renal cell cancer . * adjusted for age in months , bmi ( kg / m , continuous ) , hypertension ( yes , no ) , smoking status ( never , past , current ) , pack - years of smoking ( continuous ) , and parity ( nulliparous , 12 , 3 , 4 , 5 children ) ; calculated among women with type 2 diabetes using time since diagnosis of diabetes ( months , continuous ) . in stratified analyses by levels of bmi , history of hypertension , and smoking status , the positive associations between type 2 diabetes and renal cell cancer were consistent across different strata ( pinteraction  0.32 ) . in addition , combined effects of obesity , hypertension , and type 2 diabetes on the risk of renal cell cancer were observed ( fig . women who had both obesity and diabetes had a significantly increased risk of renal cell cancer than obese nondiabetic women ( hr 1.92 [ 95% ci 1.262.91 ] ) . compared with nonobese nondiabetic women , obese diabetic women had a hr of 2.34 ( 1.623.39 ) ; however , obese nondiabetic women did not show a significantly increased hr ( 1.22 [ 0.911.64 ] ) . exclusion of women with bmi < 18.5 kg / m did not alter the association ( data not shown ) . similarly , women who had both hypertension and diabetes had a higher hr of 1.71 ( 1.232.36 ) compared with women who had hypertension but no diabetes . when we considered the conditions of obesity , hypertension , and type 2 diabetes together , a higher number of comorbid conditions increased the risk of renal cell cancer with significant linear trend ( ptrend < 0.001 ) . women who had all three conditions showed a strikingly elevated risk than women without any comorbidity ( hr 4.13 [ 95% ci 2.766.18 ] ) . combined effects of type 2 diabetes , obesity , and hypertension on the risk of renal cell cancer in the nurses health study , 19762008 . comorbid conditions include obesity ( bmi 30 kg / m ) , history of hypertension , and type 2 diabetes . hrs were derived from cox proportional models adjusted for age in months , bmi ( kg / m , continuous ) , history of hypertension , smoking ( status and pack - years ) , and parity ( nulliparous , 12 , 3 , 4 , 5 + children ) as appropriate . t2d , type 2 diabetes ; ht , hypertension . * p < 0.01 with each referent of leftmost category . * * p < 0.002 . obesity , hypertension , and type 2 diabetes accounted for 31% ( population - attributable risk ) of incident renal cell cancer among this population of women . in this large prospective study of women , type 2 diabetes was significantly associated with an increased risk of renal cell cancer . moreover , the risk was dose dependently elevated with an increasing number of comorbid metabolic conditions . prior epidemiologic studies suggested some but inconclusive evidence for the relationship between diabetes and renal cell cancer . most case  control studies reported no association ( 8,10,11 ) . in the cohorts of hospitalized diabetic patients , the incidence rates of renal cell cancer were higher than in the general populations ( 12,13 ) . some limitations of prior studies have hampered interpretation : sampling prevalent cases that are not ideal for etiologic research when prognosis of outcome is related to exposure ( 8,10,11 ) , lack of generalizability ( 12,13 ) , relatively short duration of follow - up given the slow proliferation and unknown latency of renal cell cancer ( 9,13 ) , and failure to update diabetes status during follow - up ( 9,19 ) . insulin acts as a growth factor for tumor cell proliferation and stimulates igf-1 production , which also plays a role in carcinogenesis ( 2,4,20 ) . growth factors might be important contributors for renal cell cancer development given its peculiar biologic characteristics ( i.e. , spontaneous regression of metastatic lesions after primary tumor excision ) ( 21 ) and laboratory evidence ( 22 ) . second , hyperglycemia may affect carcinogenesis , since increased glucose metabolism is one of the central characteristics of malignant tissues ( 4,23 ) . third , renal hypertrophy , which develops in the earlier course of diabetes , might have implications in carcinogenesis , although pathogenic significance of this mechanical change is unclear ( 12 ) . finally , inflammatory cytokines , reactive oxygen , and lipid peroxidation are other possible mechanisms . this study supports hyperinsulinemia as a plausible mechanism of renal cell cancer development with some evidence . first , comorbidity of obesity , hypertension , and type 2 diabetes elevated the risk of renal cell cancer dose dependently . all these conditions are the components of metabolic syndrome , and