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Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study.
Dybjer, E, Engström, G, Helmer, C, Nägga, K, Rorsman, P, Nilsson, PM
Diabetic medicine : a journal of the British Diabetic Association. 2020;(7):1157-1166
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Abstract
AIM: The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. METHODS Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. RESULTS Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. CONCLUSIONS Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.
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Mediterranean diet, physical activity and subcutaneous advanced glycation end-products' accumulation: a cross-sectional analysis in the ILERVAS project.
Sánchez, E, Betriu, À, Salas-Salvadó, J, Pamplona, R, Barbé, F, Purroy, F, Farràs, C, Fernández, E, López-Cano, C, Mizab, C, et al
European journal of nutrition. 2020;(3):1233-1242
Abstract
PURPOSE Adherence to Mediterranean diet (MedDiet) and physical activity have been associated to lower cardiovascular risk and mortality. Our purpose was to test the modification of advanced glycation end-products (AGEs) as one of the underlying mechanisms explaining this relationship. METHODS Cross-sectional study assessing the adherence to MedDiet (14-item Mediterranean Diet Adherence Screener) and physical activity (International Physical Activity Questionnaire short form) in 2646 middle-aged subjects without known cardiovascular disease and type 2 diabetes from the ILERVAS study. Skin autofluorescence (SAF), a non-invasive assessment of subcutaneous AGEs, was measured. Multivariable logistic regression models were done to study interactions and independent associations with a likelihood ratio test. RESULTS Participants with a high adherence to MedDiet had lower SAF than those with low adherence (1.8 [IR 1.6; 2.1] vs. 2.0 [IR 1.7; 2.3] arbitrary units, p < 0.001), without differences according to categories of physical activity. There was an independent association between high adherence to MedDiet and the SAF values [OR 0.59 (0.37-0.94), p = 0.026]. When adherence to MedDiet was substituted by its individual food components, high intake of vegetables, fruits and nuts, and low intake of sugar-sweetened soft beverages were independently associated with a decreased SAF (p ≤ 0.045). No interaction between MedDiet and physical activity on SAF values was observed except for nuts consumption (p = 0.047). CONCLUSIONS Adherence to the MedDiet, but not physical activity, was negatively associated to SAF measurements. This association can be explained by some typical food components of the MedDiet. The present study offers a better understanding of the plausible biological conditions underlying the prevention of cardiovascular disease with MedDiet. ClinTrials.gov identifier: NCT03228459.
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The cardiovascular complications of diabetes: a striking link through protein glycation.
Ahmad, MN, Farah, AI, Al-Qirim, TM
Romanian journal of internal medicine = Revue roumaine de medecine interne. 2020;(4):188-198
Abstract
Diabetes mellitus is a predominant cause of mortality and morbidity worldwide. One of its serious health problems is cardiovascular complications. Advanced glycation end products (AGEs) are a group of heterogeneous toxic oxidant compounds that are formed after a non-enzymatic reaction between monosaccharides and free amino groups of proteins, compound lipids, and nucleic acids. AGE interacts with various types of cells through a receptor for AGE (RAGE). The interaction between AGE and RAGE is responsible for a cascade of inflammation, oxidative stress, and disruption of calcium homeostasis in cardiac cells of diabetic patients. There is striking evidence that the AGE/RAGE axis with its consequences on inflammation and oxidative stress plays a major role in the development of cardiovascular complications. Therefore, considering AGE as a therapeutic target with foreseeable results would be a wise direction for future research. Interestingly, several studies on nutraceutical, pharmaceutical, and natural products have begun to reveal promising therapeutic results, and this could lead to better health outcomes for many diabetic patients worldwide. This article discusses the current literature addressing the connection between protein glycation and diabetes cardiovascular complications and suggests future avenues of research.
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Endothelial Dysfunction and Advanced Glycation End Products in Patients with Newly Diagnosed Versus Established Diabetes: From the CORDIOPREV Study.
de la Cruz-Ares, S, Cardelo, MP, Gutiérrez-Mariscal, FM, Torres-Peña, JD, García-Rios, A, Katsiki, N, Malagón, MM, López-Miranda, J, Pérez-Martínez, P, Yubero-Serrano, EM
Nutrients. 2020;(1)
Abstract
Endothelial dysfunction and intima-media thickness of common carotid arteries (IMT-CC) are considered subclinical markers of atherosclerotic cardiovascular disease (ASCVD). Advanced glycation end products (AGEs) are increased in type 2 diabetes mellitus (T2DM) patients, compared with non-diabetics, being implicated in micro- and macrovascular complications. Our aim was to compare serum AGEs levels and subclinical atherosclerotic markers between patients with established and newly diagnosed T2DM. Among 540 patients with T2DM and coronary heart disease from the CORDIOPREV study, 350 patients had established T2DM and 190 patients had newly diagnosed T2DM. Serum levels of AGEs (methylglyoxal (MG) and N-carboxymethyl lysine (CML)) and subclinical atherosclerotic markers (brachial flow-mediated vasodilation (FMD) and IMT-CC) were measured. AGEs levels (all p < 0.001) and IMT-CC (p = 0.025) were higher in patients with established vs. newly diagnosed T2DM, whereas FMD did not differ between the two groups. Patients with established T2DM and severe endothelial dysfunction (i.e., FMD < 2%) had higher serum MG levels, IMT-CC, HOMA-IR and fasting insulin levels than those with newly diagnosed T2DM and non-severe endothelial dysfunction (i.e., FMD ≥ 2%) (all p < 0.05). Serum CML levels were greater in patients with established vs. newly diagnosed T2DM, regardless of endothelial dysfunction severity. Serum AGEs levels and IMT-CC were significantly higher in patients with established vs. newly diagnosed T2DM, highlighting the progressively increased risk of ASCVD in the course of T2DM. Establishing therapeutic strategies to reduce AGEs production and delay the onset of cardiovascular complications in newly diagnosed T2DM patients or minimize ASCVD risk in established T2DM patients is needed.
