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1.
PLoS One ; 16(4): e0247939, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33830998

RESUMO

BACKGROUND: Beyond antihyperglycemic effects, metformin may improve cardiovascular outcomes. Patients with type 2 diabetes often have an elevated plasma level of N-terminal pro B-type as a marker of (sub) clinical cardiovascular disease. We studied whether metformin was associated with a reduction in the serum level of N-terminal pro B-type natriuretic peptide (NT-proBNP) in these patients. METHODS: In the HOME trial 390 insulin-treated patients with type 2 diabetes were randomized to 850 mg metformin or placebo three times daily. Plasma samples were drawn at baseline, 4, 17, 30, 43 and 52 months. In a post-hoc analysis we analyzed the change in NT-proBNP in both groups. We used a longitudinal mixed model analysis adjusting for age, sex and prior cardiovascular disease. In a secondary analysis we assessed a possible immediate treatment effect post baseline. RESULTS: Metformin did not affect NT-proBNP levels over time in the primary analysis (-1% [95%CI -4;3, p = 0.62]). In the secondary analysis there was also no sustained time independent immediate treatment effect (initial increase of 17% [95%CI 4;30, p = 0.006] followed by yearly decrease of -4% [95%CI -7;0, p = 0.07]). CONCLUSIONS: Metformin as compared to placebo did not affect NT-proBNP plasma levels in this 4.3-year placebo-controlled trial. Potential cardioprotective effects of metformin cannot be explained by changes in cardiac pressures or volumes to the extent reflected by NT-proBNP.

2.
Carcinogenesis ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33780524

RESUMO

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 ε-(carboxy-methyl)lysine (CML), N ε-(carboxy-ethyl)lysine (CEL) and N δ-(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 1,378 incident primary colorectal cancer cases and 1,378 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, ORQ5vs.Q1=0.40, 95%CI:0.27-0.59), MG-H1 (ORQ5vs.Q1=0.73, 95%CI:0.53 - 1.00) and total AGEs (OR Q5vs.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 (ORQ5vs.Q1=1.91, 95%CI:1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical subsite. 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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33715205

RESUMO

OBJECTIVE: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. DESIGN: A cross-sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. PARTICIPANTS: Healthy men (n = 34) and women (n = 21) were combined from two cross-sectional studies. Forty-two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). RESULTS: DNL was inversely associated with SHBG in women (ß: -0.015, 95% CI: -0.030; 0.000), but not in men (ß: 0.007, 95% CI: -0.005; 0.019) (p for interaction = .068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. CONCLUSIONS: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women.

4.
J Clin Lipidol ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33612457

RESUMO

BACKGROUND: Plasma lipoproteins contain heterogeneous subclasses. Previous studies on the associations of the complement system with lipids and lipoproteins are mainly limited to the major lipid classes, and associations of complement with lipoprotein subclass characteristics remain unknown. OBJECTIVE: We investigated the associations of C3 and other components of the alternative complement pathway with plasma lipoprotein subclass profile. METHODS: Plasma complement concentrations (complement component 3 [C3], properdin, factor H, factor D, MASP-3, C3a, Bb), and lipoprotein subclass profile (as measured by nuclear magnetic resonance spectroscopy) were obtained in 523 participants (59.6 ± 6.9 years, 60.8% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression was used to investigate the associations of C3 (primary determinant) and other alternative pathway components (secondary determinants) with characteristics (particle concentration and size [main outcomes], and lipid contents [secondary outcomes]) of 14 lipoprotein subclasses, ranging from extremely large VLDL to small HDL (all standardized [std] values). RESULTS: Participants with higher C3 concentrations had more circulating VLDL (stdßs ranging from 0.27 to 0.36), IDL and LDL (stdßs ranging from 0.14 to 0.17), and small HDL (stdß = 0.21). In contrast, they had fewer very large and large HDL particles (stdßs = -0.36). In persons with higher C3 concentrations, all lipoprotein subclasses were enriched in triglycerides. Similar but weaker associations were observed for properdin, factor H, factor D, and MASP-3, but not for C3a and Bb. CONCLUSIONS: The alternative complement pathway, and most prominently C3, is associated with an adverse lipoprotein subclass profile that is characterized by more triglyceride-enriched lipoproteins but fewer large HDL.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33431599

