Low Advanced Glycation End Products Research Articles

A 4-week high-AGE diet does not impair glucose metabolism and vascular function in obese individuals.

BACKGROUNDAccumulation of advanced glycation endproducts (AGEs) may contribute to the pathophysiology of type 2 diabetes and its vascular complications. AGEs are widely present in food, but whether restricting AGE intake improves risk factors for type 2 diabetes and vascular dysfunction is controversial.METHODSAbdominally obese but otherwise healthy individuals were randomly assigned to a specifically designed 4-week diet low or high in AGEs in a double-blind, parallel design. Insulin sensitivity, secretion, and clearance were assessed by a combined hyperinsulinemic-euglycemic and hyperglycemic clamp. Micro- and macrovascular function, inflammation, and lipid profiles were assessed by state-of-the-art in vivo measurements and biomarkers. Specific urinary and plasma AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were assessed by mass spectrometry.RESULTSIn 73 individuals (22 males, mean ± SD age and BMI 52 ± 14 years, 30.6 ± 4.0 kg/m2), intake of CML, CEL, and MG-H1 differed 2.7-, 5.3-, and 3.7-fold between the low- and high-AGE diets, leading to corresponding changes of these AGEs in urine and plasma. Despite this, there was no difference in insulin sensitivity, secretion, or clearance; micro- and macrovascular function; overall inflammation; or lipid profile between the low and high dietary AGE groups (for all treatment effects, P > 0.05).CONCLUSIONThis comprehensive RCT demonstrates very limited biological consequences of a 4-week diet low or high in AGEs in abdominally obese individuals.TRIAL REGISTRATIONClinicaltrials.gov, NCT03866343; trialregister.nl, NTR7594.FUNDINGDiabetesfonds and ZonMw.

Effects of dietary advanced glycation end-products restriction on renal function in patients with diabetic nephropathy; a randomized, double-blind clinical trial

Introduction: It has been proposed that advanced glycation end-products (AGEs) are contributory factors in diabetic nephropathy (DN) pathogenesis. Interventions regarding restriction dietary AGEs (dAGEs) intake indicate improvement in clinical outcomes. Objectives: The present study aimed to compare the effects of 10-week low AGEs diet (LAGEsd) based on recommended diabetic diet (DD) versus DD alone on glycemic status, lipid profile, serum creatinine (sCr), blood urea nitrogen (BUN), urine albumin to creatinine ratio, eGFR and urine albumin in patients with DN. Patients and Methods: This randomized, double-blind clinical trial was conducted on 62 patients with DN. Patients were assigned randomly to LAGEsd (n=31) and DD (n=31) groups for 10 weeks. All patients were prescribed calorie adjusted diet in regards to American Diabetes Association’s recommendation. In addition, patients in the LAGEsd group were instructed how to reduce dAGEs intake based on established guidelines. Demographic data were collected and dietary intakes, physical activity level, fasting blood sugar (FBS), hemoglobin A1C (HbA1c), lipid profile, sCr, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio (Alb/Cr), and urine albumin were measured before and after of 10-weeks intervention, and compared between the two groups. Results: The results showed that dAGEs intake decreased significantly in the LAGEsd group compared with the DD group (P<0.001). In the LAGEsd group, eGFR improved significantly compared with the DD group (18.77±20.99 mL/min/1.73 m2 versus 1.57±21.06 mL/min/1.73 m2 , P=0.002); however there were no significant difference in FBS, HbA1c, lipid profile, sCr, BUN, urine Alb/Cr, and urine albumin between the two groups (P>0.05). Conclusion: In sum, dAGEs restriction plus DD is superior to DD alone in improvement of renal function marker in patients with DD. Trial Registration: This study was registered at Iranian Registry of Clinical Trials (identifier: IRCT20191004044979N1, https://en.irct.ir/trial/42914, ethical code #IR.SUMS.REC.1398.798).

