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Abstract Background Epidemiological and toxicological studies indicate that increased exposure to air pollutants can lead to neurodegenerative diseases. To further confirm this relationship, we evaluated the association between exposure to ambient air pollutants and corneal nerve measures as a surrogate for neurodegeneration, using corneal confocal microscopy. Methods We used population-based observational cross-sectional data from The Maastricht Study including N = 3635 participants (mean age 59.3 years, 51.6% were women, and 19.9% had type 2 diabetes) living in the Maastricht area. Using the Geoscience and hEalth Cohort COnsortium (GECCO) data we linked the yearly average exposure levels of ambient air pollutants at home address-level [particulate matter with diameters of ≤ 2.5 µm (PM2.5), and ≤ 10.0 µm (PM10), nitrogen dioxide (NO2), and elemental carbon (EC)]. We used linear regression analysis to study the associations between Z-score for ambient air pollutants concentrations (PM2.5, PM10, NO2, and EC) and Z-score for individual corneal nerve measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length, and fractal dimension). Results After adjustment for potential confounders (age, sex, level of education, glucose metabolism status, corneal confocal microscopy lag time, inclusion year of participants, smoking status, and alcohol consumption), higher Z-scores for PM2.5 and PM10 were associated with lower Z-scores for corneal nerve bifurcation density, nerve density, nerve length, and nerve fractal dimension [stβ (95% CI): PM2.5 -0.10 (-0.14; -0.05), -0.04 (-0.09; 0.01), -0.11 (-0.16; -0.06), -0.20 (-0.24; -0.15); and PM10 -0.08 (-0.13; -0.03), -0.04 (-0.09; 0.01), -0.08 (-0.13; -0.04), -0.17 (-0.21; -0.12)], respectively. No associations were found between NO2 and EC and corneal nerve measures. Conclusions Our population-based study demonstrated that exposure to higher levels of PM2.5 and PM10 are associated with higher levels of corneal neurodegeneration, estimated from lower corneal nerve measures. Our results suggest that air pollution may be a determinant for neurodegeneration assessed in the cornea and may impact the ocular surface health as well.

Abstract Background Type 2 diabetes mellitus (T2DM) is a common chronic disease that disproportionally affects disadvantaged groups. People with a low socioeconomic position (SEP) have increased risk of T2DM and people with a low SEP and T2DM have higher HbA1c-levels compared to people with T2DM and high SEP. The aim of this study is to analyze longitudinal socioeconomic differences in health-related functioning in people with T2DM. Methods Longitudinal data from 1,537 participants of The Maastricht Study with T2DM were used (32.6% female, mean (SD) age 62.9 (7.7) years). SEP was determined by baseline measures of education, occupation and income. Health-related functioning (physical, mental and social) was measured with the Short-Form Health Survey and the Impact on Participation and Autonomy survey (all scored from 0 to 100). Associations of SEP and health-related functioning were studied annually over a 10-year period (median (IQR) 7.0 (5.0) years, baseline 2010–2018) using linear mixed methods adjusting for demographics, HbA1c-levels and lifestyle factors. Results Participants with a low SEP had significantly worse health-related functioning compared to those with a high SEP. For example, participants with low income had lower scores for physical (-4.49[CI -5.77;-3.21]), mental (-2.61[-3.78,-1.44]) and social functioning (-9.76[-12.30;-7.23]) compared to participants with high income on a scale from 0 to 100. In addition, participants with a low education significantly declined more over time in mental (score for interaction education with time − 0.23[-0.37;-0.09]) and social functioning (-0.44[-0.77;-0.11]) compared to participants with high education. Participants with low and intermediate incomes significantly declined more over time in physical functioning (-0.17 [-0.34, -0.01 and − 0.18 [-0.36, 0.00]) compared to participants with high income. Conclusions Among people with T2DM, those with a lower SEP had worse health-related functioning in general than people with a higher SEP. Additionally, people with T2DM and low education developed poorer mental and social functioning over time compared to people with T2DM and high education. People with T2DM and low or intermediate income declined more in physical functioning over time than those with high incomes. In addition to HbA1c-levels and lifestyle patterns, more attention is needed for socioeconomic differences in health-related functioning for people living with T2DM.

Abstract Background Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. Methods A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. Results Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. Conclusion SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect.

Abstract Background Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. Objective Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. Design We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. Results The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction

Abstract Background Glucose metabolism has been reported to be affected by dietary patterns, while the underlying mechanisms involved remain unclear. This study aimed to investigate the potential mediation role of circulating metabolites in relation to dietary patterns for prediabetes and type 2 diabetes. Methods Data was derived from The Maastricht Study that comprised of 3441 participants (mean age of 60 years) with 28% type 2 diabetes patients by design. Dietary patterns were assessed using a validated food frequency questionnaire (FFQ), and the glucose metabolism status (GMS) was defined according to WHO guidelines. Both cross-sectional and prospective analyses were performed for the circulating metabolome to investigate their associations and mediations with responses to dietary patterns and GMS. Results Among 226 eligible metabolite measures obtained from targeted metabolomics, 14 were identified to be associated and mediated with three dietary patterns (i.e. Mediterranean Diet (MED), Dietary Approaches to Stop Hypertension Diet (DASH), and Dutch Healthy Diet (DHD)) and overall GMS. Of these, the mediation effects of 5 metabolite measures were consistent for all three dietary patterns and GMS. Based on a 7-year follow-up, a decreased risk for apolipoprotein A1 (APOA1) and docosahexaenoic acid (DHA) (RR 0.60, 95% CI 0.55, 0.65; RR 0.89, 95% CI 0.83, 0.97, respectively) but an increased risk for ratio of ω-6 to ω-3 fatty acids (RR 1.29, 95% CI 1.05, 1.43) of type 2 diabetes were observed from prediabetes, while APOA1 showed a decreased risk of type 2 diabetes from normal glucose metabolism (NGM; RR 0.82, 95% CI 0.75, 0.89). Conclusions In summary, this study suggests that adherence to a healthy dietary pattern (i.e. MED, DASH, or DHD) could affect the GMS through circulating metabolites, which provides novel insights into understanding the biological mechanisms of diet on glucose metabolism and leads to facilitating prevention strategy for type 2 diabetes.

Abstract Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively − 0.16 [− 0.25; − 0.08]; − 0.05 [− 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively − 0.05 [− 0.08; − 0.01]; − 0.06 [− 0.09; − 0.02]; − 0.05 [− 0.08; − 0.02]; − 0.04 [− 0.07; − 0.01]; − 0.06 [− 0.12; − 0.01]; and − 0.07 [− 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.

Abstract Background More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. Methods IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (≥ 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4–6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 × 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. Discussion With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for. Trial registration EudraCT 2021-005059-35 . Registered on 12 December 2021. Study Code TMP-2204-2021-47.

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

In population-based cohort studies, magnetic resonance imaging (MRI) is vital for examining brain structure and function. Advanced MRI techniques, such as diffusion-weighted MRI (dMRI) and resting-state functional MRI (rs-fMRI), provide insights into brain connectivity. However, biases in MRI data acquisition and processing can impact brain connectivity measures and their associations with demographic and clinical variables. This study, conducted with 5110 participants from The Maastricht Study, explored the relationship between brain connectivity and various image quality metrics (e.g., signal-to-noise ratio, head motion, and atlas–template mismatches) that were obtained from dMRI and rs-fMRI scans. Results revealed that in particular increased head motion (R2 up to 0.169, p < 0.001) and reduced signal-to-noise ratio (R2 up to 0.013, p < 0.001) negatively impacted structural and functional brain connectivity, respectively. These image quality metrics significantly affected associations of overall brain connectivity with age (up to −59%), sex (up to −25%), and body mass index (BMI) (up to +14%). Associations with diabetes status, educational level, history of cardiovascular disease, and white matter hyperintensities were generally less affected. This emphasizes the potential confounding effects of image quality in large population-based neuroimaging studies on brain connectivity and underscores the importance of accounting for it.

Abstract N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

Abstract Mortality in type 2 diabetes, is determined not only by classical complications, but also by comorbidities, and is linked to hyperglycaemia and apparent even in prediabetes. We aimed to comprehensively investigate, in a population-based cohort, health burden defined as the presence of comorbidities in addition to classical complications and cardiometabolic risk factors, in not only type 2 diabetes but also prediabetes. Such population-based study has not been performed previously. Extensive phenotyping was performed in 3,410 participants of the population-based Maastricht Study (15.0% prediabetes and 28.6% type 2 diabetes) to assess presence of 17 comorbidities, six classical complications, and ten cardiometabolic risk factors. These were added up into individual and combined sum scores and categorized. Group differences were studied with multinomial regression analyses adjusted for age and sex. Individuals with type 2 diabetes and prediabetes, as compared to normal glucose metabolism (NGM), had greater comorbidities, classical complications, cardiometabolic risk factors and combined sum scores (comorbidities sum score ≥ 3: frequencies (95% CI) 61.5% (57.6;65.4) and 41.2% (36.5;45.9) vs. 25.4% (23.5;27.4), p-trend

Abstract Background Metformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo. Methods This study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease. Results This study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [− 8.4% (− 18.6, 3.2), p = 0.150, and − 4.6% (− 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [− 1.6% (− 2.9, − 0.2), p = 0.021] but not troponin I concentrations [− 1.5% (− 4.2, 1.2), p = 0.263]. Conclusions In this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinically relevant effect on cardiac troponin I and cardiac troponin T levels when compared to placebo. Cardioprotective effects of the drug observed in clinical studies are not reflected by a reduction in these biomarkers of subclinical myocardial injury. Trial registration ClinicalTrials.gov identifier NCT00375388.

