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1.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Summary
Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.
doi:10.1016/S0140-6736(14)61183-1
PMCID: PMC4322187  PMID: 25262344
2.  Long working hours, socioeconomic status, and the risk of incident type 2 diabetes: a meta-analysis of published and unpublished data from 222 120 individuals 
Summary
Background
Working long hours might have adverse health effects, but whether this is true for all socioeconomic status groups is unclear. In this meta-analysis stratified by socioeconomic status, we investigated the role of long working hours as a risk factor for type 2 diabetes.
Methods
We identified four published studies through a systematic literature search of PubMed and Embase up to April 30, 2014. Study inclusion criteria were English-language publication; prospective design (cohort study); investigation of the effect of working hours or overtime work; incident diabetes as an outcome; and relative risks, odds ratios, or hazard ratios (HRs) with 95% CIs, or sufficient information to calculate these estimates. Additionally, we used unpublished individual-level data from 19 cohort studies from the Individual-Participant-Data Meta-analysis in Working-Populations Consortium and international open-access data archives. Effect estimates from published and unpublished data from 222 120 men and women from the USA, Europe, Japan, and Australia were pooled with random-effects meta-analysis.
Findings
During 1·7 million person-years at risk, 4963 individuals developed diabetes (incidence 29 per 10 000 person-years). The minimally adjusted summary risk ratio for long (≥55 h per week) compared with standard working hours (35–40 h) was 1·07 (95% CI 0·89–1·27, difference in incidence three cases per 10 000 person-years) with significant heterogeneity in study-specific estimates (I2=53%, p=0·0016). In an analysis stratified by socioeconomic status, the association between long working hours and diabetes was evident in the low socioeconomic status group (risk ratio 1·29, 95% CI 1·06–1·57, difference in incidence 13 per 10 000 person-years, I2=0%, p=0·4662), but was null in the high socioeconomic status group (1·00, 95% CI 0·80–1·25, incidence difference zero per 10 000 person-years, I2=15%, p=0·2464). The association in the low socioeconomic status group was robust to adjustment for age, sex, obesity, and physical activity, and remained after exclusion of shift workers.
Interpretation
In this meta-analysis, the link between longer working hours and type 2 diabetes was apparent only in individuals in the low socioeconomic status groups.
Funding
Medical Research Council, European Union New and Emerging Risks in Occupational Safety and Health research programme, Finnish Work Environment Fund, Swedish Research Council for Working Life and Social Research, German Social Accident Insurance, Danish National Research Centre for the Working Environment, Academy of Finland, Ministry of Social Affairs and Employment (Netherlands), Economic and Social Research Council, US National Institutes of Health, and British Heart Foundation.
doi:10.1016/S2213-8587(14)70178-0
PMCID: PMC4286814  PMID: 25262544
3.  Age trajectories of glycaemic traits in non-diabetic South Asian and white individuals: the Whitehall II cohort study 
Diabetologia  2014;58:534-542.
Aims/hypothesis
South Asian individuals have an increased prevalence of type 2 diabetes, but little is known about the development of glycaemic traits in this ethnic group. We compared age-related changes in glycaemic traits between non-diabetic South Asian and white participants.
Methods
In a prospective British occupational cohort with 5-yearly clinical examinations (n = 230/5,749 South Asian/white participants, age 39–79 years at baseline), age-related trajectories of fasting glucose (FG) and 2 h post-load glucose (PLG), log-transformed fasting insulin (FINS) and 2 h post-load insulin (PLINS), HOMA insulin sensitivity (HOMA2-%S) and HOMA insulin secretion (HOMA2-%B) were fitted for South Asian and white individuals who remained free of diabetes between 1991 and 2009.
Results
In sex-adjusted multilevel models, FG was stable in white participants but increased with age in South Asians (0.12 [SE = 0.04] mmol/l per decade). PLG, FINS and PLINS levels were lower among white participants (by 0.271 [SE = 0.092] mmol/l, 0.306 [SE = 0.046] log pmol/l, 0.707 [SE = 0.059] log pmol/l at age 50, respectively) compared with South Asians, although their age-related trajectories were parallel. HOMA2-%S was higher (0.226 [SE = 0.038] at age 50) and HOMA2-%B lower (by 0.189 [SE = 0.026] at age 50) among white than South Asian participants. The age-related decline in HOMA2-%S was similar in these groups, but the age-related increase in HOMA2-%B was greater in white participants (0.04 [SE = 0.02] per decade). This difference was explained by obesity, lifestyle and social status.
