Interaction between plasma phospholipid odd-chain fatty acids and GAD65 autoantibodies on the incidence of adult-onset diabetes: the EPIC-InterAct case-cohort study.

AIMS/HYPOTHESIS: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes. METHODS: We used the European EPIC-InterAct case-cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP). RESULTS: Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]). CONCLUSIONS/INTERPRETATION: Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes.

A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes: Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study.

BACKGROUND: Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. METHODS AND FINDINGS: We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. CONCLUSIONS: These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860.

Are doctors using more preventive medication for cardiovascular disease? A Swedish cross-sectional study.

BACKGROUND: Despite decreasing mortality from cardiovascular disease (CVD), there are persistent inequities in mortality between socioeconomic groups. Primary preventative medications reduce mortality in CVD; thus, inequitable treatments will contribute to unequal outcomes. Physicians might contribute to inequality by prescribing preventative medication for CVD to themselves in a biased manner. AIM: To determine whether primary medications for preventing CVD were prescribed inequitably between physicians and non-physicians. DESIGN AND SETTING: This retrospective study retrieved registry data on prescribed medications for all physicians in Sweden aged 45-74 years, during 2013, and for reference non-physician individuals, matched by sex, age, residence, and level of education. The outcome was any medication for preventing CVD, received at least once during 2013. METHOD: Age and the sex-specific prevalence of myocardial infarction (MI) among physicians and non-physicians were used as a proxy for the need for medication. Thereafter, to limit the analysis to preventative medication, we excluded individuals that were diagnosed with CVD or diabetes. To analyse differences in medication usage between physicians and matched non-physicians, we estimated odds ratios (ORs) with conditional logistic regression and adjusted for need and household income. RESULTS: MI prevalences were 5.7% for men and 2.3% for women, among physicians, and 5.4% for men and 1.8% for women, among non-physicians. We included 25,105 physicians and 44,366 non-physicians. The OR for physicians receiving any CVD preventative medication, compared to non-physicians, was 1.65 (95% confidence interval 1.59-1.72). CONCLUSION: We found an inequity in prescribed preventative CVD medications, which favoured physicians over non-physicians.

KEYPOINTSGroups with low socioeconomic status have lower rates of using medication that prevents cardiovascular disease, compared to groups with high socioeconomic status.Physicians are responsible for prescribing all medicines to prevent cardiovascular disease; thus, biased prescriptions could have effects on the equality of care in the population.Compared to individuals with equivalent education, physicians had higher rates of using medication that prevents cardiovascular disease.This study highlights the need for systematic population-based evaluation of CVD risk in order to promote equitable CVD outcomes.

Fasting C-peptide at type 2 diabetes diagnosis is an independent risk factor for total and cancer mortality.

AIMS: We assessed the association between insulin resistance and blood glucose concentrations at type 2 diabetes diagnosis and future development of diabetes-related complications and mortality. MATERIALS AND METHODS: This retrospective cohort study included 864 individuals with type 2 diabetes (median age 60 years) whose fasting C-peptide and HbA1c were measured at diabetes diagnosis. The median follow-up time until death or study end was 16.4 years (interquartile range 13.3-19.6). The association between C-peptide and mortality/complications was estimated by Cox regression adjusted for sex, age at diabetes diagnosis, smoking, hypertension, BMI, total cholesterol, and HbA1c. C-peptide and HbA1c were converted to Z scores before the Cox regression analysis. RESULTS: An increase by one standard deviation in fasting C-peptide at diabetes diagnosis was associated with all-cause (hazard ratio [HR] 1.33; 95% confidence intervals [CI] 1.12-1.58; p = 0.001) and cancer mortality (HR 1.51; 95% CI 1.13-2.01; p = 0.005) in the fully adjusted model. An increase by one standard deviation in HbA1c at diabetes diagnosis was associated with all-cause mortality (HR 1.24; 95% CI 1.07-1.44; p = 0.005), major cardiovascular events (HR 1.20; 95% CI 1.04-1.39; p = 0.015), stroke (HR 1.36; 95% CI 1.09-1.70; p = 0.006), and retinopathy (HR 1.54; 95% CI 1.34-1.76; p < 0.0001) in the fully adjusted model. CONCLUSIONS: Fasting C-peptide at type 2 diabetes diagnosis is an independent risk factor for total and cancer-related mortality. Thus, treatment of type 2 diabetes should focus not only on normalising blood glucose levels but also on mitigating insulin resistance.

Impact of cumulative body mass index and cardiometabolic diseases on survival among patients with colorectal and breast cancer: a multi-centre cohort study.

