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1.  Association of Genetic Loci With Glucose Levels in Childhood and Adolescence 
Diabetes  2011;60(6):1805-1812.
OBJECTIVE
To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.
RESEARCH DESIGN AND METHODS
A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9–16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.
RESULTS
Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021–0.031) for each unit increase in the score.
CONCLUSIONS
Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards.
doi:10.2337/db10-1575
PMCID: PMC3114379  PMID: 21515849
2.  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
3.  Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study 
Summary
Background
Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach.
Methods
Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes.
Findings
All four SNPs were associated with 25(OH)D concentrations (p<10−6). The mendelian randomisation-derived unconfounded odds ratio for type 2 diabetes was 1·01 (95% CI 0·75–1·36; p=0·94) per 25·0 nmol/L (1 SD) lower 25(OH)D concentration. The corresponding (potentially confounded) relative risk from the meta-analysis of data from observational studies was 1·21 (1·16–1·27; p=7·3 × 10−19). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p>0·25).
Interpretation
The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes.
Funding
UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.
doi:10.1016/S2213-8587(14)70184-6
PMCID: PMC4286815  PMID: 25281353
4.  The Association Between Dietary Flavonoid and Lignan Intakes and Incident Type 2 Diabetes in European Populations 
Diabetes Care  2013;36(12):3961-3970.
OBJECTIVE
To study the association between dietary flavonoid and lignan intakes, and the risk of development of type 2 diabetes among European populations.
RESEARCH DESIGN AND METHODS
The European Prospective Investigation into Cancer and Nutrition-InterAct case-cohort study included 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants from among 340,234 participants with 3.99 million person-years of follow-up in eight European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the Phenol-Explorer, the U.K. Food Standards Agency, and the U.S. Department of Agriculture databases. Hazard ratios (HRs) from country-specific Prentice-weighted Cox regression models were pooled using random-effects meta-analysis.
RESULTS
In multivariable models, a trend for an inverse association between total flavonoid intake and type 2 diabetes was observed (HR for the highest vs. the lowest quintile, 0.90 [95% CI 0.77–1.04]; P valuetrend = 0.040), but not with lignans (HR 0.88 [95% CI 0.72–1.07]; P valuetrend = 0.119). Among flavonoid subclasses, flavonols (HR 0.81 [95% CI 0.69–0.95]; P valuetrend = 0.020) and flavanols (HR 0.82 [95% CI 0.68–0.99]; P valuetrend = 0.012), including flavan-3-ol monomers (HR 0.73 [95% CI 0.57–0.93]; P valuetrend = 0.029), were associated with a significantly reduced hazard of diabetes.
CONCLUSIONS
Prospective findings in this large European cohort demonstrate inverse associations between flavonoids, particularly flavanols and flavonols, and incident type 2 diabetes. This suggests a potential protective role of eating a diet rich in flavonoids, a dietary pattern based on plant-based foods, in the prevention of type 2 diabetes.
doi:10.2337/dc13-0877
PMCID: PMC3836159  PMID: 24130345
5.  Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity 
Diabetes  2014;63(12):4378-4387.
We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance and secretion, and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs-per-allele [95%CI]:−0.03[−0.04,−0.01];p=0.004). This score was associated with lower BMI (−0.01[−0.01,−0.0;p=0.02) and gluteofemoral fat-mass (−0.03[−0.05,−0.02;p=1.4×10−6), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (0.02[0.01,0.03];p=0.001). While the secretion score had a stronger association with T2D in leaner individuals (pinteraction=0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI- or waist-strata(pinteraction>0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
doi:10.2337/db14-0319
PMCID: PMC4241116  PMID: 24947364
Genetics; type 2 diabetes; insulin resistance; insulin secretion; adipose expandability
6.  Dietary vitamin D intake and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition – the EPIC-InterAct study 
Background
Prospective cohort studies have indicated that serum vitamin D levels are inversely related to risk of type 2 diabetes. However, such studies cannot determine the source of vitamin D. Therefore, we examined the association of dietary vitamin D intake with incident type 2 diabetes within the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study in a heterogeneous European population including 8 countries with large geographical variation.
Methods
Using a case-cohort design, 11,245 incident cases of type 2 diabetes and a representative subcohort (N=15,798) were included in the analyses. Hazard ratios (HR) and 95% confidence intervals (CIs) for type 2 diabetes were calculated using a Prentice-weighted Cox regression adjusted for potential confounders. 24-h diet recall data from a subsample (N=2347) were used to calibrate habitual intake data derived from dietary questionnaires.
