The AGE-RAGE axis in an Arab population: The United Arab Emirates Healthy Futures (UAEHFS) pilot study (original) (raw)
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Metabolic Dysfunction in Emirati Subjects in Abu Dhabi: Relationship to Levels of Soluble RAGEs
Journal of Clinical & Translational Endocrinology, 2019
Background: The United Arab Emirates is experiencing increasing rates of type 2 diabetes (T2D) and its complications. As soluble levels of the receptor for advanced glycation end products, (sRAGE), and endogenous secretory RAGE (esRAGE), the latter an alternatively spliced form of AGER (the gene encoding RAGE), have been reported to be associated with T2D and its complications, we tested for potential relationships between these factors and T2D status in Emirati subjects. Methods: In a case-control study, we recruited Emirati subjects with T2D and controls from the Sheikh Khalifa Medical City in Abu Dhabi. Anthropomorphic characteristics, levels of plasma sRAGE and esRAGE, and routine chemistry variables were measured. Results: Two hundred and sixteen T2D subjects and 215 control subjects (mean age, 57.4 ± 12.1 vs. 50.7 ± 15.4 years; P < 0.0001, respectively) were enrolled. Univariate analyses showed that levels of sRAGE were significantly lower in the T2D vs. control subjects (1033.9 ± 545.3 vs. 1169.2 ± 664.1 pg/ml, respectively; P = 0.02). Multivariate analyses adjusting for age, sex, systolic blood pressure, pulse, body mass index, Waist/Hip circumference ratio, fasting blood glucose, HDL, LDL, insulin, triglycerides, Vitamin D and urea levels revealed that the difference in sRAGE levels between T2D and control subjects remained statistically-significant, P = 0.03, but not after including estimated glomerular filtration rate in the model, P = 0.14. There were no significant differences in levels of esRAGE. Levels of plasma insulin were significantly higher in the control vs. the T2D subjects (133.6 ± 149.9 vs. 107.6 ± 93.3 pg/L. respectively; P = 0.01, after adjustment for age and sex). Conclusion/discussion: Levels of sRAGE, but not esRAGE, were associated with T2D status in Abu Dhabi, but not after correction for eGFR. Elevated levels of plasma insulin in both control and T2D subjects suggests the presence of metabolic dysfunction, even in subjects without diabetes.
Clinical chemistry, 2017
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 differ...
Obesity is one of the diagnostic criteria of metabolic syndrome (MS). It is correlated with insulin resistance (IR) and high vascular risk as well. Advanced glycation end products (AGEs) and their receptor (RAGE) play an important role in abnormal metabolic components in obese women. This study aimed to explore the serum levels of sRAGE in Egyptian obese women and compare with healthy non-obese controls and investigate the relationship between serum sRAGE, metabolic parameters, and obesity complications. The soluble form of receptor for advanced glycation end products (sRAGE), anthropometry, metabolic and biochemical biomarkers were measured in 100 obese women and 100 age-matched healthy control non-obese women. The homeostasis model assessment estimate of insulin resistance (HOMA-IR) has been determined from serum insulin and glucose values. Serum sRAGE levels were significantly lower in obese cases than controls and inversely correlated with obesity and metabolic parameters. Results of univariate and multivariate analyses for determinants of serum sRAGE levels in obese cases showed that parameters statistically and significantly related were body mass index (BMI), waist circumference (WC), LDL-C, TG, BP, HOMA-IR, ALT and AST. sRAGE is a novel biomarker for metabolic dys-function in Egyptian obese women and might predict the future cardio-metabolic events.
PLOS ONE, 2016
The purpose of the study was the simultaneous measurement of all the different components of the AGE-RAGE axis as well as several non-invasive markers of cardiovascular disease (CVD) in a cohort of newly diagnosed diabetic patients. Materials and Methods In 80 newly diagnosed diabetic patients we measured serum carboxymethyllysine (CML), soluble RAGE (sRAGE) and peripheral mononuclear (PMNC) RAGE and AGER1 mRNA together with ICAM-1, VCAM-1, and malondialdehyde (MDA). We also assessed cardiovascular function by measurement of flow-mediated vasodilation (FMD), intima-media thickness (IMT) and arterial stiffness. Univariant correlation analysis was used to determine correlation between the variables in the study and multiple regression analysis was used to examine the association between the AGE-RAGE axis components and FMD, IMT and arterial stiffness.
American journal of physiology. Endocrinology and metabolism, 2017
The soluble receptor for advanced glycation endproducts (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms, and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, versus normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE ...
Diabetologia, 2011
Aims/hypothesis Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. Methods Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine-Gray proportional-hazards models. Results The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA 1c and insulin dose (all p<0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA 1c , triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. Conclusions/interpretation Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2005
Objectives— 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. Methods and Results— 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...
Clinical Chemistry and Laboratory Medicine, 2000
Background: Interaction of advanced glycation end products (AGEs) with their specific cell-surface receptor for AGEs (RAGE) induces production of reactive oxygen species, pro-diabetic, pro-inflammatory, and pro-atherogenic responses. The metabolic syndrome (Metsy) imposes a high risk of development of cardiovascular disease and unequivocally predisposes the non-diabetics to type 2 diabetes mellitus. The aim of the study was to investigate the association between circulating soluble RAGE (sRAGE), N ε -(carboxymethyl)lysine (CML) or AGE-associated fluorescence of plasma (AGE-Fl) with the number of manifested Metsy risk factors in young-to-middleaged medication-free non-diabetic subjects. Methods: Metsy was classified according to NCEP/ATP III criteria; plasma sRAGE and total CML were determined by ELISA methods and AGE-Fl fluorimetrically. Results: From among 437 participants aged 33 ± 11 years, 58% were females. In total 174 subjects were Metsy risk factors-free, 142 presented one, 59 presented two risk factors, and 62 suffered from Metsy. Plasma sRAGE and CML/albumin levels decreased with increasing number of Metsy risk factors (p < 0.01, both), while AGE-Fl/albumin levels remained similar. Multivariate analysis selected waist circumference as a main determinant of plasma sRAGE as well as CML/albumin levels.
Cellular and molecular biology, 2016
In recent years, studies related to advanced glycation end products (AGE) and their interaction with their receptors (RAGE) have advanced our knowledge of the roles of these molecules in different diseases. However, studies concerning AGE-RAGE interaction in obesity are limited and the results are conflicting. RAGE gene is located on 6p21.3, has several polymorphic sites including -374T/A, a functional polymorphism in the promoter region, and Gly82Ser, present within the ligand-binding domain. In the present study, the determination of possible risks in the development of obesity according to RAGE polymorhisms and plasma levels of RAGE (sRAGE) was aimed. 87 obese and 78 healthy children were included in this study. Genomic DNA was isolated with salting-out procedure. RAGE polymorphisms were analyzed by PCR based techniques. In contrast to Gly82Ser, -374T/A allelic and genotypic frequencies were not different between study groups. Ser(SerSer+GlySer genotype) allele frequency was high...
Diabetology & Metabolic Syndrome, 2014
Background: Although several studies showed that decreased soluble receptor for advanced glycation end products (sRAGE) is associated with metabolic syndrome (MetS), inflammation level has not been considered, even though ligand-RAGE interaction induces inflammation. The objective of the study was to determine the association between sRAGE and MetS among Japanese adult in a cross-sectional survey, taking the level of low grade inflammation into consideration. Methods: Serum soluble RAGE (sRAGE) were measured in 712 men and 176 women aged 30-83 years with serum C-reactive protein (hsCRP) concentration below 3 mg/L. MetS was defined using the criteria of the American Heart Association Scientific Statements of 2009. Results: After multivariable adjustment, among men, higher sRAGE levels were associated with lower odds of MetS as well as central obesity and elevated blood pressure. Comparing the extreme tertiles of sRAGE, odds ratios (95% confidence interval) were 0.58 (0.36-0.95; P for trend = 0.001) for MetS; 0.41 (0.25-0.52; P for trend < 0.001) for central obesity; and 0.45 (0.29-0.70; P for trend < 0.001) for elevated blood pressure. Moreover, participants were categorized according to their median hsCRP and sRAGE values. Men in the higher hsCRP/higher sRAGE category had a 40% lower odds ratio for MetS than those in the higher hsCRP/lower sRAGE category (P = 0.031). Among women, there was no association between sRAGE levels and the prevalence of MetS. Conclusions: Higher circulating RAGE concentrations were associated with lower prevalence of MetS and its components among Japanese men.