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Supplementary Table S1. Characteristics of NSCLC cases, smoking-habit controls and non-smoking controls.

Supplementary Table S2. Scaffold 'Sample view' of all proteins and protein clusters identified in protein band 1 to 5.

Supplementary Figure 1. Standard curve of rabbit monoclonal antibody to recombinant survivin using DAC-ELISA (A) and sandwich ELISA (B). Supplementary Figure 2. Antibody response to recombinant survivin was measured in seven NSCLC sera previously reported to be positive for survivin antibodies and in seven healthy non-smoking control sera. Supplementary Figure 3. Standard curve of rabbit anti-survivin spiked in non-smoking control sera using sandwich ELISA. Supplementary Figure 4. Standard curve of rabbit anti-survivin spiked in NSCLC patient sera using sandwich ELISA. Supplementary Figure 5. Standard curve of human autoantibodies to HuD using sandwich ELISA. Supplementary Figure 6. Results of sandwich ELISA were confirmed by western blot analysis.

The high mortality rate in lung cancer is largely attributable to late diagnosis. Case–control studies suggest that autoantibodies to the survivin protein are potential biomarkers for early diagnosis. We tested the hypothesis that sandwich ELISA can detect autoantibodies to survivin before radiologic diagnosis in patients with early-stage non–small cell lung cancer (NSCLC). Because previous studies assayed survivin autoantibodies with the direct antigen-coating ELISA (DAC-ELISA), we first compared that assay with the sandwich ELISA. Based on the more robust results from the sandwich ELISA, we used it to measure survivin autoantibodies in the serum of 100 individuals from a well-controlled population study [the Dutch–Belgian Lung Cancer Screening Trial (NELSON) trial] composed of current and former smokers (50 patients with NSCLC, both before and after diagnosis, and 50 matched, smoking-habit control subjects), and another 50 healthy nonsmoking control subjects. We found no difference in specific autoantibodies to survivin in NSCLC patients, although nonspecific median optical densities were 24% higher (P < 0.001) in both NSCLC patients and smokers, than in healthy nonsmokers. Finally, we confirmed the ELISA results with Western blot analysis of recombinant and endogenous survivin (HEK-293), which showed no anti-survivin reactivity in patient sera. We conclude that specific anti-survivin autoantibody reactivity is most likely not present in sera before or after diagnosis. Autoantibody studies benefit from a comparison to a well-controlled population, stratified for smoking habit. Cancer Immunol Res; 4(2); 165–72. ©2015 AACR.

ObjectivesOsteoarthritis (OA) of the foot-ankle complex is understudied. Understanding determinants of pain and activity limitations is necessary to improve management of foot OA. The aim of the present study was to investigate demographic, foot-specific and comorbidity-related factors associated with pain and activity limitations in patients with foot OA.MethodsThis exploratory cross-sectional study included 75 patients with OA of the foot and/or ankle joints. Demographic and clinical data were collected with questionnaires and by clinical examination. The outcome variables of pain and activity limitations were measured using the Foot Function Index (FFI). Potential determinants were categorized into demographic factors (e.g., age, sex), foot-specific factors (e.g., plantar pressure and gait parameters), and comorbidity-related factors (e.g., type and amount of comorbid diseases). Multivariable regression analyses with backward selection (p-out≥0.05) were performed in two steps, leading to a final model.ResultsOf all potential determinants, nine factors were selected in the first step. Five of these factors were retained in the second step (final model): female sex, pain located in the hindfoot, higher body mass index (BMI), neurological comorbidity, and Hospital Anxiety and Depression Scale (HADS) score were positively associated with the FFI score. The explained variance (R2) for the final model was 0.580 (adjusted R2 ​= ​0.549).ConclusionFemale sex, pain located in the hindfoot, higher BMI, neurological comorbidity and greater psychological distress were independently associated with a higher level of foot-related pain and activity limitations. By addressing these factors in the management of foot OA, pain and activity limitations may be reduced.

The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r =0.40 versus 0.30; WC: r =0.40 versus 0.30, both P ID and II ACE genotypes in both sexes ( P ACE genotype only in women ( P =0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15–2.10], P =0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09–3.20], P =0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.

Summary Objectives Weakness of upper leg muscles has a negative impact on future disease and functional status in subjects with knee osteoarthritis (OA). The aims of the present study were to (i) describe the course of muscle strength over 48 months and (ii) identify baseline predictors for a decline in upper leg muscle strength over time in subjects with knee OA. Methods Data were obtained from the Osteoarthritis Initiative (OAI) database, a multicenter, observational study of knee OA. Upper leg muscle strength (in N/kg) was measured at baseline, 24 and 48 months. Potential baseline predictors included demographics, OA-specific and health and lifestyle related factors. Linear mixed model analyses were performed. Results A total of 1390 subjects with knee osteoarthritis were included. A statistically significant decline of muscle strength was found between baseline and 24 months (B = −0.186, 95%CI [-0.358,-0.014], p = 0.03), but not between other time points (24–48 months p = 0.89, and baseline and 48 months p = 0.058). Predictors of a decline in muscle strength over time included demographic predictors (older age, being female, higher body mass index (BMI)), one lifestyle predictor (lower dietary protein intake) and one OA-specific predictor (radiographic severity). Conclusions Muscle strength declined over time in subjects with knee OA. The identified predictors may help clinicians to select and treat subjects with knee OA at risk of a decline in muscle strength.

AimTo test whether a low serum 25-hydroxyvitamin D level explains the greater prevalence of depression among people with Type 2 diabetes.MethodsWe performed a cross-sectional analysis of 527 people, aged 60-87 years, who participated in a population-based cohort study. Type 2 diabetes, impaired glucose tolerance, impaired fasting glucose and normal glucose tolerance were defined according to the 2006 WHO criteria. The Centre for Epidemiologic Studies Depression questionnaire was administered, using a cut-off score of 16 to determine clinically relevant depressive symptoms.ResultsLogistic regression analysis confirmed that women with impaired glucose tolerance/impaired fasting glucose and people with Type 2 diabetes did have a higher risk of depressive symptoms [unadjusted odds ratios 3.66 (95% CI 1.59 to 8.43) and 3.04 (95% CI 1.57 to 5.88), respectively], compared with people with normal glucose tolerance. Serum 25-hydroxyvitamin D level was not a mediating factor in the association between impaired glucose tolerance/impaired fasting glucose or Type 2 diabetes and depressive symptoms [unstandardized indirect effect 0.001 (95% CI -0.063 to 0.079) and 0.004 (95% CI -0.025 to 0.094), respectively].ConclusionsThe study found no evidence that low vitamin D levels are a contributing factor to higher depression scores in people with Type 2 diabetes.