The role of serum and dietary advanced glycation endproducts in relation to cardiac function and structure: The Hoorn Study

Background and aimsThis study aims to investigate the relationship of serum and dietary advanced glycation endproducts (AGEs) with cardiac function and structure after eight years of follow-up. Methods and resultsWe included 370 Hoorn Study participants (aged 66.4 ± 6.1, 47% women). Serum protein-bound AGEs [Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and pentosidine], as well as echocardiography to assess left atrium volume index (LAVI), left ventricle ejection fraction (LVEF), and left ventricle mass index (LVMI), were measured at baseline and after 8 years of follow-up. Dietary AGEs [Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine] were estimated at baseline with a validated food-frequency questionnaire and an AGEs database. Increased pentosidine [-1.4% (−2.6;-0.2)] and overall serum AGEs Z-scores over time [-2.1% (−3.8;-0.5)] were associated with decreased LVEF at follow-up, adjusted for confounders. Glucose metabolism status was an effect modifier (P-for-interaction = 0.04). In participants with impaired glucose metabolism, but not type 2 diabetes, increased pentosidine was associated with decreased LVEF [-4.2 (−8.0;-0.3)%]. Higher dietary Nε-(carboxyethyl)lysine [1.9 (0.1; 3.7)%] and overall dietary AGEs Z-scores [2.1 (0.1; 4.2)%] were associated with higher LVEF at follow-up. However, prior cardiovascular disease (CVD) was an effect modifier (P = 0.02). We found a stronger, non-significant, association of higher dietary (carboxyethyl)lysine with higher LVEF at follow-up in participants without CVD [2.3 (−0.1; 4.7)%] compared to participants with CVD [0.6 (−2.1; 3.4)%]. ConclusionOverall serum AGEs were longitudinally associated with impaired systolic function. Future research should focus on including changes in dietary AGEs intake over time and the relation of dietary AGEs with cardiac measures needs to be established in intervention studies using low AGEs diets.

The Impact of Low Advanced Glycation End Products Diet on Metabolic Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Several randomized clinical trials have investigated the effect of dietary advanced glycation end products (AGEs) on metabolic syndrome risk factors in adults. However, the results of these studies were conflicting. Therefore, our aim was to assess the effect of dietary AGEs on metabolic syndrome risk factors. We searched the PubMed-MEDLINE, Scopus, Cochrane Databases, Google Scholar, Web of Science, and Embase databases for papers published up to October 2019 that investigated the effect of dietary AGEs on metabolic syndrome risk factors. From the eligible trials, 13 articles were selected for inclusion in this systematic review and meta-analysis. The meta-analysis was performed using a random-effects model. Heterogeneity was determined by I2 statistics and Cochrane Q test. Pooled results from the random-effects model showed a significant reduction for insulin resistance [weighted mean difference (WMD): -1.204; 95% CI: -2.057, -0.358; P=0.006], fasting insulin (WMD: -5.472 μU/mL; 95% CI: -9.718, -1.234 μU/mL; P=0.011), total cholesterol (WMD: -5.486 mg/dL; 95% CI: -10.222, -0.747 mg/dL; P=0.023), and LDL (WMD: -6.263 mg/dL; 95% CI: -11.659, -0.866 mg/dL; P=0.023) in the low-AGEs groups compared with the high-AGEs groups. There were no changes in the other components of the metabolic syndrome. The results of this review suggest that a diet with a low AGEs content has beneficial effects on insulin resistance, fasting insulin, total cholesterol, and LDL. Moreover, following a diet low in AGEs may be a helpful strategy to decrease the burden of metabolic syndrome risk factors in adults and particularly in patients with diabetes.

