ORCID Profile
0000-0002-2989-1631
Current Organisations
Maastricht University
,
Utrecht University
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Publisher: Wiley
Date: 06-05-2009
DOI: 10.1111/J.1365-2362.2009.02129.X
Abstract: Low-grade inflammation has been hypothesized to underlie the coronary artery disease (CAD) risk associated with the metabolic syndrome, but the evidence is not conclusive. For peripheral arterial disease (PAD as measured by the ankle-arm index), this association has not been studied before. The aim was to study whether the association between the metabolic syndrome and CAD or the severity of PAD can be explained by low-grade inflammation. The Cohort study Diabetes and Atherosclerosis Maastricht population includes 574 subjects, with an increased risk of type 2 diabetes, of whom 560 were included in the analyses (343 males age: 59.5 +/- 7.0 years). The inflammation markers that were measured were C-reactive protein, interleukin 6, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and serum amyloid A. All analyses were adjusted for age, sex and smoking. Logistic regression showed that the metabolic syndrome was significantly associated with CAD [odds ratio (OR) = 1.86, 95% CI: 1.21 2.84, P = 0.004]. Further adjustment for inflammatory status, as captured in a combination of the inflammation markers (using an averaged Z-score), resulted in significant associations of both the metabolic syndrome and inflammatory status with CAD [OR(metabolic syndrome) (95% CI) = 1.58 (1.01 2.46), P = 0.044 OR(inflammation) (95% CI) = 1.59 (1.14 2.21), P = 0.007]. Linear regression analysis showed similar results for the ankle-arm index. The association between the metabolic syndrome, on the one hand, and prevalence of CAD or the severity of PAD, on the other, can be partly but not completely, 26% and 29% respectively, explained by low-grade inflammation.
Publisher: The Endocrine Society
Date: 03-2013
DOI: 10.1210/JC.2012-3442
Abstract: The BclI polymorphism in the glucocorticoid receptor (GR) gene is associated with enhanced glucocorticoid (GC) sensitivity. Our objective was to investigate the association of the BclI polymorphism with body fatness and insulin resistance. We conducted an observational cohort study, combining data from 2 cohort studies enriched with in iduals with impaired glucose metabolism and/or diabetes mellitus type 2 (DM2). 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). 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: β = 0.94 kg/m(2) (95% confidence interval, 0.24-1.63), β = 2.84 cm (0.95 .73) and β = 2.38 cm (0.88-3.87), respectively. Similar results were obtained when comparing homozygous carriers with heterozygous carriers: β = 1.03 kg/m(2) (0.34-1.72), β = 2.20 cm (0.31-4.08) and β = 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 [β = 0.09 (0.01-0.17)], but this effect was attenuated after adjustment for BMI [β = 0.04 (-0.04 to 0.11)]. 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.
Publisher: Elsevier BV
Date: 03-2015
Abstract: A healthy diet rich in fish, fruit, and vegetables, but moderate in alcohol and low in dairy products and meat, has been associated with a lower rate of incident cardiovascular disease (CVD). The underlying mechanisms, however, remain unclear. Endothelial dysfunction and low-grade inflammation play important roles in CVD. A healthy diet might modify these phenomena. We investigated the associations between the above food groups and overall biomarker scores of endothelial dysfunction and low-grade inflammation in a 7-y longitudinal study. Using longitudinal data from 557 participants at increased CVD risk from the CODAM (Cohort on Diabetes and Atherosclerosis Maastricht) Study, we assessed diet intake by food-frequency questionnaire and measured plasma biomarkers of endothelial dysfunction [von Willebrand factor, soluble vascular cell adhesion molecule 1, soluble endothelial selectin, soluble thrombomodulin, soluble intercellular adhesion molecule 1 (sICAM-1)] and low-grade inflammation [C-reactive protein, serum amyloid A, interleukin (IL)-6, IL-8, tumor necrosis factor α, and sICAM-1]. At baseline, participants were aged 59.6 ± 6.9 y. Measurements were performed then and after 7 y. Biomarkers were combined into overall scores (sum of z scores higher scores indicating worse function). Longitudinal data were analyzed with generalized estimating equations and adjusted for sex, age, glucose metabolism, energy intake, body mass index, physical