Aims: We aimed to identify baseline predictors of mortality in patients with a severe mental illness (SMI) over a 6-year period and to describe mortality rates as standardised mortality ratios (SMRs). We hypothesised that cardiovascular diseases, older age, cigarette smoking, more severe psychiatric symptoms and more severe psychotropic side effects, and alcohol or drug use were independent risk factors for mortality. Method: Medical examinations were conducted at baseline in a cohort of 322 SMI patients. SMRs were estimated after 6 years and an evaluation was made of the impact of a wide range of variables on survival time. Results: Almost 11% of the SMI patients had died at the end of the study period. All-cause SMRs were 4.51 (95% CI 3.07–5.95) for all SMI patients (4.89, 95% CI 2.97–6.80 for men, and 3.94, 95% CI 1.78–6.10 for women). Natural causes accounted for 86% of excess mortality and unnatural causes for 14%. Cardiovascular disease was a major contributor to this excess mortality. Multivariate Cox regression analyses showed that premature death was associated with a longer history of tobacco use (HR: 1.03, 95% CI 1.02–1.03) and more severe symptoms of disorganisation (HR: 2.36, 95% CI 2.21–2.52). Conclusions: The high SMR and the incidence of cardiovascular disease-related death in SMI patients in our study justify concern. This study underscores the urgent need for interventions to reduce excess mortality in patients with SMI.

Background The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. Design Meta-analysis of individual participant data. Method From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. Results Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. Conclusions The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

Background Reduced sleep quality is a major concern in patients with chronic widespread pain (CWP).1 2 Poor sleep quality in CWP has received relatively little attention in both multidisciplinary treatment and clinical research in multidisciplinary treatment.3 4 Objectives (i) To investigate the prevalence of poor sleep quality and (ii) to explore the associations between clinical, cognitive and emotional factors and quality of sleep in patients with CWP indicated for multidisciplinary treatment. Methods Baseline data were used from 163 CWP patients referred for multidisciplinary treatment. Linear regression models, adjusted for age and gender, were used to assess the relationship of clinical (pain, fatigue, pain interference and disability), emotional (anxiety, depression and psychological distress) and cognitive factors (catastrophizing, acceptance, self-efficacy, kinesiofobia and illness beliefs) with sleep quality, as measured with the Pittsburgh Sleep Quality Index (PSQI). Results Poor sleep quality was found in 92% of the patients. The multivariate model showed that a higher level of fatigue, psychological distress and more concerns about the illness were independently associated with poorer quality of sleep. The model explained 27.9% of the variance of sleep quality. Conclusions The high prevalence of poor sleep quality in patients with CWP referred for multidisciplinary treatment emphasises the need to target sleep during the treatment program. Poorer quality of sleep is related to a higher level of fatigue, psychological distress and more concerns about the illness. Attention to these factors during multidisciplinary treatment could contribute to improvement in quality of sleep. References [1] Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain2006;10(4):287–333. [2] Arnold LM, Crofford LJ, Mease PJ, et al. Patient perspectives on the impact of fibromyalgia. Patient Educ Couns2008;73(1):114–20. [3] Scascighini L, Toma V, Dober-Spielmann, et al. Multidisciplinary treatment for chronic pain: a review of inter ventions and outcomes. Rheumatology (Oxford)2008;47(5):670–678. [4] Dworkin RH, Turk DC, Farrar JT, et al. core outcome measures for chronic pain clinical trials:IMMPACT recommendation. Pain2005;113(1–2):9–19. Disclosure of Interest None declared

Background There is strong evidence that exercise therapy is effective in reducing pain and activity limitations in knee osteoarthritis (OA), but effect sizes are low to moderate. Stratified exercise therapy tailored to clinically relevant subgroups of patients is expected to optimise treatment effects in a cost-effective manner. Objectives This study aimed to explore the feasibility of a newly developed model of stratified exercise therapy in primary care. Methods A mixed method design was used, consisting of an uncontrolled pretest-posttest design and a process evaluation. Eligible patients visiting a participating primary care physical therapist (PT) were included. Based on our model, participants were allocated to the ‘high muscle strength subgroup’, ‘low muscle strength subgroup’, ‘obesity subgroup’ or ‘depression subgroup’, and received subgroup-specific, protocolised, 4 month exercise therapy. Feasibility of stratified exercise therapy according to this model was evaluated by a process evaluation (process documentation, semi-structured interviews and focus group meeting) and outcome (physical functioning (KOOS-ADL) and knee pain (NRS), assessed at baseline and 4 months follow-up). Results We included 50 patients, of which 3 patients dropped out. The process evaluation suggests that our model is feasible for patients and PTs, with some adaptations for further optimisation. We found clinically relevant improvements on physical functioning (p Conclusions Our model of stratified exercise therapy is feasible in primary care. Minor adaptations could further optimise the feasibility. Future research should determine the (cost-)effectiveness of this model, compared to usual, non-stratified exercise therapy. Disclosure of Interest None declared

Aims To test a simulation model, the MICADO model, for estimating the long-term effects of interventions in people with and without diabetes.Methods The MICADO model includes micro-and macrovascular diseases in relation to their risk factors. The strengths of this model are its population scope and the possibility to assess parameter uncertainty using probabilistic sensitivity analyses. Outcomes include incidence and prevalence of complications, quality of life, costs and cost-effectiveness. We externally validated MICADO's estimates of micro-and macrovascular complications in a Dutch cohort with diabetes (n = 498 400) by comparing these estimates with national and international empirical data.Results For the annual number of people undergoing amputations, MICADO's estimate was 592 (95% interquantile range 291-842), which compared well with the registered number of people with diabetes-related amputations in the Netherlands (728). The incidence of end-stage renal disease estimated using the MICADO model was 247 people (95% interquartile range 120-363), which was also similar to the registered incidence in the Netherlands (277 people). MICADO performed well in the validation of macrovascular outcomes of population-based cohorts, while it had more difficulty in reflecting a highly selected trial population.Conclusions Validation by comparison with independent empirical data showed that the MICADO model simulates the natural course of diabetes and its micro-and macrovascular complications well. As a population-based model, MICADO can be applied for projections as well as scenario analyses to evaluate the long-term (cost-) effectiveness of population-level interventions targeting diabetes and its complications in the Netherlands or similar countries.

