Advanced glycation end products and diabetic complications

Diabetic complications are major cause of morbidity and mortality in patients with diabetes. While the precise pathogenic mechanism(s) underlying conditions such as diabetic retinopathy, diabetic nephropathy and increased risk of atherosclerosis remain ill-defined, it is clear that hyperglycaemia is a primary factor that initiates and promotes complications. Formation of advanced glycation end products (AGEs) correlate with glycaemic control, and these reactive adducts form on DNA, lipids and proteins where they represent pathophysiological modifications that precipitate dysfunction at a cellular and molecular level. Many of these adducts form rapidly during diabetes and promote progression of a raft of diabetes-related complications. Recent evidence also suggests an important interaction with other pathogenic mechanisms activated within the diabetic milieu. This review outlines the nature of AGE formation in biological systems and highlights accumulative evidence that implicates these adducts in diabetic complications. As more therapeutic agents are developed to inhibit AGE formation or limit their pathogenic influence during chronic diabetes, it is becoming clear that these anti-AGE strategies have an important role to play in the treatment of diabetic patients.     

Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complications

Background: Diabetic vascular complications are leading causes of acquired blindness, end-stage renal failure, a variety of neuropathies, and accelerated atherosclerosis, which together could account for disabilities and high mortality rates in patients with diabetes. Since there is accumulating evidence that the advanced glycation end product (AGE)–RAGE (receptor for AGEs)–oxidative stress axis is involved in diabetic vascular complications, inhibition of the AGE–RAGE system may be a promising target for therapeutic intervention in these devastating disorders. Objective: In this review, we discuss several types of agent that may be able to inhibit the AGE–RAGE–oxidative stress system, and their therapeutic implications in vascular complications in diabetes. Methods: We have analyzed currently available scientific literature in the field of AGE–RAGE to create a comprehensive review on novel therapeutic agents for vascular complications in diabetes. Results/conclusion: Inhibition of AGE formation, blockade of the AGE–RAGE interaction, and suppression of RAGE expression or its downstream pathways may be novel therapeutic strategies for the treatment of vascular complications in diabetes.     

Possible participation of advanced glycation endproducts and their receptor system in the development of diabetic vascular complications

Diabetes causes vascular injuries in various organs and tissues, among which the lesions in retina and kidney are called retinopathy and nephropathy, respectively. As the number of diabetic patients is increasing in Japan, the population with the vascular complications is also elevating. For preventing diabetic complications, it is necessary to develop new drugs that target for key molecules in the development of this disease and useful animal models for the evaluation of their therapeutic potentials. We have focused on the non-enzymatic glycation reaction under prolonged hyperglycemia, which results in the formation and accumulation of advanced glycation endproducts (AGE). The interaction of AGE with the receptor for AGE (RAGE) has been implicated in the development of the vascular complications. AGE elicited vascular cell changes typical of diabetes, including angiogenic and thrombogenic responses of endothelial cells (EC), and a decrease in pericytes, the hallmarks of diabetic retinopathy. Our recent in vivo study revealed that transgenic mice overexpressing human RAGE in vascular EC developed advanced nephropathy when they were made diabetic. This mouse is thus regarded as a useful animal model of diabetic vascular disease. These results suggest that the AGE-RAGE system plays an active role in the development of diabetic vasculopathy and is a promising target in the prophylaxis and therapy of this disease. Recently, we identified three RAGE variants: novel C-terminally and N-terminally truncated forms and the known full-length form. The C-terminally truncated variant was found to be a soluble form and actually detected in human sera, and it was found to have neutralizing activities against AGE-induced EC injury. The endogenous soluble decoy against the AGE-RAGE system may contribute to the individual resistance to the development of diabetic vascular complications. The stimulation of secretion of this protein can be a new means for the prevention of chronic vascular disease in diabetes.     

Advanced glycation end products (AGEs) and their receptor (RAGE) system in diabetic retinopathy

Vascular complications are a leading cause of blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. There is a growing body of evidence that formation and accumulation of advanced glycation end products (AGEs) progress during normal aging, and at an extremely accelerated rate in diabetes, thus being involved in the pathogenesis of diabetic vascular complications. Furthermore, the interaction by AGEs of their receptor, RAGE, activates down-stream signaling and evokes inflammatory responses in vascular wall cells. Therefore, inhibition of AGE formation or blockade of the RAGE signaling may be a promising target for therapeutic intervention to prevent diabetic vascular complications. This review discusses the molecular mechanisms of diabetic retinopathy, especially focusing on the AGE-RAGE system. Several types of inhibitors of the AGE-RAGE system and their therapeutic implications are also reviewed here.     

