Publications by authors named "Marleen M J van Greevenbroek"

103 Publications

Greater daily glucose variability and lower time in range assessed with continuous glucose monitoring are associated with greater aortic stiffness: The Maastricht Study.

Diabetologia 2021 May 15. Epub 2021 May 15.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.

Aims: CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis.

Methods: We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) (n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SD] and CGM-assessed CV [CV]) and time in range (TIR) with carotid-femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima-media thickness, ankle-brachial index and circumferential wall stress via multiple linear regression.

Results: Higher SD was associated with higher cf-PWV after adjusting for demographics, cardiovascular risk factors and lifestyle factors (regression coefficient [B] per 1 mmol/l SD [and corresponding 95% CI]: 0.413 m/s [0.147, 0.679], p = 0.002). In the model additionally adjusted for CGM-assessed mean sensor glucose (MSG), SD and MSG contributed similarly to cf-PWV (respective standardised regression coefficients [st.βs] and 95% CIs of 0.065 [-0.018, 0.167], p = 0.160; and 0.059 [-0.043, 0.164], p = 0.272). In the fully adjusted models, both higher CV (B [95% CI] per 10% CV: 0.303 m/s [0.046, 0.559], p = 0.021) and lower TIR (B [95% CI] per 10% TIR: -0.145 m/s [-0.252, -0.038] p = 0.008) were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures.

Conclusions: Our findings show that greater daily glucose variability and lower TIR are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIR to prevent CVD.
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http://dx.doi.org/10.1007/s00125-021-05474-8DOI Listing
May 2021

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: The Maastricht Study.

Cardiovasc Diabetol 2021 05 7;20(1):102. Epub 2021 May 7.

Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.

Background: Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures.

Methods: In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders.

Results: Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation.

Conclusions: Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.
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http://dx.doi.org/10.1186/s12933-021-01290-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106227PMC
May 2021

Carotid stiffness is associated with retinal microvascular dysfunction-The Maastricht study.

Microcirculation 2021 Apr 27:e12702. Epub 2021 Apr 27.

CARIM School for Cardiovascular Diseases, Maastricht University (UM), Maastricht, The Netherlands.

Objective: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy.

Research Design And Methods: This study used cross-sectional data from the Maastricht Study, a type 2 diabetes-enriched population-based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid-femoral pulse wave velocity with retinal microvascular diameters and flicker light-induced dilation and adjusted for cardiovascular and lifestyle risk factors.

Results: The retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light-induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non-significantly, but directionally similarly, associated with greater retinal venular flicker light-induced dilation (0.04 [-0.02; 0.10]). Carotid-femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light-induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light-induced dilation were two- to threefold stronger in individuals with type 2 diabetes than in those without.

Conclusion: In this population-based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light-induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction.
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http://dx.doi.org/10.1111/micc.12702DOI Listing
April 2021

Towards precision medicine in diabetes? A critical review of glucotypes.

PLoS Biol 2021 Mar 11;19(3):e3000890. Epub 2021 Mar 11.

Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.

In response to a study previously published in PLOS Biology, this Formal Comment thoroughly examines the concept of 'glucotypes' with regard to its generalisability, interpretability and relationship to more traditional measures used to describe data from continuous glucose monitoring.
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http://dx.doi.org/10.1371/journal.pbio.3000890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951846PMC
March 2021

The relation of depression with structural brain abnormalities and cognitive functioning: the Maastricht study.

Psychol Med 2021 Feb 26:1-10. Epub 2021 Feb 26.

Alzheimer Centrum Limburg, Maastricht, the Netherlands.

Background: Individuals with depression often experience widespread and persistent cognitive deficits, which might be due to brain atrophy and cerebral small vessel disease (CSVD). We therefore studied the associations between depression, markers of brain atrophy and CSVD, and cognitive functioning.

Methods: We used cross-sectional data from the population-based Maastricht study (n = 4734; mean age 59.1 ± 8.6 years, 50.2% women), which focuses on type 2 diabetes. A current episode of major depressive disorder (MDD, n = 151) was assessed by the Mini-International Neuropsychiatric Interview. Volumes of cerebral spinal fluid, white matter, gray matter and white matter hyperintensities, presence of lacunar infarcts and cerebral microbleeds, and total CSVD burden were assessed by 3 T magnetic resonance imaging. Multiple linear and logistic regression analyses tested the associations between MDD, brain markers and cognitive functioning in memory, information processing speed, and executive functioning & attention, and presence of cognitive impairment. Structural equation modeling was used to test mediation.

Results: In fully adjusted models, MDD was associated with lower scores in information processing speed [mean difference = -0.18(-0.28;-0.08)], executive functioning & attention [mean difference = -0.13(-0.25;-0.02)], and with higher odds of cognitive impairment [odds ratio (OR) = 1.60(1.06;2.40)]. MDD was associated with CSVD in participants without type 2 diabetes [OR = 1.65(1.06;2.56)], but CSVD or other markers of brain atrophy or CSVD did not mediate the association with cognitive functioning.

