DIABETES/METABOLISM RESEARCH AND REVIEWS
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19S24.
Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.861
Advanced glycation end products and diabetic foot
disease
Maya S. P. Huijberts*
Nicolaas C. Schaper
Casper G. Schalkwijk
Department of Internal Medicine,
University Hospital Maastricht,
Maastricht, The Netherlands
*Correspondence to:
Maya S. P. Huijberts, Department of
Internal Medicine, University
Hospital Maastricht, PO Box 5800,
6202 AZ Maastricht, The
Netherlands.
E-mail: mhuij@sint.azm.nl
Received: 9 October 2007
Revised: 12 February 2008
Accepted: 15 February 2008
Copyright 2008 John Wiley & Sons, Ltd.
REVIEW ARTICLE
Summary
Diabetic foot disease is an important complication of diabetes. The
development 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
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 and
impaired function of growth factors. In the last decade, many experimental
studies have shown that these effects of AGE formation may play a role in
the pathogenesis of micro- and macrovascular complications of diabetes, dia-
betic neuropathy and impaired wound healing. In recent years also, several
clinical studies have shown that glycation is an important pathway in the
pathophysiology of those complications that predispose to the development
of foot ulcers. Currently, there are a number of ways to prevent or decrease
glycation and glycation-induced tissue damage. Although not in the area of
neuropathy or wound healing, recent clinical studies have shown that the
AGE-breakers may be able to decrease adverse vascular effects of glycation
with few side effects. Copyright 2008 John Wiley & Sons, Ltd.
Keywords advanced glycation end products; diabetic foot disease; neuropathy;
atherosclerosis; wound healing
Introduction
Diabetes and its associated complications have become a public health
problem of considerable magnitude. Because of the huge premature mor-
bidity and mortality associated with diabetes, prevention of complications
is a key issue and therefore, it is essential to understand the basic
mechanisms that lead to tissue damage. The results of large studies in
type 1 and type 2 diabetes have clearly established that hyperglycaemia
plays 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]. Several
mechanisms 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
S20
implicated in the effects of intracellular hyperglycaemia.
These include (1) increased flux through the polyol
pathway, which leads to increased intracellular oxidative
stress, (2) increased hexosamine pathway activity that
results in pathologic gene expression through activation
of serine and threonine residues of transcription factors
by UDP N-acetyl glucosamine, (3) PKC activation with
subsequent effects such as increased expression of NF-B,
PAI-1 and TGF-b as well as downregulation of eNOS, and
(4) and non-enzymatic glycation leading to the formation
of advanced glycation end products (AGEs) [3].
Diabetic foot disease has been recognized in recent
years as an important and very costly complication of
diabetes. One in every four patients with diabetes will be
confronted with a foot ulcer during their lifetime [4,5].
Treatment of diabetic foot ulcers is long and intensive
and the associated costs are high. Several mechanisms
and processes play a role in this condition, including
neuropathy, peripheral arterial disease, biomechanical
factors, infection and wound healing. The aim of this
review is to present an overview of the general principles
of non-enzymatic glycation, to consider the current
evidence for the role of non-enzymatic glycation in the
development of diabetic foot disease and to describe
recent data on potential therapeutic modalities.
Formation of glyc(oxid)ation products
Non-enzymatic glycation, first described by Louis Camille
Maillard in the early 1900s, involves the condensation
reaction of the carbonyl group of sugar aldehydes with
the N-terminus or free-amino groups of proteins via a
nucleophilic addition, resulting first in the rapid for-
mation of a Schiff base. Through acid-base catalysis,
this labile adduct then undergoes rearrangements to
the more stable Amadori-products. During the lifetime
of most cellular and plasma proteins, Amadori-products
are in equilibrium with glucose and, therefore, the
levels of Amadori-products will tend to rise and fall
depending on the glucose concentration. Several studies
have demonstrated that the Amadori-product of albu-
min, i.e. Amadori-albumin, is not inert and may play
a direct role in diabetic vascular complications. There-
fore, pharmacological approaches to mitigate the dele-
terious effects of Amadori-albumin may be therapeutic
approaches to adverse cardiovascular consequences of
diabetes. Only a small part of these relatively stable
intermediate Amadori-products undergo further oxida-
tive reactions and can give rise to irreversibly formed
AGEs. When oxidation is involved in their formation,
the so-called glycoxidation products such as pentosidine
and N -(carboxymethyl)lysine are formed. It should be
emphasized, however, that it has just recently been under-
stood that a large portion of AGEs in the body is derived
from exogenous sources, e.g. from regular food, smoking
etc [6].