Background Salt restriction may lower blood pressure variability (BPV), but previous studies have shown inconsistent results. Therefore, we investigated in an observational study and intervention trial whether urinary sodium excretion and salt intake are associated with 24‐hour BPV. Methods and Results We used data from the cross‐sectional population‐based Maastricht Study (n=2652; 60±8 years; 52% men) and from a randomized crossover trial (n=40; 49±11 years; 33% men). In the observational study, we measured 24‐hour urinary sodium excretion and 24‐hour BPV and performed linear regression adjusted for age, sex, mean blood pressure, lifestyle, and cardiovascular risk factors. In the intervention study, participants adhered to a 7‐day low‐ and high‐salt diet (50 and 250 mmol NaCl/24 h) with a washout period of 14 days, 24‐hour BPV was measured during each diet. We used linear mixed models adjusted for order of diet, mean blood pressure, and body mass index. In the observational study, 24‐hour urinary sodium excretion was not associated with 24‐hour systolic or diastolic BPV (β, per 1 g/24 h urinary sodium excretion: 0.05 mm Hg [95% CI, −0.02 to 0.11] and 0.04 mm Hg [95% CI, −0.01 to 0.09], respectively). In the intervention trial, mean difference in 24‐hour systolic and diastolic BPV between the low‐ and high‐salt diet was not statistically significantly different (0.62 mm Hg [95% CI, −0.10 to 1.35] and 0.04 mm Hg [95% CI, −0.54 to 0.63], respectively). Conclusions Urinary sodium excretion and salt intake are not independently associated with 24‐hour BPV. These findings suggest that salt restriction is not an effective strategy to lower BPV in the White general population. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02068781

Dysfunction of the neurovascular coupling unit may be an important contributor to dementia. The neurovascular coupling unit comprises neuronal structures (e.g. astrocytes) and vascular structures (e.g. endothelial cells) that functionally interact both at the level of the arterioles as well as at the capillary level (blood-brain barrier) to regulate optimal metabolic conditions in the brain. However, it remains unclear how and to what extent dysfunction of the neurovascular coupling unit contributes to the early-stage pathobiology of dementia. Currently, limited data are available on the association between neurovascular coupling unit dysfunction, as quantified by cerebral imaging techniques, and cognitive performance. In particular, there is a lack of population-based human data (defined as studies with a sample size ~n>500). This is an important limitation because population-based studies, in comparison with smaller clinical studies, provide data which is better representative of the general population; are less susceptible to selection bias; and have a larger statistical power to detect small associations. To acquire population-based data, however, alternative imaging techniques than cerebral imaging techniques may be required. Disadvantages of cerebral imaging techniques, which limit use in population-based studies, are that these techniques are relatively expensive, time-consuming, and/or invasive. In this review, we propose that retinal imaging techniques can be used for population-based studies: on the one hand the retina and brain have many anatomical and physiological similarities; and on the other hand retinal imaging techniques are non-invasive, highly accurate, relatively inexpensive, and require relatively short measurement time. To provide support for this concept, we provide an overview on the human (population-based) evidence on the associations of retinal indices of neurodegeneration, microvascular dysfunction, and dysfunction of the neurovascular coupling unit with magnetic resonance imaging (MRI) features of structural brain abnormalities and cognitive performance.

Abstract Background Vitamin K is associated with reduced cardiovascular disease risk such as heart failure, possibly by carboxylation of matrix-gla protein (MGP), a potent inhibitor of vascular calcification. The relationship of vitamin K intake or status with cardiac structure and function is largely unknown. Therefore this study aims to investigate the prospective association of vitamin K status and intake with echocardiographic measures. Methods This study included 427 participants from the Hoorn Study, a population-based cohort. Vitamin K status was assessed at baseline by plasma desphospho-uncarboxylated MGP (dp-ucMGP) with higher concentrations reflecting lower vitamin K status. Vitamin K intake was assessed at baseline with a validated food-frequency questionnaire. Echocardiography was performed at baseline and after a mean follow-up time of 7.6, SD=±0.7 years. We used linear regression for the association of vitamin K status and intake with left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI), adjusted for potential confounders. Results The mean age was 66.8, SD=±6.1 years (51% were male). A high vitamin K status was prospectively associated with decreased LVMI (change from baseline to follow-up: -5.0, 95% CI: -10.5;0.4 g/m2.7) for the highest quartile compared to the lowest in women (P-interaction sex=0.07). No association was found in men. Vitamin K status was not associated with LVEF or LAVI. Vitamin K intake was not associated with any of the echocardiographic measures. Conclusions This study showed a high vitamin K status being associated with decreased LVMI only in women, while intakes of vitamin K were not associated with any cardiac structure or function measures. These results extend previous findings for a role of vitamin K status to decrease heart failure risk.

Abstract We investigated the prospective associations of body composition with cardiac structure and function and explored effect modification by sex and whether inflammation was a mediator in these associations. Total body (BF), trunk (TF) and leg fat (LF), and total lean mass (LM) were measured at baseline by a whole body DXA scan. Inflammatory biomarkers and echocardiographic measures were determined both at baseline and follow-up in the Hoorn Study (n = 321). We performed linear regression analyses with body composition measures as determinant and left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) or left atrial volume index (LAVI) at follow-up as outcome. Additionally, we performed mediation analysis using inflammation at follow-up as mediator. The study population was 67.7 ± 5.2 years and 50% were female. After adjustment, BF, TF and LF, and LM were associated with LVMI with regression coefficients of 2.9 (0.8; 5.1)g/m2.7, 2.3 (0.6; 4.0)g/m2.7, 2.0 (0.04; 4.0)g/m2.7 and − 2.9 (− 5.1; − 0.7)g/m2.7. Body composition measures were not associated with LVEF or LAVI. These associations were not modified by sex or mediated by inflammation. Body composition could play a role in the pathophysiology of LV hypertrophy. Future research should focus on sex differences in regional adiposity in relation with diastolic dysfunction.