Results
Median follow-up time was 10.8 years. Dietary vitamin D intake was not significantly associated with the risk of type 2 diabetes. HR and 95 % CIs for the highest compared to the lowest quintile of uncalibrated vitamin D intake was 1.09 (0.97-1.22), (ptrend=0.17). No associations were observed in a sex-specific analysis. The overall pooled effect [HR (95% CI)] using the continuous calibrated variable was 1.00 (0.97-1.03) per increase of 1 μg/day dietary vitamin D.
Conclusion
This observational study does not support an association between higher dietary vitamin D intake and type-2 diabetes incidence. This result has to be interpreted in light of the limited contribution of dietary vitamin D on the overall vitamin D status of a person.
doi:10.1038/ejcn.2013.235
PMCID: PMC4234029  PMID: 24253760
vitamin D; type-2 diabetes; dietary intake; observational study; EPIC
7.  Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome 
In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/−). We hypothesized that BDNF+/− would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6–28y), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7–54y), and 20 healthy controls (4–32y) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/− subjects (n=15), compared with BDNF intact (+/+) subjects (n=13), had lower adaptive behaviour (p=.02), reduced cognitive functioning (p=.04), higher levels of reported historical (p=.02) and current (p=.02) social impairment, and higher percentage meeting cut-off score for autism (p=.047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgment, 3 subjects (2 BDNF+/− and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/− subjects had a mean Vineland Adaptive Behaviour Compose score that was 14 points lower and a mean IQ that was 20 points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.
doi:10.1016/j.cortex.2013.02.009
PMCID: PMC3762943  PMID: 23517654
brain-derived neurotrophic factor; WAGR syndrome; 11p deletion; IQ; autism
8.  Age at Menarche and Type 2 Diabetes Risk 
Diabetes Care  2013;36(11):3526-3534.
OBJECTIVE
Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity.
RESEARCH DESIGN AND METHODS
The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI.
RESULTS
Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8–11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49–1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18–1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes.
CONCLUSIONS
Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.
doi:10.2337/dc13-0446
PMCID: PMC3816901  PMID: 24159179
9.  Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study 
Summary
Background
Conflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants.
Methods
The EPIC-InterAct case-cohort study includes 12 403 people with incident type 2 diabetes and a representative subcohort of 16 154 individuals who were selected from a cohort of 340 234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis.
Findings
SFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 [myristic acid], 16:0 [palmitic acid], and 18:0 [stearic acid]) were positively associated with incident type 2 diabetes (HR [95% CI] per SD difference: myristic acid 1·15 [95% CI 1·09–1·22], palmitic acid 1·26 [1·15–1·37], and stearic acid 1·06 [1·00–1·13]). By contrast, measured odd-chain SFAs (15:0 [pentadecanoic acid] and 17:0 [heptadecanoic acid]) were inversely associated with incident type 2 diabetes (HR [95% CI] per 1 SD difference: 0·79 [0·73–0·85] for pentadecanoic acid and 0·67 [0·63–0·71] for heptadecanoic acid), as were measured longer-chain SFAs (20:0 [arachidic acid], 22:0 [behenic acid], 23:0 [tricosanoic acid], and 24:0 [lignoceric acid]), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses.
Interpretation
Different individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed.
Funding
EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.
doi:10.1016/S2213-8587(14)70146-9
PMCID: PMC4196248  PMID: 25107467
10.  A Review of Published Analyses of Case-Cohort Studies and Recommendations for Future Reporting 
PLoS ONE  2014;9(6):e101176.
The case-cohort study design combines the advantages of a cohort study with the efficiency of a nested case-control study. However, unlike more standard observational study designs, there are currently no guidelines for reporting results from case-cohort studies. Our aim was to review recent practice in reporting these studies, and develop recommendations for the future. By searching papers published in 24 major medical and epidemiological journals between January 2010 and March 2013 using PubMed, Scopus and Web of Knowledge, we identified 32 papers reporting case-cohort studies. The median subcohort sampling fraction was 4.1% (interquartile range 3.7% to 9.1%). The papers varied in their approaches to describing the numbers of individuals in the original cohort and the subcohort, presenting descriptive data, and in the level of detail provided about the statistical methods used, so it was not always possible to be sure that appropriate analyses had been conducted. Based on the findings of our review, we make recommendations about reporting of the study design, subcohort definition, numbers of participants, descriptive information and statistical methods, which could be used alongside existing STROBE guidelines for reporting observational studies.
doi:10.1371/journal.pone.0101176
PMCID: PMC4074158  PMID: 24972092
11.  Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study 
PLoS Medicine  2014;11(5):e1001647.
In this study, Wareham and colleagues quantified the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. The authors found that the relative effect of a type 2 diabetes genetic risk score is greater in younger and leaner participants, and the high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Please see later in the article for the Editors' Summary
Background
Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.
Methods and Findings
The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10−4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10−3) and waist circumference (p for interaction  = 7.49×10−9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.
