recruitment to the whitehall ii study took place between 1985 and 1988 among all office staff , aged 3555 years , in 20 london - based civil service departments ( 22 ) .
informed consent was obtained from all participants , and the university college london medical school committee on the ethics of human research approved the protocol .
the target population for the current study was a sample of 5,932 participants ( 4,189 men and 1,743 women , mean age 54.6 years ) for whom data were collected in at least two of the following cycles : from 19911993 to 19971999 , from 19971999 to 20022004 , and from 20022004 to 20072009 .
included participants had complete data on type 2 diabetes , psychological distress , frs ( 21 ) , and covariates ( age , sex , socioeconomic status [ ses ] , ethnicity , antidepressant use , smoking , and physical activity ) at baseline .
those included in the analyses were free of diabetes at the baseline cycle(s ) and had data on their prediabetes status and frs ( fig .
1 ) . each participant could thus contribute to a minimum of one and a maximum of three cycles .
the 5,932 eligible participants produced 13,207 person - observations ; mean follow - up time between baseline and follow - up for each cycle was 5.46 ( sd 0.51 ) years .
, venous blood samples were taken from individuals who were fasting 8 h ( those whose clinic visit was in the afternoon had a light fat - free breakfast and they were asked to fast for 5 h ) before undergoing a standard 2-h 75-g oral glucose tolerance test ( ogtt ) ( 1 ) .
mmol / l ( 2326 ) , self - reported doctor - diagnosed diabetes , or use of diabetes medication .
blood samples were handled at all phases using similar standard protocols , and baseline cases were excluded from the prospective analyses .
prediabetes was defined as impaired fasting glucose ( ifg ; a fasting glucose of 5.66.9 mmol / l and 2-h glucose
< 7.8 mmol / l ) and/or impaired glucose tolerance ( a fasting glucose < 7 mmol / l and a 2-h postload glucose of 7.811.0
the frs is based on a previously published detailed algorithm ( 21 ) with the following components : ifg , overweight or obesity , low level of hdl , high level of triglycerides , elevated blood pressure or antihypertensive medication , and parental diabetes .
, participants with impaired glucose tolerance received the same score as those with ifg ( 10 points in both cases ) . in the framingham offspring study , participants with > 19 points had an 8-year incidence of type 2 diabetes > 15% ( 21 ) ; thus we used this score to determine high risk status .
participants with normoglycemia scored 018 in the frs and were further classified into the low - risk group ( 09 points ) and intermediate - risk group ( 1019 ) , the latter range corresponding to the lower ( i.e. , intermediate)-risk group ( 1019 points ) among participants with prediabetes .
based on the baseline information on prediabetes status and the frs , participants were classified into four groups : 1 ) no prediabetes , low frs ( 09 ) ; 2 ) no prediabetes , intermediate frs ( 1019 ) ; 3 ) prediabetes , intermediate frs ( 1019 ) ; and 4 ) prediabetes , high frs ( > 19 ) . the 30-item general health questionnaire ( ghq-30 ) was used to assess psychological distress ( 27 ) .
the ghq is a screening instrument designed to detect common psychological symptoms , such as depression and anxiety .
it is widely used in population - based surveys and trials and has been validated in the whitehall ii study ( 28 ) .
each questionnaire item inquires about a specific symptom ; response categories are scored as either 1 or 0 to indicate presence or absence of the symptom . a total score of 5 or more led to individuals being defined as ghq - symptom  cases  and scores 04 as  noncases  ( 28 ) .
sociodemographic covariates included age , sex , ses ( based on the last known occupational grade and divided into high , intermediate , and low ) , and ethnicity ( white , south asian , or other ) and were all based on survey responses ( 22 ) .
antidepressant use ( yes / no ) and smoking ( yes / no ) were based on self - reported information at the baseline survey of each cycle .
physical activity was assessed at cycle 1 based on answers to questions about the frequency and duration of participation in mildly energetic ( e.g. , weeding , general housework , bicycle repair ) , moderately energetic ( e.g. , dancing , cycling , leisurely swimming ) , and vigorous physical activity ( e.g. , running , hard swimming , playing squash ) . at cycles 2 and 3 ,
the questionnaire included 20 items on frequency and duration of participation in different physical activities ( e.g. , walking , cycling , sports ) that were used to compute hours per week of each intensity level .