Abstract 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.

AimThis observational study aimed to examine the association between the A Body Shape Index (ABSI) and/or sarcopenia and total, cardiovascular, and cancer mortality.MethodsThe associations of sarcopenia and ABSI with all-cause, cardiovascular, and cancer mortality were assessed in 4,488 participants from the 1999–2004 National Health and Nutrition Examination Survey (NHANES) who were followed up until December 31, 2015. Models were analyzed separately for men and women and adjusted for age, race, and other confounding factors. ABSI was assessed as a continuous measurement by quartile for men and women. Population attributable fractions (PAFs) were calculated to assess mortality caused by sarcopenia and/or ABSI in the study population.ResultsWhen ABSI was assessed as a continuous variable, the ABSI quartile showed a linear trend for total (p = 0.0001), cardiovascular (p = 0.04), and cancer (p = 0.02) mortality in men and for total (p = 0.06) and cardiovascular (p = 0.06) mortality in women. The hazard ratios (HRs) of the fourth ABSI quartile were 1.51 [95% confidence interval (CI): 1.20–1.89] in men and 1.23 (95% CI: 0.93–1.64) in women, compared with those in the first quartile. When ABSI was assessed by quartile, the appendicular skeletal mass index (ASMI) was lower in the groups with high ABSI. When high ABSI was combined with sarcopenia, the HRs of all-cause mortality were 2.05 (95% CI: 1.60–2.62) in men and 1.51 (95% CI: 1.19–1.92) in women. In the subpopulation (sarcopenia group or higher ABSI), the PAFs of mortality due to sarcopenia were 26.16% (95% CI: 12.68–37.56) in men and 21.89% (95% CI: 5.64–35.35) in women, and the PAF of mortality due to higher ABSI was 23.70% (95% CI: 12.11–33.77) in men.ConclusionThe ABSI value was significantly associated with all-cause and cardiovascular mortality, and the co-existence of higher ABSI values and sarcopenia can contribute to a more significant death risk in comparison with high ABSI values or sarcopenia. Moreover, the ABSI values in combination with the ASMI can be used to preliminarily evaluate the content and distribution of fat and muscle and to predict the risk of death in obese and sarcopenic populations.

BackgroundType 2 diabetes (T2D) is frequently reported to be associated with an increased fracture risk. Epidemiological data on prevalent morphometric vertebral fractures (VFs) in T2D are sparse and even less is known in the prediabetic state.PurposeTo determine the association between prevalence and severity of morphometric VFs and glucose metabolism state: normal glucose metabolism (NGM), impaired glucose metabolism (prediabetes) or T2D.MethodsThis study included cross-sectional data from 3625 participants of the Maastricht Study who had a vertebral fracture assessment on lateral Dual Energy X-Ray Absorptiometry images. VFs were classified based on morphometric assessment into mild, moderate and severe VFs (respectively 20–24%, 25–39% or ≥40% reduction in expected vertebral body height). Logistic regression models were used to investigate the association between glucose metabolism status and the prevalence and severity of VFs. Analyses were adjusted for subject characteristics and life-style factors.ResultsT2D individuals were older (62.8 ± 7.5 years old) and less often female (30.5%) compared to the NGM group (57.7 ± 8.5 years old, and 58.8% female, respectively). At least one mild, moderate or severe prevalent VF was found in 8.6% of the men and 2.2% of the women in the T2D group, in 9.4% and 8.4% in the prediabetes group and in 9.1% and 4.8% in the NGM group, respectively. After adjustment T2D in women was associated with a lower probability of having a prevalent VF compared to NGM [adjusted OR 0.25 (95% CI 0.09-0.65)], while this was not the case for prediabetes. Furthermore, women with T2D had a significantly lower probability of a prevalent moderate or severe VF [adjusted OR 0.32 (95% CI 0.11-0.96)]. In men there was no significant association between T2D or prediabetes and prevalent VFs.ConclusionWomen with T2D had a lower probability of prevalent VFs compared to women with a normal glucose metabolism, while this was not the case for men with T2D and participants with prediabetes.

Abstract 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

Abstract 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.

Abstract 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 HbA1c 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 [CWSmean] and pulsatile [CWSpuls] circumferential wall stress), and microvascular function (retinal arteriolar average dilatation; heat-induced skin hyperemia) via multiple linear regression with adjustment for age, sex, HbA1c, 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 CWSmean (B: 0.227 kPa [0.008; 0.446]). IGP was not independently associated with carDC (B: − 0.026 10−3/kPa [− 0.112; 0.060]), cIMT (B: − 2.745 µm [− 5.736; 0.245]), CWSpuls (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.