The impact of low advanced glycation end products diet on obesity and related hormones: a systematic review and meta-analysis

Several randomized clinical trials (RCTs) have investigated the effect of dietary advanced glycation end products (AGE) on obesity factors and related hormones in adults; results were conflicting. Therefore, a study was performed to assess the effect of low advanced glycation end products diet on obesity and related hormones. A comprehensive literature search without any limitation on language was conducted using the following bibliographical databases: Web of Science, Scopus, Ovid MEDLINE, Cochrane, and Embase up to October, 2019. From the eligible trials, 13 articles were selected for the systematic review and meta-analysis. Our systematic reviews and meta-analyses have shown a significant decrease in BMI (WMD: − 0.3 kg/m2; 95% CI: − 0.52, − 0.09, p = 0.005; I2 = 55.8%), weight (WMD: − 0.83 kg; 95% CI: − 1.55, − 0.10, p = 0.026; I2 = 67.0%), and leptin (WMD: − 19.85 ng/ml; 95% CI: − 29.88, − 9.82, p < 0.001; I2 = 81.8%) and an increase in adiponectin (WMD: 5.50 µg/ml; 95% CI: 1.33, 9.67, p = 0.010; I2 = 90.6%) levels after consumption of the low AGE diets compared to the high AGE diets. Also, the effect of intake of low AGE compared to high AGE diets was more pronounced in subgroup with duration > 8 weeks for the BMI and weight. Overall, according to our results, although low AGE diets appeared to be statistically significant in reducing the prevalence of obesity and chronic diseases compared to high consumption of dietary AGEs. But, no clinical significance was observed. Therefore, to confirm these results clinically, further prospective studies should be conducted in this regard. The study protocol was registered in the in International prospective register of systematic reviews (PROSPERO) database as CRD42020203734.

Influence of Metastatic Bone Lesion Type and Tumor Origin on Human Vertebral Bone Architecture, Matrix Quality, and Mechanical Properties.

Metastatic spine disease is incurable, causing increased vertebral fracture risk and severe patient morbidity. Here, we demonstrate that osteolytic, osteosclerotic, and mixed bone metastasis uniquely modify human vertebral bone architecture and quality, affecting vertebral strength and stiffness. Multivariable analysis showed bone metastasis type dominates vertebral strength and stiffness changes, with neither age nor gender having an independent effect. In osteolytic vertebrae, bone architecture rarefaction, lower tissue mineral content and connectivity, and accumulation of advanced glycation end-products (AGEs) affected low vertebral strength and stiffness. In osteosclerotic vertebrae, high trabecular number and thickness but low AGEs, suggesting a high degree of bone remodeling, yielded high vertebral strength. Our study found that bone metastasis from prostate and breast primary cancers differentially impacted the osteosclerotic bone microenvironment, yielding altered bone architecture and accumulation of AGEs. These findings indicate that therapeutic approaches should target the restoration of bone structural integrity. © 2022 American Society for Bone and Mineral Research (ASBMR).

Consumption of diets with low advanced glycation end products improves cardiometabolic outcomes: Meta-analysis of randomised controlled trials

Consumption of diets with low advanced glycation end products improves cardiometabolic outcomes: Meta-analysis of randomised controlled trials

Effects of a Low Advanced Glycation End Products Diet on Insulin Levels: The Feasibility of a Crossover Comparison Test

BackgroundAdvanced glycation end products (AGEs) are associated with diabetes mellitus. Digested food-derived AGEs have been implicated in the pathogenesis of AGE-related disorders, and restricting diet-derived AGEs improves insulin resistance in animal models. The AGE content in foods changes according to cooking method, and it is higher in baked or oven-fried foods than in those prepared by steaming or simmering. Here, we examined the feasibility of crossover comparison tests for determining how different cooking methods (normal diet vs. low-AGE diet) affect insulin levels in non-diabetic Japanese subjects.MethodsFive adult men and women (age, 41 ± 7 years; body mass index (BMI), 21.7 ± 2.6 kg/m2) were enrolled. The following dietary regimen was used: days 1 - 3, control meal; day 4, test meal (normal diet vs. low-AGE diet); day 5, washout day; and day 6, test meal. On days 4 and 6, blood samples were collected before and at 2, 4, and 6 h after meals.ResultsBlood levels of N-(carboxymethyl) lysine (CML) increased with dietary intake, but the increase was similar for the normal diet and low-AGE diet groups. Mean plasma glucose, insulin, triglycerides (TG), and CML did not differ significantly between the two groups. The area under the curve (AUC) for insulin levels was lower in the low-AGE diet group (d = 0.8). The sample size calculated from the effect size of the insulin AUC change was 22.ConclusionsTwenty-two subjects may be needed to investigate the changes in clinical parameters attributable to cooking method in non-diabetic Japanese subjects.

