Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes

Güçlü, Metin; Ali, Asuman; Eroğlu, Derya; Büyükuysal, Sema Oral; Cander, Soner; Ocak, Nihal

doi:10.1089/met.2015.0078

Cited by 20 publications

(11 citation statements)

References 54 publications

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“…Our primary finding was that lean, NGT individuals possessed the greatest concentration of sRAGE isoforms compared with states of obesity, IGT, T2DM, or both. These findings are in accord with previous reports of lower sRAGE with obesity (5,13,18) and impaired glucose tolerance (3, 12, 22, 46). Importantly, we also demonstrate for the first time that reduced circulating concentrations of sRAGE isoforms are associated with greater proportional odds for the development of T2DM.…”

Section: Discussionsupporting

confidence: 93%

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Miranda

Somal

Mey

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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The soluble receptor for advanced glycation end products (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, vs. 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 (cRAGE:esRAGE) was only lower ( < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT ( < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; < 0.01) and cRAGE (odds ratio, 0.84; < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes.

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Section: Discussionsupporting

confidence: 93%

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Miranda

Somal

Mey

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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“…We found a strong inverse association between liver fat and sRAGE, but this association was largely dependent on BMI. Several studies have shown that obesity is a strong determinant of sRAGE levels explaining why the association is no longer present after adjustment for this confounder [32, 33]. In accordance with our data, Palma-Duran et al reported a decrease of sRAGE in NAFLD patients [27].…”

Section: Discussionsupporting

confidence: 91%

Hepatic Fat Content and Liver Enzymes Are Associated with Circulating Free and Protein-Bound Advanced Glycation End Products, Which Are Associated with Low-Grade Inflammation: The CODAM Study

Bijnen

Greevenbroek

Kallen

et al. 2019

Journal of Diabetes Research

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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 (β=0.090; 95% CI 0.041; 0.139) but inversely with protein-bound CML (β=−0.071; 95% CI -0.108; -0.034). Similarly, the LE score was positively associated with free CML (β=0.044; 95% CI 0.012; 0.076) and CEL (β=0.040; 95% CI 0.009; 0.072) but inversely with protein-bound CML (β=−0.037; 95% CI -0.060; -0.013). Free CML (β=0.297; 95% CI 0.049; 0.545) was positively associated with LGI, while protein-bound CML (β=−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.

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“…Specifically among those with diabetes, sRAGE studies have generally shown a positive association with risk of cardiovascular disease (7, 8, 12), mortality (12–13), and renal outcomes (13). However, among community-based populations, sRAGE has been reported to be inversely associated with diabetes (14), body mass index (BMI), LDL-cholesterol (15), inflammation (16), cardiovascular events (17–20), and chronic kidney disease (CKD) (21). esRAGE has been studied less, although higher levels have been associated with an increased risk of major adverse cardiovascular events in people with diabetes (22).…”

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confidence: 99%

Cross-sectional Analysis of AGE-CML, sRAGE, and esRAGE with Diabetes and Cardiometabolic Risk Factors in a Community-Based Cohort

et al. 2017

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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.

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Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes

Cited by 20 publications

References 54 publications

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Hepatic Fat Content and Liver Enzymes Are Associated with Circulating Free and Protein-Bound Advanced Glycation End Products, Which Are Associated with Low-Grade Inflammation: The CODAM Study

Cross-sectional Analysis of AGE-CML, sRAGE, and esRAGE with Diabetes and Cardiometabolic Risk Factors in a Community-Based Cohort

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