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Advanced glycation end products in diabetes, cancer and phytochemical therapy.
Dariya, B, Nagaraju, GP
Drug discovery today. 2020;(9):1614-1623
Abstract
The irreversible glycation and oxidation of proteins and lipids produces advanced glycation end products (AGEs). These modified AGEs are triggered to bind the receptor for AGE (RAGE), thereby activating its downstream signaling pathways, such as nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)/Akt, ultimately leading to diabetes and cancers. In this review, we focus on the interaction of AGE-RAGE and their associated pathways. We also consider the activity of phytochemicals, such as genistein and curcumin, that trap dicarbonyl compounds including methylglyoxal (MG) and glyoxalase that arise from multiple pathways to block AGE formation and prevent its interaction with RAGE.
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Advanced glycation end products derived from serum albumin modification by glucose (AGE-1) reflect clustering of lipid-associated metabolic abnormalities and are decreased in patients treated with acarbose: A cross-sectional study.
Bronowicka-Szydełko, A, Krzystek-Korpacka, M, Kuzan, A, Gostomska-Pampuch, K, Gacka, M, Jakobsche-Policht, U, Adamiec, R, Gamian, A
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2020;(3):275-284
Abstract
BACKGROUND Advanced glycation end products (AGEs) are formed during protein modification by a reduction of sugars or reactive aldehydes. Depending on the pathology, various AGEs may be formed. They are stable compounds and are considered as potential diseases markers. OBJECTIVES The objective of this study was to assess glucose-mediated albumin modification that yields non-standard epitopes of AGEs (AGE-1) in diabetes and in associated metabolic abnormalities. MATERIAL AND METHODS The AGE-1, expressed as median AGE-1 level and AGE-1 positivity, was determined in 246 individuals (198 with prediabetes/diabetes) using a new slot-dot-blot method (allowing for detection of barely traceable analytes) and related to the presence of diabetes-associated metabolic abnormalities and complications, and treatment. RESULTS The AGE-1 level was higher in patients with prediabetes/diabetes than in controls. Its elevation was associated with metabolic syndrome (MetS), obesity, hyperlipidemia, and non-alcoholic fatty liver disease (NAFLD) but not with diabetic control or microand macroangiopathy, except for atherosclerotic plaques formation in carotid arteries. The AGE-1-positive patients had higher triglycerides and lower high-density lipoprotein (HDL)-cholesterol. In patients untreated with aspirin, AGE-1 positivity was associated with higher C-reactive protein (CRP) level. Treatment with aspirin, sulfonylureas and gliptins was associated with higher AGE-1 level and with dyslipidemia medications with higher AGE-1 positivity. In patients with abnormal glucose metabolism, acarbose treatment was associated with lower AGE-1 positivity. Multivariate analysis showed MetS, carotid artery plaques, NAFLD, and treatment with aspirin and acarbose to be independently associated with AGE-1 positivity. CONCLUSIONS Unlike standard AGEs, AGE-1 is more tightly associated with abnormalities in lipid than glucose metabolism, and lower in patients treated with acarbose but not with other antidiabetics.
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Functional and biological properties of Maillard conjugates and their potential application in medical and food: A review.
Nooshkam, M, Varidi, M, Verma, DK
Food research international (Ottawa, Ont.). 2020;:109003
Abstract
Protein and peptides are usually sensitive to environmental stresses, such as pH changes, high temperature, ionic strength, and digestive enzymes amongst other, which limit their food and medicinal applications. Maillard reaction (also called Maillard conjugation or glycation) occurs naturally without the addition of chemical agents and has been vastly applied to boost protein/peptide/amino acid functionalities and biological properties. Protein/peptide-saccharide conjugates are currently used as emulsifiers, antioxidants, antimicrobials, gelling agents, and anti-browning compounds in food model systems and products. The conjugates also possess the excellent stabilizing ability as a potent delivery system to enhance the stability and bioaccessibility of many bioactive compounds. Carbonyl scavengers such as polyphenols are able to significantly inhibit the formation of advanced glycation end products without a significant effect on early Maillard reaction products (MRPs) and melanoidins, which are currently applied as functional ingredients. This review paper highlights the technological functionality and biological properties of glycoconjugates in food model systems and products. Recent applications of MRPs in medical sciences are also presented.
