Netherlands Epidemiology Of Obesity Research Articles

Validation of the SQUASH physical activity questionnaire using accelerometry: The NEO study

ObjectiveTo investigate the construct validity of the SQUASH (Short QUestionnaire to ASsess Health-enhancing physical activity). DesignThis is a cross-sectional analysis using baseline measurements from middle-aged participants in the Netherlands Epidemiology of Obesity (NEO) study. The SQUASH consists of questions on eleven physical activities investigating days per week, average duration per day and intensity, leading to a summed score in Metabolic Equivalent of Task hours (MET h) per week. To assess convergent validity, a Spearman's rank correlation between SQUASH and ActiHeart was calculated. To assess extreme group validity, three groups expected to differ in SQUASH total physical activity outcome were compared. For discriminative validity, a Spearman's rank correlation between SQUASH physical activity and participant height was investigated. ResultsSQUASH data were available for 6550 participants (mean age 56 years, 44% men, mean BMI 26.3, 15% with knee OA, 13% with hand OA). Median physical activity (interquartile range) was 118 (76; 154) MET h/week according to SQUASH and 75 (58; 99) according to ActiHeart. Convergent validity was weak (rho ​= ​0.20). For all three extreme group comparisons, a statistically significant difference was present. Discriminative validity was present (rho ​= ​0.01). Compared with the reference quintile, those with a discrepancy SQUASH ​> ​ActiHeart and SQUASH ​< ​ActiHeart were relatively younger and more often male. ConclusionsThe construct validity of the SQUASH seems sub-optimal. Physical activity reported by the SQUASH was generally higher than reported by ActiHeart. Whether the differences between SQUASH and ActiHeart are e.g. due to different underlying domains, limitations to our study, or reflect true differences needs further investigation.

The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study

BackgroundMetabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI, kg/m2). ObjectivesIn this study, we used the Netherlands Epidemiology of Obesity (NEO) study data to identify observational and causal associations between BMI and metabolite response to a liquid meal. MethodsA liquid meal challenge was performed, and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample Mendelian randomization (MR) analysis were conducted to estimate the effect of BMI on metabolites (n = 229) in the fasting, postprandial, and response (or change in abundance) states. ResultsWe observed 473 associations with BMI (175 fasting, 188 postprandial, and 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, and 3 response) to be associated with BMI. MR associations included the glucogenic amino acid alanine, which was inversely associated with BMI in the response state (β: −0.081; SE: 0.023; P = 5.91 × 10−4), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI. ConclusionsOverall, this study showed that MR estimates were strongly correlated with observational effect estimates, suggesting that the broad associations seen between BMI and metabolite variation has a causal underpinning. Specific effects in previously unassessed postprandial and response states are detected, and these may likely mark novel life course risk exposures driven by regular nutrition.

Prevalence of non-alcoholic fatty liver in the general Dutch population and in groups at increased risk

Background and aimNon-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content ≥5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination of metabolic risk factors. We aimed to examine the prevalence of NAFLD, including groups with metabolic risk factors. Methods and resultsIn this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, liver fat content was assessed using proton magnetic resonance spectroscopy (H-MRS). Participants with excessive alcohol consumption or missing values were excluded, leaving a total of 1570 participants for the analyses.Mean (SD) age of the population was 55 years, BMI 25.9 (4.0) kg/m2 and 46% were men. The prevalence of NAFLD was 27% (95% CI 24–30). The prevalence of NAFLD was increased in participants with hypertriglyceridemia (57%, 52–63), obesity (62%, 58–66) and diabetes (69%, 61–77). The prevalence of NAFLD was highest in those with diabetes and obesity (79%, 71–87), obesity and hypertriglyceridemia (81%, 76–86) and with diabetes and hypertriglyceridemia (86%, 77–95). NAFLD was also present in 12% (8-16) of participants without overweight. ConclusionsThe prevalence of NAFLD in a middle-aged population in the Netherlands in 2010 was 27%. The prevalence of NAFLD is particularly increased in individuals with diabetes, obesity, and hypertriglyceridemia. This information may help clinicians and general practitioners in the risk stratification of their patients in daily practice.

