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Objective.Cardiovascular (CV) disease (CVD) risk is increased in rheumatoid arthritis (RA). However, longterm followup studies investigating this risk are scarce.Methods.The CARRÉ (CARdiovascular research and RhEumatoid arthritis) study is a prospective cohort study investigating CVD and its risk factors in 353 patients with longstanding RA. CV endpoints were assessed at baseline and 3, 10, and 15 years after the start of the study and are compared to a reference cohort (n = 2540), including a large number of patients with type 2 diabetes (DM).Results.Ninety-five patients with RA developed a CV event over 2973 person-years, resulting in an incidence rate of 3.20 per 100 person-years. Two hundred fifty-seven CV events were reported in the reference cohort during 18,874 person-years, resulting in an incidence rate of 1.36 per 100 person-years. Age- and sex-adjusted HR for CV events were increased for RA (HR 2.07, 95% CI 1.57–2.72, p < 0.01) and DM (HR 1.51, 95% CI 1.02–2.22, p = 0.04) compared to the nondiabetic participants. HR was still increased in RA (HR 1.82, 95% CI 1.32–2.50, p < 0.01) after additional adjustment for CV risk factors. Patients with both RA and DM or insulin resistance had the highest HR for developing CVD (2.21, 95% CI 1.01–4.80, p = 0.046 and 2.67, 95% CI 1.30–5.46, p < 0.01, respectively).Conclusion.The incidence rate of CV events in established RA was more than double that of the general population. Patients with RA have an even higher risk of CVD than patients with DM. This risk remained after adjustment for traditional CV risk factors, suggesting that systemic inflammation is an independent contributor to CV risk.

Background/objectives Despite considerable literature supporting the potential health benefits of reducing postprandial glucose (PPG), and insulin (PPI) exposures, the size of a clinically relevant reduction is currently unknown. We performed a systematic review and meta-analysis to quantify effects of alpha-glucosidase-inhibiting (AGI) drugs on acute PPG and PPI responses. Methods We searched EMBASE and MEDLINE until March 13, 2018 for controlled studies using AGI drugs together with a standardized carbohydrate load or mixed meal. The mean incremental PPG and PPI levels were calculated as outcomes. Meta-analyses, stratified by diabetes state, were performed by using random effects models. Results The 66 included publications comprised 127 drug-control comparisons for PPG, and 106 for PPI, mostly testing acarbose or miglitol. The absolute effects on PPG were larger among individuals with diabetes (−1.5 mmol/l mean PPG [95% CI −1.9, −1.1] by acarbose, and −1.6 [−1.9, −1.4] by miglitol) as compared to individuals without diabetes (−0.4 [95% CI −0.5, −0.3] by acarbose, and −0.6 [−0.8, −0.4] by miglitol). Relative reductions in PPG by both drugs were similar for diabetic and non-diabetic individuals (43−54%). Acarbose and miglitol also significantly reduced mean PPI, with absolute and relative reductions being largest among individuals without diabetes. Conclusions The present meta-analyses provide quantitative estimates of reductions of PPG and PPI responses by AGI drugs in diabetes and non-diabetic individuals. These data can serve as benchmarks for clinically relevant reductions in PPG and PPI via drug or diet and lifestyle interventions.

Aims: The ESCAPE-NET project (“European Sudden Cardiac Arrest network– towards Prevention, Education and New Effective Treatments”) aims to study: (1) risk factors and mechanisms for the occurrence of sudden cardiac arrest (SCA) in the population, and (2) risk factors and treatment strategies for survival after SCA on a European scale. Methods: This is an Horizon2020 funded program of the European Union, performed by a European publicprivate consortium of 16 partners across 10 EU countries. There are 11 deep-phenotyped SCA cohorts for the study of risk factors and treatment strategies for survival after SCA, and 5 deep-phenotyped observational prospective population cohorts for the study of risk factors for occurrence of SCA. Personalized risk scores for predicting SCA onset and for predicting survival after SCA will be derived and validated. Results: The 11 clinical studies with SCA cases comprise 85,790 SCA cases; the 5 observational prospective population cohorts include 53,060 subjects. A total of 15,000 SCA samples will be genotyped for common and rare variants at the Helmholtz Zentrum München (Germany) using the Illumina Global Screening Array which contains > 770,000 SNPs, and after imputation, a database of an estimated > 9 million variants will be available for genome wide association studies. Standardization of risk factors definition and outcomes is ongoing. An Executive Committee has been created along with a Collaboration Policy document. Conclusion: ESCAPE-NET will complement ongoing efforts on SCA outside Europe and within Europe including the EuReCa project.

Aims/hypothesis: Glycaemic markers and fasting insulin are frequently measured outcomes of intervention studies. To extrapolate accurately the impact of interventions on the risk of diabetes incidence, we investigated the size and shape of the associations of fasting plasma glucose (FPG), 2 h post-load glucose (2hPG), HbA1c, fasting insulin and HOMA-IR with incident type 2 diabetes mellitus. Methods: The study population included 1349 participants aged 50–75 years without diabetes at baseline (1989) from a population-based cohort in Hoorn, the Netherlands. Incident type 2 diabetes was defined by the WHO 2011 criteria or known diabetes at follow-up. Logistic regression models were used to determine the associations of the glycaemic markers, fasting insulin and HOMA-IR with incident type 2 diabetes. Restricted cubic spline logistic regressions were conducted to investigate the shape of the associations. Results: After a mean follow-up duration of 6.4 (SD 0.5) years, 152 participants developed diabetes (11.3%); the majority were screen detected by high FPG. In multivariate adjusted models, ORs (95% CI) for incident type 2 diabetes for the highest quintile in comparison with the lowest quintile were 9.0 (4.4, 18.5) for FPG, 6.1 (2.9, 12.7) for 2hPG, 3.8 (2.0, 7.2) for HbA1c, 1.9 (0.9, 3.6) for fasting insulin and 2.8 (1.4, 5.6) for HOMA-IR. The associations of FPG and HbA1c with incident diabetes were non-linear, rising more steeply at higher values. Conclusions/interpretation: FPG was most strongly associated with incident diabetes, followed by 2hPG, HbA1c, HOMA-IR and fasting insulin. The strong association with FPG is probably because FPG is the most frequent marker for diabetes diagnosis. Non-linearity of associations between glycaemic markers and incident type 2 diabetes should be taken into account when estimating future risk of type 2 diabetes based on glycaemic markers.