RESUMO

INTRODUCTION: Distal sensorimotor polyneuropathy (DSPN) is common in people with diabetes but is also found in pre-diabetes. Peripheral nerve myelin damage, which can be assessed by reduced nerve conduction velocity (NCV), is an essential feature of DSPN. Emerging evidence indicates that the development of DSPN may involve the activation of the immune system. However, available studies have mainly investigated circulating immune mediators, whereas the role of immune cells remains unclear. Therefore, we aimed to test whether leukocyte subsets are associated with NCV. RESEARCH DESIGN AND METHODS: This cross-sectional study analyzed data from 850 individuals (of whom 252 and 118 had type 2 diabetes and pre-diabetes, respectively) of the Maastricht Study. NCV was measured in the peroneal and tibial motor nerves and the sural sensory nerve and summed to calculate a standardized NCV sum score. Associations between percentages of leukocyte subsets and NCV sum scores were estimated using linear regression models adjusted for demographic, lifestyle, metabolic and clinical covariates. RESULTS: After adjustment for covariates, higher percentages of basophils and CD4+ T cells were associated with lower NCV (p=0.014 and p=0.005, respectively). The percentage of CD8+ T cells was positively associated with NCV (p=0.022). These associations were not modified by glucose metabolism status (all pinteraction >0.05). No associations were found for monocytes, eosinophils, neutrophils, lymphocytes, total T cells, Treg cells and B cells. CONCLUSIONS: The associations of basophils, CD4+ and CD8+ T cells with NCV suggest that cell types from both innate and adaptive immunity may be implicated in the development of DSPN.

6.
Sci Rep ; 11(1): 2671, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514757

RESUMO

Ex vivo characterisation of arterial biomechanics enables detailed discrimination of the various cellular and extracellular contributions to arterial stiffness. However, ex vivo biomechanical studies are commonly performed under quasi-static conditions, whereas dynamic biomechanical behaviour (as relevant in vivo) may differ substantially. Hence, we aim to (1) develop an integrated set-up for quasi-static and dynamic biaxial biomechanical testing, (2) quantify set-up reproducibility, and (3) illustrate the differences in measured arterial stiffness between quasi-static and dynamic conditions. Twenty-two mouse carotid arteries were mounted between glass micropipettes and kept fully vasodilated. While recording pressure, axial force (F), and inner diameter, arteries were exposed to (1) quasi-static pressure inflation from 0 to 200 mmHg; (2) 300 bpm dynamic pressure inflation (peaking at 80/120/160 mmHg); and (3) axial stretch (λz) variation at constant pressures of 10/60/100/140/200 mmHg. Measurements were performed in duplicate. Single-point pulse wave velocities (PWV; Bramwell-Hill) and axial stiffness coefficients (cax = dF/dλz) were calculated at the in vivo value of λz. Within-subject coefficients of variation were ~ 20%. Dynamic PWVs were consistently higher than quasi-static PWVs (p < 0.001); cax increased with increasing pressure. We demonstrated the feasibility of ex vivo biomechanical characterisation of biaxially-loaded murine carotid arteries under pulsatile conditions, and quantified reproducibility allowing for well-powered future study design.

7.
Food Chem ; 339: 128063, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152865

RESUMO

Dicarbonyls are reactive precursors of advanced glycation endproducts. They are formed endogenously and during food processing. Currently, a comprehensive database on dicarbonyls in foods that covers the entire range of food groups is lacking, limiting knowledge about the amount of dicarbonyls that is ingested via food. The aim of this study was to analyze the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) in commonly-consumed products in a Western diet. We validated a UHPLC-MS/MS method to quantify MGO, GO, and 3-DG. We present a dietary dicarbonyl database of 223 foods and drinks. Total dicarbonyl concentrations were highest in dried fruit, Dutch spiced cake, and candy bars (>400 mg/kg). Total dicarbonyl concentrations were lowest in tea, dairy, light soft drinks, and rice (<10 mg/kg). The presented database of MGO, GO, and 3-DG opens the possibility to accurately estimate dietary exposure to these dicarbonyls, and explore their physiological impact on human health.


