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Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases.Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status.Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 +/- 11.77 years, mean +/- SD) and had significantly lower SAF (1.90 +/- 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 +/- 12.07 years; SAF: 2.27 +/- 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (beta= -0.002, 95% confidence interval (95%CI): -0.002 to -0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (beta= 3.2 x 10(-5), 95%CI: 0.000-0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (beta= 4.2 x 10(-4), 95%CI: 0.000-0.001, p < 0.001), but this association was not found in the chronic disease population (beta = -3.2 x 10(-4), 95%CI: -0.001 to 0.000, p = 0.347).Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.Objectives: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.Methods: In 2566 individuals of the population-based Maastricht Study (age: 60 +/- 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in> 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using theAGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (beta: 0.08; 95% CI: 0.02, 0.13) and SAF (beta: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (beta: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Background and aims: This 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 results: We included 370 Hoorn Study participants (aged 66.4 +/- 6.1, 47% women). Serum protein-bound AGEs [N-epsilon-(carboxymethyl)lysine, N-epsilon-(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 [N-epsilon-(carboxymethyl)lysine and N-epsilon-(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 N-epsilon-(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)%].Conclusion: Overall 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. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University.

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, Nε‐[carboxymethyl]lysine (CML), Nε‐[1‐carboxyethyl]lysine (CEL) and Nδ‐[5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl]‐ornithine (MG‐H1), was estimated using country‐specific dietary questionnaires linked to an AGEs database. Cause‐specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow‐up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR‐CML = 0.87, 95% CI: 0.76‐0.99, HR‐CEL = 0.84, 95% CI: 0.74‐0.96 and HR‐MH‐G1 = 0.84, 95% CI: 0.74‐0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR‐CML = 1.28, 95% CI: 1.05‐1.56, HR‐CEL = 1.17; 95% CI: 0.96‐1.40, HR‐MH‐G1 = 1.27, 95% CI: 1.06‐1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer., What's new? Advanced glycation endproducts (AGEs) are proteins or lipids with sugars added to them, and they can form in foods during cooking. They have pro‐inflammatory and pro‐oxidative properties in the body. These authors investigated whether dietary consumption of AGEs affect risk of liver cancer, using the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants filled out food questionnaires to determine AGE consumption. Higher intakes of AGEs were associated with reduced risk of hepatocellular carcinoma (HCC) and increased risk of gallbladder cancer. However, it's still not entirely clear how much AGEs in the diet contribute to circulating AGE levels.

Chronic kidney disease (CKD) promotes development of cardiac abnormalities and is highly prevalent in patients with heart failure, particularly in those with preserved ejection fraction. CKD is associated with endothelial dysfunction, however, whether CKD can induce impairment of endothelium-to-cardiomyocyte crosstalk leading to impairment of cardiomyocyte function is not known. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, reduced cardiovascular events in diabetic patients with or without CKD, suggesting its potential as a new treatment for heart failure with preserved ejection fraction. We hypothesized that uremic serum from patients with CKD would impair endothelial control of cardiomyocyte relaxation and contraction, and that empagliflozin would protect against this effect. Using a co-culture system of human cardiac microvascular endothelial cells with adult rat ventricular cardiomyocytes to measure cardiomyocyte relaxation and contraction, we showed that serum from patients with CKD impaired endothelial enhancement of cardiomyocyte function which was rescued by empagliflozin. Exposure to uremic serum reduced human cardiac microvascular endothelial cell nitric oxide bioavailability, and increased mitochondrial reactive oxygen species and 3-nitrotyrosine levels, indicating nitric oxide scavenging by reactive oxygen species. Empagliflozin attenuated uremic serum-induced generation of endothelial mitochondrial reactive oxygen species, leading to restoration of nitric oxide production and endothelium-mediated enhancement of nitric oxide levels in cardiomyocytes, an effect largely independent of sodium-hydrogen exchanger-1. Thus, empagliflozin restores the beneficial effect of cardiac microvascular endothelial cells on cardiomyocyte function by reducing mitochondrial oxidative damage, leading to reduced reactive oxygen species accumulation and increased endothelial nitric oxide bioavailability.

Glycotoxins termed as advanced glycation endproducts (AGEs) are made endogenously and exogenously. Maillard reaction is a chemical non-enzymatic process, between sugars and a free amino acid group of nucleic acids, proteins, and lipids which happens exogenously when handled with high temperature for a prolonged period and in a dry environment, resulting in glycotoxins (AGEs) formations. This reaction is responsible for the taste, color, and smell of food. Glycotoxins derived from food are absorbed in the intestine and store in cells and tissues. Also, glycotoxins are derived exogenously from smoking. While endogenous glycotoxins are generated by normal body physiology. Obesity and insulin resistance may induce glycotoxins (AGEs) accumulation. The objective of this study was to evaluate the relationship between glycotoxins (AGEs) and obesity. 66 infertile females who were undergoing intracytoplasmic sperm injection ICSI. These females were classified into three groups according to their body mass index. On the day of ova pick up the collect serum and follicular fluid for subsequent measurement of glycotoxins (AGEs) by ELISA kits. there was a significant difference in the concentration of glycotoxins in follicular fluid and serum between the three ICSI groups of patients. As well as there was a significant difference in the concentration of glycotoxins (AGEs) in follicular fluid and serum in the same ICSI groups of patients. there is a significant positive relation between glycotoxins (AGEs) and increase BMI.

Advanced glycation endproducts (AGE) are a group of complex and heterogeneous molecules, sharing some common characteristics such as covalent cross-link formation among proteins, the effect of transforming the colour of food products into yellow-brown colours and fluorescence formation. AGE are linked to many diseases including diabetes, renal diseases, CVD, liver diseases, neuro-degenerative and eye disorders, female reproductive dysfunction, and even cancer. AGE are formed endogenously but are also provided from exogenous sources including diet and tobacco. Western diet, rich in processed and/or heat-treated foods, fat and sugar, increases the exposure to AGE. The foods that contain high levels of fat and protein are generally rich in terms of AGE, and are also prone to AGE formation during cooking compared with carbohydrate-rich foods such as vegetables, fruits, legumes and whole grains. The present article aimed to review the literature about the effects of different cooking methods and conditions on the AGE content of food and AGE formation mechanisms using a comprehensive approach.