Conclusions
The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people currently have diabetes, and the condition is becoming increasingly common. Diabetes is characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest type of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes can often initially be controlled with diet and exercise (lifestyle changes) and with antidiabetic drugs such as metformin and sulfonylureas, but patients may eventually need insulin injections to control their blood sugar levels. Long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes.
Why Was This Study Done?
Type 2 diabetes is thought to originate from the interplay between genetic and lifestyle factors. But although rapid progress is being made in understanding the genetic basis of type 2 diabetes, it is not known whether the consequences of adverse lifestyles (for example, being overweight and/or physically inactive) differ according to an individual's underlying genetic risk of diabetes. It is important to investigate this question to inform strategies for prevention. If, for example, obese individuals with a high level of genetic risk have a higher risk of developing diabetes than obese individuals with a low level of genetic risk, then preventative strategies that target lifestyle interventions to obese individuals with a high genetic risk would be more effective than strategies that target all obese individuals. In this case-cohort study, researchers from the InterAct consortium quantify the combined effects of genetic and lifestyle factors on the risk of type 2 diabetes. A case-cohort study measures exposure to potential risk factors in a group (cohort) of people and compares the occurrence of these risk factors in people who later develop the disease with those who remain disease free.
What Did the Researchers Do and Find?
The InterAct study involves 12,403 middle-aged individuals who developed type 2 diabetes after enrollment (incident cases) into the European Prospective Investigation into Cancer and Nutrition (EPIC) and a sub-cohort of 16,154 EPIC participants. The researchers calculated a genetic type 2 diabetes risk score for most of these individuals by determining which of 49 gene variants associated with type 2 diabetes each person carried, and collected baseline information about exposure to lifestyle risk factors for type 2 diabetes. They then used various statistical approaches to examine the combined effects of the genetic risk score and lifestyle factors on diabetes development. The effect of the genetic score was greater in younger individuals than in older individuals and greater in leaner participants than in participants with larger amounts of body fat. The absolute risk of type 2 diabetes, expressed as the ten-year cumulative incidence of type 2 diabetes (the percentage of participants who developed diabetes over a ten-year period) increased with increasing genetic score in normal weight individuals from 0.25% in people with the lowest genetic risk scores to 0.89% in those with the highest scores; in obese people, the ten-year cumulative incidence rose from 4.22% to 7.99% with increasing genetic risk score.
What Do These Findings Mean?
These findings show that in this middle-aged cohort, the relative association with type 2 diabetes of a genetic risk score comprised of a large number of gene variants is greatest in individuals who are younger and leaner at baseline. This finding may in part reflect the methods used to originally identify gene variants associated with type 2 diabetes, and future investigations that include other genetic variants, other lifestyle factors, and individuals living in other settings should be undertaken to confirm this finding. Importantly, however, this study shows that young, lean individuals with a high genetic risk score have a low absolute risk of developing type 2 diabetes. Thus, this sub-group of individuals is not a logical target for preventative interventions. Rather, suggest the researchers, the high absolute risk of type 2 diabetes associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001647.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals and the general public, including detailed 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 and about living with diabetes; it also provides people's stories about diabetes
The charity Diabetes UK provides detailed information for patients and carers in several languages, including information on healthy lifestyles for people with diabetes
The UK-based non-profit organization Healthtalkonline has interviews with people about their experiences of diabetes
The Genetic Landscape of Diabetes is published by the US National Center for Biotechnology Information
More information on the InterAct study is available
MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention (in English and Spanish)
doi:10.1371/journal.pmed.1001647
PMCID: PMC4028183  PMID: 24845081
12.  Age at Menopause, Reproductive Life Span, and Type 2 Diabetes Risk 
Diabetes Care  2013;36(4):1012-1019.
OBJECTIVE
Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk.
RESEARCH DESIGN AND METHODS
Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied.
RESULTS
Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04–1.69), 1.09 (0.90–1.31), 0.97 (0.86–1.10), and 0.85 (0.70–1.03) for women with menopause at ages <40, 40–44, 45–49, and ≥55 years, respectively, relative to those with menopause at age 50–54 years. The HR per SD younger age at menopause was 1.08 (1.02–1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [1.01–1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all > 0.05).
CONCLUSIONS
Early menopause is associated with a greater risk of type 2 diabetes.
doi:10.2337/dc12-1020
PMCID: PMC3609516  PMID: 23230098
13.  Change in cardiovascular risk factors following early diagnosis of type 2 diabetes: a cohort analysis of a cluster-randomised trial 
The British Journal of General Practice  2014;64(621):e208-e216.
Background
There is little evidence to inform the targeted treatment of individuals found early in the diabetes disease trajectory.
Aim
To describe cardiovascular disease (CVD) risk profiles and treatment of individual CVD risk factors by modelled CVD risk at diagnosis; changes in treatment, modelled CVD risk, and CVD risk factors in the 5 years following diagnosis; and how these are patterned by socioeconomic status.
