Publications by authors named "Carla J H van der Kallen"

137 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

Sex Disparities in Cardiovascular Risk Factor Assessment and Screening for Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review.

Front Endocrinol (Lausanne) 2021 30;12:617902. Epub 2021 Mar 30.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Background: Insight in sex disparities in the detection of cardiovascular risk factors and diabetes-related complications may improve diabetes care. The aim of this systematic review is to study whether sex disparities exist in the assessment of cardiovascular risk factors and screening for diabetes-related complications.

Methods: PubMed was systematically searched up to April 2020, followed by manual reference screening and citations checks (snowballing) using Google Scholar. Observational studies were included if they reported on the assessment of cardiovascular risk factors (HbA1c, lipids, blood pressure, smoking status, or BMI) and/or screening for nephropathy, retinopathy, or performance of feet examinations, in men and women with diabetes separately. Studies adjusting their analyses for at least age, or when age was considered as a covariable but left out from the final analyses for various reasons (i.e. backward selection), were included for qualitative analyses. No meta-analyses were planned because substantial heterogeneity between studies was expected. A modified Newcastle-Ottawa Quality Assessment Scale for cohort studies was used to assess risk of bias.

Results: Overall, 81 studies were included. The majority of the included studies were from Europe or North America (84%).The number of individuals per study ranged from 200 to 3,135,019 and data were extracted from various data sources in a variety of settings. Screening rates varied considerably across studies. For example, screening rates for retinopathy ranged from 13% to 90%, with half the studies reporting screening rates less than 50%. Mixed findings were found regarding the presence, magnitude, and direction of sex disparities with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, with some evidence suggesting that women, compared with men, may be more likely to receive retinopathy screening and less likely to receive foot exams.

Conclusion: Overall, no consistent pattern favoring men or women was found with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, and screening rates can be improved for both sexes.
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http://dx.doi.org/10.3389/fendo.2021.617902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043152PMC
March 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

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

Accelerometer-derived sedentary time and physical activity and the incidence of depressive symptoms - The Maastricht Study.

Psychol Med 2020 Dec 18:1-8. Epub 2020 Dec 18.

Department of Social Medicine, Maastricht University, The Netherlands.

Background: This study examined the associations between accelerometer-derived sedentary time (ST), lower intensity physical activity (LPA), higher intensity physical activity (HPA) and the incidence of depressive symptoms over 4 years of follow-up.

Methods: We included 2082 participants from The Maastricht Study (mean ± s.d. age 60.1 ± 8.0 years; 51.2% men) without depressive symptoms at baseline. ST, LPA and HPA were measured with the ActivPAL3 activity monitor. Depressive symptoms were measured annually over 4 years of follow-up with the 9-item Patient Health Questionnaire (PHQ-9). Cox regression analysis was performed to examine the associations between ST, LPA, HPA and incident depressive symptoms (PHQ-9 ⩾ 10). Analyses were adjusted for total waking time per day, age, sex, education level, type 2 diabetes mellitus, body mass index, total energy intake, smoking status and alcohol use.

Results: During 7812.81 person-years of follow-up, 203 (9.8%) participants developed incident depressive symptoms. No significant associations [Hazard Ratio (95% confidence interval)] were found between sex-specific tertiles of ST (lowest v. highest tertile) [1.13 (0.76-1.66], or HPA (highest v. lowest tertile) [1.14 (0.78-1.69)] and incident depressive symptoms. LPA (highest v. lowest tertile) was statistically significantly associated with incident depressive symptoms in women [1.98 (1.19-3.29)], but not in men (p-interaction <0.01).

Conclusions: We did not observe an association between ST or HPA and incident depressive symptoms. Lower levels of daily LPA were associated with an increased risk of incident depressive symptoms in women. Future research is needed to investigate accelerometer-derived measured physical activity and ST with incident depressive symptoms, preferably stratified by sex.
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http://dx.doi.org/10.1017/S0033291720004924DOI Listing
December 2020

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

The association of hyperglycaemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study.

Diabetologia 2020 11 5;63(11):2315-2328. Epub 2020 Aug 5.

Department of Psychiatry and Neuropsychology, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands.

Aims/hypothesis: Depression is twice as common in individuals with type 2 diabetes as in the general population. However, it remains unclear whether hyperglycaemia and insulin resistance are directly involved in the aetiology of depression. Therefore, we investigated the association of markers of hyperglycaemia and insulin resistance, measured as continuous variables, with incident depressive symptoms over 4 years of follow-up.