SARS-CoV-2 started spreading toward the end of 2019 causing COVID-19, a disease that reached pandemic proportions among the human population within months. The reasons for the spectrum of differences in the severity of the disease across the population, and in particular why the disease affects more severely the aging population and those with specific preconditions are unclear. We developed machine learning models to mine 240,000 scientific articles openly accessible in the CORD-19 database, and constructed knowledge graphs to synthesize the extracted information and navigate the collective knowledge in an attempt to search for a potential common underlying reason for disease severity. The machine-driven framework we developed repeatedly pointed to elevated blood glucose as a key facilitator in the progression of COVID-19. Indeed, when we systematically retraced the steps of the SARS-CoV-2 infection, we found evidence linking elevated glucose to each major step of the life-cycle of the virus, progression of the disease, and presentation of symptoms. Specifically, elevations of glucose provide ideal conditions for the virus to evade and weaken the first level of the immune defense system in the lungs, gain access to deep alveolar cells, bind to the ACE2 receptor and enter the pulmonary cells, accelerate replication of the virus within cells increasing cell death and inducing an pulmonary inflammatory response, which overwhelms an already weakened innate immune system to trigger an avalanche of systemic infections, inflammation and cell damage, a cytokine storm and thrombotic events. We tested the feasibility of the hypothesis by manually reviewing the literature referenced by the machine-generated synthesis, reconstructing atomistically the virus at the surface of the pulmonary airways, and performing quantitative computational modeling of the effects of glucose levels on the infection process. We conclude that elevation in glucose levels can facilitate the progression of the disease through multiple mechanisms and can explain much of the differences in disease severity seen across the population. The study provides diagnostic considerations, new areas of research and potential treatments, and cautions on treatment strategies and critical care conditions that induce elevations in blood glucose levels., Graphical Abstract Most of the patients at risk of severe COVID-19, present with high blood glucose levels or dysregulated glycemia. Subsequent increased concentrations of glucose in the ASL and intracellularly, provide ideal conditions for SARS-CoV-2 to evade the innate defence of the lungs and replicate in the pulmonary cells. High blood glucose also facilitates the hyper-inflammation observed in the cytokine storm. The subsequent high viral load (1) correlates with SARS-CoV-2 specific inactivation of ACE2 and increased concentration of AngII, that aggravates the dysregulation of the glycemic control in a vicious circle of viral infection (2). Finally, the combination of high blood glucose and overproduction of AngII (3) leads to the phenomenon involved in the complications observed in severe cases such as multi-organ failures and thrombotic events.

The aim of our work was to test whether thymosin beta 4 protected endothelial progenitor cells against apoptosis induced by advanced glycation endproducts and investigate the underlying mechanism. Treatment with thymosin beta 4 or transfection with microRNA-34a inhibitor enhanced cell viability, reduced apoptosis, abated oxidative stress, and attenuated mitochondrial dysfunction in endothelial progenitor cells exposed to advanced glycation endproducts. Incubation with advanced glycation endproducts led to increased levels of microRNA-34a, which was attenuated by treatment with thymosin beta 4. Transfection with microRNA-34a reversed the beneficial effect of thymosin beta 4 against injuries induced by advanced glycation endproducts. The microRNA-34a could directly bind to the 3′UTRs of the mRNA of B-cell lymphoma 2, and thymosin beta 4 treatment upregulated B-cell lymphoma 2 expression in endothelial progenitor cells exposed to advanced glycation endproducts. More importantly, knockdown of B-cell lymphoma 2 abolished the protection of thymosin beta 4 and microRNA-34a inhibitor against advanced glycation endproducts. In conclusion, inhibition of microRNA-34a mediated protection of thymosin beta 4 in endothelial progenitor cells against advanced glycation endproducts by targeting B-cell lymphoma 2, which was helpful for understanding the therapeutic potential of thymosin beta 4 for diabetic patients.

Background: Advanced glycation endproducts (AGEs) and their precursors (dicarbonyls) are associated with the progression of diseases such as diabetes and cardiovascular disease. Plasma concentrations of dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) are increased after an oral glucose load indicating that consumption of diets high in carbo hydrates may induce the endogenous formation of dicarbonyls and AGEs.Objective: To examine the associations of dietary glycemic index (GI) and glycemic load (GL) with concentrations of dicarbonyls and AGEs in plasma and urine.Methods: Cross-sectional analyses were performed in a human observational cohort [Cohort on Diabetes and Atherosclerosis Maastricht (CODAM), n = 494, 59 +/- 7 y, 25% type 2 diabetes]. GI and GL were derived from FFQs. Dicarbonyls and AGEs were measured in the fasting state by ultra-performance liquid chromatography-tandem MS. MGO, GO, and 3-DG and protein-bound N-epsilon-(carboxymethyl)lysine (CML), N-epsilon-(1-carboxyethyl)lysine (CEL), and pentosidine were measured in plasma. Free forms of CML, CEL, and N-delta-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured in both plasma and urine. Multiple linear regression was performed with dicarbonyls and AGEs as dependent variables, and dietary GI or GL as main independent variables (all standardized). Models were adjusted for health and lifestyle factors, dietary factors, and reciprocally for GI and GL. As this was an explorative study, we did not adjust for multiple testing.Results: GI was not associated with any of the dicarbonyls or AGEs. GL was positively associated with free urinary MG-H1 (beta = 0.34; 95% CI: 0.12, 0.55). Furthermore, GL was positively associated with free plasma MG-H1 and free urinary CML (beta = 0.23; 95% CI: 0.02, 0.43; and beta = 0.28; 95% CI: 0.06, 0.50), but these associations were not independent of dietary AGE intake.Conclusions: A habitual diet higher in GL is associated with higher concentrations of free urinary MG-H1. This urinary AGE is most likely a reflection of AGE accumulation and degradation in tissues, where they may be involved in tissue dysfunction.

Background: Methylglyoxal (MGO) is the most potent precursor of advanced glycation end products (AGEs). MGO and AGEs have been associated with diabetes, its complications, and other age-related diseases. Experimental studies have shown that the flavonoids quercetin and epicatechin are able to scavenge MGO and lower AGE formation.Objective: Data on the effects of these flavonoids on MGO and AGE concentrations in humans are not yet available. We therefore investigated the effect of quercetin and epicatechin on the concentrations of MGO and AGEs in a post hoc analysis.Methods: Thirty-seven apparently healthy, nonsmoking adults with a systolic blood pressure between 125 and 160 mm Hg at screening were included in a randomized, double-blind, placebo-controlled crossover trial. Participants ingested (-)-epicatechin (100 mg/d), quercetin 3-glucoside (160 mg/d), or placebo capsules for periods of 4 wk separated by 4-wk washout periods. Fasting blood samples were collected at the start and end of each intervention period. Liquid chromatography-tandem mass spectrometry was used to determine plasma concentrations of the dicarbonyl compounds MGO, glyoxal (GO), and 3-deoxyglucosone (3-DG) and free and protein-bound AGEs. Gene expression of glyoxalase 1 (GLO1), the enzyme involved in the degradation of MGO, was determined by either microarray or quantitative reverse transcriptase-polymerase chain reaction.Results: The treatment effect (Delta treatment - Delta placebo) of quercetin on MGO was -40.2 nmol/L (95% CI: -73.6, -6.8 nmol/L; P = 0.019), a decrease of 11% from baseline values, whereas GO, 3-DG, and free and protein-bound AGEs did not change significantly. Epicatechin did not affect the concentrations of dicarbonyls and free and protein-bound AGEs. We did not find a significant change in expression of GLO1.Conclusions: In apparently healthy (pre)hypertensive men and women, quercetin but not epicatechin decreased plasma MGO concentrations. Quercetin may potentially form a new treatment strategy for diseases in which MGO plays a pivotal role.