Objective. With depression being present in approximately 20% of people with type 2 diabetes mellitus (T2DM), we expect equally frequent prescription of antidepressants, anxiolytics, and hypnotics. Nevertheless, prescription data in people with T2DM is missing and the effect of depression on glycaemic control is contradictory. The aim of this study was to assess the prevalence of antidepressants, anxiolytics, and/or hypnotics use in a large, managed, primary care system cohort of people with T2DM and to determine the sociodemographic characteristics, comorbidities, T2DM medication, and metabolic control associated with its use. Method. The prevalence of antidepressants, anxiolytics, and/or hypnotics use in the years 2007–2012 was assessed in the Hoorn Diabetes Care System Cohort from the Netherlands. Results. From the 7016 people with T2DM, 500 people (7.1%) used antidepressants only, 456 people (6.5%) used anxiolytics and/or hypnotics only, and 254 people (3.6%) used a combination. Conclusion. We conclude that in our managed, primary care system 17% of all people with T2DM used antidepressants, anxiolytics, and/or hypnotics. Users of antidepressants, anxiolytics, and/or hypnotics were more often female, non-Caucasian, lower educated, and more often treated with insulin.

BackgroundEndothelial dysfunction (ED), low-grade inflammation (LGI) and oxidative stress (OxS) may be involved in the pathobiology of depression. Previous studies on the association of these processes in depression have yielded contradictory results. We therefore investigated comprehensively, in a population-based cohort study, the association between ED, LGI and OxS on the one hand and depressive symptoms on the other.MethodWe used data from the Hoorn Study and determined biomarkers of ED [flow-mediated dilatation (FMD), von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble thrombomodulin and soluble endothelial selectin], LGI [C-reactive protein, tumour necrosis factor-α, interleukin 6, interleukin 8, serum amyloid A, myeloperoxidase (MPO) and sICAM-1] and OxS (oxidized low density lipoprotein and MPO). Depressive symptoms were quantified by the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaire (n = 493; age 68 years; 49.9% female). Regression analyses were performed with the use of biomarker Z scores. Adjustments were made for age, sex and glucose metabolism status (cohort stratification variables) and prior cardiovascular disease, hypertension, waist-to-hip ratio, cholesterol levels, education level, physical activity, dietary habits, and the use of antihypertensive and/or lipid-lowering medication and/or metformin (potential confounders).ResultsAfter adjustment for age, sex and glucose metabolism status, one standard deviation increase in the ED Z score was associated with a 1.9 [95% confidence interval (CI) 0.7–3.1] higher CES-D score. Additional adjustments did not materially change this result. LGI and OxS were not associated with the CES-D score.ConclusionsED, as quantified by an array of circulating biomarkers and FMD, was independently associated with depressive symptoms. This study supports the hypothesis that ED plays an important role in the pathobiology of depression.

Aims To study symptom burden among older people and its associations with change in glucose metabolism status over a 7-year period. Methods We conducted a prospective population-based cohort study among 397 older people. We used the revised Diabetes Symptom Checklist to assess symptom burden. Glucose metabolism status was determined using an oral glucose tolerance test. Analyses were adjusted for multiple confounders, including cardiovascular risk and risk of depression (Center for Epidemiological Studies Depression Scale score 16). Results Revised Diabetes Symptom Checklist total scores (range 0-100) increased slightly over time among people with normal glucose metabolism (mean difference 1.04; P = 0.04) and those with impaired glucose metabolism (1.96; P = 0.01), but not among people with Type 2 diabetes (0.46; P = 0.55). These associations between symptom burden and glucose status were attenuated after full adjustment for multiple confounders and remained statistically significant for those with impaired glucose status. Linear mixed models showed significant mean differences in revised Diabetes Symptom Checklist total scores over time when comparing people with Type 2 diabetes with those with normal or impaired glucose metabolism, but not when comparing subjects with impaired vs normal glucose metabolism; these results did not alter after full adjustment. Conclusions Symptom burden increased gradually over time in the people with impaired glucose metabolism and those with normal glucose metabolism, but not in patients with Type 2 diabetes over a 7-year follow-up period. What's new? This is the first study investigating diabetes-related symptom burden among older people and its associations with a change in glucose metabolism status over a 7-year period. The results indicate that symptom burden increases gradually over time among the participants with impaired glucose and those with normal glucose status, but not among patients with Type 2 diabetes. Prospective studies are needed in larger populations, including data on comorbidities and information about diabetes treatment, given the potential of treatment to reduce diabetes complications and subsequent symptom burden .

OBJECTIVE To investigate risk of a recurrent cardiovascular event and its predictors in a population-based cohort. RESEARCH DESIGN AND METHODS Participants of the Hoorn Study who had experienced a first cardiovascular event after baseline (n = 336) were followed with respect to a recurrent event. Absolute risk of a recurrent event was calculated for individuals with normal glucose metabolism, intermediate hyperglycemia, and type 2 diabetes. Cox regression models were used to investigate which variables, measured before the first vascular event, predicted a recurrent event using the stepwise backward procedure. RESULTS During a median follow-up of 4.1 years, 44% (n = 148) of the population developed a recurrent vascular event. The rate of recurrent events per 100 person-years was 7.2 (95% CI 5.8–8.7) in individuals with normal glucose metabolism, compared with 9.8 (6.6–14.0) in individuals with intermediate hyperglycemia and 12.5 (8.5–17.6) in individuals with type 2 diabetes. Higher age (hazard ratio 1.02 [95% CI 1.00–1.04]), male sex (1.56 [1.08–2.25]), waist circumference (1.02 [1.02–1.03]), higher systolic blood pressure (1.01 [1.01–1.02]), higher HbA1c (%, 1.13 [0.97–1.31]/ mmol/mol, 1.01 [1.00–1.03]), and family history of myocardial infarction (1.38 [0.96–2.00]) predicted a recurrent cardiovascular event. CONCLUSIONS Individuals with type 2 diabetes, but not individuals with intermediate hyperglycemia, are at increased risk for a recurrent vascular event compared with individuals with normal glucose metabolism. In people with a history of cardiovascular disease, people at increased risk of a recurrent event can be identified based on the patient’s risk profile before the first event.