Purpose Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting and 2 h post-load plasma glucose and glycated hemoglobin (HbA1c). Method This study included 667 participants from third examination (2000) of the population-based Hoorn study in which individuals with glucose intolerance were overrepresented. Fatty acid profiles in serum total lipids were measured at baseline, in 2000. Diabetes risk markers were measured at baseline and follow-up in 2008. Linear regression models were used in cross-sectional and prospective analyses. Results In cross-sectional analyses (n = 667), serum LA was inversely associated with plasma glucose, both in fasting conditions (B = −0.024 [−0.045, −0.002]) and 2 h after glucose tolerance test (B = −0.099 [−0.158, −0.039]), but not with HbA1c (B = 0.000 [−0.014, 0.013]), after adjustment for relevant factors. In prospective analyses (n = 257), serum LA was not associated with fasting (B = 0.003 [−0.019, 0.025]) or post-load glucose (B = −0.026 [−0.100, 0.049]). Furthermore, no significant associations were found between serum ALA and glucose metabolism in cross-sectional or prospective analyses. Conclusions In this study, serum LA was inversely associated with fasting and post-load glucose in cross-sectional, but not in prospective analyses. Further studies are needed to elucidate the exact role of serum LA and ALA levels and dietary polyunsaturated fatty acids in glucose metabolism. Electronic supplementary material The online version of this article (doi:10.1007/s00394-016-1261-6) contains supplementary material, which is available to authorized users.

AIMS: To investigate, in the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) trial (NCT00723307), whether the influence of metformin on the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM) is sustained and related to changes in glycaemia or weight, and to investigate basal and post-meal GLP-1 levels in patients with T2DM in the cross-sectional Diabetes Research on Patient Stratification (DIRECT) study.MATERIALS AND METHODS: CAMERA was a double-blind randomized placebo-controlled trial of metformin in 173 participants without diabetes. Using 6-monthly fasted total GLP-1 levels over 18 months, we evaluated metformin's effect on total GLP-1 with repeated-measures analysis and analysis of covariance. In the DIRECT study, we examined active and total fasting and 60-minute post-meal GLP-1 levels in 775 people recently diagnosed with T2DM treated with metformin or diet, using Student's t-tests and linear regression.RESULTS: In CAMERA, metformin increased total GLP-1 at 6 (+20.7%, 95% confidence interval [CI] 4.7-39.0), 12 (+26.7%, 95% CI 10.3-45.6) and 18 months (+18.7%, 95% CI 3.8-35.7), an overall increase of 23.4% (95% CI 11.2-36.9; P < .0001) vs placebo. Adjustment for changes in glycaemia and adiposity, individually or combined, did not attenuate this effect. In the DIRECT study, metformin was associated with higher fasting active (39.1%, 95% CI 21.3-56.4) and total GLP-1 (14.1%, 95% CI 1.2-25.9) but not post-meal incremental GLP-1. These changes were independent of potential confounders including age, sex, adiposity and glycated haemoglobin.CONCLUSIONS: In people without diabetes, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated patients with T2DM also have higher fasted GLP-1 levels, independently of weight and glycaemia.

In the past decade, over 3 dozen studies reported a relationship between self-reported short sleep and disturbed glucose metabolism. A study with insulin sensitivity assessed according to the gold standard hyperinsulinemic-euglycemic clamp is, however, still missing.To evaluate the cross-sectional association of sleep duration with insulin sensitivity and β-cell function in the European group for the study of insulin resistance (EGIR-RISC) study cohort.We used data from the baseline measurements of the European, multicentre EGIR-RISC study that included 1319 clinically healthy participants. Sleep and physical activity were measured using a single-axis accelerometer. Insulin sensitivity and β-cell function were estimated by hyperinsulinemic-euglycemic clamp and from the oral glucose insulin sensitivity index model, using an oral glucose tolerance test. Associations of sleep duration with insulin sensitivity and β-cell function were analyzed by multiple linear regression, stratified by sex.In our current analysis, we included 788 participants (57% women, age 44 ± 8 y), who had an average sleep duration of 7.3 ± 1.5 hours. In men, we observed an inverted U-shaped association between sleep duration categorized per hour and M/I (in μmol/min per kgFFM/nM per hour) (β-estimate [95% confidence intervals] 41 [2, 80]; P = .04 and β(2)-estimate -3 [-6, -0.2], P = .04) as well as a trend for the oral glucose insulin sensitivity index (in mL/min per kgFFM) (β-estimate [95% confidence intervals] 0.8 [-0.4, 2]; P = .17). In women, we observed a U-shaped association between sleep duration and β-cell function (in pmol/min per m(2)/mM per hour) (β-estimate -45 [-86, -3]; P = .04 and β(2)-estimate 3 [0.2, 6]; P = .04).Sleep duration is associated with insulin sensitivity and β-cell function in a sex-specific manner in clinically healthy people.

Objective: To investigate whether serum advanced glycation endproducts are associated with left ventricular systolic and diastolic function in participants with normal glucose metabolism, impaired glucose metabolism and type 2 diabetes mellitus. Methods: Participants from a cross-sectional, population-based study ( n = 280 with normal glucose metabolism, n = 171 with impaired glucose metabolism, n = 242 with type 2 diabetes mellitus) underwent echocardiography. Serum protein-bound advanced glycation endproducts [i.e. Nε-(carboxymethyl)lysine, pentosidine and Nε-(carboxyethyl)lysine] were measured. Linear regression analyses were used and stratified according to glucose metabolism status. Results: In normal glucose metabolism, higher Nε-(carboxymethyl)lysine and pentosidine levels were associated with worse diastolic function (left atrial volume index and left atrial volume × left ventricular mass index product term) and higher Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine levels with worse systolic function (ejection fraction). In impaired glucose metabolism, a similar pattern emerged, though less consistent. In type 2 diabetes mellitus, these associations were non-existent for diastolic function or even reversed for systolic function. Conclusion: This suggests that serum advanced glycation endproducts are associated with impaired left ventricular function in normal glucose metabolism, but that with deteriorating glucose metabolism status, serum advanced glycation endproducts may not mirror heart failure risk.