Glyoxalase 1 (Glo1) is the rate-limiting enzyme in the detoxification of methylglyoxal (MGO) into D-lactate. MGO is a major precursor of advanced glycation endproducts (AGEs), and both are associated with development of age-related diseases. Since genetic variation in GLO1 may alter the expression and/or the activity of Glo1, we examined the association of nine SNPs in GLO1 with Glo1 expression and markers of MGO stress (MGO in fasting plasma and after an oral glucose tolerance test, D-lactate in fasting plasma and urine, and MGO-derived AGEs CEL and MG-H1 in fasting plasma and urine). We used data of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM, n = 546, 60 ± 7 y, 25% type 2 diabetes). Outcomes were compared across genotypes using linear regression, adjusted for age, sex, and glucose metabolism status. We found that SNP4 (rs13199033) was associated with Glo1 expression (AA as reference, standardized beta AT = −0.29, p = 0.02 and TT = −0.39, p = 0.3). Similarly, SNP13 (rs3799703) was associated with Glo1 expression (GG as reference, standardized beta AG = 0.17, p = 0.14 and AA = 0.36, p = 0.005). After correction for multiple testing these associations were not significant. For the other SNPs, we observed no consistent associations over the different genotypes. Thus, polymorphisms of GLO1 were not associated with Glo1 expression or markers of MGO stress, suggesting that these SNPs are not functional, although activity/expression might be altered in other tissues.

BACKGROUND: In recent years, American Diabetes Association started to strongly advocate the Mediterranean diet (MD) over other diets in patients with diabetes mellitus (DM) because of its beneficial effects on glycemic control and cardiovascular (CV) risk factors. Tissue levels of advanced glycation endproducts (AGEs) emerged as an indicator of CV risk in DM. Skin biopsy being invasive, the use of AGE Reader has been shown to reflect tissue AGEs reliably. AIM: To examine the association between adherence to MD and AGEs in patients with DM type II. METHODS: This cross-sectional study was conducted on 273 patients with DM type II. A survey questionnaire was composed of 3 separate sections. The first part of the questionnaire included general data and the habits of the participants. The second part aimed to assess the basic parameters of participants’ diseases and associated conditions. The third part of the questionnaire was the Croatian version of the 14- item MD service score (MDSS). AGEs levels and associated CV risk were measured using AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). RESULTS: A total of 27 (9.9%) patients fulfilled criteria for adherence to MD, with a median score of 8.0 (6.0-10.0). Patients with none/limited CV risk had significantly higher percentage of MD adherence in comparison to patients with increased/definite CV risk (15.2% vs 6.9%, P = 0.028), as well as better adherence to guidelines for nuts (23.2% vs 12.6%, P = 0.023) and legumes (40.4% vs 25.9%, P = 0.013) consumption. Higher number of patients with glycated hemoglobin (HbA1c) < 7% adhered to MD when compared to patients with HbA1c > 7% (14.9% vs 7.3%, P = 0.045). Moreover, those patients followed the MDSS guidelines for eggs (33.0% vs 46.8%, P = 0.025) and wine (15.6% vs 29.8%, P = 0.006) consumption more frequently. MDSS score had significant positive correlation with disease duration (r = 0.179, P = 0.003) and negative correlation with body mass index (BMI) values (r = -0.159, P = 0.008). In the multiple linear regression model, BMI (β ± SE, -0.09 ± 0.04, P = 0.037) and disease duration (β ± SE, 0.07 ± 0.02, P < 0.001) remained significant independent correlates of the MDSS score. Patients with HbA1c > 7% think that educational programs on nutrition would be useful for patients in significantly more cases than patients with HbA1c < 7% (98.9% vs 92.6%, P = 0.009). CONCLUSION: Although adherence to MD was very low among people with diabetes, we demonstrated that adherence to MD is greater in patients with lower CV risk, longer disease duration, and well- controlled glycaemia.

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo. Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80–85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially. Results: Glyoxalase-1 mRNA expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (P Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention.

OBJECTIVE Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity, and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI. RESEARCH DESIGN AND METHODS We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography–tandem mass spectrometry at baseline in 160 patients (64.8 ± 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes (n = 86, comprising n = 53 deaths and n = 49 amputations [first event counted]) over the 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker. RESULTS Higher plasma MGO levels were associated with more adverse outcomes (relative risk 1.44; 95% CI 1.11–1.86) and amputations separately (1.55; 1.13–2.21). We observed a similar but weaker trend for mortality (1.28; 0.93–1.77). The MGO-derived AGE Nε-(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00–2.15) and amputations (1.71; 1.04–2.79). d-Lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells. CONCLUSIONS Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.

Aims Advanced glycation endproducts (AGEs) are sugar modified adducts which arise during non-enzymatic glycoxidative stress. These compounds may become systemically elevated in disease states, and accumulate in tissue, especially on long-lived proteins. AGEs have been implicated in various acute, and chronic diseases, stressing the need for reliable and comprehensive measuring techniques. Measurement of AGEs in tissue such as skin requires skin biopsies, which is an invasive procedure. The AGE Reader has been developed to assess skin autofluorescence (SAF) non-invasively by the fluorescent properties of several AGEs. Results/Conclusion Various studies have shown that SAF is a useful marker of disease processes associated with oxidative stress. It is prospectively associated with development of cardiovascular events in patients with diabetes, renal or cardiovascular disease, and it predicts diabetes, cardiovascular disease and mortality in the general population. However, when measuring SAF in individual subjects, several factors may limit the reliability of the measurement, and hamper its use as a systemic biomarker for AGEs. These include endogenous factors present in the skin that absorb emission light such as melanin in dark-skinned subjects, but also factors that lead to temporal changes in SAF such as acute diseases and strenuous physical exercise associated with glycoxidative stress. Also, exogenous factors could potentially influence SAF levels inadvertently such as nutrition, and for example the application of skin care products. This review will give an overview of the AGE Reader functionality and the intrinsic, and exogenous factors which potentially influence the SAF assessment in individual subjects.