Because of the slow formation, it was long believed
that AGEs accumulate only on long-lived extracellular
Copyright 2008 John Wiley & Sons, Ltd.
M. S. P. Huijberts et al.
proteins. However, a rapid extracellular AGE formation
on short-lived proteins and intracellular AGE formation
by reactive dicarbonyl compounds have attracted atten-
tion [7,8]. In the context of intracellular glycation, it
is important to emphasize that glucose has the slow-
est rate in the glycation reaction of any sugar. Because
the rate of glycation is directly proportional to the
percentage of sugar in the open-chain form, different gly-
colytic intermediates such as glyceraldehyde-3-phosphate
forms much more glycated protein than do equimolar
amounts of glucose [9]. Thus, glycolytic intermediates
such as dihydroxyacetone-phosphate, glyceraldehyde-
3-phosphate and the dicarbonyl compounds glyoxal,
methylglyoxal and 3-deoxyglucosone are of importance
for the intracellular Maillard reaction. Furthermore,
the sorbitol pathway generates reactive intermediates
such as fructose, fructose-3-phosphate, glyceraldehyde-
3-phosphate and 3-deoxyglucosone and may also sub-
stantially contribute to intracellular AGE formation by the
reaction of these intermediates with proteins [10]. Among
these reactive compounds, methylglyoxal is believed to
be the most potent glycating agent [11]. Methylglyoxal
is mainly formed by the conversion of glyceraldehyde-
3-phosphate and dihydroxyacetone-phosphate that are
derived from glucose and fructose metabolism [12].
Methylglyoxal is detoxified by the conversion to S-D-
lactoylglutathione and D-lactate, catalysed in the cytosol
of all cells by glyoxalase I and II and reduced glu-
tathione. Overexpression of glyoxalase I in endothelial
cells completely prevented the hyperglycaemia-induced
AGE formation, thus demonstrating the importance of
methylglyoxal in the formation of AGEs [13].
Similar to the formation of AGEs, peroxidation of
lipids may lead to the formation of reactive carbonyl
compounds that react with proteins, thus leading to
the formation of advanced lipoxidation end products.
(Carboxymethyl)lysine, one of the best-characterized of
these compounds, can be regarded as either an AGE or
an advanced lipoxidation end product because it can
be formed on proteins by both glycoxidation and lipid
peroxidation pathways. N -(Carboxyethyl)lysine, another
AGE/advanced lipoxidation endproduct, is a homolog of
(carboxymethyl)lysine that is formed by the reaction of
lysine residues in proteins with methylglyoxal.
Biological effects of AGEs and
pathological consequences
It was not until 1980 that the pathophysiological
significance of AGEs emerged in medical science,
particularly in relation to diabetic complications and
ageing [14]. The physiological consequences of the
Maillard reaction in ageing and in the aetiology of a range
of important diabetic complications have been described
in excellent reviews [1518]. In addition, a large body
of evidence has been accumulating that the Maillard
reaction is not only implicated in diabetic complications
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19S24.
DOI: 10.1002/dmrr
Glycation and the Foot
but also in the development of age-related diseases
such as inflammation [19], atherosclerosis [2022] and
neurodegenerative disorders [23,24].
Several mechanisms have been proposed by which
AGEs lead to diabetic complications: (1) the accumulation
of AGEs in the extracellular matrix causing aberrant cross-
linking, resulting in a decrease of elasticity of vessels,
(2) the binding of AGEs to AGE-receptors on different
cell types and activation of key cell signalling pathways
such as NF-B activation with subsequent modulation
of gene expression in vascular cells such as endothelial
cells, smooth muscle cells and macrophages [25,26] and
(3) intracellular AGE formation leading to quenching of
nitric oxide and impaired function of growth factors [13].
In endothelial cells, basic fibroblast growth factor is one
of the main cellular AGE-modified proteins accompanied
by markedly decreased mitogenic activity [8].
AGE and the receptor for AGEs (RAGE)
Some of the biological effects of AGEs are modulated
through the interaction with the receptor for AGEs
(RAGE) [27]. RAGE is a multiligand receptor of the
immunoglobulin superfamily of cell surface molecules
acting as a receptor not only for several molecules
including AGEs but also for S100/calgranulins and
amyloid -peptides. The receptor recognizes three-
dimensional structures such as -sheets and fibrils rather
than amino acid sequences. The ligands of RAGE have
a common feature, in that they accumulate in tissues
during ageing, inflammation and degenerative diseases.