Conclusions/interpretation
Findings from a diabetes-free population suggest an inadequate pancreatic beta cell reserve in South Asians, as a significantly steeper age-related increase in FG was observed in this ethnic group compared with white individuals.
doi:10.1007/s00125-014-3448-9
PMCID: PMC4320303  PMID: 25431266
Cohort study; Ethnicity; Fasting glucose; Fasting insulin; Glycaemic trajectory; Insulin resistance; Insulin secretion; Insulin sensitivity; Post-load glucose; South Asian
4.  Negative Aspects of Close Relationships as Risk Factors for Cognitive Aging 
American Journal of Epidemiology  2014;180(11):1118-1125.
The extent to which social relationships influence cognitive aging is unclear. In this study, we investigated the association of midlife quality of close relationships with subsequent cognitive decline. Participants in the Whitehall II Study (n = 5,873; ages 45–69 years at first cognitive assessment) underwent executive function and memory tests 3 times over a period of 10 years (1997–1999 to 2007–2009). Midlife negative and positive aspects of close relationships were assessed twice using the Close Persons Questionnaire during the 8 years preceding cognitive assessment. Negative aspects of close relationships, but not positive aspects, were associated with accelerated cognitive aging. Participants in the top third of reported negative aspects of close relationships experienced a faster 10-year change in executive function (−0.04 standard deviation, 95% confidence interval: −0.08, −0.01) than those in the bottom third, which was comparable with 1 extra year of cognitive decline for participants aged 60 years after adjustment for sociodemographic and health status. Longitudinal analysis found no evidence of reverse causality. This study highlights the importance of differentiating aspects of social relationships to evaluate their unique associations with cognitive aging.
doi:10.1093/aje/kwu236
PMCID: PMC4239796  PMID: 25342204
aging; cognitive decline; longitudinal studies; social relationships
5.  Association of body mass index and waist circumference with successful ageing: 16 year follow-up of the Whitehall II study 
Obesity (Silver Spring, Md.)  2013;22(4):1172-1178.
Objective
We examined whether midlife body mass index (BMI) and waist circumference (WC) predict successful ageing.
Design and Methods
BMI/WC were assessed in 4869 persons (mean age 51.2, range 42–63 in 1991/93) and survival and successful ageing (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory, and cardiovascular, and mental health) ascertained over a 16-year follow-up, analysed using logistic regression adjusted for socio-demographic factors and health behaviours.
Results
507 participants died, 1008 met the criteria for successful ageing. Those with BMI≥30 kg/m2 had lower odds of successful ageing (Odds Ratio (OR)=0.37; 95% Confidence Interval (CI): 0.27, 0.50) and survival (OR=0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5–25 kg/m2. Those with a large waist circumference (≥102/88 cm in men/women) had lower odds of successful ageing (OR=0.41; 95% CI: 0.31, 0.54) and survival (OR=0.57; 95% CI: 0.44, 0.73) compared to those with a small waist (<94/80 cm in men/women). Analysis with finer categories showed lower odds of successful ageing starting at BMI ≥23.5 kg/m2 and waist circumference 82/68 cm in men/women.
Conclusions
Optimal midlife BMI and waist circumference for successful ageing might be substantially below the current thresholds used to define obesity.
doi:10.1002/oby.20651
PMCID: PMC3968224  PMID: 24167036
obesity; body mass index; waist circumference; ageing
6.  Association between protein signals and type 2 diabetes incidence 
Acta diabetologica  2012;50(5):697-704.
Understanding early determinants of type 2 diabetes is essential for refining disease prevention strategies. Proteomic technology may provide a useful approach to identify novel protein patterns potentially related to pathophysiological changes that lead up to diabetes. In this study, we sought to identify protein signals that are associated with diabetes incidence in a middle-aged population. Serum samples from 519 participants in a nested case–control selection (167 cases and 352 age-, sex- and BMI-matched normoglycemic control subjects, median follow-up 14.0 years) within the Whitehall-II cohort were analyzed by linear matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Nine protein peaks were found to be associated with incident diabetes. Rate ratios for high peak intensity ranged between 0.4 (95% CI, 0.2–0.8) and 4.0 (95% CI, 1.7–9.2) and were robust to adjustment for main potential confounders, including obesity, lipids and C-reactive protein. The proteins associated with these peaks may reflect diabetes pathogenesis. Our study exemplifies the utility of an approach that combines proteomic and epidemiological data.
doi:10.1007/s00592-012-0376-3
PMCID: PMC4181558  PMID: 22310914
MALDI-TOF; Type 2 diabetes; Proteomics; Biomarker; Whitehall-II study; Random Forests
7.  Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study 
European journal of epidemiology  2012;27(7):537-546.
