Glycation End-Products and their Receptors: Pathophysiology and Therapeutic Targeting in Diabetes Mellitus

2021 ◽  
Vol 1 ◽  
pp. 19-35
Author(s):  
Hussein Saad Alzadi ◽  
Naza Mohammed Ali Mahmood
Keyword(s):  
Diabetes Mellitus ◽  
Signaling Pathway ◽  
Cellular Metabolism ◽  
Fragility Fractures ◽  
Clinical Results ◽  
Diabetic Patients ◽  
Advanced Glycation ◽  
Soluble Rage ◽  
Glycation End Products ◽  
End Products

Diabetes mellitus (DM) compromises cell metabolism and function in many organs, resulting in increased risks of complications in many organs such as kidney, nervous system, eye, and fragility fractures. Advanced glycation end products (AGEs) are chemical moieties produced during long-term hyperglycemia; they interact with the specific receptors for AGEs (RAGEs) and make a meaningful contribution to cellular metabolism and/or alteration of their functions. Searches in PubMed using the keywords "advanced glycation end product "RAGE", "sRAGE", "DM", and "complications” were made to reveal some of the clinical outcomes of DM in cellular metabolism and organ function through the AGE-RAGE signaling pathway. All published experimental and clinical studies were included in tables. The AGE-RAGE signaling is involved in diabetic complications such as nephropathy, neuropathy, retinopathy, and osteopathy. Some clinical results in diabetic patients could be potentially attributed to AGE-RAGE signaling consequences. However, the AGE-RAGE signaling pathway has some helpful roles in many tissues, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either condition of RAGE production or destruction, and then it cannot always reflect the AGE-RAGE signaling. Although various medicines are capable to target the AGE-RAGE axis. They can also limit the associated damaging consequences. Recombinant sRAGE can block the AGE-RAGE signaling pathway; however, it is associated with some limitations such as accessibility to AGEs, increase in other RAGE ligands, and a long half-life (24 hours). It is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess the activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.

scholarly journals Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature

2019 ◽  
Vol 3 (10) ◽  
pp. 1799-1818 ◽  
Author(s):  
Kamyar Asadipooya ◽  
Edilfavia Mae Uy
Keyword(s):  
Signaling Pathway ◽  
Advanced Glycation End Products ◽  
Cell Metabolism ◽  
Bone Cell ◽  
Diabetic Patients ◽  
Advanced Glycation ◽  
Soluble Rage ◽  
Increased Risk ◽  
Glycation End Products ◽  
End Products

AbstractDiabetes compromises bone cell metabolism and function, resulting in increased risk of fragility fracture. Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) and can make a meaningful contribution to bone cell metabolism and/or alter function. Searches in PubMed using the key words “advanced glycation end-product,” “RAGE,” “sRAGE,” “bone,” and “diabetes” were made to explain some of the clinical outcomes of diabetes in bone metabolism through the AGE–RAGE signaling pathway. All published clinical studies were included in tables. The AGE–RAGE signaling pathway participates in diabetic complications, including diabetic osteopathy. Some clinical results in diabetic patients, such as reduced bone density, suppressed bone turnover markers, and bone quality impairment, could be potentially due to AGE–RAGE signaling consequences. However, the AGE–RAGE signaling pathway has some helpful roles in the bone, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either conditions of RAGE production or destruction, and then it cannot always reflect the AGE–RAGE signaling. Recombinant sRAGE can block the AGE–RAGE signaling pathway but is associated with some limitations, such as accessibility to AGEs, an increase in other RAGE ligands, and a long half-life (24 hours), which is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.

scholarly journals Advanced Glycation end product profile of Diabetic and Non-Diabetic patients with cataract

2021 ◽  
pp. 14-20
Author(s):  
Emma-Okon B.O ◽  
Onakpoya O.H ◽  
Kolawole B.A ◽  
Owolabi F.A ◽  
Akinde M.O ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Lipid Peroxidation ◽  
Advanced Glycation End Products ◽  
Fasting Blood Glucose ◽  
Diabetic Patients ◽  
Healthy Controls ◽  
Reaction Products ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

