Advanced glycation end products and diabetic foot disease
R E V I E W A R T I C L E Diabetes Metab Res Rev 2008; 24(Suppl 1): S19–S24. Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.861 Advanced glycation end products and diabetic foot disease
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. Keywords
advanced glycation end products; diabetic foot disease; neuropathy;
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) .
amounts of glucose . 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 . 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 . 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 . 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 .
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. Nε -(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-
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 Nε-(carboxymethyl)lysine are formed. It should be
particularly in relation to diabetic complications and
emphasized, however, that it has just recently been under-
ageing . 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 , 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 . 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 . In the recent years, very
nitric oxide and impaired function of growth factors .
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 .
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 . 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 . Meerwaldt et al.
(RAGE) . 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 . 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 . In addition to
macrophages is enhanced, which will lead to increased
these effects, cellular-signalling cascades such as the
foam cell formation . 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 . 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 .
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 Nε-(carboxymethyl)lysine
Peripheral neuropathy is present in majority (90%)
in intramyocardial arteries of individuals with acute
of the individuals with diabetic foot disease .
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
. 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 . Recently,
that may lead to demyelination . 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 .
by intervention at one of the many steps involved inthe formation of AGEs such as by aminoguanidine . 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
. 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 . 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-
. 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 .
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
placebo controlled trial treatment with ALT-711 for
8 weeks, it was shown to reduce pulse pressure andimprove arterial compliance in elderly patients . The
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