New potential agents in treating diabetic kidney disease: the fourth act

Despite the worldwide epidemic of chronic kidney disease complicating diabetes mellitus, current therapies directed against nephroprogression are limited to angiotensin conversion or receptor blockade. Nonetheless, additional therapeutic possibilities are slowly emerging. The diversity of therapies currently in development reflects the pathogenic complexity of diabetic nephropathy. The three most important candidate drugs currently in development include a glycosaminoglycan, a protein kinase C (PKC) inhibitor and an inhibitor of advanced glycation. In targeting primary mechanisms by which hyperglycaemia contributes to diabetic complications, these drugs could provide risk reduction complementary to the partial reduction proven for ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers). Glycosaminoglycans act to restore glycoproteins present in reduced amounts in the glomerular basement membrane and mesangium of diabetic animal models. Components of the drug sulodexide prevent pathological changes and proteinuria in diabetic rats. Reductions in albuminuria, a hallmark of early diabetic kidney disease, have been reported in initial human trials. In the US, a multicentre phase II study has been completed, with an interim analysis indicating reduction in urinary albumin losses. Pivotal phase II trials have begun in patients with type 2 diabetes. A second metabolic pathway of diabetic complications is overexpression of PKC. Several activators of this family of intracellular kinases have been identified and PKC activation may result in tissue damage through a variety of mechanisms. In animal models, the inhibitor ruboxistaurin reduces albuminuria, diabetic histological changes and kidney injury. Like sulodexide, drug development of ruboxistaurin has reached completion of a phase II evaluation with mixed results. The third metabolic target is the nonenzymatic formulation of advanced glycation end-products (AGEs) through well described biochemical pathways. Multiple pathways lead to AGE accumulation in tissues in diabetes and diverse AGE products are formed. AGE deposition has been implicated in animal models of diabetic nephropathy. The leading AGE inhibitor currently in development is pyridoxamine, which has multiple actions that inhibit glycation. Pyridoxamine is an efficient AGE inhibitor in experimental diabetes. A phase II study in diabetic patients with nephropathy reported mixed efficacy results and a favourable safety profile. Phase III evaluation of pyridoxamine has not begun. These three classes of potential therapies, if successfully developed, will confirm that diabetic kidney disease has entered the era of biochemical treatments.     

The AGE of the matrix: chemistry, consequence and cure

Accumulation of advanced glycation endproducts (AGEs) plays a crucial part in the development of age-related diseases and diabetic complications. AGEs are formed in vivo via the so-called Maillard reaction: a reducing sugar reacts with a protein to form a labile Amadori product that is subsequently stabilized, producing an irreversible, non-enzymatic post-translational modification of the protein involved. Recently, it has become clear that, in addition to sugars, lipids play an important role in the initiation of AGE formation, and that genetic factors contribute to an individual's AGE levels. The highest AGE levels are found in tissues with slow turnover, such as tendon, skin, bone, amyloid plaques and cartilage. AGEs exert their effects by adversely affecting the mechanical properties of the matrix and by modulating tissue turnover. In cartilage, these detrimental effects result in tissue that is more prone to the development of osteoarthritis. As such, the accumulation of AGEs provides the first molecular mechanism explaining the age-related increase in the incidence of osteoarthritis. Ongoing research into anti-AGE-ing therapies, such as pyrodoxamine and thiazolium compounds, which are often developed to prevent AGE-induced diabetic complications, might also prove beneficial for the prevention of osteoarthritis.     

Advanced glycation end product (age) inhibitors and their therapeutic implications in diseases

Nonenzymatic modification of proteins by reducing sugars, a process that is also known as the Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. There is a growing body of evidence that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, and are thus involved in the pathogenesis of various diseases such as diabetic vascular complications and neurodegenerative diseases. Therefore, inhibition of AGE formation may be a promising target for therapeutic intervention in AGE-related disorders. In this review, we discuss several types of AGE inhibitors and their therapeutic implications in diseases.     

