Soluble Receptor For Advanced Glycation End-products Research Articles

The potential role of advanced glycation end products (AGEs) and soluble receptors for AGEs (sRAGE) in the pathogenesis of adult-onset still's disease.

BackgroundAccumulating evidence has demonstrated a pathogenic role of advanced glycation end products (AGEs) and receptors for AGEs (RAGE) in inflammation. Soluble RAGE (sRAGE), with the same ligands-binding capacity as full-length RAGE, acts as a “decoy” receptor. However, there has been scanty data regarding AGEs and sRAGE in adult-onset Still’s disease (AOSD). This study aimed to investigate AGEs and sRAGE levels in AOSD patients and examine their association with clinical characteristics.MethodsUsing ELISA, plasma levels of AGEs and sRAGE were determined in 52 AOSD patients, 36 systemic lupus erythematosus(SLE) patients and 16 healthy controls(HC). Their associations with activity parameters and disease courses were evaluated.ResultsSignificantly higher median levels of AGEs were observed in active AOSD patients (16.75 pg/ml) and active SLE patients (14.80 pg/ml) than those in HC (9.80 pg/ml, both p < 0.001). AGEs levels were positively correlated with activity scores (r = 0.836, p < 0.001), ferritin levels (r = 0.372, p < 0.05) and CRP levels (r = 0.396, p < 0.005) in AOSD patients. Conversely, significantly lower median levels of sRAGE were observed in active AOSD patients (632.2 pg/ml) and active SLE patients (771.6 pg/ml) compared with HC (1051.7 pg/ml, both p < 0.001). Plasma sRAGE levels were negatively correlated with AOSD activity scores (r = −0.320, p < 0.05). In comparison to AOSD patients with monocyclic pattern, significantly higher AGEs levels were observed in those with polycyclic or chronic articular pattern. With treatment, AGEs levels declined while sRAGE levels increased in parallel with the decrease in disease activity.ConclusionThe elevation of AGEs levels with concomitant decreased sRAGE levels in active AOSD patients, suggests their pathogenic role in AOSD.

The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes.

Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. The receptor for advanced-glycation-end-products (RAGE) regulates immune responses and inflammation and has been linked to diabetes and possibly CF. We performed a pilot study to determine if CF and CF-related diabetes (CFRD) are associated with enhanced RAGE expression. Full length (fl)RAGE, soluble (s)RAGE, endogenous soluble (es)RAGE, S100A12 (enRAGE) and advanced-glycation-end-products (AGE) expression was assessed in serum, white blood cells and sputum of patients with CF; diabetes; CFRD and healthy subjects. Sputum enRAGE/sRAGE ratios were high in CF but particularly in CFRD which negatively correlated with % predicted FEV1. Serum AGE and AGE/sRAGE ratios were high in diabetics but not in CF. A complex, multifaceted approach was used to assess the role of RAGE and its ligands which is fundamental to determining their impact on airway inflammation. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD.

Altered serum glyceraldehyde-derived advanced glycation end product (AGE) and soluble AGE receptor levels indicate carbonyl stress in patients with schizophrenia

Recent cross-sectional and longitudinal studies indicate that measurements of peripheral blood carbonyl stress markers such as the advanced glycation end product (AGE) pentosidine and the reactive carbonyl-detoxifying B6 vitamin pyridoxal could be used as therapeutic biological markers in subpopulations of schizophrenia patients. Glyceraldehyde-derived AGEs (Glycer-AGE) have strong neurotoxicity, and soluble receptors for AGEs (sRAGE) may ameliorate the effects of AGEs. In the present study, we measured Glycer-AGEs and sRAGE levels to determine their potential as diagnostic, therapeutic, or clinical biological markers in patients with schizophrenia. After enrollment of 61 admitted Japanese patients with acute schizophrenia and 39 healthy volunteers, 54 patients were followed up from the acute stage to remission. Serum biomarkers were measured in blood samples taken before breakfast using competitive enzyme-linked immunosorbent assays, and Glycer-AGEs were significantly higher and sRAGE levels were significantly lower in patients with acute schizophrenia than in healthy controls. Glycer-AGEs/sRAGE ratios were also higher in schizophrenia patients and were stable during the clinical course. Furthermore, discriminant analyses confirmed that Glycer-AGEs and Glycer-AGEs/sRAGE ratios are significant diagnostic markers for schizophrenia, and distinguished between patients and healthy controls in 70.0% of cases. However, these markers of carbonyl stress were not correlated with clinical features, including disease severity, or with daily chlorpromazine doses. These data indicate the potential of Glycer-AGEs, RAGEs, and their relative ratios as diagnostic markers for patients with schizophrenia.

Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes.

We selected the most informative protein biomarkers for the prediction of incident cardiovascular disease (CVD) in people with type 2 diabetes. In this nested case-control study we measured 42 candidate CVD biomarkers in 1,123 incident CVD cases and 1,187 controls with type 2 diabetes selected from five European centres. Combinations of biomarkers were selected using cross-validated logistic regression models. Model prediction was assessed using the area under the receiver operating characteristic curve (AUROC). Sixteen biomarkers showed univariate associations with incident CVD. The most predictive subset selected by forward selection methods contained six biomarkers: N-terminal pro-B-type natriuretic peptide (OR 1.69 per 1 SD, 95% CI 1.47, 1.95), high-sensitivity troponin T (OR 1.29, 95% CI 1.11, 1.51), IL-6 (OR 1.13, 95% CI 1.02, 1.25), IL-15 (OR 1.15, 95% CI 1.01, 1.31), apolipoprotein C-III (OR 0.79, 95% CI 0.70, 0.88) and soluble receptor for AGE (OR 0.84, 95% CI 0.76, 0.94). The prediction of CVD beyond clinical covariates improved from an AUROC of 0.66 to 0.72 (AUROC for Framingham Risk Score covariates 0.59). In addition to the biomarkers, the most important clinical covariates for improving prediction beyond the Framingham covariates were estimated GFR, insulin therapy and HbA1c. We identified six protein biomarkers that in combination with clinical covariates improved the prediction of our model beyond the Framingham Score covariates. Biomarkers can contribute to improved prediction of CVD in diabetes but clinical data including measures of renal function and diabetes-specific factors not included in the Framingham Risk Score are also needed.

Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients

Chronic obstructive pulmonary disease (COPD) is a severe and progressive lung disease characterised by destruction of lung parenchyma and chronic airway inflammation [1]. A major cause of COPD is chronic exposure to noxious gases and particles, including cigarette smoke. During exacerbation, COPD patients experience a worsening of symptoms that coincides with increased inflammation and accelerated decline in lung function, resulting in a decrease in quality of life and increased healthcare costs. Approximately half of the COPD exacerbations causing hospitalisation are associated with respiratory viral and/or bacterial infections [2]. However, the underlying mechanisms causing COPD exacerbations are unknown [3]. Molecules derived from viruses and bacteria during airway infection can trigger the activation of pattern recognition receptors (PRRs) on lung structural and innate immune cells, and may thus contribute to the aggravation of inflammation during COPD exacerbations [1]. Interestingly, damage-associated molecular patterns (DAMPs) released from damaged or necrotic cells are also known to activate PRRs, including Toll-like receptors (TLRs) and the receptor for advanced glycation end-products (RAGE) [4]. A role for DAMPs has been proposed in the pathogenesis of COPD, as various DAMPs have been found to be increased in lung fluids and serum of COPD patients [5, 6]. Furthermore, Ager , the gene encoding RAGE, has been identified by genome-wide association studies as a susceptibility gene for COPD [7, 8]. Moreover, the serum levels of soluble RAGE (sRAGE), a decoy receptor for RAGE, were shown to be significantly lower in COPD patients, while the RAGE ligand EN-RAGE (also known as S100 calcium-binding protein (S100)A12) was significantly higher in COPD patients compared with smoking and nonsmoking controls [9]. It is currently unknown, however, whether DAMPs play a role in COPD exacerbations. Here, we hypothesised that the release of DAMPs is increased during exacerbations of COPD. Serum levels of the RAGE-activating DAMPs LL37, HMGB1 and S100A9 are increased during exacerbation in COPD patients http://ow.ly/Idh3r

Soluble RAGE and the RAGE ligands HMGB1 and S100A12 in critical illness: impact of glycemic control with insulin and relation with clinical outcome.

Systemic inflammation often leads to complications in critically ill patients. Activation of the receptor for advanced glycation end-products (RAGE) generates inflammatory cytokines, proteases, and oxidative stress and may link inflammation to subsequent organ damage. Furthermore, hyperglycemia-induced oxidative stress increases RAGE ligands and RAGE expression. We hypothesized that preventing hyperglycemia during critical illness reduces the risk of excessively enhanced RAGE signaling, which could relate to clinical outcomes and risk of death. In 405 long-stay surgical intensive care unit patients randomized to intensive or conventional insulin treatment, serum concentrations of soluble RAGE (decoy receptor) and the RAGE ligands high-mobility group box 1 (HMGB1) and S100A12 were measured on admission, day 7, and last day. These were compared with levels in 71 matched control subjects and with C-reactive protein (CRP) as a routinely monitored inflammation marker. On admission, soluble RAGE, HMGB1, S100A12, and CRP were higher in patients than in controls. The HMGB1, S100A12, and CRP remained elevated throughout intensive care unit stay, whereas soluble RAGE decreased to levels lower than in controls by day 7. Unexpectedly, insulin treatment did not affect the circulating levels of these markers. In univariable analysis, elevated levels of soluble RAGE on admission were associated with adverse outcome, including circulatory failure, kidney failure, liver dysfunction, and mortality. The associations with circulatory and kidney failure remained significant in multivariable logistic regression analysis corrected for baseline risk factors. Critical illness affects components of RAGE signaling, unaffected by insulin treatment. Elevated on-admission soluble RAGE was associated with adverse outcomes.

Decrease in circulating concentrations of soluble receptors for advanced glycation end products at the time of seroconversion to autoantibody positivity in children with prediabetes.

Dietary advanced glycation end products (AGEs) and their interactions with the receptor for AGEs (RAGE) may play a role in the pathogenesis of type 1 diabetes. This study set out to assess whether there is any association of circulating concentrations of soluble RAGE (sRAGE), AGEs, and their ratio with the appearance of diabetes-associated autoantibodies in children progressing to clinical diabetes. Serum concentrations of sRAGE, N-ε(carboxymethyl)lysine (CML) adducts, and the sRAGE/CML ratio were analyzed in children who progressed to type 1 diabetes. The samples were taken at four time points: before seroconversion, at the time of the first autoantibody-positive sample, at the time of the first sample positive for multiple (>2) autoantibodies, and close to the disease diagnosis. Samples of autoantibody-negative controls matched for age, sex, and HLA-conferred diabetes risk were analyzed at corresponding time points. The prediabetic children had higher sRAGE concentrations before seroconversion (Pc = 0.03), at the appearance of multiple autoantibodies (Pc = 0.008), and close to diagnosis (Pc = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (Pc = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (Pc = 0.008) and at diagnosis (Pc < 0.001). Prediabetic children have higher concentrations of sRAGE and a higher sRAGE/CML ratio than healthy controls. Circulating sRAGE concentrations seem to decline with the appearance of diabetes-predictive autoantibodies in children progressing to type 1 diabetes. The higher sRAGE/CML ratio in prediabetic children may reflect a higher AGE scavenger capacity.

Vascular effects of advanced glycation end-products: content of immunohistochemically detected AGEs in radial artery samples as a predictor for arterial calcification and cardiovascular risk in asymptomatic patients with chronic kidney disease.

Objectives. Our aim was to determine whether vascular deposition of advanced glycation end-products (AGEs) is associated with arterial calcification and cardiovascular mortality in chronic kidney disease (CKD) patients and to assess the relationships between vascular content of AGEs and selected clinical and biochemical parameters. Materials and Methods. The study comprised 54 CKD patients (33 hemodialyzed, 21 predialyzed). Examined parameters included BMI, incidence of diabetes, plasma fasting glucose, AGEs, soluble receptor for AGEs and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging, serum C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), and fetuin-A. Fragments of radial artery obtained during creation of hemodialysis access were stained for calcifications using alizarin red. AGEs deposits were identified immunohistochemically and their relative content was quantified. Results. Vascular content of AGEs was positively correlated with BMI, hsCRP, fetuin-A, PAI-1, and DPPH scavenging in simple regression; only fetuin-A was an independent predictor in multiple regression. There was a significant positive trend in the intensity of AGEs immunostaining among patients with grades 1, 2, and 3 calcifications. AGEs immunostaining intensity predicted 3-year cardiovascular mortality irrespective of patient's age. Conclusions. The present study demonstrates an involvement of AGEs in the development of medial arterial calcification and the impact of arterial AGE deposition on cardiovascular mortality in CKD patients.

Is vitamin D deficiency related to accumulation of advanced glycation end products, markers of inflammation, and oxidative stress in diabetic subjects?

Objectives. In diabetes accumulated advanced glycation end products (AGEs) are involved in the striking cardiovascular morbidity/mortality. We asked whether a hypovitaminosis D associates with an increased formation and toxicity of AGEs in diabetes. Methods. In 276 diabetics (160 M/116 F, age: 65.0 ± 13.4; 43 type 1,T1DM, and 233 type 2 patients, T2DM) and 121 nondiabetic controls (60 M/61 F; age: 58.6 ± 15.5 years) routine biochemistry, levels of 25-hydroxyvitamin D3 (25-(OH)D), skin autofluorescence (SAF), plasma AGE-associated fluorescence (AGE-FL), Nε-(carboxymethyl)lysine (CML), soluble receptor for AGEs (sRAGE), soluble vascular adhesion protein-1 (sVAP-1), high sensitive C-reactive protein (hs-CRP), and renal function (eGFR) were determined. Results. In the diabetics SAF and AGE-Fl were higher than those of the controls and correlated with age, duration of diabetes, and degree of renal impairment. In T2DM patients but not in T1DM the age-dependent rise of SAF directly correlated with hs-CRP and sVAP-1. 25-(OH)D levels in diabetics and nondiabetics were lowered to a similar degree averaging 22.5 ng/mL. No relationship between 25-(OH)D and studied markers except for sVAP-1 was observed in the diabetics. Conclusion. In diabetics hypovitaminosis D does not augment accumulation of AGEs and studied markers of microinflammation and oxidative stress except for sVAP-1.

Elevated levels of soluble RAGE predict impaired alveolar fluid clearance in a translational mouse model of acute respiratory distress syndrome

Receptor for advanced glycation endproducts (RAGE) is a transmembrane receptor expressed in the lung and primarily located on alveolar type I cells. RAGE is implicated in acute respiratory distress syndrome to alveolar inflammation and, when its soluble form sRAGE is assayed in plasma or pulmonary edema fluid, as a marker of AT I cell injury. Functional activity of AT 1 cells can be assessed by the measurement of the alveolar fluid clearance (AFC) rate [1], but the relationship between sRAGE plasma levels of sRAGE and AFC rates has never been investigated. Our objectives were to report plasma levels of sRAGE in a mouse model of direct acid-induced epithelial injury, and to test their correlation with AFC rates.

Receptor for advanced glycation end-products regulates lung fluid balance via protein kinase C-gp91(phox) signaling to epithelial sodium channels.

The receptor for advanced glycation end-products (RAGE), a multiligand member of the Ig family, may play a crucial role in the regulation of lung fluid balance. We quantified soluble RAGE (sRAGE), a decoy isoform, and advanced glycation end-products (AGEs) from the bronchoalveolar lavage fluid of smokers and nonsmokers, and tested the hypothesis that AGEs regulate lung fluid balance through protein kinase C (PKC)-gp91(phox) signaling to the epithelial sodium channel (ENaC). Human bronchoalveolar lavage samples from smokers showed increased AGEs (9.02 ± 3.03 μg versus 2.48 ± 0.53 μg), lower sRAGE (1,205 ± 292 pg/ml versus 1,910 ± 263 pg/ml), and lower volume(s) of epithelial lining fluid (97 ± 14 ml versus 133 ± 17 ml). sRAGE levels did not predict ELF volumes in nonsmokers; however, in smokers, higher volumes of ELF were predicted with higher levels of sRAGE. Single-channel patch clamp analysis of rat alveolar epithelial type 1 cells showed that AGEs increased ENaC activity measured as the product of the number of channels (N) and the open probability (Po) (NPo) from 0.19 ± 0.08 to 0.83 ± 0.22 (P = 0.017) and the subsequent addition of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl decreased ENaC NPo to 0.15 ± 0.07 (P = 0.01). In type 2 cells, human AGEs increased ENaC NPo from 0.12 ± 0.05 to 0.53 ± 0.16 (P = 0.025) and the addition of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl decreased ENaC NPo to 0.10 ± 0.03 (P = 0.013). Using molecular and biochemical techniques, we observed that inhibition of RAGE and PKC activity attenuated AGE-induced activation of ENaC. AGEs induced phosphorylation of p47(phox) and increased gp91(phox)-dependent reactive oxygen species production, a response that was abrogated with RAGE or PKC inhibition. Finally, tracheal instillation of AGEs promoted clearance of lung fluid, whereas concomitant inhibition of RAGE, PKC, and gp91(phox) abrogated the response.

Abstract 13855: The Impact of Plasma Levels of Receptor for Advanced Glycation End-products and High Mobility Group Box 1 in Patients With Pulmonary Hypertension

Background: In pulmonary hypertension (PH), the increase of pulmonary artery pressure by vasoconstriction, remodeling of small pulmonary arteries, and chronic pulmonary thromboembolism result in right ventricular failure and ultimately death. Nuclear protein, high mobility group box 1 (HMGB1), stabilizes nucleosome, and on release into extracellular environment, HMGB1 acts as a pro-inflammatory cytokine by activating pattern recognition receptors including receptor for advanced glycation end-products (RAGE). HMGB1 is one of endogenous ligands of RAGE, and HMGB1 and RAGE are ubiquitously expressed in various organs. Several reports have recently revealed that RAGE is expressed in pulmonary artery in patients with PH, and HMGB1 contributes to migration of vascular smooth muscle cells in PH patient. The purpose of this study was to examine the clinical significance of circulating levels of HMGB1 and RAGE in patients with PH. Methods and Results: Plasma levels of HMGB1 and soluble RAGE were measured in 33 patients with PH (9 in idiopathic PH, 7 in PH related to collagen disease, 9 in chronic thromboembolic PH (CTEPH), 8 in others) and 30 normal subjects as control. Plasma levels of HMGB1 were not difference between PH patients and control subjects, however, plasma levels of soluble RAGE were significantly higher in patients with PH than in control (1464.2 vs. 831.7 pg/ml, P=0.008). Plasma soluble RAGE levels were higher in idiopathic PH (P&lt;0.001), PH related to collagen disease (P=0.050), and CTEPH (P=0.002) than control. In addition, there was statistically significant positive correlation between pressure gradient of tricuspid valve and plasma level of soluble RAGE (R=0.403, P=0.019). Conclusions: Plasma levels of soluble RAGE, but not HMGB1, might be a novel marker which reflects the pathological conditions in patients with PH.

Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine‐injected diabetic patients

Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients.

Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and humans.

Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration.

Effect of dietary prebiotic supplementation on advanced glycation, insulin resistance and inflammatory biomarkers in adults with pre-diabetes: a study protocol for a double-blind placebo-controlled randomised crossover clinical trial.

BackgroundAdvanced glycation endproducts (AGEs) contribute to the development of vascular complications of diabetes and have been recently implicated in the pathogenesis of diabetes. Since AGEs are generated within foodstuffs upon food processing, it is increasingly recognised that the modern diet is replete with AGEs. AGEs are thought to stimulate chronic low-grade inflammation and promote oxidative stress and have been linked to the development of insulin resistance. Simple therapeutic strategies targeted at attenuating the progression of chronic low-grade inflammation and insulin resistance are urgently required to prevent or slow the development of type 2 diabetes in susceptible individuals. Dietary modulation of the human colonic microbiota has been shown to confer a number of health benefits to the host, but its effect on advanced glycation is unknown. The aim of this article is to describe the methodology of a double-blind placebo-controlled randomised crossover trial designed to determine the effect of 12 week consumption of a prebiotic dietary supplement on the advanced glycation pathway, insulin sensitivity and chronic low-grade inflammation in adults with pre-diabetes.Methods/DesignThirty adults with pre-diabetes (Impaired Glucose Tolerance or Impaired Fasting Glucose) aged between 40–60 years will be randomly assigned to receive either 10 grams of prebiotic (inulin/oligofructose) daily or 10 grams placebo (maltodextrin) daily for 12 weeks. After a 2-week washout period, study subjects will crossover to receive the alternative dietary treatment for 12 weeks. The primary outcome is the difference in markers of the advanced glycation pathway carboxymethyllysine (CML) and methylglyoxal (MG) between experimental and control treatments. Secondary outcomes include HbA1c, insulin sensitivity, lipid levels, blood pressure, serum glutathione, adiponectin, IL-6, E-selectin, myeloperoxidase, C-reactive protein, Toll-like Receptor 4 (TLR4), soluble receptor for AGE (sRAGE), urinary 8-isoprostanes, faecal bacterial composition and short chain fatty acid profile. Anthropometric measures including BMI and waist circumference will be collected in addition to comprehensive dietary and lifestyle data.DiscussionPrebiotics which selectively stimulate the growth of beneficial bacteria in the human colon might offer protection against AGE-related pathology in people at risk of developing type 2 diabetes.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000130763.

Dietary Intake of Advanced Glycation End Products Did Not Affect Endothelial Function and Inflammation in Healthy Adults in a Randomized Controlled Trial

When food is heated to high temperatures, the characteristic “browning” generates advanced glycation end products (AGEs). AGEs are associated with an increased risk of cardiovascular disease, diabetes, and other adverse outcomes. Whether dietary AGEs are absorbed and are harmful to human health remains highly controversial. The objective of this study was to compare the effects of a diet high or low in AGEs on endothelial function, circulating AGEs, inflammatory mediators, and circulating receptors for AGEs in healthy adults. A randomized, parallel-arm, controlled dietary intervention was conducted for 6 wk with 24 healthy adults, aged 50–69 y, that compared isocaloric, food-equivalent diets that were prepared at either high or mild temperatures. Peripheral arterial tonometry, serum and urine carboxymethyl-lysine (CML), inflammatory mediators (interleukin-6, C-reactive protein, vascular adhesion molecule-1, and tumor necrosis factor-α receptors I and II), soluble receptor for AGEs, and endogenous secretory receptor for AGEs were measured at baseline and after 6 wk of dietary intervention. In the low-AGE diet group, the following changed from baseline to 6 wk (mean ± SE): serum CML from 763 ± 24 to 679 ± 29 ng/mL (P = 0.03) and urine CML from 1.37 ± 1.47 to 0.77 ± 2.01 μg/mL creatinine (P = 0.02). There were no significant changes in serum and urinary CML concentrations from baseline to follow-up in the high-AGE diet group. A high- or low-AGE diet had no significant impact on peripheral arterial tonometry or any inflammatory mediators after 6 wk of dietary intervention. In healthy middle-aged to older adults, consumption of a diet high or low in AGEs for 6 wk had no impact on endothelial function and inflammatory mediators, 2 precursors of cardiovascular disease. This trial was registered at clinicaltrials.gov as NCT01402973.

Fructosamine 3-kinase and glyoxalase I polymorphisms and their association with soluble RAGE and adhesion molecules in diabetes.

Advanced glycation end-products (AGEs) are key players in pathogenesis of long-term vascular diabetes complications. Several enzymes such as fructosamine 3-kinase (FN3K) and glyoxalase I (GLO I) are crucial in preventing glycation processes. The aim of our study was to evaluate an association of FN3K (rs1056534, rs3848403) and GLO1 rs4746 polymorphisms with parameters of endothelial dysfunction and soluble receptor for AGEs (sRAGE) in 595 diabetic and non-diabetic subjects. Genotypic and allelic frequencies of mentioned polymorphisms did not differ between subgroups. In diabetic patients significant differences were observed in sRAGE concentrations according to their rs1056534 and rs3848403 genotype. While GG and CG genotypes of rs1056534 with mutated G allele were associated with significant decrease of sRAGE (GG: 1055+/-458 and CG: 983+/-363 vs. CC: 1796+/-987 ng/l, p<0.0001), in rs3848403 polymorphism TT genotype with mutated T allele was related with significant sRAGE increase (TT: 1365+/-852 vs. CT: 1016+/-401 and CC: 1087+/-508 ng/l, p=0.05). Significant differences in adhesion molecules were observed in genotype subgroups of GLO1 rs4746 polymorphism. In conclusion, this is the first study describing significant relationship of FN3K (rs1056534) and (rs3848403) polymorphisms with concentration of sRAGE in patients with diabetes.

Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: Randomized controlled trial (PioRAGE)

ObjectiveThe receptor for advanced glycation end-products (RAGE) is involved in vascular complications in diabetic patients. Pioglitazone, in contrast to glimepiride, has been shown to be protective against atherosclerotic disorders. In this study, we directly compared the effects of those drugs on RAGE system. MethodsSixty-three type 2 diabetic patients (age 20–80 years, hemoglobin A1c 6.4–10.3%) being treated with sulfonylurea (glimepiride 0.5–2.0 mg/day, glyclazide 20–80 mg/day, glibenclamide 1.25–5.0 mg/day), or with nateglinide or metiglynide were randomly assigned to receive either pioglitazone (n = 31) or glimepiride (n = 32). Levels in plasma of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE), and RAGE expression in peripheral mononuclear cells were determined at 0, 12, and 24 weeks. ResultsTwenty-seven patients in the pioglitazone group (15–30 mg) and 30 in the glimepiride group (0.5–4 mg) completed the 24-week trial. Increases in plasma esRAGE were significantly greater in the pioglitazone group (12 weeks: 55 ± 15 pg/mL, p = 0.018; 24 weeks: 90 ± 14 pg/mL, p = 0.003) as compared to the glimepiride group (12 weeks: 12 ± 9 pg/mL; 24 weeks: 29 ± 14 pg/mL). Increases in plasma sRAGE were also significantly (p = 0.037) higher in the pioglitazone group at 24 weeks (170 ± 166 vs.74 ± 171 pg/mL). Furthermore, RAGE expression in mononuclear cells was significantly (p = 0.008) decreased to a greater degree in the pioglitazone group at 24 weeks (−7.39 ± 5.18 vs. −3.39 ± 5.72 MFI). Changes in HbA1c, IRI, and insulin resistance index (HOMA) at 24 weeks were not significantly different between the groups. ConclusionPioglitazone suppresses RAGE expression and increases circulating sRAGE/esRAGE, and those activities are not necessarily dependent on plasma glucose or insulin resistance levels. Clinical trial NoUMIN000002055.

Abstract MP87: Circulating sRAGE Levels And The Risk Of Heart Failure

Introduction: Myocardial fibrosis is a key feature of heart failure, and its mechanisms are incompletely understood. It has been postulated that advanced glycation end-products (AGEs) form an etiologic link between diabetes and its vascular complications. Binding of AGEs to the cellular receptor for AGEs (RAGE) induces a state of increased oxidative stress, inflammation and fibrosis. Circulating soluble RAGEs (sRAGE) compete with cellular RAGE for the binding of AGEs which reduces the activation of the AGE-RAGE mediated pro-inflammatory and pro-fibrotic signaling pathways. We hypothesize that low levels of sRAGE will be associated with higher risk of heart failure. Methods: We conducted a prospective analysis of a random subsample of 1,157 participants from the ARIC Study who attended visit 2 (1990-1992). We included participants without a history of heart disease or heart failure, and with measured plasma sRAGE levels. Incident heart failure was defined as death from health failure or hospitalization due to heart failure. Results: In this community-based population (mean age 63 years, 60% women, 78% white), there were 132 incident cases of heart failure during approximately 20 years of follow up. Lower levels of sRAGE were significantly and independently associated with an increased risk of heart failure (Table). Analyses stratified by diabetes status at baseline showed that the risk of heart failure among those in the lowest quartile, compared to those in the upper quartile, was consistent but stronger among persons with diabetes compared to those without diabetes with HR=5.31 (95%CI 1.05-26.76) versus HR=2.50 (95%CI, 1.22-5.13), respectively. We did not observe any significant interactions by race or obesity status. Conclusions: Lower circulating levels of sRAGE are independently associated with the development of heart failure in older adults. These results highlight the pathophysiological role of the AGE-RAGE-sRAGE axis even among persons without diabetes.