Background End-stage renal disease (ESRD) is strongly associated with cardiovascular disease (CVD) risk. Advanced glycation endproducts (AGEs) and dicarbonyls, major precursors of AGEs, may contribute to the pathophysiology of CVD in ESRD. However, detailed data on the courses of AGEs and dicarbonyls during the transition of ESRD patients to renal replacement therapy are lacking. Methods We quantified an extensive panel of free and protein-bound serum AGEs [N∈-(carboxymethyl)lysine (CML), N∈-(carboxyethyl)lysine (CEL), Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)], serum dicarbonyls [glyoxal (GO), methylglyoxal (MGO), 3-deoxyglucosone (3-DG)] and tissue AGE accumulation [estimated by skin autofluorescence (SAF)] in a combined cross-sectional and longitudinal observational study of patients with ESRD transitioning to dialysis or kidney transplantation (KTx), prevalent dialysis patients and healthy controls. Cross-sectional comparisons were performed with linear regression analyses, and courses following renal replacement therapy were analysed with linear mixed models. Results Free and protein-bound AGEs, dicarbonyls and SAF were higher in chronic kidney disease (CKD) Stage 5 non-dialysis (CKD 5-ND; n = 52) and CKD Stage 5 dialysis (CKD 5-D; n = 35) than in controls (n = 42). In addition, free AGEs, protein-bound CML, GO and SAF were even higher in CKD 5-D than in CKD5-ND. Similarly, following dialysis initiation (n = 43) free and protein-bound AGEs, and GO increased, whereas SAF remained similar. In contrast, following KTx (n = 21), free and protein-bound AGEs and dicarbonyls, but not SAF, markedly declined. Conclusions AGEs and dicarbonyls accumulate in uraemia, which is even exaggerated by dialysis initiation. In contrast, KTx markedly reduces AGEs and dicarbonyls. Given their associations with CVD risk in high-risk populations, lowering AGE and dicarbonyl levels may be valuable.

The chaperone activity of α-crystallin is important for maintaining the transparency of the human lens. αB-crystallin (αBC) is a long-lived protein in the lens that accumulates chemical modifications during aging. The formation of advanced glycation end products (AGEs) through glycation is one such modification. αBC is a small heat shock protein that exhibits chaperone activity. We have previously shown that αBC-client protein complexes can undergo AGE-mediated interprotein cross-linking. Here, we demonstrate that short-term (1 h) exposure to elevated temperatures and methylglyoxal (MGO) during the chaperoning of client proteins by αBC promotes AGE-mediated interprotein cross-linking. Liquid chromatography/mass spectrometry (LC-MS/MS) analyses revealed the rapid formation of AGEs by MGO. Interestingly, we found that despite protein cross-linking, the chaperone activity of αBC increased during the transient elevation of temperature in the presence of MGO. Together, these results imply that transient and subtle elevation of temperature in the lens of the eye can promote protein cross-linking through AGEs, and if this phenomenon recurs over a period of many years, it could lead to early onset of presbyopia and age-related cataracts.

Background The association between coronary artery disease (CAD) and diabetes mellitus (DM) is strong but the physiologic mechanisms responsible for this association remain unclear. Patients with DM exhibit high circulating levels of glycated proteins and lipoproteins called advanced glycation end products (AGEs) which have been implicated in the development of oxidative damage to vascular endothelium. We examined the relationships between the presence and extent of CAD and AGEs in patients undergoing elective coronary artery catheterization in an urban teaching hospital. Methods Patients with possible CAD (n = 364) were recruited prior to elective cardiac catheterization (52% male, 48% diabetic). Regression and correlation analyses were used to examine the relationship between serum AGE concentrations, soluble AGE receptor (sRAGE) concentration, HbA1c, LDL and the presence of obstructive CAD along with the burden of CAD measured by SYNTAX and SYNTAX II scores. Results AGE and sRAGE levels did not significantly correlate with any of the studied coronary artery disease parameters. HbA1c showed positive correlation with both SYNTAX and SYNTAX II scores in patients with and without diabetes. Conclusion In this cross-sectional study of patients with possible CAD, serum AGEs and sRAGE concentrations did not correlate with SYNTAX or SYNTAX II scores regardless of diabetic status. HbA1C correlated positively with the SYNTAX and SYNTAX II scores in both diabetic and non-diabetic populations., Highlights • Serum AGE levels do not correlate with severity of CAD as measured by SYNTAX or SYNTAX II scores. • SYNTAX scores are correlated with HbA1C regardless of diabetes status. • Serum AGE levels do not correlate with LDL levels.

The prevalence of inflammatory bowel diseases (IBD) is increasing in the world. The introduction of the Western diet has been suggested as a potential explanation of increased prevalence. The Western diet includes highly processed food products, and often include thermal treatment. During thermal treatment, the Maillard reaction can occur, leading to the formation of dietary advanced glycation endproducts (dAGEs). In this review, different biological effects of dAGEs are discussed, including their digestion, absorption, formation, and degradation in the gastrointestinal tract, with an emphasis on their pro-inflammatory effects. In addition, potential mechanisms in the inflammatory effects of dAGEs are discussed. This review also specifically elaborates on the involvement of the effects of dAGEs in IBD and focuses on evidence regarding the involvement of dAGEs in the symptoms of IBD. Finally, knowledge gaps that still need to be filled are identified.

Patients with Type 2 Diabetes (T2D) are at increased fracture risk despite having relatively normal or even increased BMD by DXA. The critical aspect of bone quality deterioration in T2D patients could explain this clinically important discrepancy. Material composition is a component of bone quality that has emerged as a potential factor contributing to fragility fractures in T2D patients. However, there is sparse evidence regarding whether T2D patients have decreased bone material properties compared with non-diabetic controls. We hypothesized that increased production of advanced glycation endproducts (AGEs) has an important role in reducing bone material strength in patients with and without diabetes. Thus, we used the OsteoProbe®, a bone microindentation device that provides an index of cortical bone material properties (Bone Material Strength index – BMSi) in men with T2D age ≥ 50 yrs or postmenopausal women with T2D and nondiabetic controls. We also utilized a non-invasive measure of skin AGEs (AGE Reader®) to evaluate AGEs accumulation through skin autofluorescence. Linear regression models were used to assess group differences with and without adjusting for age, Body Mass Index (BMI), and sex. Relationships between variables were assessed using adjusted Pearson correlations. A total of 152 T2D patients (mean age 68.5 ±7.6 yrs.; 59.2% men; HbA1C=7.7 ±1.0%; mean diabetes duration 15.5 yrs.) and 105 non-diabetic controls (mean age 67.2±8.8 yrs.; 41.0% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was no difference in BMSi between T2DM and control subjects: unadjusted (p= 0.636); adjusted (p= 0.695). However, skin AGEs were negatively correlated with BMSi (r= -0.23, p

Increasing clinical and experimental evidence accumulated during the past few decades supports an important role for dietary advanced glycation endproducts (AGE) in the pathogenesis of many chronic non-infectious diseases, such as type 2 diabetes, CVD and others, that are reaching epidemic proportions in the Western world. Although AGE are compounds widely recognised as generated in excess in the body in diabetic patients, the potential importance of exogenous AGE, mostly of dietary origin, has been largely ignored in the general nutrition audience. In the present review we aim to describe dietary AGE, their mechanisms of formation and absorption into the body as well as their main mechanisms of action. We will present in detail current evidence of their potential role in the development of several chronic non-infectious clinical conditions, some general suggestions on how to restrict them in the diet and evidence regarding the potential benefits of lowering their consumption.

