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Advanced glycation end products and diabetic foot disease

Diabetes Metab Res Rev 2008; 24(Suppl 1): S19–S24.
Published online in Wiley InterScience ( DOI: 10.1002/dmrr.861
Advanced glycation end products and diabetic foot

Diabetic foot disease is an important complication of diabetes. Thedevelopment and outcome of foot ulcers are related to the interplay between numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and microvascular and/or macrovascular disease.
The formation of advanced glycation end products (AGEs) has been rec- ognized as an important pathophysiological mechanism in the development of diabetic complications. Several mechanisms have been proposed by which Maya S. P. Huijberts, Department ofInternal Medicine, University AGEs lead to diabetic complications such as the accumulation of AGEs in the extracellular matrix causing aberrant cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and activation of key cell signalling pathways with subsequent modulation of gene expression, and intracellular AGE formation leading to quenching of nitric oxide andimpaired function of growth factors. In the last decade, many experimentalstudies have shown that these effects of AGE formation may play a role inthe pathogenesis of micro- and macrovascular complications of diabetes, dia-betic neuropathy and impaired wound healing. In recent years also, severalclinical studies have shown that glycation is an important pathway in thepathophysiology of those complications that predispose to the developmentof foot ulcers. Currently, there are a number of ways to prevent or decreaseglycation and glycation-induced tissue damage. Although not in the area ofneuropathy or wound healing, recent clinical studies have shown that theAGE-breakers may be able to decrease adverse vascular effects of glycationwith few side effects. Copyright  2008 John Wiley & Sons, Ltd.
advanced glycation end products; diabetic foot disease; neuropathy; Introduction
Diabetes and its associated complications have become a public healthproblem of considerable magnitude. Because of the huge premature mor-bidity and mortality associated with diabetes, prevention of complicationsis a key issue and therefore, it is essential to understand the basicmechanisms that lead to tissue damage. The results of large studies intype 1 and type 2 diabetes have clearly established that hyperglycaemiaplays an important role in the pathogenesis of nephropathy, retinopathy,neuropathy and accelerated atherosclerosis, and emphasised that hypergly-caemia is an independent risk factor for these complications [1,2]. Severalmechanisms have been shown to be involved in the effects of hyper-glycaemia on vascular, renal and neural tissues. The endothelial cells, renal mesangial cells and neuronal and Schwann cells cannot efficiently regulate their intracellular glucose concentration, which renders them par- ticularly susceptible to hyperglycaemia induced damage. Several processes are Copyright  2008 John Wiley & Sons, Ltd.
M. S. P. Huijberts et al.
implicated in the effects of intracellular hyperglycaemia.
proteins. However, a rapid extracellular AGE formation These include (1) increased flux through the polyol on short-lived proteins and intracellular AGE formation pathway, which leads to increased intracellular oxidative by reactive dicarbonyl compounds have attracted atten- stress, (2) increased hexosamine pathway activity that tion [7,8]. In the context of intracellular glycation, it results in pathologic gene expression through activation is important to emphasize that glucose has the slow- of serine and threonine residues of transcription factors est rate in the glycation reaction of any sugar. Because by UDP N-acetyl glucosamine, (3) PKC activation with the rate of glycation is directly proportional to the subsequent effects such as increased expression of NF-κB, percentage of sugar in the open-chain form, different gly- PAI-1 and TGF-b as well as downregulation of eNOS, and colytic intermediates such as glyceraldehyde-3-phosphate (4) and non-enzymatic glycation leading to the formation forms much more glycated protein than do equimolar of advanced glycation end products (AGEs) [3].
amounts of glucose [9]. Thus, glycolytic intermediates Diabetic foot disease has been recognized in recent such as dihydroxyacetone-phosphate, glyceraldehyde- years as an important and very costly complication of 3-phosphate and the dicarbonyl compounds glyoxal, diabetes. One in every four patients with diabetes will be methylglyoxal and 3-deoxyglucosone are of importance confronted with a foot ulcer during their lifetime [4,5].