participants were classified as active ( > 2.5 h / week of moderate physical activity or > 1 h / week of vigorous physical activity ) , inactive ( < 1 h / week of moderate physical activity and < 1 h / week of vigorous physical activity ) , or moderately active ( if not active or inactive ) ( 29 ) .
after harmonization of data across cycles , we examined associations between psychological distress at baseline and incident type 2 diabetes at follow - up for each cycle .
we used generalized estimation equations ( gees ) with a logistic link to control for intraindividual correlation between repeated measurements to estimate odds ratios ( ors ) and their 95% cis .
gee analysis was used because repeated measurements were nested within participants ( i.e. , the same individuals could contribute more than one observation to the dataset ) , and the gee method takes into account nonindependence of the within - participant observations when estimating standard errors .
we first analyzed the association between psychological distress and the incidence of type 2 diabetes in the total cohort .
then we grouped the participants according to their baseline prediabetes status , frs , and psychological distress into eight groups as follows : 1 ) normoglycemia , frs 09 , no distress ( reference group ) ; 2 ) normoglycemia , score 09 , distress ; 3 ) normoglycemia , score 1019 , no distress ; 4 ) normoglycemia , score 1019 , distress ; 5 ) prediabetes , score 1019 , no distress ; 6 ) prediabetes , score 1019 , distress ; 7 ) prediabetes , score > 19 , no distress ; and 8) prediabetes , score > 19 , distress .
models were adjusted for age , sex , ses , ethnicity , antidepressant use , smoking , and physical activity .
sas version 9.2 ( sas , cary , nc ) was used for all analyses .
recruitment to the whitehall ii study took place between 1985 and 1988 among all office staff , aged 3555 years , in 20 london - based civil service departments ( 22 ) .
informed consent was obtained from all participants , and the university college london medical school committee on the ethics of human research approved the protocol .
the target population for the current study was a sample of 5,932 participants ( 4,189 men and 1,743 women , mean age 54.6 years ) for whom data were collected in at least two of the following cycles : from 19911993 to 19971999 , from 19971999 to 20022004 , and from 20022004 to 20072009 .
included participants had complete data on type 2 diabetes , psychological distress , frs ( 21 ) , and covariates ( age , sex , socioeconomic status [ ses ] , ethnicity , antidepressant use , smoking , and physical activity ) at baseline .
those included in the analyses were free of diabetes at the baseline cycle(s ) and had data on their prediabetes status and frs ( fig .
1 ) . each participant could thus contribute to a minimum of one and a maximum of three cycles .
the 5,932 eligible participants produced 13,207 person - observations ; mean follow - up time between baseline and follow - up for each cycle was 5.46 ( sd 0.51 ) years .
at each clinical phase , venous blood samples were taken from individuals who were fasting 8 h ( those whose clinic visit was in the afternoon had a light fat - free breakfast and they were asked to fast for 5 h ) before undergoing a standard 2-h 75-g oral glucose tolerance test ( ogtt ) ( 1 ) .
mmol / l ( 2326 ) , self - reported doctor - diagnosed diabetes , or use of diabetes medication .
blood samples were handled at all phases using similar standard protocols , and baseline cases were excluded from the prospective analyses .
prediabetes was defined as impaired fasting glucose ( ifg ; a fasting glucose of 5.66.9 mmol / l and 2-h glucose
< 7.8 mmol / l ) and/or impaired glucose tolerance ( a fasting glucose < 7 mmol / l and a 2-h postload glucose of 7.811.0 mmol / l ) ( 23 ) .
the frs is based on a previously published detailed algorithm ( 21 ) with the following components : ifg , overweight or obesity , low level of hdl , high level of triglycerides , elevated blood pressure or antihypertensive medication , and parental diabetes .
, participants with impaired glucose tolerance received the same score as those with ifg ( 10 points in both cases ) . in the framingham offspring study , participants with > 19 points had an 8-year incidence of type 2 diabetes > 15% ( 21 ) ; thus we used this score to determine high risk status .
participants with normoglycemia scored 018 in the frs and were further classified into the low - risk group ( 09 points ) and intermediate - risk group ( 1019 ) , the latter range corresponding to the lower ( i.e. , intermediate)-risk group ( 1019 points ) among participants with prediabetes .
based on the baseline information on prediabetes status and the frs , participants were classified into four groups : 1 ) no prediabetes , low frs ( 09 ) ; 2 ) no prediabetes , intermediate frs ( 1019 ) ; 3 ) prediabetes , intermediate frs ( 1019 ) ; and 4 ) prediabetes , high frs ( > 19 ) .