activity, alcohol consumption, and smoking. Higher consumption of fish (per 100 g/wk), but not total consumption of vegetables, fruit, alcohol-containing beverages, dairy products, or meat, was associated with a lower overall endothelial dysfunction score over 7 y (β: -0.027 95% CI: -0.051, -0.004). No associations were observed with the overall low-grade inflammation score. Further food component analyses indicated that consumption of more lean fish (per 100 g/wk) and raw vegetables (per 100 g/d), and fewer high-fat dairy products (per 100 g/d) was associated with less endothelial dysfunction [(β: -0.038 95% CI: -0.072, -0.005), (β: -0.095 95% CI: -0.191, 0.000), and (β: -0.070 95% CI: -0.131, -0.009), respectively]. Consumption of more fresh fruit (per 100 g/d), wine (per 100 mL/wk), and poultry (per 100 g/d), and fewer high-fat dairy products (per 100 g/d) was associated with less low-grade inflammation [(β: -0.074 95% CI: -0.133, -0.015), (β:-0.006 95% CI: -0.013, 0.001), (β:-0.247 95% CI: -0.479, -0.014), and (β:-0.100 95% CI: -0.182, -0.019), respectively]. These data suggest that the dietary modification of endothelial dysfunction and low-grade inflammation, processes that are important in atherothrombosis, is possible.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.ATHEROSCLEROSIS.2011.03.023
Abstract: Type 2 diabetes mellitus (T2DM) is associated with elevated plasma apolipoprotein B and triglycerides levels, reduced HDL cholesterol and the presence of small-dense LDL particles. The present study was conducted to investigate the role of plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels, a regulator of LDL-receptor expression, in the occurrence of diabetic dyslipidemia. Plasma PCSK9 was measured in a cohort of subjects with normal glucose metabolism (NGM n=288), impaired glucose metabolism (IGM n=121) and type 2 diabetes mellitus (T2DM n=139) to study whether its relation with plasma apolipoprotein B, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol and HDL cholesterol differed by levels of glucose metabolism status. Plasma PCSK9 levels were not different between the three groups (82, 82 and 80 ng/mL in NGM, IGM and T2DM, respectively). PCSK9 was positively associated with total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B and triglycerides levels in all subgroups. The regression slopes for the associations with non-HDL cholesterol were steeper among in iduals with T2DM than with NGM (β = 0.016 versus β=0.009, p-interaction=0.05). Similar results were obtained for the relation with apolipoprotein B (β = 0.004 versus β = 0.002, p-interaction=0.09). Although glucose metabolism status per se is not associated with plasma PCSK9 levels, the presence of T2DM may modify the relation between plasma PCSK9 and non-HDL cholesterol and apolipoprotein B. These observations should be regarded as hypothesis generating for further studies aimed at elucidating the role of PCSK9 in the pathogenesis and treatment of diabetic dyslipidemia.
Publisher: Wiley
Date: 16-04-2013
DOI: 10.1111/ECI.12093
Abstract: The complement system may be involved in the pathogenesis of alcoholic and nonalcoholic liver disease, although studies in humans are scarce. For this reason, we investigated whether circulating levels of activated complement factor 3 (C3a) were associated with hepatic steatosis and hepatocellular damage. Plasma C3a, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were determined in 523 in iduals (61% men, age 59 ± 7 years). Liver enzymes (LEs) were standardized and compiled into a LE score. Liver fat content was estimated using a predictive equation that has recently been validated with magnetic resonance spectrometry. Cross-sectional associations between C3a and liver fat or LE s were investigated with multiple linear regression analyses, stratified in no-to-moderate vs. heavy alcohol consumers (men: > 30 g/day women: > 20 g/day). C3a was associated with liver fat percentage both in the no-to-moderate (β = 0.223 95%CI 0.036 0.409) and in the heavy alcohol consumers (β = 0.632 95%CI 0.259-1.004 P-interaction = 0.047). C3a was also associated with the LE score in heavy alcohol consumers (β = 0.917 95%CI 0.443-1.392), but not in no-to-moderate alcohol consumers (β = 0.042 95%CI -0.198 to 0.281 P-interaction = 0.001). C3a levels, as a marker of complement activation, were associated with liver fat content and hepatocellular injury, at least in subjects who consume considerable amounts of alcohol daily.