Conclusions: MDD is associated with more impaired information processing speed and executive functioning & attention, and overall cognitive impairment. Furthermore, MDD was associated with CSVD in participants without type 2 diabetes, but this association did not explain an impaired cognitive profile.
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http://dx.doi.org/10.1017/S0033291721000222DOI Listing
February 2021

C3 and alternative pathway components are associated with an adverse lipoprotein subclass profile: The CODAM study.

J Clin Lipidol 2021 Mar-Apr;15(2):311-319. Epub 2021 Feb 9.

Department of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands. Electronic address:

Background: Plasma lipoproteins contain heterogeneous subclasses. Previous studies on the associations of the complement system with lipids and lipoproteins are mainly limited to the major lipid classes, and associations of complement with lipoprotein subclass characteristics remain unknown.

Objective: We investigated the associations of C3 and other components of the alternative complement pathway with plasma lipoprotein subclass profile.

Methods: Plasma complement concentrations (complement component 3 [C3], properdin, factor H, factor D, MASP-3, C3a, Bb), and lipoprotein subclass profile (as measured by nuclear magnetic resonance spectroscopy) were obtained in 523 participants (59.6 ± 6.9 years, 60.8% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression was used to investigate the associations of C3 (primary determinant) and other alternative pathway components (secondary determinants) with characteristics (particle concentration and size [main outcomes], and lipid contents [secondary outcomes]) of 14 lipoprotein subclasses, ranging from extremely large VLDL to small HDL (all standardized [std] values).

Results: Participants with higher C3 concentrations had more circulating VLDL (stdβs ranging from 0.27 to 0.36), IDL and LDL (stdβs ranging from 0.14 to 0.17), and small HDL (stdβ = 0.21). In contrast, they had fewer very large and large HDL particles (stdβs = -0.36). In persons with higher C3 concentrations, all lipoprotein subclasses were enriched in triglycerides. Similar but weaker associations were observed for properdin, factor H, factor D, and MASP-3, but not for C3a and Bb.

Conclusions: The alternative complement pathway, and most prominently C3, is associated with an adverse lipoprotein subclass profile that is characterized by more triglyceride-enriched lipoproteins but fewer large HDL.
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http://dx.doi.org/10.1016/j.jacl.2021.01.011DOI Listing
February 2021

Polymorphisms in Glyoxalase I Gene Are Not Associated with Glyoxalase I Expression in Whole Blood or Markers of Methylglyoxal Stress: The CODAM Study.

Antioxidants (Basel) 2021 Feb 2;10(2). Epub 2021 Feb 2.

Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands.

Glyoxalase 1 (Glo1) is the rate-limiting enzyme in the detoxification of methylglyoxal (MGO) into D-lactate. MGO is a major precursor of advanced glycation endproducts (AGEs), and both are associated with development of age-related diseases. Since genetic variation in may alter the expression and/or the activity of Glo1, we examined the association of nine SNPs in with Glo1 expression and markers of MGO stress (MGO in fasting plasma and after an oral glucose tolerance test, D-lactate in fasting plasma and urine, and MGO-derived AGEs CEL and MG-H1 in fasting plasma and urine). We used data of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM, = 546, 60 ± 7 y, 25% type 2 diabetes). Outcomes were compared across genotypes using linear regression, adjusted for age, sex, and glucose metabolism status. We found that SNP4 (rs13199033) was associated with Glo1 expression (AA as reference, standardized beta AT = -0.29, = 0.02 and TT = -0.39, = 0.3). Similarly, SNP13 (rs3799703) was associated with Glo1 expression (GG as reference, standardized beta AG = 0.17, = 0.14 and AA = 0.36, = 0.005). After correction for multiple testing these associations were not significant. For the other SNPs, we observed no consistent associations over the different genotypes. Thus, polymorphisms of were not associated with Glo1 expression or markers of MGO stress, suggesting that these SNPs are not functional, although activity/expression might be altered in other tissues.
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http://dx.doi.org/10.3390/antiox10020219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913097PMC
February 2021

Exercise SBP response and incident depressive symptoms: The Maastricht Study.

J Hypertens 2021 Mar;39(3):494-502

Department of Internal Medicine, Maastricht University Medical Centre.

Objective: : An exaggerated exercise SBP, which is potentially modifiable, may be associated with incident depressive symptoms via an increased pulsatile pressure load on the brain. However, the association between exaggerated exercise SBP and incident depressive symptoms is unknown. Therefore, we examined whether exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time.

Methods: : We used longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2121; 51.3% men; age 59.5 ± 8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on four standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 min after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of at least 10.

Results: : After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A 1 SD higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms [hazard ratio: 1.27 (95% confidence interval: 1.04-1.54)]. Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness.

Conclusion: : A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms.
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http://dx.doi.org/10.1097/HJH.0000000000002657DOI Listing
March 2021

Metabolic Age Based on the BBMRI-NL H-NMR Metabolomics Repository as Biomarker of Age-related Disease.

Circ Genom Precis Med 2020 10 14;13(5):541-547. Epub 2020 Aug 14.

Department of Internal Medicine, Maastricht University Medical Center, the Netherlands (C.D.A.S., C.J.H.v.d.K., M.M.J.v.G.).

