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Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

Infections with Coxsackieviruses have been linked to beta cell dysfunction. Given the importance of beta cell dysfunction in the aetiology of type 2 diabetes, we hypothesised that prior infection with Coxsackieviruses B would increase the risk of type 2 diabetes. The aims of the study were to estimate cross-sectional associations between potential predictors of previous infection and seropositivity for Coxsackievirus B serotypes 1-5 (CBV1-5), and then to assess the association between seropositivity and incident type 2 diabetes.Using a case-cohort design nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk study, we ascertained n = 603 cases of incident type 2 diabetes. From within the entire cohort we identified a random subcohort of n = 835, without diabetes at baseline. The presence of Coxsackievirus B neutralising antibodies against serotypes 1-5 was assessed using a plaque neutralisation assay. Weighted Cox regression was used to examine the association between presence of antibodies to CBV1-5 and the development of type 2 diabetes.Seropositivity in the subcohort for CBV1-5 was 50%, 67%, 66%, 75% and 45%, respectively. After adjustment for age, sex, BMI, physical activity and family history of diabetes, the presence of antibodies against CBV1-5 was not associated with incident type 2 diabetes, over a mean follow-up of 5.7 years (HR [95% CIs] 0.94 [0.72,1.25], 0.92 [0.68, 1.23], 1.33 [0.98,1.81], 1.16 [0.83,1.61] and 1.03 [0.77,1.39] for CBV1-5, respectively).The presence of antibodies against any of five serotypes of Coxsackievirus B was not associated with incident type 2 diabetes.

Aims/hypothesis The association between the mitochondrial DNA 16181–16193 polycytosine variant (known as the OriB variant as it maps to the OriB origin of replication) and type 2 diabetes has not been reliably characterised, with studies reporting conflicting results. We report a systematic review of published literature in Europid populations, new data from the Norfolk Diabetes Case–Control Study and a meta-analysis to help quantify this association. Methods We performed a systematic review identifying all the studies of the OriB variant and type 2 diabetes in Europid populations published before January 2013. We typed the OriB variant by pyrosequencing and sequencing in the Norfolk Diabetes Case–Control Study, which comprised 5,574 type 2 diabetes cases and 6,950 population-based controls. Results Overall, the meta-analysis included eight published studies plus the current new results, with a total of 11,794 type 2 diabetes cases and 14,465 controls. In the Norfolk Diabetes Case–Control Study, the OR for type 2 diabetes for the OriB variant was 1.09 (95% CI 0.96, 1.24). In a combined analysis, the relative risk for type 2 diabetes for the OriB variant in Europid populations was 1.10 (95% CI 1.01, 1.20; p = 0.03) Conclusions/interpretation Results from this systematic review and meta-analysis suggest that the mitochondrial DNA OriB variant is modestly associated with an increased risk of type 2 diabetes in Europid populations, with an effect size comparable with that of recently identified variants from genome-wide association studies. Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-2945-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Epidemiological evidence is suggestive, but limited, for an association between circulating 25-hydroxyvitamin D (25[OH]D) and risk of type 2 diabetes. We conducted a systematic review and meta-analysis that included new data from previously unpublished studies.Using a nested case-cohort design in the European Prospective Investigation into Cancer (EPIC)-Norfolk study, we identified a random subcohort and incident type 2 diabetes cases occurring between baseline (1993-1997) and 2006. In the Ely prospective study we identified incident type 2 diabetes cases between 1990 and 2003. We conducted a systematic review of prospective studies on 25(OH)D and type 2 diabetes published in MEDLINE or EMBASE until 31 January 2012, and performed a random-effects meta-analysis combining available evidence with results from the EPIC-Norfolk and Ely studies.In EPIC-Norfolk, baseline 25(OH)D was lower among incident type 2 diabetes cases (mean [SD] 61.6 [22.4] nmol/l; n=621) vs non-case subcohort participants (mean 65.3 [23.9] nmol/l; n=826). There was an inverse association between baseline 25(OH)D and incident type 2 diabetes in multivariable-adjusted analyses: HR (95% CI) 0.66 (0.45, 0.97), 0.53 (0.34, 0.82), 0.50 (0.32, 0.76), p trend0.001, comparing consecutive increasing 25(OH)D quartiles with the lowest. In Ely, 37 incident type 2 diabetes cases were identified among 777 participants. In meta-analysis, the combined RR of type 2 diabetes comparing the highest with lowest quartile of 25(OH)D was 0.59 (0.52, 0.67), with little heterogeneity (I (2) =2.7%, p=0.42) between the 11 studies included (3,612 cases and 55,713 non-cases).These findings demonstrate an inverse association between circulating 25(OH)D and incident type 2 diabetes. However, causal inference should be addressed through adequately dosed randomised trials of vitamin D supplementation or genetic Mendelian randomisation experiments.