Although it has been hypothesized that the association of physical activity with depressive and anxiety symptoms is bidirectional, few studies have examined this issue in a prospective setting. We studied this bidirectional association using data on physical activity and symptoms of anxiety and depression at three points in time over 8 years. A total of 9,309 participants of the British Whitehall II prospective cohort study provided data on physical activity, anxiety and depression symptoms and 10 covariates at baseline in 1985. We analysed the associations of physical activity with anxiety and/or depression symptoms using multinomial logistic regression (with anxiety and depression symptoms as dependent variables) and binary logistic regression (with physical activity as the dependent variable). There was a cross-sectional inverse association between physical activity and anxiety and/or depressive symptoms at baseline (ORs between 0.63 and 0.72). In cumulative analyses, regular physical activity across all three data waves, but not irregular physical activity, was associated with reduced likelihood of depressive symptoms at follow-up (OR = 0.71, 95 % CI 0.54, 0.99). In a converse analysis, participants with anxiety and depression symptoms at baseline had higher odds of not meeting the recommended levels of physical activity at follow-up (OR = 1.79, 95 % CI 1.17, 2.74). This was also the case in individuals with anxiety and/or depression symptoms at both baseline and follow-up (OR = 1.70, 95 % CI 1.10, 2.63). The association between physical activity and symptoms of anxiety and/or depression appears to be bidirectional.
doi:10.1007/s10654-012-9692-8
PMCID: PMC4180054  PMID: 22623145
Common mental disorders; Physical activity; Bidirectional association; Longitudinal studies
8.  Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study 
European Heart Journal  2013;34(34):2697-2705.
Aim
Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact.
Methods and results
Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health ‘a lot or extremely’ had a 2.12 times higher (95% CI 1.52–2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01–2.22).
Conclusions
In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health.
doi:10.1093/eurheartj/eht216
PMCID: PMC3766148  PMID: 23804585
Epidemiology; Stress; Coronary heart disease; Prospective studies
9.  Midlife stroke risk and cognitive decline: A 10-year follow-up of the Whitehall II cohort study 
Background
Stroke is associated with an increased risk of dementia. However, it is unclear if risk of stroke in those free of stroke, particularly in non-elderly populations, leads to differential rates of cognitive decline. Our aim was to assess whether risk of stroke in midlife was associated with cognitive decline over 10 years of follow-up.
Methods
We studied 4,153 men and 1,657 women, mean age 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We used the Framingham Stroke Risk Profile (FSRP) that incorporates age, systolic blood pressure, diabetes mellitus, smoking, prior cardiovascular disease, atrial fibrillation, left ventricular hypertrophy, and use of antihypertensive medication. Cognitive tests included reasoning, memory, verbal fluency, and vocabulary assessed three times over ten years. Longitudinal associations between FSRP and its components were tested using mixed effects models and rates of cognitive change over 10 years were estimated.
Results
Higher stroke risk was associated with faster decline in verbal fluency, vocabulary and global cognition. For example, for global cognition there was greater decline in the highest FSRP quartile (−0.25 of a standard deviation; 95% CI: −0.28 to −0.21) compared to the lowest risk quartile (P=0.03). No association was observed for memory and reasoning. Of the individual components of FSRP only diabetes was independently associated with faster cognitive decline (β=−0.06; 95% CI:−0.01, −0.003, P=0.03).
Conclusion
Elevated stroke risk is associated with accelerated cognitive decline over 10 years. Aggregation of risk factors may be especially important in this association.
doi:10.1016/j.jalz.2012.07.001
PMCID: PMC3918666  PMID: 23199495
vascular risk factors; cognitive decline; Framingham Stroke Risk Profile; aging; midlife
11.  Study protocol: the Whitehall II imaging sub-study 
BMC Psychiatry  2014;14:159.
Background
The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study.
Methods/design
A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012–2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60–85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study.
Discussion
The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
doi:10.1186/1471-244X-14-159
PMCID: PMC4048583  PMID: 24885374
Epidemiology; Magnetic resonance imaging; Diffusion tensor imaging; White matter; Functional MRI; Connectome; Resting state brain networks; Neuropsychology; Dementia; Affective disorders
12.  Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study 
Summary
Background
Type 2 diabetes increases the risk for dementia, but whether it affects cognition before old age is unclear. We investigated whether duration of diabetes in late midlife and poor glycaemic control were associated with accelerated cognitive decline.
Methods
5653 participants from the Whitehall II cohort study (median age 54·4 years [IQR 50·3–60·3] at first cognitive assessment), were classified into four groups: normoglycaemia, prediabetes, newly diagnosed diabetes, and known diabetes. Tests of memory, reasoning, phonemic and semantic fluency, and a global score that combined all cognitive tests, were assessed three times over 10 years (1997–99, 2002–04, and 2007–09). Mean HbA1c was used to assess glycaemic control during follow-up. Analyses were adjusted for sociodemographic characteristics, health-related behaviours, and chronic diseases.