Publisher: American Diabetes Association
Date: 12-06-2014
DOI: 10.2337/DC13-2804
Abstract: Immune dysregulation can affect insulin resistance (IR) and β-cell function and hence contribute to development of type 2 diabetes mellitus (T2DM). The complement system, as a regulator of immune and inflammatory homeostasis, may be a relevant contributor therein. However, longitudinal studies focusing on complement as a determinant of T2DM and IR are scarce. Therefore, we prospectively investigated the association of plasma complement factor 3 (C3) with (estimates of) IR in muscle, liver, and adipocytes, as well as with glucose tolerance, including incident T2DM. Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) were measured at baseline (n = 545) and after 7 years of follow-up (n = 394) in a prospective cohort study. Over the 7-year period, C3 levels (per 0.1 g/L) were longitudinally associated with higher homeostasis model assessment of IR (HOMA2-IR β = 15.2% [95% CI 12.9–17.6]), hepatic IR (β = 6.1% [95% CI 4.7–7.4]), adipocyte IR (β = 16.0% [95% CI 13.0–19.1]), fasting glucose (β = 1.8% [95% CI 1.2–2.4]), 2-h glucose (β = 5.2% [95% CI 3.7–6.7]), and area under the curve for glucose (β = 3.6% [95% CI 2.7–4.6]). In addition, greater changes in C3 (per 0.1 g/L) were associated with greater changes in HOMA2-IR (β = 0.08 [95% CI 0.02–0.15]) and greater changes in hepatic IR (β = 0.87 [95% CI 0.12–1.61]) over 7 years, but not glucose tolerance. Moreover, baseline C3 was associated with the 7-year incidence of T2DM (odds ratio 1.5 [95% CI 1.1–2.0]). Changes in C3 were associated with changes in several measures of IR and may reflect progression of metabolic dysregulation, which eventually leads to abnormalities in glucose tolerance and T2DM.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-02-2022
DOI: 10.1126/SCITRANSLMED.ABJ0264
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 s les passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
Publisher: Wiley
Date: 08-2011
DOI: 10.1038/OBY.2010.337
Abstract: Abdominal fat-related activation of the innate immune system and insulin resistance (IR) are implicated in the pathogenesis of cardiovascular diseases. Recent data support an important role of the adaptive immune system as well. In this study, we investigate the association between waist circumference and markers of systemic adaptive immune activation, and the potential mediating role of innate immune activation and/or IR herein. The study population consisted of 477 (304 men) in iduals (mean age: 59.4 ± 7.0 years) in whom waist circumference, HOMA2-IR (IR derived from homeostasis model assessment), and markers of innate (C-reactive protein (CRP), interleukin (IL)-6, serum amyloid A (SAA)) and adaptive (neopterin, soluble CD25 (sCD25)) immune activation were measured. These markers were compiled into an adaptive and innate immune activation score by averaging the respective z-scores. After adjustments for age, sex, glucose metabolism, smoking status, prior cardiovascular disease, and other risk factors, waist circumference was associated with the adaptive (standardized regression coefficient β = 0.12 (95% confidence intervals: 0.04-0.20)) and the innate immune activation scores (β = 0.24 (0.17-0.31)), and with HOMA2-IR (β = 0.49 (0.42-0.56)). The innate immune activation score and HOMA2-IR were also positively associated with the adaptive immune activation score (β = 0.31 (0.21-0.40) and β = 0.11 (0.02-0.21), respectively). The association between waist circumference and the adaptive immune activation score was completely abolished when further adjusted for innate immune activation and HOMA2-IR (to β = -0.01 (-0.10-0.08)), and the specific mediation "effects" attributable to each of these variables were 58% and 42%, respectively. We conclude that abdominal obesity is associated with systemic adaptive immune activation and that innate immune activation and IR constitute independent and equally important pathways explaining this association.
Publisher: Wiley
Date: 09-12-2011
Publisher: Elsevier BV
Date: 12-2013
Abstract: Diet may be associated with the development of type 2 diabetes through its effects on low-grade inflammation. We investigated whether an adapted dietary inflammatory index (ADII) is associated with a summary score for low-grade inflammation and markers of glucose metabolism. In addition, we investigated the mediating role of inflammation in the association between ADII and markers of glucose metabolism. We performed cross-sectional analyses of 2 Dutch cohort studies (n= 1024). An ADII was obtained by multiplying standardized energy-adjusted intakes of dietary components by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Subsequently, these multiplications were summed. Six biomarkers of inflammation were compiled in a summary score. Associations of the ADII (expressed per SD) with the summary score for inflammation and markers of glucose metabolism were investigated by using multiple linear regression models. Inflammation was considered a potential mediator in the analysis with markers of glucose metabolism. A higher ADII was associated with a higher summary score for inflammation [β-adjusted = 0.04 per SD (95% CI: 0.01, 0.07 per SD)]. The ADII was also adversely associated with insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR): β-adjusted = 3.5% per SD (95% CI: 0.6%, 6.3% per SD)]. This association was attenuated after the inclusion of the summary score for inflammation [β-adjusted+inflammation = 2.2% (95% CI: -0.6%, 5.0%)]. The ADII was also adversely associated with fasting glucose and postload glucose but not with glycated hemoglobin. The significant mediating role of low-grade inflammation in the association between the ADII and HOMA-IR suggests that inflammation might be one of the pathways through which diet affects insulin resistance.
Publisher: American Diabetes Association
Date: 17-01-2013
DOI: 10.2337/DC12-0505
Abstract: Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism–related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin. Serum ferritin, transferrin, total iron, non–transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 in iduals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers. Serum ferritin (β = 1.00% increase in adipocyte IR per 10 μg/L [95% CI 0.66–1.34]), transferrin (4.18% per 0.1 g/L [2.88–5.50]), total iron (1.36% per μmol/L [0.61–2.12]), and NTBI (5.14% per μmol/L [1.88–8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P & 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P & 0.01). The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM.