for the intracellular Maillard reaction. Furthermore, Treatment of diabetic foot ulcers is long and intensive the sorbitol pathway generates reactive intermediates and the associated costs are high. Several mechanisms such as fructose, fructose-3-phosphate, glyceraldehyde- and processes play a role in this condition, including 3-phosphate and 3-deoxyglucosone and may also sub- neuropathy, peripheral arterial disease, biomechanical stantially contribute to intracellular AGE formation by the factors, infection and wound healing. The aim of this reaction of these intermediates with proteins [10]. Among review is to present an overview of the general principles these reactive compounds, methylglyoxal is believed to of non-enzymatic glycation, to consider the current be the most potent glycating agent [11]. Methylglyoxal evidence for the role of non-enzymatic glycation in the is mainly formed by the conversion of glyceraldehyde- development of diabetic foot disease and to describe 3-phosphate and dihydroxyacetone-phosphate that are recent data on potential therapeutic modalities.
derived from glucose and fructose metabolism [12].
Methylglyoxal is detoxified by the conversion to S-D-lactoylglutathione and D-lactate, catalysed in the cytosol Formation of glyc(oxid)ation products
of all cells by glyoxalase I and II and reduced glu-tathione. Overexpression of glyoxalase I in endothelial Non-enzymatic glycation, first described by Louis Camille cells completely prevented the hyperglycaemia-induced Maillard in the early 1900s, involves the condensation AGE formation, thus demonstrating the importance of reaction of the carbonyl group of sugar aldehydes with methylglyoxal in the formation of AGEs [13].
the N-terminus or free-amino groups of proteins via a Similar to the formation of AGEs, peroxidation of nucleophilic addition, resulting first in the rapid for- lipids may lead to the formation of reactive carbonyl mation of a Schiff base. Through acid-base catalysis, compounds that react with proteins, thus leading to this labile adduct then undergoes rearrangements to the formation of advanced lipoxidation end products.
the more stable Amadori-products. During the lifetime (Carboxymethyl)lysine, one of the best-characterized of of most cellular and plasma proteins, Amadori-products these compounds, can be regarded as either an AGE or are in equilibrium with glucose and, therefore, the an advanced lipoxidation end product because it can levels of Amadori-products will tend to rise and fall be formed on proteins by both glycoxidation and lipid depending on the glucose concentration. Several studies peroxidation pathways. -(Carboxyethyl)lysine, another have demonstrated that the Amadori-product of albu- AGE/advanced lipoxidation endproduct, is a homolog of min, i.e. Amadori-albumin, is not inert and may play (carboxymethyl)lysine that is formed by the reaction of a direct role in diabetic vascular complications. There- lysine residues in proteins with methylglyoxal.
fore, pharmacological approaches to mitigate the dele-terious effects of Amadori-albumin may be therapeuticapproaches to adverse cardiovascular consequences of Biological effects of AGEs and
diabetes. Only a small part of these relatively stableintermediate Amadori-products undergo further oxida- pathological consequences
tive reactions and can give rise to irreversibly formedAGEs. When oxidation is involved in their formation, It was not until 1980 that the pathophysiological the so-called glycoxidation products such as pentosidine significance of AGEs emerged in medical science, and -(carboxymethyl)lysine are formed. It should be particularly in relation to diabetic complications and emphasized, however, that it has just recently been under- ageing [14]. The physiological consequences of the stood that a large portion of AGEs in the body is derived Maillard reaction in ageing and in the aetiology of a range from exogenous sources, e.g. from regular food, smoking of important diabetic complications have been described in excellent reviews [15–18]. In addition, a large body Because of the slow formation, it was long believed of evidence has been accumulating that the Maillard that AGEs accumulate only on long-lived extracellular reaction is not only implicated in diabetic complications Copyright  2008 John Wiley & Sons, Ltd.
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19–S24.
Glycation and the Foot
but also in the development of age-related diseases aminoguanidine was shown to prevent the decrease such as inflammation [19], atherosclerosis [20–22] and in, both, motor and sensory nerve conduction velocity neurodegenerative disorders [23,24].
that is associated with experimental diabetes [34,35].
