Annemieke M. W. Spijkerman

Arterial Stiffness Increases With Deteriorating Glucose Tolerance Status The Hoorn Study

Background—Type 2 diabetes (DM-2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. In nondiabetic individuals, increased arterial stiffness is an important cause of cardiovascular disease. Associations between DM-2 and IGM and arterial stiffness have not been systematically investigated. Methods and Results—In a population-based cohort (n=747; 278 with normal glucose metabolism, 168 with IGM, and 301 with DM-2; mean age, 68.5 years), arterial stiffness was ultrasonically estimated by distensibility and compliance of the carotid, femoral, and brachial arteries and by the carotid elastic modulus. After adjustment for age, sex, and mean arterial pressure, DM-2 was associated with increased carotid, femoral, and brachial stiffness, whereas IGM was associated only with increased femoral and brachial stiffness. Carotid but not femoral or brachial stiffness increased from IGM to DM-2. Standardized &bgr;s (95% CI) for IGM and DM-2, compared with normal glucose metabolism, were −0.06 (−0.23 to 0.10) and −0.37 (−0.51 to −0.23) for carotid distensibility; −0.02 (−0.18 to 0.18) and −0.25 (−0.40 to −0.09) for carotid compliance; −0.05 (−0.23 to 0.13) and 0.25 (0.10 to 0.40) for carotid elastic modulus; −0.70 (−0.89 to −0.51) and −0.67 (−0.83 to −0.52) for femoral distensibility; and −0.62 (−0.80 to −0.44) and −0.79 (−0.94 to −0.63) for femoral compliance. The brachial artery followed a pattern similar to that of the femoral artery. Increases in stiffness indices were explained by decreases in distension, increases in pulse pressure, an increase in carotid intima-media thickness, and, for the femoral artery, a decrease in diameter. Hyperglycemia or hyperinsulinemia explained only 30% of the arterial changes associated with glucose tolerance. Adjustment for conventional cardiovascular risk factors did not affect these findings. Conclusions—IGM and DM-2 are associated with increased arterial stiffness. An important part of the increased stiffness occurs before the onset of DM-2 and is explained neither by conventional cardiovascular risk factors nor by hyperglycemia or hyperinsulinemia.

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.

Dietary Intake of Total, Animal, and Vegetable Protein and Risk of Type 2 Diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL Study

OBJECTIVE Dietary recommendations are focused mainly on relative dietary fat and carbohydrate content in relation to diabetes risk. Meanwhile, high-protein diets may contribute to disturbance of glucose metabolism, but evidence from prospective studies is scarce. We examined the association among dietary total, vegetable, and animal protein intake and diabetes incidence and whether consuming 5 energy % from protein at the expense of 5 energy % from either carbohydrates or fat was associated with diabetes risk. RESEARCH DESIGN AND METHODS A prospective cohort study was conducted among 38,094 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study. Dietary protein intake was measured with a validated food frequency questionnaire. Incident diabetes was verified against medical records. RESULTS During 10 years of follow-up, 918 incident cases of diabetes were documented. Diabetes risk increased with higher total protein (hazard ratio 2.15 [95% CI 1.77–2.60] highest vs. lowest quartile) and animal protein (2.18 [1.80–2.63]) intake. Adjustment for confounders did not materially change these results. Further adjustment for adiposity measures attenuated the associations. Vegetable protein was not related to diabetes. Consuming 5 energy % from total or animal protein at the expense of 5 energy % from carbohydrates or fat increased diabetes risk. CONCLUSIONS Diets high in animal protein are associated with an increased diabetes risk. Our findings also suggest a similar association for total protein itself instead of only animal sources. Consumption of energy from protein at the expense of energy from either carbohydrates or fat may similarly increase diabetes risk. This finding indicates that accounting for protein content in dietary recommendations for diabetes prevention may be useful.