ObjectiveThe aim of this study was to assess the time to insulin initiation in type 2 diabetes mellitus (T2DM) patients treated with oral glucose-lowering agents and to determine the baseline characteristics associated with time to insulin initiation. This was evaluated in T2DM patients with HbA1c levels consistently ≥7.0% during total follow up and in those with fluctuating HbA1c levels around 7.0%.Design and methodsProspective, observational study was performed, comprising 2418 persons with T2DM aged ≥40 years who entered the Diabetes Care System between 1998 and 2012 with a minimum follow up of at least 3 years, following the first HbA1c level ≥7.0%. Cox regression analyses were performed to assess the determinants of time to insulin initiation. Data related to long-term effects of insulin initiation were studied at baseline and at the end of follow up using descriptive summary statistics.ResultsTwo-thirds of the patients initiated insulin during follow up. The time to insulin varied from 1.2 years (range 0.3–3.1) in patients with HbA1c levels consistently ≥7.0% to 5.4 years (range 3.0–7.5) in patients with fluctuating HbA1c levels around 7.0%. Longer diabetes duration (hazard ratio (HR) 1.04 95% CI 1.03–1.05) and lower age (HR 1.00 95% CI 0.99–1.00) at baseline were associated with a shorter time to initiation. More insulin initiators had retinopathy compared with patients that remained on oral glucose-lowering agents during follow up.ConclusionThe time to insulin initiation was short, and most of the patients with HbA1c levels consistently ≥7.0% were initiating insulin. Longer diabetes duration and younger age shortened the time to insulin.

Aims Subclinical systemic inflammation may contribute to the development of type 2 diabetes, but its association with early progression of glycaemic deterioration in persons without diabetes has not been fully investigated. Our primary aim was to assess longitudinal associations of changes in pro-inflammatory (leukocytes, high-sensitivity C-reactive protein (hsCRP)) and anti-inflammatory (adiponectin) markers with changes in markers that assessed glycaemia, insulin resistance, and secretion (HbA(1c), HOMA-IR, and HOMA-beta). Furthermore, we aimed to directly compare longitudinal with cross-sectional associations. Materials and methods Results This study includes 819 initially nondiabetic individuals with repeated measurements from the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort study (median follow-up: 7.1 years). Longitudinal and cross-sectional associations were simultaneously examined using linear mixed growth models. Changes in markers of inflammation were used as independent and changes in markers of glycaemia/insulin resistance/insulin secretion as dependent variables. Models were adjusted for age, sex, major lifestyle and metabolic risk factors for diabetes using time-varying variables in the final model. Changes of leukocyte count were positively associated with changes in HbA(1c) and HOMA-beta while changes in adiponectin were inversely associated with changes in HbA(1c). All examined cross-sectional associations were statistically significant; they were generally stronger and mostly directionally consistent to the longitudinal association estimates. Conclusions Adverse changes in low-grade systemic inflammation go along with glycaemic deterioration and increased insulin secretion independently of changes in other risk factors, suggesting that low-grade inflammation may contribute to the development of hyperglycaemia and a compensatory increase in insulin secretion.

We aimed to examine heterogeneity in glucose response curves during an oral glucose tolerance test with multiple measurements and to compare cardiometabolic risk profiles between identified glucose response curve groups.We analyzed data from 1,267 individuals without diabetes from five studies in Denmark, the Netherlands and the USA. Each study included between 5 and 11 measurements at different time points during a 2-h oral glucose tolerance test,resulting in 9,602 plasma glucose measurements. Latent class trajectories with a cubic specification for time were fitted to identify different patterns of plasma glucose change during the oral glucose tolerance test. Cardiometabolic riskfactor profiles were compared between the identified groups. Using latent class trajectory analysis, five glucose response curves were identified. Despite similar fasting and 2-h values, glucose peaks and peak times varied greatly between groups, ranging from 7–12 mmol/L, and 35–70 min. The group with the lowest and earliest plasma glucose peak had the lowest estimated cardiovascular risk, while the group with the most delayed plasma glucose peak and the highest 2-h value had the highest estimated risk. One group, with normal fasting and 2-h values, exhibited an unusual profile, with the highest glucose peak and the highest proportion of smokers and men. The heterogeneity in glucose response curves and the distinct cardiometabolic risk profiles may reflect different underlying physiologies. Our results warrant more detailed studies to identify the source of the heterogeneity across the different phenotypes and whether these differences play a role in the development of type 2 diabetes and cardiovascular disease.

Aim: Most people with type 2 diabetes eventually require insulin treatment because of progressive loss of beta-cell function. The most common adverse effect of insulin therapy is hypoglycemia. Recurrent hypoglycemia may lead to impaired awareness of hypoglycemia (IAH) and a consequently high risk for severe hypoglycemia. The aim of this study was to determine the prevalence of IAH and severe hypoglycemia in a large cohort of people with insulin-treated type 2 diabetes. Methods: The Dutch Diabetes Pearl is a contemporary cohort of people with type 2 diabetes from primary, secondary and tertiary medical centers in the Netherlands. We collected data from people on insulin therapy who had completed the validated Dutch version of the Clarke questionnaire on IAH, where 3 out of 5 points indicate IAH. Descriptive statistics, T-tests and Chi-square tests were performed. Results: Our study included 1923 patients of whom 59% were men. Median age was 62.1 years (interquartile range 55.1-68.3), median diabetes duration was 13.9 years (8.8-20.1) and median HbA1c was 7.6 % (7.0-8.5). 2individuals (10.8%) were classified as having IAH; these people were more likely to be non-Caucasian and have a lower educational level, and less likely to have a partner. Severe hypoglycemia was reported in 617 patients (32.1%) and severe hypoglycemia requiring medical intervention in the past year in 166 patients (8.6%). People with severe hypoglycemia were more likely to be non-Caucasian, to have a lower educational level, to have a history of cardiovascular events and neuropathic pain, and to use over 10 different types of drugs. No significant associations between HbA1c-levels and IAH or severe hypoglycemia were observed. Conclusion: IAH and severe hypoglycemia are common in people with type 2 diabetes treated with insulin. Non- Caucasian ethnicity, lower educational level, and being single may be risk factors for IAH in patients with type 2 diabetes. Disclosure L. van Meijel: None. F. de Vegt: None. C. Tack: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Novo Nordisk A/S. E.J. Abbink: None. F. Rutters: None. J.M. Dekker: None. B.H. Wolffenbuttel: None. F. Holleman: Other Relationship; Self; Sanofi-Aventis, Bioton, AstraZeneca. J. DeVries: Research Support; Self; Dexcom, Inc., Medtronic, Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Sanofi. Research Support; Self; Senseonics. Speaker's Bureau; Self; Senseonics. Advisory Panel; Self; Zealand Pharma A/S. N. Masurel: None. H. Pijl: None. B. Ozcan: None. B. Silvius: None. B.E. de Galan: Research Support; Self; AstraZeneca, Sanofi. Advisory Panel; Self; Novo Nordisk A/S.

