Plasma Advanced Glycation End Products Research Articles

Association of plasma advanced glycation end-products and their soluble receptor with type 2 diabetes among Chinese adults.

Population-based evidence regarding circulating advanced glycation end-products (AGEs) and the risk of type 2 diabetes (T2D) is conflicting and insufficient. We aimed to examine the association of plasma AGEs and plasma soluble receptors for AGEs (sRAGE) with T2D. We conducted a hospital-based case-control study including 1072 pairs (53.9±9.7years, 56.0% male) of newly diagnosed T2D and age- and sex-matched controls. We further performed a nested case-control study within an ongoing prospective cohort consisting of 127 incident T2D cases and 381 well-matched controls (62.2±5.1years, 71.7% male). Plasma AGEs were detected using liquid chromatography-tandem mass spectrometry, and plasma sRAGE was measured by enzyme-linked immunosorbent assay. Conditional logistic regression was used to evaluate the association of plasma AGEs and sRAGE concentrations with T2D. Higher plasma AGEs and lower sRAGE concentrations were associated with higher odds of T2D. The multivariable-adjusted odds ratios of T2D comparing the highest with the lowest quartile levels were 3.28 (95% CI: 2.14, 5.02) for plasma AGEs and 0.25 (95% CI: 0.16, 0.39) for plasma sRAGE. Participants in the highest quartile of plasma AGEs and the lowest quartile of sRAGE concentrations had the greatest odds of T2D. The positive association of AGEs and inverse association of sRAGE with T2D risk was confirmed in the replication-nested case-control study. Increased circulating AGEs and decreased sRAGE concentrations were associated with elevated T2D risk. Our findings may have implications for the strategies of T2D prevention and management.

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats.

Exercise training is an encouraging approach to treat cardiac dysfunction in type 2 diabetes (T2DM), but the impact of its intensity is not understood. We aim to investigate whether and, if so, how moderate-intensity training (MIT) and high-intensity interval training (HIIT) alleviate adverse cardiac remodeling and dysfunction in rats with T2DM. Male rats received standard chow (n = 10) or Western diet (WD) to induce T2DM. Hereafter, WD rats were subjected to a 12-week sedentary lifestyle (n = 8), running MIT (n = 7) or HIIT (n = 7). Insulin resistance and glucose tolerance were assessed during the oral glucose tolerance test. Plasma advanced glycation end-products (AGEs) were evaluated. Echocardiography and hemodynamic measurements evaluated cardiac function. Underlying cardiac mechanisms were investigated by histology, western blot and colorimetry. We found that MIT and HIIT lowered insulin resistance and blood glucose levels compared to sedentary WD rats. MIT decreased harmful plasma AGE levels. In the heart, MIT and HIIT lowered end-diastolic pressure, left ventricular wall thickness and interstitial collagen deposition. Cardiac citrate synthase activity, mitochondrial oxidative capacity marker, raised after both exercise training modalities. We conclude that MIT and HIIT are effective in alleviating diastolic dysfunction and pathological cardiac remodeling in T2DM, by lowering fibrosis and optimizing mitochondrial capacity.

The relationships between plasma advanced glycation end products level and cognitive function in middle-aged and elderly Chinese subjects.

To determine the relationships between circulating representative advanced glycation end products (AGEs) and cognitive performance in middle-aged and elderly Chinese adults. A cross-sectional study with 1834 participants were included. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Plasma free AGEs including Nε-carboxymethyl-L-lysine (CML), Nε-(1-carboxyethyl) lysine (CEL), S-carboxymethyl-L-cysteine (CMC) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Multivariate adjusted linear and logistic regression analysis were used to explore the associations between plasma AGEs and cognitive function. The prevalence of mild cognitive impairment (MCI) was 17.94%. Plasma CMC and MG-H1 level were negatively associated with MMSE score (β=-0.42, p<0.001 for all) in the multivariate linear regression analysis. In the multivariate logistic regression analysis, compared to the lowest tertile, participants within the highest tertile of CMC and MG-H1 had increased risk of MCI [ORs (95% CI): 1.62 (1.21-2.17), P trend <0.001, and ORs (95% CI): 1.30 (0.97-1.76), P trend=0.069, respectively]. In addition, the weighted quantile sum (WQS) index was negatively associated with MMSE (β=-0.48, P<0.001) and increased risk of MCI [ORs (95% CI): 1.35 (1.20-1.52), P<0.001]. Combined exposure of plasma free AGEs including CML, CEL, CMC and MG-H1 were associated with increased risk of cognitive impairment. Plasma CMC and MG-H1 might the main contributors for cognitive impairment, while further longitudinal studies are required to verify the associations.