Background: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status.

Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts.

Results: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data.

Conclusions: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.
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http://dx.doi.org/10.1161/CIRCGEN.119.002610DOI Listing
October 2020

Association of the Amount and Pattern of Physical Activity With Arterial Stiffness: The Maastricht Study.

J Am Heart Assoc 2020 10 15;9(20):e017502. Epub 2020 Oct 15.

CAPHRI Care and Public Health Research Institute Maastricht University Maastricht the Netherlands.

Background Arterial stiffness is an independent risk factor for cardiovascular disease and can be beneficially influenced by physical activity. However, it is not clear how an individual's physical activity pattern over a week is associated with arterial stiffness. Therefore, we examined the associations of the amount and pattern of higher intensity physical activity with arterial stiffness. Methods and Results Data from the Maastricht Study (n=1699; mean age: 60±8 years, 49.4% women, 26.9% type 2 diabetes mellitus) were used. Arterial stiffness was assessed by carotid-to-femoral pulse wave velocity and carotid distensibility. The amount (continuous variable as h/wk) and pattern (categorical variable) of higher intensity physical activity were assessed with the activPAL3. Activity groups were: inactive (<75 min/wk), insufficiently active (75-150 min/wk), weekend warrior (>150 min/wk in ≤2 sessions), and regularly active (>150 min/wk in ≥3 sessions). In the fully adjusted model (adjusted for demographic, lifestyle, and cardiovascular risk factors), higher intensity physical activity was associated with lower carotid-to-femoral pulse wave velocity (amount: β = -0.05, 95% CI, -0.09 to -0.01; insufficiently active: β = -0.33, 95% CI, -0.55 to -0.11; weekend warrior: β = -0.38, 95% CI, -0.64 to -0.12; and regularly active: β = -0.46, 95% CI, -0.71 to -0.21 [reference: inactive]). These associations were stronger in those with type 2 diabetes mellitus. There was no statistically significant association between higher intensity physical activity with carotid distensibility. Conclusions Participating in higher intensity physical activity was associated with lower carotid-to-femoral pulse wave velocity, but there was no difference between the regularly actives and the weekend warriors. From the perspective of arterial stiffness, engaging higher intensity physical activity, regardless of the weekly pattern, may be an important strategy to reduce the risk of cardiovascular disease, particularly in individuals with type 2 diabetes mellitus.
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http://dx.doi.org/10.1161/JAHA.120.017502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763372PMC
October 2020

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference.

Genome Biol 2020 08 28;21(1):220. Epub 2020 Aug 28.

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands.

Background: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.

Results: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.

Conclusion: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
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http://dx.doi.org/10.1186/s13059-020-02114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453518PMC
August 2020

Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes.

J Clin Endocrinol Metab 2020 07;105(7)

Department of Epidemiology and Biostatistics, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Context: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease.

Objective: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D).

Design: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts.

Main Outcome Measures: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.

Results: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after.

Conclusions: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.
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http://dx.doi.org/10.1210/clinem/dgaa173DOI Listing
July 2020

Metabolic profiling of tissue-specific insulin resistance in human obesity: results from the Diogenes study and the Maastricht Study.

Int J Obes (Lond) 2020 06 17;44(6):1376-1386. Epub 2020 Mar 17.

Department of Epidemiology, Maastricht University, Maastricht, The Netherlands.

Background: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles.

Methods: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m; 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation.

Results: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study.

Conclusions: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.
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http://dx.doi.org/10.1038/s41366-020-0565-zDOI Listing
June 2020

Incidence of type 2 diabetes in familial combined hyperlipidemia.

BMJ Open Diabetes Res Care 2020 03;8(1)

Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

Objective: Familial combined hyperlipidemia (FCHL) is common among survivors of a premature myocardial infarction. FCHL patients are characterized by visceral obesity, fatty liver, and insulin resistance. The aim of the present study was to determine the incidence and determinants of type 2 diabetes (T2D) in a longitudinal cohort of FCHL pedigrees.

Research Design And Methods: FCHL patients, their unaffected relatives and spouses included in our baseline cohort in 1998-2005 (n=596) were re-invited to determine the incidence of self-reported T2D (that was confirmed by medical records), used as the primary outcome measure. The Fatty Liver Index (FLI) and Homeostasis Model Assessment Insulin Resistance (HOMA2-IR) were used as markers of fatty liver and insulin resistance, respectively. A subset of the original cohort underwent ultrasound of the liver, and subcutaneous and visceral fat in 2002-2005 (n=275; 'ultrasound subcohort').

Results: Follow-up data (median: 15 years) was acquired for 76%. The incidence rate of T2D was significantly higher in FCHL patients compared with spouses (19.2 per 1000 person-years vs 2.8 per 1000 person-years; HR : 6.3, 95% CI: 2.4 to 16.8), whereas no differences were observed between unaffected relatives and spouses (HR: 0.9, 95% CI: 0.3 to 2.6). Cox's proportional hazard regression analyses showed that baseline HOMA2-IR and FLI≥60, but not waist circumference, BMI, or the FCHL affected state, were independently associated with incident T2D. Similar results were obtained in the ultrasound subcohort (median follow-up: 11 years), in which baseline HOMA2-IR and fatty liver (assessed by ultrasound) were independently associated with incident T2D.