Several mechanisms have been proposed by which More recent studies have shown that dorsal root ganglia AGEs lead to diabetic complications: (1) the accumulation neurons express functional RAGE and respond to ligands of AGEs in the extracellular matrix causing aberrant cross- for RAGE with downstream signalling, increased oxidative linking, resulting in a decrease of elasticity of vessels, stress and cellular injury [36]. There is also evidence (2) the binding of AGEs to AGE-receptors on different that RAGE is involved in nerve dysfunction in non- cell types and activation of key cell signalling pathways diabetes–related disease such as vasculitic neuropathies, such as NF-κB activation with subsequent modulation and may be a central inflammatory pathway in peripheral of gene expression in vascular cells such as endothelial nerve damage [37,38]. Also, regeneration of dorsal root cells, smooth muscle cells and macrophages [25,26] and ganglia was shown to be affected by AGE accumulation on (3) intracellular AGE formation leading to quenching of laminin and collagen type IV [39]. In the recent years, very nitric oxide and impaired function of growth factors [13].
interesting data from clinical studies have been published, In endothelial cells, basic fibroblast growth factor is one which suggest that the findings in experimental studies are of the main cellular AGE-modified proteins accompanied relevant for clinical diabetic neuropathy. Bierhaus et al.
by markedly decreased mitogenic activity [8].
have demonstrated that ligands of RAGE, the receptoritself, activated NF-κB, p65 and IL-6 co-localized in themicrovasculature of sural nerves from individuals with AGE and the receptor for AGEs (RAGE)
diabetic neuropathy [40]. This was supported by findingsfrom another group that demonstrated pronounced AGEimmunoreactivity on axons and myelin sheaths in 90% Some of the biological effects of AGEs are modulated of type 2 diabetic patients with both distal symmetric through the interaction with the receptor for AGEs as well as proximal neuropathy [41]. Meerwaldt et al.
(RAGE) [27]. RAGE is a multiligand receptor of the have shown that using the skin autofluorescence reader, immunoglobulin superfamily of cell surface molecules accumulation of skin AGEs correlates with both clinical acting as a receptor not only for several molecules and pre-clinical signs of autonomic and sensory diabetic including AGEs but also for S100/calgranulins and amyloid β-peptides. The receptor recognizes three-dimensional structures such as β-sheets and fibrils ratherthan amino acid sequences. The ligands of RAGE havea common feature, in that they accumulate in tissues AGEs and atherosclerosis
during ageing, inflammation and degenerative diseases.
Engagement of RAGE results in intracellular signalling In approximately 50% of patients with diabetic foot that leads to the activation of NF-κB, a pro-inflammatory ulcers, atherosclerotic disease of the lower extremities transcription factor, which upon binding with the ligand or peripheral arterial disease can be diagnosed [32,43].
is translocated to the nucleus and subsequently activates Glycation of low density lipoprotein was one of the first the transcription of target genes [28]. These include discoveries that related glycation to the development genes for cytokines, adhesion molecules, prothrombotic and progression of atherosclerosis. Glycated low density and vasoconstrictive products, as well as anti-apoptotic lipoprotein is not cleared from the circulation by the factors. The activation of NF-κB is prolonged and results low density lipoprotein receptor but the uptake in in upregulation of the receptor [29]. In addition to macrophages is enhanced, which will lead to increased these effects, cellular-signalling cascades such as the foam cell formation [44]. The induction of diabetes ERK signalling pathway and PI-3 kinases are activated in atherosclerosis prone apo-E null mice resulted in a by the binding of ligands with RAGE [30]. Also, cellular more than five-fold increase in atherosclerotic lesions defense mechanisms are downregulated as a result of the together with increased expression of AGEs and RAGE.
suppression of reduced gluthathione and ascorbic acid Progression of atherosclerosis could be prevented by levels that increase intracellular oxidative stress [31].