In rats, dietary restriction of the cysteine precursor methionine suppresses hepatic stearoyl-CoA desaturase (SCD)-1 expression and activity, whereas cysteine supplementation reverses these effects. In 2 independent cohorts: Hordaland Health Study (HUSK; N=2021, aged 71-74y), Norway, and Hoorn study (N=686, aged 50-87y), Netherlands, we examined the cross-sectional associations of plasma sulfur-containing compounds (SCC; methionine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, cystathionine, total cysteine (tCys), glutathione and cysteinylglycine) with SCD-16 index (16:1n-7/16:0), estimated from fatty acid profiles of total plasma or serum lipids. Only tCys was consistently associated with SCD-16 index after adjustments for sex and age (HUSK: partial r=0.14; Hoorn: partial r=0.11, P

Aim. This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years.Methods. The study population was derived from the 3-year follow-up of the Relationship between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score >= 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin sensitivity (OGIS) index. Insulin secretion was estimated using three model-based parameters of insulin secretion (beta-cell glucose sensitivity, the potentiation factor ratio, and beta-cell rate sensitivity).Results. A total of 162 out of 1027 participants (16%) had significant depressive symptoms. Having significant depressive symptoms was not related to either OGIS [standardized beta (beta) -0.033; P=0.24] or beta-cell glucose sensitivity ([3 0.007; P=0.82). Significant depressive symptoms were related to decreased beta-cell rate sensitivity (odds ratio for significant depressive symptoms of the lowest vs. highest quartile of beta-cell rate sensitivity was 2.04; P =0.01). Also, significant depressive symptoms were associated with a statistically significant decrease in the potentiation factor ratio in unadjusted models, but not in the fully adjusted model.Conclusion. Depressive symptoms were not related to insulin sensitivity and tended to be weakly associated to some parameters of insulin secretion in non-diabetic individuals. Prospective studies are needed to study the temporal association between depression and insulin secretion. (C) 2012 Elsevier Masson SAS. All rights reserved.

Context: The BclI polymorphism in the glucocorticoid receptor (GR) gene is associated with enhanced glucocorticoid (GC) sensitivity. Objective: Our objective was to investigate the association of the BclI polymorphism with body fatness and insulin resistance. Design and Setting: We conducted an observational cohort study, combining data from 2 cohort studies enriched with individuals with impaired glucose metabolism and/or diabetes mellitus type 2 (DM2). Patients and Methods: We examined 1228 participants (mean age 64.7 years, 45% women) from the Cohort Study on Diabetes and Atherosclerosis Maastricht (CODAM, n = 543) and the Hoorn Study (n = 685). Body mass index (BMI), waist and hip circumferences, and waist-to-hip ratio (WHR) were obtained; insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA2-IR). Results: We identified 519 noncarriers (CC), 540 heterozygous (CG) carriers, and 169 homozygous (GG) carriers of the G-allele of the BclI polymorphism. Homozygous carriers had a higher BMI (28.9 vs 27.9 kg/m(2)) and waist (99.6 vs 97.2 cm) and hip (105.5 vs 103.2 cm) circumference compared with noncarriers, also after adjustment for age, sex, cohort, glucose tolerance, and lifestyle risk factors: beta = 0.94 kg/m(2) (95% confidence interval, 0.24-1.63), beta = 2.84 cm (0.95; 4.73) and beta = 2.38 cm (0.88-3.87), respectively. Similar results were obtained when comparing homozygous carriers with heterozygous carriers: beta = 1.03 kg/m(2) (0.34-1.72), beta = 2.20 cm (0.31-4.08) and beta = 1.99 cm (0.51-3.48), respectively. There were no differences in WHR. Ln-HOMA2-IR was higher in GG carriers compared with CG carriers; 0.29 vs 0.17 [beta = 0.09 (0.01-0.17)], but this effect was attenuated after adjustment for BMI [beta = 0.04 (-0.04 to 0.11)]. Conclusion: Homozygous carriers of the BclI polymorphism of the GR gene have significantly greater total body fatness, contributing to higher HOMA2-IR, compared with heterozygous carriers and noncarriers. (J Clin Endocrinol Metab 98: E595-E599, 2013)

BACKGROUND/OBJECTIVES:Lower circulating polyunsaturated fatty acids (PUFAs) may induce loss of heart function. We investigated whether lower concentrations of n-3 and n-6 PUFAs were associated with less favourable echocardiographic measures and higher heart rate in older Caucasians, cross-sectionally and after 7 years of follow-up.SUBJECTS/METHODS:We used data from the Hoorn Study, a population-based cohort. Cross-sectional data were available for 621 participants and longitudinal data for 336 participants. Mean age was 68.6±6.8 years at baseline. We performed linear regression analyses using n-3 and n-6 PUFAs quartiles - assayed by gas liquid chromatography - with left ventricular ejection fraction (LVEF), left ventricular mass index, left atrial volume index and heart rate.RESULTS:In multivariable analyses (regression coefficient (95% confidence interval)), the lowest eicosapentaenoic acid and docosahexaenoic acid quartiles compared with the highest quartiles were cross-sectionally associated with lower LVEF. Lower eicosapentaenoic acid and docosahexaenoic acid concentrations were associated with higher heart rate: 3.7 b.p.m. (1.5, 6.0; P for trend

Aims: Tobacco smoking is known to increase the long-term risk of developing Type 2 diabetes mellitus, but the mechanisms involved are poorly understood. This observational, cross-sectional study aims to compare measures of insulin sensitivity and β-cell function in current, ex- and never-smokers. Methods: The study population included 1246 people without diabetes (mean age 44 years, 55% women) from the EGIR-RISC population, a large European multicentre cohort. Insulin sensitivity was measured using a hyperinsulinaemic, euglycaemic clamp and the homeostatic model assessment – insulin resistance (HOMA-IR) index. Two β-cell function parameters were derived from measures during an oral glucose tolerance test: the early insulin response index and β-cell glucose sensitivity. Additionally, the areas under the curve during the oral glucose tolerance test were calculated for glucose, insulin and C-peptide. Results: According to smoking habits, there were differences in insulin sensitivity, which was lower in women who smoked, and in β-cell glucose sensitivity, which was lower in men who smoked, but these associations lost significance after adjustment. However, after adjustment, the areas under the glucose and the C-peptide curves during the oral glucose tolerance test were significantly higher in men who smoked. Conclusions: Smoking habits were not independently associated with insulin sensitivity or β-cell function in a healthy middle-aged European population. Health-selection bias, methodological shortcomings or a true lack of causal links between smoking and impaired insulin sensitivity/secretion are possible explanations. The mechanisms behind the observed increased glucose and C-peptide areas under the curve during the oral glucose tolerance test in male smokers need to be further evaluated.

AIMS: To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy.METHODS: The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time.RESULTS: Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment.CONCLUSIONS: Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control.