Design and setting
Cohort analysis of a cluster-randomised trial (ADDITION-Europe) in general practices in Denmark, England, and the Netherlands.
Method
A total of 2418 individuals with screen-detected diabetes were divided into quartiles of modelled 10-year CVD risk at diagnosis. Changes in treatment, modelled CVD risk, and CVD risk factors were assessed at 5 years.
Results
The largest reductions in risk factors and modelled CVD risk were seen in participants who were in the highest quartile of modelled risk at baseline, suggesting that treatment was offered appropriately. Participants in the lowest quartile of risk at baseline had very similar levels of modelled CVD risk at 5 years and showed the least variation in change in modelled risk. No association was found between socioeconomic status and changes in CVD risk factors, suggesting that treatment was equitable.
Conclusion
Diabetes management requires setting of individualised attainable targets. This analysis provides a reference point for patients, clinicians, and policymakers when considering goals for changes in risk factors early in the course of the disease that account for the diverse cardiometabolic profile present in individuals who are newly diagnosed with type 2 diabetes.
doi:10.3399/bjgp14X677833
PMCID: PMC3964458  PMID: 24686885
cardiovascular diseases; diabetes mellitus, type 2; prevention and control; primary health care; risk assessment; risk factors; treatment heterogeneity
14.  Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals 
Background
There is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear. Emerging evidence suggests that in addition to being associated with insulin resistance, NAFLD may be associated with relative beta-cell dysfunction. We sought to determine the influence of liver fat on hepatic insulin extraction and indices of beta-cell function in a cohort of apparently healthy older white adults.
Methods
We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin and C-Peptide levels measured every 30 minutes over two hours. The areas under the concentration curve for glucose, insulin and C-Peptide were used to quantify hepatic insulin extraction (HIE), the insulinogenic index (IGI), the C-Peptide increment (CGI), the Disposition Index (DI) and Adaptation Index (AI). Visceral fat was quantified with magnetic resonance (MR) imaging and IHL with MR spectroscopy. Insulin sensitivity was measured with the Oral Glucose Insulin Sensitivity (OGIS) model.
Results
29 of 70 participants (41%) exceeded our arbitrary threshold for NAFLD, i.e. IHL >5.5%. Compared to those with normal IHL, those with NAFLD had higher weight, BMI, waist and MR visceral fat, with lower insulin sensitivity and hepatic insulin extraction. Alcohol consumption, age, HbA1c and alanine aminotransferase (ALT) levels were similar in both groups. Insulin and C-Peptide excursions after oral glucose loading were higher in the NAFLD group, but the CGI and AI were significantly lower, indicating a relative defect in beta-cell function that is only apparent when C-Peptide is measured and when dynamic changes in glucose levels and also insulin sensitivity are taken into account. There was no difference in IGI or DI between the groups.
Conclusions
Although increased IHL was associated with greater insulin secretion, modelled parameters suggested relative beta-cell dysfunction with NAFLD in apparently healthy older adults, which may be obscured by reduced hepatic insulin extraction. Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.
Trial registration
ISRCTN60986572
doi:10.1186/1758-5996-6-43
PMCID: PMC3974597  PMID: 24669786
Adaptation index; Beta cell dysfunction; C-peptide-genic index; Disposition index; Hepatic insulin extraction; Insulinogenic index; Intrahepatic lipid; Non-alcoholic fatty liver disease
15.  Usefulness of the addition of Beta-2-microglobulin, Cystatin C and C-reactive protein to an Established Risk Factors Model to Improve Mortality Risk Prediction in Patients Undergoing Coronary Angiography 
The American journal of cardiology  2013;111(6):851-856.
Evidence-based therapies are available to reduce the risk of death from cardiovascular disease, yet many patients go untreated. Novel methods are needed to identify those at highest risk of cardiovascular death. Here, the biomarkers beta-2-microglobulin, cystatin C and C-reactive protein were measured at baseline in a cohort of participants undergoing coronary angiography. Adjusted Cox proportional-hazards models were used to determine whether the biomarkers predicted all-cause and cardiovascular mortality. Additionally, improvements in risk reclassification and discrimination were evaluated by calculating the net reclassification improvement (NRI), C-index and the integrated discrimination improvement (IDI) with the addition of the biomarkers to a baseline model of risk factors for cardiovascular disease and death. During a median follow-up period of 5.6 years, there were 78 deaths among 470 participants. All biomarkers independently predicted future all-cause and cardiovascular mortality. A significant improvement in risk reclassification was observed for all-cause (NRI, 35.8%; P=0.004) and cardiovascular (NRI, 61.9%; P=0.008) mortality compared to the baseline risk factors model. Additionally, we observed significantly increased risk discrimination with a C-index of 0.777 (change in C-index [ΔC], 0.057; 95% CI, 0.016–0.097) and 0.826 (ΔC, 0.071; 95% CI, 0.010–0.133) for all-cause and cardiovascular mortality respectively. Improvements in risk discrimination were further supported using the integrated discrimination improvement index. In conclusion, we provide evidence that beta-2-microglobulin, cystatin C and C-reactive protein predict mortality and improve risk reclassification and discrimination for a high-risk cohort undergoing coronary angiography.