/SummaryBackground and aims:Understanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a person’s susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).Materials and methods:From a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.Results:Using ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].Conclusion:The epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.Abbreviations:ASATAbdominal subcutaneous adipose tissueDIRECTDiabetes Research on Patient StratificationEUEuropean UnionMMTTMixed-meal tolerance testMRIMagnetic resonance imaginghpfVMHigh-pass filtered vector magnitudeIAATIntra-abdominal adipose tissueIGRImpaired glucose regulationIMIInnovative Medicines InitiativeMEmultiechoNGRNormal glucose regulationOGTTOral glucose tolerance testPAPhysical activityTAATTotal abdominal adipose tissueT2DType 2 Diabetes

Introduction: Excessive alcohol consumption is an important risk factors for cardiovascular disease, however, the underlying mechanisms are not well understood. Hypothesis: We assessed the hypothesis whether alcohol consumption is prospectively associated with unfavorable measures of cardiac structure and function. Methods: We used data from the Hoorn Study, a population-based, prospective cohort study. Data on self-reported alcohol consumption were collected with a validated food frequency questionnaire in 2000/2001(baseline for the current analyses). Echocardiography was performed in 2000/2001 in 582 participants and in 2007/2009 in 339 participants. Participants were classified into 5 categories based on self-reported alcohol consumption (glasses per week): 0 (non-drinkers), 0- 3 (light-drinkers), ≥3-7 (light to moderate drinkers), ≥7-14 (moderate drinkers) and ≥14 (heavy drinkers). Light drinking was considered the reference group. We studied the association of alcohol consumption with echocardiographic measures after 8 years of follow-up using linear regression analyses, adjusting for potential confounders. Results: The mean age was 69.8±6.5 years and 50% was female. After 7.4±0.5 years follow-up, moderate and heavy alcohol consumption were associated with a decreased left ventricular ejection fraction of -5.1% (-8.7, -1.4) for moderate and -4.8% (-8.8, -0.8) for heavy drinkers (Table). Heavy drinking was also associated with a decrease in left atrial volume index: -3.9mL/m 2 (-7.6, -0.2). No longitudinal associations were found between alcohol consumption and left ventricular mass index. Conclusion: Both moderate and heavy drinking were associated with decreased systolic function after 8 years follow-up. The toxic effect of alcohol could lead to underfilling of the left atrium which could lead to lower systolic function. These findings may explain the increased cardiovascular risk among people with excessive alcohol use.

Introduction: Low vitamin D and vitamin K status are both associated with cardiovascular disease risk. New evidence from experimental studies on bone health suggest an interaction between vitamin D and K, however, a joint association with vascular health outcomes is largely unknown. Hypothesis: We assessed the hypothesis that combined low vitamin D and low vitamin K status is prospectively associated with unfavorable measures of cardiac structure and function. Methods: In the Hoorn Study, a population-based cohort study of 598 participants, mean age 70.1±6.6 years, 51% female, had physical examinations in 2000-2001 (baseline for the current analyses), and of these 265 had a follow-up in 2007-2009. In baseline samples, vitamin D and K status were assessed by measuring 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix gla protein (dp-ucMGP). High dp-ucMGP is indicative of a low vitamin K status. We studied the combined association of 25(OH)D and dp-ucMGP with echocardiographic measures of left ventricular mass index, left ventricular ejection fraction and left atrium volume index after 8 years of follow-up using linear regression analyses. The group high 25(OH)D/low dp-ucMGP was the reference group. We adjusted our analyses for potential confounders including follow-up time and baseline echocardiographic measures. Results: Mean 25(OH)D was 57.8 nmol/L and median was dp-ucMGP was 567 pmol/L. The low 25(OH)D/high dp-ucMGP category was associated with a greater left ventricle mass index:4.8 g/m 2.7 (95% CI 0.6, 9.1) at follow-up compared to the reference group, in the fully adjusted model (Table 1). No associations were observed between 25(OH)D and dp-ucMGP categories with systolic and diastolic function after 8 years of follow-up. Conclusion: In conclusion, these results suggest that high levels of 25(OH)D and low levels of dp-ucMGP are associated with a greater left ventricle mass index. Vitamin D and K supplementation trials are the next step to assess a causal relationship with cardiac structure.

OBJECTIVE Glucose measurements during an oral glucose tolerance test (OGTT) are useful in predicting diabetes and its complications. However, knowledge of the pathophysiology underlying differences in glucose curve shapes is sparse. We examined the pathophysiological characteristics that create different glucose curve patterns and studied their stability and reproducibility over 3 years of follow-up. RESEARCH DESIGN AND METHODS We analyzed data from participants without diabetes from the observational cohort from the European Group for the Study of Insulin Resistance: Relationship between Insulin Sensitivity and Cardiovascular Disease study; participants had a five–time point OGTT at baseline (n = 1,443) and after 3 years (n = 1,045). Measures of insulin sensitivity and secretion were assessed at baseline with a euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance test. Heterogeneous glucose response patterns during the OGTT were identified using latent class trajectory analysis at baseline and at follow-up. Transitions between classes were analyzed with multinomial logistic regression models. RESULTS We identified four different glucose response patterns, which differed with regard to insulin sensitivity and acute insulin response, obesity, and plasma levels of lipids and inflammatory markers. Some of these associations were confirmed prospectively. Time to glucose peak was driven mainly by insulin sensitivity, whereas glucose peak size was related to both insulin sensitivity and secretion. The glucose patterns identified at follow-up were similar to those at baseline, suggesting that the latent class method is robust. We integrated our classification model into an easy-to-use online application that facilitates the assessment of glucose curve patterns for other studies. CONCLUSIONS The latent class analysis approach is a pathophysiologically insightful way to classify individuals without diabetes based on their response to glucose during an OGTT.