Background and aims: Vitamin D deficiency may contribute to impaired glucose metabolism and type 2 diabetes, especially in the elderly population. We aimed to evaluate whether baseline 25-hydroxyvitamin D (25[OH] D) levels are prospectively associated with deterioration of glucose metabolism and the incidence of diabetes. Methods and results: We examined a subsample from the population based Hoorn study among older men and women. Physical examinations were performed from 2000 to 2001 and included measurements of 25(OH) D. Glucose tolerance tests and HbA1c measurements were performed at baseline and at a follow-up between 2007 and 2009. We included 351 study participants (51% females; 67.9 +/- 5.7 years). Baseline 25(OH) D levels were 56.7 +/- 18.8 nmol/L and follow-up visits were performed after 7.5 +/- 0.5 years. Among 280 study participants without diabetes at baseline we recorded 45 cases of incident diabetes. There was no significant association of 25(OH) D with the incidence of diabetes and with fasting and 2 h postload glucose levels at follow-up. In analyses adjusted for age, sex, and baseline HbA1c there was, however, a significant association of 25(OH) D with follow-up HbA1c levels (beta coefficient = -0.085, p = 0.085). This association was attenuated after further adjustments for BMI (beta coefficient = -0.079, p = 0.064). Conclusions: In this study among the older population we observed no significant association of baseline 25(OH) D with glucose metabolism and incident diabetes. We found, however, a nonsignificant trend towards an inverse association of 25(OH) D with prospective changes in HbA1c that deserves further investigations.

Background Statins play an important role in the prevention of cardiovascular disease in type 2 diabetes. Several studies have reported low adherence with statins among patients with type 2 diabetes. Studies comparing discontinuation of statins compared with discontinuation of oral anti-diabetics within the same individuals before and after initiation of oral anti-diabetic drugs are not available. The aim of this study was to describe discontinuation among patients with type 2 diabetes prescribed statins prior to and after initiation of oral anti-diabetics and to compare statin discontinuation with discontinuation of oral anti-diabetics. Methods We report an observational cohort study among patients initiating treatment with statins prior to or after initiation of oral anti-diabetics between 1999 and 2007. Patients were classified as starting statins prior to initiation (Prior users) or after initiation (After users) of anti-diabetics. Discontinuation was defined as an interval of 180 days or more between the theoretical end date of a statin/anti-diabetic prescription and the dispensing date of the next statin/anti-diabetic prescription. Results and Conclusions We included 3323 starters with oral anti-diabetic drugs in our study; 2072 patients initiated statins in the period of observation. Discontinuation rates for statins were higher compared with oral anti-diabetics (52.1 vs 15.0%). After users discontinued statin therapy more frequently compared to prior users (62.8 vs 48.2%). Discontinuation of statins is higher compared with anti-diabetic discontinuation. Patients starting statins after the initiation of oral anti-diabetic treatment are more likely to discontinue treatment than patients who initiate statins before the start of oral anti-diabetics. Copyright © 2011 John Wiley & Sons, Ltd.

Background and Aims: To investigate associations between baseline serum 25-hydroxyvitamin D [25(OH)D] levels and myocardial structure and function after 8 years of follow-up in older Dutch subjects. Methods: We included 256 subjects of the Hoorn Study, a population-based cohort. They underwent a standardized 2-dimensional echocardiogram at baseline between 2000 and 2001, and again between 2007 and 2009. We studied the association of 25(OH)D quartiles with echocardiographic measures of the left ventricular mass index (LVMI), left ventricular systolic function and markers of diastolic function using linear regression analyses. Results: At baseline, subjects had a mean age of 67.4 ± 5.2 years and 41.4% had prior cardiovascular disease (CVD). Low serum 25(OH)D levels were only associated with higher LVMI at 8-year follow-up in subjects without prior CVD and in subjects with low kidney function (median estimated glomerular filtration rate ≤77.5 ml/min/1.73m2). The associations attenuated after adjustments for parathyroid hormone (PTH), which was associated with higher LVMI (g/m2.7) in subjects with low kidney function (regression coefficient highest quartile 6.3, 95% CI: 0.2, 12.5). Conclusion: This study showed no strong associations of 25(OH)D with myocardial structure and function. However, PTH - a possible modifiable mediator in the relation between 25(OH)D and myocardial structure - was positively associated with LVMI in subjects with low kidney function.

Aims/hypothesis In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. Methods Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA1c reduction and treatment success, defined as the ability to reach the treatment target of an HbA1c ≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. Results In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10−6, respectively). Conclusions/interpretation A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2537-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Aim: Hypoglycaemia may have a detrimental impact on quality of life for patients with Type2 diabetes. There are few clinical studies exploring the impact of experiencing hypoglycaemia on beliefs about diabetes and health status. The aim of this study was to explore associations between experience of hypoglycaemia and changes in diabetes beliefs and self-reported health status in patients with non-insulin-treated Type2 diabetes using a blood glucose meter. Methods One-year prospective cohort analysis of 226 patients recruited to a randomized trial evaluating the impact of self-monitoring of blood glucose. Self-reported hypoglycaemia over 1year was categorized into three groups: (1) no experience of hypoglycaemia; (2) blood glucose measurements

Diabet. Med. 28, 1078–1081 (2011) Abstract Aims The Finnish Diabetes Risk Score (FINDRISC) is widely used for risk stratification in Type 2 diabetes prevention programmes. Estimates of β-cell function vary widely in people without diabetes and reduced insulin secretion has been described in people at risk for diabetes. The aim of this analysis was to evaluate FINDRISC as a tool to characterize reduced β-cell function in individuals without known diabetes. Methods In this population-based cohort from the Hoorn municipal registry, subjects received an oral glucose tolerance test and a meal tolerance test on separate days, in random order, within 2 weeks. One hundred and eighty-six subjects, age 41–66 years, with no known Type 2 diabetes were included. Of those, 163 (87.6%) had normal glucose metabolism and 23 (12.4%) had abnormal glucose metabolism (19 with impaired glucose metabolism; four with newly diagnosed Type 2 diabetes based on study results). Insulin sensitivity and β-cell function (classical: insulinogenic index; ratio of areas under insulin/glucose curves; model-based: glucose sensitivity; rate sensitivity; potentiation) estimates were calculated from oral glucose tolerance test and meal tolerance test data. Results FINDRISC was associated with insulin sensitivity (r = −0.41, P

Aims/hypothesis: The Finnish diabetes risk questionnaire is a widely used, simple tool for identification of those at risk for drug-treated type 2 diabetes. We updated the risk questionnaire by using clinically diagnosed and screen-detected type 2 diabetes instead of drug-treated diabetes as an endpoint and by considering additional predictors.Methods: Data from 18,301 participants in studies of the Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) project with baseline and follow-up information on oral glucose tolerance status were included. Incidence of type 2 diabetes within 5 years was used as the outcome variable. Improvement in discrimination and classification of the logistic regression model was assessed by the area under the receiver-operating characteristic (ROC) curve and by the net reclassification improvement. Internal validation was by bootstrapping techniques.Results: Of the 18,301 participants, 844 developed type 2 diabetes in a period of 5 years (4.6%). The Finnish risk score had an area under the ROC curve of 0.742 (95% CI 0.726–0.758). Re-estimation of the regression coefficients improved the area under the ROC curve to 0.766 (95% CI 0.750–0.783). Additional items such as male sex, smoking and family history of diabetes (parent, sibling or both) improved the area under the ROC curve and net reclassification. Bootstrapping showed good internal validity.Conclusions/interpretation: The predictive value of the original Finnish risk questionnaire could be improved by adding information on sex, smoking and family history of diabetes. The DETECT-2 update of the Finnish diabetes risk questionnaire is an adequate and robust predictor for future screen-detected and clinically diagnosed type 2 diabetes in Europid populations.