Methods: We used data from the longitudinal population-based Maastricht Study (n = 2848; mean age 59.9 ± 8.1 years, 48.8% women, 265 incident depression cases, 10,932 person-years of follow-up). We assessed hyperglycaemia by fasting and 2 h post-load OGTT glucose levels, HbA and skin autofluorescence (reflecting AGEs) at baseline. We used the Matsuda insulin sensitivity index and HOMA-IR to calculate insulin resistance at baseline. Depressive symptoms (nine-item Patient Health Questionnaire score ≥10) were assessed at baseline and annually over 4 years. We used Cox regression analyses, and adjusted for demographic, cardiovascular and lifestyle risk factors.

Results: Fasting plasma glucose, 2 h post-load glucose and HbA levels were associated with an increased risk for incident depressive symptoms after full adjustment (HR 1.20 [95% CI 1.08, 1.33]; HR 1.25 [1.08, 1.44]; and HR 1.22 [1.09, 1.37] per SD, respectively), while skin autofluorescence, insulin sensitivity index and HOMA-IR were not (HR 0.99 [0.86, 1.13]; HR 1.02 [0.85, 1.25]; and HR 0.93 [0.81, 1.08], per SD, respectively).

Conclusions/interpretation: The observed temporal association between hyperglycaemia and incident depressive symptoms in this study supports the presence of a mechanistic link between hyperglycaemia and the development of depressive symptoms. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05247-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527373PMC
November 2020

Association of Markers of Microvascular Dysfunction With Prevalent and Incident Depressive Symptoms: The Maastricht Study.

Hypertension 2020 08 8;76(2):342-349. Epub 2020 Jul 8.

Department of Internal Medicine (A.F.J.G., M.J.M.v.A., C.D.A.S., B.M.S., N.C.S., R.M.A.H., C.J.H.v.d.K., T.T.v.S., M.T.S., A.J.H.M.H.), Maastricht University Medical Center (MUMC+), the Netherlands.

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial dysfunction; sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [Von Willebrand Factor]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00-1.11] and RR 1.06 [1.01-1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09-1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04-1.46] and HR, 1.19 [1.05-1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in the etiology of LLD and might help in finding additional targets for the prevention and treatment of LLD.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15260DOI Listing
August 2020

Associations of (pre)diabetes with right ventricular and atrial structure and function: the Maastricht Study.

Cardiovasc Diabetol 2020 06 15;19(1):88. Epub 2020 Jun 15.

Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

Backgrounds: The role of right ventricular (RV) and atrial (RA) structure and function, in the increased heart failure risk in (pre)diabetes is incompletely understood. The purpose of this study is to investigate the associations between (pre)diabetes and RV and RA structure and function, and whether these are mediated by left ventricular (LV) alterations or pulmonary pressure.

Methods: Participants of the Maastricht Study; a population-based cohort study (426 normal glucose metabolism (NGM), 142 prediabetes, 224 diabetes), underwent two-dimensional and tissue Doppler echocardiography. Multiple linear regression analyses with pairwise comparisons of (pre)diabetes versus NGM, adjusted for cardiovascular risk factors, and mediation analyses were used.

Results: In general, differences were small. Nevertheless, in individuals with prediabetes and diabetes compared to NGM; RA volume index was lower (both p < 0.01, p < 0.01), RV diameter was lower (both p < 0.01, p < 0.01) and RV length was significantly smaller in diabetes (p = 0.67 and p = 0.03 respectively, p = 0.04), TDI S'RV was lower (p = 0.08 and p < 0.01 respectively, p < 0.01), TDI E'RV was lower (p = 0.01 and p = 0.02 respectively, p = 0.01) and TDI A'RV was lower (p < 0.01 and p = 0.07 respectively, p = 0.04). Only the differences in RA volume index (7.8%) and RV diameter (6.2%) were mediated by the maximum tricuspid gradient, but no other LV structure and function measurements.

Conclusions: (Pre)diabetes is associated with structural RA and RV changes, and impaired RV systolic and diastolic function, independent of cardiovascular risk factors. These associations were largely not mediated by indices of LV structure, LV function or pulmonary pressure. This suggests that (pre)diabetes affects RA and RV structure and function due to direct myocardial involvement.
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http://dx.doi.org/10.1186/s12933-020-01055-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296751PMC
June 2020

Cardiometabolic risk factors as determinants of peripheral nerve function: the Maastricht Study.

Diabetologia 2020 08 15;63(8):1648-1658. Epub 2020 Jun 15.