Conclusion: This study further corroborates the suggestion that the liver plays a central role in the pathogenesis of cardiometabolic complications in FCHL. It supports periodical screening for T2D in this high-risk population.
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http://dx.doi.org/10.1136/bmjdrc-2019-001107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103854PMC
March 2020

Associations of dicarbonyl stress with complement activation: the CODAM study.

Diabetologia 2020 05 28;63(5):1032-1042. Epub 2020 Jan 28.

Department of Internal Medicine, Maastricht University Medical Centre, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, the Netherlands.

Aims/hypothesis: Reactive α-dicarbonyl compounds are major precursors of AGEs and may lead to glycation of circulating and/or cell-associated complement regulators. Glycation of complement regulatory proteins can influence their capacity to inhibit complement activation. We investigated, in a human cohort, whether greater dicarbonyl stress was associated with more complement activation.

Methods: Circulating concentrations of dicarbonyl stress markers, i.e. α-dicarbonyls (methylglyoxal [MGO], glyoxal [GO] and 3-deoxyglucosone [3-DG]), and free AGEs (N-(carboxymethyl)lysine [CML], N-(carboxyethyl)lysine [CEL] and N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine [MG-H1]), and protein-bound AGEs (CML, CEL, pentosidine), as well as the complement activation products C3a and soluble C5b-9 (sC5b-9), were measured in 530 participants (59.5 ± 7.0 years [mean ± SD], 61% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression analyses were used to investigate the associations between dicarbonyl stress (standardised) and complement activation (standardised) with adjustment of potential confounders, including age, sex, lifestyle, use of medication and markers of obesity. In addition, the associations of two potentially functional polymorphisms (rs1049346, rs2736654) in the gene encoding glyoxalase 1 (GLO1), the rate-limiting detoxifying enzyme for MGO, with C3a and sC5b-9 (all standardized) were evaluated.

Results: After adjustment for potential confounders, plasma concentration of the dicarbonyl GO was inversely associated with sC5b-9 (β -0.12 [95% CI -0.21, -0.02]) and the protein-bound AGE CEL was inversely associated with C3a (-0.17 [-0.25, -0.08]). In contrast, the protein-bound AGE pentosidine was positively associated with sC5b-9 (0.15 [0.05, 0.24]). No associations were observed for other α-dicarbonyls and other free or protein-bound AGEs with C3a or sC5b-9. Individuals with the AG and AA genotype of rs1049346 had, on average, 0.32 and 0.40 SD lower plasma concentrations of sC5b-9 than those with the GG genotype, while concentrations of C3a did not differ significantly between rs1049346 genotypes. GLO1 rs2736654 was not associated with either C3a or sC5b-9.

Conclusions/interpretation: Plasma concentrations of dicarbonyl stress markers showed distinct associations with complement activation products: some of them were inversely associated with either C3a or sC5b-9, while protein-bound pentosidine was consistently and positively associated with sC5b-9. This suggests different biological relationships of individual dicarbonyl stress markers with complement activation.
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http://dx.doi.org/10.1007/s00125-020-05098-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145776PMC
May 2020

The endothelial function biomarker soluble E-selectin is associated with nonalcoholic fatty liver disease.

Liver Int 2020 05 29;40(5):1079-1088. Epub 2020 Jan 29.

Department of Internal Medicine, Division of Endocrinology and Metabolic Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.

Background & Aims: Plasma soluble E-selectin (sE-selectin) is a frequently used biomarker of systemic endothelial dysfunction. The present study explored the relationship between nonalcoholic fatty liver disease (NAFLD) and plasma sE-selectin levels.

Methods: Expression of E-selectin in liver, visceral adipose tissue (VAT) and muscle was studied in relation to plasma sE-selectin in severely obese individuals (n = 74). The course of hepatic E-selectin expression in relation to hepatic steatosis and inflammation was examined in C57BL/6J LDLR mice on a Western-type diet. The relationship between biomarkers of NAFLD, that is, plasma aminotransferase (ALT) and NAFLD susceptibility genes (rs738409 [PNPLA3] and rs1260326 [GCKR]), and plasma sE-selectin was studied in the combined CODAM (n = 571) and Hoorn (n = 694) studies.

Results: E-selectin expression in liver, not VAT or muscle, was associated with plasma sE-selectin in severely obese individuals (β = 0.26; 95% CI: 0.05-0.47). NAFLD severity was associated with hepatic E-selectin expression (P = .02) and plasma sE-selectin (P = .003). LDLR mice on a Western-type diet displayed increased hepatic E-selectin expression that followed the same course as hepatic inflammation, but not steatosis. In the CODAM study, plasma ALT was associated with plasma sE-selectin, independent of potential confounders (β = 0.25; 95% CI: 0.16-0.34). Both rs738409 and rs1260326 were associated with higher plasma sE-selectin in the combined CODAM and Hoorn studies (P = .01 and P = .004 respectively).