doi:10.1016/j.amjcard.2012.11.055
PMCID: PMC3594484  PMID: 23290308
Angiography; Cardiovascular diseases; Proteins; Mortality
16.  Combined influence of epoch length, cut-point and bout duration on accelerometry-derived physical activity 
Background
It is difficult to compare accelerometer-derived estimates of moderate-to-vigorous physical activity (MVPA) between studies due to differences in data processing procedures. We aimed to evaluate the effects of accelerometer processing options on total and bout-accumulated time spent in MVPA in adults.
Methods
267 participants from the ProActive Trial provided 1236 days of valid physical activity (PA) data, collected using a 5-s epoch with ActiGraph GT1M accelerometers. We integrated data over 5-s to 60-s epoch lengths (EL) and applied two-level mixed effects regression models to MVPA time, defined using 1500 to 2500 counts/minute (cpm) cut-points (CP) and bout durations (BD) from 1 to 15 min.
Results
Total MVPA time was lower on longer EL and higher CP (47 vs 26 min/day and 26 vs 5 min/day on 1500 vs 2500 cpm on 5-s and 60-s epoch, respectively); this could be approximated as MVPA = exp[2.197 + 0.279*log(CP) + 6.120*log(EL) - 0.869*log(CP)*log(EL)] with an 800 min/day wear-time. In contrast, EL was positively associated with time spent in bout-accumulated MVPA; the approximating equation being MVPA = exp[54.679 - 6.268*log(CP) + 6.387*log(EL) - 10.000*log(BD) - 0.162*log(EL)*log(BD) - 0.626*log(CP)*log(EL) + 1.033*log(CP)*log(BD)]. BD and CP were inversely associated with MVPA, with higher values attenuating the influence of EL.
Conclusions
EL, CP and BD interact to influence estimates of accelerometer-determined MVPA. In general, higher CP and longer BD result in lower MVPA but the direction of association for EL depends on BD. Reporting scaling coefficients for these key parameters across their frequently used ranges would facilitate comparisons of population-level accelerometry estimates of MVPA.
doi:10.1186/1479-5868-11-34
PMCID: PMC4008000  PMID: 24612726
Moderate-to-vigorous; Adults; Measurement; Wear-time; Actigraph; Objective
17.  Objectively measured physical activity in four-year-old British children: a cross-sectional analysis of activity patterns segmented across the day 
Background
Little is known about preschool-aged children’s levels of physical activity (PA) over the course of the day. Using time-stamped data, we describe the levels and patterns of PA in a population-based sample of four-year-old British children.
Methods
Within the Southampton Women’s Survey the PA levels of 593 4-year-old children (51% female) were measured using (Actiheart) accelerometry for up to 7 days. Three outcome measures: minutes spent sedentary (<20 cpm); in light (LPA: ≥20 – 399 cpm) and in moderate-to-vigorous activity (MVPA: ≥400 cpm) were derived. Average daily activity levels were calculated and then segmented across the day (morning, afternoon and evening). MVPA was log-transformed. Two-level random intercept models were used to analyse associations between activity level and temporal and demographic factors.
Results
Children were active for 67% (mean 568.5 SD 79.5 minutes) of their daily registered time on average, with 88% of active time spent in LPA. All children met current UK guidelines of 180 minutes of daily activity. There were no differences in children’s average daily levels of sedentary activity and LPA by temporal and demographic factors: differences did emerge when activity was segmented across the day. Sex differences were largest in the morning, with girls being more sedentary, spending fewer minutes in LPA and 18% less time in MVPA than boys. Children were more sedentary and less active (LPA and MVPA) in the morning if they attended childcare full-time compared to part-time, and on weekend mornings compared to weekdays. The reverse was true for weekend afternoons and evenings. Children with more educated mothers were less active in the evenings. Children were less sedentary and did more MVPA on summer evenings compared to winter evenings.
Conclusions
Preschool-aged children meet current physical activity guidelines, but with the majority of their active time spent in LPA, investigation of the importance of activity intensity in younger children is needed. Activity levels over the day differed by demographic and temporal factors, highlighting the need to consider temporality in future interventions. Increasing girls’ morning activity and providing opportunities for daytime activity in winter months may be worthwhile.
doi:10.1186/1479-5868-11-1
PMCID: PMC3896827  PMID: 24405936
18.  Dietary Intakes of Individual Flavanols and Flavonols Are Inversely Associated with Incident Type 2 Diabetes in European Populations123 
The Journal of Nutrition  2013;144(3):335-343.
Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)–InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile: 0.81; 95% CI: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% CI: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% CI: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.
doi:10.3945/jn.113.184945
PMCID: PMC3927546  PMID: 24368432
19.  School-level correlates of physical activity intensity in 10-year old children 
Purpose
Little is known about school environmental factors that promote or inhibit activity, especially from studies using objective measures in large representative samples. We therefore aimed to study associations between activity intensities and physical and social school environmental factors.
Methods
A population-based sample of 1908 British children (SPEEDY study), mean age 10.3 years (SD: 0.3), recruited from 92 schools across Norfolk, UK, with valid activity data (assessed with Actigraph accelerometers). Outcome measures were school-based (8am-4pm on weekdays) time (in minutes) spent in sedentary (<100 counts/min), moderate (2000-3999 counts/min) and vigorous (≥4000 counts/min) activity. A total of 40 school physical and social environmental factors were assessed. Multivariable multilevel linear regression analyses adjusted for children’s sex and body mass index were conducted; interactions with sex were investigated.
Results
Availability of a ‘Park and Stride’ scheme was negatively associated with sedentary minutes (−7.74; 95%CI: −14.8;−0.70). Minutes of moderate activity were associated with the availability of a lollypop person (1.33, 95%CI: 0.35;2.62) and objectively-assessed walking provision (1.70, 95%CI: 0.85;2.56). The number of sports facilities of at least medium quality (0.47, 95%CI: 0.16;0.79), not having a policy on physical activity (−2.28, 95%CI: −3.62;−0.95), and, in boys only, provision of pedestrian training (1.89; 95%CI: 0.77;3.01) were associated with minutes of vigorous activity.
Conclusions
Only a small number of school-level factors were associated with children’s objectively-measured physical activity intensity, giving few pointers for potential future intervention efforts. Further research should focus on using objective measures to elucidate what factors may explain the school-level variance in activity levels.
doi:10.3109/17477166.2010.518239
PMCID: PMC3839262  PMID: 20854106
school; physical activity; behaviour; correlates; physical environment; social environment
20.  Increasing objectively measured sedentary time increases clustered cardiometabolic risk: a 6 year analysis of the ProActive study 
Diabetologia  2013;57(2):305-312.
Aims/hypothesis
We aimed to quantify the associations between change in objectively measured sedentary and moderate-to-vigorous physical activity (MVPA) times and self-reported television viewing over 6 years and change in a clustered cardiometabolic risk score (CCMR), including and excluding waist circumference (CCMR without adiposity component, CCMRno adip), and its individual components, among the adult children of people with type 2 diabetes.
Methods
In 171 adults (mean ± SD age 42.52 ± 6.30 years; 46% men) with a parental history of diabetes (ProActive UK), physical activity accelerometer measures and self-reported television viewing were assessed at baseline and a mean ± SD of 6.27 ± 0.46 years later. Associations between change in sedentary time, MVPA time and television viewing and cardiometabolic risk and mediation by adiposity change were examined by multiple linear regression and the product of coefficients method, respectively.
Results
Greater increases in sedentary time (h/day) were associated with larger increases in clustered cardiometabolic risk (CCMR: 0.08 [95% CI 0.01, 0.15]; CCMRno adip: 0.08 [0.01, 0.16]) and triacylglycerol (0.15 [0.01, 0.29]), independent of baseline sedentary and MVPA times, change in MVPA time and other confounders. No evidence was found for mediation by change in waist circumference and BMI for the associations with CCMRno adip and triacylglycerol. Greater increases in MVPA time (h/day) were associated with larger decreases in waist circumference (−3.86 [−7.58, −0.14]), independently of baseline MVPA and sedentary times, change in sedentary time and other confounders. Television viewing was not independently associated with any of the cardiometabolic outcomes.
Conclusions/interpretation
Increasing sedentary time is independently related to increasing clustered cardiometabolic risk and triacylglycerol in adults at high risk of developing diabetes. Strategies to prevent diabetes might target reducing sedentary time.
Trial registration ISRCTN61323766
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-3102-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-013-3102-y
PMCID: PMC3889989  PMID: 24194101
Adiposity; Cardiovascular disease risk; Longitudinal study; Moderate-to-vigorous physical activity; Sedentary behaviour; Television viewing
21.  The effects of vitamin D2 or D3 supplementation on glycaemic control and related metabolic parameters in people at risk of type 2 diabetes: protocol of a randomised double-blind placebo-controlled trial 
BMC Public Health  2013;13:999.