Timing of physical activity in relation to liver fat content and insulin resistance

Aims/hypothesisWe hypothesised that the insulin-sensitising effect of physical activity depends on the timing of the activity. Here, we examined cross-sectional associations of breaks in sedentary time and timing of physical activity with liver fat content and insulin resistance in a Dutch cohort.MethodsIn 775 participants of the Netherlands Epidemiology of Obesity (NEO) study, we assessed sedentary time, breaks in sedentary time and different intensities of physical activity using activity sensors, and liver fat content by magnetic resonance spectroscopy (n=256). Participants were categorised as being most active in the morning (06:00–12:00 hours), afternoon (12:00–18:00 hours) or evening (18:00–00:00 hours) or as engaging in moderate-to-vigorous-physical activity (MVPA) evenly distributed throughout the day. Most active in a certain time block was defined as spending the majority (%) of total daily MVPA in that block. We examined associations between sedentary time, breaks and timing of MVPA with liver fat content and HOMA-IR using linear regression analyses, adjusted for demographic and lifestyle factors including total body fat. Associations of timing of MVPA were additionally adjusted for total MVPA.ResultsThe participants (42% men) had a mean (SD) age of 56 (4) years and a mean (SD) BMI of 26.2 (4.1) kg/m2. Total sedentary time was not associated with liver fat content or insulin resistance, whereas the amount of breaks in sedentary time was associated with higher liver fat content. Total MVPA (−5%/h [95% CI −10%/h, 0%/h]) and timing of MVPA were associated with reduced insulin resistance but not with liver fat content. Compared with participants who had an even distribution of MVPA throughout the day, insulin resistance was similar (−3% [95% CI −25%, 16%]) in those most active in morning, whereas it was reduced in participants who were most active in the afternoon (−18% [95% CI −33%, −2%]) or evening (−25% [95% CI −49%, −4%]).Conclusions/interpretationThe number of daily breaks in sedentary time was not associated with lower liver fat content or reduced insulin resistance. Moderate-to-vigorous activity in the afternoon or evening was associated with a reduction of up to 25% in insulin resistance. Further studies should assess whether timing of physical activity is also important for the occurrence of type 2 diabetes.Graphical abstract

Mendelian randomization study of the relation between adiponectin and heart function, unravelling the paradox

High adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk, specifically heart failure, in individuals at high cardiovascular risk. We aimed to investigate the association between adiponectin and heart function parameters, and inversely, we estimated the effect of genetically-determined heart function and NT-proBNP as the main marker of heart failure on adiponectin using Mendelian randomisation.Observational analyses between adiponectin and measures of heart function, i.e. E/A ratio, left, and right ventricular ejection fraction, were performed in participants of the Netherlands Epidemiology of Obesity (NEO) study, assessed by MRI of the heart (n = 1,138). Two-sample Mendelian randomisation analyses were conducted to estimate the effect of NT-proBNP and heart function on adiponectin concentrations using publicly-available summary statistics (ADIPOGen; the PLATO trial).The mean (standard deviation) age was 56 (6) years and mean body mass index was 26 (4) kg/m2. Per five μg/mL higher adiponectin, the E/A ratio was −0.05 (95 % CI: −0.10, −0.01) lower, left ventricle ejection fraction was −0.5 % (95 % CI: −1.1, 0.1) lower, and right ventricle ejection fraction was 0.5 % (95 % CI: −0.1, 1.2) higher. Genetically-determined NT-proBNP was causally related to adiponectin concentrations in ADIPOGen: per doubling of genetically-determined NT-proBNP, adiponectin concentrations were 11.4 % (95 % CI: 1.7, 21.6) higher.With causal MR methods we showed that NT-proBNP affects adiponectin concentrations, while adiponectin is not associated with heart function parameters. Therefore, reverse causation may explain the adiponectin paradox observed in previous studies.