Consumption of diets with low advanced glycation end products improves cardiometabolic parameters: meta-analysis of randomised controlled trials

Studies examining the effects of consumption of diets low in advanced glycation end products (AGEs) on cardiometabolic parameters are conflicting. Hence, we performed a meta-analysis to determine the effect of low AGE diets in reducing cardiometabolic risk factors. Seventeen randomised controlled trials comprising 560 participants were included. Meta-analyses using random effects models were used to analyse the data. Low AGE diets decreased insulin resistance (mean difference [MD] −1.3, 95% CI −2.3, −0.2), total cholesterol (MD −8.5 mg/dl, 95% CI −9.5, −7.4) and low-density lipoprotein (MD −2.4 mg/dl, 95% CI −3.4, −1.3). There were no changes in weight, fasting glucose, 2-h glucose and insulin, haemoglobin A1c, high-density lipoprotein or blood pressure. In a subgroup of patients with type 2 diabetes, a decrease in fasting insulin (MD −7 µU/ml, 95% CI −11.5, −2.5) was observed. Tumour necrosis factor α, vascular cell adhesion molecule-1, 8-isoprostane, leptin, circulating AGEs and receptor for AGEs were reduced after consumption of low AGE diets with increased adiponectin and sirtuin-1. Our findings suggest that diets low in AGEs may be an effective strategy for improving cardiometabolic profiles in individuals with and without type 2 diabetes.

Disparity in the micronutrient content of diets high or low in advanced glycation end products (AGEs) does not explain changes in insulin sensitivity

We have previously shown that an isoenergetic low advanced glycation end products (AGEs) diet matched for macronutrient content improved insulin sensitivity compared to high AGE diet. Here, we evaluated the differences in micronutrient intake of these two dietary patterns and if they could explain differences in insulin sensitivity. Participants consumed the intervention diets each for 2 weeks with 4 weeks of habitual dietary intake (washout) in-between. Dietary analysis revealed that the high AGE diet contained greater levels of retinol equivalents (RE) (478.9 + 151.3 μg/day versus 329.0 + 170.0 μg/day; p < .006), vitamin A (806.3 + 223.5 (μg RE)/day versus 649.1 + 235.8 (μg RE)/day; p < .05) and thiamine (2.3 + 0.6 mg/day versus 1.6 + 0.4 mg/day; p = .014) compared to the low AGE diet. The changes in polyunsaturated fat, retinol, vitamin A and thiamine did not correlate with changes in insulin sensitivity (all p > .1) therefore are unlikely to explain observed changes in insulin sensitivity. (clinicaltrials.gov:NCT00422253).

Dietary Advanced Glycation End Products and Risk Factors for Chronic Disease: A Systematic Review of Randomised Controlled Trials.

Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic reviews indicate that consumption of dietary AGEs may promote inflammation, oxidative stress and insulin resistance. Experimental evidence indicates that dietary AGEs may also induce renal damage, however, this outcome has not been considered in previous systematic reviews. The purpose of this review was to examine the effect of consumption of a high AGE diet on biomarkers of chronic disease, including chronic kidney disease (CKD), in human randomized controlled trials (RCTs). Six databases (SCOPUS, CINHAL, EMBASE, Medline, Biological abstracts and Web of Science) were searched for randomised controlled dietary trials that compared high AGE intake to low AGE intake in adults with and without obesity, diabetes or CKD. Twelve dietary AGE interventions were identified with a total of 293 participants. A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all populations. A high AGE diet increased 8-isoprostanes in healthy adults, and vascular cell adhesion molecule-1 (VCAM-1) in patients with diabetes. Markers of CKD were not widely assessed. The evidence presented indicates that a high AGE diet may contribute to risk factors associated with chronic disease, such as inflammation and oxidative stress, however, due to a lack of high quality randomised trials, more research is required.