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Skin auto-fluorescence as a measure of advanced glycation end-products is associated with microvascular health in patients with COPD.
Vaes, AW, Spruit, MA, Reynaert, NL, Franssen, FME, Wouters, EFM, Theunis, J, De Boever, P
Microvascular research. 2020;:104053
Abstract
BACKGROUND AND OBJECTIVES Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These physiological processes can lead to increased formation and accumulation of advanced glycation end-products (AGEs), that can play a role in vascular complications. In this cross-sectional study, we determined the association between skin AGEs and microvascular health in patients with COPD. METHODS Clinical characteristics and cardiovascular parameters, including pulmonary function, metabolic and inflammatory parameters, and blood pressure, were obtained in this observational study with patients with COPD. Skin concentrations of AGEs were assessed non-invasively by measuring skin autofluorescence (AF). Retinal vessel analysis was used as a marker of microvascular health. RESULTS 62 patients with COPD (52% males; mean age: 64.4 ± 8.4 years; mean FEV1: 45.0 ± 20.7%pred.) were analysed. Mean skin AF was 2.75 ± 0.64 arbitrary units. Skin AF in patients with COPD was negatively associated with retinal arteriolar diameter (β -0.021, 95% CI -0.040 to -0.002; p = 0.031) and arteriole-to-venular ratio (β -7.233, 95% CI -9.732 to -4.734; p < 0.001) and positively associated with retinal venular diameter (β 0.029, 95% CI 0.019 to 0.038; p < 0.001) after adjustment for sex, age, lung function, pack-years of smoking and conventional cardiovascular risk factors. CONCLUSION We document for the first time that skin AF in patients with COPD is independently associated with retinal arteriolar and venular vessel diameters, biological indicators for microvascular health. This adds to the evidence that AGEs are an accessible marker of microvascular health.
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Physical activity and markers of glycation in older individuals: data from a combined cross-sectional and randomized controlled trial (EXAMIN AGE).
Van den Eynde, MDG, Streese, L, Houben, AJHM, Stehouwer, CDA, Scheijen, JLJM, Schalkwijk, CG, Hanssen, NMJ, Hanssen, H
Clinical science (London, England : 1979). 2020;(9):1095-1105
Abstract
BACKGROUND Advanced glycation end products (AGEs) are protein modifications that are predominantly formed from dicarbonyl compounds that arise from glucose and lipid metabolism. AGEs and sedentary behavior have been identified as a driver of accelerated (vascular) aging. The effect of physical activity on AGE accumulation is unknown. Therefore, we investigated whether plasma AGEs and dicarbonyl levels are different across older individuals that were active or sedentary and whether plasma AGEs are affected by high-intensity interval training (HIIT). METHODS We included healthy older active (HA, n=38, 44.7% female, 60.1 ± 7.7 years old) and healthy older sedentary (HS, n=36, 72.2% female, 60.0 ± 7.3 years old) individuals as well as older sedentary individuals with increased cardiovascular risk (SR, n=84, 50% female, 58.7 ± 6.6 years old). The SR group was randomized into a 12-week walking-based HIIT program or control group. We measured protein-bound and free plasma AGEs and dicarbonyls by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) at baseline and after the HIIT intervention. RESULTS Protein-bound AGE Nε-(carboxymethyl)lysine (CML) was lower in SR (2.6 ± 0.5 μmol/l) and HS (3.1 ± 0.5 μmol/l) than in HA (3.6 ± 0.6 μmol/l; P<0.05) and remained significantly lower after adjustment for several potential confounders. None of the other glycation markers were different between HS and HA. HIIT did not change plasma AGEs and dicarbonyls in SR. DISCUSSION Although lifestyle interventions may act as important modulators of cardiovascular risk, HIIT is not a potent short-term intervention to reduce glycation in older individuals, underlining the need for other approaches, such as pharmacological agents, to reduce AGEs and lower cardiovascular risk in this population.
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Inhibitory effect of phenolic compounds and plant extracts on the formation of advance glycation end products: A comprehensive review.
Khan, M, Liu, H, Wang, J, Sun, B
Food research international (Ottawa, Ont.). 2020;:108933
Abstract
Advance glycation end products (AGEs) are a diverse group of compounds formed through the non-enzymatic maillard reaction of reducing sugars with the free amino groups in proteins, lipids or nucleic acids. Accumulation of AGEs has been suggested to be a pathogenic mechanism of oxidative stress, inflammation and structural tissue damage leading to chronic vascular problems in many ailments including diabetes, atherosclerosis, neuropathy, retinopathy, nephropathy, aging, and chronic renal disease. Treatment with AGEs inhibitors is believed to be a potential strategy for preventing lifestyle-related diseases. To inhibit the AGEs development is supposed to show part in the inhibition of diabetic problems. Study of dietary bioactive combinations with antiglycation properties delivers future views for inhibition or mediation associated to AGEs complications. Many study show the possibility of dietary constituents to stop AGE development. Therefore, search for natural compounds able to prevent glycation and have the potential therapeutic ability to inhibit diabetes and age associated diseases. The purpose of this review is to critically evaluate the existing literature on different phenolics on AGEs inhibition.