the 30-item general health questionnaire ( ghq-30 ) was used to assess psychological distress ( 27 ) .
the ghq is a screening instrument designed to detect common psychological symptoms , such as depression and anxiety .
it is widely used in population - based surveys and trials and has been validated in the whitehall ii study ( 28 ) .
each questionnaire item inquires about a specific symptom ; response categories are scored as either 1 or 0 to indicate presence or absence of the symptom . a total score of 5 or more led to individuals being defined as ghq - symptom  cases  and scores 04 as  noncases  ( 28 ) .
sociodemographic covariates included age , sex , ses ( based on the last known occupational grade and divided into high , intermediate , and low ) , and ethnicity ( white , south asian , or other ) and were all based on survey responses ( 22 ) .
antidepressant use ( yes / no ) and smoking ( yes / no ) were based on self - reported information at the baseline survey of each cycle .
physical activity was assessed at cycle 1 based on answers to questions about the frequency and duration of participation in mildly energetic ( e.g. , weeding , general housework , bicycle repair ) , moderately energetic ( e.g. , dancing , cycling , leisurely swimming ) , and vigorous physical activity ( e.g. , running , hard swimming , playing squash ) . at cycles 2 and 3 ,
the questionnaire included 20 items on frequency and duration of participation in different physical activities ( e.g. , walking , cycling , sports ) that were used to compute hours per week of each intensity level .
participants were classified as active ( > 2.5 h / week of moderate physical activity or > 1 h / week of vigorous physical activity ) , inactive ( < 1 h / week of moderate physical activity and < 1 h / week of vigorous physical activity ) , or moderately active ( if not active or inactive ) ( 29 ) .
after harmonization of data across cycles , we examined associations between psychological distress at baseline and incident type 2 diabetes at follow - up for each cycle .
we used generalized estimation equations ( gees ) with a logistic link to control for intraindividual correlation between repeated measurements to estimate odds ratios ( ors ) and their 95% cis .
gee analysis was used because repeated measurements were nested within participants ( i.e. , the same individuals could contribute more than one observation to the dataset ) , and the gee method takes into account nonindependence of the within - participant observations when estimating standard errors .
we first analyzed the association between psychological distress and the incidence of type 2 diabetes in the total cohort .
then we grouped the participants according to their baseline prediabetes status , frs , and psychological distress into eight groups as follows : 1 ) normoglycemia , frs 09 , no distress ( reference group ) ; 2 ) normoglycemia , score 09 , distress ; 3 ) normoglycemia , score 1019 , no distress ; 4 ) normoglycemia , score 1019 , distress ; 5 ) prediabetes , score 1019 , no distress ; 6 ) prediabetes , score 1019 , distress ; 7 ) prediabetes , score
> 19 , no distress ; and 8) prediabetes , score > 19 , distress .
models were adjusted for age , sex , ses , ethnicity , antidepressant use , smoking , and physical activity .
sas version 9.2 ( sas , cary , nc ) was used for all analyses .
table 1 shows the characteristics of participants at the baseline of each study cycle and in total .
the proportion of participants who were male and white , had high ses , were without psychological distress , and had incident type 2 diabetes was greater at the last cycle than at the first .
antidepressant use was more prevalent and smoking less prevalent and both high and low physical activity were more prevalent in the latter cycles .
characteristics of the participants at the baseline of the three cycles figures are number ( % ) unless otherwise stated .
* total n refers to the sum of participants ( n of person - observations ) in total and across the three study cycles ( one participant can contribute to one or more study cycle ) ; n in each study cycle refers to number of participants at that cycle .
associations between baseline covariates for participants with normoglycemia and prediabetes by psychological distress are presented in supplementary table 1 .
irrespective of the participant s prediabetes status , psychological distress was associated with younger age , female sex , intermediate ses , nonwhite ethnicity , antidepressant use , smoking , and low physical activity . in the total cohort ,
psychological distress did not predict type 2 diabetes after adjustment for age , sex , ses , and ethnicity ( or 1.16 [ 95% ci 0.941.42 ] ; data not shown ) .
we found no interaction between sex and psychological distress ( p = 0.37 ) or between ethnicity and psychological distress ( p = 0.91 ) in the prediction of type 2 diabetes .
we then examined whether combinations of prediabetes status , frs , and psychological distress predicted the incidence of type 2 diabetes .