Reduction of serum advanced glycation end-products with a low calorie Mediterranean diet.

Dietary intake of advanced glycation end-products (AGEs) increases circulating and tissue levels of these substances, contributing to a state of increased oxidative stress and inflammation. A low dietary AGE intervention has been shown to reduce body AGE content. Mediterranean diets (MD) are theoretically considered low in AGEs, but the specific effects of a MD on AGEs serum levels has not been tested. Forty-seven overweight and obese premenopausal women underwent a three-month calorie restriction treatment (20 kcal/kg initial weight) with a Mediterranean-type diet that excluded wine intake. The adherence to the MD was assessed before and at the end of treatment using an on-line questionnaire, which scores from 0 to 14 (minimal to maximal adherence). Body composition, insulin resistance, lipoproteins and carboxymethyl-lisine (CML) serum levels were measured at both time periods. Serum CML was assessed through ELISA (enzyme-linked immunosorbent assay). Compliance to calorie restriction was assessed according to weight loss (< or > 5% initial weight). Mean body weight, body fat, waist circumference, total cholesterol, triglycerides and serum CML fell significantly, together with an increase in the Mediterranean score, although none of the patients reached the highest score. Significant changes in CML and insulin resistance were observed in 17 women classified as compliant to caloric restriction, but not in the 27 participants who were considered adherent to the MD (according to improvement of the Mediterranean Score). CML serum levels can be reduced through calorie restricted-Mediterranean-type diet. We could not reach a high enough MD score, so we cannot conclude whether the MD itself has an additive effect to caloric restriction.

Interrelationship of elevated serum Advanced Glycation End-product levels and malnutrition (Subjective Global Assessment) scores with the severity of retinopathy in type II diabetes

Hyperglycemia in diabetes causes endogenous formation of Advanced Glycation End-products (AGEs) which accumulate in various body parts including retina causing diabetic retinopathy. AGEs also originate from exogenous dietary sources contributing to the body's AGE pool. Currently, curing of diabetic retinopathy is mainly focused on medication, surgical or laser interventions and not much emphasis is given on preventing or halting its occurrence or advancement to more severe stages, nutritionally. Planning a 'low glycemic index-lowAGE' diet therapy for diabetic subjects can reduce endogenous and exogenous origin AGEs in the body and help in controlling retinopathy. Sound and accurate assessment of nutritional status is a crucial step for planning a therapeutic diet for this condition. As this aspect has not gained sufficient attention till now we are assessing the association of serum Advanced Glycation End-product (AGE) levels with the severity of diabetic retinopathy and for the first time estimating the nutritional status of subjects with this eye disorder for long term patient care. This was a tertiary care centre-based, case-control study involving sixty three consecutive cases with diabetes divided as 21 cases with diabetes but no retinopathy, 21 cases with non proliferative diabetic retinopathy (NPDR), 21 cases with proliferative diabetic retinopathy (PDR) along with 21 healthy controls. Serum AGE levels of all the cases and controls were evaluated by Enzyme Linked Immuno Sorbent Assay (ELISA) and nutritional status was assessed by anthropometric measurements and SGA scores. Serum AGE levels were found significantly elevated in PDR group when compared with no retinopathy (p<0.05) and control (p<0.001) group. Control group was also significantly different from (p<0.05) from NPDR group. Increase in SGA scores was statistically significant amongst the four study groups though other indices of nutritional status showed no definite trend with the increasing severity of retinopathy. Our study shows that serum AGE levels are potential risk markers of diabetic retinopathy and SGA can be used as a regular tool for the assessment of nutritional status of diabetic retinopathy subjects which will help planning a 'low glycemic index-low AGE' therapeutic diet for halting this morbidity.

