•We present a validated LC–MS/MS method to determine AGE concentration in foods.•Three major AGEs were determined; CML, CEL and MG-H1.•High-heat processed food items were high in AGE content.•Fruits, ...vegetables, butter and coffee had the lowest AGE content.•We present a 190-item AGE database that can be used to quantify dietary AGE intake.
The aim of this study was to validate an ultra-performance liquid chromatography tandem mass-spectrometry (UPLC–MS/MS) method for the determination of advanced glycation endproducts (AGEs) in food items and to analyze AGEs in a selection of food items commonly consumed in a Western diet. Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were quantified in the protein fractions of 190 food items using UPLC–MS/MS. Intra- and inter-day accuracy and precision were 2–29%. The calibration curves showed perfect linearity in water and food matrices. We found the highest AGE levels in high-heat processed nut or grain products, and canned meats. Fruits, vegetables, butter and coffee had the lowest AGE content. The described method proved to be suitable for the quantification of three major AGEs in food items. The presented dietary AGE database opens the possibility to further quantify actual dietary exposure to AGEs and to explore its physiological impact on human health.
Reactive α-dicarbonyls (α-DCs), such as methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), are potent precursors in the formation of advanced glycation end products (AGEs). In ...particular, MGO and MGO-derived AGEs are thought to be involved in the development of vascular complications in diabetes. Experimental studies showed that citrus and pomegranate polyphenols can scavenge α-DCs. Therefore, the aim of this study was to evaluate the effect of a citrus and pomegranate complex (CPC) on the α-DCs plasma levels in a double-blind, placebo-controlled cross-over trial, where thirty-six elderly subjects were enrolled. They received either 500 mg of Citrus sinensis peel extract and 200 mg of Punica granatum concentrate in CPC capsules or placebo capsules for 4 weeks, with a 4-week washout period in between. For the determination of α-DCs concentrations, liquid chromatography tandem mass spectrometry was used. Following four weeks of CPC supplementation, plasma levels of MGO decreased by 9.8% (−18.7 nmol/L; 95% CI: −36.7, −0.7 nmol/L; p = 0.042). Our findings suggest that CPC supplementation may represent a promising strategy for mitigating the conditions associated with MGO involvement. This study was registered on clinicaltrials.gov as NCT03781999.
Summary Background & aims Advanced glycation endproducts (AGEs) are formed by the reaction between reducing sugars and proteins. AGEs in the body have been associated with several age-related ...diseases. High-heat treated and most processed foods are rich in AGEs. The aim of our study was to investigate whether dietary AGEs, are associated with plasma and urinary AGE levels. Methods In 450 participants of the Cohort on Diabetes and Atherosclerosis Maastricht study (CODAM study) we measured plasma and urine concentrations of the AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) using UPLC-MS/MS. We also estimated dietary intake of CML, CEL and MG-H1 with the use of a dietary AGE database and a food frequency questionnaire (FFQ). We used linear regression to investigate the association between standardized dietary AGE intake and standardized plasma or urinary AGE levels, after adjustment for age, sex, glucose metabolism status, waist circumference, kidney function, energy- and macro-nutrient intake, smoking status, physical activity, alcohol intake, LDL-cholesterol and markers of oxidative stress. Results We found that higher intake of dietary CML, CEL and MG-H1 was associated with significantly higher levels of free plasma and urinary CML, CEL and MG-H1 (βCML = 0.253 (95% CI 0.086; 0.415), βCEL = 0.194 (95% CI 0.040; 0.339), βMG-H1 = 0.223 (95% CI 0.069; 0.373) for plasma and βCML = 0.223 (95% CI 0.049; 0.393), βCEL = 0.180 (95% CI 0.019; 0.332), βMG-H1 = 0.196 (95% CI 0.037; 0.349) for urine, respectively). In addition, we observed non-significant associations of dietary AGEs with their corresponding protein bound plasma AGEs. Conclusion We demonstrate that higher intake of dietary AGEs is associated with higher levels of AGEs in plasma and urine. Our findings may have important implications for those who ingest a diet rich in AGEs.
The reactive α-oxoaldehydes glyoxal (GO), methylglyoxal (MGO) and 3-deoxyglucosone (3-DG) have been linked to diabetic complications and other age-related diseases. Numerous techniques have been ...described for the quantification of α-oxoaldehydes in blood or plasma, although with several shortcomings such as the need of large sample volume, elaborate extraction steps or long run-times during analysis. Therefore, we developed and evaluated an improved method including sample preparation, for the quantification of these α-oxoaldehydes in blood and plasma with ultra performance liquid chromatography tandem mass spectrometry (UPLC MS/MS).