Findings
Compared with normoglycaemic participants, those with known diabetes had a 45% faster decline in memory (10 year difference in decline −0·13 SD, 95% CI −0·26 to −0·00; p=0·046), a 29% faster decline in reasoning (−0·10 SD, −0·19 to −0·01; p=0·026), and a 24% faster decline in the global cognitive score (−0·11 SD, −0·21 to −0·02; p=0·014). Participants with prediabetes or newly diagnosed diabetes had similar rates of decline to those with normoglycaemia. Poorer glycaemic control in participants with known diabetes was associated with a significantly faster decline in memory (−0·12 [–0·22 to −0·01]; p=0·034) and a decline in reasoning that approached significance (−0·07 [–0·15 to 0·00]; p=0·052).
Interpretation
The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control.
Funding
US National Institutes of Health, UK Medical Research Council.
doi:10.1016/S2213-8587(13)70192-X
PMCID: PMC4274502  PMID: 24622753
13.  Educational Inequalities in Obesity among Mexican Women: Time-Trends from 1988 to 2012 
PLoS ONE  2014;9(3):e90195.
Background
Obesity is one of the leading causes of global morbidity and mortality. Trends in educational inequalities in obesity prevalence among Mexican women have not been analysed systematically to date.
Methods
Data came from four nationally representative surveys (1988, 1999, 2006, and 2012) of a total of 51 220 non-pregnant women aged 20 to 49. Weight and height were measured during home visits. Education level (higher education, high school, secondary, primary or less) was self-reported. We analysed trends in relative and absolute educational inequalities in obesity prevalence separately for urban and rural areas.
Results
Nationally, age-standardised obesity prevalence increased from 9.3% to 33.7% over 25 years to 2012. Obesity prevalence was inversely associated with education level in urban areas at all survey waves. In rural areas, obesity prevalence increased markedly but there was no gradient with education level at any survey. The relative index of inequality in urban areas declined over the period (2.87 (95%CI: 1.94, 4.25) in 1988, 1.55 (95%CI: 1.33, 1.80) in 2012, trend p<0.001). Obesity increased 5.92 fold (95%CI: 4.03, 8.70) among urban women with higher education in the period 1988–2012 compared to 3.23 fold (95%CI: 2.88, 3.63) for urban women with primary or no education. The slope index of inequality increased in urban areas from 1988 to 2012. Over 0.5 M cases would be avoided if the obesity prevalence of women with primary or less education was the same as for women with higher education.
Conclusions
The expected inverse association between education and obesity was observed in urban areas of Mexico. The declining trend in relative educational inequalities in obesity was due to a greater increase in obesity prevalence among higher educated women. In rural areas there was no social gradient in the association between education level and obesity across the four surveys.
doi:10.1371/journal.pone.0090195
PMCID: PMC3943903  PMID: 24599098
14.  Trajectories of the Framingham general cardiovascular risk profile in midlife and poor motor function later in life: The Whitehall II study☆☆☆ 
Background
Vascular risk factors are associated with increased risk of cognitive impairment and dementia, but their association with motor function, another key feature of aging, has received little research attention. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FRS) over midlife and motor function later in life.
Methods
A total of 5376 participants of the Whitehall II cohort study (29% women) who had up to four repeat measures of FRS between 1991–1993 (mean age = 48.6 years) and 2007–2009 (mean age = 65.4 years) and without history of stroke or coronary heart disease in 2007–2009 were included. Motor function was assessed in 2007–2009 through objective tests (walking speed, chair rises, balance, finger tapping, grip strength). We used age- and sex-adjusted linear mixed models.
Results
Participants with poorer performances for walking speed, chair rises, and balance in 2007–2009 had higher FRS concurrently and also in 1991–1993, on average 16 years earlier. These associations were robust to adjustment for cognition, socio-economic status, height, and BMI, and not explained by incident mobility limitation prior to motor assessment. No association was found with finger tapping and grip strength.
Conclusions
Cardiovascular risk early in midlife is associated with poor motor performances later in life. Vascular risk factors play an important and under-recognized role in motor function, independently of their impact on cognition, and suggest that better control of vascular risk factors in midlife may prevent physical impairment and disability in the elderly.
doi:10.1016/j.ijcard.2013.12.051
PMCID: PMC3991855  PMID: 24461963
CVD, cardiovascular disease; FRS, Framingham general cardiovascular disease risk score; SES, socioeconomic status; BMI, body mass index; SD, standard deviation; Cardiovascular risk score; Motor function; Aging; Stroke; Cohort study
15.  Patterns of Obesity Development before the Diagnosis of Type 2 Diabetes: The Whitehall II Cohort Study 
PLoS Medicine  2014;11(2):e1001602.