Assuntos
Bebidas/análise , Bases de Dados Factuais , Análise de Alimentos/métodos , Compostos Orgânicos/análise , Manipulação de Alimentos , Humanos , Compostos Orgânicos/química , Espectrometria de Massas em Tandem
8.
Am J Clin Nutr ; 113(2): 391-400, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33381794

RESUMO

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.


Assuntos
Dieta , Frutose/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Adulto , Glicemia , Carboidratos da Dieta/administração & dosagem , Método Duplo-Cego , Feminino , Intolerância à Glucose , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade
9.
Heliyon ; 6(11): e05364, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33241137

RESUMO

Aims: Non-invasively assessed skin autofluorescence (SAF) measures advanced glycation endproducts (AGEs) in the dermis. SAF correlates with dermal AGEs in Caucasians and Asians, but studies in dark-skinned subjects are lacking. In this pilot we aimed to assess whether SAF signal is representative of intrinsic fluorescence (IF) and AGE accumulation in dark skin. Methods: Skin biopsies were obtained in 12 dark-skinned subjects (6 healthy subjects, median age 22 years; 6 diabetes mellitus (DM) subjects, 65 years). SAF was measured with the AGE Reader, IF using confocal microscopy, and AGE distribution with specific antibodies. CML and MG-H1 were quantified with UPLC-MS/MS and pentosidine with HPLC and fluorescent detection. Results: SAF correlated with IF from the dermis (405nm, r = 0.58, p < 0.05), but not with CML (r = 0.54, p = 0.07). CML correlated with IF from the dermis (405nm, r = 0.90, p < 0.01). UV reflectance and the coefficient of variation of SAF were negatively correlated (r = -0.80, p < 0.01). CML and MG-H1 were predominantly present around blood vessels, in collagen and fibroblasts in the dermis. Conclusion: This proof of concept study is the first to compare non-invasive SAF with AGE levels measured in skin biopsies in dark-skinned subjects. SAF did not correlate with individual AGEs from biopsies, but was associated with IF. However, the intra-individual variance was high, limiting its application in dark-skinned subjects on an individual basis.

11.
Diabetes Care ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144352

RESUMO

OBJECTIVE: Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity, and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI. RESEARCH DESIGN AND METHODS: We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography-tandem mass spectrometry at baseline in 160 patients (64.8 ± 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes (n = 86, comprising death n = 53 or amputations n = 49 [first event counted]) over 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker. RESULTS: Higher plasma MGO levels were associated with more adverse outcomes (relative risk 1.44; 95% CI 1.11-1.86) and amputations separately (1.55; 1.13-2.21). We observed a similar but weaker trend for mortality (1.28; 0.93-1.77). The MGO-derived AGE Nε-(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00-2.15) and amputations (1.71; 1.04-2.79). d-Lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells. CONCLUSIONS: Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.

13.
Front Cardiovasc Med ; 7: 570553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195459

RESUMO

Clinical trials investigating whether glucose lowering treatment reduces the risk of CVD in diabetes have thus far yielded mixed results. However, this doesn't rule out the possibility of hyperglycemia playing a major causal role in promoting CVD or elevating CVD risk. In fact, lowering glucose appears to promote some beneficial long-term effects, and continuous glucose monitoring devices have revealed that postprandial spikes of hyperglycemia occur frequently, and may be an important determinant of CVD risk. It is proposed that these short, intermittent bursts of hyperglycemia may have detrimental effects on several organ systems including the vasculature and the hematopoietic system collectively contributing to the state of elevated CVD risk in diabetes. In this review, we summarize the potential mechanisms through which hyperglycemic spikes may increase atherosclerosis and how new and emerging interventions may combat this.

14.
J Hypertens ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33186329

RESUMO

OBJECTIVE: An exaggerated exercise SBP, which is potentially modifiable, may be associated with incident depressive symptoms via an increased pulsatile pressure load on the brain. However, the association between exaggerated exercise SBP and incident depressive symptoms is unknown. Therefore, we examined whether exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time. METHODS: We used longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2121; 51.3% men; age 59.5 ±â€Š8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on four standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 min after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of at least 10. RESULTS: After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A 1 SD higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms [hazard ratio: 1.27 (95% confidence interval: 1.04-1.54)]. Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness. CONCLUSION: A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33082206

RESUMO

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; P heterogeneity 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.