Publisher: The Endocrine Society
Date: 12-2009
DOI: 10.1210/JC.2009-1067
Abstract: The receptor for advanced glycation end products (RAGE)-ligand interaction has been linked to vascular complications. The family of soluble forms of RAGE (sRAGE) consists of splice variants and proteolytically cleaved and shed forms of RAGE. sRAGE may be a reflection of cell-bound RAGE. Because genetic variation in the RAGE gene may be associated with in idual differences in sRAGE concentration and outcome, we investigated whether RAGE single-nucleotide polymorphisms (SNPs) were associated with circulating levels of sRAGE. Nine SNPs, covering the common RAGE gene variation, were genotyped in a Dutch cohort of subjects with normal glucose metabolism (n = 301), impaired glucose metabolism (n = 127), and type 2 diabetes mellitus (n = 146). We used linear regression analyses adjusted for age, sex, and glucose metabolism status to compare sRAGE levels across genotypes. SNP rs2060700 (Gly82Ser) showed an association with sRAGE levels. Specifically, after adjustments for age, sex, and glucose metabolism, subjects with CT genotype had -527 pg/ml (95% confidence interval -724 to -330, P < 0.001) lower sRAGE levels compared with the CC genotype (age, sex, and glucose metabolism adjusted mean +/- SE values of 836 +/- 99 and 1369 +/- 26 pg/ml, respectively, P < 0.001). These results were confirmed in a subs le of a second cohort study of subjects with CT (n = 37) and CC genotype (n = 37). Immunoblotting using antibodies against amino acids 39-55 and 100-116 of RAGE also showed a similar decrease of sRAGE levels in the CT genotypes. No other SNPs showed an association with sRAGE levels. In addition, no associations between SNPs and the advanced glycation end products N(epsilon)-(carboxymethyl)lysine and N(epsilon)-(carboxyethyl)lysine were found. The CC genotype of SNP rs2070600 (Gly82Ser) was strongly associated with higher sRAGE levels in a Dutch population. The mechanism by which Gly82Ser polymorphism alters the sRAGE levels remains to be elucidated.
Publisher: Elsevier BV
Date: 2014
Abstract: Complement factor 3 (C3) has been identified as a novel risk factor for obesity-associated cardiometabolic diseases. Data in the literature suggest that C3 concentrations may be influenced by diet. Therefore, we investigated the associations of intake of total fat, specific fatty acids, and fat-soluble vitamin E (and in idual tocopherols) and vitamin A (and its dietary precursors) with circulating C3. In a white cohort [Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) n = 501 59.4 ± 7.1 y 61% men], associations of habitual nutrient intake (assessed by a food-frequency questionnaire) with circulating C3 were evaluated by using cross-sectional multiple linear regression analyses. Adjustments were first performed for age, sex, glucose metabolism status (i.e., impaired glucose metabolism or type 2 diabetes), and energy intake and subsequently for BMI, waist circumference, alcohol intake, smoking behavior, and season of blood collection. No associations with C3 were observed for total dietary fat intake or intake of specific fatty acids [saturated, monounsaturated, polyunsaturated, n-6 (ω-6), and n-3 (ω- 3) fatty acids], vitamin E, or in idual tocopherols. We observed an inverse association with intake of provitamin A carotenoids α-carotene (in μg/d regression coefficient β = -0.075 95% CI: -0.140, -0.010 P = 0.025) and β-carotene (in μg/d β = -0.021 95% CI: -0.044, 0.002 P = 0.068) with C3 (in mg/L). In contrast, and only in women, dietary retinol intake (in μg/d) was positively associated with C3 (β = 0.116 95% CI: 0.014, 0.218 P = 0.026 n = 196). In conclusion, these data suggest that fasting concentrations of C3 may, in a complex manner, be modifiable by variation in dietary provitamin A carotenoids and/or retinol content of the usual diet but most likely not by variations in fat composition and vitamin E content.