Background
The global prevalence of type 2 diabetes is increasing. Effective strategies to address this public health challenge are currently lacking. A number of epidemiological studies have reported associations between low concentrations of 25-hydroxy vitamin D and the incidence of diabetes, but a causal link has not been established. We investigate the effect of vitamin D supplementation on the metabolic status of individuals at increased risk of developing type 2 diabetes.
Methods/design
In a randomised double-blind placebo-controlled trial individuals identified as having a high risk of type 2 diabetes (non-diabetic hyperglycaemia or positive diabetes risk score) are randomised into one of three groups and given 4 doses of either placebo, or 100,000 IU Vitamin D2 (ergocalciferol) or 100,000 IU Vitamin D3 (cholecalciferol) at monthly intervals. The primary outcome measure is the change in glycated haemoglobin level between baseline and 4 months. Secondary outcome measures include blood pressure, lipid levels, apolipoproteins, highly sensitive C-reactive protein, parathyroid hormone (PTH) and safety of supplementation. and C-reactive protein. The trial is being conducted at two sites (London and Cambridge, U.K.) and a total of 342 participants are being recruited.
Discussion
Trial data examining whether supplementation of vitamin D improves glycaemic status and other metabolic parameters in people at risk of developing type 2 diabetes are sparse. This trial will evaluate the causal role of vitamin D in hyperglycaemia and risk of type 2 diabetes. Specific features of this trial include recruitment of participants from different ethnic groups, investigation of the relative effectiveness and safety of vitamin D2 and D3 and an evidence based approach to determination of the dose of supplementation.
Trial registration
EudraCT2009-011264-11; ISRCTN86515510
doi:10.1186/1471-2458-13-999
PMCID: PMC3819003  PMID: 24152375
Vitamin D2; Vitamin D3; Placebo; Type 2 diabetes; Randomised; Trial; Intervention
22.  Impact of Personalised Feedback about Physical Activity on Change in Objectively Measured Physical Activity (the FAB Study): A Randomised Controlled Trial 
PLoS ONE  2013;8(9):e75398.
Background
Low levels of physical activity are a major public health concern, and interventions to promote physical activity have had limited success. Whether or not personalised feedback about physical activity following objective measurement motivates behaviour change has yet to be rigorously examined.
Methods
And Findings: In a parallel group, open randomised controlled trial, 466 healthy adults aged 32 to 54 years were recruited from the ongoing population-based Fenland Study (Cambridgeshire, UK). Participants were randomised to receive either no feedback until the end of the trial (control group, n=120) or one of three different types of feedback: simple, visual, or contextualised (intervention groups, n=346). The primary outcome was physical activity (physical activity energy expenditure (PAEE) in kJ/kg/day and average body acceleration (ACC) in m/s2) measured objectively using a combined heart rate monitor and accelerometer (Actiheart®). The main secondary outcomes included self-reported physical activity, intention to increase physical activity, and awareness of physical activity (the agreement between self-rated and objectively measured physical activity). At 8 weeks, 391 (83.9%) participants had complete physical activity data. The intervention had no effect on objectively measured physical activity (PAEE: β=-0.92, 95% CI=-3.50 to 1.66, p=0.48 and ACC: β=0.01, 95% CI=-0.00 to 0.02, p=0.21), self-reported physical activity (β=-0.39, 95% CI=-1.59 to 0.81), or intention to increase physical activity (β=-0.05, 95% CI=-0.22 to 0.11). However, it was associated with an increase in awareness of physical activity (OR=1.74, 95% CI=1.05 to 2.89). Results did not differ according to the type of feedback.
Conclusions
Personalised feedback about physical activity following objective measurement increased awareness but did not result in changes in physical activity in the short term. Measurement and feedback may have a role in promoting behaviour change but are ineffective on their own.
Trial Registration
Current Controlled Trials ISRCTN92551397 http://www.controlled-trials.com/ISRCTN92551397
doi:10.1371/journal.pone.0075398
PMCID: PMC3774634  PMID: 24066178
23.  A Prospective Study of the Association Between Quantity and Variety of Fruit and Vegetable Intake and Incident Type 2 Diabetes 
Diabetes Care  2012;35(6):1293-1300.
OBJECTIVE
The association between quantity of fruit and vegetable (F&V) intake and risk of type 2 diabetes (T2D) is not clear, and the relationship with variety of intake is unknown. The current study examined the association of both quantity and variety of F&V intake and risk of T2D.
RESEARCH DESIGN AND METHODS
We examined the 11-year incidence of T2D in relation to quantity and variety of fruit, vegetables, and combined F&V intake in a case-cohort study of 3,704 participants (n = 653 diabetes cases) nested within the European Prospective Investigation into Cancer and Nutrition-Norfolk study, who completed 7-day prospective food diaries. Variety of intake was derived from the total number of different items consumed in a 1-week period. Multivariable, Prentice-weighted Cox regression was used to estimate hazard ratios (HRs) and 95% CIs.