Conclusions: NAFLD and related markers are associated with higher expression of hepatic E-selectin and higher levels of plasma sE-selectin. Further studies are required to investigate the role of E-selectin in the pathogenesis of NAFLD and the applicability of sE-selectin as a plasma biomarker of NAFLD/NASH.
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http://dx.doi.org/10.1111/liv.14384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317803PMC
May 2020

Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas.

Nat Med 2020 01 13;26(1):110-117. Epub 2020 Jan 13.

Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).
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http://dx.doi.org/10.1038/s41591-019-0722-xDOI Listing
January 2020

Glucose Variability Assessed with Continuous Glucose Monitoring: Reliability, Reference Values, and Correlations with Established Glycemic Indices-The Maastricht Study.

Diabetes Technol Ther 2020 05 17;22(5):395-403. Epub 2020 Jan 17.

Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands.

Glucose variability (GV) measured by continuous glucose monitoring (CGM) has become an accepted marker of glycemic control. Nevertheless, several methodological aspects of GV assessment require further study. We, therefore, investigated the minimum number of days needed to reliably measure GV, assessed GV reference values, and studied the correlation of GV with established glycemic indices (i.e., HbA, seven-point oral glucose tolerance test [OGTT]-derived indices). We used cross-sectional data from The Maastricht Study, an observational population-based cohort enriched with type 2 diabetes. Participants with more than 48 h of CGM (iPro2; Medtronic) were included for analysis ( = 851; age: 60 ± 9years; 49% women; 23% type 2 diabetes). We used mean sensor glucose (MSG), standard deviation (SD), and coefficient of variation (CV) as CGM-derived indices (the latter two for GV quantification). We calculated reliability using the Spearman-Brown prophecy formula, established reference values by calculating 2.5th-97.5th percentiles, and studied correlations using Spearman's rho. Sufficient reliability ( > 0.80) was achieved with two (MSG and SD), or three monitoring days (CV). The reference ranges, assessed in individuals with normal glucose metabolism ( = 470), were 90.5-120.6 mg/dL (MSG), 7.9-24.8 mg/dL (SD), and 7.74%-22.45% (CV). For MSG, the strongest correlation was found with fasting plasma glucose (rho = 0.65 [0.61; 0.69]); for SD, with the 1-h OGTT value (rho = 0.61 [0.56; 0.65]); and for CV, with both the incremental glucose peak (IGP) during the OGTT (rho = 0.50 [0.45; 0.55]) and the 1-h OGTT value (rho = 0.50 [0.45; 0.55]). The reliability findings and reference values are relevant for studies that aim to investigate CGM-measured GV. One-hour OGTT and IGP values can be used as GV indices when CGM is unavailable.
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http://dx.doi.org/10.1089/dia.2019.0385DOI Listing
May 2020

Adverse differences in cardiometabolic risk factor levels between individuals with pre-diabetes and normal glucose metabolism are more pronounced in women than in men: the Maastricht Study.

BMJ Open Diabetes Res Care 2019 15;7(1):e000787. Epub 2019 Nov 15.

Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.

Objective: To investigate whether adverse differences in levels of cardiovascular risk factors in women than men, already established when comparing individuals with and without diabetes, are also present before type 2 diabetes onset.

Research Design And Methods: In a population-based cohort study of individuals aged 40-75 years (n=3410; 49% women, 29% type 2 diabetes (oversampled 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 individuals, of continuous levels of hemoglobin A1c (HbA1c). Age-adjusted sex differences were analyzed using linear and logistic regression models with sex interaction terms.

Results: 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 individuals 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.

Conclusion: 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.
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http://dx.doi.org/10.1136/bmjdrc-2019-000787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861068PMC
September 2020

High-density lipoprotein cholesterol efflux capacity is not associated with atherosclerosis and prevalence of cardiovascular outcome: The CODAM study.

J Clin Lipidol 2020 Jan - Feb;14(1):122-132.e4. Epub 2019 Oct 31.

Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address:

Background: Cholesterol Efflux Capacity (CEC) is considered to be a key atheroprotective property of high-density lipoproteins (HDL). However, the role of HDL-CEC in atherosclerosis and cardiovascular (CV) risk is still controversial, and data in individuals with diabetes are limited.

Objective: In this study, we have investigated the relationship of CEC and other HDL characteristics with clinical and subclinical atherosclerosis in subjects with elevated cardiovascular diseases (CVD) risk and Type 2 Diabetes Mellitus (T2DM).

Methods: Using multiple linear regression analyses, we determined the relationship of HDL-CEC with carotid intima-media thickness (cIMT, Z-Score), an endothelial dysfunction (EnD) Score (Z-Score), prevalent CVD (n = 150 cases) and history of CV events (CVE, n = 85 cases) in an observational cohort (CODAM, n = 574, 59.6 ± 0.3 yr, 61.3% men, 24.4% T2DM). Stratified analyses were performed to determine if the associations differed between individuals with normal glucose metabolism (NGM) and those with disturbed glucose metabolism.