Plasma AGE and Oxidation Products, Renal Function, and Preeclampsia in Pregnant Women with Type 1 Diabetes: A Prospective Observational Study.

We aimed to determine whether plasma advanced glycation end products or oxidation products (AGE/oxidation-P) predict altered renal function and/or preeclampsia (PE) in pregnant women with type 1 diabetes. Prospectively, using a nested case-control design, we studied 47 pregnant women with type 1 diabetes, of whom 23 developed PE and 24 did not. Nineteen nondiabetic, normotensive pregnant women provided reference values. In plasma obtained at ~12, 22, and 32 weeks' gestation (visits 1, 2, and 3; V1-V3), we measured five AGE products (carboxymethyllysine (CML), carboxyethyl-lysine (CEL), methylglyoxal-hydroimidazolone (MGH1), 3-deoxyglucosone hydroimidazolone (3DGH), and glyoxal-hydroimidazolone (GH1)) and four oxidation products (methionine sulfoxide (MetSO), 2-aminoadipic acid (2-AAA), 3-nitrotyrosine (3NT), and dityrosine (DT)), by liquid chromatography/mass spectroscopy. Clinical outcomes were "estimated glomerular filtration rate" (eGFR) at each visit and onset of PE. In diabetic women, associations between AGE/oxidation-P and eGFR were found only in those who developed PE. In this group, CEL, MGH1, and GH1 at V2 and CML, CEL, MGH1, and GH1 at V3 were inversely associated with contemporaneous eGFR, while CEL, MGH1, 3DGH, and GH1 at V2 were inversely associated with eGFR at V3 (all p < 0.05). There were no associations of plasma AGE or oxidation-P with pregnancy-related development of proteinuria or PE. Inverse associations of second and early third trimester plasma AGE with eGFR among type 1 diabetic women who developed PE suggest that these patients constitute a subset susceptible to AGE-mediated injury and thus to cardiorenal complications later in life. However, AGE/oxidation-P did not predict PE in type 1 diabetic women.

Plasma Advanced Glycation End Products and Dicarbonyl Compounds Are Not Associated with Coronary Atherosclerosis in Athletes.

Coronary atherosclerosis is the leading cause of sudden death among athletes >35 yr old, but current cardiovascular risk prediction algorithms have not been validated for athletes. Advanced glycation end products (AGE) and dicarbonyl compounds have been associated with atherosclerosis and rupture-prone plaques in patients and ex vivo studies. The detection of AGE and dicarbonyl compounds might be a novel screening tool for high-risk coronary atherosclerosis in older athletes. Concentrations of three different AGE and the dicarbonyl compounds methylglyoxal, glyoxal, and 3-deoxyglucosone were measured in plasma with ultraperformance liquid chromatography tandem mass spectrometry in athletes from the Measuring Athletes' Risk of Cardiovascular Events 2 study cohort. Coronary plaques, plaque characteristics (calcified, noncalcified or mixed), and coronary artery calcium (CAC) scores were assessed with coronary computed tomography, and potential associations with AGE and dicarbonyl compounds were analyzed using linear and logistic regression. A total of 289 men were included (60 [quartiles 1-3 = 56-66] yr old, body mass index = 24.5 [22.9-26.6] kg·m -2 ), with a weekly exercise volume of 41 (25-57) MET-hours. Coronary plaques were detected in 241 participants (83%), with a dominant plaque type of calcified plaques in 42%, noncalcified plaques in 12% and mixed plaques in 21%. No AGE or dicarbonyl compounds were associated with total number of plaques or any of the plaque characteristics in adjusted analyses. Similarly, AGE and dicarbonyl compounds were not associated with CAC score. Concentrations of plasma AGE and dicarbonyl compounds do not predict the presence of coronary plaques, plaque characteristics or CAC scores, in middle-age and older athletes.

N-Acetylcysteine Enhances the Recovery of Ischemic Limb in Type-2 Diabetic Mice

Critical limb ischemia (CLI) is a severe complication of diabetes mellitus that occurs without effective therapy. Excessive reactive oxygen species (ROS) production and oxidative stress play critical roles in the development of diabetic cardiovascular complications. N-acetylcysteine (NAC) reduces ischemia-induced ROS production. The present study aimed to investigate the effect of NAC on the recovery of ischemic limb in an experimental model of type-2 diabetes. TALLYHO/JngJ diabetic and SWR/J non-diabetic mice were used for developing a CLI model. For NAC treatment, mice received NAC (1 mg/mL) in their drinking water for 24 h before initiating CLI, and continuously for the duration of the experiment. Blood flow, mechanical function, histology, expression of antioxidant enzymes including superoxide dismutase (SOD)-1, SOD-3, glutathione peroxidase (Gpx)-1, catalase, and phosphorylated insulin receptor substrate (IRS)-1, Akt, and eNOS in ischemic limb were evaluated in vivo or ex vivo. Body weight, blood glucose, plasma advanced glycation end-products (AGEs), plasma insulin, insulin resistance index, and plasma TNF-a were also evaluated during the experiment. NAC treatment effectively attenuated ROS production with preserved expressions of SOD-1, Gpx-1, catalase, phosphorylated Akt, and eNOS, and enhanced the recovery of blood flow and function of the diabetic ischemic limb. NAC treatment also significantly decreased the levels of phosphorylated IRS-1 (Ser307) expression and plasma TNF-α in diabetic mice without significant changes in blood glucose and AGEs levels. In conclusion, NAC treatment enhanced the recovery of blood flow and mechanical function in ischemic limbs in T2D mice in association with improved tissue redox/inflammatory status and insulin resistance.

Plasma advanced glycation end products and soluble receptor for advanced glycation end products as indicators of sterol content in human carotid atherosclerotic plaques.

Advanced glycation end products (AGEs) are independently related to cardiovascular disease (CVD) and favor cholesterol and oxysterol accumulation in macrophage foam cells. Soluble RAGE (sRAGE) impairs cellular AGE signaling alleviating the deleterious effects of AGE in atherogenesis. The association between plasma AGEs and sRAGE with the content of cholesterol, markers of cholesterol synthesis and absorption, and oxysterols in atherosclerotic plaques was evaluated in subjects undergoing carotid endarterectomy.Plasma and carotid plaques were obtained from symptomatic (n = 23) and asymptomatic subjects (n = 40). Lipids from plaques were extracted and sterols (oxysterols, cholesterol, desmosterol, lathosterol, sitosterol, and campesterol) were determined by using gas chromatography/mass spectrometry. Plasma total AGEs and pentosidine were measured by using fluorimetry and sRAGE by using ELISA.In symptomatic subjects´ atherosclerotic plaques, an increased amount of cholesterol (3x) and oxysterols [7 α-hydroxycholesterol (1.4x); 7 β−hydroxycholesterol (1.2x); 25-hydroxycholesterol (1.3x); 24-hydroxycholesterol (2.7x), and 27-hydroxycholesterol, (1.15x)], with exception to 7 ketocholesterol, were found in comparison to asymptomatic individuals. Plasma total AGEs and pentosidine significantly and positively correlated to sterols accumulated in the atherosclerotic lesion, including cholesterol, desmosterol, campesterol, sitosterol, and oxysterols. On the other hand, sRAGE inversely correlated to total AGEs and pentosidine in plasma, and with major species of oxysterols, cholesterol, and markers of cholesterol synthesis and absorption in the atherosclerotic lesion. In multiple regression analyses, it was observed a significant inverse correlation between sRAGE and 24-hydroxycholesterol and desmosterol, and a positive significant correlation between pentosidine and 24-hydroxycholesterol, 27-hydroxycholesterol, and campesterol.In conclusion, the plasma concentration of AGEs and sRAGE is a tool to predict the accumulation of sterols in atherosclerotic lesions in symptomatic and asymptomatic individuals, helping to prevent and improve the management of acute cardiovascular complications.

Plasma advanced glycation end products and the subsequent risk of microvascular complications in type 1 diabetes in the DCCT/EDIC

IntroductionTo assess impact of glycemic control on plasma protein-bound advanced glycation end products (pAGEs) and their association with subsequent microvascular disease.Research design and methodsEleven pAGEs were measured by liquid chromatography-mass...

Advanced Glycation End Products and Inflammatory Cytokine Profiles in Maintenance Hemodialysis Patients After the Ingestion of a Protein-Dense Meal

The goal of this investigation was to evaluate circulating and skeletal muscle inflammatory biomarkers between maintenance hemodialysis (MHD) and demographic-matched control subjects (CON) before and after ingestion of a protein-rich meal. CON (n=8; 50±2years; 31±1kg/m2) and MHD patients (n=8; 56±5years; 32±2kg/m2) underwent a basal blood draw and muscle biopsy and serial blood draws after the ingestion of a mixed meal on a nondialysis day. Plasma advanced glycation end products (AGEs) and markers of oxidation were assessed via liquid chromatography-tandem mass spectrometry before and after the meal (+240min). Circulating inflammatory cytokines and soluble receptors for AGE (sRAGE) isoforms (endogenous secretory RAGEs and cleaved RAGEs) were determined before and after the meal (+240min). Basal muscle was probed for inflammatory cytokines and protein expression of related signaling components (RAGE, Toll-like receptor 4, oligosaccharyltransferase subunit 48, TIR-domain-containing adapter-inducing interferon-β, total IκBα, and pIκBα). Basal circulating AGEs were 7- to 343-fold higher (P<.001) in MHD than those in CON, but only MG-H1 increased in CON after the meal (P<.001). There was a group effect (MHD>CON) for total sRAGEs (P=.02) and endogenous secretory RAGEs (P<.001) and a trend for cleaved RAGEs (P=.09), with no meal effect. In addition, there was a group effect (MHD<CON; P<.05) for circulating fractalkine, interleukin (IL)10, IL17A, and IL1β and a trend (P<.10) for IL6 and macrophage inflammatory protein 1 alpha, whereas tumor necrosis factor alpha was higher in MHD (P<.001). In muscle, Toll-like receptor 4 (P=.03), TIR-domain-containing adapter-inducing interferon-β (P=.002), and oligosaccharyltransferase subunit 48 (P=.02) expression was lower in MHD than that in CON, whereas IL6 was higher (P=.01) and IL8 (P=.08) tended to be higher in MHD. Overall, MHD exhibited an exaggerated, circulating, and skeletal muscle inflammatory biomarker environment, and the meal did not appreciably affect the inflammatory status.

Clinic and ambulatory blood pressure in relation to the interaction between plasma advanced glycation end products and sodium dietary intake and renal handling.

Advanced glycation end product (AGE) clearance may cause renal tubular injuries, such as changes in sodium reabsorption. We hypothesize that AGEs interact with sodium metabolism to influence blood pressure (BP). The study participants were outpatients who were suspected of having hypertension but had not been treated with antihypertensive medication. Clinic and ambulatory blood pressures were measured at baseline (n = 989) and during follow-up (median, 4.4 years, n = 293). Plasma AGE concentrations were measured by enzyme-linked immunosorbent assay. Twenty-four-hour urine was collected for measurements of creatinine, sodium and lithium. In a cross-sectional analysis (n = 989), subjects in the top quintile versus quintiles 1-4 of plasma AGE concentration had significantly (P ≤ 0.004) lower fractional excretion of lithium (18.3% vs. 21.6%) and fractional distal reabsorption rate of sodium (95.0% vs. 95.8%) but similar BP (P ≥ 0.25). However, there was an interaction between plasma AGE concentration and urinary sodium excretion in relation to diastolic BP (P ≤ 0.058). Only in participants with low urinary sodium chloride excretion (≤6 grams/day, n = 189), clinic (84.3 vs. 80.2 mmHg), 24-h (83.9 vs. 80.4 mmHg), daytime (87.8 vs. 84.8 mmHg) and nighttime (75.1 vs. 72.1 mmHg) diastolic BP at baseline were higher (P ≤ 0.05) in the top quintile than in quintiles 1-4 of plasma AGE concentration. In the longitudinal study (n = 383), similar trends were observed, with significant (P ≤ 0.05) differences in the increment in daytime diastolic BP (6.8 vs. -1.7 mmHg) and incidence of ambulatory and treated hypertension (hazard ratio 3.73) during follow-up. In conclusion, AGEs were associated with high BP, probably via enhanced proximal sodium handling and on low dietary sodium intake.

Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice

Diabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.

Advanced glycation end products and cognitive impairment in schizophrenia.

Advanced glycation end products play a key role in the pathophysiology of schizophrenia. Cognitive impairment is one of the central features of schizophrenia; however, the association between advanced glycation end products and cognitive impairment remains unknown. This study investigated whether advanced glycation end products affect the cognitive domain in patients with schizophrenia. A total of 58 patients with chronic schizophrenia were included in this cross-sectional study. Plasma advanced glycation end products were measured using high-performance liquid chromatography (HPLC). Neuropsychological and cognitive functions were assessed using the Wechsler Adult Intelligence Scale, Third Version, and the Wisconsin Card Sorting Test Keio-FS version. Multiple regression analysis adjusted for age, sex, body mass index, educational years, daily dose of antipsychotics, and psychotic symptoms revealed that processing speed was significantly associated with plasma pentosidine, a representative advanced glycation end product (standardized β = -0.425; p = 0.009). Processing speed is the cognitive domain affected by advanced glycation end products. Considering preceding evidence that impaired processing speed is related to poor functional outcome, interventions targeted at reducing advanced glycation end products may contribute to promoting recovery of patients with schizophrenia as well as cognitive function improvement.

Plasma advanced glycation end products positively correlates to oxysterols levels in carotid atherosclerotic plaques

Plasma advanced glycation end products positively correlates to oxysterols levels in carotid atherosclerotic plaques

Systematic review of diagnostic methods for acute respiratory distress syndrome.

RationaleAcute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS.MethodsMedline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising.ResultsForty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72–0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population.ConclusionThis systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed.

Status of oxidative stress markers, advanced glycation index, and polyol pathway in age-related cataract subjects with and without diabetes

One of the major public health issues is the rising prevalence of cataracts, a primary reason for preventable blindness. The causes for the development of age-related cataracts and accelerated cataractogenesis in diabetes are multifactorial. Hence, this study was designed to examine the status and relationship between the three majorly associated molecular events, namely, oxidative stress, non-enzymatic glycation, and polyol pathway in age-related cataracts with and without diabetes. A total of 472 subjects were distributed into four groups: non-diabetic subjects with clear lens (135), diabetic subjects with clear lens (40), non-diabetic subjects with cataract (174), and diabetic subjects with cataract (123). Cataracts were graded by slit-lamp examination according to the Lens Opacities Classification System III. Age at onset of cataract, type of opacity, anthropometric measurements, and sociodemographic characteristics were recorded, and clinical profile was examined. Plasma oxidative stress markers were assessed by estimating the lipid peroxidation end product malondialdehyde, protein oxidation products protein carbonyls, and DNA oxidative damage marker 8-hydroxy-2-deoxyguanosine. Plasma advanced glycation end products index, erythrocyte aldose reductase activity, and sorbitol levels were evaluated. After adjusting for age, plasma malondialdehyde levels were significantly higher in diabetic cataracts (P < 0.001) and non-diabetic cataract subjects (P < 0.05), compared to non-diabetic subjects with clear lens. Plasma advanced glycation end products index was significantly higher (P < 0.05) only in diabetic cataracts, but not in non-diabetic subjects with cataracts. Aldose reductase activity and sorbitol levels were significantly higher (P < 0.001) in both diabetic and non-diabetic subjects with cataract compared to non-diabetic subjects with clear lens. The data indicated that plasma lipid peroxidation in age-related cataracts was independent of diabetes. An association of pronounced glycation was observed only in diabetic cataracts but not in non-diabetic cataracts and polyol flux between diabetic cataracts and non-diabetic cataracts was comparable.

Selected Atherosclerosis-Related Diseases May Differentially Affect the Relationship between Plasma Advanced Glycation End Products, Receptor sRAGE, and Uric Acid.

Our study aimed to identify the relationship between advanced glycation end products (AGEs), soluble receptor for advanced glycation end products (sRAGE), the AGEs/sRAGE, and uric acid (UA) levels in selected atherosclerosis diseases, i.e., abdominal aortic aneurysms (AAA), aortoiliac occlusive disease (AIOD), and chronic kidney disease (CKD), resulting from apparent differences in oxidative stress intensity. Furthermore, we suggest that increased AGEs levels may stimulate an antioxidant defense system reflected by the UA level. The studied group size consisted of 70 AAA patients, 20 AIOD patients, 50 patients in the pre-dialyzed group (PRE), and 35 patients in the hemodialyzed group (HD). The enzyme-linked immunosorbent assay was used to measure AGEs and sRAGE levels. We found a significantly higher concentration of AGEs in CKD patients as compared to AAA and AIOD patients. Furthermore, the sRAGE level was higher in the CKD patients in comparison to AIOD and AAA patients. UA level was significantly higher in the PRE group compared to AAA patients. In conclusion, the diseases included in this study differ in the anti- and prooxidant defense system, which is reflected in the relations between the AGEs, the sRAGE, the AGEs/sRAGE ratio, as well as the UA levels.

Effect of Dipeptidyl-Peptidase 4 Inhibitors on Circulating Oxidative Stress Biomarkers in Patients with Type 2 Diabetes Mellitus.

Pre-clinical studies suggested potential cardiovascular benefits of dipeptidyl peptidase-4 inhibitors (DPP4i), however, clinical trials showed neither beneficial nor detrimental effects in patients with type 2 diabetes mellitus (T2DM). We examined the effects of DPP4i on several circulating oxidative stress markers in a cohort of 32 T2DM patients (21 males and 11 post-menopausal females), who were already on routine antidiabetic treatment. Propensity score matching was used to adjust demographic and clinical characteristics between patients who received and who did not receive DPP4i. Whole-blood reactive oxygen species (ROS), plasma advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), carbonyl residues, as well as ferric reducing ability of plasma (FRAP) and leukocyte DNA oxidative damage (Fpg sites), were evaluated. With the exception of Fpg sites, that showed a borderline increase in DPP4i users compared to non-users (p = 0.0507), none of the biomarkers measured was affected by DPP4i treatment. An inverse correlation between estimated glomerular filtration rate and AGEs (p < 0.0001) and Fpg sites (p < 0.05) was also observed. This study does not show any major effect of DPP4i on oxidative stress, assessed by several circulating biomarkers of oxidative damage, in propensity score-matched cohorts of T2DM patients.

Bradykinin and oxidative stress in patients with hereditary angioedema due to C1 inhibitor deficiency.

Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by genetic dysfunction of C1 inhibitor (C1-INH) due to mutations in the SERPING1 gene. The disorder is mediated mainly by bradykinin. The clinical course of the disease is varied and not related to genetic changes. We aimed to evaluate redox homeostasis of peripheral blood mononuclear cells (PBMCs) in patients with HAE due to C1-INH deficiency (C1 INH HAE) by measuring the levels of reactive oxygen species (ROS) of PBMCs as well as plasma advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs). We also aimed to assess the effect of bradykinin on ROS levels. We enrolled 30 adults with C1-INH-HAE and 15 healthy individuals. The levels of ROS were measured by flow cytometry, while the plasma levels of AGEs and AOPPs were determined spectrophotometrically by enzyme‑ linked immunosorbent assays. Basal and hydrogen peroxide (H2O2)-induced ROS levels were higher in patients with HAE when compared with controls (P = 0.002 and P = 0.001, respectively), indicating abnormalities in redox homeostasis. Plasma AOPP and AGE levels were similar in both groups. Bradykinin reduced basal and H2O2-induced ROS generation in PBMCs only in patients with HAE (P = 0.03). The higher basal and H2O2-induced ROS levels in patients with C1 INH HAE indicate redox imbalance. However, by reducing basal and H2O2-induced ROS levels, bradykinin shows antioxidant action in this disorder.

1540-P: Plasma Advanced Glycation End Products (AGEs) at Three Time Points during the DCCT/EDIC Are Associated with Subsequent Risk of Microvascular Complications in Type 1 Diabetes

We previously showed that skin collagen AGEs at DCCT trial closeout were strongly associated with progression of microvascular disease even after adjustment for A1c (Glyconj. J. 33: 569, 2016). We now tested whether plasma protein AGEs are associated with subsequent progression of retinopathy, nephropathy and neuropathy. Methods: Fourteen AGEs were measured by LC/MS/MS in banked plasmas from 466 DCCT participants at three time points (TPs): DCCT year 4 (TP1), year 8 (TP2) and EDIC year 5/6 (TP3). Data were analyzed using correlation coefficients, while associations with risk of complications used Cox proportional hazards models were determined without adjustment for multiplicity. Results: Fructose-lysine (FL), glucosepane (GSPN) and carboxymethyl-lysine (CML) were lower in the former intensive glycemic control group at both TP1 and TP2 (P&amp;lt;0.0001) but not at TP3. At all 3 TPs, mean A1C was positively correlated with levels of FL (r=0.44), GSPN (r=0.33) and CML (r=0.35). In unadjusted Cox models using all three TPs, higher levels of FL, GSPN and CML were associated with subsequent risk of proliferative diabetic retinopathy (PDR, P&amp;lt;0.0001), clinically significant macular edema (CSME, P&amp;lt;0.0008) and confirmed clinical neuropathy (CCN, P&amp;lt;0.005). After adjustment for mean A1C, all three AGEs (FL, GSPN, CML) remained significantly associated with PDR (P&amp;lt;0.021), FL and GSPN remained significant for CCN (P≤0.005), and CML remained significant for CSME (P=0.033). Methylglyoxal hydroimidazolone (MG-H1) and methionine sulfoxide (MetSOX) were positively associated with sustained eGFR&amp;lt;60 and cardiac autonomic neuropathy before and after adjustment for A1C (P&amp;lt;0.05, P=0.031, respectively). In conclusion, after adjustment for A1C, FL, GSPN, CML and MG-H1 are the plasma AGEs most strongly associated with progression of microvascular complications in type 1 diabetes. Disclosure V.M. Monnier: Consultant; Self; Juvenescence Ltd. D. Sell: None. J. Lachin: Board Member; Self; Tolerion, Inc. I. Bebu: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK101123-01)

Increased Prevalence of Type 2 Diabetes-Related Complications in Combined Type 2 Diabetes and Sickle Cell Trait.

The prevalence of type 2 diabetes (T2D) is rapidly increasing in sub-Saharan Africa, where sickle cell trait (SCT) is also frequent. Although SCT is generally considered a benign condition, evidence suggests that SCT could exaggerate vascular dysfunction in T2D. However, it remains unclear whether SCT could increase the risk of the development of T2D complications. Therefore, this study was conducted to determine whether T2D complications were more prevalent among Senegalese individuals with SCT and T2D than among those with T2D only. Rates of hypertension, retinopathy, peripheral neuropathy, peripheral artery disease, and impaired renal function as well as arterial stiffness, blood rheology, and concentrations of plasma advanced glycation end products (AGEs) and cytokines were compared between groups of Senegalese individuals with combined SCT and T2D (T2D-SCT) (n = 60), T2D (n = 52), SCT (n = 53), and neither T2D nor SCT (control) (n = 56). Human aortic endothelial cell (HAEC) expression of inflammatory and adhesion factors was measured after treatment with tumor necrosis factor-α and subjects' plasma. Effects of AGE inhibition or tiron on HAEC expression of E-selectin were measured. Retinopathy, hypertension, and reduced renal function were more prevalent, and arterial stiffness, blood viscosity at high shear rates, and thixotropic index were higher, in the SCT group compared with the other groups. Multivariable analysis showed that plasma AGE concentration was significantly associated with arterial stiffness. E-selectin expression was elevated in HAECs treated with T2D-SCT plasma compared with the other groups, but AGE inhibition reversed this. SCT could potentially augment the risk of the development of T2D-related complications, including retinopathy, nephropathy, and hypertension.