The Relation Between Adult Weight Gain, Adipocyte Volume, and the Metabolic Profile at Middle Age.

ContextWeight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy.ObjectiveWe aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume.MethodsNuclear magnetic resonance–based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n = 6347, discovery) and Oxford Biobank (n = 6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n = 114) to estimate adipocyte volume.ResultsMean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 μm3 (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain.ConclusionAdult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.

Triglyceride-lowering LPL alleles combined with LDL-C-lowering alleles are associated with an additively improved lipoprotein profile

Background and aimsMendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles. MethodsWe quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference. ResultsCompared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10−3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. ConclusionsOur findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.

The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity

AimsTo evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL).MethodsTo investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic–euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (1H-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON).ResultsWe observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 ± 3.0% pre-exercise to 8.1 ± 2.0% post exercise, p < 0.05) and CON (from 2.4 ± 0.6% pre-exercise to 1.6 ± 1.4% post exercise, p < 0.05), and improved peripheral insulin sensitivity in NAFL as well by ~23% (p < 0.05).ConclusionsThe association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels.Trial registrationTrial registry number: NCT01317576.

Normal and reference values for cardiovascular magnetic resonance-based pulse wave velocity in the middle-aged general population

BackgroundAortic stiffness, assessed through pulse wave velocity (PWV), is an independent predictor for cardiovascular disease risk. However, the scarce availability of normal and reference values for cardiovascular magnetic resonance imaging (CMR) based PWV is limiting clinical implementation. The aim of this study was to determine normal and reference values for CMR assessed PWV in the general population.MethodsFrom the 2,484 participants of the Netherlands Epidemiology of Obesity (NEO) study that have available CMR-PWV data, 1,394 participants free from cardiovasculard disease, smokers or treatment for diabetes, hypertension or dyslipidaemia were selected (45–65 years, 51% female). Participants were divided into sex, age and blood pressure (BP) subgroups. Normal values were specified for participants with a BP < 130/80 mmHg and reference values for elevated BP subgroups (≥ 130/80 and < 140/90 mmHg; and ≥ 140/90 mmHg). Differences between groups were tested with independent samples t-test or ANOVA. Due to an oversampling of obese individuals in this study, PWV values are based on a weighted analysis making them representative of the general population.ResultsNormal mean PWV was 6.0 m/s [95% CI 5.8–6.1]. PWV increased with advancing age and BP categories (both p < 0.001). There was no difference between sex in normal PWV, however in the BP > 140/90 mmHg women had a higher PWV (p = 0.005). The interpercentile ranges were smaller for participants < 55 years old compared to participants ≥ 55 years, indicating an increasing variability of PWV with age. PWV upper limits were particularly elevated in participants ≥ 55 years old in the high blood pressure subgroups.ConclusionThis study provides normal and reference values for CMR-assessed PWV per sex, age and blood pressure category in the general population.

Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals

Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis. We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH. Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease.

A Workflow for Missing Values Imputation of Untargeted Metabolomics Data.

Metabolomics studies have seen a steady growth due to the development and implementation of affordable and high-quality metabolomics platforms. In large metabolite panels, measurement values are frequently missing and, if neglected or sub-optimally imputed, can cause biased study results. We provided a publicly available, user-friendly R script to streamline the imputation of missing endogenous, unannotated, and xenobiotic metabolites. We evaluated the multivariate imputation by chained equations (MICE) and k-nearest neighbors (kNN) analyses implemented in our script by simulations using measured metabolites data from the Netherlands Epidemiology of Obesity (NEO) study (n = 599). We simulated missing values in four unique metabolites from different pathways with different correlation structures in three sample sizes (599, 150, 50) with three missing percentages (15%, 30%, 60%), and using two missing mechanisms (completely at random and not at random). Based on the simulations, we found that for MICE, larger sample size was the primary factor decreasing bias and error. For kNN, the primary factor reducing bias and error was the metabolite correlation with its predictor metabolites. MICE provided consistently higher performance measures particularly for larger datasets (n > 50). In conclusion, we presented an imputation workflow in a publicly available R script to impute untargeted metabolomics data. Our simulations provided insight into the effects of sample size, percentage missing, and correlation structure on the accuracy of the two imputation methods.

Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts

Background and aimsOutdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics. Methods and resultsCross-sectional analyses were undertaken in non-diabetic individuals from the Oxford BioBank (OBB; N = 6368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N = 5916; mean age 55.6 years, males 43%) study. Data on mean outdoor bright sunlight and temperature were collected from local weather stations in the week prior to blood sampling. Fasting serum levels of 148 metabolites, including 14 lipoprotein subclasses, were measured using NMR spectroscopy. Linear regression analyses were performed to assess the associations between mean outdoor temperature and bright sunlight duration with metabolomics adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. A higher mean outdoor temperature was associated with increased serum concentrations of lipoprotein (sub)particles (β (SE) = 0.064 (0.018) SD per 5 °C, p = 5.03e−4) and certain amino acids such as phenylalanine (0.066 (0.016) SD, p = 6.44e−05) and leucine (0.111 (0.018) SD, p = 1.25e−09). In contrast, longer duration of bright sunlight was specifically associated with lower concentrations of very low-density lipoprotein (sub)particles (e.g., VLDL cholesterol (−0.024 (0.005) SD per 1-h bright sunlight, p = 8.06e−6)). The direction of effects was generally consistent between the OBB and NEO, although effect sizes were generally larger in the OBB. ConclusionsIncreased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.

Genome-wide Association Study of the Postprandial Triglyceride Response Yields Common Genetic Variation in Hepatic Lipase (LIPC)

The increase in serum triglyceride (TG) concentrations in response to a meal is considered a risk factor for cardiovascular disease. We aimed to elucidate the genetics of the postprandial TG response through genome-wide association studies (GWAS). Participants of the NEO (Netherlands Epidemiology of Obesity) study (n=5630) consumed a liquid mixed meal after an overnight fast. GWAS of fasting and postprandial serum TG at 150 minutes were performed. To identify genetic variation of postprandial TG independent of fasting TG, we calculated the TG response at 150 minutes by the residuals of a nonlinear regression that predicted TG at 150 minutes as a function of fasting TG. Association analyses were adjusted for age, sex, and principal components in a linear regression model. Next, using the identified variants as determinants, we performed linear regression analyses on the residuals of the postprandial response of 149 nuclear magnetic resonance-based metabolite measures. GWAS of fasting TG and postprandial serum TG at 150 minutes resulted in completely overlapping loci, replicating previous GWAS. From GWAS of the TG response, we identified rs7350789-A (allele frequency=0.36), mapping to hepatic lipase (LIPC), to be associated with a smaller increase in TG concentrations at 150 minutes (β=-0.11; P-value=5.1×10-8). Rs7350789-A was associated with responses of 33 metabolite measures (P-value <1.34×10-3), mainly smaller increases of the TG-component in almost all HDL (high-density lipoprotein) subparticles (HDL-TG), a smaller decrease of HDL diameter and smaller increases of most components of VLDL (very low density lipoprotein) subparticles. GWAS of the TG response identified a variant near LIPC as a main contributor to postprandial TG metabolism independent of fasting TG concentrations, resulting in smaller increases of HDL-TG and VLDL subparticles.

