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Diabetes is associated with vascular injury and the onset of macrovascular complications. Advanced glycation endproducts (AGEs) and the AGE precursor methylglyoxal (MGO) have been identified as key players in establishing the relationship between diabetes and vascular injury. While most research has focused on the link between AGEs and vascular injury, less is known about the effects of MGO on vasculature. In this review, we focus on the mechanisms linking AGEs and MGO to the development of atherosclerosis. AGEs and MGO are involved in many stages of atherosclerosis progression. However, more research is needed to determine the exact mechanisms underlying these effects. Nevertheless, AGEs and MGO could represent valid therapeutic targets for the macrovascular complications of diabetes. The reactive dicarbonyl methylglyoxal (MGO) is the major precursor of endogenously formed advanced glycation endproducts (AGEs). MGO is an important factor contributing to endothelial dysfunction by inducing oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress. AGEs stimulate cholesterol accumulation in macrophages and phenotype switching of vascular smooth muscle cells (VSMCs) into macrophage-like cells, while the impact of MGO is less understood. AGEs and MGO can inhibit angiogenesis, but promote atherosclerosis-linked inflammation by inducing inflammatory polarization of macrophages and the induction of inflammatory pathways. AGEs promote calcification of VSMCs by increasing the expression of osteogenic proteins and transcription factors. The impact of MGO on calcification remains to be elucidated. [ABSTRACT FROM AUTHOR]

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—Nε-(carboxy-methyl)lysine (CML), Nε-(carboxy-ethyl)lysine (CEL) and Nδ-(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. [ABSTRACT FROM AUTHOR]

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD. [ABSTRACT FROM AUTHOR]

The immune system plays an essential role in protecting the body against pathogens. Immune cells are activated during infections, resulting in a metabolic shift from oxidative phosphorylation to glycolysis. During glycolysis, methylglyoxal (MGO) can be formed as a by-product. As a highly reactive dicarbonyl compound, MGO can rapidly react with proteins to form advanced glycation end products (AGEs). MGO and MGO-derived AGEs have been implicated in the development of insulin resistance, type 2 diabetes and its complications and several other age-related inflammatory diseases. MGO has been found in adipose tissue, atherosclerosis plaques and inflamed livers. Aside from the potential harmful role of MGO, there are studies showing beneficial effects of MGO as a defense mechanism during infections and diseases. In this review, we summarize anti-microbial effects of MGO and the link between MGO and immune cell activation, as potential mediator during host defense. • Immune cell activation is associated with enhanced glycolysis, leading to the formation of the reactive dicarbonyl methylglyoxal (MGO). • MGO rapidly leads to the formation of protein adducts and is cytotoxic. • MGO has direct anti-microbial effects and immunomodulatory effects. • The extent of MGO production in immune cells and its contribution to host defense remain to be further elucidated. [ABSTRACT FROM AUTHOR]

The complement system, particularly the alternative complement pathway, may contribute to vascular damage and development of cardiovascular disease (CVD). We investigated the association of factor D, the rate-limiting protease in alternative pathway activation, with adverse cardiovascular outcomes. In 2947 participants (50.6% men, 59.9 ± 8.2 years, 26.5% type 2 diabetes [T2D], oversampled) we measured markers of low-grade inflammation (LGI, composite score, in SD) and, endothelial dysfunction (ED, composite score, in SD), carotid intima-media thickness (cIMT, μm), ankle-brachial index (ABI), CVD (yes/no) and plasma concentrations of factor D (in SD). Associations were estimated using multiple linear and logistic regression, adjusting for demographic, lifestyle, and dietary factors. Factor D (per SD) significantly associated with LGI (0.171 SD [0.137; 0.205]), ED (0.158 SD [0.123; 0.194]) and CVD (OR 1.15 [1.04; 1.27]) but not significantly with cIMT (−6.62 μm [-13.51; 0.27]) or ABI (−0.003 [-0.007; 0.001]). Interaction analyses show that factor D more strongly associated with ED in non-diabetes (0.237 SD [0.189; 0.285] than in T2D (0.095 SD [0.034; 0.157]), p interaction <0.05. These results were largely corroborated by additional analyses with C3 and C3a. In contrast, factor D inversely associated with cIMT in non-diabetes (−13.37 μm [-21.84; −4.90]), but not in T2D (4.49 [-7.91; 16.89]), p interaction <0.05. Plasma factor D is independently associated with LGI, ED, and prevalent CVD but not with ABI or cIMT. Hence, greater plasma factor D concentration in CVD may potentially induce complement activation which, in turn, might contribute to further disease progression via a process that may involve inflammation and endothelial dysfunction but was not directly related to atherosclerosis or arterial injury. The observation that, in participants without diabetes, factor D associated with worse ED but smaller cIMT warrants further investigation. [Display omitted] • Greater plasma concentration of factor D significantly associates with multiple markers of low-grade inflammation and endothelial dysfunction. • Greater plasma concentration of factor D significantly associates with more cardiovascular disease. • These observations for factor D were largely corroborated in analyses with complement C3 and C3a. • The association of factor D with cardiovascular disease manifested particularly as cerebral cardiovascular disease in men. • Factor D was not positively associated with either a marker of subclinical atherosclerosis or a marker of arterial injury. [ABSTRACT FROM AUTHOR]