Blockade of diabetic vascular injury by controlling of AGE-RAGE system

Vascular complications result in disabilities and short life expectancy in diabetic patients. During prolonged hyperglycemic exposure, non-enzymatically glycated protein derivatives termed advanced glycation endproducts (AGE) are formed at an accelerated rate and accumulated in blood and in tissues. Studies performed in vitro and in vivo revealed AGE and their receptor RAGE as the major accounts for vascular cell derangement characteristic of diabetes. The AGE-RAGE system would thus be considered as a candidate molecular target for overcoming diabetic vascular complications. Potential preventive and therapeutic approaches toward it include inhibition of AGE formation, breakage of preformed AGE-proteins crosslinks, blockade of AGE-RAGE interactions with RAGE competitors or antagonists and RAGE-specific signaling inhibition.     

Serum levels of glucose-derived advanced glycation end products are associated with the severity of diabetic retinopathy in type 2 diabetic patients without renal dysfunction

Reducing sugars can react nonenzymatically with the amino groups of proteins to form Amadori products and subsequently cross-linked, heterogeneous fluorescent derivatives called advanced glycation end products (AGE). AGE can arise in vivo from various types of reducing sugars or dicarbonyl compounds and their formation and accumulation are known to progress during normal aging. In individuals with diabetes mellitus, this progression is greatly accelerated. The aim of the present study was to investigate which kinds of serum AGE components were associated with the severity of diabetic retinopathy in 72 type 2 diabetic patients without renal dysfunction. Serum levels of glucose-, glyceraldehyde- or methylglyoxal-derived AGE (methyl-AGE) were measured by an enzyme-linked immunosorbent assay. No significant correlations were found between serum levels of various AGE and HbA1c level, current age, systolic and diastolic pressure, diabetes duration, serum creatinine or blood urea nitrogen level in type 2 diabetic patients. A significant elevation of serum glucose-AGE was found to be associated with severity of diabetic retinopathy. While no differences in serum methyl-AGE levels were found between patients with diabetic retinopathy and those without, serum levels of glyceraldehyde-AGE showed a tendency to increase as normal retinal status advanced to simple and proliferative retinopathy (p = 0.06). The present results suggest that among various types of AGE, glucose-AGE serum levels may be a useful marker of diabetic retinopathy in type 2 diabetic patients without renal dysfunction.     

Advanced glycation and advanced lipoxidation: possible role in initiation and progression of diabetic retinopathy

Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pathogenic mechanisms have been proposed, the underlying dysfunctional biochemical and molecular pathways that lead to initiation and progression of this complication remain largely unresolved. There is little doubt that the pathogenesis of diabetic retinopathy is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or limit retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. The formation and accumulation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) are among several pathogenic mechanisms that may contribute to diabetic retinopathy. AGEs/ALEs can form on the amino groups of proteins, lipids and DNA through a number of complex pathways including non-enzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intra-molecular and intermolecular cross-link formation. AGEs/ALEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function, as determined by a growing number of in vitro and in vivo studies. Evidence now points towards a pathogenic role for advanced glycation/lipoxidation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE/ALE-related pathology in the diabetic retina at a cellular and molecular level. It will also outline how recent pharmaceutical strategies to inhibit AGE/ALE formation or limit their pathogenic influence during chronic hyperglycaemia may play a significant role in the treatment of diabetic retinopathy.     

Antihyperglycemic activity and inhibition of advanced glycation end product formation by Cuminum cyminum in streptozotocin induced diabetic rats

Cuminum cyminum is widely used as a spice in many countries. The aim of the present study was to investigate the effect of methanolic extract of seeds of C. cyminum (CC) on diabetes, oxidative stress and formation of advanced glycated end products (AGE) and obtain comparison with glibenclamide. In vitro studies indicated that CC inhibited free radicals and AGE formation. Treatment of streptozotocin-diabetic rats with CC and glibenclamide for 28 days caused a reduction in blood glucose, glycosylated hemoglobin, creatinine, blood urea nitrogen and improved serum insulin and glycogen (liver and skeletal muscle) content when compared to diabetic control rats. Significant reduction in renal oxidative stress and AGE was observed with CC when compared to diabetic control and glibenclamide. CC and glibenclamide improved antioxidant status in kidney and pancreas of diabetic rats. Diabetic rats showed increase in rat tail tendon collagen, glycated collagen, collagen linked fluorescence and reduction in pepsin digestion. Treatment with CC significantly improved these parameters when compared to diabetic control and glibenclamide group. Though the antidiabetic effect of CC was comparable to glibenclamide it had better effect in controlling oxidative stress and inhibiting the AGE formation, which are implicated in the pathogenesis of diabetic microvascular complications.     

