Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes

We have recently found that soluble form of receptor for advanced glycation end products (sRAGE) levels are positively associated with inflammatory biomarkers and the presence of coronary artery disease (CAD) in type 2 diabetic patients. Since advanced glycation end products (AGEs) up-regulate RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, it is conceivable that sRAGE is positively associated with circulating AGEs levels in diabetes. In this study, we examined whether sRAGE were correlated to circulating levels of AGEs and soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes. Eighty-two Japanese type 2 diabetic patients underwent a complete history and physical examination, determination of blood chemistries, sRAGE, AGEs, sVCAM-1 and sICAM-1. Multiple regression analysis revealed that serum levels of AGEs and sVCAM-1 were independently correlated with sRAGE. This study demonstrated that serum levels of sRAGE were positively associated with circulating AGEs and sVCAM-1 levels in type 2 diabetic patients. Our present observations suggest sRAGE level may be elevated in response to circulating AGEs, thus being a novel marker of vascular injury in patients with type 2 diabetes.     

Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease

BACKGROUND: Advanced glycation end products (AGEs)-receptor (RAGE) axis is implicated in diabetic vascular complication. Since a soluble form of RAGE (sRAGE) could be generated from the cleavage of cell surface RAGE in endothelial cells (ECs), serum sRAGE levels may be elevated in diabetes consequent to EC damage. In this study, we examined whether sRAGE levels were elevated in type 2 diabetic patients compared with non-diabetic healthy subjects. METHODS: Serum sRAGE levels were examined in 75 Japanese type 2 diabetic patients (29 men and 46 women; mean age 66 +/- 11 years) and 75 age- and sex-matched non-diabetic healthy control subjects. We explored the association between sRAGE levels and coronary artery disease (CAD) in diabetic patients. RESULTS: Serum sRAGE levels were significantly higher in diabetic patients than in non-diabetic subjects (965.3 +/- 544.2 vs 415 +/- 150.4 pg/mL, p < 0.001). In the univariate analysis, diastolic blood pressure (inversely), LDL cholesterol, triglycerides, HDL cholesterol, hemoglobin A(1c), and creatinine were significantly associated with sRAGE. After performing multivariate analyses, the presence of diabetes (p < 0.0001) was a sole independent determinant of sRAGE. Furthermore, there was a significant difference in sRAGE levels between diabetic patients with CAD and those without CAD (1680.6 +/- 891.1 vs 855.2 +/- 372.1 pg/mL, p < 0.001). Multiple stepwise regression analysis revealed that sRAGE and creatinine levels were independent determinants of CAD. CONCLUSIONS: The present study demonstrated that serum sRAGE levels were significantly higher in type 2 diabetic patients than in non-diabetic subjects and positively associated with the presence of CAD.     

Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes

Aims/hypothesis Activation of the receptor for advanced glycation end products (RAGE, also known as AGE-specific receptor [AGER]) has been implicated in the development of diabetic vascular complications. Blockade of RAGE using a soluble form of the receptor (sRAGE) suppressed vascular hyperpermeability and atherosclerosis in animal models. Since little is known about the regulation of endogenous sRAGE levels, we determined whether serum sRAGE is influenced by circulating AGEs and the severity of nephropathy in type 2 diabetic patients.Materials and methods We recruited 150 healthy control and 318 diabetic subjects. Diabetic subjects were subdivided into those with proteinuria, microalbuminuria or normoalbuminuria. Serum sRAGE was assayed by ELISA and serum AGEs by competitive ELISA using a polyclonal rabbit antiserum raised against AGE-RNase.Results Diabetic subjects had higher sRAGE (1,029.5 pg/ml [766.1–1,423.0] interquartile range vs 1,002.6 [726.5–1,345.3], p<0.05) and AGEs (4.07±1.13, SD, unit/ml vs 3.39±1.05, p<0.01) than controls. Proteinuric subjects had the highest sRAGE levels and there was a significant trend between the severity of nephropathy and sRAGE (p=0.01). In diabetic subjects, serum log(sRAGE) correlated with AGEs (r=0.27, p<0.001), log(plasma creatinine) (r=0.31, p<0.001), log(urine AER) (r=0.24, p<0.01) and log(triglycerides) (r=0.15, p<0.01). On stepwise linear regression analysis, AGEs and creatinine levels were the main independent determinants of sRAGE concentration.Conclusions/interpretation Serum sRAGE levels and circulating AGEs are associated with the severity of nephropathy in type 2 diabetic patients. Prospective studies are required to determine whether endogenous sRAGE potentially influences the development of diabetic vascular complications.     