Abstract 11598: Increased Advanced Glycation End-Products Accelerate the Progress of Left Ventricular Hypertrophy Under Condition of Elevated Oxidative Stress or Insulin Resistance in Patients With Hypertension

Background: Elevated oxidative stress or insulin resistance has been shown to promote the production of advanced glycation end-products (AGEs) in patients with hypertension (HT). Because AGEs enhance left ventricular hypertrophy (LVH) via the activation of nuclear factor-kappa B, it is considered that increased AGEs contribute to LVH in HT patients. The aim of this study was to investigate the effect of increased AGEs on LVH in them. Methods: Eighty five HT patients aged 65 ± 9 years were prospectively followed up for a year, whose blood pressure was controlled under 140/90mmHg. We assessed patients’ glucose and lipid metabolism and neurohumoral factors including plasma noradrenaline and renin activity as clinical characteristics. We measured serum malondialdehyde-modified LDL-cholesterol (MDA-LDL) and plasma pentosidine as parameters of oxidative stress and AGEs, respectively. Homeostasis model assessment ratio (HOMA-R), estimate glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) were assessed as parameters of insulin resistance, renal function and LVH, respectively. All parameters were assessed before and after one-year observation period. We examined the change in each parameter from baseline to the value measured after the observation period ([[Unable to Display Character: &amp;#8895;]]MDA-LDL, [[Unable to Display Character: &amp;#8895;]]pentosidine, [[Unable to Display Character: &amp;#8895;]]HOMA-R and [[Unable to Display Character: &amp;#8895;]]LVMI). We divided patients into two groups based on the median of baseline pentosidine: high AGEs and low AGEs groups. We compared baseline values between the two groups. We analyzed the relationships among [[Unable to Display Character: &amp;#8895;]]MDA-LDL, [[Unable to Display Character: &amp;#8895;]]HOMA-R, [[Unable to Display Character: &amp;#8895;]]Pentosidine and [[Unable to Display Character: &amp;#8895;]]LVMI, and performed stepwise multiple regression analysis using parameters of clinical characteristics and AGEs to detect the predictors for the LVH progress after one year. Results: Baseline LVMI was significantly higher in the high AGEs group than in the low AGEs group (P&lt;0.05). [[Unable to Display Character: &amp;#8895;]]Pentosidine was positively correlated with [[Unable to Display Character: &amp;#8895;]]MDA-LDL (r=0.34, P&lt;0.01),[[Unable to Display Character: &amp;#8895;]]HOMA-R (r=0.37, P&lt;0.01) and [[Unable to Display Character: &amp;#8895;]]LVMI (r=0.39, P&lt;0.05). Multiple regression analysis detected pentosidine as a significant independent predictor for the LVH progress (β=0.407, P=0.005) (R2=0.315). Conclusion: Increased AGEs accelerated the LVH progress under condition of elevated oxidative stress or insulin resistance in HT patients.

Markers of the progression of complications in patients with type 2 diabetes: a one-year longitudinal study.

Hyperglycemia induces tissue damage and complications by mechanisms that produce advanced glycation end-products (AGEs) and inflammation.To investigate the factors associated with the progression of complications in Type 2 diabetes patients.We recruited 157 patients (110 women and 47 men) with diabetes for more than 5 years who were non-smokers and did not have current infections or chronic diseases. Patients were grouped according to neuropathy, nephropathy, and retinopathy status: without (I), slight or moderate (II), and severe complications (III). We measured glucose, lipids and HbA1c, low molecular weight AGEs (LMW AGEs), high sensitivity C-reactive protein (CRP), TNF-α, IL-6, and malondialdehyde (MDA). Patients were re-evaluated 1 year later.Patients were 52.2±6.8 years old with 11.0±4.9 years since diagnosis. After 1 year, circulating AGEs increased (p<0.0001) and eGFR decreased (p<0.0007) in groups II and III. IL-6 and MDA decreased in groups I and II. CRP (p<0.029) and AGEs (p<0.0001) increased in group II. At baseline in group I, TNF-α levels were higher (p<0.002) in patients who later developed complications. In group II, TNF-α levels (p<0.015) and microalbuminuria (p<0.00004) were higher in patients whose complications progressed. Logistic regression analysis showed that complication progress was significantly associated with log(albuminuria) (p<0.004) and log(TNF-α) (p<0.008). In the total group, AGEs were associated with age (p<0.024) and HbA1c (p<0.026).Our results suggest that baseline TNF-α is an important predictor of complication progression in Type 2 diabetes patients. AGEs also increased during the deterioration of renal function after 1 year of follow-up observation.