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

Aims/hypothesis: We aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function.

Methods: In 2401 adults (aged 40-75 years) we previously determined fasting glucose, HbA, triacylglycerol, HDL- and LDL-cholesterol, inflammation, waist circumference, blood pressure, smoking, glucose metabolism status (by OGTT) and medication use. Using nerve conduction tests, we measured compound muscle action potential, sensory nerve action potential amplitudes and nerve conduction velocities (NCVs) of the peroneal, tibial and sural nerves. In addition, we measured vibration perception threshold (VPT) of the hallux and assessed neuropathic pain using the DN4 interview. We assessed cross-sectional associations of risk factors with nerve function (using linear regression) and neuropathic pain (using logistic regression). Associations were adjusted for potential confounders and for each other risk factor. Associations from linear regression were presented as standardised regression coefficients (β) and 95% CIs in order to compare the magnitudes of observed associations between all risk factors and outcomes.

Results: Hyperglycaemia (fasting glucose or HbA) was associated with worse sensorimotor nerve function for all six outcome measures, with associations of strongest magnitude for motor peroneal and tibial NCV, β = -0.17 SD (-0.21, -0.13) and β = -0.18 SD (-0.23, -0.14), respectively. Hyperglycaemia was also associated with higher VPT and neuropathic pain. Larger waist circumference was associated with worse sural nerve function and higher VPT. Triacylglycerol, HDL- and LDL-cholesterol, and blood pressure were not associated with worse nerve function; however, antihypertensive medication usage (suggestive of history of exposure to hypertension) was associated with worse peroneal compound muscle action potential amplitude and NCV. Smoking was associated with worse nerve function, higher VPT and higher risk for neuropathic pain. Inflammation was associated with worse nerve function and higher VPT, but only in those with type 2 diabetes. Type 2 diabetes and, to a lesser extent, prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were associated with worse nerve function, higher VPT and neuropathic pain (p for trend <0.01 for all outcomes).

Conclusions/interpretation: Hyperglycaemia (including the non-diabetic range) was most consistently associated with early-stage nerve damage. Nonetheless, larger waist circumference, inflammation, history of hypertension and smoking may also independently contribute to worse nerve function.
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http://dx.doi.org/10.1007/s00125-020-05194-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351845PMC
August 2020

Type 2 diabetes and HbA are independently associated with wider retinal arterioles: the Maastricht study.

Diabetologia 2020 07 8;63(7):1408-1417. Epub 2020 May 8.

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

Aims/hypothesis: Retinal microvascular diameters are biomarkers of cardio-metabolic risk. However, the association of (pre)diabetes with retinal microvascular diameters remains unclear. We aimed to investigate the association of prediabetes (impaired fasting glucose or impaired glucose tolerance) and type 2 diabetes with retinal microvascular diameters in a predominantly white population.

Methods: In a population-based cohort study with oversampling of type 2 diabetes (N = 2876; n = 1630 normal glucose metabolism [NGM], n = 433 prediabetes and n = 813 type 2 diabetes, 51.2% men, aged 59.8 ± 8.2 years; 98.6% white), we determined retinal microvascular diameters (measurement unit as measured by retinal health information and notification system [RHINO] software) and glucose metabolism status (using OGTT). Associations were assessed with multivariable regression analyses adjusted for age, sex, waist circumference, smoking, systolic blood pressure, lipid profile and the use of lipid-modifying and/or antihypertensive medication.

Results: Multivariable regression analyses showed a significant association for type 2 diabetes but not for prediabetes with arteriolar width (vs NGM; prediabetes: β = 0.62 [95%CI -1.58, 2.83]; type 2 diabetes: 2.89 [0.69, 5.08]; measurement unit); however, there was a linear trend for the arteriolar width across glucose metabolism status (p for trend = 0.013). The association with wider venules was not statistically significant (prediabetes: 2.40 [-1.03, 5.84]; type 2 diabetes: 2.87 [-0.55, 6.29], p for trend = 0.083; measurement unit). Higher HbA levels were associated with wider retinal arterioles (standardised β = 0.043 [95% CI 0.00002, 0.085]; p = 0.050) but the association with wider venules did not reach statistical significance (0.037 [-0.006, 0.080]; p = 0.092) after adjustment for potential confounders.

Conclusions/interpretation: Type 2 diabetes, higher levels of HbA and, possibly, prediabetes, are independently associated with wider retinal arterioles in a predominantly white population. These findings indicate that microvascular dysfunction is an early phenomenon in impaired glucose metabolism.
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http://dx.doi.org/10.1007/s00125-020-05146-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286946PMC
July 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

Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study.