Epidemiological and experimental evidence suggests that uric acid has a role in the aetiology of type 2 diabetes. Using a Mendelian randomisation approach, we investigated whether there is evidence for a causal role of serum uric acid for development of type 2 diabetes.We examined the associations of serum-uric-acid-raising alleles of eight common variants recently identified in genome-wide association studies and summarised this in a genetic score with type 2 diabetes in case-control studies including 7,504 diabetes patients and 8,560 non-diabetic controls. We compared the observed effect size to that expected based on: (1) the association between the genetic score and uric acid levels in non-diabetic controls; and (2) the meta-analysed uric acid level to diabetes association.The genetic score showed a linear association with uric acid levels, with a difference of 12.2 μmol/l (95% CI 9.3, 15.1) by score tertile. No significant associations were observed between the genetic score and potential confounders. No association was observed between the genetic score and type 2 diabetes with an OR of 0.99 (95% CI 0.94, 1.04) per score tertile, significantly different (p = 0.046) from that expected (1.04 [95% CI 1.03, 1.05]) based on the observed uric acid difference by score tertile and the uric acid to diabetes association of 1.21 (95% CI 1.14, 1.29) per 60 μmol/l.Our results do not support a causal role of serum uric acid for the development of type 2 diabetes and limit the expectation that uric-acid-lowering drugs will be effective in the prevention of type 2 diabetes.

Type 2 diabetes is a major risk factor for CHD. We hypothesised that diabetes genetic susceptibility variants might be associated with increased CHD risk.We examined the individual and cumulative effect of 38 common genetic variants previously reported to be associated with type 2 diabetes on risk of incident CHD in 20,467 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Study who had been free of CHD at baseline.During a mean follow-up of 10.7 years, 2,190 participants had a CHD event. Two individual variants next to the TSPAN8 (HR 1.07, 95% CI 1.00-1.14) and the CDKN2A/B region (1.11, 1.04-1.17) were significantly associated with increased CHD risk. A genetic score based on the 38 diabetes variants was significantly associated with an increased risk of CHD (1.08, 1.01-1.14 per score tertile). Adjustment for prevalent and incident diabetes attenuated the association of the TSPAN8 variant (1.06, 0.99-1.13) and the genetic score (1.05, 0.99-1.12 per score tertile) with CHD risk, but not that of the CDKN2A/B variant (1.11, 1.05-1.18). Addition of the genetic score did not improve risk discrimination based on clinical risk factors.The increased risk of CHD observed with genetic susceptibility to type 2 diabetes was at least partly mediated by its diabetes-predisposing effect and was not useful for clinical risk discrimination. The potential role of pathways associated with the variant CDKN2A/B in linking diabetes and CHD needs further exploration.

To the Editor: Glucose uptake into muscle and fat is impaired in insulin-resistant states [1]. In response to insulin, vesicles containing GLUT4 are redistributed from the cell interior to the plasma membrane where they dock and fuse with the plasma membrane (GLUT4 translocation), enabling glucose uptake [2]. In vitro studies suggest that Tre-2 BUB2 CDC16, 1 domain family member 4 (TBC1D4), which is also known as Akt substrate of 160 kDa (AS160), plays an important role in GLUT4 translocation [3] making TBC1D4 an excellent candidate gene for insulin resistance.

Aims/hypothesis Intake of dietary fibre has been associated with a reduced risk of type 2 diabetes, but few European studies have been published on this. We evaluated the association between intake of dietary fibre and type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study and in a meta-analysis of prospective studies. Methods During 10.8 years of follow-up, 11,559 participants with type 2 diabetes were identified and a subcohort of 15,258 participants was selected for the case-cohort study. Country-specific HRs were estimated using Prentice-weighted Cox proportional hazards models and were pooled using a random effects meta-analysis. Eighteen other cohort studies were identified for the meta-analysis. Results In the EPIC-InterAct Study, dietary fibre intake was associated with a lower risk of diabetes (HRQ4 vs Q1 0.82; 95% CI 0.69, 0.97) after adjustment for lifestyle and dietary factors. Similar inverse associations were observed for the intake of cereal fibre and vegetable fibre, but not fruit fibre. The associations were attenuated and no longer statistically significant after adjustment for BMI. In the meta-analysis (19 cohorts), the summary RRs per 10 g/day increase in intake were 0.91 (95% CI 0.87, 0.96) for total fibre, 0.75 (95% CI 0.65, 0.86) for cereal fibre, 0.95 (95% CI 0.87, 1.03) for fruit fibre and 0.93 (95% CI 0.82, 1.05) for vegetable fibre. Conclusions/interpretation The overall evidence indicates that the intake of total and cereal fibre is inversely related to the risk of type 2 diabetes. The results of the EPIC-InterAct Study suggest that the association may be partially explained by body weight. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3585-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Aims/hypothesis We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. Methods We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. Results The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 × 10−5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (−0.19 [−0.28, −0.10], p = 1.7 × 10−5), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all). Conclusions/interpretation Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B. Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1392-x) contains a list of the members of the RISC Consortium, which is available to authorised users.

Aims/hypothesis Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort. Methods We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39–79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models. Results Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005–1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967–1.039; p = 0.89). Conclusions/interpretation The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect. Electronic supplementary material The online version of this article (doi:10.1007/s00125-011-2044-5) contains supplementary material, which is available to authorized users.