Engagement of RAGE results in intracellular signalling
that leads to the activation of NF-B, a pro-inflammatory
transcription factor, which upon binding with the ligand
is translocated to the nucleus and subsequently activates
the transcription of target genes [28]. These include
genes for cytokines, adhesion molecules, prothrombotic
and vasoconstrictive products, as well as anti-apoptotic
factors. The activation of NF-B is prolonged and results
in upregulation of the receptor [29]. In addition to
these effects, cellular-signalling cascades such as the
ERK signalling pathway and PI-3 kinases are activated
by the binding of ligands with RAGE [30]. Also, cellular
defense mechanisms are downregulated as a result of the
suppression of reduced gluthathione and ascorbic acid
levels that increase intracellular oxidative stress [31].
AGEs and neuropathy
Peripheral neuropathy is present in majority (90%)
of the individuals with diabetic foot disease [32].
Several studies have shown that glycation may play a
role in the development of neuropathy. Older studies
have demonstrated that AGEs on myelin can quench
immunoglobulins and elicit immunological responses
that may lead to demyelination [33]. Treatment with
Copyright 2008 John Wiley & Sons, Ltd.
S21
aminoguanidine was shown to prevent the decrease
in, both, motor and sensory nerve conduction velocity
that is associated with experimental diabetes [34,35].
More recent studies have shown that dorsal root ganglia
neurons express functional RAGE and respond to ligands
for RAGE with downstream signalling, increased oxidative
stress and cellular injury [36]. There is also evidence
that RAGE is involved in nerve dysfunction in non-
diabetesrelated disease such as vasculitic neuropathies,
and may be a central inflammatory pathway in peripheral
nerve damage [37,38]. Also, regeneration of dorsal root
ganglia was shown to be affected by AGE accumulation on
laminin and collagen type IV [39]. In the recent years, very
interesting data from clinical studies have been published,
which suggest that the findings in experimental studies are
relevant for clinical diabetic neuropathy. Bierhaus et al.
have demonstrated that ligands of RAGE, the receptor
itself, activated NF-B, p65 and IL-6 co-localized in the
microvasculature of sural nerves from individuals with
diabetic neuropathy [40]. This was supported by findings
from another group that demonstrated pronounced AGE
immunoreactivity on axons and myelin sheaths in 90%
of type 2 diabetic patients with both distal symmetric
as well as proximal neuropathy [41]. Meerwaldt et al.
have shown that using the skin autofluorescence reader,
accumulation of skin AGEs correlates with both clinical
and pre-clinical signs of autonomic and sensory diabetic
neuropathy [42].
AGEs and atherosclerosis
In approximately 50% of patients with diabetic foot
ulcers, atherosclerotic disease of the lower extremities
or peripheral arterial disease can be diagnosed [32,43].
Glycation of low density lipoprotein was one of the first
discoveries that related glycation to the development
and progression of atherosclerosis. Glycated low density
lipoprotein is not cleared from the circulation by the
low density lipoprotein receptor but the uptake in
macrophages is enhanced, which will lead to increased
foam cell formation [44]. The induction of diabetes
in atherosclerosis prone apo-E null mice resulted in a
more than five-fold increase in atherosclerotic lesions
together with increased expression of AGEs and RAGE.
Progression of atherosclerosis could be prevented by
treatment with soluble RAGE that reduces AGE/RAGE
interaction [45,46]. AGEs have been also demonstrated
in human atherosclerotic plaques and were shown to
co-localize with NF-B and tissue factor. Recently, our
group has demonstrated that N -(carboxymethyl)lysine
in intramyocardial arteries of individuals with acute
myocardial infarction; the highest levels were observed
in diabetic subjects with acute myocardial infarction
[47]. Increased skin autofluorescence that reflects tissue
accumulation of fluorescent AGEs was shown to predict
cardiac mortality in diabetic patients [48]. Recently,
a study was published in which the role of AGEs in
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19S24.
DOI: 10.1002/dmrr
S22
peripheral arterial disease was described. Lapolla et al.
observed increased levels of AGEs such as pentosidine in
diabetic patients with peripheral arterial disease, which
correlated with the Ankle Brachial Index [49].
AGEs and wound healing
Repair of tissue damage is an essential process in diabetic
foot disease. It is generally believed that wound heal-
ing is impaired in diabetes. Wound healing is a complex
process in which several pathophysiological mechanisms
are involved. These mechanisms are related to tissue
remodelling and include among others cellular migra-
tion, inflammation, matrix deposition and angiogenesis.
Currently, there is some evidence from experimental
studies that glycation is involved in impaired wound
healing in diabetes. High AGE diets are associated with
delayed (experimental) wound healing [50]. Goova et al.
have demonstrated that blockade of RAGE using soluble
RAGE restores impaired wound healing in diabetic mice
[51]. Treatment with aminoguanidine was also shown to
prevent impaired angiogenesis following femoral artery
ligation in diabetic mice. However, there are currently no
clinical studies in which a role for glycation in diabetic
wound healing has been established.