Novel therapeutics for diabetic micro- and macrovascular complications

Diabetic patients have a two- to four-fold increased risk for the development of microvascular (renal, neuronal and retinal) and macrovascular complications. Unfortunately, these complications may develop in both Type 1 and Type 2 diabetic patients even with careful glycaemic, blood pressure and lipid control. With the worldwide increase in the incidence diabetes, new strategies to prevent the complications are urgently needed. Mediators of vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities, hypertension, oxidative stress, inflammation and advanced glycation end-products (AGEs), which are modified proteins formed by non-enzymatic glycation. AGEs are resistant to enzymatic degradation and therefore very stable, thus their accumulation continues throughout aging. AGE accumulation causes arterial stiffening in the vessel wall, glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through their interaction with their putative receptor the so-called receptor for AGEs (RAGE), AGEs activate endothelial cells and macrophages, generate reactive oxygen species (ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological treatment currently available for either Type 1 or Type 2 diabetic patients does not directly address the excess accumulation of AGEs. Novel compounds that inhibit AGE formation, cleave AGE cross-links or reverse their interaction with RAGE are now accessible and could prove useful in meeting this challenge. Other strategies such as inhibition of the hexosamine pathway, vitamin therapy to reduce oxidation and AGE accumulation, reduction of the ROS, or blocking the actions of growth factors or intracellular messengers of cell differentiation are also currently under research. This review will recount recent advances in the development of therapeutic approaches for inhibiting and treating the development of diabetic end-organ damage.     

Antibodies to advanced glycation end products in children with diabetes mellitus

The tissue accumulation of advanced glycation end products (AGE) alters the structure and function of long-lived proteins. A number of studies have shown that tissue accumulation of AGE correlates with the severity of diabetic complications. Proteins containing AGE are highly immunogenic and anti-AGE antibodies were found in sera of diabetic rats and human. Considering the potential use of anti-AGE antibodies as a marker of AGE deposition during diabetes, we have investigated, by competitive ELISA, the presence of anti-AGE antibodies in sera of 58 children with Type 1 diabetes mellitus. The patients were studied for the period of 5 years. Positive for anti-AGE antibodies were 19 children with diabetes. Fourteen of them showed initial data for vascular complications. Anti-AGE antibodies were related to age (r = .25, P = .024), duration of diabetes (r = .41, P = .0001), HbA1c (r = .27, P = .016), microalbuminuria (r = .41, P = .0001), retinopathy (r = .35, P = .001), triglycerides (r = .27, P = .016), and total cholesterol (r = .19, P = .05). In conclusion, our study showed that the investigation of the levels and dynamics of anti-AGE antibodies might give the possibility for early diagnosis and prognosis of the severity of diabetic late complications.     

The AGE/RAGE axis in diabetes-accelerated atherosclerosis

1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE(-/-) mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.     

Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury

Diabetic patients have shorter life span and poorer Quality of Life mainly due to diabetic vascular complications. Recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vascular complications through their engagement of the receptor for AGE (RAGE). In this review, we summarize our recent studies on the roles of the AGE-RAGE system in diabetes-induced vascular injury. In vitro experiments showed that AGE engagement of RAGE leads to changes in endothelial cells (EC) and pericytes, which are characteristic of diabetic microangiopathy. Diabetic RAGE transgenic mice that overexpress RAGE in vascular cells exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. RAGE overexpression also caused calcium handling impairment in cardiac myocytes. In contrast to the RAGE-overexpressing mice, diabetic RAGE knockout mice showed marked improvement of nephropathy. We found that human vascular cells express a novel splice variant coding for a soluble RAGE protein and named it endogenous secretory RAGE (esRAGE). The esRAGE neutralizes AGE actions on EC and is present in human sera. Individual variations in circulating esRAGE could be a determinant for individual differences in susceptibility or resistance to the development of diabetic vascular complications. The AGE-RAGE system should be, therefore, a candidate molecular target for overcoming diabetic vascular complications.     

Diabetic cardiomyopathy: how much does it depend on AGE?

