Advanced glycation endproducts--role in pathology of diabetic complications

Diabetes mellitus is a common endocrine disorder characterised by hyperglycaemia and predisposes to chronic complications affecting the eyes, blood vessels, nerves and kidneys. Hyperglycaemia has an important role in the pathogenesis of diabetic complications by increasing protein glycation and the gradual build-up of advanced glycation endproducts (AGEs) in body tissues. These AGE form on intra- and extracellular proteins, lipids, nucleic acids and possess complex structures that generate protein fluorescence and cross-linking. Protein glycation and AGE are accompanied by increased free radical activity that contributes towards the biomolecular damage in diabetes. There is considerable interest in receptors for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGEs with RAGE alter intracellular signalling, gene expression, release of pro-inflammatory molecules and free radicals that contribute towards the pathology of diabetic complications. This review introduces the chemistry of glycation and AGEs and examines the mechanisms by which they mediate their toxicity. The role of AGEs in the pathogenesis of retinopathy, cataract, atherosclerosis, neuropathy, nephropathy, diabetic embryopathy and impaired wound healing are considered. There is considerable interest in anti-glycation compounds because of their therapeutic potential. The mechanisms and sites of action of selected inhibitors, together with their potential in preventing diabetic complications are discussed.     

A systematic review of antiglycation medicinal plants

Background and objectivesThe present review shows a list of anti-glycation plants with their anti-glycation activity mechanisms that can attract the attention of pharmacologist for further scientific research towards finding better remedy for diabetic complications.MaterialsGoogle scholar, Pubmed, Web of Science and Scopus were searched. The terms were advanced glycation end products (AGEs), medicinal plants, antiglycation products.Resultsplants that studied in this review inhibit glycation in several possible mechanisms. Some of these plants inhibit the production of shiff base and amadori products. The others inhibit the generation of amadori products in the advanced phase. Some others blocked the aggregation of AGEs and some plants have antioxidant activity and reduce AGEs formation by preventing oxidation of amadori product and metal-catalyzed glucoxidation.ConclusionThis review can help pharmacologist to find antiglycation natural substance that can be useful in treatment of diabetic complications.     

Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes

A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and to the development and progression of various age-related disorders such as vascular complications of diabetes, Alzheimer's disease, cancer growth and metastasis, insulin resistance and degenerative bone disease. Under hyperglycemic and/or oxidative stress conditions, this process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently-bound Amadori rearrangement products. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversibly crossed-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence that AGE and their receptor RAGE (receptor for AGEs) interaction elicits oxidative stress, inflammatory reactions and thrombosis, thereby being involved in vascular aging and damage. These observations suggest that the AGE-RAGE system is a novel therapeutic target for preventing diabetic vascular complications. In this paper, we review the pathophysiological role of the AGE-RAGE-oxidative stress system and its therapeutic intervention in vascular damage in diabetes. We also discuss here the potential utility of the restriction of food-derived AGEs in diabetic vascular complications.     

高糖代谢记忆与糖尿病并发症

高糖"代谢记忆"是影响糖尿病并发症的重要因素,早期血糖控制情况可对并发症产生持久影响.氧化应激和晚期槠基化终末产物(AGEs)是形成高糖"代谢记忆"的基础,同时也是高糖"代谢记忆"参与糖尿病并发症的主要途径.在氧化应激途径中,活性氧簇(ROS)激活与糖尿病并发症相关;在AGEs途径中,AGEs引发的后续效应介导并发症的发生.减弱氧化应激和AGEs的作用,清除有害的代谢记忆,有望成为延缓糖尿病慢性并发症的治疗措施.     

AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?

In Alzheimer's disease, age-related cellular changes such ascompromised energy production and increased radical formation areworsened by the presence of AGEs as additional, AD specificstress factors. Intracellular AGEs (most likely derived frommethylglyoxal) crosslink cytoskeletal proteins and render theminsoluble. These aggregates inhibit cellular functions includingtransport processes and contribute to neuronal dysfunction anddeath. Extracellular AGEs, which accumulate in ageing tissue (butmost prominently on long-lived protein deposits like the senileplaques) exert chronic oxidative stress on neurons. In addition,they activate glial cells to produce free radicals (superoxideand NO) and neurotoxic cytokines such as TNF-. Drugs, whichinhibit the formation of AGEs by specific chemical mechanisms(AGE-inhibitors), including aminoguanidine, carnosine,tenilsetam, OPB-9195 and pyridoxamine, attenuate the developmentof (AGE-mediated) diabetic complications. Assuming that `carbonylstress' contributes significantly to the progression ofAlzheimer's disease, AGE-inhibitors might also becomeinteresting novel therapeutic drugs for treatment of AD.     