Low Levels of Serum Soluble Receptors for Advanced Glycation End Products,Biomarkers for Disease State: Myth or Reality

Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) on the membrane and induce deleterious effects via activation of nuclear factor kappa-B, and increased oxidative stress and inflammatory mediators. AGEs also combine with circulating soluble receptors (endogenous secretory RAGE [esRAGE] and soluble receptor for RAGE [sRAGE]) and sequester RAGE ligands and act as a cytoprotective agent. esRAGE is secreted from the cells and is a spliced variant of RAGE. The sRAGE on the other hand is proteolytically cleaved from cell surface receptor via matrix metalloproteinase (MMPs). sRAGE is elevated in type 1 and type 2 diabetes and in patients with decreased renal function. Serum levels of sRAGE are reduced in diseases including coronary artery disease, atherosclerosis, essential hypertension, chronic obstructive lung disease, heart failure, and hypercholesterolemia. Serum levels of AGEs are elevated in patients with coronary artery disease and atherosclerosis. However, the increases in serum AGEs are very high in patients with diabetes and renal disease. There is a positive correlation between serum levels of AGEs and RAGE and sRAGE. The elevated levels of sRAGE in patients with diabetes and impaired renal function may be due to increased levels of MMPs. AGEs increase in the expression and production of MMPs, which would increase the cleavage of sRAGE from cell surface. In conclusion, low level of serum sRAGE is a good biomarker for disease other than diabetes and renal disease. A unified formula that takes into consideration of AGEs, sRAGE, and esRAGE such as AGE/sRAGE or AGEs/esRAGE would be better biomarker than sRAGE or esRAGE for all AGE-RAGE–associated diseases including diabetes and renal disease.     

Advanced glycation end products (AGEs) and their soluble receptors (sRAGE) as early predictors of reno-vascular complications in patients with uncontrolled type 2 diabetes mellitus

AimTo evaluate the role of advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) expression levels as predictors of vascular complications in uncontrolled type 2 diabetes mellitus (T2DM).MethodsCross-sectional study was conducted on T2DM adults of both sexes who attended the outpatient service of Al-Karak Teaching Hospital, Jordan during the period from June 2017 to August 2018. Participants were categorized in two groups according to their glycemic control and the presence of reno-vascular complications. Twenty healthy subjects were recruited as control group. Blood sample was obtained from all participants and used for the assessment of FBG, HbA1c, serum AGEs and sRAGE, serum urea and creatinine; 24 h urine was also collected for the determination of urinary albumin.ResultsDiabetic subjects with vascular complication had a significantly higher serum AGEs 50.3 ± 13 vs. 28.9 ± 8 pg/ml) and AGEs/sRAGE ratio (0.058 ± 0.02 vs. 0.037 ± 0.02) associated with significantly lower serum sRAGE (868.7 ± 50.8 vs. 912.8 ± 294.3) compared to those with no complications. Serum AGEs and sRAGE showed weak negative and non-significant association in both groups of patients. However, the AGEs/sRAGE ration was inversely and significantly associated with the urinary albumin/creatinine ratio (r = − 0.51, P = 0.009) only in DM patients with reno-vascular complications.ConclusionWe found an association between AGEs/sRAGE ratio and urinary albumin/serum creatinine ratio in T2DM patients with reno-vascular complications; providing evidence that serum AGEs and sRAGE can be considered as predictors of vascular complications in uncontrolled T2DM patients.     

Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients

BACKGROUND:

Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress – all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis.

OBJECTIVES:

To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI.

METHODS:

Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients.

RESULTS:

sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients.

CONCLUSIONS:

Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.     