Examining patterns of change in body mass index (BMI) and other cardiometabolic risk factors in individuals during the years before they were diagnosed with diabetes, Kristine Færch and colleagues report that few of them experienced dramatic BMI changes.
Please see later in the article for the Editors' Summary
Background
Patients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis.
Methods and Findings
We studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991–2009 for a median of 14.1 years (interquartile range [IQR]: 8.7–16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the “stable overweight” group (n = 604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of “progressive weight gainers” (n = 15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The “persistently obese” (n = 26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations.
Conclusions
Three patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 350 million people have diabetes, a metabolic disorder characterized by high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes, which was previously called adult-onset diabetes, can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. Long-term complications, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. The number of people with diabetes is expected to increase dramatically over the next decades, coinciding with rising obesity rates in many countries. To better understand diabetes development, to identify people at risk, and to find ways to prevent the disease are urgent public health goals.
Why Was This Study Done?
It is known that people who are overweight or obese have a higher risk of developing diabetes. Because of this association, a common assumption is that people who experienced recent weight gain are more likely to be diagnosed with diabetes. In this prospective cohort study (an investigation that records the baseline characteristics of a group of people and then follows them to see who develops specific conditions), the researchers tested the hypothesis that substantial weight gain precedes a diagnosis of diabetes and explored more generally the patterns of body weight and composition in the years before people develop diabetes. They then examined whether changes in body weight corresponded with changes in other risk factors for diabetes (such as insulin resistance), lipid profiles and blood pressure.
What Did the Researchers Do and Find?
The researchers studied participants from the Whitehall II study, a prospective cohort study initiated in 1985 to investigate the socioeconomic inequalities in disease. Whitehall II enrolled more than 10,000 London-based government employees. Participants underwent regular health checks during which their weight and height were measured, blood tests were done, and they filled out questionnaires for other relevant information. From 1991 onwards, participants were tested every five years for diabetes. The 6,705 participants included in this study were initially free of diabetes, and most of them were followed for at least 14 years. During the follow-up, 645 participants developed diabetes, while 6,060 remained free of the disease.
The researchers used a statistical tool called “latent class trajectory analysis” to study patterns of changes in body mass index (BMI) in the years before people developed diabetes. BMI is a measure of human obesity based on a person's weight and height. Latent class trajectory analysis is an unbiased way to subdivide a number of people into groups that differ based on specified parameters. In this case, the researchers wanted to identify several groups among all the people who eventually developed diabetes each with a distinct pattern of BMI development. Having identified such groups, they also examined how a variety of tests associated with diabetes risk, and risks for heart disease and stroke changed in the identified groups over time.
They identified three different patterns of BMI changes in the 645 participants who developed diabetes. The vast majority (606 individuals, or 94%) belonged to a group they called “stable-overweight.” These people showed no dramatic change in their BMI in the years before they were diagnosed. They were overweight when they first entered the study and gained or lost little weight during the follow-up years. They showed only minor signs of insulin-resistance, starting five years before they developed diabetes. A second, much smaller group of 15 people gained weight consistently in the years before diagnosis. As they were gaining weight, these people also had raises in blood pressure and substantial gains in insulin resistance. The 26 remaining participants who formed the third group were persistently obese for the entire time they participated in the study, in some cases up to 18 years before they were diagnosed with diabetes. They had some signs of insulin resistance in the years before diagnosis, but not the substantial gain often seen as the hallmark of “pre-diabetes.”
What Do These Findings Mean?
These results suggest that diabetes development is a complicated process, and one that differs between individuals who end up with the disease. They call into question the common notion that most people who develop diabetes have recently gained a lot of weight or are obese. A substantial rise in insulin resistance, another established risk factor for diabetes, was only seen in the smallest of the groups, namely the people who gained weight consistently for years before they were diagnosed. When the scientists applied a commonly used predictor of diabetes called the “Framingham diabetes risk score” to their largest “stably overweight” group, they found that these people were not classified as having a particularly high risk, and that their risk scores actually declined in the last five years before their diabetes diagnosis. This suggests that predicting diabetes in this group might be difficult.