Background There is strong evidence that exercise therapy is effective in reducing pain and activity limitations in knee osteoarthritis (OA), but effect sizes are low to moderate. Stratified exercise therapy tailored to clinically relevant subgroups of patients is expected to optimise treatment effects in a cost-effective manner. Objectives This study aimed to explore the feasibility of a newly developed model of stratified exercise therapy in primary care. Methods A mixed method design was used, consisting of an uncontrolled pretest-posttest design and a process evaluation. Eligible patients visiting a participating primary care physical therapist (PT) were included. Based on our model, participants were allocated to the ‘high muscle strength subgroup’, ‘low muscle strength subgroup’, ‘obesity subgroup’ or ‘depression subgroup’, and received subgroup-specific, protocolised, 4 month exercise therapy. Feasibility of stratified exercise therapy according to this model was evaluated by a process evaluation (process documentation, semi-structured interviews and focus group meeting) and outcome (physical functioning (KOOS-ADL) and knee pain (NRS), assessed at baseline and 4 months follow-up). Results We included 50 patients, of which 3 patients dropped out. The process evaluation suggests that our model is feasible for patients and PTs, with some adaptations for further optimisation. We found clinically relevant improvements on physical functioning (p Conclusions Our model of stratified exercise therapy is feasible in primary care. Minor adaptations could further optimise the feasibility. Future research should determine the (cost-)effectiveness of this model, compared to usual, non-stratified exercise therapy. Disclosure of Interest None declared

Background: Vitamin D deficiency is frequently observed in heart failure patients and it has been shown that vitamin D exerts various effects on the heart that may be relevant for the pathogenesis of myocardial diseases. Aims: We aimed to elucidate the largely unknown association of 25-hydroxyvitamin D [25(OH)D] serum levels with echocardiographic measures of left ventricular (LV) structure and function. Material/Subjects and methods: We measured 25(OH)D serum levels and performed standardized LV chocardiograms in 614 persons from a population-based cohort of older men and women. Echocardiographic data were used to calculate LV mass and geometry and for classification of systolic and diastolic dysfunction. To consider the seasonal variations of 25(OH)D levels we categorized our study participants according to season-specific 25(OH)D quartiles. Resuits: LV systolic function, mass and geometry were not significantly associated with 25(OH)D serum levels. In binary logistic regression analyses, the prevalence of LV diastolic dysfunction was significantly higher in the first season-specific 25(OH)D quartile when compared to the fourth quartile [odds ratio 2.32 (95% Cl: 1.42-3.80); p=0.001] but significance was lost after adjustments for age [odds ratio 1.51 (0.89-2.57); p=0.123] and established risk factors for heart failure [odds ratio 1.47 (0.84-2.59); p=0.178]. Conclusions: Serum levels of 25(OH)D are not significantly associated with LV structure and function but a non-significant trend towards increased risk of diastolic dysfunction in persons with vitamin D deficiency warrants further studies. ©2010, Editrice Kurtis.

Objective: This brief report presents initial data from the Amsterdam Study of Acute Psychiatry (ASAP-I) about factors associated with the decision to admit patients compulsorily (involuntarily) to emergency psychiatric services in the Amsterdam region of the Netherlands. Methods: The study was a prospective cohort study of 1,970 consecutive patients who came into contact with the Psychiatric Emergency Service Amsterdam. Results: A history of more than 14 outpatient contacts the previous year was associated with a low risk of compulsory admission (OR=.3). An involuntary admission in the previous five years was associated with a higher risk (OR=3.7). Referral by a general practitioner was associated with a low risk compared with referral by police (OR= 2.4) or by mental health services (OR=2.3). Conclusions: The hypothesis that outpatient treatment may help to prevent compulsory admission found some support in this study. More research is needed to understand the mechanisms of the associations so that an intervention study can be developed to test this hypothesis. (Psychiatric Services 60:1543–1546, 2009)

Objective Vitamin D deficiency is common among the elderly and may contribute to cardiovascular disease. The aim of our study was to elucidate whether low serum levels of 25-hydroxyvitamin D [25(OH)D] are associated with an increased risk of all-cause and cardiovascular mortality. Design and patients The Hoorn Study is a prospective population-based study among older men and women. Measurements Fasting serum 25(OH)D was determined in 614 study participants at the follow-up visit in 2000-2001, the baseline for the present analysis. To account for sex differences and seasonal variations of 25(OH)D levels we formed sex-specific quartiles, which were calculated from the 25(OH)D values of each season. Results After a mean follow-up period of 6·2 years, 51 study participants died including 20 deaths due to cardiovascular causes. Unadjusted Cox proportional hazard ratios (HRs; with 95% confidence intervals) for all-cause and cardiovascular mortality in the first when compared with the upper three 25(OH)D quartiles were 2·24 (1·28- 3·92; P = 0·005) and 4·78 (1·95-11·69; P = 0·001), respectively. After adjustment for age, sex, diabetes mellitus, smoking status, arterial hypertension, high-density lipoprotein-cholesterol, glomerular filtration rate and waist-to-hip ratio, the HRs remained significant for all-cause [1·97 (1·08-3·58; P = 0·027)] and for cardiovascular mortality [5·38 (2·02-14·34; P = 0·001)]. Conclusions Low 25(OH)D levels are associated with all-cause mortality and even more pronounced with cardiovascular mortality, but it remains unclear whether vitamin D deficiency is a cause or a consequence of a poor health status. Therefore, intervention studies are warranted to evaluate whether vitamin D supplementation reduces mortality and cardiovascular diseases. © 2009 Blackwell Publishing Ltd.