ObjectiveTo evaluate the association between overweight and obesity on the clinical course and outcomes in patients hospitalized with COVID-19.DesignRetrospective, observational cohort study.MethodsWe performed a multicenter, retrospective, observational cohort study of hospitalized COVID-19 patients to evaluate the associations between overweight and obesity on the clinical course and outcomes.ResultsOut of 1634 hospitalized COVID-19 patients, 473 (28.9%) had normal weight, 669 (40.9%) were overweight, and 492 (30.1%) were obese. Patients who were overweight or had obesity were younger, and there were more women in the obese group. Normal-weight patients more often had pre-existing conditions such as malignancy, or were organ recipients. During admission, patients who were overweight or had obesity had an increased probability of acute respiratory distress syndrome [OR 1.70 (1.26-2.30) and 1.40 (1.01-1.96)], respectively and acute kidney failure [OR 2.29 (1.28-3.76) and 1.92 (1.06-3.48)], respectively. Length of hospital stay was similar between groups. The overall in-hospital mortality rate was 27.7%, and multivariate logistic regression analyses showed that overweight and obesity were not associated with increased mortality compared to normal-weight patients.ConclusionIn this study, overweight and obesity were associated with acute respiratory distress syndrome and acute kidney injury, but not with in-hospital mortality nor length of hospital stay.

Purpose: Carotid artery properties can be evaluated with high accuracy and reproducibility using multiple M-line ultrasound. However, the cost of multiple M-line-based imaging modalities and the extensive operator expertise requirements hamper the large-scale application for arterial properties assessment, particularly in resource-constrained settings. This study is aimed to assess the performance of a single M-line approach as an affordable and easy-to-use alternative to multiple M-line imaging for screening purposes.Methods: We used triplicate longitudinal common carotid artery (CCA) ultrasound recordings (17 M-lines covering about 16 mm, at 500 frames per second) of 500 subjects from The Maastricht Study to assess the validity and reproducibility of a single against multiple M-line approach. The multiple M-line measures were obtained by averaging over all available 17 lines, whereas the middle M-line was used as a proxy for the single M-line approach.Results: Diameter, intima-media thickness (IMT), and Young's elastic modulus (YEM) were not significantly different between the single and multiple M-line approaches (p > 0.07). Distension and distensibility coefficient (DC) did differ significantly (p < 0.001), however, differences were technically irrelevant. Similarly, Bland-Altman analysis revealed good agreement between the two approaches. The single M-line approach, compared to multiple M-line, exhibited an acceptable reproducibility coefficient of variation (CV) for diameter (2.5 vs. 2.2%), IMT (11.9 vs. 7.9%), distension (10 vs. 9.4%), DC (10.9 vs. 10.2%), and YEM (26.5 vs. 20.5%). Furthermore, in our study population, both methods showed a similar capability to detect age-related differences in arterial stiffness.Conclusion: Single M-line ultrasound appears to be a promising tool to estimate anatomical and functional CCA properties with very acceptable validity and reproducibility. Based on our results, we might infer that image-free, single M-line tools could be suited for screening and for performing population studies in low-resource settings worldwide. Whether the comparison between single and multiple M-line devices will yield similar findings requires further study.

AimWe performed a meta-analysis of observational studies to evaluate the association between the presence of sarcopenia and HbA1c, prediabetes, diabetes and diabetic complications.MethodThe PubMed, Embase, Cochrane and Web of Science databases were searched from inception to May 2021. We included full-text English language articles that reported the prevalence of sarcopenia in patients with and without diabetes. Quality assessment was performed according to the Newcastle- Ottawa scale for observational studies.ResultsSixteen studies were included in the meta-analysis. Three studies showed that high HbA1c levels lead to loss of muscle mass, and one study involving prediabetes showed that people with prediabetes had lower muscle mass, strength, and performance than non-diabetic population. Seven studies showed that people with diabetes had a higher risk of sarcopenia than those without diabetes (combined OR: 2.09, 95% CI:1.62-2.70). The remaining five studies suggested that diabetic complications increased the risk of sarcopenia (combined OR: 2.09,95% CI:1.62-2.70).ConclusionHigh HbA1c levels, prediabetes, diabetes and diabetes complications were associated with an increased risk of sarcopenia. Therapeutic strategies addressed to avoid the conversion of IGT to diabetes and to optimize glycemic control are warranted to prevent or arrest sarcopenia in the diabetic population

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community‐based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima‐media thickness, Young’s elastic modulus, carotid‐femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid‐femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5±6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9±8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima‐media thickness (β=0.21; 0.17–0.26), Young’s elastic modulus (β=0.21; 0.17–0.25), carotid‐femoral pulse wave velocity (β=0.24; 0.14–0.34), carotid pulse wave velocity (β=0.31; 0.26–0.35), and carotid diameter (β=0.43; 0.38–0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

Abstract Objective A recent Mendelian randomization study has suggested a causal role for sex hormone‐binding globulin (SHBG), total testosterone and free testosterone in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to assess the relationships of SHBG, androstenedione, total and free testosterone with the individual metabolic and reproductive features of PCOS. Design Cross‐sectional data in PCOS patients (n=96) prospectively collected in a secondary/tertiary clinic for menstrual cycle disorders. Methods Multivariable regression analyses were conducted to study the associations between SHBG, androstenedione, total and free testosterone with metabolic (BMI, waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homeostatic model assessment for insulin resistance [HOMA2‐IR]) and reproductive features (menstrual cycle length, antral follicle count, anti‐Müllerian hormone, luteinizing hormone, follicle‐stimulating hormone and Ferriman‐Gallwey score) of PCOS. Results Serum SHBG and free testosterone, but not total testosterone or androstenedione, were significantly associated with BMI, waist circumference, serum triglycerides, HDL cholesterol, LDL cholesterol and HOMA2‐IR. The strength of the associations with serum lipids was reduced after adjustment for BMI, but not for HOMA2‐IR. Total testosterone was significantly associated with antral follicle count. SHBG, total testosterone and androstenedione were significantly associated with serum AMH. Only the strength of the association for SHBG was reduced after adjustment for BMI. Conclusions Serum SHBG is associated with primarily metabolic features, whereas total testosterone and androstenedione are associated with reproductive features of PCOS. These results suggest a differential underlying pathophysiology for the metabolic and reproductive features of PCOS.