BACKGROUND: Chronic cardiometabolic diseases, including cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD), share many modifiable risk factors and can be prevented using combined prevention programs. Valid risk prediction tools are needed to accurately identify individuals at risk.OBJECTIVE: We aimed to validate a previously developed non-invasive risk prediction tool for predicting the combined 7-year-risk for chronic cardiometabolic diseases.DESIGN: The previously developed tool is stratified for sex and contains the predictors age, BMI, waist circumference, use of antihypertensives, smoking, family history of myocardial infarction/stroke, and family history of diabetes. This tool was externally validated, evaluating model performance using area under the receiver operating characteristic curve (AUC)-assessing discrimination-and Hosmer-Lemeshow goodness-of-fit (HL) statistics-assessing calibration. The intercept was recalibrated to improve calibration performance.PARTICIPANTS: The risk prediction tool was validated in 3544 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab).KEY RESULTS: Discrimination was acceptable, with an AUC of 0.78 (95% CI 0.75-0.81) in men and 0.78 (95% CI 0.74-0.81) in women. Calibration was poor (HL statistic: p CONCLUSIONS: Validation of our previously developed tool showed robust discriminative performance across populations. Model recalibration is recommended to account for different disease rates. Our risk prediction tool can be useful in large-scale prevention programs for identifying those in need of further risk profiling because of their increased risk for chronic cardiometabolic diseases.

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy.Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698).Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 x 10(-19)). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; P

Background People with chronic renal disease are insulin resistant. We hypothesized that in a healthy population, baseline renal function is associated with insulin sensitivity three years later. Methods We studied 405 men and 528 women from the European Group for the study of Insulin Resistance - Relationship between Insulin Sensitivity and Cardiovascular disease cohort. Renal function was characterized by the estimated glomerular filtration rate (eGFR) and by the urinary albumin-creatinine ratio (UACR). At baseline only, insulin sensitivity was quantified using a hyperinsulinaemic-euglycaemic clamp; at baseline and three years, we used surrogate measures: the Matsuda insulin sensitivity index (ISI), the HOmeostasis Model Assessment of Insulin Sensitivity (HOMA-IS). Associations between renal function and insulin sensitivity were studied cross-sectionally and longitudinally. Results In men at baseline, no associations were seen with eGFR, but there was some evidence of a positive association with UACR. In women, all insulin sensitivity indices showed the same negative trend across eGFR classes, albeit not always statistically significant; for UACR, women with values above the limit of detection, had higher clamp measured insulin sensitivity than other women. After three years, in men only, ISI and HOMA-IS showed a U-shaped relation with baseline eGFR; women with eGFR> 105 ml/min/1.73m2 had a significantly higher insulin sensitivity than the reference group (eGFR: 90–105 ml/min/1.73m2). For both men and women, year-3 insulin sensitivity was higher in those with higher baseline UACR. All associations were attenuated after adjusting on significant covariates. Conclusions There was no evidence to support our hypothesis that markers of poorer renal function are associated with declining insulin sensitivity in our healthy population. Electronic supplementary material The online version of this article (10.1186/s12882-018-0918-1) contains supplementary material, which is available to authorized users.

Aims: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Methods: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (µg/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. Results: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA β = 0.28, ALA β = 0.13, EPA β = 0.34, and DHA β = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction Conclusions: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA.

Background: Ethnic minority populations inWestern societies suffer froma disproportionate burden of type 2 diabetes (T2D). Insight into the role of dietary patterns in T2D may assist public health nutrition efforts in addressing these health disparities. Objective: We explored the association between dietary patterns and biomarkers of T2D in 5 ethnic groups living in Amsterdam, Netherlands. Methods: A total of 3776 men and women aged 18–70 y of Dutch, South Asian Surinamese, African-Surinamese, Turkish, and Moroccan origin from the HELIUS (HEalthy LIfe in an Urban Setting) study were included. Diet was assessed by using a food-frequency questionnaire, and dietary patterns were derived separately per ethnic group. First, food group–based dietary patterns were derived by using principal components analysis and the association with glycated hemoglobin (HbA1c) and plasma fasting glucose was assessed by using multivariable linear regression. Second, biomarker-driven dietary patterns based on HbA1c and fasting glucose concentrations were derived by applying reduced rank regression. Results: Two comparable food group–based dietary patterns were identified in each ethnic group: a ‘‘meat and snack’’ pattern and a ‘‘vegetable’’ pattern. The meat-and-snack pattern derived within the Dutch origin populationwas significantly associated with HbA1c (b = 0.09; 95% CI: 0.00, 0.19) and fasting glucose (b = 0.18; 95% CI: 0.09, 0.26) concentrations. A biomarkerderived pattern characterized by red and processed meat was observed among Dutch-origin participants; however, among ethnic minority groups, this pattern was characterized by other foods including ethnicity-specific foods (e.g., roti, couscous). Conclusions: Although similar food group dietary patterns were derived within 5 ethnic groups, the association of the meat-and-snack pattern with fasting glucose concentrations differed by ethnicity. Taken together with the finding of ethnic differences in biomarker-driven dietary patterns, our results imply that addressing T2D risk in multiethnic populations requires ethnicity-specific approaches.

Background Low plasma leptin levels can be a risk factor for Alzheimer's disease (AD) but the relation of leptin with disease progression in clinical AD is unknown. Objective The aim of this study was to investigate the relation between serum leptin concentrations and cognitive decline in clinical AD. Methods Serum leptin levels were analyzed in 295 non-obese subjects including healthy controls (n = 65), patients with subjective memory complaints (n = 99), patients with AD (n = 100), and patients with vascular dementia (n = 31). Leptin levels were related to hippocampal atrophy, baseline Mini-Mental State Examination (MMSE) scores and annual decline in MMSE measured over 2 years (range 0.4-4.5 years). Results Serum leptin levels were similar in AD patients compared to healthy controls and patients with subjective memory complaints. No correlation was observed between leptin concentrations and MMSE, annual change in MMSE during follow-up or atrophy. Conclusion Serum leptin levels are not altered in this population of relatively young AD or vascular dementia patients (mean 60) compared to healthy and clinical control groups and were not related to cognitive decline. These results suggest that peripheral leptin levels do not play a role in evolution of AD pathology.