Publisher: Elsevier BV
Date: 12-2018
Publisher: BMJ
Date: 11-2019
DOI: 10.1136/BMJDRC-2019-000787
Abstract: To investigate whether adverse differences in levels of cardiovascular risk factors in women than men, already established when comparing in iduals with and without diabetes, are also present before type 2 diabetes onset. In a population-based cohort study of in iduals aged 40-75 years (n=3410 49% women, 29% type 2 diabetes (overs led by design)), we estimated associations with cardiometabolic and lifestyle risk factors of (1) pre-diabetes and type 2 diabetes (reference category: normal glucose metabolism) and (2) among non-diabetic in iduals, of continuous levels of hemoglobin A1c (HbA1c). Age-adjusted sex differences were analyzed using linear and logistic regression models with sex interaction terms. In pre-diabetes, adverse differences in cardiometabolic risk factors were greater in women than men for systolic blood pressure (difference, 3.02 mm Hg 95% CI:−0.26 to 6.30), high-density lipoprotein (HDL) cholesterol (difference, −0.10 mmol/L 95% CI: −0.18 to −0.02), total-to-HDL cholesterol ratio (difference, 0.22 95% CI: −0.01 to 0.44), triglycerides (ratio: 1.11 95% CI: 1.01 to 1.22), and inflammation markers Z-score (ratio: 1.18 95% CI: 0.98 to 1.41). In type 2 diabetes, these sex differences were similar in direction, and of greater magnitude. Additionally, HbA1c among non-diabetic in iduals was more strongly associated with several cardiometabolic risk factors in women than men: per one per cent point increase, systolic blood pressure (difference, 3.58 mm Hg 95% CI: −0.03 to 7.19), diastolic blood pressure (difference, 2.10 mm Hg 95% CI: −0.02 to 4.23), HDL cholesterol (difference, −0.09 mmol/L 95% CI: −0.19 to 0.00), and low-density lipoprotein cholesterol (difference, 0.26 mmol/L 95% CI: 0.05 to 0.47). With regard to lifestyle risk factors, no consistent pattern was observed. Our results are consistent with the concept that the more adverse changes in cardiometabolic risk factors in women (than men) arise as a continuous process before the onset of type 2 diabetes.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.METABOL.2012.05.015
Abstract: To investigate the role of low-grade inflammation and insulin resistance (HOMA2-IR) in adiposity-related increases in serum complement factor 3 (C3). Although C3 has been linked to type 2 diabetes and cardiovascular diseases, and C3 levels are closely related to body fat, the underlying mechanisms explaining this association are still unknown. Adiposity measures (including BMI, waist circumference (WC), sagittal diameter and several skinfolds), HOMA2-IR and markers of inflammation (hs-CRP, IL-6, SAA, haptoglobin, ceruloplasmin, sICAM-1) were determined in 532 in iduals (62% men, mean age 59±6.9 yrs) from the Cohort on Diabetes and Atherosclerosis Maastricht study. Markers of inflammation were standardized and compiled into an averaged inflammation score. Cross-sectional associations between adiposity measures and C3 and the mediating role of low-grade inflammation and/or HOMA2-IR herein were analysed with multiple linear regression models. Adiposity measurements were significantly associated with C3 levels, with the strongest (adjusted) associations found for WC (β=0.383 95%CI 0.302-0.464) and sagittal diameter (β=0.412 95%CI 0.333-0.490). Further adjustment for inflammation and HOMA2-IR attenuated these associations to β=0.115 (95%CI 0.030-0.200) and β=0.163 (95%CI 0.082-0.244) respectively. Multiple mediation analyses showed that inflammation [β=0.090 (95%CI 0.060-0.126)] and HOMA2-IR [β=0.179 (95%CI 0.128-0.236)] each explained, independently of one another, a significant portion of the association between WC and C3 (23% and 47%, respectively). Similar mediation by inflammation (19-27%) and HOMA2-IR (37-56%) was found for other adiposity measures. Systemic low-grade inflammation and insulin resistance may represent two independent pathways by which body fat leads to elevated C3 levels.