Background This cross‐sectional study evaluated associations between structural and functional measures of left ventricular diastolic function and cardiorespiratory fitness (CRF) in a well‐characterized population‐based cohort stratified according to glucose metabolism status. Methods and Results Six hundred seventy‐two participants from The Maastricht Study (mean±SD age, 61±9 years; 17.4% prediabetes and 25.4% type 2 diabetes mellitus) underwent both echocardiography to determine left atrial volume index, left ventricular mass index, maximum tricuspid flow regurgitation, average e′ and E/e′ ratio; and submaximal cycle ergometer test to determine CRF as maximum power output per kilogram body mass. Associations were examined with linear regression adjusted for cardiovascular risk and lifestyle factors, and interaction terms. After adjustment, in normal glucose metabolism but not (pre)diabetes, higher left atrial volume index (per 1 mL/m2), left ventricular mass index (per 1 g/m2.7), maximum tricuspid regurgitation flow (per 1 m/s) were associated with higher CRF (maximum power output per kilogram body mass; β in normal glucose metabolism 0.015 [0.008–0.023], Pinteraction (pre)diabetes 0.10; for left atrial volume index, left ventricular mass index, maximum tricuspid regurgitation flow, respectively). Furthermore, after adjustment, in all individuals, higher average E/e′ ratio (per unit), but not average e′, was associated with lower CRF (normal glucose metabolism −0.044 [−0.071 to −0.016]), Pinteraction >0.10). Conclusions In this population‐based study, structural and functional measures of left ventricular diastolic function were independently differentially associated with CRF over the strata of glucose metabolism status. This suggests that deteriorating left ventricular diastolic function, although of small effect, may contribute to the pathophysiological process of impaired CRF in the general population. Moreover, the differential effects in these structural measures may be the consequence of cardiac structural adaptation to effectively increase CRF in normal glucose metabolism, which is absent in (pre)diabetes.

Abstract Background The gut microbiota evolves from birth and is in early life influenced by events such as birth mode, type of infant feeding, and maternal and infant antibiotics use. However, we still have a gap in our understanding of gut microbiota development in older children, and to what extent early events and pre-school lifestyle modulate the composition of the gut microbiota, and how this impinges on whole body metabolic regulation in school-age children. Results Taking advantage of the KOALA Birth Cohort Study, a long-term prospective birth cohort in the Netherlands with extensive collection of high-quality host metadata, we applied shotgun metagenomics sequencing and systematically investigated the gut microbiota of children at 6–9 years of age. We demonstrated an overall adult-like gut microbiota in the 281 Dutch school-age children and identified 3 enterotypes dominated by the genera Bacteroides, Prevotella, and Bifidobacterium, respectively. Importantly, we found that breastfeeding duration in early life and pre-school dietary lifestyle correlated with the composition and functional competences of the gut microbiota in the children at school age. The correlations between pre-school dietary lifestyle and metabolic phenotypes exhibited a striking enterotype dependency. Thus, an inverse correlation between high dietary fiber consumption and low plasma insulin levels was only observed in individuals with the Bacteroides and Prevotella enterotypes, but not in Bifidobacterium enterotype individuals in whom the gut microbiota displayed overall lower microbial gene richness, alpha-diversity, functional potential for complex carbohydrate fermentation, and butyrate and succinate production. High total fat consumption and elevated plasma free fatty acid levels in the Bifidobacterium enterotype are associated with the co-occurrence of Streptococcus. Conclusions Our work highlights the persistent effects of breastfeeding duration and pre-school dietary lifestyle in affecting the gut microbiota in school-age children and reveals distinct compositional and functional potential in children according to enterotypes. The findings underscore enterotype-specific links between the host metabolic phenotypes and dietary patterns, emphasizing the importance of microbiome-based stratification when investigating metabolic responses to diets. Future diet intervention studies are clearly warranted to examine gut microbe-diet-host relationships to promote knowledge-based recommendations in relation to improving metabolic health in children.