Stroke is the second leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Advanced glycation endproducts (AGEs) are known to be increased in several chronic diseases and induce inflammation and protein intercalation. The only drug approved for the treatment ischemic stroke is recombinant tissue plasminogen activator (r-TPA). The current study was designed to investigate the protective effect of benfotiamine (70 mg/kg/day), perindopril (2 mg/kg/day) and alagebrium (2 mg/kg/day) on experimentally-induced ischemic brain damage. All drugs were administered daily for one week before and 2 days after middle cerebral artery occlusion (MCAO). Benfotiamine, perindopril and alagebrium ameliorated the deleterious effects of MCAO as indicated by the improvement in the performance of the animals in initiation of walking test and improvement of the deteriorated brain histology. This was associated with normalization of the level of AGEs that was increased following MCAO. The result of the current study represent a new indication for benfotiamine, perindopril, alagebrium in the management of ischemic stroke.

Women with polycystic ovary syndrome (PCOS) have a considerable risk of metabolic dysfunction. This review aims to present contemporary knowledge on obesity, insulin resistance and PCOS with emphasis on the diagnostic and methodological challenges encountered in research and clinical practice. Variable diagnostic criteria for PCOS and associated phenotypes are frequently published. Targeted searches were conducted to identify all available data concerning the association of obesity and insulin resistance with PCOS up to September 2016. Articles were considered if they were peer reviewed, in English and included women with PCOS. Obesity is more prevalent in women with PCOS, but studies rarely reported accurate assessments of adiposity, nor split the study population by PCOS phenotypes. Many women with PCOS have insulin resistance, though there is considerable variation reported in part due to not distinguishing subgroups known to have an impact on insulin resistance as well as limited methodology to measure insulin resistance. Inflammatory markers are positively correlated with androgen levels, but detailed interactions need to be identified. Weight management is the primary therapy; specific advice to reduce the glycaemic load of the diet and reduce the intake of pro-inflammatory SFA and advanced glycation endproducts have provided promising results. It is important that women with PCOS are educated about their increased risk of metabolic complications in order to make timely and appropriate lifestyle modifications. Furthermore, well-designed robust studies are needed to evaluate the mechanisms behind the improvements observed with dietary interventions.

Purpose To determine if skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin is associated with AMD. Methods SIF was measured with the SCOUT DS skin fluorescence spectrometer in a cross-sectional cohort study of 969 persons aged 68 to 102 years from the 1181 who participated in the 25-year follow-up examination in the Beaver Dam Eye Study (BDES) in 2014 to 2016. The SCOUT DS skin fluorescence spectrometer uses five light-emitting diodes, centered at 375 nm to 456 nm. AMD was assessed by grading of digital color 45° stereoscopic fundus photographs of the macula using the Wisconsin Age-Related Maculopathy grading scheme. Analyses included logistic regression with generalized estimating equations to account for correlation between the eyes of a person. Results There were data for 1827 eyes for analyses. Early AMD was present in 22% and late AMD in 4% of the eyes. While adjusting for age, sex, smoking status, and history of cardiovascular disease, there were no significant associations of any SIF measure with any AMD or exudative AMD. SIF01 (odds ratio per 1 SD difference on the log scale, 95% confidence interval) (1.66, 1.00-2.74, P = 0.05) and SIF03 (1.81, 1.16-2.81, P = 0.008) were associated with geographic atrophy. Conclusions There was a suggestive relationship of two SIF measures, SIF01 and SIF03, using different correction factors from the excitation centered at 375 nm, with the prevalence of geographic atrophy in the BDES. Longitudinal follow-up is indicated to assess a temporal relationship.

Category: Diabetes Introduction/Purpose: Advanced glycation endproducts (AGEs) accumulate in tendon tissue in individuals with diabetes mellitus (DM). Although AGEs have been shown to impact tendon function by decreasing collagen sliding, this relationship has not been explored in humans with diabetes. Despite the prevalence of foot deformity in this population and implications of posterior tibialis dysfunction, the mechanical behavior of the posterior tibialis tendon has only been reported in a small (n=5), cadaveric study that did not report DM status. Therefore, the purpose of this study is to determine the effects of DM-associated AGEs accumulation on the mechanical properties of the posterior tibialis tendon. Methods: Posterior tibialis tendons were collected from individuals with and without DM undergoing lower extremity amputation. A 1-2 mm tendon transection was used for AGEs quantification. AGEs were quantified via fluorescence following papain digestion and hydrolyzation as described previously. Fluorescence was compared to a quinine standard to calculate AGEs content, which was normalized to sample wet weight. Tensile mechanical testing was completed with the remaining specimen (˜25 mm long). Tendon cross-sectional area was measured with a non-contact laser scanning device. Specimens were preloaded to 10 N and preconditioned for 10 cycles at 6% strain, subjected to stress-relaxation at 6% strain for 10 minutes, and loaded with a triangular waveform to a maximum of 10% strain at a rate of 1% strain per second. Individual values and group descriptive statistics are reported for AGEs content and mechanical testing. Relationships between AGEs content and various mechanical testing parameters were evaluated using Spearman correlation. Results: Six individuals (5 with DM, 4 male, mean(SD) age: 56(5)years) were included. AGEs content was increased in DM tendon (DM: 20.5(5.1), non-DM: 9.5 ng quinine/mg wet weight). Compared to non-DM tendon, DM tendons had larger cross-sectional area (DM: 44.3(4.9), non-DM: 11mm2). From stress relaxation, DM tendons had smaller peak (DM: 0.41(0.25), non-DM: 1.16 MPa) and equilibrium stress (DM: 0.23(0.13), non-DM: 0.83 MPa), and larger percent relaxation (DM: 46(6)%, non-DM: 29%)(Figure 1-A). DM tendons had decreased maximum stress at 10% strain (DM: 0.63(0.45), non-DM: 1.75 MPa), increased linear stiffness (DM: 35.2(27.6), non-DM: 19.2N/mm), and decreased linear modulus (DM: 8.5(7.0), non-DM: 20.1 MPa)(Figure 1-B, C) compared to non- DM tendon. Hysteresis (i.e., energy loss upon unloading) was higher in DM tendons (DM: 0.35(0.05), non-DM: 0.22), and positively correlated to AGEs (rho=0.943, p=0.005, Figure 1-D). Conclusion: Posterior tibialis tendons with DM exhibited increased AGEs content and altered mechanical properties. DM tendons were less stiff when accounting for cross-sectional area but had 2-4x the cross-sectional area of non-DM tendon, with inconsistent patterns in total tendon stiffness potentially attributable to several factors. DM tendons showed impaired energy storage and return, which was most strongly associated with AGEs. Non-DM samples were limited and the linear modulus was smaller than previously reported, however, all but one DM tendon had a modulus less than 50% of the non-DM sample. Future work will explore the mechanisms of AGEs-associated DM tendon impairments.

Objective: The aim of this research is to study skin autofluorescence and the associations between skin glycated proteins and clinical characteristics of healthy and unhealthy subjects for...

Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia, and astrocytes switch their metabolism toward glycolysis, resulting in the formation of alpha-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound Nd-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 +/- 11 vs. 154 +/- 21, p < 0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, alpha-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS. Special Research Fund UHasselt [12N31BOF] We would like to thank Marleen van Greevenbroek for her advice regarding the statistical analysis and Marjo van de Waarenburg and Bieke Broux for technical assistance.

This thesis investigates the role of saccharified proteins in multiple sclerosis (MS). In MS, the shell of the nerves in the brain is attacked by the immune system. Saccharified proteins can activate specific cells of the immune system. Our research shows that MS patients have high levels of saccharified proteins in their brains. This result has been confirmed with the use of a mouse model. It has also been shown that the consumption of a diet rich in saccharified proteins causes an accumulation of these saccharified proteins in the brain. The effect of lowering saccharified proteins will need to be investigated further.

AIM: The aim of the present study was to investigate whether skin autofluorescence would improve the Finnish Diabetes Risk Score (FINDRISC) in detecting undiagnosed diabetes in a large population-based cohort.METHODS: Included were participants from the Dutch LifeLines Cohort Study. Skin autofluorescence was assessed in an unselected subset of participants using the AGE Reader. After the exclusion of participants with previously diagnosed diabetes (n=1635), pregnant women (n=58) and those using corticosteroids (n=345), 79,248 subjects were eligible for analysis. Diabetes was defined as fasting plasma glucose ≥7.0mmol/L, non-fasting plasma glucose ≥11.1mmol/L or HbA1c ≥6.5% (48mmol/mol).RESULTS: Diabetes was detected in 1042 participants (aged 55±12 years; 54% male). Skin autofluorescence improved the area under the receiver operating characteristic (AUROC) curve of the FINDRISC model from 0.802 to 0.811 (P30%) in the intermediate (1% to CONCLUSION: Skin autofluorescence is a non-invasive tool that can be used to further improve the FINDRISC for diabetes detection. The new resultant model is especially useful for reclassifying people in the intermediate-risk categories, where additional blood glucose testing is needed to confirm the presence of diabetes.

Aims: Reactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown. Methods: Subjects with normal glucose metabolism (n = 1796; age: 57.9 ± 8.2 years; 43.3% men), prediabetes (n = 478; age: 61.6 ± 7.6 years; 54.0% men) and T2DM (n = 669; age: 63.0 ± 7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2 h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA 1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO. Results: Fasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥ 30 mg/24 h [fasting: 1.12 (95% CI: 0.97–1.29); post-OGTT: 1.19 (1.01–1.41)], eGFR < 60 mL/min/1.73 m 2 [fasting: 1.58 (95% CI: 1.38–1.82), post-OGTT: 1.57 (1.34–1.83)] and retinopathy [fasting: 1.59 (95% CI: 1.01–2.53), post-OGTT: 1.38 (0.77–2.48)]. No associations with prior CVD were found. Conclusion: Fasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.

Purpose Diabetes is accompanied by fundamental rearrangements in redox homeostasis. Hyperglycemia triggers the production of reactive oxygen and nitrogen species which contributes to tissue damage in various target organs. Proliferative diabetic retinopathy (PDR) is a common manifestation of diabetic complications but information on the possible role of reactive intermediates in this condition with special regard to the involvement of the vitreous in PDR-associated redox alterations is scarce. The aim of the study was to determine key parameters of redox homeostasis [advanced glycation endproducts (AGE); protein carbonyl and glutathione (GSH)] content in the vitreous in PDR patients. Methods The study population involved 10 diabetic patients undergoing surgery for complications of proliferative diabetic retinopathy and 8 control (non-diabetic) patients who were undergoing surgery for epiretinal membranes. Vitreal fluids were assayed for the above biochemical parameters. Results We found elevated levels of AGE in the vitreous of PDR patients (812.10 vs 491.69 ng AGE/mg protein). Extent of protein carbonylation was also higher in the samples of diabetic patients (2.08 vs 0.67 A/100 μg protein). The GSH content also increased in the vitreous of PDR patients as compared to the control group (4.54 vs 2.35 μmol/μg protein), respectively. Conclusion The study demonstrates that diabetes-associated redox alterations also reach the vitreous with the most prominent changes being increased protein carbonylation and increased antioxidant levels., Graphical abstract fx1, Highlights • Vitreal AGE levels are elevated in PDR patients. • Extent of protein carbonylation is higher in the vitreal samples of PDR patients. • The glutathione content is increased in the vitreous of PDR patients.

In nature, proteins, lipids, and nucleic acids can nonenzymatically react with sugars and sugar degradation products to give rise to a diverse range of modifications, known as advanced glycation endproducts (AGEs). These AGEs typically occur at lysine and arginine residues of long-lived proteins, such as collagen, and can modify the structure and function of the native protein. AGEs accumulate during the normal aging process, and AGE formation is dramatically accelerated with diabetes. AGEs have also been implicated in a wide range of debilitating conditions including cardiovascular, renal failure, and neurodegenerative diseases. Thus, there is an ongoing interest in studying the role of AGEs in different aspects of these disorders. Typically, glycated proteins are prepared using nonspecific in vitro incubation techniques. However, this method results in a complex mixture of products which is then employed without further purification. In order to determine the effect of individual AGEs in a peptide sequence, in this Account, we highlight our synthetic methods for site-specifically introducing five frequently occurring AGEs, namely, N

Objective: To investigate whether serum advanced glycation endproducts are associated with left ventricular systolic and diastolic function in participants with normal glucose metabolism, impaired glucose metabolism and type 2 diabetes mellitus. Methods: Participants from a cross-sectional, population-based study ( n = 280 with normal glucose metabolism, n = 171 with impaired glucose metabolism, n = 242 with type 2 diabetes mellitus) underwent echocardiography. Serum protein-bound advanced glycation endproducts [i.e. Nε-(carboxymethyl)lysine, pentosidine and Nε-(carboxyethyl)lysine] were measured. Linear regression analyses were used and stratified according to glucose metabolism status. Results: In normal glucose metabolism, higher Nε-(carboxymethyl)lysine and pentosidine levels were associated with worse diastolic function (left atrial volume index and left atrial volume × left ventricular mass index product term) and higher Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine levels with worse systolic function (ejection fraction). In impaired glucose metabolism, a similar pattern emerged, though less consistent. In type 2 diabetes mellitus, these associations were non-existent for diastolic function or even reversed for systolic function. Conclusion: This suggests that serum advanced glycation endproducts are associated with impaired left ventricular function in normal glucose metabolism, but that with deteriorating glucose metabolism status, serum advanced glycation endproducts may not mirror heart failure risk.