Publisher: Oxford University Press (OUP)
Date: 10-06-2014
DOI: 10.1093/RHEUMATOLOGY/KEU239
Abstract: The aims of this study were to investigate (i) associations between uric acid and prevalent cardiovascular disease (CVD), ankle-arm blood pressure index (AAIx) and carotid intima-media thickness (CIMT) in the total population and in predefined subgroups according to glucose metabolism status and (ii) the extent to which these associations are explained by low-grade inflammation. Cross-sectional analyses were conducted among 530 in iduals [60.6% men, mean age 58.9 years (s.d. 6.9), 52.6% normal glucose metabolism (NGM)] at increased risk of CVD from the Cohort of Diabetes and Atherosclerosis Maastricht study. A low-grade inflammation score was computed by averaging the z-scores of eight inflammation markers [CRP, TNF-α, IL-6, IL-8, serum amyloid A, intercellular adhesion molecule 1 (ICAM-1), ceruloplasmin and haptoglobin]. After adjustment for traditional CVD risk factors, plasma uric acid (per s.d. of 81 μmol/l) was associated with CVD in in iduals with NGM [odds ratio (OR) = 1.66, 95% CI 1.06, 2.58] but not with disturbed glucose metabolism (DGM) (OR = 0.81, 95% CI 0.55, 1.19, P interaction = 0.165). Uric acid was associated with CIMT in the total population (β = 0.024, 95% CI 0.007, 0.042) and slightly more strongly in in iduals with NGM (β = 0.030, 95% CI 0.006, 0.054) than DGM (β = 0.018, 95% CI -0.009, 0.044, P interaction = 0.443). There was no association between uric acid and AAIx in any group (P interaction = 0.058). Uric acid was associated with low-grade inflammation in the total population (β = 0.074, 95% CI 0.013, 0.134, P interaction = 0.737). Adding low-grade inflammation to the models did not attenuate any of the associations. The associations for uric acid with CIMT, and with CVD in NGM only, were not explained by low-grade inflammation. A difference in the strength of the associations between in iduals with NGM and DGM was suggested.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
DOI: 10.1161/ATVBAHA.115.306106
Abstract: Adipose tissue inflammation contributes to the development of complications, such as insulin resistance and type 2 diabetes mellitus. We previously reported that plasma levels of N ε -(carboxymethyl)lysine (CML) were decreased in obese subjects resulting from CML accumulation in adipose tissue and that this CML accumulation plays an important role in adipose tissue inflammation. The objective of this study is to investigate associations between obesity (body mass index, waist circumference, and trunk fat mass), plasma CML (as an inversely correlated marker of CML accumulation in adipose tissue), and low-grade inflammation (LGI) in a large s le of in iduals whose weight status ranged from normal to morbid obesity. We studied 1270 in iduals of the Cohort on Diabetes and Atherosclerosis Maastricht Study and Hoorn Study, in whom protein-bound CML levels were measured by UPLC-Tandem MS (ultra performance liquid chromatography-tandem mass spectrometry), and 6 inflammatory markers were measured with multiarrays. These inflammatory markers were compiled into an LGI score. Multiple linear regression, adjusted for covariates, showed that (1) waist circumference was inversely associated with protein-bound CML plasma levels (standardized regression coefficient [β]=−0.357 [95% confidence interval: −0.414 −0.301]) (2) protein-bound CML was inversely associated with LGI score (β=−0.073 [−0.130 -0.015]) and (3) the association between waist circumference and LGI (β=0.262 [0.203 .321]) was attenuated after adjustment for protein-bound CML plasma levels and other potential mediators (to β=0.202 [0.138 .266]), with CML explaining the greatest portion of the attenuation (≈12%). Further analysis with dual-energy X-ray absorptiometry measures of body composition confirmed a strong inverse association of fat mass preferentially accumulated in the trunk with protein-bound CML plasma levels, significantly explaining ≈21% of the trunk fat–LGI association. Obesity, in particular central obesity, is characterized by greater levels of LGI but by lower levels of circulating CML the latter significantly explaining a portion of the positive association between central obesity and inflammation.
Publisher: Oxford University Press (OUP)
Date: 27-11-2012
Abstract: Common carotid artery intima-media thickness (CCIMT) is widely used as a surrogate marker of atherosclerosis, given its predictive association with cardiovascular disease (CVD). The interpretation of CCIMT values has been h ered by the absence of reference values, however. We therefore aimed to establish reference intervals of CCIMT, obtained using the probably most accurate method at present (i.e. echotracking), to help interpretation of these measures. We combined CCIMT data obtained by echotracking on 24 871 in iduals (53% men age range 15-101 years) from 24 research centres worldwide. In iduals without CVD, cardiovascular risk factors (CV-RFs), and BP-, lipid-, and/or glucose-lowering medication constituted a healthy sub-population (n = 4234) used to establish sex-specific equations for percentiles of CCIMT across age. With these equations, we generated CCIMT Z-scores