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OBJECTIVE To investigate the association between accelerometer-derived physical activity energy expenditure (PAEE) and incident type 2 diabetes (T2D) in a cohort of middle-aged adults and within subgroups. RESEARCH DESIGN AND METHODS Data were from 90,096 UK Biobank participants without prevalent diabetes (mean 62 years of age; 57% women) who wore a wrist accelerometer for 7 days. PAEE was derived from wrist acceleration using a population-specific method validated against doubly labeled water. Logistic regressions were used to assess associations between PAEE, its underlying intensity, and incident T2D, ascertained using hospital episode and mortality data up to November 2020. Models were progressively adjusted for demographic, lifestyle factors, and BMI. RESULTS The association between PAEE and T2D was approximately linear (n = 2,018 events). We observed 19% (95% CI 17–21) lower odds of T2D per 5 kJ · kg−1 · day−1 in PAEE without adjustment for BMI and 11% (9–13) with BMI adjustment. The association was stronger in men than women and weaker in those with obesity and higher genetic susceptibility to obesity. There was no evidence of effect modification by genetic susceptibility to T2D or insulin resistance. For a given level of PAEE, odds of T2D were lower among those engaging in more moderate-to-vigorous activity. CONCLUSIONS There was a strong linear relationship between PAEE and incident T2D. A difference in PAEE equivalent to an additional daily 20-min brisk walk was associated with 19% lower odds of T2D. The association was broadly similar across population subgroups, supporting physical activity for diabetes prevention in the whole population.

OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

OBJECTIVE Various definitions of metabolic health have been proposed to explain differences in the risk of type 2 diabetes within BMI categories. The goal of this study was to assess their predictive relevance. RESEARCH DESIGN AND METHODS We performed systematic searches of MEDLINE records for prospective cohort studies of type 2 diabetes risk in categories of BMI and metabolic health. In a two-stage meta-analysis, relative risks (RRs) specific to each BMI category were derived by network meta-analysis and the resulting RRs of each study were pooled using random-effects models. Hierarchical summary receiver operating characteristic curves were used to assess predictive performance. RESULTS In a meta-analysis of 140,845 participants and 5,963 incident cases of type 2 diabetes from 14 cohort studies, classification as metabolically unhealthy was associated with higher RR of diabetes in all BMI categories (lean RR compared with healthy individuals 4.0 [95% CI 3.0–5.1], overweight 3.4 [2.8–4.3], and obese 2.5 [2.1–3.0]). Metabolically healthy obese individuals had a high absolute risk of type 2 diabetes (10-year cumulative incidence 3.1% [95% CI 2.6–3.5]). Current binary definitions of metabolic health had high specificity (pooled estimate 0.88 [95% CI 0.84–0.91]) but low sensitivity (0.40 [0.31–0.49]) in lean individuals and satisfactory sensitivity (0.81 [0.76–0.86]) but low specificity (0.42 [0.35–0.49]) in obese individuals. However, positive (0.4) likelihood ratios were consistent with insignificant to small improvements in prediction. CONCLUSIONS Although individuals classified as metabolically unhealthy have a higher RR of type 2 diabetes compared with individuals classified as healthy in all BMI categories, current binary definitions of metabolic health have limited relevance to the prediction of future type 2 diabetes.

OBJECTIVE The long-term association between dietary protein and type 2 diabetes incidence is uncertain. We aimed to investigate the association between total, animal, and plant protein intake and the incidence of type 2 diabetes. 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 eight European countries, with an average follow-up time of 12.0 years. Pooled country-specific hazard ratios (HRs) and 95% CI of prentice-weighted Cox regression analyses were used to estimate type 2 diabetes incidence according to protein intake. RESULTS After adjustment for important diabetes risk factors and dietary factors, the incidence of type 2 diabetes was higher in those with high intake of total protein (per 10 g: HR 1.06 [95% CI 1.02–1.09], Ptrend < 0.001) and animal protein (per 10 g: 1.05 [1.02–1.08], Ptrend = 0.001). Effect modification by sex (P < 0.001) and BMI among women (P < 0.001) was observed. Compared with the overall analyses, associations were stronger in women, more specifically obese women with a BMI >30 kg/m2 (per 10 g animal protein: 1.19 [1.09–1.32]), and nonsignificant in men. Plant protein intake was not associated with type 2 diabetes (per 10 g: 1.04 [0.93–1.16], Ptrend = 0.098). CONCLUSIONS High total and animal protein intake was associated with a modest elevated risk of type 2 diabetes in a large cohort of European adults. In view of the rapidly increasing prevalence of type 2 diabetes, limiting iso-energetic diets high in dietary proteins, particularly from animal sources, should be considered.

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.

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 0.05). CONCLUSIONS Early menopause is associated with a greater risk of type 2 diabetes.