Background: Low circulating levels of total vitamin D [25(OH)D] and 25(OH)D3 have been associated with vascular complications in few studies on individuals with type 1 diabetes. However, these measures are affected by UV light exposure. Circulating 25(OH)D2, however, solely represents dietary intake of vitamin D2, but its association with complications of diabetes is currently unknown. We investigated the associations between 25(OH)D2 and 25(OH)D3 and the prevalence of albuminuria, retinopathy and cardiovascular disease (CVD) in individuals with type 1 diabetes. Methods: We measured circulating 25(OH)D2 and 25(OH)D3 in 532 individuals (40 ± 10 years old, 51 % men) with type 1 diabetes who participated in the EURODIAB Prospective Complications Study. Cross-sectional associations of 25(OH)D2 and 25(OH)D3 with albuminuria, retinopathy and CVD were assessed with multiple logistic regression analyses adjusted for age, sex, season, BMI, smoking, HbA1c, total-HDL-cholesterol-ratio, systolic blood pressure, antihypertensive medication, eGFR, physical activity, alcohol intake, albuminuria, retinopathy and CVD, as appropriate. Results: Fully adjusted models revealed that 1 nmol/L higher 25(OH)D2 and 10 nmol/L higher 25(OH)D3 were associated with lower prevalence of macroalbuminuria with ORs (95 % CI) of 0.56 (0.43;0.74) and 0.82 (0.72;0.94), respectively. These vitamin D species were not independently associated with microalbuminuria, non-proliferative and proliferative retinopathy or CVD. Conclusions: In individuals with type 1 diabetes, both higher 25(OH)D2 and 25(OH)D3 are associated with a lower prevalence of macroalbuminuria, but not of retinopathy and CVD. Prospective studies are needed to further examine the associations between 25(OH)D2 and 25(OH)D3 and the development of microvascular complications and CVD in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: The reactive α-oxoaldehydes glyoxal (GO), methylglyoxal (MGO) and 3-deoxyglucosone (3-DG) have been linked to diabetic complications and other age-related diseases. Numerous techniques have been described for the quantification of α-oxoaldehydes in blood or plasma, although with several shortcomings such as the need of large sample volume, elaborate extraction steps or long run-times during analysis. Therefore, we developed and evaluated an improved method including sample preparation, for the quantification of these α-oxoaldehydes in blood and plasma with ultra performance liquid chromatography tandem mass spectrometry (UPLC MS/MS). Methods: EDTA plasma and whole blood samples were deproteinized using perchloric acid (PCA) and subsequently derivatized with o-phenylenediamine (oPD). GO, MGO and 3-DG concentrations were determined using stable isotope dilution UPLC MS/MS with a run-to-run time of 8 min. Stability of α-oxoaldehyde concentrations in plasma and whole blood during storage was tested. The concentration of GO, MGO and 3-DG was measured in EDTA plasma of non-diabetic controls and patients with type 2 diabetes (T2DM). Results: Calibration curves of GO, MGO and 3-DG were linear throughout selected ranges. Recoveries of these α-oxoaldehydes were between 95% and 104%. Intra- and inter-assay CVs were between 2% and 14%. Conclusions: To obtain stable and reliable α-oxoaldehyde concentrations, immediate centrifugation of blood after blood sampling is essential and the use of EDTA as anticoagulant is preferable. Moreover, immediate precipitation of plasma protein with PCA stabilized α-oxoaldehyde concentrations for at least 120 min. With the use of the developed method, we found increased plasma concentrations of GO, MGO and 3-DG in T2DM as compared with non-diabetic controls. [ABSTRACT FROM AUTHOR]

Statins can protect endothelial activation independent from their lipid-lowering effects. To gain more insight in mechanisms via which HMG-CoA inhibition may attenuate endothelial activation, we assessed the effects of mevastatin on eNOS expression of non- and modified-LDL treated endothelial cells and on basal and hydrogen peroxide-induced lipid peroxidation. Oxidized-LDL (Ox-LDL), but not glycated or acylated LDL decreased eNOS expression in human endothelial cells. The extent to which Ox-LDL decreases eNOS expression depends on the extent of modification of Ox-LDL. Mevastatin increased eNOS-expression, both in the presence and absence of Ox-LDL. In addition, mevastatin decreased the H2O2-induced (100 μM) lipid peroxidation in endothelial cells. This study shows that mevastatin has protective effects on endothelial cells by inducing eNOS and by inhibiting lipid peroxidation. [ABSTRACT FROM AUTHOR]

Abstract: In endothelial cells cultured under high glucose conditions, methylglyoxal is the major intracellular precursor in the formation of advanced glycation endproducts. We found that endothelial cells incubated with 30mM d-glucose produced approximately 2-fold higher levels of methylglyoxal but not 3-deoxyglucosone and glyoxal, as compared to 5mM d-glucose. Under hyperglycaemic conditions, the methylglyoxal-arginine adduct argpyrimidine as detected with a specific antibody, but not Ne-(carboxymethyl)lysine and Ne-(carboxyethyl)lysine, was significantly elevated. The glyoxylase I inhibitor HCCG and the PPARγ ligand troglitazone also increased argpyrimidine levels. Increased levels of argpyrimidine by glucose, HCCG and troglitazone are accompanied by a decrease in proliferation of endothelial cells. A 27kDa protein was detected as a major argpyrimidine-modified protein. With in-gel digestion and mass spectrometric analysis, we identified this major protein as heat-shock protein 27 (Hsp27). This argpyrimidine modification of Hsp27 may contribute to changes in endothelial cell function associated to diabetes. [Copyright &y& Elsevier]