Soluble receptors for advanced glycation end products (sRAGE) as a predictor of restenosis following percutaneous coronary intervention

Background:

Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) increases expression of inflammatory mediators (tumor necrosis factor alpha [TNF‐α] and soluble vascular cell adhesion molecule‐1 [sVCAM‐1]) and induces oxygen radicals that are implicated in atherosclerosis. Balloon‐injury‐induced atherosclerosis is associated with increased expression of AGEs and RAGE. The soluble receptor for AGE (sRAGE), which acts as a decoy for RAGE ligands (AGEs), prevents atherosclerosis in this model.

Hypothesis:

We evaluated: 1) whether post‐percutaneous coronary intervention (PCI) restenosis is associated with low pre‐PCI serum sRAGE, high serum AGEs, TNF‐α, and sVCAM‐1, and high AGE/sRAGE ratio; 2) whether pre‐PCI and post‐PCI levels of these markers are similar in patients with or without restenosis; and 3) whether sRAGE and AGE/sRAGE ratio have predictive value for post‐PCI restenosis.

Methods:

Angiography was performed in 46 patients with non–ST‐segment elevation myocardial infarction for assessment of restenosis. Serum sRAGE, AGEs, TNF‐α, and sVCAM‐1 were measured in these patients and 20 control subjects.

Results:

Nineteen of the 46 patients developed post‐PCI restenosis, which was associated with lower sRAGE and higher TNF‐α and sVCAM‐1 levels, and higher AGE/sRAGE ratio compared with patients without restenosis. Pre‐PCI and post‐PCI levels of these biomarkers were similar in both groups, except in patients with restenosis, in whom the post‐PCI level of sRAGE was lower and TNF‐α was higher than the pre‐PCI levels. The sensitivity and negative predictive value of sRAGE were 100%, and were higher than those of AGE/sRAGE ratio in identifying post‐PCI restenosis.

Conclusions:

Both low serum sRAGE levels and high AGE/sRAGE ratio have predictive value for post‐PCI restenosis. Copyright © 2008 Wiley Periodicals, Inc. This research was supported by grants from the Heart and Stroke Foundation of Saskatchewan and the Pollack Research Foundation, Saskatoon, Saskatchewan. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Relationship of soluble RAGE and RAGE ligands HMGB1 and EN-RAGE to endothelial dysfunction in type 1 and type 2 diabetes mellitus

Receptor for advanced glycation end-products (RAGE) plays the essential role in the pathogenesis of diabetic vascular complications. The aim of the study was to compare concentration of soluble RAGE and its ligands (EN-RAGE and HMGB1) with different biochemical parameters in Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus.Total number of 154 persons (45 T1DM, 68 T2DM, 41 controls) was examined and concentrations of sRAGE, EN-RAGE and HMGB1 were measured and compared to diabetes control, albuminuria, cell adhesion molecules and metalloproteinases (MMPs).Mean serum sRAGE concentration was higher in T1DM as compared to controls (1137±532 ng/l vs. 824±309 ng/l, p<0.01). Similarly, EN-RAGE was significantly higher in both diabetic groups (p<0.001) and HMGB1 concentrations were elevated in T2DM patients (p<0.01). Significant relationship was found between MMP9 and HMGB1 and EN-RAGE in diabetic patients. Inverse relationship was observed between MMP2 and MMP9 in both types of diabetic patients (r= - 0.602, p<0.002 and r= - 0.771, p<0.001). Significant positive correlation was found between sRAGE and ICAM-1, VCAM-1 or vWF (p<0.01 to p<0.001).We conclude that serum sRAGE and RAGE ligands concentrations reflect endothelial dysfunction developing in diabetes.     

Time course of specific AGEs during optimised glycaemic control in type 2 diabetes

BACKGROUND: Several advanced glycation endproducts (AGEs) are formed in the hyperglycaemic state. Although serum AGEs correlate with average glycaemic control in patients with type 2 diabetes and predict the development of complications, it is not known how serum AGEs change during optimisation of diabetes therapy. METHODS: We evaluated the change in serum levels of total AGE and the AGEs CML (Nepsilon-carboxymethyllysine) and MGHI (methylglyoxal-derived hydroimidazolone), as well as markers of endothelial function in 28 subjects with type 2 diabetes, who were poorly controlled on oral agents,before and after the institution of insulin therapy. RESULTS: Mean subject age (+/- SEM) was 58 +/- 2 years,body mass index 27.7 +/- 0.8 kg/m2, and known duration of diabetes was 8.1 +/- 0.9 years. With insulin treatment fasting blood glucose levels dropped from 12.1 +/- 0.9 mmol/l to 6.9 +/- 0.3 and 8.1 +/- 0.4 mmol/l after three and six months, respectively (both p<0.001), while HbA1c decreased from 10.0 +/- 0.3 to 7.8 +/- 0.2% (p<0.001). Endothelial function improved as indicated by a small but significant decrease in soluble intercellular cell adhesion molecule (sICAM-1) (152 +/- 10 to 143 +/- 8 ng/ml, p<0.02)and sE-selectin (111 +/- 16 to 102 +/-12 ng/ml, p<0.02)levels. In contrast, we observed only a tendency towards a decrease in CML levels (110 +/-22 to 86 +/- 13 microg/mg protein, p=ns), but a small increase of MGHI (from 0.23 +/- 0.02 to 0.29 +/- 0.04 U/mg protein, p<0.02). At baseline, 16 patients were on metformin, which is known to reduce methylglyoxal levels and reduce generation of reactive oxygen species. They had similar levels of CML and MGHI to the 12 non-metformin users, although their HbA1c was lower (9.4 +/- 0.3 vs 10.7 +/- 0.6 %). During insulin, patients receiving concomitant metformin therapy showed a similar course of CML and MGHI to those not taking metformin. CONCLUSION: Although insulin therapy improved HbA1c and markers of endothelial function, the levels of serum AGEs did not follow the same time course. This suggests that these specific AGEs are influenced by other factors in addition to overall glycaemia, such as oxidative stress.     

Serum concentrations of advanced glycation endproducts are associated with the development of atherosclerosis as well as diabetic microangiopathy in patients with type 2 diabetes

We measured serum concentrations of advanced glycation endproducts (AGEs) in patients with type 2 diabetes, to elucidate the mechanisms underlying the elevated serum concentrations of AGEs and to clarify the relationship between serum AGE concentrations and the development of microangiography and macroangiopathy. Serum AGEs were significantly higher in diabetic patients than in age-matched control subjects (p < 0.0001). In diabetic patients, serum AGEs were positively correlated with HbA1c (r = 0.47, p < 0.0001), urinary albumin excretion (UAE) (r = 0.42, p < 0.0001), diabetes duration (r = 0.31, p = 0.0030), and fasting plasma glucose (r = 0.34, p = 0.0010). Multiple regression analysis disclosed that only the HbA1c and UAE levels independently correlated with serum AGE levels. Serum AGEs in diabetic patients with progressive retinopathy and overt nephropathy were significantly higher than in those with less severe retinopathy and nephropathy. Serum AGEs were significantly higher in the diabetic patients with coronary heart disease (CHD) than in those without CHD. These results suggest that the HbA1c and UAE levels are independent risk factors for increased serum AGE concentrations in type 2 diabetic patients, and that higher serum AGE concentrations are associated with increased severity of diabetic retinopathy and nephropathy. Serum AGE concentrations may be a useful marker not only for the severity of diabetic microangiopathy but also for the development of CHD in patients with type 2 diabetes mellitus. Received: 8 May 2000 / Accepted in revised form: 5 September 2000     

强化治疗对2型糖尿病患者动脉内中膜厚度及其危险因素的影响

目的 评估强化控制血糖、血压、血脂对于新诊断2型糖尿病患者的颈、股动脉内中膜厚度(IMT)、血清晚期糖基化终末产物(AGE)及其可溶性受体(sRAGE)水平的影响.方法跟踪随访132例新诊断2型糖尿病患者5年,分3组:强化血糖、血压控制组(20例),强化血糖、血压、血脂控制组(80例),常规治疗组(32例).记录颈、股动脉IMT及其他相关指标水平变化情况,测定实验终点各组血清AGE和sRAGE水平.结果长期强化治疗较常规治疗,可明显减少颈、股动脉IMT增厚,同时可有效抑制血清中AGE的蓄积(P=0.009).经多元回归分析提示AGE为股动脉IMT的独立危险因素.sRAGE与研究终点HbA1C水平的比值,与5年间HbA1C的均数及波动情况呈负相关(P＜0.05).结论长期强化治疗较常规治疗可明显减少2型糖尿病患者颈、股动脉IMT增厚,同时可减少AGE在其体内的累积.

Abstract：

Objective To analyze the changes of the intima-media thickness(IMT)of carotid and femoral arteries, serum advanced glycosylation end-products(AGEs),and AGEs soluble receptor(sRAGE)after intensively controlling blood glucose, blood pressure, and lipid. Methods One hundred and thirty-two type 2 diabetic patients were divided into 3 groups and followed for 5 years: 20 patients were treated with intensive control of blood glucose and blood pressure, 80 patients with intensive control of blood glucose, blood pressure, and lipid; and 32 patients with conventional therapy. AGEs, sRAGE, and IMT of carotid and femoral arteries were measured and compared among different groups. Results The IMT of carotid and femoral arteries and serum level of AGEs were significantly decreased after intensive treatment. The ratio of sRAGE and HbA1C(sRAGE/HbA1C)were negatively correlated with the mean of HbA1Cin the past five years(r=-0.417, P＜0.001)and the fluctuation of HbA1C(r=-0.309,P＜0.001). Multinomial regression analysis showed that AGEs were the important risk factors of IMT of femoral artery(β=0.152,P=0.068). Conclusion Intensive treatment is significant in controlling the growing IMT of carotid and femoral arteries, while decreasing serum level of AGEs.     

N(carboxymethyl)lysine as a biomarker for microvascular complications in type 2 diabetic patients

AIMS: Hyperglycemia is linked to vascular dysfunction in patients with diabetes mellitus, either directly or through advanced glycation end product (AGE) formation. Experimental evidence has indicated the possible involvement of AGEs in the genesis of vascular complications. We investigated whether serum levels of AGEs and of the glycoxidation compound carboxymethyl-lysine (CML) were increased and correlated with vascular complications in type II diabetes mellitus. METHODS: Serum levels of AGEs and CML-human serum protein (CML-HSP) were measured by a specific immunoassay in 51 men and 26 women aged 58 +/- 6.1 years (mean +/- SD) who had been treated for type II diabetes mellitus for 11 +/- 8 years, and in a non-diabetic control group consisting of 39 men and 21 women aged 55.5 +/- 7.5 years. Patients with macroalbuminuria or abnormal creatinine clearance were excluded from the study. RESULTS: The serum levels of AGEs were significantly increased in patients with type II diabetes compared to controls (P<0.001). Blood levels of CML-HSP were significantly increased in diabetic patients compared to normal subjects [35.3 +/- 27.4 and 9.3 +/- 7.2 (mean +/- SD) pmol/mg of protein, respectively; P<0.0001]. In diabetic patients with retinopathy or microalbuminuria (urinary albumin excretion: UAE > 30 mg/24 h), CML-HSP levels were significantly higher (P<0.02), and even more elevated in patients with both complications. CONCLUSION: In patients with type II diabetes, CML-HSP levels that are at variance with the HbA(1c) index for blood glucose may be a biomarker of glycoxidation, and related to the development of microvascular complications.     

AGEs and chronic subclinical inflammation in diabetes: disorders of immune system

Chronic subclinical inflammation represents a risk factor of type 2 diabetes and several diabetes complications, including neuropathy and atherosclerosis including macro‐vasculopathy and micro‐vasculopathy. However, the inflammatory response in the diabetic wound was shown to be remarkably hypocellular, unregulated and ineffective. Advanced glycation end products (AGEs) and one of its receptors, RAGE, were involved in inducing chronic immune imbalance in diabetic patients. Such interactions attracts immune cell into diffused glycated tissue and activates these cells to induce inflammatory damage, but disturbs the normal immune rhythm in diabetic wound. Traditional measurements of AGEs are high‐performance liquid chromatography and immunohistochemistry staining, but their application faces the limitations including complexity, cost and lack of reproducibility. A new noninvasive method emerged in 2004, using skin autofluorescence as indicator for AGEs accumulation. It had been reported to be informative in evaluating the chronic risk of diabetic patients. Studies have indicated therapeutic potentials of anti‐AGE recipes. These recipes can reduce AGE absorption/de novo formation, block AGE–RAGE interaction and arrest downstream signaling after RAGE activation. Copyright © 2014 John Wiley & Sons, Ltd.     

Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control

Aims/hypothesis Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs).Methods We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O₂^– generation in monocytes were analysed in vitro after stimulation with serum from patients or controls.Results Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O₂^– generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA₁c levels.Conclusions/interpretation Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.     

LV systolic impairment in patients with asymptomatic coronary heart disease and type 1 diabetes is related to coronary atherosclerosis, glycaemic control and advanced glycation endproducts

AIMS: To evaluate whether heart failure in type 1 diabetes is linked to poor glycaemic control, coronary atherosclerosis or advanced glycation endproducts (AGEs). METHODS: Twenty six patients with type 1 diabetes (mean duration 32+/-5 years), and 16 age matched controls were recruited. Mean HbA(1c) through 18 years (HbA(1c)18), serum levels of AGEs and coronary atherosclerotic burden (CAB) were determined by IVUS. Peak tissue velocities and strain by tissue Doppler imaging were measured in 12 LV regions as an evaluation of LV function. RESULTS: Systolic tissue velocity was inversely correlated to CAB (r=0.53, p<0.01), to HbA(1c)18 (r=0.46, p<0.05) and to the duration of diabetes (r=0.46, p<0.05). Systolic strain was inversely correlated to HbA(1c)18 (r=0.45, p<0.05), to duration of diabetes (r=0.41, p<0.05), and tended to correlate with AGEs (r=0.37, p=0.07). In multiple regression analyses, CAB and HbA(1c)18 were significant independent predictors for systolic velocity, while AGEs and duration of diabetes were significant predictors of systolic strain. CONCLUSION: LV systolic function was impaired by increasing coronary atherosclerosis and worsening of glycaemic control. AGEs might be another mechanism for the increased risk of heart failure in type 1 diabetes.     

Formation of plasma advanced glycosylation end products (AGEs) has no influence on plasma viscosity

Plasma viscosity is mainly determined by large non-spherical proteins. In Type 1 diabetes mellitus, plasma viscosity increases with deterioration of diabetic control. Since protein glycation and formation of advanced glycosylation end products (AGEs) alter the structural and functional properties of proteins, AGEs might influence the rheological properties of plasma proteins. Therefore, we investigated the influence of plasma-AGEs on plasma viscosity in 34 normoalbuminuric diabetic patients (17 Type 1, 17 Type 2) with normal renal and liver function. In an additional experiment, 6 ml plasma of 9 healthy volunteers were incubated under sterile conditions for 14 days at 37.5 °C in the presence of 5.2 and 32.9 mmol l⁻¹ glucose. In diabetic patients, plasma-AGE levels were not correlated with plasma viscosity. Plasma-AGE levels in healthy controls (246 ± 37 U ml⁻¹, mean ± SD) were raised significantly (p<0.001) after the incubation at 37.5 °C (392 ± 57 U ml⁻¹ and 552 ± 58 U ml⁻¹, respectively). However, no difference was found in plasma viscosity pre- and post-incubation (pre-incubation: 1.25 ± 0.04 mPas, post-incubation: 1.23 ± 0.03 and 1.24 ± 0.03, respectively). We conclude that there is no influence of plasma-AGEs on plasma viscosity. © 1997 John Wiley & Sons, Ltd.     

Inhibitors of advanced glycation end products (AGEs): potential utility for the treatment of cardiovascular disease

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, stroke, blindness, and end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Recent clinical studies have substantiated the concept of "hyperglycemic memory" in the pathogenesis of cardiovascular disease (CVD) in diabetes. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that intensive therapy during the DCCT reduces the risk of cardiovascular events by about 50% in type 1 diabetic patients 11 years after the end of the trial. Among various biochemical pathways activated under diabetic conditions, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory "hyperglycemic memory." Further, there is a growing body of evidence that AGEs play an important role in CVD in diabetes. These observations suggest that the inhibition of AGEs formation may be a promising target for therapeutic intervention in diabetic vascular complications. Therefore, in this article, we review several agents with inhibitory effects on AGEs formation and their therapeutic implications in CVD in diabetes.     

Independent determinants of soluble form of receptor for advanced glycation end products in elderly hypertensive patients

Advanced glycation end product receptor (RAGE) interaction plays an important role in atherosclerosis. Although exogenously administered soluble form of RAGE (sRAGE) has been shown to suppress the development and progression of atherosclerosis in animals, the kinetics and role of endogenous sRAGE in humans are not fully understood. In this study, to clarify whether endogenous sRAGE could capture and efficiently eliminate RAGE ligands such as circulating AGEs and high-mobility group box-1 (HMGB-1), we investigated the correlation between sRAGE and RAGE ligands and examined independent determinants of serum levels of sRAGE in hypertensive humans. Two-hundred seventy-one consecutive nondiabetic outpatients with essential hypertension (83 male and 188 female; mean age, 76.5 ± 9.2 yeas) underwent a complete history, physical examination, and determination of blood chemistries, including serum levels of sRAGE, AGEs, and HMGB-1. Univariate regression analysis showed that serum levels of sRAGE were associated with body mass index (r = −0.313, P < .0001), waist (r = −0.214, P < .0001), alanine aminotransferase (r = −0.172, P = .005), γ-glutamyltranspeptidase (r = −0.213, P < .0001), 24-hour creatinine clearance (r = −0.348, P < .0001), B-type natriuretic peptide (r = 0.138, P = .027), tumor necrosis factor-α (r = 0.138, P = .002), and alcohol intake (r = −0.155, P = .010). By the use of multiple stepwise regression analyses, 24-hour creatinine clearance (P < .0001), γ-glutamyltranspeptidase (P < .001), body mass index (P = .007), and tumor necrosis factor-α (P = .024) remained significant independently. The present study demonstrated for the first time that there was no significant correlation between serum levels of sRAGE and RAGE ligands such as circulating AGEs and HMGB-1 in hypertensive patients. Anthropometric and inflammatory variables and liver and renal function may be the determinants of endogenous sRAGE levels in nondiabetic hypertensive patients.     

Serum Levels of Advanced Glycation End Products (AGEs) are Independent Correlates of Insulin Resistance in Nondiabetic Subjects

Background: Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans. Methods: Three hundred twenty‐two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme‐linked immunosorbent assay. Results: Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low‐density lipoprotein (LDL) cholesterol, triglycerides, high‐density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C‐reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA‐IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age‐adjusted HOMA‐IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females. Conclusion: The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA‐IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.     

Fatty acid binding protein 1 (FABP1) and fatty acid binding protein 2 (FABP2) as a link between diabetic nephropathy and subclinical atherosclerosis in children and adolescents with type 1 diabetes

BackgroundDiabetic nephropathy is a major cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). Fatty acid binding proteins (FABP1 and FABP2) play a role in the development and progression of chronic kidney disease including type 2 diabetes mellitus.AimWe assessed serum FABP1 and FABP2 levels in children and adolescents with T1DM as potential markers for diabetic nephropathy and their relation to carotid intima media thickness (CIMT).MethodsSixty patients with T1DM were divided into 2 groups according to the presence of nephropathy and compared with 30 healthy controls. CIMT, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), urinary albumin creatinine ratio (UACR), fasting lipid profile and serum FABP1 and FABP2 levels were assessed.ResultsFABP1 and FABP2 levels were significantly higher among type 1 diabetic patient with and without nephropathy compared with healthy controls with the highest levels among patients with nephropathy (p < 0.001). There were significant positive correlations between FABP1 and FABP2 and each of systolic blood pressure, CIMT, FBG, HbA1c and total cholesterol among T1DM patients. FABP1 was negatively correlated to glomerular filtration rate. Multivariable linear regression analysis showed that systolic blood pressure, CIMT, FBG and HbA1c were the significant independent variables related to FABP1 levels in type 1 diabetic patients with nephropathy. ROC curve analysis was performed to determine the cutoff value of FABP1 and FABP2 that could detect nephropathy.ConclusionFABP1 and FABP2 levels are elevated in children and adolescents with T1DM and could represent a link between diabetic nephropathy and subclinical atherosclerosis.