Advanced Glycation End Products and Receptor–Oxidative Stress System in Diabetic Vascular Complications

Reducing sugars can react non‐enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reactions, such as rearrangement, dehydration, and condensation, to become irreversibly cross‐linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress at an accelerated rate in patients with diabetes mellitus, thus being involved in the development and progression of diabetic micro‐ and macroangiopathy. Indeed, there is accumulating evidence that an interaction between an AGE and its receptor (RAGE) generates oxidative stress and subsequently evokes vascular inflammation and thrombosis, thereby playing a central role in diabetic vascular complications. In this paper, we review the pathophysiological role of AGE‐RAGE–oxidative stress system and its therapeutic interventions in diabetic micro‐ and macroangiopathy.     

Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes

Chronic hyperglycemia causes increased level of reactive oxygen species which is thought to be involved in the pathogenesis of diabetes associated complications including cataract. In diabetic cataractous lens, over production of free radicals and decreased capacity of antioxidant defense system are the major contributors to oxidative damage by polyol pathway and advanced glycation end products. The current study focused on analysis of factors associated with osmotic imbalance and oxidative stress in aging and diabetic human cataractous lenses. We examined activities of polyol pathway enzymes, G6PD and glutathione system in lenses from subjects suffering from cataract due to aging and diabetes. We observed elevated activities of aldose reductase and sorbitol dehydrogenase while G6PD and glutathione system enzyme activities were found to be lower in cataractous subjects suffering from diabetes. The findings from the current study support the premise that osmotic imbalance, AGEs formation and oxidative stress contribute synergistically to the development of lens opacity in hyperglycemia.     

Advanced glycation endproducts: what is their relevance to diabetic complications?

Glycation is a major cause of spontaneous damage to proteins in physiological systems. This is exacerbated in diabetes as a consequence of the increase in glucose and other saccharides derivatives in plasma and at the sites of vascular complications. Protein damage by the formation of early glycation adducts is limited to lysine side chain and N-terminal amino groups whereas later stage adducts, advanced glycation endproducts (AGEs), modify these and also arginine and cysteine residues. Metabolic dysfunction in vascular cells leads to the increased formation of methylglyoxal which adds disproportionately to the glycation damage in hyperglycaemia. AGE-modified proteins undergo cellular proteolysis leading to the formation and urinary excretion of glycation free adducts. AGEs may potentiate the development of diabetic complications by activation of cell responses by AGE-modified proteins interacting with specific cell surface receptors, activation of cell responses by AGE free adducts, impairment of protein-protein and enzyme-substrate interactions by AGE residue formation, and increasing resistance to proteolysis of extracellular matrix proteins. The formation of AGEs is suppressed by intensive glycaemic control, and may in future be suppressed by thiamine and pyridoxamine supplementation, and several other pharmacological agents. Increasing expression of enzymes of the enzymatic defence against glycation provides a novel and potentially effective future therapeutic strategy to suppress protein glycation.     

Plasma glycation adducts and various RAGE isoforms are intricately associated with oxidative stress and inflammatory markers in type 2 diabetes patients with vascular complications

BackgroundThe secondary vascular complications in diabetes mellitus (DM) are contributed by acute as well as inflammatory responses which get activated due to interaction between glycation adducts and respective receptors.AimThe present work was performed to understand the relationship between Advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE) interaction with oxidative stress and inflammation in vascular complications.MethodsFor the present work we recruited 103 controls, 200 patients with type 2 DM, and 200 patients with Diabetic complications. Different Plasma glycation adducts (fructosamine, carbonyls, AGEs, β-amyloid content, free amino groups, and free thiol groups); RAGE isoforms, level of antioxidant such as glutathione, catalase activity, nitric oxide level, total antioxidant capacity, and superoxide dismutase activity, as well as oxidative markers, and expression of Nε-carboxymethyl-lysine (CML), different isoforms of RAGE, NF-κB, and inflammatory markers were analyzed.ResultsGlycation adducts were higher in DM patients and more elevated in nephropathy patients where free amino groups and thiol groups lowered as compared to controls. sRAGE levels and expression were increased mainly in nephropathy. CML expression was higher in nephropathy patients. The antioxidant profile indicates a reduced level of different antioxidants while increased lipid peroxidation and intracellular ROS generation in DM and much higher in nephropathy patients. Expression of membrane RAGE, NF-κB, and inflammatory markers showed a remarkably increased level in DM patients with nephropathy.ConclusionThis work provides the first evidence of four different RAGE isoforms in diabetes and in complications. The glycation via the activation of RAGE, oxidative stress, and resultant inflammation plays a crucial role in the development of diabetic complications.     