Prediction models for risk of developing type 2 diabetes: systematic literature search and independent external validation study

Objective To identify existing prediction models for the risk of development of type 2 diabetes and to externally validate them in a large independent cohort. Data sources Systematic search of English, German, and Dutch literature in PubMed until February 2011 to identify prediction models for diabetes. Design Performance of the models was assessed in terms of discrimination (C statistic) and calibration (calibration plots and Hosmer-Lemeshow test).The validation study was a prospective cohort study, with a case cohort study in a random subcohort. Setting Models were applied to the Dutch cohort of the European Prospective Investigation into Cancer and Nutrition cohort study (EPIC-NL). Participants 38 379 people aged 20-70 with no diabetes at baseline, 2506 of whom made up the random subcohort. Outcome measure Incident type 2 diabetes. Results The review identified 16 studies containing 25 prediction models. We considered 12 models as basic because they were based on variables that can be assessed non-invasively and 13 models as extended because they additionally included conventional biomarkers such as glucose concentration. During a median follow-up of 10.2 years there were 924 cases in the full EPIC-NL cohort and 79 in the random subcohort. The C statistic for the basic models ranged from 0.74 (95% confidence interval 0.73 to 0.75) to 0.84 (0.82 to 0.85) for risk at 7.5 years. For prediction models including biomarkers the C statistic ranged from 0.81 (0.80 to 0.83) to 0.93 (0.92 to 0.94). Most prediction models overestimated the observed risk of diabetes, particularly at higher observed risks. After adjustment for differences in incidence of diabetes, calibration improved considerably. Conclusions Most basic prediction models can identify people at high risk of developing diabetes in a time frame of five to 10 years. Models including biomarkers classified cases slightly better than basic ones. Most models overestimated the actual risk of diabetes. Existing prediction models therefore perform well to identify those at high risk, but cannot sufficiently quantify actual risk of future diabetes.

Fruit and vegetable intake and type 2 diabetes: EPIC-InterAct prospective study and meta-analysis

Fruit and vegetable intake (FVI) may reduce the risk of type 2 diabetes (T2D), but the epidemiological evidence is inconclusive. The aim of this study is to examine the prospective association of FVI with T2D and conduct an updated meta-analysis. In the European Prospective Investigation into Cancer-InterAct (EPIC-InterAct) prospective case–cohort study nested within eight European countries, a representative sample of 16 154 participants and 12 403 incident cases of T2D were identified from 340 234 individuals with 3.99 million person-years of follow-up. For the meta-analysis we identified prospective studies on FVI and T2D risk by systematic searches of MEDLINE and EMBASE until April 2011. In EPIC-InterAct, estimated FVI by dietary questionnaires varied more than twofold between countries. In adjusted analyses the hazard ratio (95% confidence interval) comparing the highest with lowest quartile of reported intake was 0.90 (0.80–1.01) for FVI; 0.89 (0.76–1.04) for fruit and 0.94 (0.84–1.05) for vegetables. Among FV subtypes, only root vegetables were inversely associated with diabetes 0.87 (0.77–0.99). In meta-analysis using pooled data from five studies including EPIC-InterAct, comparing the highest with lowest category for FVI was associated with a lower relative risk of diabetes (0.93 (0.87–1.00)). Fruit or vegetables separately were not associated with diabetes. Among FV subtypes, only green leafy vegetable (GLV) intake (relative risk: 0.84 (0.74–0.94)) was inversely associated with diabetes. Subtypes of vegetables, such as root vegetables or GLVs may be beneficial for the prevention of diabetes, while total FVI may exert a weaker overall effect.

Physical Activity and Mortality in Individuals With Diabetes Mellitus: A Prospective Study and Meta-analysis.

BACKGROUND Physical activity (PA) is considered a cornerstone of diabetes mellitus management to prevent complications, but conclusive evidence is lacking. METHODS This prospective cohort study and meta-analysis of existing studies investigated the association between PA and mortality in individuals with diabetes. In the EPIC study (European Prospective Investigation Into Cancer and Nutrition), a cohort was defined of 5859 individuals with diabetes at baseline. Associations of leisure-time and total PA and walking with cardiovascular disease (CVD) and total mortality were studied using multivariable Cox proportional hazards regression models. Fixed- and random-effects meta-analyses of prospective studies published up to December 2010 were pooled with inverse variance weighting. RESULTS In the prospective analysis, total PA was associated with lower risk of CVD and total mortality. Compared with physically inactive persons, the lowest mortality risk was observed in moderately active persons: hazard ratios were 0.62 (95% CI, 0.49-0.78) for total mortality and 0.51 (95% CI, 0.32-0.81) for CVD mortality. Leisure-time PA was associated with lower total mortality risk, and walking was associated with lower CVD mortality risk. In the meta-analysis, the pooled random-effects hazard ratio from 5 studies for high vs low total PA and all-cause mortality was 0.60 (95% CI, 0.49-0.73). CONCLUSIONS Higher levels of PA were associated with lower mortality risk in individuals with diabetes. Even those undertaking moderate amounts of activity were at appreciably lower risk for early death compared with inactive persons. These findings provide empirical evidence supporting the widely shared view that persons with diabetes should engage in regular PA.