Diabetic cardiomyopathy refers to dysfunction of cardiac muscle in patients with diabetes that cannot be directly ascribed to hypertension, coronary heart disease or other defined cardiac abnormalities per se. The development of diabetic cardiomyopathy may involve several distinct mechanisms, including increased formation of advanced glycation end products (AGEs) secondary to hyperglycaemia. AGEs may alter structural proteins and lead to increased arterial and myocardial stiffness. Therefore, therapies that prevent or retard development of AGEs in diabetes may be valuable strategies to treat or prevent diabetic cardiomyopathy. In this issue of British Journal of Pharmacology, Wu and colleagues demonstrate that aminoguanidine (inhibitor of AGE formation and protein cross-linking) treatment of a rat model of type I diabetes (rats made insulin deficient with streptozotocin and nicotinamide treatment) ameliorates detrimental changes in left ventricular structure and function. Results from this study are in agreement with previous investigations, suggesting that aminoguanidine is effective in preventing cardiac hypertrophy and arterial stiffening in experimental animal models of diabetes and emphasize the potential pathogenic role of AGEs in diabetic cardiomyopathy.     

Advanced glycation end products of DNA: quantification of N2-(1-Carboxyethyl)-2'-deoxyguanosine in biological samples by liquid chromatography electrospray ionization tandem mass spectrometry

Methylglyoxal (MG) and related alpha-oxoaldehydes react with proteins, lipids, and DNA to give rise to covalent adducts known as advanced glycation end products (AGEs). Elevated levels of AGEs have been implicated in the pathological complications of diabetes, uremia, Alzheimer's disease, and possibly cancer. There is therefore widespread interest in developing sensitive methods for the in vivo measurement of AGEs as prognostic biomarkers and for treatment monitoring. The two diastereomeric MG-DNA adducts of N(2)-(1-carboxyethyl)-2'-deoxyguanosine (CEdG) are the primary glycation products formed in DNA; however, accurate assessment of their distribution in vivo has not been possible since there is no readily available quantitative method for CEdG determination in biological samples. To address these issues, we have developed a sensitive and quantitative liquid chromatography electrospray ionization tandem mass spectrometry assay using the stable isotope dilution method with an (15)N(5)-CEdG standard. Methods for CEdG determination in urine or tissue extracted DNA are described. Changes in urinary CEdG in diabetic rats in response to oral administration of the AGE inhibitor LR-90 are used to demonstrate the potential utility of the method for treatment monitoring. Both stereoisomeric CEdG adducts were detected in a human breast tumor and normal adjacent tissue at levels of 3-12 adducts/10(7) dG, suggesting that this lesion may be widely distributed in vivo. Strategies for dealing with artifactual adduct formation due to oxoaldehyde generation during DNA isolation and enzymatic workup procedures are described.     

AGE-RAGE system and carcinogenesis

Recent clinical studies have reported an increased risk for various types of cancers in patients with diabetes. Diabetes is characterized by increased oxidative stress conditions. Hyperglycemia induces oxidative stress generation in a variety of cells via various metabolic pathways, thus causing oxidative DNA damage, an initial step of carcinogenesis. There is accumulating evidence that advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate under normal aging process and diabetes, are involved in the development and progression of cancers. AGE stimulate oxidative stress generation through the interaction with a receptor for AGE (RAGE), while oxidative stress generation promotes the formation of AGE and increases the expression of RAGE. These findings suggest that the crosstalk between the AGE-RAGE system and oxidative stress generation may form a positive feedback loop, thus further increasing the risk for cancers in patients with diabetes. This paper reviews current knowledge about the role of AGE-RAGE system in the development of various types of cancers.     

Advanced Glycation End Products and Diabetic Complications

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.     

Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links

Glucose and other reducing sugars react non-enzymatically with proteins leading to the formation of advanced glycosylation end products (AGEs) and AGE-derived protein cross-linking. Formation of AGEs is a normal physiological process, which is accelerated under the hyperglycaemic condition in diabetes. Under normal conditions, AGEs build up slowly and accumulate as one ages. Numerous studies have indicated that AGEs contribute to the pathological events leading to diabetic complications, such as age-related diseases, including nephropathy, retinopathy, vasculopathy and neuropathy. Potential therapeutic approaches to prevent these complications include pharmacological inhibition of AGE formation and disruption of pre-formed AGE-protein cross-links. Studies using animal models and preliminary clinical trials have shown the ability of the AGE-inhibitor, pimagedine and the cross-link breaker, ALT-711, to reduce the severity of pathologies of advanced glycosylation. These agents offer potential treatments for glucose-derived complications of diabetes and ageing.