Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study

Nin, J. W. M.; Ferreira, Isabel; Schalkwijk, Casper G.; Prins, Martin H.; Chaturvedi, Nish; Fuller, John; Stehouwer, Coen D. A.

doi:10.1007/s00125-009-1263-5

Cited by 64 publications

(59 citation statements)

References 51 publications

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“…There are additional controversial results regarding sRAGE levels in atherosclerosis. Nin et al 34 showed in a cross-sectional study that sRAGE levels are higher in type 1 diabetic patients with CV diseases than in those without the disease; Humpert et al 5 demonstrated a positive association between sRAGE and urinary albumin excretion in 90 patients with type 2 diabetess.…”

Section: Discussionmentioning

confidence: 99%

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

Höllerl

et al. 2012

Int J Obes

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OBJECTIVE:The increased cardiovascular (CV) disease risk in patients with morbid obesity (MO) cannot be fully explained by traditional CV risk factors. Activation of the receptor of Advanced Glycation Endproducts (RAGE) leads to inflammation via the NF kb (nuclear factor kb) pathway. The soluble form of RAGE (sRAGE), which is present in plasma, can bind to ligands of RAGE and avoids interaction of RAGE with proinflammatory ligands. We investigated sRAGE levels in patients with MO and compared them with healthy lean controls (CO), before and after bariatric surgery. DESIGN: We conducted a cross-sectional study and a 24-month longitudinal study. SUBJECTS: We included 85 patients (mean age: 41±12 years; mean body mass index (BMI): 45.4±7.9 kg m À 2 ) with MO in comparison with 40 CO (mean age: 42 ± 13 years; mean BMI: 26.0 ± 5.5 kg m À 2 ). All patients were investigated before and 2 years after bariatric surgery. Apart from weight and CV risk markers (blood pressure, lipids), a glucose tolerance test (75 g), renal and inflammation parameters were assessed. sRAGE levels were assessed by a commercial ELISA. To investigate the associations of the observed reductions of values, delta (D) of parameters were calculated. RESULTS: Patients with MO had significant lower sRAGE levels than CO: 1010 ± 514 vs 1501 ± 674 pg ml À 1 ; Po0.001. In the longitudinal study, sRAGE levels increased significantly after bariatric surgery from 1010±514 to 1261±710 pg ml À 1 ; P ¼ 0.008. In the correlation analysis, DsRAGE levels were associated with D1-h and D2-h postprandial glucose, Dfasting insulin, D2-h postprandial insulin, DHOMA (homeostatic model assessment)-insulin resistance (DHOMA-IR), Dg-glutamyl transferase and Dtriglycerides. In a multivariate model, D1-h and D2-h postprandial glucose, D2-h postprandial insulin and DHOMA-IR predicted DsRAGE. CONCLUSION: Patients with MO have significantly lower sRAGE levels compared with non-obese CO, but sRAGE levels increase significantly after weight loss induced by bariatric surgery. As high sRAGE levels inhibit the activation of inflammatory pathways, our results might help understand the beneficial effects of bariatric surgery regarding CV morbidity and mortality. Keywords: morbid obesity; sRAGE; insulin resistance; prospective INTRODUCTION Hyperglycemia leads to non-enzymatic glycation of intracellular and extracellular protein by forming advanced glycation endproducts (AGEs). 1 The RAGE (receptor of AGEs), a multi-ligand member of the immunoglobulin superfamily of transmembrane cell surface molecules, is a specific membrane-bound receptor for AGEs, 2 and activation of the RAGE by AGEs has a major role in the pathogenesis of diabetic vascular complications by way of activation of the NF kb (nuclear factor kb) pathway. 3 sRAGE is the soluble receptor of RAGE existing in the circulation. sRAGE levels have been found to be associated with chronic inflammatory diseases, including atherosclerosis and diabetes. 4-6 sRAGE acts as a decoy to prevent an interaction between AGE and RAGE and ther...

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Section: Discussionmentioning

confidence: 99%

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

Höllerl

et al. 2012

Int J Obes

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“…Plasma levels of C-reactive protein (CRP) were measured by a highly sensitive in-house ELISA, and plasma levels of interleukin 6 (IL6) and tumour necrosis factor a (TNFa) were measured using commercially available ELISA kits (R&D Systems). The intra-and inter-assay CV for CRP, IL6 and TNFa were 3.9 and 8.7%, 4.5 and 9.0%, and 7.3 and 8.5% respectively (2,26).…”

Section: Biomarkersmentioning

confidence: 92%

“…Soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) were measured in duplicate by sandwich enzyme immunoassays (R&D Systems, Oxon, UK). The intra-and inter-assay CV for sVCAM-1 were 4.0 and 9.1%, respectively, and for sE-selectin were 2.1 and 3.1% respectively (2,26).…”

Section: Biomarkersmentioning

confidence: 93%

“…with no evidence of CVD, albuminuria and retinopathy; nZ195). The present crosssectional nested case-control study (2,25,26,27,28,29,30,31) includes 463 of the subjects whose complete data on serum levels of HMGB1 and other covariates of interest were available.…”

Section: Subjects and Study Designmentioning

confidence: 99%

“…One of the proposed mechanisms involves advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) (1,2,3,4). Besides AGEs, RAGE can also be activated by other ligands such as high-mobility group box-1 (HMGB1) (5).…”

Section: Introductionmentioning

confidence: 99%

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Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

Nin¹,

Ferreira²,

Schalkwijk³

et al. 2012

European Journal of Endocrinology

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Context and objective: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro-and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. Design and methods: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40G10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Results: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised bZ0.07 (95% confidence interval (CI): 0.02-0.12) and bZ0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro-and macroalbuminuria: odds ratio (OR)Z1.24 (95% CI: 0.90-1.71) and ORZ1.61 (95% CI: 1.15-2.25) respectively, P for trendZ0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. Conclusions: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes.

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An update on advanced glycation endproducts and atherosclerosis

2012

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Advanced glycation endproducts (AGEs) are a group of modified molecular species formed by nonenzymatic reactions between the aldehydic group of reducing sugars with proteins, lipids, or nucleic acids. Formation and accumulation of AGEs are related to the aging process and are accelerated in diabetes. AGEs are generated in hyperglycemia, but their production also occurs in settings characterized by oxidative stress and inflammation. These species promote vascular damage and acceleration of atherosclerotic plaque progression mainly through two mechanisms: directly, altering the functional properties of vessel wall extracellular matrix molecules, or indirectly, through activation of cell receptor-dependent signaling. Interaction between AGEs and the key receptor for AGEs (RAGE), a transmembrane signaling receptor which is present in all cells relevant to atherosclerosis, alters cellular function, promotes gene expression, and enhances the release of proinflammatory molecules. The importance of the AGE-RAGE interaction and downstream pathways, leading to vessel wall injury and plaque development, has been amply established in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. Blocking the vicious cycle of AGE-RAGE axis signaling may be essential in controlling and preventing cardiovascular complications. In this article, we review the pathogenetic role of AGEs in the development, progression and instability of atherosclerosis, and the potential targets of this biological system for the prevention and treatment of cardiovascular disease.

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Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study

Cited by 64 publications

References 51 publications

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

An update on advanced glycation endproducts and atherosclerosis

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