Association Between Low-Density Lipoprotein Cholesterol–Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis

Importance Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. Objective To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting, and Participants The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Exposures Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Main Outcomes and Measures Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Results Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. Conclusions and Relevance In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

Carbohydrate quantity and quality and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition–Netherlands (EPIC-NL) study

BACKGROUND Carbohydrate quantity and quality may play an important role in the development of type 2 diabetes. OBJECTIVE We investigated the associations of dietary glycemic load (GL), glycemic index (GI), carbohydrate, and fiber intake with the incidence of type 2 diabetes. DESIGN A prospective cohort study was conducted in 37,846 participants of the EPIC-NL (European Prospective Investigation into Cancer and Nutrition-Netherlands) study, aged 21-70 y at baseline and free of diabetes. Dietary intake was assessed with the use of a validated food-frequency questionnaire. Incident diabetes cases were mainly self-reported and verified against general practitioner records. RESULTS During a mean follow-up of 10 y, 915 incident diabetes cases were documented. Dietary GL was associated with an increased diabetes risk after adjustment for age, sex, established diabetes risk factors, and dietary factors [hazard ratio (HR) per SD increase: 1.27; 95% CI: 1.11, 1.44; P < 0.001] [corrected]. GI tended to increase diabetes risk (HR: 1.08; 95% CI: 1.00, 1.17; P = 0.05). Dietary fiber was inversely associated with diabetes risk (HR: 0.92; 95% CI: 0.85, 0.99; P < 0.05), whereas carbohydrate intake was associated with increased diabetes risk (HR: 1.15; 95% CI: 1.01, 1.32; P < 0.05). Of the carbohydrate subtypes, only starch was related to increased diabetes risk [HR: 1.25 (1.07, 1.46), P < 0.05]. All associations became slightly stronger after exclusion of energy misreporters. CONCLUSIONS Diets high in GL, GI, and starch and low in fiber were associated with an increased diabetes risk. Both carbohydrate quantity and quality seem to be important factors in diabetes prevention. Energy misreporting contributed to a slight attenuation of associations.

Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study.

A collaborative re-analysis of data from the InterAct case-control study conducted by Claudia Langenberg and colleagues has established that waist circumference is associated with risk of type 2 diabetes, independently of body mass index.

Mediterranean Style Diet and 12-Year Incidence of Cardiovascular Diseases : The EPIC-NL Cohort Study

Background A recent meta-analysis showed that a Mediterranean style diet may protect against cardiovascular diseases (CVD). Studies on disease-specific associations are limited. We evaluated the Mediterranean Diet Score (MDS) in relation to incidence of total and specific CVDs. Methods The EPIC-NL Study is a cohort of 40,011 men and women aged 20–70 years, examined between 1993 and 1997, with 10–15 years of follow-up. Diet was assessed with a validated food frequency questionnaire and the MDS was based on the daily intakes of vegetables, fruits, legumes and nuts, grains, fish, fatty acids, meat, dairy, and alcohol. Cardiovascular morbidity and mortality were ascertained through linkage with national registries. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for age, sex, cohort, smoking, physical activity, total energy intake, and educational level. Results In 34,708 participants free of CVD at baseline, 4881 CVD events occurred, and 487 persons died from CVD. A two unit increment in MDS (range 0–9) was inversely associated with fatal CVD (HR: 0.78; 95%CI: 0.69–0.88), total CVD (HR: 0.95 (0.91–0.98)), myocardial infarction (HR: 0.86 (0.79–0.93)), stroke (HR: 0.88 (0.78–1.00)), and pulmonary embolism (HR: 0.74 (0.59–0.92)). The MDS was not related to incident angina pectoris, transient ischemic attack and peripheral arterial disease. Conclusion Better adherence to a Mediterranean style diet was more strongly associated with fatal CVD than with total CVD. Disease specific associations were strongest for incident myocardial infarction, stroke and pulmonary embolism.