Results: HDL-CEC was not associated with either marker of atherosclerosis (cIMT, EnD Score) nor with CVD or CVE. In contrast, other HDL characteristics that is, HDL-Cholesterol (HDL-C, Z-Score), apolipoprotein A-I (apoA-I, Z-Score), HDL size (Z-Score) and HDL particle number (HDL-P, Z-Score) were inversely and significantly associated with the EnD Score (s -0.226 to -0.097, P < .05) and CVE (ORs 0.61 to 0.68, P < .05). In stratified analyses, HDL size and HDL-P were significantly associated with the EnD Score in individuals with NGM (P .039 and .005, respectively), but not in those with (pre)diabetes. HDL-C and apoA-I were inversely associated with prevalent CVD in individuals with (pre)diabetes (P = .074 and .034, respectively), but not in those with NGM.

Conclusion: HDL-CEC is not associated with clinical or subclinical atherosclerosis, neither in the whole population nor in individuals with (pre)diabetes, while other HDL characteristics show atheroprotective associations. The atheroprotective associations of HDL-size and HDL-P are lost in (pre)diabetes, while higher concentrations of HDL-C and apoA-I are associated with a lower prevalence of CVD in (pre)diabetes.
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http://dx.doi.org/10.1016/j.jacl.2019.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176544PMC
June 2021

The oral glucose tolerance test-derived incremental glucose peak is associated with greater arterial stiffness and maladaptive arterial remodeling: The Maastricht Study.

Cardiovasc Diabetol 2019 11 14;18(1):152. Epub 2019 Nov 14.

Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.

Background: Daily glucose variability may contribute to vascular complication development irrespective of mean glucose values. The incremental glucose peak (IGP) during an oral glucose tolerance test (OGTT) can be used as a proxy of glucose variability. We investigated the association of IGP with arterial stiffness, arterial remodeling, and microvascular function, independent of HbA and other confounders.

Methods: IGP was calculated as the peak minus baseline plasma glucose value during a seven-point OGTT in 2758 participants (age: 60 ± 8 years; 48% women) of The Maastricht Study, an observational population-based cohort. We assessed the cross-sectional associations between IGP and arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV], carotid distensibility coefficient [carDC]), arterial remodeling (carotid intima-media thickness [cIMT]; mean [CWS] and pulsatile [CWS] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA, cardiovascular risk factors, lifestyle factors, and medication use.

Results: Higher IGP was independently associated with higher cf-PWV (regression coefficient [B]: 0.054 m/s [0.020; 0.089]) and with higher CWS (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: - 0.026 10/kPa [- 0.112; 0.060]), cIMT (B: - 2.745 µm [- 5.736; 0.245]), CWS (B: 0.108 kPa [- 0.054; 0.270]), retinal arteriolar average dilatation (B: - 0.022% [- 0.087; 0.043]), or heat-induced skin hyperemia (B: - 1.380% [- 22.273; 19.513]).

Conclusions: IGP was independently associated with aortic stiffness and maladaptive carotid remodeling, but not with carotid stiffness, cIMT, and microvascular function measures. Future studies should investigate whether glucose variability is associated with cardiovascular disease.
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http://dx.doi.org/10.1186/s12933-019-0950-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857146PMC
November 2019

Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans.

Diabetes 2019 12 6;68(12):2247-2258. Epub 2019 Sep 6.

Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands

Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort ( = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) ( = 325) and the Maastricht Study ( = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.
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http://dx.doi.org/10.2337/db19-0560DOI Listing
December 2019

High dietary glycemic load is associated with higher concentrations of urinary advanced glycation endproducts: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) Study.

Am J Clin Nutr 2019 08;110(2):358-366

CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, Netherlands; and Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands.

Background: Advanced glycation endproducts (AGEs) and their precursors (dicarbonyls) are associated with the progression of diseases such as diabetes and cardiovascular disease. Plasma concentrations of dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) are increased after an oral glucose load indicating that consumption of diets high in carbohydrates may induce the endogenous formation of dicarbonyls and AGEs.

Objective: To examine the associations of dietary glycemic index (GI) and glycemic load (GL) with concentrations of dicarbonyls and AGEs in plasma and urine.

Methods: Cross-sectional analyses were performed in a human observational cohort [Cohort on Diabetes and Atherosclerosis Maastricht (CODAM), n = 494, 59 ± 7 y, 25% type 2 diabetes]. GI and GL were derived from FFQs. Dicarbonyls and AGEs were measured in the fasting state by ultra-performance liquid chromatography-tandem MS. MGO, GO, and 3-DG and protein-bound Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and pentosidine were measured in plasma. Free forms of CML, CEL, and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured in both plasma and urine. Multiple linear regression was performed with dicarbonyls and AGEs as dependent variables, and dietary GI or GL as main independent variables (all standardized). Models were adjusted for health and lifestyle factors, dietary factors, and reciprocally for GI and GL. As this was an explorative study, we did not adjust for multiple testing.

Results: GI was not associated with any of the dicarbonyls or AGEs. GL was positively associated with free urinary MG-H1 (β = 0.34; 95% CI: 0.12, 0.55). Furthermore, GL was positively associated with free plasma MG-H1 and free urinary CML (β = 0.23; 95% CI: 0.02, 0.43; and β = 0.28; 95% CI: 0.06, 0.50), but these associations were not independent of dietary AGE intake.