The study determined the levels of advanced glycation end-products (AGEs) and malondialdehyde (MDA) in Nigerian cataract patients with and without diabetes mellitus, those with DM but no cataract as well as apparently healthy controls with a view to further elucidating putative pathophysiologic mechanisms for the occurrence of cataracts among our diabetic population. Participants comprised of 30 diabetic patients with operable cataract, 30 non-diabetic patients with operable cataract, 30 diabetic patients without cataract and 17 healthy controls all matched for age and sex, Glycated Haemoglobin levels in whole blood samples were determined using an affinity assay while fasting blood glucose was estimated by the glucose oxidase reaction. AGE was measured using a competitive ELISA kit while the level of lipid peroxidation in plasma was determined by measuring the reaction products between malondialdehyde and thiobarbituric acid. Statistical analysis was carried out using SPSS software (version 23). P<0.05 was taken as significant. The age range of participants was 52-90 years with a mean of 67.2±0.8. Mean levels of AGE were comparable in patients who had diabetes and cataract, those with cataract but no diabetes and those with Diabetes but no cataracts while healthy controls of similar age group had significantly lower levels. Patients with diabetes mellitus and cataract had significantly higher levels of MDA than those with diabetes only. There was positive, significant correlation between AGE and fasting glucose levels. No significant differences existed between AGE and MDA levels in male and female respondents. We conclude that AGE may serve as a useful index of pathologic conditions, including cataract and diabetes. Keywords: Advanced Glycation End-Products; Cataract; Diabetes; Lipid Peroxidation

scholarly journals Soluble Receptor for Advanced Glycation End Products and Its Forms in COVID-19 Patients with and without Diabetes Mellitus: A Pilot Study on Their Role as Disease Biomarkers

2020 ◽  
Vol 9 (11) ◽  
pp. 3785
Author(s):  
Elena Dozio ◽  
Clementina Sitzia ◽  
Lara Pistelli ◽  
Rosanna Cardani ◽  
Roberta Rigolini ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Advanced Glycation End Products ◽  
Potential Role ◽  
Healthy Individuals ◽  
Advanced Glycation ◽  
Disease Biomarkers ◽  
Soluble Rage ◽  
Glycation End Products ◽  
End Products ◽  
Inflammatory Burden

The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.

scholarly journals Serum Fluorescence of Advanced Glycation End Products: A Potential Screening Tool to Distinguish Between Diabetic Patients with and without Microvascular Complications

2020 ◽  
Author(s):  
Sadaf Ali ◽  
Nivedita L Rao
Keyword(s):  
Diabetes Mellitus ◽  
Screening Tool ◽  
Microvascular Complications ◽  
Diabetic Patients ◽  
Advanced Glycation ◽  
Type 2 Diabetic Patients ◽  
Glycation End Products ◽  
End Products ◽  
Type 2 Diabetic

Introduction: Enhanced formation and accumulation of Fluorescent Advanced Glycation End products (F-AGEs) in diabetes mellitus have been linked to increased risk of developing the associated vascular complications. Aim: To evaluate the potential of serum fluorescence levels of F-AGEs as screening tools to distinguish between type 2 diabetic patients with and without microvascular complications such as retinopathy, neuropathy. Materials and Methods: This cross-sectional study was conducted between June 2016 and June 2017, included 95 type 2 diabetic patients with more than 1 year of diabetes duration. Fasting blood glucose, glycated haemoglobin and total protein levels were estimated by automated methods. Serum F-AGEs were estimated by using a simple spectrofluorometric method. Microvascular complications due to diabetes mellitus were studied in each patient from medical records data on fundus examination for retinopathy and touch, vibration sensation detection for neuropathy. Diabetic patients were categorised into two groups as those without microvascular complications and those with microvascular complications-retinopathy and neuropathy. Statistical tests used for comparisons between groups were chi-square test for gender distribution, independent t-test for other parameters and Pearson’s correlations. The p-value <0.05 indicated significant difference between variables. Results: Mean age of the population was 55.1±5.3 years. Diabetic patients with microvascular complications (n=26) in the form of retinopathy, neuropathy had significantly higher levels of serum F-AGEs with mean 7.4±1.8 AU/g protein compared with diabetic patients without complications with mean value 1.5±0.7 AU/g protein (p<0.01). Conclusion: Two categories of serum fluorescent AGE values, without overlap, could be distinguished between diabetic patients with and without complications. Measurement of serum F-AGEs products has the potential to emerge as a simple, valuable screening tool to distinguish between diabetic patients with and without microvascular complications.