The researchers applied their methodology only to this one cohort of white civil servants in England. Before drawing more firm conclusions on the process of diabetes development, it will be important to test whether similar results are seen in other cohorts and among more diverse individuals. If the three groups identified here are found in other cohorts, another question is whether they are as unequal in size as in this example. And if they are, can the large group of stably overweight people be further subdivided in ways that suggest specific mechanisms of disease development? Even without knowing how generalizable the provocative findings of this study are, they should stimulate debate on how to identify people at risk for diabetes and how to prevent the disease or delay its onset.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001602.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes; it includes people's stories about diabetes
The charity Diabetes UK also provides detailed information about diabetes for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the charity Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
More information about the Whitehall II study is available
doi:10.1371/journal.pmed.1001602
PMCID: PMC3921118  PMID: 24523667
16.  Effect of secular trends on age-related trajectories of cardiovascular risk factors: the Whitehall II longitudinal study 1985–2009 
Background: Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort.
Methods: Development of cardiovascular risk factors over the past three decades was analysed using serial measurements from 10 308 participants aged from 35 to 80 years over 25 years of follow-up from five clinical examination phases of the Whitehall II study. Changes of body mass index, waist circumference, blood pressure and total and high-density lipoprotein cholesterol distribution characteristics were analysed with quantile regression models in the 57–61 age group. Age-related trajectories of risk factors were assessed by fitting mixed-effects models with adjustment for year of birth to reveal secular trends.
Results: Average body mass index and waist circumference increased faster with age in women than in men, but the unfavourable secular trend was more marked in men. Distributions showed a fattening of the right tail in each consecutive phase, meaning a stronger increase in higher percentiles. Despite the higher obesity levels in younger birth cohorts, total cholesterol decreased markedly in the 57–61 age group along the entire distribution rather than in higher extremes only.
Conclusion: The past three decades brought strong and heterogeneous changes in cardiovascular risk factor distributions. Secular trends appear to modify age-related trajectories of cardiovascular risk factors, which may be a source of bias in longitudinal analyses.
doi:10.1093/ije/dyt279
PMCID: PMC4052135  PMID: 24464190
Obesity; blood pressure; cholesterol; secular trend; ageing; quantile regression
17.  Prediabetes: A high-risk state for developing diabetes 
Lancet  2012;379(9833):2279-2290.
Summary
Prediabetes (or “intermediate hyperglycaemia”), based on glycaemic parameters above normal but below diabetes thresholds is a high risk state for diabetes with an annualized conversion rate of 5%–10%; with similar proportion converting back to normoglycaemia. The prevalence of prediabetes is increasing worldwide and it is projected that >470 million people will have prediabetes in 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and β-cell dysfunction, abnormalities that start before glucose changes are detectable. Observational evidence shows associations of prediabetes with early forms of nephropathy, chronic kidney disease, small fibre neuropathy, diabetic retinopathy, and increased risk of macrovascular disease. Multifactorial risk scores could optimize the estimation of diabetes risk using non-invasive parameters and blood-based metabolic traits in addition to glycaemic values. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention with evidence of a 40%–70% relative risk reduction. Accumulating data also suggests potential benefits from pharmacotherapy.
doi:10.1016/S0140-6736(12)60283-9
PMCID: PMC3891203  PMID: 22683128
18.  Is There an Association between Work Stress and Diurnal Cortisol Patterns? Findings from the Whitehall II Study 
PLoS ONE  2013;8(12):e81020.
Objective
The evidence on whether there is work stress related dysregulation of the hypothalamic-pituitary-adrenal axis is equivocal. This study assessed the relation between work stress and diurnal cortisol rhythm in a large-scale occupational cohort, the Whitehall II study.
Methods
Work stress was assessed in two ways, using the job-demand-control (JDC) and the effort-reward-imbalance (ERI) models. Salivary cortisol samples were collected six times over a normal day in 2002–2004. The cortisol awakening response (CAR) and diurnal cortisol decline (slope) were calculated.
Results
In this large occupational cohort (N = 2,126, mean age 57.1), modest differences in cortisol patterns were found for ERI models only, showing lower reward (β = −0.001, P-value = 0.04) and higher ERI (β = 0.002, P-value = 0.05) were related to a flatter slope in cortisol across the day. Meanwhile, moderate gender interactions were observed regarding CAR and JDC model.
Conclusions
We conclude that the associations of work stress with cortisol are modest, with associations apparent for ERI model rather than JDC model.
doi:10.1371/journal.pone.0081020
PMCID: PMC3849138  PMID: 24312516
19.  Adiponectin Trajectories Before Type 2 Diabetes Diagnosis 
Diabetes Care  2012;35(12):2540-2547.
OBJECTIVE
The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes.
RESEARCH DESIGN AND METHODS
In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991–1993, 1997–1999, and 2003–2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year0) based on 755/5,095 (case/noncase) person-examinations.