BACKGROUND: Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients. METHODS: Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease. RESULTS: In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02-1.10). The HR for CMD was 1.25 (95% CI: 0.97-1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00-1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01-2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa. CONCLUSIONS: Our results suggest that cumulative exposure to higher BMI during early to mid-adulthood was associated with poorer survival in patients with breast and colorectal cancer, independent of CMD prior to cancer diagnosis. The association between a CMD diagnosis prior to cancer and survival in patients with breast and colorectal cancer was independent of BMI.

Temporal trend of small nerve fibre degeneration in people with and without type 2 diabetes mellitus.

AIMS: We investigated the long-term temporal trend of intraepidermal nerve fibre density (IENFD) and the association between changes in IENFD and metabolic factors in individuals with and without type 2 diabetes. METHODS: A total of 66 participants were enrolled in this longitudinal population-based study, at baseline consisting of 35 individuals (median 61 years) without diabetes and 31 individuals with type 2 diabetes mellitus. Participants underwent clinical and electrophysiological examinations, as well as a skin biopsy both at baseline and at the follow-up visit (mean 8.1 ± 0.5 years). IENFD was assessed in thin sections of 5 µm, stained with the protein gene product 9.5-antibody and compared between the groups. RESULTS: IENFD decreased during the period in both groups, with a greater decline in the group without diabetes than in type 2 diabetes (-2.3 and -0.6 fibres/mm respectively; p < 0.001). While IENFD at baseline was significantly reduced in type 2 diabetes relative to people without (p < 0.001), no difference in IENFD was found between groups at the follow-up (p = 0.183). Linear mixed model analysis indicated that age, weight and HbA1c were associated with decrease in IENFD in the total population (p < 0.007). IENFD also decreased with increasing age and weight, but not with HbA1c , in the separate groups (p < 0.049). CONCLUSIONS: Despite lower IENFD levels at baseline in type 2 diabetes, IENFD was equal between the groups at follow-up. A decrease in IENFD is to a limited extent affected by body weight, and HbA1c , but age seems to be the long-term determinant of IENFD in an elderly population.

Mortality in first- and second-generation immigrants to Sweden diagnosed with type 2 diabetes: a 10 year nationwide cohort study.

AIMS/HYPOTHESIS: Non-Western immigrants to Europe are at high risk for type 2 diabetes. In this nationwide study including incident cases of type 2 diabetes, the aim was to compare all-cause mortality (ACM) and cause-specific mortality (CSM) rates in first- and second-generation immigrants with native Swedes. METHODS: People living in Sweden diagnosed with new-onset pharmacologically treated type 2 diabetes between 2006 and 2012 were identified through the Swedish Prescribed Drug Register. They were followed until 31 December 2016 for ACM and until 31 December 2012 for CSM. Analyses were adjusted for age at diagnosis, sex, socioeconomic status, education, treatment and region. Associations were assessed using Cox regression analysis. RESULTS: In total, 138,085 individuals were diagnosed with type 2 diabetes between 2006 and 2012 and fulfilled inclusion criteria. Of these, 102,163 (74.0%) were native Swedes, 28,819 (20.9%) were first-generation immigrants and 7103 (5.1%) were second-generation immigrants with either one or both parents born outside Sweden. First-generation immigrants had lower ACM rate (HR 0.80 [95% CI 0.76, 0.84]) compared with native Swedes. The mortality rates were particularly low in people born in non-Western regions (0.46 [0.42, 0.50]; the Middle East, 0.41 [0.36, 0.47]; Asia, 0.53 [0.43, 0.66]; Africa, 0.47 [0.38, 0.59]; and Latin America, 0.53 [0.42, 0.68]). ACM rates decreased with older age at migration and shorter stay in Sweden. Compared with native Swedes, first-generation immigrants with ≤ 24 years in Sweden (0.55 [0.51, 0.60]) displayed lower ACM rates than those spending >24 years in Sweden (0.92 [0.87, 0.97]). Second-generation immigrants did not have better survival rates than native Swedes but rather displayed higher ACM rates for people with both parents born abroad (1.28 [1.05, 1.56]). CONCLUSIONS/INTERPRETATION: In people with type 2 diabetes, the lower mortality rate in first-generation non-Western immigrants compared with native Swedes was reduced over time and was equalised in second-generation immigrants. These findings suggest that acculturation to Western culture may impact ACM and CSM in immigrants with type 2 diabetes but further investigation is needed. Graphical abstract.