The metabolic syndrome (MetS) increases cardiovascular disease (CVD) risk. How MetS increases CVD risk is incompletely understood, but increasing arterial stiffness is one candidate link, which in turn could be explained by (low-grade) inflammation, endothelial dysfunction (ED) or insulin resistance (IR). However, MetS-related increases in stiffness may not be uniformly distributed over muscular and elastic arteries. Therefore, the purpose of this study was to determine: (1) the associations between the MetS, and muscular and elastic arterial stiffness, and (2) whether any such associations could be explained by inflammation, ED or IR. These questions were addressed in the Hoorn Study. MetS was defined according to the NCEP (National Cholesterol Education Program) criteria. Arterial stiffness was determined by ultrasound, tonometry and echocardiography. Inflammation, ED and IR were estimated by C-reactive protein, flow-mediated vasodilation and the homoeostatic model for the assessment of IR, respectively. The results showed that MetS was associated with both femoral and brachial arterial stiffness, significantly so for the distensibility coefficients and for the femoral compliance coefficient. In the carotid artery and aorta, no particular pattern emerged. Additional adjustment for either inflammation, ED or IR did not materially alter the results. The results therefore indicate that muscular arteries may stiffen preferentially over elastic arteries and that distensibility is affected to a greater extent than compliance, thus maintaining volume compliance over vessel wall stiffening. Additionally, the increase in stiffness was not explained by inflammation, ED or IR and suggests that stiffening of the muscular arteries in MetS may not be the consequence of these phenomena.Journal of Human Hypertension advance online publication, 12 March 2009; doi:10.1038/jhh.2009.8.

Early insulin secretion following a meal is representative for normal physiology and may depend on meal composition. To compare the effects of a fat-rich and a carbohydrate-rich mixed meal on insulinogenic index as a measure of early insulin secretion in normoglycemic women (NGM) and in women with type 2 diabetes mellitus (DM2), and to assess the relationship of anthropometric and metabolic factors with insulinogenic index.Postmenopausal women, 76 with NGM and 64 with DM2, received a fat-rich meal and a carbohydrate-rich meal on separate occasions. Early insulin response was estimated as insulinogenic index ( big up tri, Deltainsulin(0-30 min)/ big up tri, Deltaglucose(0-30 min)) for each meal. Associations of fasting and postprandial triglycerides, body mass index, waist and hip circumference and alanine aminotransferase with insulinogenic indices were determined.Women with NGM present with higher insulinogenic index than women with DM2. The insulinogenic index following the fat-rich meal ( big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat)) was higher than the index following the carbohydrate-rich meal (big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH)) (P0.05 in women with DM2, and not significant in women with NGM). In women with DM2, homeostasis model assessment for insulin resistance was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH). In women with NGM, waist circumference was independently and inversely associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat) and with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH); hip circumference was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat).The insulinogenic index following the fat-rich meal was higher than following the isocaloric carbohydrate-rich meal, which might favorably affect postprandial glucose excursions, especially in women with DM2. The association between a larger waist circumference and a lower meal-induced insulinogenic index in women with NGM requires further mechanistic studies.

Background: We hypothesized that acarbose would delay conversion from impaired glucose tolerance (IGT) to type 2 diabetes by alleviating postprandial hyperglycaemia. Our study's main objective was to investigate the effect of acarbose in IGT-persons on their 2-h plasma glucose level and beta-cell function. Subjects and Methods: The study included a random sample of 45-70-year-old residents of Hoorn, Netherlands, with mean fasting plasma glucose

The present study aimed to compare the associations of postprandial glucose (ppGL) and postprandial triglycerides (ppTG) with carotid intima media thickness (cIMT) in women with normal glucose metabolism (NGM) and type 2 diabetes (DM2). Post-menopausal women (76 with NGM, 78 with DM2), received two consecutive fat-rich and two consecutive carbohydrate-rich meals on separate occasions. Blood samples were taken before and 1, 2, 4, 6 and 8h following breakfast; lunch was given at t=4. Ultrasound imaging of the carotid artery was performed to measure cIMT. In women with NGM, an increase of 1.0 mmol/l glucose following the fat-rich meals was associated with a 50 microm cIMT increase (p=0.04), and following the carbohydrate meals, an increase of 1.8 mmol/l glucose was associated with a 50 microm larger cIMT (p=0.08). These associations were not explained by classical cardiovascular risk factors. However, no association between ppGL and cIMT was found in women with DM2 and ppTG were not associated with cIMT. The association between ppGL and cIMT in normoglycaemic women suggests that ppGL in the normal range is a marker or a risk factor for atherosclerosis. Postprandial glucose levels might be a better indicator of risk than post-OGTT glucose levels or triglyceride levels.

To evaluate whether the metabolic syndrome (MetS) defined by the International Diabetes Federation (IDF) criteria, which has abdominal adiposity as a mandatory element, predicts cardiovascular disease (CVD) mortality better than the cluster of other IDF-defined abnormalities not including abdominal adiposity.Data from nine European population-based studies, including 7782 men and 7739 women (aged 30-89 years), with a median follow-up of 8.55 years, were jointly analyzed. Hazard ratios for CVD mortality were calculated with Cox regression models.In total, 41% of the men and 38% of the women had the IDF MetS. Individuals with the IDF MetS were by definition more obese and had a higher prevalence of diabetes than non-obese subjects withor = 2 IDF abnormalities; whereas non-obese men withor = 3 factors had more atherogenic lipid profiles. Multivariate adjusted hazard ratio for CVD death in men and women with the IDF MetS was 2.44 (1.69-2.98) and 2.32 (1.27-4.23); in non-obese men with 2 andor = 3 factors the hazard ratio was 1.60 (1.12-2.30) and 2.44 (1.62-3.66), respectively, and in non-obese women with 2 factors the hazard ratio was 2.41 (1.09-5.33).The cluster of the CVD risk factors predicted CVD mortality regardless of the presence or absence of the abdominal adiposity. Inclusion of abdominal adiposity as a prerequisite will miss those non-obese individuals who have increased CVD mortality.