The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: avenues for a mechanistic-based therapeutic approach

A growing body of evidence suggests that oxidative stress plays a key role in the pathogenesis of micro- and macrovascular diabetic complications. The increased oxidative stress in subjects with type 2 diabetes is a consequence of several abnormalities, including hyperglycemia, insulin resistance, hyperinsulinemia, and dyslipidemia, each of which contributes to mitochondrial superoxide overproduction in endothelial cells of large and small vessels as well as the myocardium. The unifying pathophysiological mechanism that underlies diabetic complications could be explained by increased production of reactive oxygen species (ROS) via: (1) the polyol pathway flux, (2) increased formation of advanced glycation end products (AGEs), (3) increased expression of the receptor for AGEs, (4) activation of protein kinase C isoforms, and (5) overactivity of the hexosamine pathway. Furthermore, the effects of oxidative stress in individuals with type 2 diabetes are compounded by the inactivation of two critical anti-atherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Of interest, the results of clinical trials in patients with type 2 diabetes in whom intensive management of all the components of the metabolic syndrome (hyperglycemia, hypercholesterolemia, and essential hypertension) was attempted (with agents that exert a beneficial effect on serum glucose, serum lipid concentrations, and blood pressure, respectively) showed a decrease in adverse cardiovascular end points. The purpose of this review is (1) to examine the mechanisms that link oxidative stress to micro- and macrovascular complications in subjects with type 2 diabetes and (2) to consider the therapeutic opportunities that are presented by currently used therapeutic agents which possess antioxidant properties as well as new potential antioxidant substances.     

Studies on the Cardio Protective Role of Gallic Acid Against AGE-Induced Cell Proliferation and Oxidative Stress in H9C2 (2-1) Cells

Epidemiological studies have shown that high glucose levels and oxidative stress cause elevation of advanced glycation end products (AGEs) that are known to contribute to diabetic complications. Thus, agents that hamper reactive oxygen species (ROS) load can be used as a potential drug against AGEs-mediated complications. Hence, the present study investigated the protective role of gallic acid (GA) against the effects of AGEs in cardiac H9C2(2-1) cells. Exposure of cells to AGEs resulted in release of ROS (P?<?0.05) with significant (P?<?0.05) decline in antioxidant enzyme levels and increase in collagen (P?<?0.01) content. In addition, the altered mitochondrial membrane potential (mmp) (P?<?0.01) was also observed in cells exposed to AGEs, whereas AGEs-exposed cells pretreated with GA prevented the release of ROS, and there were no significant changes in the antioxidant status, collagen content and mmp. Thus, the results of the present study provide evidence that GA exhibits protective role against AGEs-induced cardiovascular complications probably through its free radical scavenging activity.     

Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes

The formation of advanced glycation end products (AGEs) is an important biochemical abnormality that accompanies diabetes mellitus and, likely, inflammation in general. Here we summarize and discuss recent studies indicating that the effects of AGEs on vessel wall homeostasis may account for the rapidly progressive atherosclerosis associated with diabetes mellitus. Driven by hyperglycemia and oxidant stress, AGEs form to a greatly accelerated degree in diabetes. Within the vessel wall, collagen-linked AGEs may "trap" plasma proteins, quench nitric oxide (NO) activity and interact with specific receptors to modulate a large number of cellular properties. On plasma low density lipoproteins (LDL), AGEs initiate oxidative reactions that promote the formation of oxidized LDL. Interaction of AGEs with endothelial cells as well as with other cells accumulating within the atherosclerotic plaque, such as mononuclear phagocytes and smooth muscle cells (SMCs), provides a mechanism to augment vascular dysfunction. Specifically, the interaction of AGEs with vessel wall components increases vascular permeability, the expression of procoagulant activity and the generation of reactive oxygen species (ROS), resulting in increased endothelial expression of endothelial leukocyte adhesion molecules. AGEs potently modulate initiating steps in atherogenesis involving blood-vessel wall interactions, triggering an inflammatory-proliferative process and, furthermore, critically contribute to propagation of inflammation and vascular perturbation in established disease. Thus, a better understanding of the biochemical mechanisms by which AGEs contribute to such processes in the vessel wall could be relevant to devise preventive and therapeutic strategies for diabetic atherosclerosis.     

Free Radicals and Glycoxidative Stress in Ageing and Age-Related Diseases

Abstract. Free radicals and glycoxidative reactions are known to be associated with ageing on the level of the cell and whole organism. Free radicals are ubiquitous in living things and they lead to irreversible reactions in cell organelles and cell metabolism. One important source of free radicals is advanced glycation end products (AGEs) resulting from non-enzymatic glycation and oxidation of proteins and lipids. Ageing, and thus life span, correlate with free radical generation and antioxidative defense as well as with advanced glycation end products. Most chronic diseases are also associated with free radicals and AGEs. Overproduction of free radicals accelerates cell ageing and is counteracted by antioxidants. Antioxidant status is in part amendable through nutritional and pharmacological interventions. AGE interaction with its receptor contributes also to accelerated ageing in many pathological conditions. Particularly vulnerable are long-lived proteins, eg. in lens crystallin and skin collagen. The analysis of the mechanism generating free radicals and of the reaction of AGEs with cellular metabolism opens new avenues for the delaying of the development of chronic diseases such as atherosclerosis and neurodegenerative disease. On the other hand, the impact of free radicals on carcinogenesis may differ according to the cancer stage and hence the preventive potential of antioxidants is proposed to be different in early and late stages of cancer development. Free radicals and AGE products are important mediators of age-related diseases and ageing per se. Intake of antioxidants over the life-time determines, among other factors, the rate of ageing and the development of degenerative diseases. Interventive strategies such as soluble receptors for AGEs and effective antioxidants might become important therapeutic strategies in the near future.     

Advanced glycation end products increase,through a protein kinase C-dependent pathway,vascular endothelial growth factor expression in retinal endothelial cells. Inhibitory effect of gliclazide

Accumulating evidence points to a causal role for advanced glycation end products (AGEs) in the development of diabetic vascular complications, including retinopathy. Possible pathogenic mechanisms linking AGEs to diabetic retinopathy include protein kinase C (PKC) activation, oxidative stress, and vascular endothelial growth factor (VEGF) expression. In the present study, we investigated the effect of AGEs on VEGF expression in bovine retinal endothelial cells (BRECs) and determined the role of PKC and oxidative stress in this effect. Incubation of BRECs with AGEs led to enhanced VEGF mRNA and protein expression. This treatment also induced PKC translocation in these cells. The AGE-induced increases in VEGF expression and PKC activation were inhibited by the pan-specific PKC inhibitor, calphostin C, and by the antioxidant drug and compounds, gliclazide, N-acetylcysteine, and vitamin E. In contrast, glyburide which does not exhibit antioxidant properties, did not affect the AGE-induced VEGF expression. Exposure of BRECs to AGEs resulted in a significant increase of nuclear protein binding to the NF-kappa B consensus sequence of the VEGF promoter region. Induction of DNA binding activity for NF-kappa B by AGEs was prevented by gliclazide. Treatment of BRECs with AGEs also increased the proliferation of these cells. This effect was abrogated by incubating the cells with an anti-VEGF antibody and was inhibited in the presence of gliclazide. Overall, these data demonstrate that AGEs increase VEGF expression in retinal endothelial cells through generation of oxidative stress and downstream activation of the PKC pathway. Targeting VEGF expression with specific pharmacological agents, such as antioxidants and PKC inhibitors, may prove efficacious for the treatment of diabetic retinopathy.     

Glycated hemoglobin and its spinoffs: Cardiovascular disease markers or risk factors?

Atherosclerosis is a major complication of diabetes, increasing the risk of cardiovascular related morbidities and mortalities. The hallmark of diabetes is hyperglycemia which duration is best predicted by elevated glycated haemoglobin A_1C (HbA_1C) levels. Diabetic complications are usually attributed to oxidative stress associated with glycation of major structural and functional proteins. This non-enzymatic glycation of long lived proteins such as collagen, albumin, fibrinogen, liver enzymes and globulins result in the formation of early and advanced glycation end products (AGEs) associated with the production of myriads of free radicles and oxidants that have detrimental effects leading to diabetic complications. AGEs have been extensively discussed in the literature as etiological factors in the advancement of atherogenic events. Mechanisms described include the effects of glycation on protein structure and function that lead to defective receptor binding, impairment of immune system and enzyme function and alteration of basement membrane structural integrity. Hemoglobin (Hb) is a major circulating protein susceptible to glycation. Glycated Hb, namely HbA_1C is used as a useful tool in the diagnosis of diabetes progression. Many studies have shown strong positive associations between elevated HbA_1C levels and existing cardiovascular disease and major risk factors. Also, several studies presented HbA_1C as an independent predictor of cardiovascular risk. In spite of extensive reports on positive associations, limited evidence is available considering the role of glycated Hb in the etiology of atherosclerosis. This editorial highlights potential mechanisms by which glycated hemoglobin may contribute, as a causative factor, to the progression of atherosclerosis in diabetics.     