Stressful life events are associated with the metabolic syndrome in cross-sectional studies, but prospective studies addressing this issue are rare and limited. We therefore evaluated whether the number of stressful life events is associated with incident metabolic syndrome. We assessed the association between the number of stressful life events experienced in the 5 years up until baseline and incident metabolic syndrome after 6.5 years at follow-up in the Hoorn study, a middle-aged and elderly population-based cohort. Participants with prevalent metabolic syndrome at baseline were excluded. Metabolic syndrome was defined according to the Adult Treatment Panel III, including fasting plasma glucose levels, HDL-C levels, triglyceride levels, waist circumference and hypertension. We included 1099 participants (47% male; age 60 ± 7 years). During 6.5 years of follow-up, 238 participants (22%) developed the metabolic syndrome. Logistic regression adjusted for age, sex, education level and follow-up duration showed a positive association between the number of stressful life events at baseline and incident metabolic syndrome [OR 1.13 (1.01–1.27) per event, p = 0.049]. In addition, a Poisson model showed a significant positive association between the number of stressful life events at baseline and the number of metabolic syndrome factors at follow-up [OR 1.05 (1.01–1.11) per event, p = 0.018]. Finally, we observed a significant association between the number of stressful life events at baseline and waist circumference at follow-up [adjusted for confounders β 0.86 (0.39–1.34) cm per event, p

Only a few studies have investigated the metabolic consequences of social jetlag. Therefore, we examined the association of social jetlag with the metabolic syndrome and type 2 diabetes mellitus in a population-based cohort. We used cross-sectional data from the New Hoorn Study cohort ( n = 1585, 47% men, age 60.8 ± 6 years). Social jetlag was calculated as the difference in midpoint sleep (in hours) between weekdays and weekend days. Poisson and linear regression models were used to study the associations, and age was regarded as a possible effect modifier. We adjusted for sex, employment status, education, smoking, physical activity, sleep duration, and body mass index. In the total population, we only observed an association between social jetlag and the metabolic syndrome, with prevalence ratios adjusted for sex, employment status, and educational levels of 1.64 (95% CI 1.1-2.4), for participants with >2 h social jetlag, compared with participants with 2 h social jetlag, compared with participants with

Purpose People with type 2 diabetes (T2D) have a doubled morbidity and mortality risk compared with persons with normal glucose tolerance. Despite treatment, clinical targets for cardiovascular risk factors are not achieved. The Hoorn Diabetes Care System cohort (DCS) is a prospective cohort representing a comprehensive dataset on the natural course of T2D, with repeated clinical measures and outcomes. In this paper, we describe the design of the DCS cohort. Participants The DCS consists of persons with T2D in primary care from the West-Friesland region of the Netherlands. Enrolment in the cohort started in 1998 and this prospective dynamic cohort currently holds 12 673 persons with T2D. Findings to date Clinical measures are collected annually, with a high internal validity due to the centrally organised standardised examinations. Microvascular complications are assessed by measuring kidney function, and screening feet and eyes. Information on cardiovascular disease is obtained by 1) self-report, 2) electrocardiography and 3) electronic patient records. In subgroups of the cohort, biobanking and additional measurements were performed to obtain information on, for example, lifestyle, depression and genomics. Finally, the DCS cohort is linked to national cancer and all-cause mortality registers. A selection of published findings from the DCS includes identification of subgroups with distinct development of haemoglobin A1c, blood pressure and retinopathy, and their predictors; validation of a prediction model for personalised retinopathy screening; the assessment of the role of genetics in development and treatment of T2D, providing options for personalised medicine. Future plans We will continue with the inclusion of persons with newly diagnosed T2D, follow-up of persons in the cohort and linkage to morbidity and mortality registries. Currently, we are involved in (inter)national projects on, among others, biomarkers and prediction models for T2D and complications and we are interested in collaborations with external researchers. Trial registration ISRCTN26257579

The aim of this study was to investigate (a) the mortality in a clinical cohort of patients with established rheumatoid arthritis in comparison with the general Dutch population over 15 years, (b) the trend in the mortality ratio during the study period, and (c) causes of death and compare these with the general population. In 1997, a sample of 1222 patients was randomly selected from the register of a large rheumatology outpatient clinic. Their mortality and primary causes of death between 1997 and 2012 were obtained from Statistics Netherlands. The standardized mortality ratio (SMR) for all-cause mortality and the number of life-years lost in the study period, adjusted for age, sex, and calendar year, were calculated. A linear poisson regression analysis was performed to evaluate change in all-cause SMR over time. Finally, the SMRs for cause-specific mortality were calculated. The mean age of the population at baseline was 60.4 (SD 15.4) years, and 72.6% of the patients were women. The estimated SMR (95% CI) for all-cause mortality was 1.54 (1.41, 1.67) with about one life-year lost over the study period. There was a trend to decreasing SMR (2% annually, p = .07). Mortality was higher compared with the general population for circulatory system diseases, respiratory system diseases, musculoskeletal system diseases, and digestive system diseases (p < .05). The observed mortality among patients with RA was 54% higher than in the general population after adjustment for age, sex and calendar year. More than one life-year was lost over 15 years, and the mortality tended to decrease over time. The mortality was higher for cardiovascular, respiratory, musculoskeletal and digestive diseases.