Conclusions: A habitual diet higher in GL is associated with higher concentrations of free urinary MG-H1. This urinary AGE is most likely a reflection of AGE accumulation and degradation in tissues, where they may be involved in tissue dysfunction.
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http://dx.doi.org/10.1093/ajcn/nqz119DOI Listing
August 2019

Hepatic Fat Content and Liver Enzymes Are Associated with Circulating Free and Protein-Bound Advanced Glycation End Products, Which Are Associated with Low-Grade Inflammation: The CODAM Study.

J Diabetes Res 2019 14;2019:6289831. Epub 2019 May 14.

Department of Internal Medicine, MUMC, Maastricht, Netherlands.

Advanced glycation end products (AGEs) accumulate in fatty livers and may contribute to low-grade inflammation (LGI), potentially via their receptor, RAGE. It is unknown if the AGE accumulation in fatty livers results in elevated circulating AGEs. In a cohort study, we investigated the association of liver fat and hepatocellular damage with circulating AGEs and soluble RAGE (sRAGE) and subsequently the association of circulating AGEs and sRAGE with LGI. Cross-sectional associations of liver fat percentage (eLF%; ln-transformed) and liver enzymes (LE score; standardized) with circulating AGEs (free CML, CEL, and MG-H1 in nM and protein-bound CML, CEL, and pentosidine in nmol/mmol lysine; ln-transformed) and sRAGE (pg/ml, ln-transformed) and additionally of AGEs and sRAGE with LGI (standardized) were determined by multiple linear regression. eLF% was positively associated with circulating free CEL ( = 0.090; 95% CI 0.041; 0.139) but inversely with protein-bound CML ( = -0.071; 95% CI -0.108; -0.034). Similarly, the LE score was positively associated with free CML ( = 0.044; 95% CI 0.012; 0.076) and CEL ( = 0.040; 95% CI 0.009; 0.072) but inversely with protein-bound CML ( = -0.037; 95% CI -0.060; -0.013). Free CML ( = 0.297; 95% CI 0.049; 0.545) was positively associated with LGI, while protein-bound CML ( = -0.547; 95% CI -0.888; -0.207) was inversely associated, although this association was absent after adjustment for BMI. eLF% and LE score were not associated with sRAGE and sRAGE not with LGI after adjustment for BMI. Liver fat and enzymes were positively associated with circulating free AGEs, which were associated with LGI. In contrast, inverse relations were observed of liver fat and enzymes with circulating protein-bound AGEs and of protein-bound AGEs with LGI. These data suggest that hepatic steatosis and inflammation affect the formation and degradation of hepatic protein-bound AGEs resulting in elevated circulating free AGE levels. These alterations in AGE levels might influence LGI, but this is likely independent of RAGE.
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http://dx.doi.org/10.1155/2019/6289831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536997PMC
January 2020

Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.

Am J Clin Nutr 2019 08;110(2):437-450

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

Background: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.

Objective: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.

Methods: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.

Results: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.

Conclusions: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.
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http://dx.doi.org/10.1093/ajcn/nqz031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669135PMC
August 2019

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.

Neurology 2019 04 3;92(16):e1899-e1911. Epub 2019 Apr 3.

From the Departments of Neurology (G.L.J.O., J.A.P., D.A.K., R.Z., I.d.B., M.D.F., G.M.T., A.M.J.M.v.d.M.), Human Genetics (A.D., L.S.V., P.A.C.'tH., A.M.J.M.v.d.M.), Molecular Epidemiology (M.B., P.E.S.), Radiology (D.A.K.), and Medical Statistics (J.J.G.), Leiden University Medical Centre; Department of Biological Psychology (L.L., R.P., D.I.B.), Vrije Universiteit Amsterdam; Amsterdam Public Health Institute (L.L.); Amsterdam Neuroscience and Amsterdam Public Health (M.B., C.S.T., Y.M., D.I.B., B.W.P.); Department of Psychiatry (M.B., C.S.T., Y.M., B.W.P.), VU University Medical Centre/GGZ inGeest, Amsterdam; Departments of Epidemiology (A.D., J.L., K.-x.W., N.A., M.A.I., C.M.v.D.) and Neurology (M.A.I.), Erasmus Medical Centre, Rotterdam; Departments of Genetics (J.F., L.F., C.W.) and Pediatrics (J.F.), University Medical Centre Groningen; Department of Internal Medicine (C.J.H.v.d.K., F.H.M.V., M.M.J.v.G., M.T.S., C.D.A.S.) and Heart and Vascular Center (M.T.S.), Maastricht University Medical Centre; CARIM School for Cardiovascular Diseases (C.J.H.v.d.K., M.M.J.v.G., I.C.W.A., M.T.S., P.C.D., C.D.A.S.), Department of Epidemiology (I.C.W.A.), MaCSBio Maastricht Centre for Systems Biology (I.C.W.A.), and Department of Epidemiology (P.C.D.), Maastricht University; Department of Radiology (M.A.I.), Erasmus MC University Medical Centre, Rotterdam; Leiden Academic Centre in Drug Research, Faculty Science (C.M.v.D.), Leiden University; and Centre for Molecular and Biomolecular Informatics (P.A.C.'tH.), Radboud University Medical Centre Nijmegen, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.