Glycation is important in the development of complications of diabetes mellitus and may have a central role in the well-described glycaemic memory effect in developing these complications. Skin fluorescence has emerged over the last decade as a non-invasive method for assessing accumulation of advanced glycation endproducts. Skin fluorescence is independently related to micro- and macrovascular complications in both type 1 and type 2 diabetes mellitus and is associated with mortality in type 2 diabetes. The relation between skin fluorescence and cardiovascular disease also extends to other conditions with increased tissue AGE levels, such as renal failure. Besides cardiovascular complications, skin fluorescence has been associated, more recently, with other prevalent conditions in diabetes, such as brain atrophy and depression. Furthermore, skin fluorescence is related to past long-term glycaemic control and clinical markers of cardiovascular disease. This review will discuss the technique of skin fluorescence, its validation as a marker of tissue AGE accumulation, and its use as a clinical tool for the prediction of long-term complications in diabetes mellitus.

Aims/hypothesis Dicarbonyl compounds are formed as byproducts of glycolysis and are key mediators of diabetic complications. However, evidence of postprandial α-dicarbonyl formation in humans is lacking, and interventions to reduce α-dicarbonyls have not yet been investigated. Therefore, we investigated postprandial α-dicarbonyl levels in obese women without and with type 2 diabetes. Furthermore, we evaluated whether a diet very low in energy (very low calorie diet [VLCD]) or Roux-en-Y gastric bypass (RYGB) reduces α-dicarbonyl stress in obese women with type 2 diabetes. Methods In lean (n = 12) and obese women without (n = 27) or with type 2 diabetes (n = 27), we measured the α-dicarbonyls, methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), and glucose in fasting and postprandial plasma samples obtained during a mixed meal test. Obese women with type 2 diabetes underwent either a VLCD or RYGB. Three weeks after the intervention, individuals underwent a second mixed meal test. Results Obese women with type 2 diabetes had higher fasting and particularly higher postprandial plasma α-dicarbonyl levels, compared with those without diabetes. After three weeks of a VLCD, postprandial α-dicarbonyl levels in diabetic women were significantly reduced (AUC MGO −14%, GO −16%, 3-DG −25%), mainly through reduction of fasting plasma α-dicarbonyls (MGO −13%, GO −13%, 3-DG −33%). Similar results were found after RYGB. Conclusions/interpretation This study shows that type 2 diabetes is characterised by increased fasting and postprandial plasma α-dicarbonyl stress, which can be reduced by improving glucose metabolism through a VLCD or RYGB. These data highlight the potential to reduce reactive α-dicarbonyls in obese individuals with type 2 diabetes. Trial registration: ClinicalTrials.gov NCT01167959 Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4009-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Summary Proteins in basement membrane (BM) are long‐lived and accumulate chemical modifications during aging; advanced glycation endproduct (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial‐to‐mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. We found age‐dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC‐MS/MS. The TGFβ2‐mediated upregulation of the mRNA levels (by qPCR) of EMT‐associated proteins was significantly enhanced in cells cultured on AGE‐modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2‐mediated α‐smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2‐mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes‐associated fibrosis.

Background/Aims: We have previously shown that advanced glycation-endproducts (AGEs) induced NFκB activation in differentiated mouse podocytes. This NFκB activation may contribute to the progression of renal disease and mediation of fibrosis by various mechanisms. This study was undertaken to test whether this detrimental response may be reversed by vitamin D3 or its analogue paricalcitol. Methods: Differentiated mouse podocytes were challenged with glycated bovine serum albumin (AGE-BSA), or non-glycated control BSA (in the presence or absence of various concentrations of vitamin D3 (decostriol, 1α,25-dihydroxyvitamin D3)) or its active analog paricalcitol. Quantitative mRNA expressions were measured by real-time PCR, whereas protein expressions were determined by Western blotting followed by densitometry. Cytoplasmic and nuclear protein expression of the NFκB subunit p65 (Rel A) were determined by Western blotting. Furthermore, the ratio of phosphorylated to non-phosphorylated IκB-α was measured using specific antibodies. Electrophoretic mobility shift assays and a capture ELISA assay were used to assess NFκB transactivation in vitro. In addition, NFκB transactivation was also monitored in HEK-NFκBIA reporter cells using live cell luminometry. Results: Podocytes expressed the receptor for vitamin D. The vitamins did not suppress receptor for AGEs (RAGE) expression; instead, they rather upregulated RAGE. Although vitamin D3 and paricalcitol partly and differentially modified some of the studied parameters, both hormones inhibited AGE-BSA-induced NFκB transactivation, presumably by various mechanisms including the upregulation of IκB-α protein, keeping NFκB sequestered in an inactive state in the cytoplasm. Conclusion: Vitamin D3 or its analog paricalcitol partly prevented AGE-mediated NFκB activation, an important feature of diabetic nephropathy (DN). Whether this in vitro finding is of clinical relevance to prevent/treat DN requires further studies.

Lifestyle choices have long been known to have a major role in the development or prevention of cancer. Diet, chronic stress, smoking, poverty, physical activity, and socioeconomic variables are recognized as significant factors in prevention of cancer. Increasingly, these behaviors are studied as variables that affect cancer survivorship and response to treatment as well. One general mechanism through which diet could affect cancer growth is through promoting or inhibiting the accumulation of advanced glycation endproducts. Advanced glycation endproducts (AGEs) are reactive metabolites produced as by-products of sugar metabolism and oxidative stress. Furthermore, among PCa patients, AGE accumulation is higher in blacks with African ancestry (AAs) than in European Americans (EAs). As AGEs appear to promote cancer survival and growth, interventions to limit their accumulation may be viewed as potential cancer therapeutic agents. Chitosan, a polysaccharide obtained from shellfish or mushrooms that is thought to be poorly absorbed, directly binds AGE-modified proteins in aqueous solutions. No studies to date have demonstrated that chitosan can reduce either serum or tissue levels of AGEs in humans with AGE-related diseases. The investigators are conducting a Phase 1, assay-guided trial of chitosan in patients with prostate cancer on ADT and propose that chitosan will act as an absorbent of pre-formed AGEs, preventing their absorption from the gut and thus reducing their levels in the body. This intervention produced an 80% reduction in the plasma level of carboxymethyl lysine (CML) AGE adducts and more remarkably there was also a reduction in tissue AGE levels as determined by skin autofluorescence. These data support the idea that chitosan could be an active AGE-reducing agent that is clinically tolerable. Plasma and stool bio-fluid specimens have been collected from the four patients enrolled in the clinical trial and will be assayed. As these mechanistic studies are ongoing, the result will document any systemic effects from the chitosan intervention on inflammation, bowel permeability and microbiome diversity. Citation Format: Shanora G Brown, Brandon Sutton, Taiwo Biotidara, Dave Turner, Robert Wilson, Michael Lilly. Mechanistic insights into phase 1b/2 study of chitosan for pharmacologic manipulation of AGE (advanced glycation endproducts) levels in prostate cancer patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D062.