EDTA plasma and whole blood samples were deproteinized using perchloric acid (PCA) and subsequently derivatized with o-phenylenediamine (oPD). GO, MGO and 3-DG concentrations were determined using stable isotope dilution UPLC MS/MS with a run-to-run time of 8 min. Stability of α-oxoaldehyde concentrations in plasma and whole blood during storage was tested. The concentration of GO, MGO and 3-DG was measured in EDTA plasma of non-diabetic controls and patients with type 2 diabetes (T2DM).
Calibration curves of GO, MGO and 3-DG were linear throughout selected ranges. Recoveries of these α-oxoaldehydes were between 95% and 104%. Intra- and inter-assay CVs were between 2% and 14%.
To obtain stable and reliable α-oxoaldehyde concentrations, immediate centrifugation of blood after blood sampling is essential and the use of EDTA as anticoagulant is preferable. Moreover, immediate precipitation of plasma protein with PCA stabilized α-oxoaldehyde concentrations for at least 120 min. With the use of the developed method, we found increased plasma concentrations of GO, MGO and 3-DG in T2DM as compared with non-diabetic controls.
α-Dicarbonyls and advanced glycation end products (AGEs) may contribute to the pathogenesis of insulin resistance by a variety of mechanisms. To investigate whether young insulin-resistant subjects ...present markers of increased dicarbonyl stress, we determined serum α-dicarbonyls-methylglyoxal, glyoxal, 3-deoxyglucosone; their derived free- and protein-bound, and urinary AGEs using the UPLC/MS-MS method; soluble receptors for AGEs (sRAGE), and cardiometabolic risk markers in 142 (49% females) insulin resistant (Quantitative Insulin Sensitivity Check Index (QUICKI) ≤ 0.319) and 167 (47% females) age-, and waist-to-height ratio-matched insulin-sensitive controls aged 16-to-22 years. The between-group comparison was performed using the two-factor (sex, presence/absence of insulin resistance) analysis of variance; multiple regression via the orthogonal projection to latent structures model. In comparison with their insulin-sensitive peers, young healthy insulin-resistant individuals without diabetes manifest alterations throughout the α-dicarbonyls-AGEs-sRAGE axis, dominated by higher 3-deoxyglucosone levels. Variables of α-dicarbonyls-AGEs-sRAGE axis were associated with insulin sensitivity independently from cardiometabolic risk markers, and sex-specifically. Cleaved RAGE associates with QUICKI only in males; while multiple α-dicarbonyls and AGEs independently associate with QUICKI particularly in females, who displayed a more advantageous cardiometabolic profile compared with males. Further studies are needed to elucidate whether interventions alleviating dicarbonyl stress ameliorate insulin resistance.
Objective:
Experimental and histological data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, the ...epidemiological evidence of an adverse association between AGEs and CVD remains inconclusive. We therefore investigated, in individuals with various degrees of glucose metabolism, the associations of plasma AGEs with prevalent CVD.
Research Design and Methods:
We measured plasma levels of protein-bound Nϵ-(carboxymethyl)lysine (CML), Nϵ-(carboxyethyl)lysine (CEL), and pentosidine, in participants from two Dutch cohort studies (n = 1291, mean age 64.7 ± 8.3 years, 45% women), including 573 individuals with normal glucose metabolism, 304 with impaired glucose metabolism, and 414 with T2DM. In addition, we measured free CML, CEL, and 5-hydro-5-methylimidazolone in a subset of participants (n = 554). Data were analyzed with multiple logistic or linear regression analyses.
Results:
CEL (32 interquartile range: 25–40 vs 28 22–35 nmol/mmol lysine) and pentosidine (0.53 0.43–0.67 vs 0.48 0.40–0.59 nmol/mmol lysine) as well as free CEL (48 39–62 vs 45 36–56 nmol/L) and 5-hydro-5-methylimidazolone (141 96–209 vs 116 84–165 nmol/L) were higher in individuals with vs without CVD, whereas protein-bound CML was lower (33 27–38 vs 34 29–39 nmol/mmol lysine). However, these differences disappeared after adjustment for confounders. The associations did not differ consistently between individuals with and without T2DM.
Conclusions:
We found no independent adverse associations of plasma AGEs with CVD in individuals with normal glucose metabolism, impaired glucose metabolism, and T2DM.