Background: Peptide-linked degradation products of advanced glycation end products (AGE peptides) accumulate in chronic haemodialysis (HD) patients and may contribute to a number of HD-related long-term complications, such as accelerated atherosclerosis. Methods: The influence of a single HD session versus long-term HD on serum AGE peptides was determined. The patients were randomized to HD with a low-flux polysulfone (PS; F 6HPS), a high-flux PS (F 60S), a superflux PS (F 500S), or a superflux cellulose triacetate (CTA; Tricea 150G) dialyzer. Results: During a single HD session, both AGE peptides and reference peptides decreased significantly (AGE peptides: Tricea 150G –37.0 ± 2.9%; F 6HPS –35.5 ± 2.4%; F 60S –39.5 ± 4.7%, and F 500S –43.3 ± 2.1%, p = 0.005; reference peptides: Tricea 150G –73.2 ± 8.8%; F 6HPS –73.2 ± 7.9%; F 60S –72.5 ± 8.2%, and F 500S –74.1 ± 7.3%, p = 0.005). After 12 weeks of HD with the superflux CTA, the AGE peptide levels decreased significantly (week 1: 2.7 ± 1.1 arbitrary units, week 12: 2.5 ± 1.2 arbitrary units, decrease 7.4%; p = 0.01), whereas the AGE peptide levels remained unchanged after HD with each of the other three modalities. The reference peptide levels did not change after 12 weeks of HD. Conclusion: Although AGE peptides can be effectively removed during a single HD session, superflux CTA seems to be the only modality capable of reducing AGE peptides in the long term. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Heart failure is a condition closely linked to diabetes. Hyperglycaemia amplifies the generation of a major advanced glycation end product Nε-(carboxymethyl)lysine (CML), which has been associated with the development of vascular and inflammatory complications. An increased accumulation of CML in hearts of diabetic patients may be one of the mechanisms related to the high risk of heart failure. Therefore, we investigated the localization of CML in diabetic hearts.To investigate the presence and accumulation of CML in tissues, a monoclonal anti-CML antibody was generated and characterised. With this novel monoclonal antibody against CML, the localization of CML was investigated by immunohistochemistry, in heart tissue of controls (n=9) and heart tissue of diabetic patients (n=8) without signs of inflammation or infarction. In addition, in the same subjects we studied the presence of CML in renal and lung tissues. CML staining was approximately sixfold higher in hearts from diabetic patients as compared to control hearts (2.0±0.3 and 0.3±0.2 A.U., respectively, P<0.01). CML deposition was localized in the small intramyocardial arteries in endothelial cells and smooth muscle cells, but not in cardiomyocytes. These arteries did not show morphological abnormalities. The intensity of staining between arteries at the epicardial, midcardial and endocardial side did not vary significantly within patients. In renal tissues, CML staining was most prominent in tubules and in atherosclerotic vessels, without differences in intensity between controls and diabetic patients. In non-infected lungs, no CML was detected.In conclusion, CML adducts are abundantly present in small intramyocardial arteries in the heart tissue of diabetic patients. The accumulation of CML in diabetic hearts may contribute to the increased risk of heart failure in hyperglycaemia. [Copyright &y& Elsevier]

Objective: Transforming growth factor (TGF)-beta1 is overexpressed in diabetes as a consequence of hyperglycemia and the creation of early glycated end products and may be responsible for the characteristic structural renal changes associated with diabetes. We sought to examine the role of both urinary and circulating TGF-beta1 and its promoter Amadori albumin in the vascular complications of type 1 diabetes.Research Design and Methods: The present article reports on a nested case-control study from the EURODIAB Prospective Complications Study of Europeans with type 1 diabetes. Case subjects (n = 356) were all individuals with one or more complications of diabetes; control subjects (n = 185) were all individuals with no evidence of complications.Results: Urinary TGF-beta1 and Amadori albumin were elevated in patients with micro- or macroalbuminuria. Standardized regression effects (SREs) for macroalbuminuria versus normoalbuminuria were 2.45 (95% CI 1.88-3.18, P = 0.0001 for urinary TGF-beta1) and 1.67 (1.34-2.07, P = 0.001 for Amadori albumin). The SRE for urinary TGF-beta1 remained statistically significant when adjusted for HbA(1c), Amadori albumin, and blood pressure. Circulating TGF-beta1 was elevated in individuals with proliferative retinopathy compared with individuals without retinopathy (SRE 1.29 [1.07-1.550], P = 0.007). This result was attenuated to 1.16 (0.95-1.43, P = 0.2) in the multivariate model, largely because of HbA(1c).Conclusions: Elevated levels of urinary TGF-beta1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA(1c) and also in blood pressure. In contrast, only circulating TGF-beta1 was related to proliferative retinopathy, and HbA(1c) largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Transforming growth factor (TGF)-β1 is overexpressed in diabetes as a consequence of hyperglycemia and the creation of early glycated end products and may be responsible for the characteristic structural renal changes associated with diabetes. We sought to examine the role of both urinary and circulating TGF-β1 and its promoter Amadori albumin in the vascular complications of type 1 diabetes. RESEARCH DESIGN AND METHODS -- The present article reports on a nested case-control study from the EURODIAB Prospective Complications Study of Europeans with type 1 diabetes. Case subjects (n = 356) were all individuals with one or more complications of diabetes; control subjects (n = 185) were all individuals with no evidence of complications. RESULTS -- Urinary TGF-β1 and Amadori albumin were elevated in patients with micro- or macroalbuminuria. Standardized regression effects (SREs) for macroalbuminuria versus normoalbuminuria were 2.45 (95% CI 1.88-3.18, P = 0.0001 for urinary TGF-β1) and 1.67 (1.34-2.07, P = 0.001 for Amadori albumin). The SRE for urinary TGF-β1 remained statistically significant when adjusted for HbA[sub1c], Amadori albumin, and blood pressure. Circulating TGF-β1 was elevated in individuals with proliferative retinopathy compared with individuals without retinopathy (SRE 1.29 [1.07-1.550], P = 0.007). This result was attenuated to 1.16 (0.95-1.43, P = 0.2) in the multivariate model, largely because of HbA[sub1c]. CONCLUSIONS -- Elevated levels of urinary TGF-β1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA[sub1c] and also in blood pressure. In contrast, only circulating TGF-β1 was related to proliferative retinopathy, and HbA[sub1c] largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aim: To study the effect of metformin on plasma levels of arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), indicators of the nitric oxide pathway. Materials and Methods: In this post hoc analysis of the HOME trial, we analysed plasma levels of arginine, ADMA and SDMA during the 4.3‐year follow‐up (comparing the effects of metformin versus placebo on top of insulin therapy). Statistical analysis was performed with a mixed model approach, in which simultaneously constant treatment effects were estimated, as well as time‐dependent treatment effects. Results: We found that metformin compared with placebo did not affect ADMA or SDMA plasma levels but rapidly decreased arginine plasma levels and hence the arginine to ADMA ratio. The constant treatment effect on ADMA was 0.99 (95% CI 0.97, 1.00) relative to placebo and the time‐dependent treatment effect was 1.00 (95% CI 1.00, 1.01). By contrast, the constant treatment effect on arginine was 0.86 (95% CI 0.84, 0.88), with only a minimal time‐dependent change of 1.01 (95% CI 1.00, 1.01). Conclusions: The potential benefits of metformin on endothelial function cannot be explained by a decrease in ADMA or by improved global arginine availability. The clinical significance of the decreased arginine plasma levels is not clear and can be harmful or beneficial, depending on the mechanism involved. However, a potential effect of metformin on the nitric oxide pathway is not restricted to the studied metabolites. [ABSTRACT FROM AUTHOR]

Nonenzymatic glycation is increased in diabetes. Most studies so far have focused on the role of advanced glycation end products (AGEs) in vascular complications, whereas the role of early glycation Amadori-modified proteins, which is the predominant form of glycated proteins, has not been systemically investigated in humans. We developed an antiserum against glycated human serum albumin (HSA) and used this to study the role of early glycation products in vascular complications in type 1 diabetic patients. Amadori albumin was determined to be the recognition epitope of the antiserum. The antibody recognized a specific glucose adduct and a conformational component specific for human albumin in Amadori albumin, with no recognition of AGEs. Plasma Amadori albumin levels were significantly higher in type 1 diabetic patients (n = 55) than in healthy control subjects (n = 60) (39.2+/-9.9 vs. 20.9+/-4.0 U/ml, P < 0.0005). Amadori albumin correlated with levels of plasma markers of endothelial function von Willebrand factor (r = 0.29, P < 0.05) and vascular cell adhesion molecule-1 (r = 0.41, P < 0.005), but not soluble E-selectin. In addition, Amadori albumin immunoreactivity was detected in the capillaries of retinas of diabetic patients. Plasma levels of Amadori albumin were determined in a second group of type 1 diabetic patients with long-standing diabetes with (n = 199) or without (n = 192) diabetic nephropathy. Patients with nephropathy had higher Amadori albumin levels than did those without it (50.9+/-9.5 vs. 45.1+/-6.3 U/ml, P < 0.0005). Age-, sex-, and diabetes duration-adjusted analyses showed that nephropathy was significantly associated with Amadori albumin with an odds ratio (OR [95% CI]) of 1.11 [1.08-1.15] per U/ml increase. After additional adjustment for levels of creatinine, glycated hemoglobin, cholesterol, triglycerides, blood pressure, preexistent retinopathy, and cardiovascular disease, Amadori albumin continued to be significantly associated with nephropathy (OR 1.06 [1.01-1.11]) per U/ml increase. Our results are consistent with a proposed pathophysiological role of Amadori albumin in microvascular complications of type 1 diabetic patients. [ABSTRACT FROM AUTHOR]

Phospholipase A2 (PLA2) is a key enzyme in the release of arachidonic acid and subsequent production of eicosanoids, which play an important role in a variety of biological processes, including mitogenic signalling by epidermal growth factor (EGF). In a previous study [Spaargaren, M. et al. (1992) Biochem J. 287, 37–43] we identified the EGF-activated PLA2 as being similar to the recently cloned high-molecular-mass cytosolic phospholipase A2 (cPLA2). In the present study we demonstrate a rapid transient EGF-induced activation of this cPLA2 and an EGF-induced increase in phosphorylafion of the cPLA2. The EGF-induced activation of cPLA2 is reversed upon phosphatase treatment showing phosphorylation-dependent activation of the cPLA2. No direct association of the cPLA2 to the EGF receptor was detected under conditions where such an association with phospholipase C-γ was demonstrated. Phosphoamino acid analysis of this cPLA2 showed that EGF induced an increase in serine phosphorylation exclusively, no tyrosine phosphorylation being observed. EGF treatment of the cells resulted in a Ca2+-dependent translocation of the cPLA2 from the cytosol to the membrane fraction. This is due to an EGF-induced [Ca2+] rise which is dependent on the influx of extracellular Ca2+ via voltage-independent Ca2+ channels. It is shown that the Ca2+-dependent association of cPLA2 to membranes does not require accessory membrane molecules. [ABSTRACT FROM AUTHOR]

Interleukin-1β induces gene expression and secretion of group-II phospholipase A2 and release of prostaglandin E2 from rat mesangial cells. The interleukin-1β-induced synthesis of group-II phospholipase A2 is prevented by transforming growth factor-β2, whereas transforming growth factor-β2 potentiated the interleukin-1β-evoked prostaglandin E2 production. Transforming growth factor-β2 itself did not induce synthesis of group-II phospholipase A2, although it stimulated prostaglandin E2 formation. Here we describe the effect of interleukin-1β and transforming growth factor-β2 on a cytosolic phospholipase A2 activity and prostaglandin E2 formation in rat mesangial cells. Based on the resistance to dithiothreitol and migration profiles on a Mono-Q anion-exchange column and a Superose 12 gel-filtration column, the cytosolic phospholipase A2 activity was assigned to a high-molecular-mass phospholipase A2. Measured with 1-stearoyl-2-[1-14C]arachidonoylglycerophosphocholine as substrate, both interleukin-1β and transforming growth factor-β2 enhanced the high-molecular-mass phospholipase A2 activity. The stimulation of rat mesangial cells with interleukin-1β and transforming growth factor-β2 was time- and dose-dependent with maximal cytosolic phospholipase A2 activities at 10 nM and at 10 ng/ml respectively, after 24 h of stimulation. Under these conditions, interleukin-1β and transforming growth factor-β2 enhanced the cytosolic phospholipase A2 activity 2.2±0.6-fold and 2.5±0.6-fold, respectively. These results strongly suggest that an enhanced cytosolic high-molecular-mass phospholipase A2 activity is involved in the formation of prostaglandin E2 mediated by transforming growth factor-β2. Whether interleukin-1β induced group-II phospholipase A2 and/or interleukin-1β-enhanced cytosolic phospholipase A2 activity is involved in prostaglandin E2 formation in rat mesangial cells is discussed. [ABSTRACT FROM AUTHOR]

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo. Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80-85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially. Results: Glyoxalase-1 mRNA expression decreased in the LPS (ß (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (P<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (P=0.003). D-Lactate was increased in all four groups. L-Lactate was increased in all groups, except in the control group. Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The brain is a highly metabolically active organ requiring a large amount of glucose. Methylglyoxal (MGO), a by-product of glucose metabolism, is known to be involved in microvascular dysfunction and is associated with reduced cognitive function. Maintenance of the blood-brain barrier (BBB) is essential to maintain optimal brain function and a large amount of evidence indicates negative effects of MGO on BBB integrity. In this review, we summarized the current literature on the effect of MGO on the different cell types forming the BBB. BBB damage by MGO most likely occurs in brain endothelial cells and mural cells, while astrocytes are most resistant to MGO. Microglia on the other hand appear to be not directly influenced by MGO but rather produce MGO upon activation. Although there is clear evidence that MGO affects components of the BBB, the impact of MGO on the BBB as a multicellular system warrants further investigation. Diminishing MGO stress can potentially form the basis for new treatment strategies for maintaining optimal brain function. [ABSTRACT FROM AUTHOR]

Reactive α-dicarbonyls (α-DCs), such as methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), are potent precursors in the formation of advanced glycation end products (AGEs). In particular, MGO and MGO-derived AGEs are thought to be involved in the development of vascular complications in diabetes. Experimental studies showed that citrus and pomegranate polyphenols can scavenge α-DCs. Therefore, the aim of this study was to evaluate the effect of a citrus and pomegranate complex (CPC) on the α-DCs plasma levels in a double-blind, placebo-controlled cross-over trial, where thirty-six elderly subjects were enrolled. They received either 500 mg of Citrus sinensis peel extract and 200 mg of Punica granatum concentrate in CPC capsules or placebo capsules for 4 weeks, with a 4-week washout period in between. For the determination of α-DCs concentrations, liquid chromatography tandem mass spectrometry was used. Following four weeks of CPC supplementation, plasma levels of MGO decreased by 9.8% (−18.7 nmol/L; 95% CI: −36.7, −0.7 nmol/L; p = 0.042). Our findings suggest that CPC supplementation may represent a promising strategy for mitigating the conditions associated with MGO involvement. This study was registered on clinicaltrials.gov as NCT03781999. [ABSTRACT FROM AUTHOR]

The article presents the discussion on showing the substitution of low- and no-calorie sweetened beverages for sugarsweetened beverages. Topics include KHK catalyzing the phosphorylation of fructose, the main caloric constituent of sugarsweetened beverages; and minor A allele, a common missense variant in KHK being associated with greater urinary fructose excretion and protection from colorectal cancer.

Purpose: Coronary atherosclerosis is the leading cause of sudden death among athletes >35 yr old, but current cardiovascular risk prediction algorithms have not been validated for athletes. Advanced glycation end products (AGE) and dicarbonyl compounds have been associated with atherosclerosis and rupture-prone plaques in patients and ex vivo studies. The detection of AGE and dicarbonyl compounds might be a novel screening tool for high-risk coronary atherosclerosis in older athletes. Methods: Concentrations of three different AGE and the dicarbonyl compounds methylglyoxal, glyoxal, and 3-deoxyglucosone were measured in plasma with ultraperformance liquid chromatography tandem mass spectrometry in athletes from the Measuring Athletes' Risk of Cardiovascular Events 2 study cohort. Coronary plaques, plaque characteristics (calcified, noncalcified or mixed), and coronary artery calcium (CAC) scores were assessed with coronary computed tomography, and potential associations with AGE and dicarbonyl compounds were analyzed using linear and logistic regression. Results: A total of 289 men were included (60 [quartiles 1–3 = 56–66] yr old, body mass index = 24.5 [22.9–26.6] kg·m−2), with a weekly exercise volume of 41 (25–57) MET-hours. Coronary plaques were detected in 241 participants (83%), with a dominant plaque type of calcified plaques in 42%, noncalcified plaques in 12% and mixed plaques in 21%. No AGE or dicarbonyl compounds were associated with total number of plaques or any of the plaque characteristics in adjusted analyses. Similarly, AGE and dicarbonyl compounds were not associated with CAC score. Conclusions: Concentrations of plasma AGE and dicarbonyl compounds do not predict the presence of coronary plaques, plaque characteristics or CAC scores, in middle-age and older athletes. [ABSTRACT FROM AUTHOR]

Objective: We investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT). Research design and methods: We used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status. Results: After full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and − 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status. Conclusion: The present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double‐blind placebo‐controlled trial in abdominally obese individuals. Materials and methods: Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m2) were randomized to an 8‐week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, β‐cell function, insulin‐mediated microvascular recruitment, skin microvascular function, flow‐mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra‐performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one‐way ANCOVA. Results: In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein‐bound Nδ‐(5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl)‐ornithine (MG‐H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule‐1 (sVCAM‐1) in the low and high PM dose group and of soluble intercellular adhesion molecule‐1 (sICAM‐1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. Conclusions: This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM‐1 and sICAM‐1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis. [ABSTRACT FROM AUTHOR]

A letter the editor is presented in response to the article "sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death," by E. Selvin et al. in the 2013 issue of "Diabetes."

The dicarbonyl compound methylglyoxal (MGO) is a major precursor in the formation of advanced glycation endproducts (AGEs). MGO and AGEs are increased in subjects with diabetes and are associated with fatal and nonfatal cardiovascular disease. Previously, we have shown that plasma MGO concentrations rapidly increase in the postprandial phase, with a higher increase in individuals with type 2 diabetes. In current study, we investigated whether postprandial MGO formation in plasma and tissues originates from exogenous glucose and whether the increased plasma MGO concentration leads to a fast formation of MGO-derived AGEs. We performed a stable isotope-labelled oral glucose tolerance test (OGTT) in 12 healthy males with universally labelled D(+)13C glucose. Analysis of plasma-labelled 13C3 MGO and glucose levels at 11 time-points during the OGTT revealed that the newly formed MGO during OGTT is completely derived from exogenous glucose. Moreover, a fast formation of protein-bound MGO-derived AGEs during the OGTT was observed. In accordance, ex-vivo incubation of MGO with plasma or albumin showed a rapid decrease in MGO and a fast increase in MGO-derived AGEs. In an intraperitoneal glucose tolerance test in C57BL/6J mice, we confirmed that the formation of postprandial MGO is derived from exogenous glucose in plasma and also showed in tissues that MGO is increased and this is also from exogenous glucose. Collectively, increased formation of MGO during a glucose tolerance test arises from exogenous glucose both in plasma and in tissues, and this leads to a fast formation of MGO-derived AGEs. [ABSTRACT FROM AUTHOR]

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 < 0.001), and glucose metabolism status (Pinteraction = 0.02). Conclusions: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions. [ABSTRACT FROM AUTHOR]

Purpose: Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. Methods: We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC–MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. Results: Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: β = 0.19 (0.09, 0.28); DMS: β = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: β = 0.15 (0.08, 0.23); DMS: β = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: β = 0.16 (0.08, 0.25); DMS: β = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. Conclusion: Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts. [ABSTRACT FROM AUTHOR]

Purpose: Advanced glycation endproducts (AGEs) and their precursors α-dicarbonyls are implicated in the progression of diabetic retinopathy. The purpose of this study was to assess AGEs and α-dicarbonyls in the vitreous of patients with type 2 diabetes mellitus (T2DM) with early stages or absence of diabetic retinopathy. Methods: We examined vitreous samples obtained during vitrectomy from 31 T2DM patients presenting themselves with rhegmatogenous retinal detachment and compared these to 62 non-diabetic rhegmatogenous retinal detachment patients, matched on age, estimated glomerular filtration rate, smoking, intra-ocular lens implantation, and proliferative vitreoretinopathy. AGEs (pentosidine, Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and 5-hydro-5-methylimidazolone) and α-dicarbonyls (3-deoxyglucosone, methylglyoxal, and glyoxal) were measured by ultra performance liquid chromatography or high performance liquid chromatography. Skin autofluorescence was measured by the AGE Reader. Results: Mean age was 64 ± 7.6 years for T2DM patients and 63 ± 8.1 years for controls. For T2DM patients, median diabetes duration was 2.2 (0.3–7.4) years. Non-proliferative diabetic retinopathy was present in 1 patient and classified as absent or background retinopathy in 30 patients. Vitreous levels of pentosidine (2.20 vs. 1.59 μmol/mol lysine, p = 0.012) and 3-deoxyglucosone (809 vs. 615 nmol/L, p = 0.001) were significantly elevated in T2DM patients compared to controls. Other AGEs and α-dicarbonyls in the vitreous were not significantly different. There was a trend for increased skin autofluorescence in T2DM patients as compared to controls (p = 0.07). Conclusions: Pentosidine and 3-deoxyglucosone concentrations were increased in the vitreous of rhegmatogenous retinal detachment patients with a relatively short duration of diabetes compared to non-diabetic rhegmatogenous retinal detachment patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes. Advanced glycation endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins, during glycolysis. This suggests that, in MS, MGO-derived AGEs are formed in glycolysis-driven cells. MGO and MGO-derived AGEs can further activate inflammatory cells by binding to the receptor for advanced glycation endproducts (RAGE). Recent studies have revealed that AGEs are increased in the plasma and brain of MS patients. Therefore, AGEs might contribute to the inflammatory status in MS. Moreover, the main detoxification system of dicarbonyl compounds, the glyoxalase system, seems to be affected in MS patients, which may contribute to high MGO-derived AGE levels. Altogether, evidence is emerging for a contributing role of AGEs in the pathology of MS. In this review, we provide an overview of the current knowledge on the involvement of AGEs in MS. [ABSTRACT FROM AUTHOR]

Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have not yet improved the clinical outcome. Therefore, new targetable mechanisms should be investigated. We hypothesize that increased dicarbonyl stress is such a mechanism. Dicarbonyl stress is the accumulation of dicarbonyl metabolites (i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone) that damages intracellular proteins, modifies extracellular matrix proteins, and alters plasma proteins. Increased dicarbonyl stress has been shown to impair the renal, cardiovascular, and central nervous system function, and possibly also the hepatic and respiratory function. In addition to hyperglycaemia, hypoxia and inflammation can cause increased dicarbonyl stress, and these conditions are prevalent in critical illness. Hypoxia and inflammation have been shown to drive the rapid intracellular accumulation of reactive dicarbonyls, i.e., through reduced glyoxalase-1 activity, which is the key enzyme in the dicarbonyl detoxification enzyme system. In critical illness, hypoxia and inflammation, with or without hyperglycaemia, could thus increase dicarbonyl stress in a way that might contribute to multi-organ failure. Thus, we hypothesize that increased dicarbonyl stress in critical illness, such as sepsis and major trauma, contributes to the development of multi-organ failure. This mechanism has the potential for new therapeutic intervention in critical care. [ABSTRACT FROM AUTHOR]

Background: Depression is a highly prevalent disease with a high morbidity and mortality risk. Its pathophysiology is not entirely clear. However, type 2 diabetes is an important risk factor for depression. One mechanism that may explain this association may include the formation of advanced glycation end products (AGEs). We therefore investigated the association of AGEs with depressive symptoms and depressive disorder. In addition, we examined whether the potential association was present for somatic and/or cognitive symptoms of depression.Methods: Cross-sectional data were used from the Maastricht Study (N = 862, mean age 59.8 ± 8.5 years, 55% men). AGE accumulation was measured with skin autofluorescence (SAF) by use of the AGE Reader. Plasma levels of protein-bound pentosidine were measured with high-performance liquid chromatography and fluorescence detection. Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL) were measured with ultraperformance liquid chromatography and tandem mass spectrometry. Depressive symptoms and depressive disorder were assessed by the nine-item Patient Health Questionnaire and the Mini-International Neuropsychiatric Interview.Results: Higher SAF was associated with depressive symptoms (β = 0.42, 95% CI 0.12-0.73, P = .007) and depressive disorder (OR = 1.42, 95% CI 1.04-1.95, P = .028) after adjustment for age, sex, type 2 diabetes, smoking, BMI, and kidney function. Plasma pentosidine, CML, and CEL were not independently associated with depressive symptoms and depressive disorder.Conclusions: This study shows that AGE accumulation in the skin is independently associated with higher levels of depressive symptoms and depressive disorder. This association is present for both somatic and cognitive symptoms of depression. This might suggest that AGEs are involved in the development of depression. [ABSTRACT FROM AUTHOR]

Background The pathogenesis of depression may involve low-grade inflammation and endothelial dysfunction. We aimed to evaluate the independent associations of inflammation and endothelial dysfunction with depressive symptoms and depressive disorder, and the role of lifestyle factors in this association. Methods In The Maastricht Study, a population-based cohort study (n = 852, 55% men, m = 59.8 ± 8.5 years), depressive symptoms were assessed with the Patient Health Questionnaire-9 and (major and minor) depressive disorder with the Mini-International Neuropsychiatric Interview. Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) and endothelial dysfunction (sVCAM-1, sICAM-1, sE-selectin, vWF) were measured with sandwich immunoassays and combined into two standardized sum scores. Results Biomarkers of inflammation (hsCRP, TNF-α, SAA, sICAM-1) and endothelial dysfunction (sICAM-1, sE-Selectin) were univariately associated with depressive symptoms and depressive disorder. The sum scores of inflammation and endothelial dysfunction were associated with depressive disorder after adjustment for age, sex, type 2 diabetes, kidney function and prior cardiovascular disease (OR 1.54, p = 0.001 and 1.40, p = 0.006). Both sum scores remained significantly associated with depressive disorder after additional adjustment for lifestyle factors smoking, alcohol consumption and body mass index. The sum score of inflammation was also independently associated with depressive symptoms, while the sum score of endothelial dysfunction was not. Conclusions Inflammation and endothelial dysfunction are both associated with depressive disorder, independent of lifestyle factors. Our results might suggest that inflammation and endothelial dysfunction are involved in depression. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background: Individuals with depression often show an adverse cardiometabolic risk profile and might represent a distinct depression subtype. The aim of this study was to investigate whether a cardiometabolic depression subtype could be identified and to investigate its association with demographics and clinical characteristics (severity, symptomatology, anti-depressant use, persistence and cognitive functioning).Methods: We used data from The Maastricht Study, a population-based cohort in the southern part of The Netherlands. A total of 248 participants with major depressive disorder were included (mean [SD] age, 58.8 ± 8.5 years; 121 [48.8 %] were men). Major depressive disorder was assessed at baseline by the Mini-International Neuropsychiatric Interview. Cardiometabolic risk factors were defined as indicators of the metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. We measured severity and persistence of depressive symptoms by use of the 9-item Patient Health Questionnaire.Results: Latent class analysis resulted in two subtypes, one with cardiometabolic depression (n = 145) and another with non-cardiometabolic depression (n = 103). The cardiometabolic depression subtype was characterized by being male, low education, more severe depressive symptoms, less symptoms of depressed mood and more symptoms of loss of energy, more use of antidepressant medication and lower cognitive functioning.Limitations: No conclusions can be made about causality.Conclusions: Latent class analysis suggested a distinct cardiometabolic depression subtype. Participants with cardiometabolic depression differed from participants with non-cardiometabolic depression in terms of demographics and clinical characteristics. The existence of a cardiometabolic depression subtype may indicate the need for prevention and treatment targeting cardiometabolic risk management. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon‐like peptide‐1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here, we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats. Methods: DM was induced in Sprague–Dawley rats (n = 15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg bodyweight). Ten control rats remained nondiabetic. From day 9 post‐STZ injection, Liraglutide (200 μg/kg bodyweight; n = 7) or vehicle (n = 8) was injected subcutaneously daily until termination on day 29. The advanced glycation endproduct N‐ε‐(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM‐1 and VCAM‐1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment with placebo. Results: In the heart, Liraglutide treatment significantly reduced the DM‐increased scores/cm2 for CML in both ventricles (from 253 ± 53 to 72 ± 12; p =.003) and atria (343 ± 29 to 122 ± 8; p =.0001) and for NOX2, ICAM‐1 and VCAM‐1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60 ± 7 (p =.0005) and 47 ± 13 (p =.02), respectively), and for NOX2 and NOX4. In the kidney, the DM‐induced expression of ICAM‐1 and VCAM‐1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or bodyweight. Conclusions: Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes‐induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been hampered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level.Research Design and Methods: We used cross-sectional data from The Maastricht Study, a population-based cohort study (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber.Results: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071).Conclusions: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level. [ABSTRACT FROM AUTHOR]

The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role. [ABSTRACT FROM AUTHOR]

Compelling evidence has shown cardiac involvement in COVID-19 patients. However, the overall majority of these studies use data obtained during the first wave of the pandemic, while recently differences have been reported in disease course and mortality between first- and second wave COVID-19 patients. The aim of this study was to analyze and compare cardiac pathology between first- and second wave COVID-19 patients. Autopsied hearts from first- (n = 15) and second wave (n = 10) COVID-19 patients and from 18 non-COVID-19 control patients were (immuno)histochemically analyzed. CD45+ leukocyte, CD68+ macrophage and CD3+ T lymphocyte infiltration, cardiomyocyte necrosis and microvascular thrombosis were quantified. In addition, the procoagulant factors Tissue Factor (TF), Factor VII (FVII), Factor XII (FXII), the anticoagulant protein Dipeptidyl Peptidase 4 (DPP4) and the advanced glycation end-product N(ε)-Carboxymethyllysine (CML), as markers of microvascular thrombogenicity and dysfunction, were quantified. Cardiac inflammation was significantly decreased in second wave compared to first wave COVID-19 patients, predominantly related to a decrease in infiltrated lymphocytes and the occurrence of lymphocytic myocarditis. This was accompanied by significant decreases in cardiomyocyte injury and microvascular thrombosis. Moreover, microvascular deposits of FVII and CML were significantly lower in second wave compared to first wave COVID-19 patients. These results show that in our cohort of fatal COVID-19 cases cardiac inflammation, cardiomyocyte injury and microvascular thrombogenicity were markedly decreased in second wave compared to first wave patients. This may reflect advances in COVID-19 treatment related to an increased use of steroids in the second COVID-19 wave. • Cardiac inflammation is decreased in second wave compared to first wave COVID-19 patients. • Cardiac injury is lower in second wave compared to first wave COVID-19 patients. • Cardiac microvascular thrombogenicity is increased in COVID-19 patients, but is lower in second wave patients. [ABSTRACT FROM AUTHOR]

Cardiovascular disease, caused predominantly by atherosclerotic plaque rupture, remains one of the leading causes of death. However, the mechanism of plaque rupture remains largely unknown. Recent studies have linked high metabolic activity in inflamed atherosclerotic plaques to the development of plaque rupture. AGEs (advanced glycation end-products) are known to be formed as a result of high metabolic activity and are higher in rupture-prone than stable plaques. Furthermore, AGEs seem to be more than mere markers of metabolic activity, as recent studies have elucidated that AGEs and their major precursor, MG (methylglyoxal), may have an important role in the progression of atherosclerosis and plaque rupture. MG can be detoxified by Glo1 (glyoxalase I), thereby preventing the accumulation of MG and MG-derived AGEs. In the present review, data concerning MG, Glo1 and AGEs in the context of plaque phenotype are discussed. [ABSTRACT FROM AUTHOR]

There has been increasing interest in finding non-invasive biomarkers for neurodegenerative diseases such as Alzheimer's disease (AD). This observational study investigated AD-specific biomarkers in tear fluid. Tear fluid was collected from a total of 65 subjects, including 23 patients with subjective cognitive decline (SCD), 22 patients with mild cognitive impairment (MCI), 11 dementia patients and 9 healthy controls (HC). Levels of amyloid-beta peptides (AB38, AB40, AB42), total-tau (t-tau) and phosphorylated-tau (p-tau) were determined using multiplex immunoassays. Levels of AB40 and t-tau were detectable in the vast majority (> 94%) of tear fluid samples. Cerebrospinal fluid (CSF) was available from a subset of patients. In this group, tear t-tau levels were significantly higher in people with dementia compared to SCD patients. Tear t-tau levels were elevated in patients with neurodegeneration (classified according to the A/T/N system) compared to patients without neurodegeneration. Negative correlations were found between CSF AB42 and CSF t-tau, and between CSF AB42 and tear t-tau. In summary, this study shows the potential of tau proteins in tear fluid to be associated with disease severity and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Arterial stiffening is a hallmark of vascular ageing and a consequence of many diseases including diabetes mellitus. Methylglyoxal (MGO), a highly reactive α-dicarbonyl mainly formed during glycolysis, has emerged as a potential contributor to the development of arterial stiffness. MGO reacts with arginine and lysine residues in proteins to form stable advanced glycation endproducts (AGEs). AGEs may contribute to arterial stiffening by increased cross-linking of collagen within the extracellular matrix (ECM), by altering the vascular structure, and by triggering inflammatory and oxidative pathways. Although arterial stiffness is mainly determined by ECM and vascular smooth muscle cell function, the effects of MGO and MGO-derived AGEs on these structures have not been thoroughly reviewed to date.Methods and Results: We conducted a PubMed search without filtering for publication date which resulted in 16 experimental and 22 clinical studies eligible for inclusion. Remarkably, none of the experimental and only three of the clinical studies specifically mentioned MGO-derived AGEs. Almost all studies reported an association between arterial stiffness and AGE accumulation in the arterial wall or increased plasma AGEs. Other studies report reduced arterial stiffness in experimental models upon administration of AGE-breakers.Conclusions: No papers published to date directly show an association between MGO or MGO-derived AGEs and arterial stiffening. The relevance of the various underlying mechanisms is not yet clear, which is particularly due to methodological challenges in the detection of MGO and MGO-derived AGEs at the molecular, intra- and pericellular, and structural levels, as well as in challenges in the assessment of intrinsic arterial wall properties at ECM- and tissue levels. [ABSTRACT FROM AUTHOR]

OBJECTIVE--In the general population, a low ankle-brachial index (ABI) (<0.9) is strongly associated with (cardiovascular) mortality. However, the association between the ABI and mortality may be weaker in individuals with diabetes, as ankle pressures may be elevated by medial arterial calcification and arterial stiffening, which occur more frequently in diabetes. Therefore, the aim of this study was to compare the association between ABI and mortality in individuals without and with diabetes. RESEARCH DESIGN AND METHODS--We studied the associations between ABI and cardiovascular and all-cause mortality in 624 individuals from the Hoorn study, a population-based cohort of 50- to 75-year-old individuals (155 with diabetes and 469 without) followed for a median period of 17.2 years. Data were analyzed using Cox proportional hazards models. RESULTS--During the follow-up period, 289 of 624 (46.3%) participants died (97 of 155 with and 192 of 469 without diabetes and 52 of 65 with and 237 of 559 without ABI <0.9): 85 (29.4%) of CVD (30 of 155 with and 55 of 469 without diabetes and 20 of 65 with and 65 of 559 without ABI <0.9). A low ABI was strongly associated with cardiovascular mortality (relative risk 2.57 [95% CI 1.50-4.40]) and all-cause mortality (2.02 [1.47-2.76]), after adjustment for Framingham risk factors. The associations of the ABI with mortality did not differ between individuals without and with diabetes for cardiovascular (Pinteraction = 0.45) or all-cause (Pinteraction = 0.63) mortality. CONCLUSIONS--In the Hoorn Study, associations between ABI and cardiovascular and all-cause mortality were similar in individuals without and with diabetes. Future studies should investigate, in both individuals without and with diabetes, whether measurement of ABI can be used to guide treatment decisions. [ABSTRACT FROM AUTHOR]

Context and objective: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro-and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. Design and methods: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40±10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study.We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Results: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised &bgr;=0.07 (95% confidence interval (CI): 0.02-0.12) and &bgr;=0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro- and macroalbuminuria: odds ratio (OR)=1.24 (95% CI: 0.90-1.71) and OR=1.61 (95% CI: 1.15-2.25) respectively, P for trend=0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. Conclusions: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes. [ABSTRACT FROM AUTHOR]