Dietary advanced glycation end-products, its pulmonary receptor, and high mobility group box 1 in aspiration lung injury

BackgroundGastric aspiration is a significant cause of acute lung injury and acute respiratory distress syndrome. Environmental risk factors, such as a diet high in proinflammatory advanced glycation end-products (AGEs), may render some patients more susceptible to lung injury after aspiration. We hypothesized that high dietary AGEs increase its pulmonary receptor, RAGE, producing an amplified pulmonary inflammatory response in the presence of high mobility group box 1 (HMGB1), a RAGE ligand and an endogenous signal of epithelial cell injury after aspiration. Materials and methodsCD-1 mice were fed either a low AGE or high AGE diet for 4 wk. After aspiration injury with acidified small gastric particles, bronchoalveolar lavage and whole-lung tissue samples were collected at 5 min, 1 h, 5 h, and 24 h after injury. RAGE, soluble RAGE (sRAGE), HMGB1, cytokine and chemokine concentrations, albumin levels, neutrophil influx, and lung myeloperoxidase activity were measured. ResultsWe observed that high AGE-fed mice exhibited greater pulmonary RAGE levels before aspiration and increased bronchoalveolar lavage sRAGE levels after aspiration compared with low AGE-fed mice. Lavage HMGB1 levels rose immediately after aspiration, peaking at 1 h, and strongly correlated with sRAGE levels in both dietary groups. High AGE-fed mice demonstrated higher cytokine and chemokine levels with increased pulmonary myeloperoxidase activity over 24 h versus low AGE-fed mice. ConclusionsThis study indicates that high dietary AGEs can increase pulmonary RAGE, augmenting the inflammatory response to aspiration in the presence of endogenous damage signals such as HMGB1.

Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review

Chronic kidney disease (CKD), especially in its end stage, is marked by extremely high cardiovascular rates of morbidity and mortality; hemodialysis patients have a five-fold shorter life expectancy than healthy subjects of the same age. In CKD the metabolic products that accumulate in the body are so-called uremic toxins. These include advanced glycation end-products (AGE). AGE levels are markedly increased in CKD patients not only because of impaired excretion but also because of increased production. AGE formation has initially been described as a non-enzymatic reaction between proteins and glucose in the so-called Maillard reaction, but they are also more rapidly formed during oxidative stress and subsequent formation of reactive carbonyl compounds like (methyl)glyoxal. AGE accumulate in tissue where they cross-link with proteins, e.g., collagen, inducing tissue stiffening of blood vessels and skin. They may also interact with receptor of AGE (RAGE) and other receptors, which lead to activation of intracellular transduction mechanisms resulting in cytokine release and further tissue damage in CKD. The accumulation of AGE in the skin can be measured non-invasively using autofluorescence. The skin autofluorescence is a strong marker of cardiovascular mortality in CKD. The focus of this review is on the role of tissue and plasma AGE, and of skin autofluorescence as a proxy of tissue AGE accumulation, in the increase in cardiovascular disease in end stage renal disease (ESRD). This review will also present the possibility of reducing the AGE accumulation in ESRD patients using the following five methods: 1) use of low AGE peritoneal dialysis solutions; 2) use of advanced hemodialysis techniques; 3) use of AGE reducing drugs; 4) optimizing the nutrition of hemodialysis patients; and 5) renal transplantation.