type 2 diabetes incidence was low among participants with normoglycemia and a low risk score , irrespective of the presence ( 1.9% ) or absence ( 1.6% ) of psychological distress . among the normoglycemic participants with an intermediate risk score of 1019 , 7.6% of distressed and 6.0% of nondistressed people
had type 2 diabetes at follow - up ; the confidence intervals suggesting no association with psychological distress .
similarly , among participants with prediabetes and an frs of 1019 , no difference was found in the incidence of type 2 diabetes between those with ( 15.6% ) and without psychological distress ( 15.0% ) .
however , among participants with prediabetes and a high frs ( > 19 ) , 40.9% of those with psychological distress developed type 2 diabetes at follow - up compared with only 28.5% of those without psychological distress .
unadjusted incidence ( 95% ci ) of type 2 diabetes among participants with normoglycemia and participants with prediabetes ; participants further stratified by the frs and psychological distress .
results of the multivariable - adjusted logistic regression models confirm those from the unadjusted analysis by showing a strong dose - response association between prediabetes and frs status , and risk of incident type 2 diabetes ( table 2 ) .
moreover , comparisons indicate no difference regarding the association between psychological distress and type 2 diabetes among normoglycemic participants or among those with prediabetes and a lower frs , whereas among participants with prediabetes and a high frs ( > 19 ) , psychological distress was associated with a doubling of the risk of type 2 diabetes . a statistically significant interaction ( p = 0.039 )
high frs group with the other groups combined , as regards the association between psychological distress and incident type 2 diabetes .
incidence of type 2 diabetes at follow - up among participants with normoglycemia and participants with prediabetes at baseline ; participants further stratified by frs and psychological distress alternative reference groups are shown in comparisons 18 .
models are adjusted for age , sex , ses , ethnicity , antidepressant use , smoking , and physical activity .
all comparisons are based on the same data , but they have a different reference group . or , odds ratio .
the findings were replicated in sensitivity analysis using an alternative , less stringent cut point of > 18 to define high frs ( supplementary table 2 ) .
we examined whether the association between psychological distress and incident type 2 diabetes differed between populations at different baseline risk levels of type 2 diabetes as assessed by the presence of prediabetes and the level of frs .
the frs is based on traditional type 2 diabetes risk factors : prediabetes , overweight or obesity , low hdl level , increased level of triglycerides , hypertension , and a history of parental diabetes . in the current study ,
our main finding was that psychological distress is associated with a doubling of diabetes risk in a high - risk populations . in the overall analysis , psychological distress was not significantly associated with type 2 diabetes .
subsequent stratified analysis revealed no association between psychological distress and type 2 diabetes in normoglycemic participants irrespective of the risk score and in participants with prediabetes and a lower frs .
however , in the group of participants with prediabetes and high risk score ( > 19 ) , the 5-year incidence of diabetes was 28.5% in those without psychological distress and 40.9% in those with psychological distress at baseline . in the multivariate - adjusted model , the or was twofold increased among those with psychological distress compared with those without .
the findings were replicated using a lower cut point ( > 18 ) for defining a high frs .
earlier literature suggests that the relationship between psychosocial factors and type 2 diabetes may be complex ( 16,17 ) .
earlier findings on the association between psychological factors , such as general stress and work stress , and incident type 2 diabetes have been mixed , including both null and positive findings ( 1017 ) .
inconsistencies in earlier research may be due not only to the use of different stress and distress indicators across studies but also , as our present findings suggest , to a failure to recognize that the  nondiabetes  group might be heterogeneous in terms of vulnerability to distress ; those at an  advanced  stage of prediabetes may be more affected by the adverse metabolic effects of psychological distress than those at lower risk levels ( 1,17 ) . indeed , the effects of psychological stress factors have been suggested to be synergistic ( 17 ) . rather than a general risk factor in all diabetes - free populations , it might be a stage - specific risk factor that has a much stronger effect among those at an advanced stage of progression toward manifest type 2 diabetes . in line with our results ,
an earlier report from the whitehall ii study showed that work stress predicted type 2 diabetes among obese , but not nonobese , women ( 14 ) .
plausible pathways through which psychological distress may accelerate progression to type 2 diabetes among high - risk individuals include health risk behaviors and direct physiological pathways , such as long - term dysregulation of the hypothalamic - pituitary - adrenal axis , leading to increased levels of glucocorticoids , especially cortisol , and changes in immune system activity , leading to increased concentrations of proinflammatory cytokines ( 1,8,16,17 ) .