RESULTS
A greater quantity of combined F&V intake was associated with 21% lower hazard of T2D (HR 0.79 [95% CI 0.62–1.00]) comparing extreme tertiles, in adjusted analyses including variety. Separately, quantity of vegetable intake (0.76 [0.60–0.97]), but not fruit, was inversely associated with T2D in adjusted analysis. Greater variety in fruit (0.70 [0.53–0.91]), vegetable (0.77 [0.61–0.98]), and combined F&V (0.61 [0.48–0.78]) intake was associated with a lower hazard of T2D, independent of known confounders and quantity of intake comparing extreme tertiles.
CONCLUSIONS
These findings suggest that a diet characterized by a greater quantity of vegetables and a greater variety of both F&V intake is associated with a reduced risk of T2D.
doi:10.2337/dc11-2388
PMCID: PMC3357245  PMID: 22474042
24.  Cardiovascular risk reduction following diagnosis of diabetes by screening: 1-year results from the ADDITION-Cambridge trial cohort 
The British Journal of General Practice  2012;62(599):e396-e402.
Background
Uncertainties persist concerning the effects of early intensive management of type 2 diabetes and which patients benefit most from such an approach.
Aim
To describe change in modelled cardiovascular risk in the 14 months following diagnosis, and to examine which baseline patient characteristics and treatment components are associated with risk reduction.
Design and setting
A cohort of individuals from a pragmatic, single-blind, cluster-randomised controlled trial of 236 females and 361 males with screen-detected type 2 diabetes and without prior cardiovascular disease (CVD), from 49 GP surgeries in eastern England, examined at baseline (2002–2006) and after 14-months’ follow-up.
Method
Multiple linear regression was used to quantify the association between baseline patient characteristics, treatment components, and change in modelled 10-year cardiovascular risk (UK Prospective Diabetes Study [UKPDS] [version 3] risk engine).
Results
There was a downward shift in the distribution of modelled CVD risk over 14 months mean 31% (standard deviation [SD] = 14%) to 26% [SD = 13%]). Older individuals, males, and those with a larger waist circumference at baseline exhibited smaller risk reductions. Individuals prescribed higher numbers of drugs over the follow-up period, and those who decreased their energy intake or reduced their weight, demonstrated larger reductions in modelled risk.
Conclusion
It is possible to achieve significant reductions in modelled CVD risk over 14 months following diagnosis of diabetes by screening. Risk reduction appeared to be driven mainly by prescription of higher numbers of drugs, decreased energy intake, and weight reduction. There was room for further risk reduction, as many patients were not prescribed recommended treatments.
doi:10.3399/bjgp12X649070
PMCID: PMC3361118  PMID: 22687231
cardiovascular diseases, prevention and control; diabetes mellitus; equity; mass screening; primary care; risk factors; socioeconomic factors
25.  The prospective association between total and type of fish intake and type 2 diabetes in 8 European countries: EPIC-InterAct Study123 
Background: Epidemiologic evidence of an association between fish intake and type 2 diabetes (T2D) is inconsistent and unresolved.
Objective: The objective was to examine the association between total and type of fish intake and T2D in 8 European countries.
Design: This was a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with 3.99 million person-years of follow-up, 12,403 incident diabetes cases, and a random subcohort of 16,835 individuals from 8 European countries. Habitual fish intake (lean fish, fatty fish, total fish, shellfish, and combined fish and shellfish) was assessed by country-specific dietary questionnaires. HRs were estimated in each country by using Prentice-weighted Cox regression models and pooled by using a random-effects meta-analysis.
Results: No overall association was found between combined fish and shellfish intake and incident T2D per quartile (adjusted HR: 1.00; 95% CI: 0.94, 1.06; P-trend = 0.99). Total fish, lean fish, and shellfish intakes separately were also not associated with T2D, but fatty fish intake was weakly inversely associated with T2D: adjusted HR per quartile 0.97 (0.94, 1.00), with an HR of 0.84 (0.70, 1.01), 0.85 (0.76, 0.95), and 0.87 (0.78, 0.97) for a comparison of the second, third, and fourth quartiles with the lowest quartile of intake, respectively (P-trend = 0.06).
Conclusions: These findings suggest that lean fish, total fish, and shellfish intakes are not associated with incident diabetes but that fatty fish intake may be weakly inversely associated. Replication of these findings in other populations and investigation of the mechanisms underlying these associations are warranted. Meanwhile, current public health recommendations on fish intake should remain unchanged.
doi:10.3945/ajcn.111.029314
PMCID: PMC3623039  PMID: 22572642

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