Dietary advanced glycation endproducts (AGEs), abundantly present in Westernized diets, are linked to negative health outcomes, but their impact on the gut microbiota has not yet been well investigated in humans. We investigated the effects of a 4-week isocaloric and macronutrient-matched diet low or high in AGEs on the gut microbial composition of 70 abdominally obese individuals in a double-blind parallel-design randomized controlled trial (NCT03866343). Additionally, we investigated the cross-sectional associations between the habitual intake of dietary dicarbonyls, reactive precursors to AGEs, and the gut microbial composition, as assessed by 16S rRNA amplicon-based sequencing. Despite a marked percentage difference in AGE intake, we observed no differences in microbial richness and the general community structure. Only the Anaerostipes spp. had a relative abundance >0.5% and showed differential abundance (0.5 versus 1.11%; p = 0.028, after low- or high-AGE diet, respectively). While the habitual intake of dicarbonyls was not associated with microbial richness or a general community structure, the intake of 3-deoxyglucosone was especially associated with an abundance of several genera. Thus, a 4-week diet low or high in AGEs has a limited impact on the gut microbial composition of abdominally obese humans, paralleling its previously observed limited biological consequences. The effects of dietary dicarbonyls on the gut microbiota composition deserve further investigation.

BackgroundInsight 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.MethodsPubMed 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.ResultsOverall, 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.ConclusionOverall, 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.

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study.

The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice.

Abstract Background Social isolation is associated with type 2 diabetes (T2DM), but it is unclear which elements play a crucial role in this association. Therefore, we assessed the associations of a broad range of structural and functional social network characteristics with normal glucose metabolism, pre-diabetes, newly diagnosed T2DM and previously diagnosed T2DM. Methods Participants originated from The Maastricht Study, a population-based cohort study (n = 2861, mean age 60.0 ± 8.2 years, 49% female, 28.8% T2DM (oversampled)). Social network characteristics were assessed through a name generator questionnaire. Diabetes status was determined by an oral glucose tolerance test. We used multinomial regression analyses to investigate the associations between social network characteristics and diabetes status, stratified by sex. Results More socially isolated individuals (smaller social network size) more frequently had newly diagnosed and previously diagnosed T2DM, while this association was not observed with pre-diabetes. In women, proximity and the type of relationship was associated with newly diagnosed and previously diagnosed T2DM. A lack of social participation was associated with pre-diabetes as well as with previously diagnosed T2DM in women, and with previously diagnosed T2DM in men. Living alone was associated with higher odds of previously diagnosed T2DM in men, but not in women. Less emotional support related to important decisions, less practical support related to jobs, and less practical support for sickness were associated with newly diagnosed and previously diagnosed T2DM in men and women, but not in pre-diabetes. Conclusion This study shows that several aspects of structural and functional characteristics of the social network were associated with newly and previously diagnosed T2DM, partially different for men and women. These results may provide useful targets for T2DM prevention efforts.

Abstract Background Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. Methods Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. Results After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [β per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [β per 1 SD higher lnMMP-1 and lnMMP-2 = − 0.83 mmHg (95% CI − 1.50; − 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. Conclusions MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets.

Abstract Interest in high-sensitivity cardiac troponin I(hs-cTnI) and T(hs-cTnT) has expanded from acute cardiac care to cardiovascular disease(CVD) risk stratification. Whether hs-cTnI and hs-cTnT are interchangeable in the ambulant setting is largely unexplored. Cardiac injury is a mechanism that may underlie the associations between troponin levels and mortality in the general population. In the population-based Maastricht Study, we assessed the correlation and concordance between hs-cTnI and hs-cTnT. Multiple regression analyses were conducted to assess the association of hs-cTnI and hs-cTnT with electrocardiographic (ECG) changes indicative of cardiac abnormalities. In 3016 eligible individuals(mean age,60 ± 8years;50.6%,men) we found a modest correlation between hs-cTnI and hs-cTnT(r = 0.585). After multiple adjustment, the association with ECG changes indicative of cardiac abnormalities was similar for both hs-cTn assays(OR,hs-cTnI:1.72,95%CI:1.40-2.10;OR,hs-cTnT:1.60,95%CI:1.22–2.11). The concordance of dichotomized hs-cTnI and hs-cTnT was κ = 0.397(≥sex-specific 75th percentile). Isolated high levels of hs-cTnI were associated with ECG changes indicative of cardiac abnormalities(OR:1.93,95%CI:1.01–3.68), whereas isolated high levels of hs-cTnT were not(OR:1.07,95%CI:0.49–2.31). In conclusion, there is a moderate correlation and limited concordance between hs-cTnI and hs-cTnT under non-acute conditions. These data suggest that associations of hs-cTnI and hs-cTnT with cardiac injury detected by ECG are driven by different mechanisms. This information may benefit future development of CVD risk stratification algorithms.

Abstract Background Using cross-sectional data from The Maastricht Study, we examined the association of socioeconomic conditions in early life with prediabetes and T2DM in adulthood. We also examined potential mediating pathways via both adulthood socioeconomic conditions and adult BMI and health behaviours. Methods Of the 3263 participants (aged 40–75 years), 493 had prediabetes and 906 were diagnosed with T2DM. By using logistic regression analyses, the associations and possible mediating pathways were examined. Results Participants with low early life socioeconomic conditions had a 1.56 times higher odds of prediabetes (95% confidence interval (CI) = 1.21-2.02) and a 1.61 times higher odds of T2DM (95% CI = 1.31-1.99). The relation between low early life socioeconomic conditions and prediabetes was independent of current socioeconomic conditions (OR = 1.38, 95% CI = 1.05-1.80), whereas the relation with T2DM was not independent of current socioeconomic conditions (OR = 1.10, 95% CI = 0.87-1.37). BMI party mediated the association between early life socioeconomic conditions and prediabetes. Conclusions Socioeconomic inequalities starting in early life were associated with diabetes-related outcomes in adulthood and suggest the usefulness of early life interventions aimed at tackling these inequalities.