Objective To study the prevalence and risk factors of depressive symptoms, comparing subjects with normal glucose metabolism (NGM), impaired glucose metabolism (IGM) or Type 2 diabetes mellitus (DM2). Research design and methods Cross-sectional data from a population-based cohort study conducted among 550 residents (276 men and 274 women) of the Hoorn region, the Netherlands. Levels of depressive symptoms were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D score ≥ 16). Glucose metabolism status was determined by means of fasting and post-load glucose levels. Results The prevalence of depressive symptoms in men with NGM, IGM and DM2 was 7.7, 7.0 and 15.0% (P = 0.19) and for women 7.7, 23.1 and 19.7% (P

Alanine aminotransferase (ALT) is a marker of non-alcoholic fatty liver disease (NAFLD) and predicts incident type 2 diabetes mellitus (DM2). Recently, ALT was shown to be also associated with endothelial dysfunction and carotid atherosclerosis. We studied the predictive value of ALT for all-cause mortality, incident cardiovascular disease (CVD) and coronary heart disease (CHD) events in a population-based cohort of Caucasian men and women aged 50-75 years, at baseline. The 10-year risk of all-cause mortality, fatal and non-fatal CVD and CHD events in relation to ALT was assessed in 1439 subjects participating in the Hoorn Study, using Cox survival analysis. Subjects with prevalent CVD/CHD and missing data were excluded. As compared with the first tertile, the age- and sex-adjusted hazard ratios (95% confidence intervals) for all-cause mortality, CVD events and CHD events were 1.30 (0.92-1.83), 1.40 (1.09-1.8 1) and 2.04 (1.35-3. 10), respectively, for subjects in the upper tertile of ALT. After adjustment for components of the metabolic syndrome and traditional risk factors, the association of ALT and CHD events remained significant for Subjects in the third relative to those in the first tertile, with a hazard ratio of 1.88 (1.21-2.92) and 1.75 (1.12-2.73), respectively. In conclusion, the predictive value of ALT for coronary events, seems independent of traditional risk factors and the features of the metabolic syndrome in a population-based cohort. Further studies should confirm these findings and elucidate the pathophysiological mechanisms.

Aims: To study the association between alanine aminotransferase (ALT) and the 6-year risk of the metabolic syndrome in a population-based study in Caucasian men and women. Methods: The association of ALT with the 6-year risk of the metabolic syndrome in 1097 subjects, aged 50-75 years, was assessed in the Hoorn Study with logistic regression analysis. Subjects with the metabolic syndrome at baseline, defined according to the Adult Treatment Panel III of the National Cholesterol Education Program, were excluded. Results: After 6.4 (range 4.4-8.1) years follow-up, 226 subjects (20.6%) had developed the metabolic syndrome. The odds ratio (95% confidence interval) for developing the metabolic syndrome, adjusted for age, sex, alcohol intake and follow-up duration was 2.25 (1.50-3.37) for subjects in the upper tertile compared with those in the lower tertile of ALT. This association persisted after additional adjustment for all the baseline metabolic syndrome features [1.62 (1.02-2.58)]. Among the individual components of the metabolic syndrome, ALT was significantly associated only with fasting plasma glucose at follow-up. Conclusions: These data suggest that ALT is associated with risk of the metabolic syndrome in a general population of middle-aged Caucasian men and women, further strengthening the role of ALT as an indicator for future metabolic derangement. These findings warrant further studies to elucidate the role of non-adipose tissue fat accumulation in the pathogenesis of complications related to the metabolic syndrome.

OBJECTIVE: A high monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) intake is associated with lower plasma low-density lipoprotein (LDL)-cholesterol. However, PUFA may increase the susceptibility of LDL to undergo oxidative modifications. The aim of this study was to analyze the association of habitual dietary fat intake with LDL size and oxidizability. DESIGN: Cross-sectional. SETTING: Cohort study. SUBJECTS: Seven hundred and fifty-eight subjects with normal, impaired glucose metabolism and type II diabetes. INTERVENTIONS: Mean LDL size was measured by high-performance gel-filtration chromatography. In vitro oxidizability of LDL was determined by measuring lag time, reflecting the resistance of LDL to copper-induced oxidation. Information about dietary fat intake was obtained by a validated food frequency questionnaire. RESULTS: PUFA intake (energy percent) was significantly and negatively associated with LDL size in subjects with type II diabetes (standardized beta (95% confidence interval) -0.17 (-0.28;-0.06)) and impaired glucose metabolism - although not statistically significant - (-0.09 (-0.24;0.05)), but not in subjects with normal glucose metabolism (0.01 (-0.10;0.12)) (P-value for interaction=0.02). No significant associations were observed for total, saturated fat and MUFA intake with LDL size. Intake of fat was associated with lag time; however, the small magnitude of the associations suggested that the composition of dietary fat is not a major factor affecting lag time. The same association with lag time was observed in all three glucose metabolism categories. CONCLUSIONS: In individuals with abnormal glucose metabolism, higher PUFA intake is associated with smaller LDL particle size, but does not alter the susceptibility of LDL to in vitro oxidation. SPONSORSHIP: Dutch Diabetes Research Foundation, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).

Introduction Central (aortic or carotid) pulse pressure (PP) is more strongly associated with local organ damage and possibly mortality than brachial PP. Aim To investigate for the first time the association of femoral (f) PP with all-cause mortality, and incident cardiovascular disease (CVD), coronary heart disease (CHD) and cerebrovascular disease (CerVD) events, as well as with markers of renal function (estimated glomerular filtration rate, eGFR, and microalbuminuria). Methods We used data from a population-based study, by design including 50% type 2 diabetes and impaired glucose metabolism (IGM). The baseline examination included non-invasive PP assessment at the brachial, aorta (Sphygmocor device), carotid and femoral (ultrasound distention waves calibrated by brachial mean and diastolic pressure) arteries. Results After 7.8 years of follow-up (n = 449, age: 68.9 ± 6.0 males: 52%), 66 participants had died, 102 had a CVD event, 45 a CHD event, and 31 a CerVD event. PP at all sites was associated with incident all-cause mortality and CVD events. Only fPP was, however, associated with incident CHD events, even after adjustment for CVD risk factors (HRs 1.31 [1.07–1.61 95% CIs]). No association between PP and incident CerVD events was found – possibly due to the small number of events. fPP was associated with renal function but this was similar to other PP indices. No interaction between each any local PP index and glucose metabolism status or renal function was present. Conclusion Beyond anatomical topography, local fPP provide important information related to CVD events. This possibility and the underlying mechanisms should be further investigated.

The category of IFG was introduced in the late 1990s to denote a state of non-diabetic hyperglycaemia defined by a fasting plasma glucose (FPG) concentration between 6.1 and 6.9 mmol/l. In 2003 the American Diabetes Association recommended that this diagnostic threshold be lowered to 5.6 mmol/l. The justification for lowering the threshold has been questioned. This simple change in cut-off value creates a pandemic of IFG, with a two- to five-fold increase in the prevalence of IFG across the world. Such a change in threshold has far-reaching public health implications. The European Diabetes Epidemiology Group (EDEG) has reviewed the evidence for this lower cut-off point for the definition of IFG and concludes that the previous definition should not be altered. EDEG further recommends that the value of all categorical definitions of non-diabetic hyperglycaemia should be reconsidered.