16.
Clin Kidney J ; 13(5): 855-866, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33123361

RESUMO

Background: End-stage renal disease (ESRD) is strongly associated with cardiovascular disease (CVD) risk. Advanced glycation endproducts (AGEs) and dicarbonyls, major precursors of AGEs, may contribute to the pathophysiology of CVD in ESRD. However, detailed data on the courses of AGEs and dicarbonyls during the transition of ESRD patients to renal replacement therapy are lacking. Methods: We quantified an extensive panel of free and protein-bound serum AGEs [N ∈-(carboxymethyl)lysine (CML), N ∈-(carboxyethyl)lysine (CEL), N δ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)], serum dicarbonyls [glyoxal (GO), methylglyoxal (MGO), 3-deoxyglucosone (3-DG)] and tissue AGE accumulation [estimated by skin autofluorescence (SAF)] in a combined cross-sectional and longitudinal observational study of patients with ESRD transitioning to dialysis or kidney transplantation (KTx), prevalent dialysis patients and healthy controls. Cross-sectional comparisons were performed with linear regression analyses, and courses following renal replacement therapy were analysed with linear mixed models. Results: Free and protein-bound AGEs, dicarbonyls and SAF were higher in chronic kidney disease (CKD) Stage 5 non-dialysis (CKD 5-ND; n = 52) and CKD Stage 5 dialysis (CKD 5-D; n = 35) than in controls (n = 42). In addition, free AGEs, protein-bound CML, GO and SAF were even higher in CKD 5-D than in CKD5-ND. Similarly, following dialysis initiation (n = 43) free and protein-bound AGEs, and GO increased, whereas SAF remained similar. In contrast, following KTx (n = 21), free and protein-bound AGEs and dicarbonyls, but not SAF, markedly declined. Conclusions: AGEs and dicarbonyls accumulate in uraemia, which is even exaggerated by dialysis initiation. In contrast, KTx markedly reduces AGEs and dicarbonyls. Given their associations with CVD risk in high-risk populations, lowering AGE and dicarbonyl levels may be valuable.

17.
Diabetologia ; 63(11): 2315-2328, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32757152

RESUMO

AIMS/HYPOTHESIS: Depression is twice as common in individuals with type 2 diabetes as in the general population. However, it remains unclear whether hyperglycaemia and insulin resistance are directly involved in the aetiology of depression. Therefore, we investigated the association of markers of hyperglycaemia and insulin resistance, measured as continuous variables, with incident depressive symptoms over 4 years of follow-up. METHODS: We used data from the longitudinal population-based Maastricht Study (n = 2848; mean age 59.9 ± 8.1 years, 48.8% women, 265 incident depression cases, 10,932 person-years of follow-up). We assessed hyperglycaemia by fasting and 2 h post-load OGTT glucose levels, HbA1c and skin autofluorescence (reflecting AGEs) at baseline. We used the Matsuda insulin sensitivity index and HOMA-IR to calculate insulin resistance at baseline. Depressive symptoms (nine-item Patient Health Questionnaire score ≥10) were assessed at baseline and annually over 4 years. We used Cox regression analyses, and adjusted for demographic, cardiovascular and lifestyle risk factors. RESULTS: Fasting plasma glucose, 2 h post-load glucose and HbA1c levels were associated with an increased risk for incident depressive symptoms after full adjustment (HR 1.20 [95% CI 1.08, 1.33]; HR 1.25 [1.08, 1.44]; and HR 1.22 [1.09, 1.37] per SD, respectively), while skin autofluorescence, insulin sensitivity index and HOMA-IR were not (HR 0.99 [0.86, 1.13]; HR 1.02 [0.85, 1.25]; and HR 0.93 [0.81, 1.08], per SD, respectively). CONCLUSIONS/INTERPRETATION: The observed temporal association between hyperglycaemia and incident depressive symptoms in this study supports the presence of a mechanistic link between hyperglycaemia and the development of depressive symptoms. Graphical abstract.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32829143