RESULTS
Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187–10,304] vs. 8,818 [6,535–12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3% per year, P < 0.0001) at higher levels in women than in men (difference at year0: 5,358 ng/mL, P < 0.0001). Female case and early-onset case (age at diagnosis <52 years) subjects had a steeper decline than control subjects (slope difference −1.1% per year, P = 0.001 in females, −1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity.
CONCLUSIONS
Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development.
doi:10.2337/dc11-2263
PMCID: PMC3507593  PMID: 22933430
20.  Job Strain and Cardiovascular Disease Risk Factors: Meta-Analysis of Individual-Participant Data from 47,000 Men and Women 
PLoS ONE  2013;8(6):e67323.
Background
Job strain is associated with an increased coronary heart disease risk, but few large-scale studies have examined the relationship of this psychosocial characteristic with the biological risk factors that potentially mediate the job strain – heart disease association.
Methodology and Principal Findings
We pooled cross-sectional, individual-level data from eight studies comprising 47,045 participants to investigate the association between job strain and the following cardiovascular disease risk factors: diabetes, blood pressure, pulse pressure, lipid fractions, smoking, alcohol consumption, physical inactivity, obesity, and overall cardiovascular disease risk as indexed by the Framingham Risk Score. In age-, sex-, and socioeconomic status-adjusted analyses, compared to those without job strain, people with job strain were more likely to have diabetes (odds ratio 1.29; 95% CI: 1.11–1.51), to smoke (1.14; 1.08–1.20), to be physically inactive (1.34; 1.26–1.41), and to be obese (1.12; 1.04–1.20). The association between job strain and elevated Framingham risk score (1.13; 1.03–1.25) was attributable to the higher prevalence of diabetes, smoking and physical inactivity among those reporting job strain.
Conclusions
In this meta-analysis of work-related stress and cardiovascular disease risk factors, job strain was linked to adverse lifestyle and diabetes. No association was observed between job strain, clinic blood pressure or blood lipids.
doi:10.1371/journal.pone.0067323
PMCID: PMC3688665  PMID: 23840664
21.  Does Overall Diet in Midlife Predict Future Aging Phenotypes? A Cohort Study 
The American Journal of Medicine  2013;126(5):411-419.e3.
Background
The impact of diet on specific age-related diseases has been studied extensively, but few investigations have adopted a more holistic approach to determine the association of diet with overall health at older ages. We examined whether diet, assessed in midlife, using dietary patterns and adherence to the Alternative Healthy Eating Index (AHEI), is associated with aging phenotypes, identified after a mean 16-year follow-up.
Methods
Data were drawn from the Whitehall II cohort study of 5350 adults (age 51.3 ± 5.3 years, 29.4% women). Diet was assessed at baseline (1991-1993). Mortality, chronic diseases, and functioning were ascertained from hospital data, register linkage, and screenings every 5 years and were used to create 5 outcomes at follow-up: ideal aging (free of chronic conditions and high performance in physical, mental, and cognitive functioning tests; 4%), nonfatal cardiovascular event (7.3%), cardiovascular death (2.8%), noncardiovascular death (12.7%), and normal aging (73.2%).
Results
Low adherence to the AHEI was associated with an increased risk of cardiovascular and noncardiovascular death. In addition, participants with a “Western-type” diet (characterized by high intakes of fried and sweet food, processed food and red meat, refined grains, and high-fat dairy products) had lower odds of ideal aging (odds ratio for top vs bottom tertile: 0.58; 95% confidence interval, 0.36-0.94; P = .02), independently of other health behaviors.
Conclusions
By considering healthy aging as a composite of cardiovascular, metabolic, musculoskeletal, respiratory, mental, and cognitive function, the present study offers a new perspective on the impact of diet on aging phenotypes.
doi:10.1016/j.amjmed.2012.10.028
PMCID: PMC3743043  PMID: 23582933
Aging; Cognitive functioning; Dietary patterns; Diet quality indices; Mortality; Nutritional epidemiology; Overall diet; Physical functioning
23.  Obesity phenotypes in midlife and cognition in early old age 
Neurology  2012;79(8):755-762.
Objective:
To examine the association of body mass index (BMI) and metabolic status with cognitive function and decline.
Methods:
A total of 6,401 adults (71.2% men), aged 39–63 years in 1991–1993, provided data on BMI (normal weight 18.5–24.9 kg/m2, overweight 25–29.9 kg/m2; and obese ≥30 kg/m2) and metabolic status (abnormality defined as 2 or more of 1) triglycerides ≥1.69 mmol/L or lipid-lowering drugs, 2) systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥85 mm Hg, or antihypertensive drugs, 3) glucose ≥5.6 mmol/L or medications for diabetes, and 4) high-density lipoprotein cholesterol <1.04 mmol/L for men and <1.29 mmol/L for women). Four cognitive tests (memory, reasoning, semantic, and phonemic fluency) were administered in 1997–1999, 2002–2004, and 2007–2009, standardized to z scores, and averaged to yield a global score.