Introduction: Vitamin K is a fat soluble vitamin and is required as a co-factor for the carboxylation of several proteins. Matrix gla-protein (MGP) requires vitamin K for its activation and is a potent vascular calcification inhibitor. High concentrations of dephosphorylated uncarboxylated MGP (dp-ucMGP) -a functional marker of vitamin K status- are associated with increased coronary artery calcification and cardiovascular disease, but the underlying mechanism remains unclear. Hypothesis: We hypothesized that higher levels of dp-ucMGP (indicating low vitamin K status) are associated with unfavorable measures of cardiac structure and function after 7 years of follow-up. Methods: In the Hoorn Study, a population-based cohort, 598 participants mean age 70.1±6.6 years, 51% female, had physical examinations in 2000-2001 (baseline for the current analyses), of whom 249 had a follow-up in 2007-2009. Plasma dp-ucMGP levels were measured with ELISA in baseline samples. We studied the cross-sectional and prospective association of dp-ucMGP with echocardiographic measures of left ventricular mass index (LVMI), ejection fraction and left atrium volume index using linear regression analyses, adjusted for age, sex, BMI, education, smoking, type 2 diabetes and LDL-cholesterol. Results: Median plasma dp-ucMGP was 567 (392-701) pmol/l and mean follow-up time was 7.0±0.7 year. Cross-sectionally, the highest dp-ucMGP quartile ≥701 pmol/l compared to the lowest quartile 2.7 (95% CI -0.8, 6.2) greater LVMI. In the prospective analysis adjusting for baseline LVMI and follow-up time, the association was more pronounced and became significant 6.5 g/m 2.7 (95% CI 1.5, 11.4). This result was confirmed by the continuous association (Figure 1). No significant associations were observed between dp-ucMGP with ejection fraction and left atrium volume index. Conclusion: In conclusion, these results suggest that a low vitamin K status is prospectively associated with a greater LVMI.

Nine patients were inadvertently omitted from the 2000-2001 follow-up visit, changing the total from 822 to 831. This affected the text, and values in Figure 1, Table 2 and Table 4. Acronyms indicating normal and impaired glucose tolerance (NGT and IGT) were used incorrectly when normal and impaired glucose tolerance (NGM and IGM) were intended. This affected the text, Figure 1 and Figure 2. The authors have added a link to the Hoorn studies website for up to date versions of Tables 2, 3 and 4, including new visits and new variables. The article has been corrected.

Objectives This study sought to investigate the association of local and segmental arterial stiffness with incident cardiovascular events and all-cause mortality. Background The association of different stiffness indices, in particular of carotid, brachial, and femoral stiffness, with cardiovascular disease and mortality is currently unknown. Methods In a population-based cohort (n = 579, mean age 67 years, 50% women, 23% with type 2 diabetes [by design]), we assessed local stiffness of carotid, femoral, and brachial arteries (by ultrasonography), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index, and systemic arterial compliance. Results After a median follow-up of 7.6 years, 130 participants had a cardiovascular event and 96 had died. The hazard ratios (HRs) (95% confidence intervals [CIs]) per 1 SD for cardiovascular events and all-cause mortality, respectively, were HR: 1.22 (95% CI: 0.95 to 1.56) and 1.51 (95% CI: 1.11 to 2.06) for lower carotid distensibility; HR: 1.19 (95% CI: 1.00 to 1.41) and 1.28 (95% CI: 1.07 to 1.53) for higher carotid elastic modulus; HR: 1.08 (95% CI: 0.88 to 1.31) and 1.43 (95% CI: 1.10 to 1.86) for lower carotid compliance; HR: 1.39 (95% CI: 1.06 to 1.83) and 1.27 (95% CI: 0.90 to 1.79) for lower femoral distensibility; HR: 1.25 (95% CI: 0.96 to 1.63) and 1.47 (95% CI: 1.01 to 2.13) for lower femoral compliance; and HR: 1.56 (95% CI: 1.23 to 1.98) and 1.13 (95% CI: 0.83 to 1.54) for higher cfPWV. These results were adjusted for age, sex, mean arterial pressure, and cardiovascular risk factors. Mutual adjustments for each of the other stiffness indices did not materially change these results. Brachial stiffness, augmentation index, and systemic arterial compliance were not associated with cardiovascular events or mortality. Conclusions Carotid and femoral stiffness indices are independently associated with incident cardiovascular events and all-cause mortality. The strength of these associations with events may differ per stiffness parameter.

Objective Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM was investigated. Methods Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1,316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype. Results Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; P = 0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (P < 0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P < 0.05) and retinyl esters levels (P < 0.001). Conclusions These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM.

Item does not contain fulltext Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure >/=140 mm Hg and a diastolic blood pressure >/= 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

The relationships between smoking and glycaemic variables have not been well explored. We compared HbA1c, fasting plasma glucose (FPG) and 2 h plasma glucose (2H-PG) in current, ex- and never-smokers. This meta-analysis used individual data from 16,886 men and 18,539 women without known diabetes in 12 DETECT-2 consortium studies and in the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) and Telecom studies. Means of three glycaemic variables in current, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I 2 statistic was used to evaluate heterogeneity among studies. HbA1c was 0.10% (95% CI 0.08, 0.12) (1.1 mmol/mol [0.9, 1.3]) higher in current smokers and 0.03% (0.01, 0.05) (0.3 mmol/mol [0.1, 0.5]) higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current and never-smokers (−0.004 mmol/l [−0.03, 0.02]) but FPG was higher in ex-smokers (0.12 mmol/l [0.09, 0.14]). In comparison with never-smokers, 2H-PG was lower (−0.44 mmol/l [−0.52, −0.37]) in current smokers, with no difference for ex-smokers (0.02 mmol/l [−0.06, 0.09]). There was a large and unexplained heterogeneity among studies, with I 2 always above 50%; I 2 was little changed after stratification by sex and adjustment for age and BMI. In this study population, current smokers had a prevalence of diabetes that was 1.30% higher as screened by HbA1c and 0.52% lower as screened by 2H-PG, in comparison with never-smokers. Across this heterogeneous group of studies, current smokers had a higher HbA1c and lower 2H-PG than never-smokers. This will affect the chances of smokers being diagnosed with diabetes.

Background: Diet may be associated with the development of type 2 diabetes through its effects on low-grade inflammation. Objectives: We investigated whether an adapted dietary inflammatory index (ADII) is associated with a summary score for low-grade inflammation and markers of glucose metabolism. In addition, we investigated the mediating role of inflammation in the association between ADII and markers of glucose metabolism. Design: We performed cross-sectional analyses of 2 Dutch cohort studies (n= 1024). An ADII was obtained by multiplying standardized energy-adjusted intakes of dietary components by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Subsequently, these multiplications were summed. Six biomarkers of inflammation were compiled in a summary score. Associations of the ADII (expressed per SD) with the summary score for inflammation and markers of glucose metabolism were investigated by using multiple linear regression models. Inflammation was considered a potential mediator in the analysis with markers of glucose metabolism. Results: A higher ADII was associated with a higher summary score for inflammation [beta-adjusted = 0.04 per SD (95% CI: 0.01, 0.07 per SD)]. The ADII was, also adversely associated with insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR): beta-adjusted = 3.5% per SD (95% CI: 0.6%, 6.-3% per SD)]. This association was attenuated after the inclusion of the summary score for inflammation [beta-adjusted+inflammation = 2.2% (95% CI: -0.6%, 5.0%)]. The ADII was also adversely associated with fasting glucose and postload glucose but not with glycated hemoglobin. Conclusion: The significant mediating role of low-grade inflammation in the association between the ADII and HOMA-IR suggests that inflammation might be one of the pathways through which diet affects insulin resistance.