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 (β=0.090; 95% CI 0.041; 0.139) but inversely with protein-bound CML (β=−0.071; 95% CI -0.108; -0.034). Similarly, the LE score was positively associated with free CML (β=0.044; 95% CI 0.012; 0.076) and CEL (β=0.040; 95% CI 0.009; 0.072) but inversely with protein-bound CML (β=−0.037; 95% CI -0.060; -0.013). Free CML (β=0.297; 95% CI 0.049; 0.545) was positively associated with LGI, while protein-bound CML (β=−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.

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 GLO1 may alter the expression and/or the activity of Glo1, we examined the association of nine SNPs in GLO1 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, n = 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, p = 0.02 and TT = −0.39, p = 0.3). Similarly, SNP13 (rs3799703) was associated with Glo1 expression (GG as reference, standardized beta AG = 0.17, p = 0.14 and AA = 0.36, p = 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 GLO1 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.

Extracellular matrix protein turnover may play an important role in left atrial (LA) remodelling. The aim is to investigate the associations between matrix metalloproteinase (MMPs), tissue inhibitor of metalloproteinase (TIMP-1) and LA volume index (LAVI) and if these associations are independent of TIMP-1 levels. Participants from The Hoorn Study, a population-based cohort study (n = 674), underwent echocardiography. Serum MMPs (i.e., MMP-1, MMP-2, MMP-3, MMP-9, and MMP-10) and TIMP-1 levels were measured with ELISA. Multiple linear regression analyses were used. MMP-1 levels were not associated with LAVI. Higher MMP-2 levels were associated with larger LAVI (regression coefficient per SD increase in MMP (95% CI); 0.03 (0.01; 0.05). Higher MMP-3 and MMP-9 levels were associated with smaller LAVI; −0.04 (−0.07; −0.01) and −0.04 (−0.06; −0.02) respectively. Only in women were higher MMP-10 levels associated with larger LAVI; 0.04 (0.00; 0.07, p-interaction 0.04). Additionally, only in women were higher TIMP-1 levels associated with smaller LAVI; −0.05 (−0.09; −0.01, p-interaction 0.03). The associations between MMPs and LAVI were independent of TIMP-1 levels. In conclusion, serum MMPs are associated with LAVI, independent of CVD risk factors and TIMP-1 levels. In addition, these associations differ according to sex and within MMP subgroups. This shows that the role of MMPs in LA remodelling is complex.

Background: In an aging population, regular physical activity (PA) and exercise have been recognized as important factors in maintaining physical function and thereby preventing loss of independence and disability. However, (older) adults spent the majority of their day sedentary and therefore insight into the consequences of sedentary behavior on physical function, independent of PA, is warranted.Objective: To examine the associations of objectively measured sedentary time (ST), patterns of sedentary behavior, overall PA, and higher intensity PA (HPA) with objective measures of physical function.Methods: This is a cross-sectional study in 1,932 men and women (aged 40–75 years) participating in The Maastricht Study. The activPAL3 was used to assess daily sedentary behavior: ST (h), sedentary breaks (n), prolonged (≥30 min) sedentary bouts (n), and to assess time spent in (H)PA (h). Measures of physical function included: covered distance during a 6 min walk test [6MWD (meters)], timed chair rise stand test performance [TCSTtime (seconds)], grip strength (kg kg−1), and elbow flexion and knee extension strength (Nm kg−1). Linear regression analyses were used to examine associations between daily sedentary behavior and PA with physical function.Results: Every additional hour ST was associated with shorter 6MWD [B = −2.69 m (95% CI = −4.69; −0.69)] and lower relative elbow extension strength (B = −0.01 Nm kg−1 (−0.02; 0.00). More sedentary breaks were associated with faster TCSTtime: B = −0.55 s (−0.85; −0.26). Longer average sedentary bout duration was associated with slower TCSTtime [B = 0.17 s (0.09; 0.25)] and lower knee extension strength [B = −0.01 Nm kg−1 (−0.02; 0.00)]. Every hour of PA and HPA were associated with greater 6MWD [BPA = 15.88 m (9.87; 21.89), BHPA = 40.72 m (30.18; 51.25)], faster TCSTtime [BPA = −0.55 s (−1.03; −0.07), BHPA = −2.25 s (−3.09; −1.41)], greater elbow flexion strength [BPA = 0.03 Nm kg−1 (0.01; 0.07)], [BHPA = 0.05 Nm kg−1 (0.01; 0.08)], and greater knee extension strength [BPA = 0.04 Nm kg−1 (0.01; 0.07)], [BHPA = 0.13 Nm kg−1 (0.06; 0.20)].Conclusion: In adults aged 40–75 years, sedentary behavior appeared to be marginally associated with lower physical function, independent of HPA. This suggests that merely reducing sedentary behavior is insufficient to improve/maintain physical function. In contrast, engaging regularly in PA, in particular HPA, is important for physical function.

Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nε-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation.