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Aims: Dicarbonyl compounds contribute to the formation of advanced glycation endproducts (AGEs) and the development of insulin resistance and vascular complications. Dicarbonyl stress may already be detrimental in obesity. We evaluated whether diet-induced weight loss can effectively reverse dicarbonyl stress in abdominally obese men. Materials and methods: Plasma samples were collected from lean (n = 25) and abdominally obese men (n = 52) in the fasting state, and during a mixed meal test (MMT). Abdominally obese men were randomized to 8 weeks of dietary weight loss or habitual diet, followed by a second MMT. The α-dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG) and AGEs were measured by UPLC-MS/MS. Skin autofluorescence (SAF) was measured using the AGE reader. T-tests were used for the cross-sectional analysis and ANCOVA to assess the treatment effect. Results: Postprandial glucose, MGO and 3-DG concentrations were higher in obese men as compared to lean men (p < 0.05 for all). Fasting dicarbonyls, AGEs, and SAF were not different between lean and obese men. After the weight loss intervention, fasting MGO levels tended to decrease by 25 nmol/L (95%-CI: -51-0.5; p = 0.054). Postprandial dicarbonyls were decreased after weight loss as compared to the control group: iAUC of MGO decreased by 57% (5280 nmol/L∙min; 95%-CI: 33–10526; p = 0.049), of GO by 66% (11,329 nmol/L∙min; 95%-CI: 495–22162; p = 0.041), and of 3-DG by 45% (20,175 nmol/L∙min; 95%-CI: 5351–35000; p = 0.009). AGEs and SAF did not change significantly after weight loss. Conclusion: Abdominal obesity is characterized by increased postprandial dicarbonyl stress, which can be reduced by a weight loss intervention. Registered under ClinicalTrials.gov Identifier no. NCT01675401.

BACKGROUND: There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. OBJECTIVES: The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. METHODS: Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. RESULTS: Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 μmol/d; 95% CI: -91.2, -10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. CONCLUSIONS: Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428.

BACKGROUND: Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation. METHODS: To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively. RESULTS: Higher sRAGE concentrations were inversely associated with colorectal cancer (ORQ5vs.Q1, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (ORQ5vs.Q1, 1.00; 95% CI, 0.68-1.48; Pheterogeneity for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99). CONCLUSIONS: Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within ADAM10 gene, pertaining to RAGE shedding, was associated with colorectal cancer risk. IMPACT: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.

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High plasma levels of the sphingolipid intermediates ceramide (Cer) and sphingosine-1-phosphate (S1P) are suggested to be involved in the development of insulin resistance (IR). Recent evidence indicates that advanced glycation endproducts (AGEs) can alter the sphingolipids metabolism equilibrium. Since enzymes responsible for sphingolipid rheostat maintenance are highly expressed in liver, we thus investigated whether AGEs accumulation can affect hepatic sphingolipids metabolism in insulin resistant mice. Two different models of IR were examined: genetically diabetic LeptrDb-/- (DbDb) and diet-induced insulin resistant C57Bl/6J mice fed a 60% trans-fat diet (HFD). In addition, a group of HFD mice was supplemented with the anti-AGEs compound pyridoxamine. AGEs were evaluated in the liver by western blotting. Cer and S1P were measured by UHPLC-MS/MS. The expression of RAGE and of enzymes involved in sphingolipid metabolism were assessed by RT-PCR and western blotting. HepG2 cells were used to study the effect of the major AGE N epsilon(carboxymethyl)lysine (CML)-albumin on sphingolipid metabolism and the role of the receptor of AGEs (RAGE). High levels of AGEs and RAGE were detected in the liver of both DbDb and HFD mice in comparison to controls. The expression of enzymes of sphingolipid metabolism was altered in both models, accompanied by increased levels of Cer and S1P. Specifically, ceramide synthase 5 and sphingosine kinase 1 were increased, while neutral ceramidase was reduced. Pyridoxamine supplementation to HFD mice diminished hepatic AGEs and prevented alterations of sphingolipid metabolism and the development of IR. CML administration to HepG2 cells evoked alterations similar to those observed in vivo, that were in part mediated by the binding to RAGE. The present study shows a direct involvement of AGEs in alterations of sphingolipid metabolism associated to the development of IR. The modulation of sphingolipids metabolism through the prevention of AGE

Scope: Dietary advanced glycation endproducts (AGEs) are associated with negative biological effects, possibly due to accumulation in plasma and tissues and through modulation of inflammation and gut microbiota. Whether these biological consequences are reversible by limiting dietary AGE intake is unknown.Methods and results: Young healthy C57BL/6 mice were fed a standard chow (n = 10) or a baked chow high AGE-diet (n = 10) (similar to 1.8-6.9 fold increased protein-bound N epsilon-(carboxymethyl)lysine (CML), N epsilon-(1-carboxyethyl) lysine (CEL), and N delta-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)) for 10 weeks or a switch diet with baked chow for 5 weeks followed by 5 weeks of standard chow (n = 10). We assessed accumulation of AGEs in plasma, kidney, and liver and measured inflammatory markers and gut microbial composition. After 10 weeks of baked chow, a substantial panel of AGEs were increased in plasma, liver, and kidney. These increases were normalized after the switch diet. The inflammatory z-score increased after the baked chow diet. Gut microbial composition differed significantly between groups, with enriched Dubosiella spp. dominating these alterations.Conclusion: A high AGE-diet led to an increase of AGEs in plasma, kidney, and liver and to more inflammation and modification of the gut microbiota. These effects were reversed or discontinued by a diet lower in AGEs.

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Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs-N epsilon-(carboxy-methyl)lysine (CML), N epsilon-(carboxy-ethyl)lysine (CEL) and N delta-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)-were measured by ultra-performance liquid chromatography-tandem mass spectrometry in baseline samples collected from 1378 incident primary colorectal cancer cases and 1378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5 (versus Q1) = 0.40, 95% CI: 0.27-0.59), MG-H1 (ORQ5 versus Q1 = 0.73, 95% CI: 0.53-1.00) and total AGEs (OR Q5 versus Q1 = 0.52, 95% CI: 0.37-0.73), whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5 versus Q1 = 1.91, 95% CI: 1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical sub-site. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.

Background: Advanced glycation end products (AGEs) are protein modifications that are predominantly formed from dicarbonyl compounds that arise from glucose and lipid metabolism. AGEs and sedentary behavior have been identified as a driver of accelerated (vascular) aging. The effect of physical activity on AGE accumulation is unknown. Therefore, we investigated whether plasma AGEs and dicarbonyl levels are different across older individuals that were active or sedentary and whether plasma AGEs are affected by high-intensity interval training (HIIT).Methods: We included healthy older active (HA, n=38, 44.7% female, 60.1 +/- 7.7 years old) and healthy older sedentary (HS, n=36, 72.2% female, 60.0 +/- 7.3 years old) individuals as well as older sedentary individuals with increased cardiovascular risk (SR, n=84, 50% female, 58.7 +/- 6.6 years old). The SR group was randomized into a 12-week walking-based HIIT program or control group. We measured protein-bound and free plasma AGEs and dicarbonyls by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) at baseline and after the HIIT intervention.Results: Protein-bound AGE Ne-(carboxymethyl)lysine (CML) was lower in SR (2.6 +/- 0.5 mu mol/l) and HS (3.1 +/- 0.5 mu mol/l) than in HA (3.6 +/- 0.6 mu mol/l; PDiscussion: Although lifestyle interventions may act as important modulators of cardiovascular risk, HIIT is not a potent short-term intervention to reduce glycation in older individuals, underlining the need for other approaches, such as pharmacological agents, to reduce AGEs and lower cardiovascular risk in this population.

Background: Effects of weight loss on postprandial vascular function have not been studied so far. We therefore examined (i) effects of diet-induced weight loss on postprandial changes in various vascular function markers after consumption of a mixed meal and (ii) differences between normal-weight and abdominally obese men of comparable age at baseline and after weight loss.Methods: Fifty-four apparently healthy abdominally obese (waist circumference: 102-110 cm) and 25 normal-weight men (waist circumference:Results: The mean weight loss was 10.3 kg in the weight-loss compared with the control group. The postprandial change in flow-mediated vasodilation of the brachial artery (FMD) was significantly higher at baseline in normal-weight as compared with the postprandial change in abdominally obese men (1.89 +/- 2.52 versus 0.48 +/- 2.50 percentage points; P = 0.027). However, no differences in postprandial changes were observed in the abdominally obese men after weight loss compared with the control treatment. Also, weight reduction did not affect postprandial changes in carotid-to-femoral pulse wave velocity, retinal microvascular caliber properties, or plasma markers of microvascular endothelial function. Even though postprandial increases in triacylglycerol (P = 0.028), insulin (P = 0.029) and C-peptide concentrations (P <0.001) were reduced in the abdominally obese men following weight loss, postprandial changes in FMD at the end of the weight-loss treatment were still more unfavorable as compared with those observed in normal-weight individuals.Conclusion: In this trial with abdominally obese men, we did not find effects of diet-induced weight loss on postprandial changes in vascular endothelial function, arterial stiffness and markers of microvascular function. (C) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