Results:
Of the participants, 31.0% had metabolic abnormalities, 52.7% were normal weight, 38.2% were overweight, and 9.1% were obese. Among the obese, the global cognitive score at baseline (p = 0.82) and decline (p = 0.19) over 10 years was similar in the metabolically normal and abnormal groups. In the metabolically normal group, the 10-year decline in the global cognitive score was similar (p for trend = 0.36) in the normal weight (−0.40; 95% confidence interval [CI] −0.42 to −0.38), overweight (−0.42; 95% CI −0.45 to −0.39), and obese (−0.42; 95% CI −0.50 to −0.34) groups. However, in the metabolically abnormal group, the decline on the global score was faster among obese (−0.49; 95% CI −0.55 to −0.42) than among normal weight individuals (−0.42; 95% CI −0.50 to −0.34), (p = 0.03).
Conclusions:
In these analyses the fastest cognitive decline was observed in those with both obesity and metabolic abnormality.
doi:10.1212/WNL.0b013e3182661f63
PMCID: PMC3421151  PMID: 22915175
24.  Sitting Behavior and Obesity 
Background
Prospective studies report associations between indicators of time spent sitting and obesity risk. Most studies use a single indicator of sedentary behavior and are unable to clearly identify whether sedentary behavior is a cause or a consequence of obesity.
Purpose
To investigate cross-sectional and prospective associations between multiple sitting time indicators and obesity and examine the possibility of reverse causality.
Methods
Using data from the Whitehall II cohort, multiple logistic models were fitted to examine associations between prevalent obesity (BMI ≥30) at Phase 5 (1997–1999), and incident obesity between Phases 5 and 7 (2003–2004) across four levels of five sitting exposures (work sitting, TV viewing, non-TV leisure-time sitting, leisure-time sitting, and total sitting). Using obesity data from three prior phases (1985–1988, 1991–1993; and recalled weight at age 25 years), linear regression models were fitted to examine the association between prior obesity and sitting time at Phase 5. Analyses were conducted in 2012.
Results
None of the sitting exposures were associated with obesity either cross-sectionally or prospectively. Obesity at one previous measurement phase was associated with a 2.43-hour/week (95% CI=0.07, 4.78) increase in TV viewing; obesity at three previous phases was associated with a 7.42-hour/week (95% CI=2.7, 12.46) increase in TV-viewing hours/week at Phase 5.
Conclusions
Sitting time was not associated with obesity cross-sectionally or prospectively. Prior obesity was prospectively associated with time spent watching TV per week but not other types of sitting.
doi:10.1016/j.amepre.2012.10.009
PMCID: PMC3550520  PMID: 23332328
25.  Influence of individual and combined healthy behaviours on successful aging 
Background:
Increases in life expectancy make it important to remain healthy for as long as possible. Our objective was to examine the extent to which healthy behaviours in midlife, separately and in combination, predict successful aging.
Methods:
We used a prospective cohort design involving 5100 men and women aged 42–63 years. Participants were free of cancer, coronary artery disease and stroke when their health behaviours were assessed in 1991–1994 as part of the Whitehall II study. We defined healthy behaviours as never smoking, moderate alcohol consumption, physical activity (≥ 2.5 h/wk moderate physical activity or ≥ 1 h/wk vigorous physical activity), and eating fruits and vegetables daily. We defined successful aging, measured over a median 16.3-year follow-up, as good cognitive, physical, respiratory and cardiovascular functioning, in addition to the absence of disability, mental health problems and chronic disease (coronary artery disease, stroke, cancer and diabetes).
Results:
At the end of follow-up, 549 participants had died and 953 qualified as aging successfully. Compared with participants who engaged in no healthy behaviours, participants engaging in all 4 healthy behaviours had 3.3 times greater odds of successful aging (95% confidence interval [CI] 2.1–5.1). The association with successful aging was linear, with the odds ratio (OR) per increment of healthy behaviour being 1.3 (95% CI 1.2–1.4; population-attributable risk for 1–4 v. 0 healthy behaviours 47%). When missing data were considered in the analysis, the results were similar to those of our main analysis.
Interpretation:
Although individual healthy behaviours are moderately associated with successful aging, their combined impact is substantial. We did not investigate the mechanisms underlying these associations, but we saw clear evidence of the importance of healthy behaviours for successful aging.
doi:10.1503/cmaj.121080
PMCID: PMC3519184  PMID: 23091184

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