Endogenous secretory receptor for advanced glycation endproducts (esRAGE) and AGEs/esRAGE ratio as biomarkers of atherosclerosis risk in type 2 diabetes
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Objective Endogenous secretory receptor for advanced glycation endproducts (esRAGE) an isoform of soluble RAGE, acts as decoy for AGEs. We hypothesized ratio of AGE-to-esRAGE could be link to atherosclerosis in diabetes. To examine this issue, we compared serum levels of esRAGE and methylglyoxal-adduct as well as the AGE-to-esRAGE ratio between type 2 diabetic patients with and without established macrovascular disease. Patients and Methods Methylglyoxal-adducts, AGEs and esRAGE were measured in type 2 diabetes (n=130) and healthy controls (n=30). A history of macrovascular events (cardiovascular disease, cerebral vasculopathy or peripheral vascular disease) was recorded in 50 subjects. Results esRAGE levels were lower in type 2 diabetic patients compared with control subjects (0.330±0.197 vs. 0.458±0.074 ng/ml, p=0.003). In diabetic population es RAGE correlated positively with MG-adducts, HbA1c, BMI, and triglyceride, and inversely with CRP, LDL and homocystein. Multiple stepwise regression analysis was performed to determine which parameters best predicted the esRAGE level. Finally, urinary MG-adduct excretion (p<0.001), AGEs (p<0.001), and AGE/esRAGE (p<0.001, inversely) remained to be independently associated circulatory esRAGE. Multiple stepwise regression model was used to evaluate the relationship between macrovascular disease as a dependent variable, and metabolic and AGE- parameters as independent variables. Analysis pointed to LDL (β=0.40 P=0.0001), HbA1c (β=0.37 P=0.0007), AGE/esRAGE (β=0.31 P=0.007) and homocysteine (β=0.25 P=0.013) as significant independent contributors to diabetic macrovascular disease. Conclusion A decreased level of esRAGE may therefore be a biomarker of atherosclerosis acting as either a decoy receptor or another mechanism.Keywords:
Macrovascular disease
Stepwise regression
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Receptor for advanced glycation end products (RAGE) activation by its ligands is implicated in obesity-related metabolic disease and accelerated atherothrombosis. Circulating soluble (sRAGE) and/or endogenous secretory RAGE (esRAGE) may counteract the detrimental effects of RAGE.This study aimed at determining the relationship between circulating RAGE and metabolic syndrome (MetS) incidence among Japanese adult men.This 2-year longitudinal study included 426 Japanese men aged 30-83 years who had no MetS at baseline. Serum esRAGE and sRAGE were assayed by ELISA at baseline. Incident metabolic syndrome, defined according to the Asian cutoff based on the 2009 criteria of the American Heart Association Scientific Statements, was evaluated after the 2-year follow-up.During the follow-up period, 55 participants (12.9%) had newly diagnosed MetS. In the multiple logistic models comparing MetS risk in the lowest with that in the highest tertile of baseline esRAGE, a high serum esRAGE level was found to be significantly associated with a low risk of MetS [odds ratios (95% confidence interval), 0.37 (0.14-0.95); P for trend = 0.038] after adjusting for lifestyle and sociodemographic factors, serum high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and MetS components at baseline. Although sRAGE and esRAGE were strongly correlated (r(s) = 0.88), the sRAGE level was not associated with MetS incidence.A high circulating esRAGE level, but not sRAGE level, was associated with a low MetS incidence among Japanese adult men.
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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.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).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.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.
Fructosamine
Albuminuria
Advanced glycation end-product
Glycated hemoglobin
Cross-sectional study
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Objective To study the serum level of endogenous secretory receptor for advanced glycation end products(esRAGE) in type 2 diabetes(T2DM) and its relationship with other related factors.Methods Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum esRAGE level in 60 T2DM 30 of which had carotid atherosclerosis and 28 normal controls,other clinical index was also tested.Results Serum esRAGE level was significantly lower in T2DM with carotid atherosclerosis than in T2DM without carotid atherosclerosis and in the normal controls(P0.01).T2DM without carotid atherosclerosis was also significantly lower than that in the normal controls(P0.05).Pearson correlation analysis showed serum esRAGE was inversely correlated with age and components of the metabolic syndrome including glycosylated hemoglobin Alc,total cholesterol,low density lipoprotein,systolic blood pressure and body mass index(P0.01).Multiple linear regression analyses showed that age,total cholesterol,glycosylated hemoglobin Alc and body index were independently associated with esRAGE(P0.05).Conclusion esRAGE is probably a potential protective factor for diabetes with atherosclerosis and metabolic syndrome.
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Objective Preeclampsia is a serious complication in pregnancy with an increased future cardiovascular risk for both mother and newborn. Recently, low levels of endogenous soluble receptor for advanced glycation endproducts (esRAGE) have been associated with increased cardiovascular risk. In the current study, we investigated esRAGE serum levels in patients with preeclampsia as compared to healthy gestational age-matched controls. Methods esRAGE was quantified by enzyme-linked immunosorbent assay in controls and patients with preeclampsia during pregnancy (control: n = 20, preeclampsia: n = 16) and 6 months after delivery (control: n = 19, preeclampsia: n = 15). Furthermore, esRAGE was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation. Results During pregnancy, median maternal serum esRAGE concentrations were more than three-fold higher in patients with preeclampsia (200 ng/l) than in controls (63 ng/l) (P < 0.01). Furthermore, esRAGE levels positively correlated with age, blood pressure, creatinine, adiponectin, and C-reactive protein, whereas a negative correlation existed with fasting insulin and the homeostasis model assessment of insulin resistance index. In multivariate analyses, homeostasis model assessment of insulin resistance and C-reactive protein independently predicted esRAGE serum levels and explained 44% of the variation in esRAGE concentrations. Surprisingly, median esRAGE concentrations 6 months after delivery were significantly lower in former patients with preeclampsia (270 ng/l) than in controls (342 ng/l) in contrast to the results obtained during pregnancy. Conclusion We showed that maternal esRAGE concentrations are significantly increased in patients with preeclampsia during pregnancy. Here, insulin sensitivity and inflammatory status independently predict serum esRAGE levels.
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Advanced glycation endproducts, AGEs, and its specific receptor, RAGE, are involved in diabetic vascular complications. Endogenous secretory RAGE, esRAGE, has been identified as an alternatively spliced form of RAGE, and shown to act as a decoy receptor for AGE. Here, we measured plasma esRAGE level with a recently developed enzyme-linked immunosorbent assay (ELISA) and examined its association with atherosclerosis in age- and gender-matched 203 type 2 diabetic and 134 nondiabetic subjects.Plasma esRAGE was inversely associated with carotid or femoral atherosclerosis, as quantitatively measured as intimal-medial thickness (IMT) by arterial ultrasound. Stepwise regression analyses revealed that plasma esRAGE was the third strongest and independent factor associated with carotid IMT, following age and systolic blood pressure. Plasma esRAGE was significantly lower in diabetic patients (0.176+/-0.092 ng/mL) than nondiabetic controls (0.253+/-0.111). Of note, in all, diabetic or nondiabetic group, plasma esRAGE was significantly and inversely correlated with components of the metabolic syndrome including body mass index, blood pressure, triglyceride, HbA1c, or an insulin resistance index. Stepwise regression analyses showed that body mass index or insulin resistance index was the major factor determining plasma esRAGE in all, nondiabetic or diabetic population.esRAGE is a novel and potential protective factor for the metabolic syndrome and atherosclerosis.
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Background: We determined serum endogenous secretory receptor of advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) concentrations and the esRAGE/sRAGE ratio in normal pregnancy and preeclampsia because esRAGE and sRAGE have been negatively linked to components of metabolic syndromes and pathologic pregnancy including preeclampsia.
Clinical Significance
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The putative protective role of esRAGE for cardiac autonomic function (CAF) remains unclear. To address this question, the present study has assessed the relationship of serum AGEs, sRAGE and esRAGE, and tissue AGEs with CAF in a high-risk population without diabetes.This study enrolled 48 subjects of mean age 52.7 ± 11.2 years and mean BMI 28.4 ± 6.3 kg/m2 , divided into two groups according to glucose tolerance: 16 with normal glucose tolerance (NGT) and 24 with prediabetes. A standard oral glucose tolerance test (OGTT) was performed. The glucose tolerance was defined according to 2006 WHO criteria. Fasting, 120-minutes glucose, lipids, creatinine, and HbA1c were measured. eGFR was calculated (CKD-EPI). Fasting, 120-minutes insulin (ECLIA method), advanced glycation end products (AGEs), plasma-soluble receptor for AGE (sRAGE), and endogenous secreted isoform of the receptor for AGE (esRAGE), (ELISA method) were assessed. HOMA-IR was calculated. Tissue AGEs were assessed by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAF was evaluated with ANX 3.0 autonomic nervous-monitoring system (ANSAR), applying deep breathing, Valsalva, and standing.There was a significant decline in CAF in prediabetes in comparison with NGT. Serum and tissue AGEs, sRAGE, and esRAGE levels were similar between groups. On the matrix analysis, both sympathetic and parasympathetic activities at baseline and after standing and sympathetic tone during Valsalva were positively related to esRAGE in prediabetes. Multivariate regression analysis showed that esRAGE is an independent contributor to sympathetic, parasympathetic, and total autonomic tone in prediabetes accounting for about 28%, 34%, and 35% of their variances, respectively.Our results have demonstrated that CAF is decreased in prediabetes. esRAGE, but not sRAGE, is reciprocally related to CAF, probably opposing the negative effects of glycation.
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Autonomic function
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Abstract Aims The endogenous secretory receptor for advanced glycation end products (esRAGE) appears to work as a scavenger for AGEs and it has been implicated in the pathogenesis of diabetic complications. The aim of the present study was to perform a longitudinal evaluation of esRAGE in young people with Type 1 diabetes (T1D) in relation to the development of microalbuminuria (MA). Methods Serum esRAGE levels were measured in longitudinally collected blood samples from 49 T1D patients with MA (MA+) and 49 matched normoalbuminuric patients (MA−), followed in the Oxford Regional Prospective Study. esRAGE levels were compared between MA+ and MA− subjects in relation to the time of MA onset. Results Overall, esRAGE levels were significantly lower in MA+ than in MA− subjects (0.727 ± 0.396 vs. 0.936 ± 0.433 ng/ml; P = 0.015). These differences between the two groups were present both before (0.725 ± 0.410 vs. 0.956 ± 0.505 ng/ml, P = 0.038) and after the onset of MA (0.750 ± 0.433 vs. 0.948 ± 0.418 ng/ml, P = 0.04). In a longitudinal analysis there was no effect of age, duration, glycated haemoglobin (HbA 1c ) or body mass index standard deviation scores on esRAGE levels (all P > 0.05). In a Cox model, esRAGE levels significantly contributed to the probability of developing MA [Exp(B)(95% confidence interval): 0.34(0.12–0.98); P = 0.04), independently of HbA 1c . Conclusions In this longitudinal study of young people with T1D, esRAGE levels were reduced in MA+ subjects, even before the onset of MA, and appeared to be related to its development, thus suggesting a potential role of esRAGE in the pathogenesis of this complication.
Microalbuminuria
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