Autoimmunity plays a role in the onset of diabetes after 40 years of age.

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.

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

BACKGROUND: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. METHODS AND FINDINGS: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. CONCLUSIONS: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.

Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study.

BACKGROUND: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. METHODS: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. RESULTS: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. CONCLUSION: Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.

Joint Analysis of Metabolite Markers of Fish Intake and Persistent Organic Pollutants in Relation to Type 2 Diabetes Risk in Swedish Adults.

BACKGROUND: There is conflicting evidence regarding the association between fish intake and type 2 diabetes (T2D) incidence, possibly owing to measurement errors in self-reported intake and coexposure to persistent organic pollutants (POPs) present in fish. OBJECTIVE: The aim of this study was to identify plasma metabolites associated with fish intake and to assess their association with T2D risk, independently of POPs, in Swedish adults. METHODS: In a case-control study nested in the Swedish Västerbotten Intervention Programme, fasting plasma samples from 421 matched T2D case-control pairs of men and women aged 30-60 y at baseline and 10-y follow-up samples from a subset of 149 pairs were analyzed using untargeted metabolomics. Moreover, 16 plasma POPs were analyzed for the 149 pairs who had repeated samples available. Fish-related plasma metabolites were identified using multivariate modelling and partial correlation analysis. Reproducibility of metabolites and metabolite patterns, derived via principal component analysis (PCA), was assessed by intraclass correlation. A unique component of metabolites unrelated to POPs was dissected by integrating metabolites and POPs using 2-way orthogonal partial least squares regression. ORs of T2D were estimated using conditional logistic regression. RESULTS: We identified 31 metabolites associated with fish intake that had poor to good reproducibility. A PCA-derived metabolite pattern strongly correlated with fish intake (ρ = 0.37, P < 0.001) but showed no association with T2D risk. Integrating fish-related metabolites and POPs led to a unique metabolite component independent of POPs, which tended to be inversely associated with T2D risk (OR: 0.75; 95% CI: 0.54, 1.02, P = 0.07). This component mainly consisted of metabolites reflecting fatty fish intake. CONCLUSIONS: Our results suggest that fatty fish intake may be beneficial for T2D prevention, after removing the counteractive effects of coexposure to POPs in Swedish adults. Integrating metabolite markers and POP exposures appears a promising approach to advance the understanding of associations between fish intake and T2D incidence.

Estimated Substitution of Tea or Coffee for Sugar-Sweetened Beverages Was Associated with Lower Type 2 Diabetes Incidence in Case-Cohort Analysis across 8 European Countries in the EPIC-InterAct Study.

INTRODUCTION: Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another. OBJECTIVE: The aim of this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992-2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D. RESULTS: Mean ± SD of estimated consumption of SSB was 55 ± 105 g/d. Means ± SDs for the other beverages were as follows: fruit juice, 59 ± 101 g/d; milk, 209 ± 203 g/d; coffee, 381 ± 372 g/d; and tea, 152 ± 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was -12.0 (95% CI: -20.0, -5.0) per 10,000 person-years among adults consuming SSBs ≥250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or -11.0 (95% CI: -20.0, -2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly. CONCLUSIONS: These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations.

Generalizability of a Diabetes-Associated Country-Specific Exploratory Dietary Pattern Is Feasible Across European Populations.

BACKGROUND: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence. OBJECTIVE: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries. METHODS: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association. RESULTS: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea. CONCLUSIONS: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.

Chlorinated persistent organic pollutants and type 2 diabetes - A population-based study with pre- and post- diagnostic plasma samples.