ObjectiveTo i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker.DesignA population-based study.MethodsA total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40–65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve.ResultsIn diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17.7–28.7) vs 18.0 (95% CI 16.9–19.1), PPConclusionThis study confirms that in type 2 diabetes, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study.

Background The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. Methods Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. Results Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. Conclusion Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters., published version, peerReviewed

Effects of a cognitive behavioural treatment (CBT) in type 2 diabetes patients were studied in a randomised controlled trial. Patients were recruited from a diabetes care system (DCS). The intervention group (n = 76) received managed care from the DCS and CBT. The control group (n = 78) received managed care only. Effects on risk of developing coronary heart disease (CHD), clinical characteristics, lifestyle, determinants of behaviour change, quality of life, and depression were assessed after 6 and 12 months. The intervention did not result in a significant reduction of CHD risk (difference between intervention and control group was -0.32 % (95 % CI: -2.27; 1.63). The amount of heavy physical activity increased significantly in the intervention group at 6 months [intervention versus control group was 20.14 min/day (95 % CI: 4.6; 35.70)]. Quality of life and level of depression improved as well. All effects disappeared after 6 months. No effects were found on clinical characteristics. © 2012 Springer Science+Business Media, LLC.

PURPOSE: Existing data from prospective cohort studies on dairy consumption and cardiovascular diseases are inconsistent. Even though the association between total dairy and cardiovascular diseases has been studied before, little is known about the effect of different types of dairy products on cardiovascular diseases (CVD). The objective of this study was to examine the relationship between (type of) dairy intake and CVD mortality and all-cause mortality in a Dutch population. METHODS: We examined the relationship between dairy intake and CVD mortality and all-cause mortality in 1956 participants of the Hoorn Study (aged 50-75 years), free of CVD at baseline. Hazard ratios with 95 % CIs were obtained for CVD mortality and all-cause mortality per standard deviation (SD) of the mean increase in dairy intake, with adjustment for age, sex, BMI, smoking, education, total energy intake, alcohol consumption, physical activity, and dietary intakes. RESULTS: During 12.4 years of follow-up, 403 participants died, of whom 116 had a fatal CVD event. Overall dairy intake was not associated with CVD mortality or all-cause mortality. Each SD increase in high-fat dairy intake was associated with a 32 % higher risk of CVD mortality (95 % CI; 7-61 %). CONCLUSION: In this prospective cohort study, the intake of high-fat dairy products was associated with an increased risk of CVD mortality.

BACKGROUNDChronic glucocorticoid excess is associated with arterial stiffening and cardiac dysfunction. The BclI glucocorticoid receptor (GR) polymorphism increases GR sensitivity and is associated with a higher body mass index (BMI) and some proxies for cardiovascular disease (CVD). Whether BclI influences arterial stiffening and cardiac dysfunction is currently unknown. Therefore, the aim of the present study was to investigate the association of the BclI polymorphism with arterial stiffening and cardiac structure and function.METHODSWe conducted an observational cohort study, combining 2 cohort studies designed to investigate genetic and metabolic determinants of CVD. We genotyped 1,124 individuals (age: 64.7 +/- 8.5 years) from the Hoorn study and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study for BclI. Several arterial stiffening indices of the carotid (Hoorn and CODAM study), brachial and femoral artery and the carotid-femoral pulse wave velocity (Hoorn study only) were determined. In addition, in the Hoorn study, we determined several variables of cardiac structure and function.RESULTSWe identified 155 homozygous carriers (GG), 498 heterozygous carriers (CG), and 471 noncarriers (CC) of the BclI polymorphism. BclI genotypes did not display significant differences in variables of arterial stiffening (e.g., carotid distensibility coefficient (DC): 12.41 +/- 5.37 vs. 12.87 +/- 5.55 10(-3)/kPa [mean +/- SD]; P = 0.38; homozygous vs. noncarriers). In addition, no clear differences in estimates of cardiac structure and function were found.CONCLUSIONSEven though BclI is associated with a higher BMI and some proxies of CVD, our results do not support the concept that BclI carrier status is associated with greater arterial stiffening or cardiac dysfunction.

OBJECTIVE Small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism. RESEARCH DESIGN AND METHODS rs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies. RESULTS The strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA1c and fasting plasma glucose. CONCLUSIONS These findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal.

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp– and oral glucose tolerance test–based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], −0.03 [−0.04, −0.01]; P = 0.004). This score was associated with lower BMI (−0.01 [−0.01, −0.0]; P = 0.02) and gluteofemoral fat mass (−0.03 [−0.05, −0.02; P = 1.4 × 10−6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Numerous studies have examined relationships between disease biomarkers (such as blood lipids) and levels of circulating or cellular fatty acids. In such association studies, fatty acids have typically been expressed as the percentage of a particular fatty acid relative to the total fatty acids in a sample. Using two human cohorts, this study examined relationships between blood lipids (TAG, and LDL, HDL or total cholesterol) and circulating fatty acids expressed either as a percentage of total or as concentration in serum. The direction of the correlation between stearic acid, linoleic acid, dihomo-γ-linolenic acid, arachidonic acid and DHA and circulating TAG reversed when fatty acids were expressed as concentrations v. a percentage of total. Similar reversals were observed for these fatty acids when examining their associations with the ratio of total cholesterol:HDL-cholesterol. This reversal pattern was replicated in serum samples from both human cohorts. The correlations between blood lipids and fatty acids expressed as a percentage of total could be mathematically modelled from the concentration data. These data reveal that the different methods of expressing fatty acids lead to dissimilar correlations between blood lipids and certain fatty acids. This study raises important questions about how such reversals in association patterns impact the interpretation of numerous association studies evaluating fatty acids and their relationships with disease biomarkers or risk.