Percentile curves for the knee injury and osteoarthritis outcome score in the middle-aged Dutch population

To improve the interpretation of the Knee injury and Osteoarthritis Outcome Score (KOOS) in individual patients, we explored associations with age, sex, BMI, history of knee injury and presence of clinical knee osteoarthritis, and developed percentile curves. We used cross-sectional data of middle-aged individuals from the population-based Netherlands Epidemiology of Obesity (NEO) study. Clinical knee osteoarthritis was defined using the ACR classification criteria. KOOS scores were handled according to the manual (zero=extreme problems, 100=no problems). Patient characteristics associated with KOOS were explored using ordered logistic regression, and sex and body mass index (BMI)-specific percentile curves were developed using quantile regression with fractional polynomials. The curves were applied as a benchmark for comparison of KOOS scores of participants with knee osteoarthritis and comorbidities. The population consisted of 6,643 participants (56% women, mean (SD) age 56(6) years). Population-based KOOS subscale scores (median; interquartile range) near optimum: pain (100;94-100), symptoms (96;86-100), ADL function (100;96-100), sport/recreation function (100;80-100), quality of life (100;75-100). Worse KOOS scores were observed in women and in participants with higher BMI. Clinical knee osteoarthritis was defined in 15% of participants, and was, in comparison to other patient characteristics, associated with the highest odds of worse KOOS scores. Furthermore, presence of any comorbidity and cardiovascular disease specifically, was associated with worse KOOS scores, particularly in women. In the middle-aged Dutch population KOOS scores were generally good, but worse in women and with higher BMI. These percentile curves may be used as benchmarks in research and clinical practice.

Metabolomics analyses in non-diabetic middle-aged individuals reveal metabolites impacting early glucose disturbances and insulin sensitivity

IntroductionSeveral plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus.ObjectivesWe aimed to identify plasma metabolites associated with different indices of early disturbances in glucose metabolism and insulin sensitivity.MethodsThis cross-sectional study was conducted in a subsample of the Leiden Longevity Study comprising individuals without a history of diabetes mellitus (n = 233) with a mean age of 63.3 ± 6.7 years of which 48.1% were men. We tested for associations of fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and glycated hemoglobin with metabolites (Swedish Metabolomics Platform) using linear regression analysis adjusted for age, sex and BMI. Results were validated internally using an independent metabolomics platform (Biocrates platform) and replicated externally in the independent Netherlands Epidemiology of Obesity (NEO) study (Metabolon platform) (n = 545, mean age of 55.8 ± 6.0 years of which 48.6% were men). Moreover, in the NEO study, we replicated our analyses in individuals with diabetes mellitus (cases: n = 36; controls = 561).ResultsOut of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. These findings were validated using a different metabolomics platform as well as in an independent cohort of non-diabetics. Moreover, tyrosine, alanine, valine, tryptophan and alpha-ketoglutaric acid levels were higher in individuals with diabetes mellitus.ConclusionWe found several plasma metabolites that are associated with early disturbances in glucose metabolism and insulin sensitivity of which five were also higher in individuals with diabetes mellitus.

The association between leptin concentration and blood coagulation: Results from the NEO study

BackgroundThe adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study. MethodsWe performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat. ResultsIn multivariable adjusted analyses a 1 μg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses. DiscussionThis study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant.

Health-related Quality of Life in Patients with Hand Osteoarthritis from the General Population and the Outpatient Clinic.