Carbonyl stress in the pathogenesis of diabetic nephropathy.

Diabetic nephropathy is a major chronic complication of diabetes mellitus and an important cause of increased morbidity and mortality in diabetic patients. Although several lines of evidence have suggested that poor glycemic control undoubtedly plays a significant role, the metabolic events responsible for its development are not understood well. Possible mediators of untowards effects of hyperglycemia include the advanced glycation end products (AGEs). AGEs, carboxymethyllysine and pentosidine, whose formation is closely linked to oxidation, accumulate in the characteristic diabetic glomerular lesions, such as the expanded mesangial matrix and nodular lesions, in co-localization with other oxidation-specific protein adducts, such as malondialdehyde-lysine, 4-hydroxynonenal-protein adduct, and acrolein-protein adduct. These five biomarkers are formed under oxidative stress by carbonyl amine chemistry between protein amino group and carbonyl compounds derived from carbohydrates, lipids, and amino acids. This article focuses on new aspects of the pathology of diabetic nephropathy, implicating an increased oxidative stress and carbonyl modification of proteins by autoxidation products of carbohydrates, lipids, and amino acids in diabetic glomerular tissue damage ("carbonyl stress").     

Oxidative protein damage with carbohydrates and lipids in uremia: 'Carbonyl stress'.

Chronic uremia appears to be in a state of an increased oxidative stress. Under oxidative stress, proteins are modified directly by reactive oxygen species with the eventual formation of oxidised amino acids. Proteins are also modified indirectly with reactive carbonyl compounds formed by the autoxidation of carbohydrates and lipids, with the eventual formation of the advanced glycation/lipoxidation end products (AGEs/ALEs). AGEs, pentosidine and carboxymethyllysine (CML), and ALE, malondialdehyde (MDA)-lysine, are elevated in plasma and matrix proteins of uremic patients several times above normal subjects. Precursor carbonyl compounds derived from carbohydrates and lipids are indeed elevated in uremic circulation. Uremia thus appears to be in a state of carbonyl overload with potentially damaging proteins (carbonyl stress). Carbonyl stress might be relevant to long-term complications associated with chronic renal failure and dialysis, such as dialysis-related amyloidosis and atherosclerosis. Immunohistochemical studies identified carbonyl stress in long-lived amyloid deposits and vascular lesions. Proteins modified under carbonyl stress exhibit several biological activities, which might, at least in part, account for the development of joint and vascular complications in uremia.     

The preventive anti-oxidant action of thiazolidinediones: a new therapeutic prospect in diabetes and insulin resistance.

BACKGROUND: Hyperglycaemia-derived oxygen free radicals may be mediators of diabetic complications. METHODS: Recent studies show that hyperglycaemia-induced overproduction of superoxide seems to be the first and key event in activation of pathways involved in the pathogenesis of diabetic complications. Superoxide overproduction is accompanied by increased nitric oxide generation and consequently formation of the powerful oxidant peroxynitrite and by poly(ADP-ribose) polymerase activation. This results in acute endothelial dysfunction and activation of inflammation in blood vessels that contribute to the development of diabetic complications. RESULTS: Thiazolidinediones are a new class of insulin-sensitizing agents. They inhibit intracellular free radical overproduction. In particular, they inhibit the same pathways involved in hyperglycaemia-derived oxidative stress, particularly iNOS and NF-kappaB. Studies in animal models suggest that thiazolidinediones can reduce oxidative stress, independent of their ability to reduce hyperglycaemia. CONCLUSIONS: The availability of compounds that simultaneously decrease hyperglycaemia, restore insulin resistance and inhibit pathways activated by high glucose producing oxidative stress signals a promising approach.     

Advanced glycation end products and cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Advanced glycation end products [AGEs] seem to play an important role for the development and/or progression of CVD mainly through induction of oxidative stress and inflammation. AGEs are a heterogenous group of molecules formed by the nonenzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. Recent studies suggest that in addition to those endogenously formed, diet constitutes an important exogenous source of AGEs. Diet-derived AGEs contribute to the whole body AGE pool and the AGE-related pathology. Recent in vitro and in vivo studies revealed significant correlations between diet-derived AGEs and several risk factors and/or markers of CVD, suggesting the dietary AGEs restriction as a promising therapeutic intervention.