Therapeutic modalities
There are several ways to prevent or modulate glycation
and its effects that lead to tissue damage. Although there
are only few studies that have specifically addressed
the prevention or modulation of tissue injury that is of
relevance to diabetic foot disease, a short overview of the
current status of these therapies is presented here, see also
Figure 1 and the detailed review of Monnier et al [52].
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.
M. S. P. Huijberts et al.
Inhibition of AGE formation
The first approach is to reduce the formation of AGEs
by intervention at one of the many steps involved in
the formation of AGEs such as by aminoguanidine [53].
Aminoguanidine was the first compound designed to
inhibit AGE formation and has undergone clinical tri-
als. Despite the earlier promising results with this drug,
aminoguanidine is unlikely to be used for therapeutic pur-
pose due to safety concerns and lack of efficacy [54,55].
Metformin that is routinely used in the treatment of type
2 diabetic patients has some structural similarities to
aminoguanidine and it was shown that in type 2 diabetes,
treatment with metformin reduced levels of methylgly-
oxal, which is an important precursor of AGE formation
[56]. One may speculate whether the beneficial effects
of metformin in type 2 diabetic patients, as reported in
the UKPDS study, are related to these specific effects on
AGE accumulation. Pyridoxamine is a natural intermedi-
ate of vitamin B6 metabolism and a potent inhibitor of
the formation of AGEs [57,58]. Marked effects of pyri-
doxamine such as delayed development of nephropathy
and retinopathy have been demonstrated in diabetic rats.
Pyridoxamine is currently being investigated in phase 3 of
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 suggest
that a marked decrease in albuminuria can be obtained.
Reduction of AGE cross-links
The second approach to reduce AGE-induced effects is
to reduce AGE cross-links in cardiovascular tissue by
so called AGE-breakers [59,60]. ALT-711 or alagebrium
is the first drug in a new class of therapeutic agents
that break established AGE cross-links. In a randomized
Diabetes Metab Res Rev 2008; 24(Suppl 1): S19S24.
DOI: 10.1002/dmrr
Glycation and the Foot
placebo controlled trial treatment with ALT-711 for
8 weeks, it was shown to reduce pulse pressure and
improve arterial compliance in elderly patients [61]. The
effect of ALT-711 on diastolic heart failure was studied
in an open-label, observational study in stable patients
with diastolic heart failure. Treatment with ALT-711 for
16 weeks was associated with regression of left ventricular
hypertrophy and improved indices of diastolic function
[62]. Other clinical trials evaluated the effectiveness
of ALT-711 in patients with elevated systolic blood
pressure with or without left ventricular hypertrophy,
and a significant effect on systolic blood pressure was
observed [63]. Recently, improvement of endothelial
dysfunction was demonstrated in patients with isolated
systolic hypertension who were treated with alagebrium
[64]. In pharmacokinetic studies in healthy individuals
and in the clinical trials described above, the occurrence
of serious adverse events in all of the patients treated with
ALT-711 is less than the corresponding incidence rates for
the general population.
Intervention in the AGERAGE pathway
The third approach to reduce the deleterious effects of
AGEs is by intervention in the AGERAGE interaction or
their induced signalling pathway [25]. The soluble form of
RAGE (sRAGE) was reported to reduce deleterious effects
of AGEs. Blockage of RAGE by sRAGE may be a new target
for therapeutic intervention in diabetic disorders.
In addition to these approaches, numerous exist-
ing drugs against diabetic complications, both natural
and pharmacological, have being investigated for their
possible therapeutic potential and most of them have
anti-AGEing effects. Thiamine and benfotiamine, drugs
with antioxidant or metal-chelation properties such as
aspirin, ibuprofen, indomethacin, and flavonoids as well
as angiotensin IIreceptor blockers and angiotensin con-
certing enzyme inhibitors, were reported to be inhibitors
in the formation of AGEs. The question is whether the
biological activities of these drugs are (partly) due to
AGE-lowering [13,65].
Conclusion
There is now substantial evidence that glycation is an
important mechanism in the development and progression
of diabetic complications that are related to diabetic foot
disease such as neuropathy, macrovascular disease and
to a lesser extent, impaired wound healing. Although
clinical intervention studies are still limited, prevention
of glycation or reduction of glycation-induced tissue
damage may open new horizons towards prevention of the
development of lower extremity complications in diabetes
and improving their outcome.
Conflict of interest
The authors have no conflicts of interest.
Copyright 2008 John Wiley & Sons, Ltd.
S23
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DOI: 10.1002/dmrr