Glyoxalase-1 (GLO1) is a ubiquitously expressed cytosolic protein which plays a role in the natural maintenance of cellular health and is abundantly expressed in human skeletal muscle. A consequence of reduced GLO1 protein expression is cellular dicarbonyl stress, which is elevated in obesity, insulin resistance and type 2 diabetes (T2DM). Both in vitro and pre-clinical models suggest dicarbonyl stress per se induces insulin resistance and is prevented by GLO1 overexpression, implicating a potential role for GLO1 therapy in insulin resistance and type 2 diabetes (T2DM). Recent work has identified the therapeutic potential of novel natural agents as a GLO1 inducer, which resulted in improved whole-body metabolism in obese adults. Given skeletal muscle is a major contributor to whole-body glucose, lipid, and protein metabolism, such GLO1 inducers may act, in part, through mechanisms in skeletal muscle. Currently, investigations examining the specificity of dicarbonyl stress and GLO1 biology in human skeletal muscle are lacking. Recent work from our lab indicates that dysregulation of GLO1 in skeletal muscle may underlie human insulin resistance and that exercise training may impart therapeutic benefits. This minireview will summarize the existing human literature examining skeletal muscle GLO1 and highlight the emerging therapeutic concepts for GLO1 gain-of-function in conditions such as insulin resistance and cardiometabolic disease.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). The immune response in MS patients leads to the infiltration of immune cells in the CNS and their subsequent activation. Immune cell activation induces a switch towards glycolysis. During glycolysis, the dicarbonyl product methylglyoxal (MGO) is produced. MGO is a glycating agent that can rapidly form advanced glycation endproducts (AGEs). In turn, AGEs are able to induce inflammatory responses. The glyoxalase system is the endogenous defense system of the body to reduce the burden of MGO thereby reducing AGE formation. This system consists of glyoxalase-1 and glyoxalase-2 which are able to detoxify MGO to D-lactate. We investigated whether AGE levels are induced in experimental autoimmune encephalitis (EAE), an inflammatory animal model of MS. Twenty seven days post EAE induction, MGO and AGE (Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1)) levels were significantly increased in the spinal cord of mice subjected to EAE. Yet, pyridoxamine treatment and glyoxalase-1 overexpression were unable to counteract AGE production during EAE and did not influence the clinical course of EAE. In conclusion, AGEs levels increase during EAE in the spinal cord, but AGE-modifying treatments do not inhibit EAE-induced AGE production and do not affect disease progression.

Limited joint mobility syndrome (LJMS) or diabetic cheiroarthropathy is a long term complication of diabetes mellitus. The diagnosis of LJMS is based on clinical features: progression of painless stiffness of hands and fingers, fixed flexion contractures of the small hand and foot joints, impairment of fine motion and impaired grip strength in the hands. As the syndrome progresses, it can also affect other joints. It is important to properly diagnose such a complication as LJMS. Moreover, it is important to diagnose LJMS because it is known that the presence of LJMS is associated with micro- and macrovascular complications of diabetes. Due to the lack of curative treatment options, the suggested method to prevent or decelerate the development of LJMS is improving or maintaining good glycemic control. Daily stretching excercises of joints aim to prevent or delay progression of joint stiffness, may reduce the risk of inadvertent falls and will add to maintain quality of life.

Types 1 and 2 diabetes are on the rise worldwide. Although the treatment of hyperglycemia has benefited from recent advances, aggressive efforts to maintain euglycemia may be fraught with risk, especially in older subjects or in subjects vulnerable to hypoglycemic unawareness. Hence, strategies to prevent and treat the complications of hyperglycemia are essential. In this review we summarize recent updates on the biology of the receptor for advanced glycation endproducts (RAGE) in the pathogenesis of both micro- and macrovascular complications of diabetes, insights from the study of mouse models of obesity and diabetic complications, and from associative studies in human subjects. The study of the mechanisms and consequences of the interaction of the RAGE cytoplasmic domain with the formin, mDia1, in RAGE signal transduction, will be discussed. Lastly, we review the “state-of-the-art” on RAGE-directed therapeutics. Tackling RAGE/mDia1 may identify a novel class of therapeutics preventing diabetes and its complications.

The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

For a whole century, the Maillard reaction and its products (MRP) have been topics of interest in the field of food science and technology. In the past recent decades the interest in the chemistry and biological activities of such compounds migrated to the biomedical field. Glycation occurs in living organisms and is pronounced in individuals with diabetes or renal impairment who display higher levels of circulating Advanced Glycation Endproducts (AGEs) than healthy individuals. AGEs bind to specific receptors (RAGEs) triggering inflammatory and oxidative processes implicated in the pathogeny of several diseases processes. There are evidence that dietary PRM diet increases the endogenous pool of AGEs, and AGEs enhance pathological conditions (e.g. insulin resistance, vascular impairment). Whether dietary MRP impacts health is, therefore, a central question. This article presents a panorama and addresses hot points that need to be discussed interdisciplinary, in future researches on this subject.

Reduction in the deposition of amyloid β (Aβ) has been the primary target for Alzheimer's disease (AD) therapeutics recently, but in clinical trials this approach has generally been unsuccessful. A common feature of AD pathology is a complex inflammatory component that could be a target for treatment. One feature of this inflammation has been the involvement of the receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation-endproduct-modified proteins as well as lipids and Aβ, which are found at elevated levels in AD brains.In this article, the authors describe the key features of RAGE and how it could have a role in AD pathogenesis. They also summarize experimental animal and clinical data that demonstrate the therapeutic effect of RAGE inhibition and consider what these findings mean for human disease.RAGE has multiple ligands, including Aβ, that are increased in AD brains. Inhibiting RAGE-ligand interactions without activating receptor signaling can reduce multiple pathological pathways relevant for AD. Several RAGE inhibitors and modulators are now being tested as therapeutics for AD. Recent Phase II studies have established the good safety and tolerability of TTP448 with some evidence of positive benefit at lower dose. This suggests that further studies are required.

Objectives Advanced glycation endproducts (AGEs) play a key role in the development of foot complications in people with diabetes. Skin autofluorescence (AF) might noninvasively determine tissue accumulation of AGEs. This study evaluated the association between skin AF and AGE contents in the deep tissues of those with diabetes and the further consequences of such contents. Methods Between September 2014 and September 2015, we studied 33 patients, with and without diabetes, who had received lower-limb amputations. Skin AF was measured. Artery, nerve and skin were harvested during surgery. AGE contents were quantified using high-performance liquid chromatography mass spectrometry and were located by immunohistochemistry staining. Inflammatory cells were also located by immunohistochemistry, immunofluorescence and scanning electron microscopy. Results Values of skin AF and AGE contents in artery, nerve and skin in patients with diabetes were higher than those in healthy patients. Skin AF was strongly affected by AGE contents in these tissues. AGE contents in various tissues were strongly correlated with each other. Differing AGEs were deposited in similar manners in the same tissues and were accompanied by inflammatory cells. Conclusions AGE contents were strongly correlated with each other and were accompanied by inflammatory cells. Skin AF measurement could provide information about the systemic accumulation of AGEs.