BACKGROUND. Salt-sensitive hypertension is often accompanied by insulin resistance in obese individuals, but the underlying mechanisms are obscure. Microvascular function is known to affect both salt sensitivity of blood pressure and metabolic insulin sensitivity. We hypothesized that excessive salt intake increases blood pressure and decreases insulin-mediated glucose disposal, at least in part by impairing insulin-mediated muscle microvascular recruitment (IMMR).METHODS. In 20 lean and 20 abdominally obese individuals, we assessed mean arterial pressure (MAP; 24-hour ambulatory blood pressure measurements), insulin-mediated whole-body glucose disposal (M/I value; hyperinsulinemic-euglycemic clamp technique), IMMR (contrast-enhanced ultrasound), osmolyte and water balance, and excretion of mineralocorticoids, glucocorticoids, and amino and organic acids after a low- and high-salt diet during 7 days in a randomized, double-blind, crossover design.RESULTS. On a low-, as compared with a high-salt, intake, MAP was lower, M/I value was lower, and IMMR was greater in both lean and abdominally obese individuals. In addition, natural logarithm IMMR was inversely associated with MAP in lean participants on a low-salt diet only. On a high-salt diet, free water clearance decreased, and excretion of glucocorticoids and of amino acids involved in the urea cycle increased.CONCLUSION. Our findings imply that hemodynamic and metabolic changes resulting from alterations in salt intake are not necessarily associated. Moreover, they are consistent with the concept that a high-salt intake increases muscle glucose uptake as a response to high salt-induced, glucocorticoid-driven muscle catabolism to stimulate urea production and thereby renal water conservation.

Insights into individual differences in gene expression and its heritability (h(2)) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h(total)(2), composed of cis-heritability (h(cis)(2), the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h(res)(2), the residual variance explained by all other genome-wide variants). Mean h(total)(2) was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h(2) = 0.14, p = 6.15 x 10(-258)). Mean h(cis)(2) was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, rho = 0.76, p <10(-308)) and with estimates from earlier RNA-Seq-based studies. Mean h(res)(2) was 0.20 and correlated with the beta of the corresponding trans-eQTL (rho = 0.04, p <1.89 x 10(-3)) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 x 10(-15)), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h(2) estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.

Microvascular dysfunction (MVD) is a common pathophysiological change that occurs in various diseases, such as type 2 diabetes mellitus (T2DM), heart failure, dementia, and depression. Recent technical advances have enabled noninvasive measurement and quantification of microvascular changes in humans. In this paper, we describe the protocols of the microvascular measurements applied in the Maastricht Study, an ongoing prospective, population-based cohort study of persons aged 40–75 years being carried out in the southern part of the Netherlands (baseline data assessment, November 2010–January 2020). The study includes a variety of noninvasive measurements in skin, retina, brain, and sublingual tissue, as well as plasma and urine biomarker assessments. Following this, we summarize our main findings involving these microvascular measurements through the end of 2018. Finally, we provide a brief perspective on future microvascular investigations within the framework of the Maastricht Study.

Background: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels. Methods: We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels. Results: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before. Conclusions: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies.

Background: Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant. Methods and results: We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00–1.08) and 1.07 (1.03–1.11), respectively], but not with other measures of MVD tested. Conclusion: Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.

Tendon pathology (tendinopathy) typically occurs in specific regions of a tendon, and growth in response to exercise also appears to be more pronounced in specific regions. In a previous study in animals we found evidence of regional differences in tendon turnover, but whether the turnover of human patellar tendon differs in different regions still remains unknown. Patellar tendons were obtained from cadavers of healthy men and women (body donation program, n = 5 donors, >60 yr of age). Samples were taken from 10 different regions along the length, width, and thickness of the tendon. Turnover was measured by 14C bomb pulse dating and also estimated from the accumulation of advanced glycation end products (AGEs) by fluorescence (340/460 nm) in addition to measurement of specific AGEs by mass spectrometry. Composition in terms of collagen, glycosaminoglycans (GAGs), and DNA was also assessed in each region. 14C results showed that all tendon regions had a similar 14C concentration, which was equal to the average atmospheric 14C concentration during the first 15 yr of the person's life. Fluorescence normalized to dry weight did not differ between regions, nor did specific AGEs. Higher GAG content was observed in the proximal and near the distal insertion of the tendon. In conclusion, healthy human patellar tendon displays no regional differences in collagen turnover throughout life.NEW & NOTEWORTHY Tendon injuries and tendinopathies typically occur in specific regions of the tendon, but the reason for this specificity is not well understood. A potential factor in injury susceptibility is tissue turnover, and previous work suggests that the tendon core has practically no turnover during adult life; however, it is not known whether this is true for other regions of the tendon. Our present results on healthy human patellar tendon clearly demonstrate that turnover does not differ between regions and thereby cannot explain differences in injury susceptibility. The

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.