scholarly journals Sweet Bones: The Pathogenesis of Bone Alteration in Diabetes

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Mohammed Al-Hariri
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Diabetic Patients ◽  
Advanced Glycation ◽  
Osteoblast Activity ◽  
Glycation End Products ◽  
End Products ◽  
The Status ◽  
Osteoid Surface ◽  
And Oxidative Stress

Diabetic patients have increased fracture risk. The pathogenesis underlying the status of bone alterations in diabetes mellitus is not completely understood but is multifactorial. The major deficits appear to be related to a deficit in mineralized surface area, a decrement in the rate of mineral apposition, deceased osteoid surface, depressed osteoblast activity, and decreased numbers of osteoclasts due to abnormal insulin signaling pathway. Other prominent features of diabetes mellitus are an increased urinary excretion of calcium and magnesium, accumulation of advanced glycation end products, and oxidative stress leading to sweet bones (altered bone’s strength, metabolism, and structure). Every diabetic patient should be assessed for risk factors for fractures and osteoporosis. The pathogenesis of the bone alterations in diabetes mellitus as well as their molecular mechanisms needs further study.

Soluble RAGE Sequesters Advanced Glycation End Products following an Overnight Fast in T1DM Patients

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 275-LB
Author(s):  
EDWIN R. MIRANDA ◽  
JR. KELLY N. FULLER ◽  
RYAN PERKINS ◽  
PAUL J. BEISSWENGER ◽  
SARAH S. FARABI ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Advanced Glycation ◽  
Soluble Rage ◽  
Glycation End Products ◽  
End Products

scholarly journals Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6136-6144 ◽  
Author(s):  
Weifei Zhu ◽  
Wei Li ◽  
Roy L. Silverstein
Keyword(s):  
Diabetes Mellitus ◽  
Mouse Models ◽  
Advanced Glycation End Products ◽  
Vascular Complications ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Drug Induced ◽  
Glycation End Products ◽  
End Products

Abstract Diabetes mellitus has been associated with platelet hyperreactivity, which plays a central role in the hyperglycemia-related prothrombotic phenotype. The mechanisms responsible for this phenomenon are not established. In the present study, we investigated the role of CD36, a class-B scavenger receptor, in this process. Using both in vitro and in vivo mouse models, we demonstrated direct and specific interactions of platelet CD36 with advanced glycation end products (AGEs) generated under hyperglycemic conditions. AGEs bound to platelet CD36 in a specific and dose-dependent manner, and binding was inhibited by the high-affinity CD36 ligand NO2LDL. Cd36-null platelets did not bind AGE. Using diet- and drug-induced mouse models of diabetes, we have shown that cd36-null mice had a delayed time to the formation of occlusive thrombi compared with wild-type (WT) in a FeCl3-induced carotid artery injury model. Cd36-null mice had a similar level of hyperglycemia and a similar level of plasma AGEs compared with WT mice under this condition, but WT mice had more AGEs incorporated into thrombi. Mechanistic studies revealed that CD36-dependent JNK2 activation is involved in this prothrombotic pathway. Therefore, the results of the present study couple vascular complications in diabetes mellitus with AGE-CD36–mediated platelet signaling and hyperreactivity.

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