in different reference sub-populations, thereby allowing for a standardized comparison between observed and predicted ('normal') values from in iduals of the same age and sex. In the sub-population without CVD and treatment (n = 14 609), and in men and women, respectively, CCIMT Z-scores were independently associated with systolic blood pressure [standardized βs 0.19 (95% CI: 0.16-0.22) and 0.18 (0.15-0.21)], smoking [0.25 (0.19-0.31) and 0.11 (0.04-0.18)], diabetes [0.19 (0.05-0.33) and 0.19 (0.02-0.36)], total-to-HDL cholesterol ratio [0.07 (0.04-0.10) and 0.05 (0.02-0.09)], and body mass index [0.14 (0.12-0.17) and 0.07 (0.04-0.10)]. We estimated age- and sex-specific percentiles of CCIMT in a healthy population and assessed the association of CV-RFs with CCIMT Z-scores, which enables comparison of IMT values for (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures obtained both in research and clinical settings.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2013
Publisher: Public Library of Science (PLoS)
Date: 30-10-2017
Publisher: Wiley
Date: 08-10-2010
DOI: 10.1111/J.1365-2362.2010.02392.X
Abstract: The metabolic syndrome is associated with coronary artery disease (CAD) and with peripheral artery disease (PAD), but the underlying mechanisms explaining these associations have not yet been completely clarified. The aim was to investigate (i) whether endothelial dysfunction can explain the association between the metabolic syndrome and CAD and/or the severity of PAD, as measured by the ankle-arm index (AAIx) and (ii) whether any such mediation is independent of that from low-grade inflammation. We studied 539 subjects (232 men) aged 59·4 ± 6·9 years, with an increased risk of type 2 diabetes and cardiovascular diseases. Endothelial dysfunction and inflammation scores were calculated from three markers of endothelial dysfunction (soluble E-selectin, soluble vascular cell adhesion molecule-1 and von Willebrand factor) and six of inflammation (C-reactive protein, interleukin 6, soluble intercellular adhesion molecule-1, serum amyloid A, ceruloplasmin and haptoglobin). The association between the metabolic syndrome and CAD and/or PAD, and the mediating role of endothelial dysfunction herein was examined with logistic and linear regression analyses, all adjusted for age, sex and smoking. Subjects with the metabolic syndrome (n = 289 54%) had higher prevalence of CAD [OR (95%CI) = 1·75 (1·14 2·69)] and lower AAIx [β (95% CI) = -0·036 (-0·056 -0·016)]. Endothelial dysfunction explained 6% of the association between the metabolic syndrome and CAD, and 19% of the association with AAIx, whereas low-grade inflammation explained 26% and 28% of these associations, respectively. Together, the two scores explained 24% and 36% of the association between the metabolic syndrome and CAD and AAIx, respectively. Endothelial dysfunction explains part of the association between the metabolic syndrome and the severity of PAD, but is not involved in the association between the metabolic syndrome and CAD. This indicates that the pathophysiologies of coronary and peripheral artery disease are essentially distinct.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2010
Publisher: Springer Science and Business Media LLC
Date: 10-2014
DOI: 10.1007/S00592-014-0646-3
Abstract: Several markers of iron metabolism have been associated with insulin resistance (IR) and type 2 diabetes mellitus in cross-sectional studies. However, prospective data on these associations are scarce, and it is currently unclear in which tissues iron metabolism may contribute to IR. Therefore, we investigated whether markers of iron metabolism were associated with IR in muscle, liver, and adipocytes, and with glucose intolerance over a 7-year follow-up period. Serum ferritin, transferrin, total iron, non-transferrin-bound iron, and transferrin saturation were determined at baseline of a prospective cohort study in 509 in iduals (60 % men, age 59 ± 6.9 years, body mass index 28.5 ± 4.3). Both at baseline and after a 7-year follow-up (n = 386), measures of glucose, insulin (during glucose tolerance tests), and non-esterified fatty acids were obtained. Using generalized estimating equations, we investigated associations between baseline iron markers and indices of muscle, liver, and adipocyte insulin resistance (adipocyte IR), as well as glucose intolerance, over the 7-year period. Over a 7-year period, baseline serum ferritin (per 10 μg/L increase) was positively associated with homeostasis model assessment insulin resistance (HOMA2-IR) [β = 0.77 % (95 % CI 0.50-1.03)], hepatic insulin resistance (hepatic IR) [β = 0.39 % (0.23-0.55)], adipocyte IR [β = 1.00 % (0.65-1.35)], and AUCglucose [β = 0.32 % (0.18-0.46)] after adjustment for several covariates, including inflammatory markers (all p < 0.001). Similarly, serum transferrin (per 0.1 g/L) was associated with HOMA2-IR [β = 2.66 % (1.55-3.78)], hepatic IR [β = 1.16 % (0.47-1.85)], adipocyte IR [β = 3.75 % (2.27-5.25)], and AUCglucose [β = 1.35 % (0.74-1.96)] over 7 years. Iron metabolism and related factors may contribute to IR in muscle, liver, and adipocytes, eventually leading to impaired glucose metabolism and hyperglycaemia.