•We developed and validated anUHPLC-MS/MS method to quantify MGO, GO, and 3-DG infoods.•We present a 223-item database, enabling estimation of dietary dicarbonyl intake.•3-DG is the most abundant ...dicarbonyl in most food and drinks.•MGO is the most abundant dicarbonyl in coffee and fish, and GO in most vegetables, fruits, and nuts.•Dried fruits, biscuit/cake, and bread condiments have highest total dicarbonyl concentrations.
Dicarbonyls are reactive precursors of advanced glycation endproducts. They are formed endogenously and during food processing. Currently, a comprehensive database on dicarbonyls in foods that covers the entire range of food groups is lacking, limiting knowledge about the amount of dicarbonyls that is ingested via food. The aim of this study was to analyze the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) in commonly-consumed products in a Western diet. We validated a UHPLC-MS/MS method to quantify MGO, GO, and 3-DG. We present a dietary dicarbonyl database of 223 foods and drinks. Total dicarbonyl concentrations were highest in dried fruit, Dutch spiced cake, and candy bars (>400 mg/kg). Total dicarbonyl concentrations were lowest in tea, dairy, light soft drinks, and rice (<10 mg/kg). The presented database of MGO, GO, and 3-DG opens the possibility to accurately estimate dietary exposure to these dicarbonyls, and explore their physiological impact on human health.
Methylglyoxal (MGO), a major precursor for advanced glycation end products, is increased in diabetes. In diabetic rodents, inhibition of MGO prevents cardiovascular disease (CVD). Whether plasma MGO ...levels are associated with incident CVD in people with type 1 diabetes is unknown. We included 159 individuals with persistent normoalbuminuria and 162 individuals with diabetic nephropathy (DN) from the outpatient clinic at Steno Diabetes Center. We measured MGO at baseline and recorded fatal and nonfatal CVD over a median follow-up of 12.3 years (interquartile range 7.6-12.5 years). Data were analyzed by Cox regression, with adjustment for sex, age, HbA
, DN, diabetes duration, smoking, systolic blood pressure, antihypertensive medication, and BMI. During follow-up, 73 individuals suffered at least one CVD event (36 fatal and 53 nonfatal). Higher MGO levels were associated with total, fatal, and nonfatal incident CVD (hazard ratios HRs 1.47 95% CI 1.13-1.91, 1.42 1.01-1.99, and 1.46 1.08-1.98, respectively). We observed a similar trend for total mortality (HR 1.24 0.99-1.56). This study shows for the first time in our knowledge that plasma MGO levels are associated with cardiovascular events in individuals with type 1 diabetes. MGO may explain, at least in part, the increased risk for CVD in type 1 diabetes.
A Western diet comprises high levels of dicarbonyls and advanced glycation endproducts (AGEs), which may contribute to flares and symptoms in inflammatory bowel disease (IBD) and irritable bowel ...syndrome (IBS). We therefore investigated the intake of dietary dicarbonyls and AGEs in IBD and IBS patients as part of the habitual diet, and their association with intestinal inflammation. Food frequency questionnaires from 238 IBD, 261 IBS as well as 195 healthy control (HC) subjects were used to calculate the intake of dicarbonyls methylglyoxal, glyoxal, and 3-deoxyglucosone, and of the AGEs Nε-(carboxymethyl)lysine, Nε-(1-carboxyethyl)lysine and methylglyoxal-derived hydroimidazolone-1. Intestinal inflammation was assessed using faecal calprotectin. The absolute dietary intake of all dicarbonyls and AGEs was higher in IBD and HC as compared to IBS (all p < 0.05). However, after energy-adjustment, only glyoxal was lower in IBD versus IBS and HC (p < 0.05). Faecal calprotectin was not significantly associated with dietary dicarbonyls and AGEs in either of the subgroups. The absolute intake of methylglyoxal was significantly higher in patients with low (<15 μg/g) compared to moderate calprotectin levels (15−<50 μg/g, p = 0.031). The concentrations of dietary dicarbonyls and AGEs generally present in the diet of Dutch patients with IBD or IBS are not associated with intestinal inflammation, although potential harmful effects might be counteracted by anti-inflammatory components in the food matrix.
Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is ...unknown.
We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal GO and 3-deoxyglucosone 3-DG) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA
, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl.
A total of 287 individuals suffered from at least one CVD event (
= 194 fatal events,
= 146 myocardial infarctions, and
= 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 95% CI 1.11-1.42) and fatal (1.49 1.30-1.71) CVD and with all-cause mortality (1.25 1.11-1.40), myocardial infarction (1.22 1.02-1.45), and amputations (1.36 1.05-1.76). MGO levels were not apparently associated with stroke (1.03 0.79-1.35). Higher GO levels were significantly associated with fatal CVD (1.17 1.00-1.37) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes.
Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes.
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