RESUMO

BACKGROUND: The study of the involvement of fructose in the pathogenesis of cardiometabolic disease requires accurate and precise measurements of serum and urinary fructose. The aim of the present study was to develop and validate such a method by Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS). METHODS: Fructose was quantified using hydrophilic interaction UPLC-MS/MS with a labelled internal standard. Serum fructose levels were determined in healthy individuals (n = 3) after a 15-gram oral fructose load. Twenty-four hours urinary fructose levels were determined in individuals consuming low (median: 1.4 g/day, interquartile range [IQR]: 0.9-2.0; n = 10), normal (31 g/day, 23-49; n = 15) and high (70 g/day, 55-84; n = 16) amounts of fructose. RESULTS: The calibration curves showed perfect linearity in water, artificial, serum, and urine matrices (r2 > 0.99). Intra- and inter-day assay variation of serum and urinary fructose ranged from 0.3 to 5.1% with an accuracy of ~98%. Fasting serum fructose levels (5.7 ± 0.6 µmol/L) increased 60 min after a 15-gram oral fructose load (to 150.3 ± 41.7 µmol/L) and returned to normal after 180 min (8.4 ± 0.6 µmol/L). Twenty-four hours urinary fructose levels were significantly lower in low fructose consumers when compared to normal and high fructose consumers (median: 36.1 µmol/24 h, IQR: 26.4-64.2; 142.3 µmol/24 h, 98.8-203.0; and 238.9 µmol/24 h, 127.1-366.1; p = 0.004 and p < 0.001, respectively). CONCLUSION: Fructose concentrations can be measured accurately and precisely with this newly-developed UPLC-MS/MS method. Its robustness makes it suitable for assessing the value of fructose in clinical studies.

19.
Int J Mol Sci ; 21(14)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668720

RESUMO

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.

20.
Diabetologia ; 63(8): 1648-1658, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32537727

RESUMO

AIMS/HYPOTHESIS: We aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function. METHODS: In 2401 adults (aged 40-75 years) we previously determined fasting glucose, HbA1c, triacylglycerol, HDL- and LDL-cholesterol, inflammation, waist circumference, blood pressure, smoking, glucose metabolism status (by OGTT) and medication use. Using nerve conduction tests, we measured compound muscle action potential, sensory nerve action potential amplitudes and nerve conduction velocities (NCVs) of the peroneal, tibial and sural nerves. In addition, we measured vibration perception threshold (VPT) of the hallux and assessed neuropathic pain using the DN4 interview. We assessed cross-sectional associations of risk factors with nerve function (using linear regression) and neuropathic pain (using logistic regression). Associations were adjusted for potential confounders and for each other risk factor. Associations from linear regression were presented as standardised regression coefficients (ß) and 95% CIs in order to compare the magnitudes of observed associations between all risk factors and outcomes. RESULTS: Hyperglycaemia (fasting glucose or HbA1c) was associated with worse sensorimotor nerve function for all six outcome measures, with associations of strongest magnitude for motor peroneal and tibial NCV, ßfasting glucose = -0.17 SD (-0.21, -0.13) and ßfasting glucose = -0.18 SD (-0.23, -0.14), respectively. Hyperglycaemia was also associated with higher VPT and neuropathic pain. Larger waist circumference was associated with worse sural nerve function and higher VPT. Triacylglycerol, HDL- and LDL-cholesterol, and blood pressure were not associated with worse nerve function; however, antihypertensive medication usage (suggestive of history of exposure to hypertension) was associated with worse peroneal compound muscle action potential amplitude and NCV. Smoking was associated with worse nerve function, higher VPT and higher risk for neuropathic pain. Inflammation was associated with worse nerve function and higher VPT, but only in those with type 2 diabetes. Type 2 diabetes and, to a lesser extent, prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were associated with worse nerve function, higher VPT and neuropathic pain (p for trend <0.01 for all outcomes). CONCLUSIONS/INTERPRETATION: Hyperglycaemia (including the non-diabetic range) was most consistently associated with early-stage nerve damage. Nonetheless, larger waist circumference, inflammation, history of hypertension and smoking may also independently contribute to worse nerve function.

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