Diabetes Care 2020 05 11;43(5):1126-1133. Epub 2020 Mar 11.

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

Objective: Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV.

Research Design And Methods: In the population-based Maastricht Study ( = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [ = 1,226], prediabetes [ = 331], and type 2 diabetes [ = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual -scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors.

Results: After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: -0.15 [-0.27; -0.03] and -0.34 [-0.46; -0.22], respectively, for trend <0.001; for frequency domain: -0.14 [-0.26; -0.02] and -0.31 [-0.43; -0.19], respectively, for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: -0.16 [-0.21; -0.12], -0.16 [-0.21; -0.12], and -0.15 [-0.20; -0.10], respectively; frequency domain: -0.14 [-0.19; -0.10], -0.14 [-0.18; -0.09], and -0.13 [-0.18; -0.08], respectively).

Conclusions: Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes.
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http://dx.doi.org/10.2337/dc19-2367DOI Listing
May 2020

Higher levels of daily physical activity are associated with better skin microvascular function in type 2 diabetes-The Maastricht Study.

Microcirculation 2020 05 10;27(4):e12611. Epub 2020 Mar 10.

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

Objective: Physical activity may provide a means for the prevention of cardiovascular disease via improving microvascular function. Therefore, this study investigated whether physical activity is associated with skin and retinal microvascular function.

Methods: In The Maastricht Study, a population-based cohort study enriched with type 2 diabetes (n = 1298, 47.3% women, aged 60.2 ± 8.1 years, 29.5% type 2 diabetes), we studied whether accelerometer-assessed physical activity and sedentary time associate with skin and retinal microvascular function. Associations were studied by linear regression and adjusted for major cardiovascular risk factors. In addition, we investigated whether associations were stronger in type 2 diabetes.

Results: In individuals with type 2 diabetes, total physical activity and higher-intensity physical activity were independently associated with greater heat-induced skin hyperemia (regression coefficients per hour), respectively, 10 (95% CI: 1; 18) and 36 perfusion units (14; 58). In individuals without type 2 diabetes, total physical activity and higher-intensity physical activity were not associated with heat-induced skin hyperemia. No associations with retinal arteriolar %-dilation were identified.

Conclusion: Higher levels of total and higher-intensity physical activity were associated with greater skin microvascular vasodilation in individuals with, but not in those without, type 2 diabetes.
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http://dx.doi.org/10.1111/micc.12611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317394PMC
May 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

Sex differences in the risk of vascular disease associated with diabetes.

Biol Sex Differ 2020 01 3;11(1). Epub 2020 Jan 3.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Diabetes is a strong risk factor for vascular disease. There is compelling evidence that the relative risk of vascular disease associated with diabetes is substantially higher in women than men. The mechanisms that explain the sex difference have not been identified. However, this excess risk could be due to certain underlying biological differences between women and men. In addition to other cardiometabolic pathways, sex differences in body anthropometry and patterns of storage of adipose tissue may be of particular importance in explaining the sex differences in the relative risk of diabetes-associated vascular diseases. Besides biological factors, differences in the uptake and provision of health care could also play a role in women's greater excess risk of diabetic vascular complications. In this review, we will discuss the current knowledge regarding sex differences in both biological factors, with a specific focus on sex differences adipose tissue, and in health care provided for the prevention, management, and treatment of diabetes and its vascular complications. While progress has been made towards understanding the underlying mechanisms of women's higher relative risk of diabetic vascular complications, many uncertainties remain. Future research to understanding these mechanisms could contribute to more awareness of the sex-specific risk factors and could eventually lead to more personalized diabetes care. This will ensure that women are not affected by diabetes to a greater extent and will help to diminish the burden in both women and men.
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http://dx.doi.org/10.1186/s13293-019-0277-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942348PMC
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

Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls.

Biol Psychiatry 2020 03 29;87(5):409-418. Epub 2019 Aug 29.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit, Amsterdam, The Netherlands.

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.

Methods: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.

Results: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.

Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.
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http://dx.doi.org/10.1016/j.biopsych.2019.08.016DOI Listing
March 2020

Validated inference of smoking habits from blood with a finite DNA methylation marker set.

Eur J Epidemiol 2019 Nov 7;34(11):1055-1074. Epub 2019 Sep 7.

Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC 0.925 ± 0.021, AUC0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.
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http://dx.doi.org/10.1007/s10654-019-00555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861351PMC
November 2019