treatment with soluble RAGE that reduces AGE/RAGEinteraction [45,46]. AGEs have been also demonstratedin human atherosclerotic plaques and were shown to AGEs and neuropathy
co-localize with NF-κB and tissue factor. Recently, ourgroup has demonstrated that -(carboxymethyl)lysine Peripheral neuropathy is present in majority (90%) in intramyocardial arteries of individuals with acute of the individuals with diabetic foot disease [32].
myocardial infarction; the highest levels were observed Several studies have shown that glycation may play a in diabetic subjects with acute myocardial infarction role in the development of neuropathy. Older studies [47]. Increased skin autofluorescence that reflects tissue have demonstrated that AGEs on myelin can quench accumulation of fluorescent AGEs was shown to predict immunoglobulins and elicit immunological responses cardiac mortality in diabetic patients [48]. Recently, that may lead to demyelination [33]. Treatment with a study was published in which the role of AGEs in Copyright  2008 John Wiley & Sons, Ltd.
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19–S24.
M. S. P. Huijberts et al.
peripheral arterial disease was described. Lapolla et al.
observed increased levels of AGEs such as pentosidine indiabetic patients with peripheral arterial disease, which The first approach is to reduce the formation of AGEs correlated with the Ankle Brachial Index [49].
by intervention at one of the many steps involved inthe formation of AGEs such as by aminoguanidine [53].
Aminoguanidine was the first compound designed to AGEs and wound healing
inhibit AGE formation and has undergone clinical tri-als. Despite the earlier promising results with this drug, Repair of tissue damage is an essential process in diabetic aminoguanidine is unlikely to be used for therapeutic pur- foot disease. It is generally believed that wound heal- pose due to safety concerns and lack of efficacy [54,55].
ing is impaired in diabetes. Wound healing is a complex Metformin that is routinely used in the treatment of type process in which several pathophysiological mechanisms 2 diabetic patients has some structural similarities to are involved. These mechanisms are related to tissue aminoguanidine and it was shown that in type 2 diabetes, remodelling and include among others cellular migra- treatment with metformin reduced levels of methylgly- tion, inflammation, matrix deposition and angiogenesis.
oxal, which is an important precursor of AGE formation Currently, there is some evidence from experimental [56]. One may speculate whether the beneficial effects studies that glycation is involved in impaired wound of metformin in type 2 diabetic patients, as reported in healing in diabetes. High AGE diets are associated with the UKPDS study, are related to these specific effects on delayed (experimental) wound healing [50]. Goova et al.
AGE accumulation. Pyridoxamine is a natural intermedi- have demonstrated that blockade of RAGE using soluble ate of vitamin B6 metabolism and a potent inhibitor of RAGE restores impaired wound healing in diabetic mice the formation of AGEs [57,58]. Marked effects of pyri- [51]. Treatment with aminoguanidine was also shown to doxamine such as delayed development of nephropathy prevent impaired angiogenesis following femoral artery and retinopathy have been demonstrated in diabetic rats.
ligation in diabetic mice. However, there are currently no Pyridoxamine is currently being investigated in phase 3 of clinical studies in which a role for glycation in diabetic clinical trials for the treatment of diabetic nephropathy. It is being reported that all doses are being well tolerated,with no serious adverse effects. The first results suggestthat a marked decrease in albuminuria can be obtained.
Therapeutic modalities
There are several ways to prevent or modulate glycation and its effects that lead to tissue damage. Although thereare only few studies that have specifically addressed The second approach to reduce AGE-induced effects is the prevention or modulation of tissue injury that is of to reduce AGE cross-links in cardiovascular tissue by relevance to diabetic foot disease, a short overview of the so called AGE-breakers [59,60]. ALT-711 or alagebrium current status of these therapies is presented here, see also is the first drug in a new class of therapeutic agents Figure 1 and the detailed review of Monnier et al [52].
that break established AGE cross-links. In a randomized Figure 1. Potential sites of intervention in the formation of AGEs (by aminoguanidine pyridoxamine, metformin and antioxidants),
AGE cross-link breaking (by ALT-711), AGE-mediated damage (by sRAGE and antioxidants)

Copyright  2008 John Wiley & Sons, Ltd.
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19–S24.
Glycation and the Foot
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