Plasma glycation levels are associated with severity in sepsis

Advanced glycation end-products (AGE) have been involved in inflammatory diseases and may have an important role in the progression of symptoms. However, few studies have analysed the levels of glycated proteins in sepsis. In this study, we evaluated the levels of the well-known AGE (N(ε) -(carboxymethyl)lysine (CML) and N(ε) -(carboxyethyl)lysine (CEL)) in the plasma of septic patients. Plasma from 36 patients admitted to an adult intensive care unit and 6 healthy controls had the levels of CML/CEL measured by ELISA. The level of AGE in plasma decreased with the increase of severity (1·40±0·46 nmol/mg of protein in sepsis, 0·58±0·23 nmol/mg of protein in severe sepsis and 0·31±0·12 nmol/mg of protein in septic shock). Control plasma presented low AGE concentration (0·06±0·01 nmol/mg protein). Also, we found a decrease in plasma AGE in those patients that died at the end of 28 days follow-up (0·80±0·50 nmol/mg of protein in survivors vs. 0·31±0·10 nmol/mg of protein in nonsurvivors), being associated with the renal component of sequential organ failure assessment (SOFA) score. In the same line, there was a decrease in plasma AGE with the increase in SOFA. Our data demonstrate that plasma AGE levels are inversely associated with the severity of sepsis and may be associated with kidney dysfunction.

Fluorescent advanced glycation end-products (ages) detected by spectro-photofluorimetry, as a screening tool to detect diabetic microvascular complications

BACKGROUND: Advanced glycation end-products (AGEs) are one of the mechanisms related to diabetic vascular complications. However, since AGEs are multiple and heterogeneous moieties, there is no universally accepted method to measure them for clinical purposes. The aim of this work was to study the utility of a simple fluorimetric assay as predictor of complications. METHODS: Blood samples from 102 type 2 diabetic patients were obtained to assess glucose, glycosylated haemoglobin, creatinine, lipoproteins and C Reactive Protein (CRP), fluorescent AGES by spectrophotofluorimetry and non-fluorescent AGEs by measurement of N(ε)-carboxymethyl-Lysine (CML) using an ELISA kit in a subsample of 82 patients. Urinary fluorescent AGEs, albumin and creatinine were also measured in a morning urine sample. Microvascular complications were studied by ophthalmologic examination, albuminuria and peripheral nerve conduction velocity. RESULTS: Patients without microvascular complications had significantly lower levels of both serum and urinary AGEs. CML was associated with retinopathy. Multiple regression analysis confirmed that AGEs, length of diabetes and glycosylated haemoglobin were all variables associated with diabetic complications, in this sample. CONCLUSIONS: A simple fluorimetric assay to measure low molecular weight fluorescent AGEs, and CML could be employed as screening tools to predict diabetic complications, at a primary care setting. AGEs should probably be considered as another therapeutic target in diabetes management.

Association of dietary AGEs with circulating AGEs, glycated LDL, IL-1α and MCP-1 levels in type 2 diabetic patients

The association of dietary advanced glycation endproducts (AGEs) intake with the oxidative and inflammatory status in type 2 diabetic patients was examined. Seventy-four healthy controls, 50 low AGEs intake and 68 high AGEs intake type 2 diabetic patients were requested to complete a 7-day dietary record. Blood levels of several oxidative and inflammatory biomarkers were determined. Diabetic patients with high AGEs intake had significantly elevated plasma levels of AGEs, HbA1c, low-density lipoprotein (LDL), LDL-cholesterol and glycated LDL than low AGEs intake patients and controls (P<0.05). These high AGEs intake patients also had significantly increased plasma levels of 8-isoprostane, interleukin (IL)-1α, tumor necrosis factor-α, monocyte chemoattractant protein (MCP)-1 and lower superoxide dismutase (SOD) activity than low AGEs intake patients (P<0.05). Correlation coefficients of dietary AGEs versus plasma AGEs, HbA1c, 8-isoprostane, IL-1α and MCP-1 were >0.6; but the correlation coefficient of dietary AGEs versus plasma SOD activity was <-0.6. Increasing dietary AGEs intake might enrich circulating AGE level and contribute to oxidative and inflammatory progression under diabetic condition. The circulating 8-isoprostane, IL-1α and MCP-1 levels and SOD activity might be appropriate biomarkers used to evaluate dietary AGEs-associated oxidative and inflammatory stress.