To investigate the association of hand osteoarthritis (OA) and concurrent hand and knee OA with health-related quality of life (HRQOL) in the general population, and in patients consulting a rheumatology outpatient clinic. In the population-based Netherlands Epidemiology of Obesity (NEO) study, participants were recruited from the greater area of Leiden, the Netherlands. In the Hand OSTeoArthritis in Secondary care (HOSTAS) study, patients with a rheumatologist's diagnosis of hand OA were recruited from a Leiden-based hospital. In both cohorts, hand and knee OA were defined by the American College of Rheumatology clinical criteria. In NEO, self-reported hospital-based specialist consultation for OA was recorded. Physical and mental HRQOL was assessed with normalized Medical Outcomes Study Short Form-36 scores. Associations were analyzed using linear regression, adjusted for age, sex, education, ethnicity, and body mass index. Hand OA alone and concurrent hand and knee OA was present in 8% and 4% of 6334 NEO participants, and in 57% and 32% of 538 HOSTAS patients. In NEO, hand OA alone, and concurrent hand and knee OA, were associated with lower physical component summary (PCS) scores [mean difference -2.4 (95% CI -3.6, -1.3) and -7.7 (95% CI -9.3, -6.2), respectively] compared with no OA. Consulting a specialist was associated with worse PCS scores. In the HOSTAS cohort, mean PCS scores were lower than norm values (-3.5 and -7.9 for hand OA and combined OA, respectively). Mental HRQOL was not clinically relevantly associated in either cohort. Hand OA was associated with reduced physical, but not mental, HRQOL in the general population and hospital patients. Physical HRQOL was further reduced in hospital care, and with concurrent knee OA.

Glucose metabolism affects coagulation factors: The NEO study

BackgroundIt is insufficiently understood if there is an association between diabetes and VT, and what the underlying mechanism would be. ObjectivesWe aimed to study the association between glucose concentrations with several coagulation factors in the general population. MethodsThis is a cross‐sectional analysis of baseline measurements within 5778 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population‐based cohort study of individuals 45 to 65 years. Associations between fasting glucose and HbA1c concentrations, and postprandial glucose response and factor (F) VIII, FIX, FXI, and fibrinogen levels were examined using linear regression analyses and by calculating mean levels per category of glucose concentrations while adjusting for confounding factors. ResultsPer each mmol/L higher fasting glucose concentration we observed higher levels of fasting FVIII (5.33%, 95% CI: 4.00‐6.65), FIX (6.19%, 95% CI: 5.15‐7.23), and FXI (2.11%, 95% CI: 1.20‐3.02). Results for fasting HbA1c and postprandial glucose response were similar. Participants with an impaired fasting glucose, high fasting glucose, and diabetes mellitus had higher mean levels of FVIII, FIX, and FXI than those with a normal glucose metabolism, with the highest differences in the levels of FVIII, FIX, and FXI between a high fasting glucose and a normal glucose metabolism. All associations attenuated after adjustment for total body fat, yet all of the above associations remained after adjustment for the confounding factors, except for fibrinogen when contrasted to glucose. ConclusionConcentrations of fasting glucose and HbA1c and postprandial glucose response were positively associated with FVIII, FIX, and FXI, and to some extent also with fibrinogen.

Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study.

Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10-8) and was also replicated successfully (β: -7.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.

The association between overall and abdominal adiposity and depressive mood: A cross-sectional analysis in 6459 participants

ObjectiveWe aimed to evaluate the association between measures of adiposity with depressive mood and specific depressive symptoms. MethodsThis study was performed in the Netherlands Epidemiology of Obesity (NEO) study, a population-based study that consists of 6671 middle-aged individuals. We examined the association between measures of overall adiposity (BMI and total body fat), and abdominal adiposity (waist circumference and visceral adipose tissue), with depressive mood severity subgroups and 30 depressive symptoms. Multinomial logistic regression was performed adjusting for potential confounding. ResultsMeasures of adiposity were associated with depressive mood in a graded fashion. Total body fat showed the strongest association with mild (Odds Ratio (OR): 1.59 per standard deviation, 95% Confidence Interval (95% CI): 1.41–1.80) and moderate to very severe (OR: 1.97, 95% CI: 1.59–2.44) depressive mood. Regarding individual symptoms of depressive mood, total body fat was associated with most depressive symptoms (strongest associations for hyperphagia and fatigability). ConclusionsIn the general population, overall and abdominal adiposity measures were associated with depressive mood. This association encompasses most of the depressive symptoms and appeared to be the strongest with specific ‘’atypical’’ neurovegetative symptoms, which may be an indication of an alteration in the energy homeostasis.