BACKGROUND: Persistent organic pollutants (POPs) have been associated with type 2 diabetes (T2D), but causality is uncertain. OBJECTIVE: Within longitudinal population-based data from northern Sweden, we assessed how POPs associated with T2D prospectively and cross-sectionally, and further investigated factors related to individual changes in POP concentrations. METHODS: For 129 case-controls pairs matched by age, sex and date of sampling, plasma concentrations of hexachlorobenzene (HCB), dichlorodiphenyl-dichloroethylene (p,p'-DDE), dioxin-like (DL) polychlorinated biphenyl congeners (PCB-118 and PCB-156), and non-dioxin like (NDL-PCB: PCB-74, -99, -138 -153, -170, -180, -183 and PCB-187) were analyzed twice (baseline and follow-up, 9-20 years apart). The cases received their T2D diagnose between baseline and follow-up. Prospective (using baseline data) and cross-sectional (using follow-up data) odds ratios (ORs) for T2D on lipid standardized POPs (HCB, p,p'-DDE, ∑DL-PCBs, ∑NDL-PCBs) were estimated using conditional logistic regression, adjusting for body mass index (BMI) and plasma lipids. The influence of BMI, weight-change, and plasma lipids on longitudinal changes in POP concentrations were evaluated among non-diabetic individuals (n = 306). RESULTS: POPs were associated with T2D in both the prospective and cross-sectional assessments. Of a standard deviation increase in POPs, prospective ORs ranged 1.42 (95% CI: 0.99, 2.06) for ∑NDL-PCBs to 1.55 (95% CI: 1.01, 2.38) for HCB (p < 0.05 only for HCB), and cross-sectional ORs ranged 1.62 (95% CI: 1.13; 2.32) for p,p'-DDE to 2.06 (95% CI: 1.29, 3.28) for ∑DL-PCBs (p < 0.05 for all POPs). In analyses of non-diabetic individuals, higher baseline BMI, decreased weight and decreased plasma lipid concentrations were associated with a slower decrease of POPs. Cases had, besides a higher BMI, reduced cholesterol and weight gain at follow-up compared to controls, which can explain the higher ORs in the cross-sectional assessments. DISCUSSION: The association between POPs and T2D was confirmed, but an indication that individuals body fat history might influence POP-T2D associations weakens the epidemiological support for a causal association. It also warrants studies based on other exposure metrics than biomonitoring. In addition, we note that a cross-sectional design overestimates the ORs if T2D cases have successfully intervened on weight and/or blood lipids, as changes in these factors cause changes in POPs.

Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the ß-amyloid cascade.

Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort.

AIMS/HYPOTHESIS: The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction. METHODS: We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case-control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case-control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index. RESULTS: We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors. CONCLUSIONS/INTERPRETATION: Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

Analysis with the exome array identifies multiple new independent variants in lipid loci.

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

Screening for type 2 diabetes: do screen-detected cases fare better?

AIMS/HYPOTHESIS: We aimed to investigate whether diabetes cases detected through screening have better health outcomes than clinically detected cases in a population-based cohort of adults who were eligible to be screened for diabetes at 10 year intervals. METHODS: The Västerbotten Intervention Programme is a community- and individual-based public health programme in Västerbotten County, Sweden. Residents are invited to clinical examinations that include screening for diabetes by OGTTs at age 30, 40, 50 and 60 years (individuals eligible for screening, n = 142,037). Between 1992 and 2013, we identified 1024 screen-detected cases and 8642 clinically detected cases of diabetes using registry data. Clinically detected individuals were either prior screening participants (n = 4506) or people who did not participate in screening (non-participants, n = 4136). Study individuals with diabetes were followed from date of detection until end of follow-up, emigration, death or incident cardiovascular disease (CVD), renal disease or retinopathy event, and compared using Cox proportional hazard regression adjusted for calendar time, age at detection, year of detection, sex and socioeconomic status. RESULTS: The average age at diabetes diagnosis was 4.6 years lower for screen-detected individuals compared with clinically detected individuals. Overall, those who were clinically detected had worse health outcomes than those who were screen-detected (HR for all-cause mortality 2.07 [95% CI 1.63, 2.62]). Compared with screen-detected study individuals, all-cause mortality was higher for clinically detected individuals who were screening non-participants (HR 2.31 [95% CI 1.82, 2.94]) than for those clinically detected who were prior screening participants (HR 1.70 [95% CI 1.32, 2.18]). Estimates followed a similar pattern for CVD, renal disease and retinopathy. CONCLUSIONS/INTERPRETATION: Individuals with screen-detected diabetes were diagnosed earlier and appeared to fare better than those who were clinically detected with regard to all-cause mortality, CVD, renal disease and retinopathy. How much of these associations can be explained by earlier treatment because of screening rather than healthy user bias, lead time bias and length time bias warrants further investigation.

A combination of plasma phospholipid fatty acids and its association with incidence of type 2 diabetes: The EPIC-InterAct case-cohort study.

BACKGROUND: Combinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated. METHODS AND FINDINGS: We measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991-1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19-0.29) adjusted for potential confounders and 0.37 (95% CI 0.27-0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding. CONCLUSIONS: A combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors.

Association between plasma phospholipid saturated fatty acids and metabolic markers of lipid, hepatic, inflammation and glycaemic pathways in eight European countries: a cross-sectional analysis in the EPIC-InterAct study.

BACKGROUND: Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. METHODS: We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even-chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested. RESULTS: Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. CONCLUSIONS: Subtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake.