Determinants of concentrations of N(?)-carboxymethyl-lysine and soluble receptor for advanced glycation end products and their associations with risk of pancreatic cancer.
ABSTRACT: The soluble receptor for advanced glycation end-products (sRAGE) is shown to mitigate pro-inflammatory effects triggered by ligation of RAGE with N(?)-carboxymethyl-lysine (CML)-AGE or other ligands. We examined the associations among host, lifestyle, and genetic determinants of CML-AGE or sRAGE and risk of pancreatic cancer in the prospective ATBC Study. We obtained baseline exposure information, data on serological and genetic biomarkers from 141 patients with pancreatic cancer and 141 subcohort controls. Stepwise linear and logistic regression models were used for data analysis. Multiple linear regression analyses showed that CML-AGE concentrations were independently inversely correlated with the minor allele of rs640742 of DDOST, physical activity, alcohol consumption, diastolic blood pressure (BP), and positively correlated with heart rate, serum sRAGE and HDL concentrations (P < 0.05). sRAGE concentrations were independently inversely correlated with the 82Ser allele of rs2070600 of RAGE, age, body mass index, heart rate, and serum HDL; and positively correlated with serum CML-AGE, sucrose consumption, and diastolic BP (P < 0.05). The minor allele of rs1035786 of RAGE was associated with reduced risk of pancreatic cancer (any T compared with CC: multivariate OR = 0.61, 95% CI: 0.38-0.98). We identified host metabolic profile, lifestyle and genetic factors that explained approximately 50% of variability of CML-AGE or sRAGE in Finnish men smokers. The association between RAGE SNPs and pancreatic cancer risk warrants further investigation.
Project description:Receptor for advanced glycation end products (RAGE) expressed on adipocytes and immune cells can bind to ligand N(?)-(carboxymethyl)-lysine (CML) and trigger dysregulation of adipokines and chronic inflammation. Soluble RAGE (sRAGE) mitigates the detrimental effect of RAGE. We examined the associations between circulating levels of CML-AGE and sRAGE and colorectal cancer (CRC).In a case-cohort study of the Women's Health Initiative Study, blood levels of CML-AGE and sRAGE were measured using ELISA. We used multivariable Cox regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CRC in relation to quartiles (Q) of biomarker levels.Average follow-up was 7.8 years for 444 cases and 805 subcohort members. In the subcohort, CML-AGE and sRAGE were inversely correlated with BMI (P values<0.0001). Levels of CML-AGE and sRAGE were not associated with CRC. In BMI-specific analysis, the association between sRAGE and CRC was observed. Among women with BMI?25kg/m(2), those with highest levels of sRAGE had significantly lower risk for CRC as compared to women with lowest levels of sRAGE (HRQ4versusQ1: 0.39; 95% CI: 0.17-0.91). This inverse association was not observed among women with BMI <25kg/m(2) (P value for interaction=0.01).Among postmenopausal women, the RAGE pathway may be involved in obesity-related CRC.
Project description:BACKGROUND:Advanced glycation end products (AGEs) and their receptors are regarded as central to the development of diabetic complications, but associations with diabetes and cardiometabolic outcomes in previous studies are mixed. METHODS:Using ELISA assays, we measured N(6)-carboxymethyllysine (AGE-CML), soluble receptor for AGEs (sRAGE), and endogenous secreted receptor for AGEs (esRAGE) in 1874 participants from the Atherosclerosis Risk in Communities study. We conducted a cross-sectional analysis to evaluate associations of these biomarkers with demographics, diabetes, hyperglycemia, cardiometabolic measures, and genetic variants in the gene encoding RAGE, AGER (advanced glycosylation end-product specific receptor). RESULTS:After adjustment for demographics and body mass index (BMI), there were no significant differences in AGE-CML, sRAGE, or esRAGE by diabetes or hemoglobin A1c. Black race and AGER genetic variants were strongly associated with lower sRAGE and esRAGE even after adjustment [percent difference (95% CI) in black vs whites in sRAGE: -29.17 (-34.86 to -23.48), esRAGE: -26.97 (-33.11 to -20.84); with rs2070600 in sRAGE: -30.13 (-40.98 to -19.29), and esRAGE: -30.32 (-42.42 to -18.21); with rs2071288 in sRAGE: -20.03 (-34.87 to -5.18), and esRAGE: -37.70 (-55.75 to -19.65)]. Estimated glomerular filtration rate and albuminuria significantly correlated with sRAGE and esRAGE. BMI and C-reactive protein significantly negatively correlated with AGE-CML, sRAGE, and esRAGE. AGE-CML was modestly correlated with fructosamine and glycated albumin. CONCLUSIONS:AGE-CML, sRAGE, and esRAGE were more related to genetic, kidney, and inflammatory measures than to diabetes in this community-based population. Our results suggest that, when measured by ELISA, these biomarkers lack specificity and are of limited value in evaluating the role of these compounds in diabetes.
Project description:Advanced glycation end products (AGEs) accumulate in fatty livers and may contribute to low-grade inflammation (LGI), potentially via their receptor, RAGE. It is unknown if the AGE accumulation in fatty livers results in elevated circulating AGEs. In a cohort study, we investigated the association of liver fat and hepatocellular damage with circulating AGEs and soluble RAGE (sRAGE) and subsequently the association of circulating AGEs and sRAGE with LGI. Cross-sectional associations of liver fat percentage (eLF%; ln-transformed) and liver enzymes (LE score; standardized) with circulating AGEs (free CML, CEL, and MG-H1 in nM and protein-bound CML, CEL, and pentosidine in nmol/mmol lysine; ln-transformed) and sRAGE (pg/ml, ln-transformed) and additionally of AGEs and sRAGE with LGI (standardized) were determined by multiple linear regression. eLF% was positively associated with circulating free CEL (? = 0.090; 95% CI 0.041; 0.139) but inversely with protein-bound CML (? = -0.071; 95% CI -0.108; -0.034). Similarly, the LE score was positively associated with free CML (? = 0.044; 95% CI 0.012; 0.076) and CEL (? = 0.040; 95% CI 0.009; 0.072) but inversely with protein-bound CML (? = -0.037; 95% CI -0.060; -0.013). Free CML (? = 0.297; 95% CI 0.049; 0.545) was positively associated with LGI, while protein-bound CML (? = -0.547; 95% CI -0.888; -0.207) was inversely associated, although this association was absent after adjustment for BMI. eLF% and LE score were not associated with sRAGE and sRAGE not with LGI after adjustment for BMI. Liver fat and enzymes were positively associated with circulating free AGEs, which were associated with LGI. In contrast, inverse relations were observed of liver fat and enzymes with circulating protein-bound AGEs and of protein-bound AGEs with LGI. These data suggest that hepatic steatosis and inflammation affect the formation and degradation of hepatic protein-bound AGEs resulting in elevated circulating free AGE levels. These alterations in AGE levels might influence LGI, but this is likely independent of RAGE.
Project description:Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case-control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor-1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1-Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aORQ4 vs. Q1 = 0.70, 95% CI: 0.50-0.99). High MCP1 (aOR Q4 vs. Q1 = 2.55, 95% CI: 1.41-4.61) and the higher CBS including MCP1, PAI1, and leptin (aORQ4 vs. Q1 = 1.82, 95% CI = 1.04-3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m2 (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE.
Project description:The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS).517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression.After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC.The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.
Project description:Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with severe sepsis.1) To explore the reliability of Skin Autofluorescence (AF) as an index of tissue AGEs in ICU patients, 2) to compare its levels to healthy controls, 3) to describe the time course of AGEs and influencing factors during ICU admission, and 4) to explore their association with disease severity, outcome, and markers of oxidative stress and inflammation.Skin AF, serum N"-(carboxyethyl)lysine (CEL), N"-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU patients with multiple organ failure and compared to age-matched healthy controls. Correlations with (changes in) clinical parameters of disease severity, LDL dienes, and CRP were studied and survival analysis for in-hospital mortality was performed.Forty-five ICU patients (age: 59±15 years; 60% male), and 37 healthy controls (59±14; 68%) were included. Skin AF measurements in ICU patients were reproducible (CV right-left arm: 13%, day-to-day: 10%), with confounding effects of skin reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients vs healthy controls (2.7±0.7 vs 1.8±0.3 au; p<0.001). Serum CEL (23±10 vs, 16±3 nmol/gr protein; p<0.001), LDL dienes (19 (15-23) vs. 9 (8-11) ?mol/mmol cholesterol; <0.001), and sRAGE (1547 (998-2496) vs. 1042 (824-1388) pg/ml; p = 0.003) were significantly higher in ICU patients compared to healthy controls, while CML was not different (27 (20-39) vs 29 (25-33) nmol/gr protein). While CRP and LDL dienes decreased significantly, Skin AF and serum AGEs and sRAGE did not change significantly during the first 7 days of ICU admission. CML and CEL were strongly correlated with SOFA scores and CML above the median at baseline was associated with increased risk for mortality (Hazard ratio 3.3 (1.3-8.3); p = 0.01). All other markers did not correlate with disease severity and did not predict mortality.This study demonstrates that markers for the AGE-RAGE axis are elevated in critically ill patients compared to healthy controls but remain stable for at least 7 days despite clearly fading inflammation and oxidative stress. Circulating AGEs may be associated with disease severity and outcome. Further research should be conducted to elucidate the role of the AGE-RAGE axis in the exaggerated inflammatory response leading to multiple organ failure and death, and whether or not this may be a target for treatment.
Project description:The purpose of this investigation was to evaluate the effects of experimental hyperglycemia on oxidative damage (OX), advanced glycation end products (AGEs), and the receptor for AGEs (RAGE) through an in vivo approach. Obese subjects (n = 10; 31.2 ± 1.2 kg·m-2; 56 ± 3 years) underwent 24 h of hyperglycemic clamp (+5.4 mM above basal), where plasma at basal and after 2 h and 24 h of hyperglycemic challenge were assayed for OX (methionine sulfoxide, MetSO, and aminoadipic acid, AAA) and AGE-free adducts (Ne-carboxymethyllysine, CML; Ne-carboxyethyllysine, CEL; glyoxal hydroimidazolone-1, GH-1; methylglyoxal hydroimidazolone-1, MG-H1; and 3-deoxyglucosone hydroimidazolone, 3DG-H) via liquid chromatography?tandem mass spectrometry (LC?MS/MS). Urine was also analyzed at basal and after 24 h for OX and AGE-free adducts and plasma soluble RAGE (sRAGE) isoforms (endogenous secretory RAGE, esRAGE, and cleaved RAGE, cRAGE), and inflammatory markers were determined via enzyme-linked immunosorbent assay (ELISA). Skeletal muscle tissue collected via biopsy was probed at basal, 2 h, and 24 h for RAGE and OST48 protein expression. Plasma MetSO, AAA, CEL, MG-H1, and G-H1 decreased (-18% to -47%; p < 0.05), while CML increased (72% at 24 h; p < 0.05) and 3DG-H remained unchanged (p > 0.05) with the hyperglycemic challenge. Renal clearance of MetSO, AAA, and G-H1 increased (599% to 1077%; p < 0.05), CML decreased (-30%; p < 0.05), and 3DG-H, CEL, and MG-H1 remained unchanged (p > 0.05). Fractional excretion of MetSO, AAA, CEL, G-H1, and MG-H1 increased (5.8% to 532%; p < 0.05) and CML and 3DG-H remained unchanged (p > 0.05). Muscle RAGE and OST48 expression, plasma sRAGE, IL-1?, IL-1Ra, and TNF? remained unchanged (p > 0.05), while IL-6 increased (159% vs. basal; p > 0.05). These findings suggest that individuals who are obese but otherwise healthy have the capacity to prevent accumulation of OX and AGEs during metabolic stress by increasing fractional excretion and renal clearance.
Project description:Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in ? cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis-induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP-induced (h-IAPP-induced) ? cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand-binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, ? cells, and smooth muscle cells from h-IAPP-induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of ? cell area, ? cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of ? cell dysfunction in metabolic disease.
Project description:BACKGROUND:Autoimmune hepatitis (AIH) is a liver disease characterized by the autoimmune-induced injury of hepatocytes which can lead to cirrhosis and hepatic failure. The diagnosis and disease management of AIH patients remain challenging due to the diversity of clinical phenotypes and the presence of confounders such as alcohol and viruses. Recently, EN-RAGE and sRAGEs have been implicated in inflammatory-immune response. Nonetheless, their natural behaviour and relationship to disease activity as well as clinical predictive values in AIH development or therapy-induced remission have not been reported. METHODS:Sixty-seven AIH patients and thirty gender- and age-matched healthy controls (HC) were enrolled. The serum concentrations of EN-RAGE, sRAGE and their ratio (EN-RAGE/sRAGE) in these subjects were measured by ELISA. Besides, the correlations of three parameters with clinical features and therapeutic response were analyzed, respectively. Furthermore, their potential predictive values for monitoring the AIH progression and therapeutic response were also evaluated. RESULTS:Higher serum EN-RAGE, lower sRAGE and higher EN-RAGE/sRAGE value were observed in AIH patients. EN-RAGE and sRAGE as well as EN-RAGE/sRAGE were correlated with liver necroinflammation parameters, cirrhosis occurrence and therapeutic response. In addition, we identified that EN-RAGE/sRAGE, EN-RAGE and sRAGE had valuable predicting power for AIH patients, AIH patients with normal ALT and cirrhosis incidence, respectively. More importantly, EN-RAGE/sRAGE also exerted predicting power for the remission in AIH patients. CONCLUSIONS:AIH patients rendered distinct patterns of serum EN-RAGE, sRAGE or EN-RAGE/sRAGE compared to healthy controls. Moreover, these three parameters exhibited potentials as novel biomarkers for AIH diagnosis and prognosis evaluation.
Project description:BACKGROUND:Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated. METHODS:We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC). RESULTS:Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to TB at 2nd month and 6th month of anti-TB treatment (ATT). RAGE ligands were increased in TB-DM individuals with bilateral and cavitary disease. sRAGE and S100A12 correlated with glycated hemoglobin levels. Within the TB-DM group, those with known diabetes (KDM) revealed significantly increased levels of AGE and sRAGE compared to newly diagnosed DM (NDM). KDM participants on metformin treatment exhibited significantly diminished levels of AGE and sRAGE in comparison to those on non-metformin regimens. CONCLUSIONS:Our data demonstrate that RAGE ligand levels reflect disease severity and extent in TB-DM, distinguish KDM from NDM and are modulated by metformin therapy.