OBJECTIVE To study the association between adherence to the Mediterranean dietary pattern (MDP) and risk of developing type 2 diabetes, across European countries. RESEARCH DESIGN AND METHODS We established a case-cohort study including 11,994 incident type 2 diabetic case subjects and a stratified subcohort of 15,798 participants selected from a total cohort of 340,234 participants with 3.99 million person-years of follow-up, from eight European cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The relative Mediterranean diet score (rMED) (score range 0–18) was used to assess adherence to MDP on the basis of reported consumption of nine dietary components characteristic of the Mediterranean diet. Cox proportional hazards regression, modified for the case-cohort design, was used to estimate the association between rMED and risk of type 2 diabetes, adjusting for confounders. RESULTS The multiple adjusted hazard ratios of type 2 diabetes among individuals with medium (rMED 7–10 points) and high adherence to MDP (rMED 11–18 points) were 0.93 (95% CI 0.86–1.01) and 0.88 (0.79–0.97), respectively, compared with individuals with low adherence to MDP (0–6 points) (P for trend 0.013). The association between rMED and type 2 diabetes was attenuated in people CONCLUSIONS In this large prospective study, adherence to the MDP, as defined by rMED, was associated with a small reduction in the risk of developing type 2 diabetes in this European population.

OBJECTIVE Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value RESULTS Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: −0.009 mmol/l glucose [−0.013 to −0.005], P < 0.0001 and −0.011 pmol/l [ln] insulin [−0.015 to −0.007], P = 0.0003). No interactions met our multiple testing–adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

OBJECTIVE Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes. RESEARCH DESIGN AND METHODS The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression. RESULTS Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (−0.019 [−0.043; 0.006]) or transferrin saturation (0.016 [−0.006; 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6 V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population (Padd = 0.16, Pmult = 0.21) but did detect a trend toward a negative interaction in men (Padd = 0.04, Pmult = 0.03). CONCLUSIONS We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures.

OBJECTIVE—To investigate associations between adult markers of childhood growth and the prevalence of diabetes and coronary heart disease (CHD) in Filipino-American women and to determine the role of social and educational differences, including the influence of social mobility between childhood and adulthood. RESEARCH DESIGN AND METHODS—Socioeconomic disadvantage and poor infant growth, resulting in short leg length, may contribute to the dramatically increased risk of diabetes and CHD in Filipino-American women, but this has not been investigated. This study is a cross-sectional study of 389 Filipino-American women (age 58.7 ± 9.4 years [mean ± SD]). Diabetes was defined by 1999 World Health Organization criteria and CHD by ischemic electrocardiogram changes, Rose angina, a history of myocardial infarction, or revascularization surgery. A score of social mobility (0–4) was calculated by summarizing childhood and adult financial circumstances. RESULTS—Diabetes prevalence (31.4%) was not associated with measures of growth but was significantly lower in women with greater education, childhood and adult income, or social mobility score. Compared with Filipinas who were poorest in childhood and adulthood, respective odds ratios (95% CI) for diabetes were 0.55 (0.18–1.68), 0.19 (0.06–0.62), and 0.11 (0.03–0.42), down to 0.07 (0.01–0.51) in the most advantaged women (P < 0.0001). Family history of diabetes [5.14 (2.72–9.70)] and larger waist [1.07 per cm (1.03–1.10)] were also significant predictors in multiple adjusted models. In contrast, CHD prevalence (22.4%) was most strongly associated with leg length, but not trunk length; compared with individuals with the shortest legs, respective odds ratios (95% CI) for CHD were 0.60 (0.31–1.19), 0.53 (0.26–1.05), and 0.44 (0.22–0.91) in the tallest group, in age- (Ptrend = 0.02) and multiple-adjusted models (Ptrend = 0.01). CONCLUSIONS—Socioeconomic disadvantage contributes to the high prevalence of diabetes in Filipinas. Factors limiting early growth of the legs may increase the risk of CHD in this comparatively short population.

Geographical differences in type 1 diabetes (T1D) prevalence in Europe have been well documented, but little is known about the geographical distribution of autoantibodies specific to GAD65 (GAD65Ab) in the general population without diabetes, which is reported to range between 0.4 and 3%. However, these studies used different methods to define GAD65Ab positivity with cutoff values based on the 97–99th centile or at +3 SD above the mean among healthy individuals without T1D or type 2 diabetes (T2D). In doing so, the prevalence of GAD65Ab among the study cohorts was, by definition, 1–3%. The application of different cutoff levels greatly impairs the direct comparison of prevalence data between studies. Our aims were to 1) explore the prevalence of GAD65Ab positivity using a cutoff defined by specific competition of antibody binding to radiolabeled GAD65 with added autoantigen across eight European countries and 2) compare characteristics of age, sex, and BMI in relation to GAD65Ab positivity. A center-stratified random subcohort of 16,835 (4.9%) individuals was selected from the original European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study (1). After exclusion of individuals with known diabetes, GAD65Ab were analyzed in 15,802 (men/women 5,927/9,875, mean age 52.4 ± 9.2 years) samples. The cutoff for GAD65Ab positivity was determined through a competition assay at ≥65 WHO units/mL, and all samples were analyzed at a single laboratory using a radioligand binding assay (2).In all, 316/15,802 (2.0%) samples were GAD65Ab positive. Sweden, Denmark, U.K., and Spain had the highest and France had the lowest prevalence of GAD65Ab positivity (Table 1); however, these differences were not statistically significant (P = 0.80). We did not detect any association between GAD65Ab positivity and age, sex, or BMI.