Publisher: Elsevier BV
Date: 12-2017
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.METABOL.2010.09.006
Abstract: The metabolic syndrome is associated with nonalcoholic fatty liver disease (NAFLD) as well as with insulin resistance, inflammatory adipokines, endothelial dysfunction, and higher plasma levels of nonesterified fatty acids (NEFA), all of which may also affect the development of NAFLD. Therefore, we investigated to what extent the association between the metabolic syndrome and alanine aminotransferase (ALT, as a surrogate of NAFLD) can be explained by different metabolic intermediates of the metabolic syndrome. Cross-sectional analyses were performed in 434 subjects from the Cohort on Diabetes and Atherosclerosis Maastricht study (264 men mean age, 59.5 ± 7.1 years). We used multiple linear regression analyses to investigate the association between the metabolic syndrome and ALT and the mediation role of potential mediators herein. The mediators considered were insulin resistance (homeostasis model assessment), an inflammatory adipokine score (based on interleukin-6, serum amyloid A, intercellular adhesion molecule, adiponectin, and leptin), an endothelial dysfunction score (based on E-selectin, vascular cell adhesion molecule, and von Willebrand factor), and plasma levels of NEFA. All analyses were adjusted for age, sex, smoking, alcohol consumption, and use of medication. Subjects with the metabolic syndrome (53.7%) had significantly higher levels of ALT (β = 0.67 SD [95% confidence interval, 0.49-0.85], P < .001). Adjustment for insulin resistance attenuated this difference by 77.3% (to 0.15 SD [-0.04 to 0.35]). Attenuation by adipose tissue-associated inflammation, endothelial dysfunction, and NEFA was more modest (20.7%, 13.1%, and 9.5%, respectively). Part of the attenuation by NEFA, but not of the other mediators, was additional to that of insulin resistance. Insulin resistance constitutes a key pathophysiological mechanism in the association between the metabolic syndrome and NAFLD (measured as ALT), which may operate through adipose tissue-associated inflammation and endothelial dysfunction and to a lesser extent through NEFA, which may have an independent role in the development of NAFLD in subjects with the metabolic syndrome.
Publisher: The Endocrine Society
Date: 08-2013
DOI: 10.1210/JC.2013-1068
Abstract: Experimental and histological data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, the epidemiological evidence of an adverse association between AGEs and CVD remains inconclusive. We therefore investigated, in in iduals with various degrees of glucose metabolism, the associations of plasma AGEs with prevalent CVD. We measured plasma levels of protein-bound N(ε)-(carboxymethyl)lysine (CML), N(ε)-(carboxyethyl)lysine (CEL), and pentosidine, in participants from two Dutch cohort studies (n = 1291, mean age 64.7 ± 8.3 years, 45% women), including 573 in iduals with normal glucose metabolism, 304 with impaired glucose metabolism, and 414 with T2DM. In addition, we measured free CML, CEL, and 5-hydro-5-methylimidazolone in a subset of participants (n = 554). Data were analyzed with multiple logistic or linear regression analyses. CEL (32 [interquartile range: 25-40] vs 28 [22-35] nmol/mmol lysine) and pentosidine (0.53 [0.43-0.67] vs 0.48 [0.40-0.59] nmol/mmol lysine) as well as free CEL (48 [39-62] vs 45 [36-56] nmol/L) and 5-hydro-5-methylimidazolone (141 [96-209] vs 116 [84-165] nmol/L) were higher in in iduals with vs without CVD, whereas protein-bound CML was lower (33 [27-38] vs 34 [29-39] nmol/mmol lysine). However, these differences disappeared after adjustment for confounders. The associations did not differ consistently between in iduals with and without T2DM. We found no independent adverse associations of plasma AGEs with CVD in in iduals with normal glucose metabolism, impaired glucose metabolism, and T2DM.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2018
Publisher: Wiley
Date: 26-11-2010
DOI: 10.1111/J.1365-2362.2010.02418.X
Abstract: Complement C3, a central component of the innate immune system is increased in subjects with obesity and type 2 diabetes and is a novel risk factor for cardiovascular disease. We hypothesized that the strong association between insulin resistance and circulating amounts of C3 may be related to hepatic fat accumulation -independent of central obesity itself and of a general low-grade inflammatory response. To what extent is the association between insulin resistance and C3 explained by plasma levels of alanine aminotransferase (ALT) as a surrogate of hepatic fat accumulation. Cross-sectional analyses conducted in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Analyses were restricted to subjects with none-to-moderate alcohol consumption (n = 453, 61·4% men). Multiple linear regression analyses were used to investigate the association between HOMA2IR (main determinant) and circulating complement C3 (main outcome), and the mediating role of ALT herein. All analyses were adjusted for age, sex, presence of type 2 diabetes mellitus or heart disease, use of medication, smoking, alcohol consumption, waist circumference and inflammation. Insulin resistance (estimated as HOMA2IR) was strongly associated with circulating C3 (standardized regression coefficient β 0·40 [95% CI: 0·30 0·49]) and also with ALT (β 0·44 [0·34 0·54]), both adjusted for the above-mentioned covariates. The association between HOMA2IR and C3 was attenuated after further adjustment for ALT (β decreased to 0·34 [0·24 0·44]). Plasma ALT can explain 14·2% of the strong association between insulin resistance and circulating concentrations of complement C3, independent of central obesity and general inflammation.
No related grants have been discovered for Marleen van Greevenbroek.