there is some evidence supporting inflammation and lifestyle factors as mediators between depressive symptoms and incident type 2 diabetes ( 8) . healthcare implications of this study include the notion that psychological distress might hamper the outcomes of intensive lifestyle and other treatment interventions targeted at high - risk groups ( 2,3 ) .
psychological distress symptoms , such as stress , anxiety , depression , feelings of hopelessness , and sleep disturbances , have previously been shown to hinder commitment to major , long - term lifestyle changes and reduce adherence to pharmacological treatments ( 30 ) .
first , although the study had a high response rate in the successive data collection phases , loss to follow - up accumulated over time , as in most long - term cohort studies . however , large differences in missing data as a function of psychological distress and type 2 diabetes seem unlikely .
second , participants of the whitehall ii study are from an occupational cohort that is likely to cover a  healthier  end of the variation in health status compared with the general population , which limits the generalizability of our findings .
as this instrument was not designed to make a psychiatric diagnosis of depression or anxiety , we can not exclude the possibility of confounding by unmeasured depression or anxiety disorders .
however , this is unlikely to be a major source of bias because the ghq-30 has been shown to be a valid screening instrument for mental disorders , particularly depression in the whitehall ii study ( 28 ) .
the strengths of this study are its large sample size and use of accurate , repeat assessments of all examined variables , use of the frs based on clinical measurements , and ascertainment of diabetes based on the standard 75-g ogtt at each clinical study cycle ( 23,24 ) .
however , part of the incident type 2 diabetes identification was based on self - report , although antihyperglycemic medication was confirmed by asking the participants to take their medications or list of medications to the study clinic . of those participants who had self - reported diagnosis of diabetes without evidence on the use of antihyperglycemic medications ( 33.4% of incident cases )
, a substantial proportion was confirmed by a repeat ogtt or by antihyperglycemic medication at the subsequent phase , leaving only 23.6% of all incident diabetes cases unconfirmed . in summary , this observational study suggests that psychological distress may be related to accelerated progression of late - stage prediabetes to clinical diabetes .
further investigations are needed to examine mechanisms linking psychological distress to onset of type 2 diabetes in this group .
current prevention guidelines do not generally consider psychological factors such as stress or depression ( 31 ) , although some recognize them as contributing factors to be taken into account in efforts to prevent type 2 diabetes ( 32 ) .
given the high comorbidity between psychological problems and diabetes and the accumulation of evidence on the role of psychological distress as a predictor of type 2 diabetes , it is important to consider whether more attention should be paid to psychological status among high - risk populations in addition to lifestyle modifications .
 objectivewe examined whether psychological distress predicts incident type 2 diabetes and if the association differs between populations at higher or lower risk of type 2 diabetes.research design and methodsthis was a prospective cohort of 5,932 diabetes - free adults ( 4,189 men and 1,743 women , mean age 54.6 years ) with three 5-year data cycles ( 19912009 ) : a total of 13,207 person - observations . 
 participants were classified into four groups according to their prediabetes status and framingham offspring type 2 diabetes risk score : normoglycemia with a risk score of 09 , normoglycemia with a risk score of 1019 , prediabetes with a risk score of 1019 , and prediabetes with a risk score of > 19 . 
 psychological distress was assessed by the general health questionnaire . 
 incident type 2 diabetes was ascertained by 2-h oral glucose tolerance test , doctor diagnosis , or use of antihyperglycemic medication at the 5-year follow - up for each data cycle . adjustments were made for age , sex , ethnicity , socioeconomic status , antidepressant use , smoking , and physical activity.resultsamong participants with normoglycemia and among those with prediabetes combined with a low risk score , psychological distress did not predict type 2 diabetes . 
 diabetes incidence in these groups varied between 1.6 and 15.6% . among participants with prediabetes and a high risk score , 
 40.9% of those with psychological distress compared with 28.5% of those without distress developed diabetes during the follow - up . 
 the corresponding adjusted odds ratio for psychological distress was 2.07 ( 95% ci 1.193.62).conclusionsthese data suggest that psychological distress is associated with an accelerated progression to manifest diabetes in a subpopulation with advanced prediabetes . 
Research Design and Methods
Participants and Procedure
Ascertainment of Type 2 Diabetes, Prediabetes, and Type 2 Diabetes Risk Status
Assessment of Psychological Distress
Assessment of Covariates
Statistical Analysis
Results
Conclusions
Supplementary Material