OBJECTIVE— Levels of adiposity-signaling hormones and inflammatory markers are less favorable in individuals with the metabolic syndrome; their role in the association between the metabolic syndrome and cardiovascular mortality remains unclear. RESEARCH DESIGN AND METHODS— We conducted a prospective study of 977 men and 1,141 women aged 40–94 years in 1984–1987, followed for mortality for a maximum of 20 years. Adiponectin, leptin, ghrelin, interleukin-6 (IL-6), C-reactive protein (CRP), and Adult Treatment Panel III–defined metabolic syndrome components were measured in fasting blood samples obtained in 1984–1987. Cox-proportional hazards models were used in survival analyses. RESULTS— The age- and sex-adjusted hazard ratio (HR) (95% CI) for coronary heart disease (CHD) mortality associated with the metabolic syndrome was 1.65 (1.25–2.18) (P < 0.001); this association did not differ significantly by sex, age, or diabetic status (P > 0.2 for each interaction). The association between the metabolic syndrome and CHD mortality was not materially changed after adjustment for adiponectin, leptin, and ghrelin; it was attenuated by 25% after adjustment for IL-6 and 35% after adjustment for CRP. CHD mortality increased linearly with greater levels of IL-6 and CRP (Ptrend < 0.001 for each); the age- and sex-adjusted HRs comparing highest versus lowest quarter were 3.0 (1.87–4.89) for IL-6 and 2.1 (1.41–3.21) for CRP. IL-6, but not CRP, remained a significant predictor of CHD mortality in models including both inflammatory markers and the metabolic syndrome. CONCLUSIONS— Adiposity-signaling hormones and inflammatory markers explain little to some of the association between the metabolic syndrome and CHD mortality. IL-6 levels predict CHD mortality independently of CRP.

The long-term association between dietary protein and type 2 diabetes incidence is uncertain. We aimed to investigate the association between total, animal, and plant protein intake and the incidence of type 2 diabetes.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 eight European countries, with an average follow-up time of 12.0 years. Pooled country-specific hazard ratios (HRs) and 95% CI of prentice-weighted Cox regression analyses were used to estimate type 2 diabetes incidence according to protein intake.After adjustment for important diabetes risk factors and dietary factors, the incidence of type 2 diabetes was higher in those with high intake of total protein (per 10 g: HR 1.06 [95% CI 1.02-1.09], P(trend)0.001) and animal protein (per 10 g: 1.05 [1.02-1.08], P(trend) = 0.001). Effect modification by sex (P0.001) and BMI among women (P0.001) was observed. Compared with the overall analyses, associations were stronger in women, more specifically obese women with a BMI30 kg/m(2) (per 10 g animal protein: 1.19 [1.09-1.32]), and nonsignificant in men. Plant protein intake was not associated with type 2 diabetes (per 10 g: 1.04 [0.93-1.16], P(trend) = 0.098).High total and animal protein intake was associated with a modest elevated risk of type 2 diabetes in a large cohort of European adults. In view of the rapidly increasing prevalence of type 2 diabetes, limiting iso-energetic diets high in dietary proteins, particularly from animal sources, should be considered.

Levels of adiposity-signaling hormones and inflammatory markers are less favorable in individuals with the metabolic syndrome; their role in the association between the metabolic syndrome and cardiovascular mortality remains unclear.We conducted a prospective study of 977 men and 1,141 women aged 40-94 years in 1984-1987, followed for mortality for a maximum of 20 years. Adiponectin, leptin, ghrelin, interleukin-6 (IL-6), C-reactive protein (CRP), and Adult Treatment Panel III-defined metabolic syndrome components were measured in fasting blood samples obtained in 1984-1987. Cox-proportional hazards models were used in survival analyses.The age- and sex-adjusted hazard ratio (HR) (95% CI) for coronary heart disease (CHD) mortality associated with the metabolic syndrome was 1.65 (1.25-2.18) (P0.001); this association did not differ significantly by sex, age, or diabetic status (P0.2 for each interaction). The association between the metabolic syndrome and CHD mortality was not materially changed after adjustment for adiponectin, leptin, and ghrelin; it was attenuated by 25% after adjustment for IL-6 and 35% after adjustment for CRP. CHD mortality increased linearly with greater levels of IL-6 and CRP (P(trend)0.001 for each); the age- and sex-adjusted HRs comparing highest versus lowest quarter were 3.0 (1.87-4.89) for IL-6 and 2.1 (1.41-3.21) for CRP. IL-6, but not CRP, remained a significant predictor of CHD mortality in models including both inflammatory markers and the metabolic syndrome.Adiposity-signaling hormones and inflammatory markers explain little to some of the association between the metabolic syndrome and CHD mortality. IL-6 levels predict CHD mortality independently of CRP.