Objective: To identify a plasma metabolomic biomarker signature for migraine.

Methods: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.

Results: Decreases in the level of apolipoprotein A1 (β -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β -0.10; 95% CI -0.15, -0.05; adjusted = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β -0.24; 95% CI -0.36, -0.12; adjusted = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.

Conclusions: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.
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http://dx.doi.org/10.1212/WNL.0000000000007313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550500PMC
April 2019

Incidence of cardiovascular disease in familial combined hyperlipidemia: A 15-year follow-up study.

Atherosclerosis 2019 01 8;280:1-6. Epub 2018 Nov 8.

Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, the Netherlands. Electronic address:

Background And Aims: Familial combined hyperlipidemia (FCHL) is a complex dyslipidemia associated with premature cardiovascular disease (CVD). The present study was conducted to 1) determine the incidence of CVD in FCHL in this era of protocolled, primary prevention; and 2) examine whether cardiovascular risk estimation based on the Systemic Coronary Risk Estimation (SCORE) chart, as proposed in the 2016 ESC/EAS guidelines for the management of dyslipidemia, is justified in FCHL.

Methods: FCHL patients, their normolipidemic (NL) relatives and spouses originally included in our baseline cohort in 1998-2005 (n = 596) were invited for a follow-up visit to determine the incidence of CVD, defined as (non-)fatal coronary artery disease, ischemic stroke and peripheral artery disease requiring invasive treatment.

Results: Follow-up data (median: 15 years) was acquired for 85% of the original cohort. The cumulative incidence of CVD was significantly higher in FCHL patients than in spouses (23.6% versus 4.7%; hazard ratio (HR): 5.4, 95%CI: 2.0-14.6; HR after adjustment for risk factors included in SCORE: 4.7, 95%CI: 1.6-13.8), but not in NL relatives compared to spouses (5.8% versus 4.7%). The SCORE chart tended to overestimate CVD risk in the spouses (observed [O]/expected [E] ratio:0.2, p = 0.01), but not in FCHL patients (O/E:1.3, p = 0.50).

Conclusions: Risk of primary CVD is still substantially increased in FCHL patients, despite preventive measures. The overestimation of CVD risk by the SCORE chart - a nowadays frequently observed phenomenon thanks to improved primary prevention - was not seen in FCHL. These results suggest that more aggressive treatment is justified to avoid excessive CVD in FCHL.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.11.013DOI Listing
January 2019

Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults.

EBioMedicine 2018 Dec 13;38:206-216. Epub 2018 Nov 13.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.

Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP).

Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels.

Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.
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http://dx.doi.org/10.1016/j.ebiom.2018.10.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306313PMC
December 2018

Plasma lipid profiling of tissue-specific insulin resistance in human obesity.

Int J Obes (Lond) 2019 05 21;43(5):989-998. Epub 2018 Sep 21.

Department of Human Biology and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Background/objectives: Obesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid profiles in overweight/obese individuals who show muscle-IR and/or liver-IR.

Subjects/methods: Baseline data of the European multicenter DiOGenes project were used (n = 640; 401 women, nondiabetic BMI: 27-45 kg/m). Muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI) were derived from a 5-point oral glucose tolerance test. The 140 plasma lipids were quantified by liquid chromatography-mass spectrometry. Linear mixed models were used to evaluate associations between MISI, HIRI and plasma lipids.

Results: MISI was comparable between sexes while HIRI and triacylglycerol (TAG) levels were lower in women than in men. MISI was associated with higher lysophosphatidylcholine (LPC) levels (standardized (std)β = 0.126; FDR-p = 0.032). Sex interactions were observed for associations between HIRI, TAG and diacylglycerol (DAG) lipid classes. In women, but not in men, HIRI was associated with higher levels of TAG (44 out of 55 species) and both DAG species (stdβ: 0.139-0.313; FDR-p < 0.05), a lower odd-chain/even-chain TAG ratio (stdβ = -0.182; FDR-p = 0.005) and a lower very-long-chain/long-chain TAG ratio (stdβ = -0.156; FDR-p = 0.037).

Conclusions: In overweight/obese individuals, muscle insulin sensitivity is associated with higher plasma LPC concentrations. Women have less hepatic IR and lower TAG than men. Nevertheless, hepatic IR is associated with higher plasma TAG and DAG concentrations and a lower abundance of odd-chain and very-long-chain TAG in women, but not in men. This suggests a more pronounced worsening of plasma lipid profile in women with the progression of hepatic IR.
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http://dx.doi.org/10.1038/s41366-018-0189-8DOI Listing
May 2019

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation.

Nat Commun 2018 09 14;9(1):3738. Epub 2018 Sep 14.

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands.

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.
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http://dx.doi.org/10.1038/s41467-018-05714-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138682PMC
September 2018