insulin resistance is underlying pathophysiology ( 20 ) . since individuals with multiple metabolic components are more closely related to hyperinsulinemia , our results support the insulin mechanism . moreover , obese diabetic women had almost twofold higher risk of renal cell cancer than obese nondiabetic women , but the risk was not different between obese nondiabetic and nonobese nondiabetic women . this finding suggests that metabolic derangement such as hyperinsulinemia is more essential for cancer development . in addition , diabetes without obesity may mainly represent a failure of insulin secretion rather than insulin resistance , thus the lack of association between diabetes without obesity and renal cell cancer adds further support to the insulin mechanism . second , increased risk was observed during the relatively early years of diabetes , but the risk plateaued in the later stages . other recent studies also observed increased risks of colorectal and breast cancer during the early years of diabetes ( 24,25 ) . this time - specific incidence pattern appears consistent with the natural course of hyperinsulinemia in type 2 diabetes . typically , type 2 diabetes develops after long - term insulin resistance and compensatory hyperinsulinemia ; then pancreatic -cell failure eventually leads to hypoinsulinemia over many years ( 12,19 ) . nonetheless , considering the small number of cases of renal cell cancer after 15 years of diabetes in this cohort , the lack of association could be obtained by chance . first , detection bias can not be ignored because diabetic patients are more likely to be under enhanced surveillance for kidney complications . however , exclusion of the cancer cases within 2 years of diabetes diagnoses still resulted in a significant association . second , despite a large cohort size , the number of cases in some subgroups ( i.e. , duration of diabetes 15 years ) was small . third , residual confounding could exist , although we adjusted for most of the important confounders . finally , this study consisted of women and thus the results may not be generalized to men . strengths of this study include a prospective design and relatively large number of renal cell cancer cases . to our knowledge , this cohort provides the longest follow - up for the largest population of women in which the association between diabetes and renal cell cancer has been evaluated . self - reports of physician - diagnosed diabetes were highly accurate according to a validation study ( 15 ) . this study examined the risk of renal cell cancer only in the diagnosed diabetic women , but misclassification as a result of undiagnosed diabetes should be low since we updated diabetes status biennially and the nurses in this study have a low rate of undiagnosed diabetes ( 15 ) . we also updated the information on most of the established risk factors for renal cell cancer . in conclusion , type 2 diabetes was independently associated with an elevated risk of renal cell cancer in this cohort of women . when combined with
objectivetype 2 diabetes is associated with increased risks of several types of cancer ; however , its relationship to renal cell cancer remains unclear.research design and methodsa total of 118,177 women aged 30 to 55 years at baseline ( 1976 ) were followed up through 2008 in the nurses health study . 
 self - reports of physician - diagnosed diabetes were collected at baseline and updated biennially . 
 hazard ratios ( hrs ) were calculated using cox proportional hazards models with adjustment for age , bmi , hypertension , smoking , and parity.resultsduring 32 years of follow - up ( 3,531,170 person - years ) , 16,819 cases of type 2 diabetes and 330 cases of pathology - confirmed incident renal cell cancer were documented . 
 after multivariate adjustment , type 2 diabetes was significantly associated with an increased risk of renal cell cancer ( hr 1.60 [ 95% ci 1.192.17 ] ) . 
 these associations were consistent across different strata of bmi , smoking , and hypertension ( pinteraction  0.32 ) 
 . the risk of renal cell cancer increased with an increasing number of comorbidities , including obesity , hypertension , and type 2 diabetes ( ptrend < 0.001 ) . when compared with women without any comorbidity , women who had all three conditions had a hr of 4.13 ( 2.766.18 ) for renal cell cancer.conclusionstype 2 diabetes 
 is independently associated with an increased risk of renal cell cancer in women . 
 in addition , comorbidity of obesity , hypertension , and type 2 diabetes substantially elevates the risk of renal cell cancer .