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Increasing evidence demonstrates that advanced glycation end products (AGEs) play a
pivotal role in the development and progression of diabetic vascular damage. AGEs are
generated as a result of chronic hyperglycemia. Then, following the interaction with
receptors for advanced glycation end products (RAGEs), a series of events leading to vessel
damage are elicited and perpetuated, which include oxidative stress, increased
inflammation, and enhanced extracellular matrix accumulation. Whereas targeting
glycemic control and treating additional risk factors, such as obesity, dyslipidemia, and
hypertension, are mandatory to reduce chronic complications and prolong life expectancy
in diabetic patients, drug therapy tailored to reducing the deleterious effects of the AGERAGE interaction is being actively investigated and showing signs of promise.
Medicographia. 2009;31:257-265 (see French abstract on page 265)
Accelerated atherosclerosis is the leading cause of morbidity and mortality in patients with
diabetes.1 Several mechanisms, including endothelial cell damage, platelet activation and
aggregation, hypercoagulability, and impaired fibrinolysis, are involved in the pathogenesis
of a thrombogenic diathesis in diabetes.1 Among various biochemical pathways implicated in
diabetic vascular complications, the process of formation and accumulation of advanced
glycation end products (AGEs) and their mode of action play a major role.2-4 AGEs are
generated in the diabetic milieu as a result of chronic hyperglycemia and enhanced oxidative
stress. Then, via pathways also involving receptor-dependent signals, they promote the
development and progression of cardiovascular disease. These compounds interact with
receptors, such as RAGEs (receptors for advanced glycation end products), to induce
oxidative stress, increase inflammation by promoting nuclear factor-B (NFB) activation,
and enhance extracellular matrix accumulation.5-7 These biological effects translate into
accelerated plaque formation and increased cardiac fibrosis, with consequent effects on
cardiac function. In this article, we will deal with the biology of AGEs and RAGEs, with
particular emphasis on their role in diabetes. Strategies to reduce the deleterious effects of the
AGE-RAGE interaction will also be discussed.
found that glucose can auto-oxidize to form reactive carbonyl compounds (glyoxal and
methylglyoxal) which can react with proteins to form glycoxidation products (Figure 2). In
addition to this, products of oxidative stress, such as peroxynitrite, can also induce the
formation of carboxymethyl lysine by oxidative cleavage of Amadori products and/or the
generation of reactive dicarbonyl compounds from glucose (Figure 2). Thus, AGEs can arise
from glucose and lipids through several, partially intermingling reactions. Once formed, they
may damage cellular structures via a number of mechanisms, including the formation of
cross-links between key molecules in the basement membrane of the extracellular matrix
(ECM) and the interaction of AGEs with RAGEs on cell surfaces, thus altering cellular
functions.2-7
Accumulation of AGEs in the ECM occurs on proteins with a slow turnover rate, with the
formation of cross-links that can trap other local macromolecules. In this way, AGEs alter the
properties of the large matrix proteins collagen, vitronectin, and laminin. AGE cross-linking
on type I collagen and elastin causes an increase in the area of ECM, resulting in increased
stiffness of the vasculature. Glycation results in increased synthesis of type III collagen, type
V collagen, type VI collagen, laminin, and fibronectin in the ECM, most likely via
upregulation of transforming growth factor- pathways. Formation of AGEs on laminin
results in reduced binding to type IV collagen, reduced polymer elongation, and lower
binding of heparan sulfate proteoglycan. Glycation of laminin and type I and type IV
collagens, key molecules in the basement membrane, causes inhibited adhesion to endothelial
cells for both matrix glycoproteins. In addition, it has been suggested that AGE formation
leads to a reduction in the binding of collagen and heparan to the adhesive matrix molecule
vitronectin. AGE-induced alterations of vitronectin and laminin may explain the reduction in
binding of heparan sulfate proteoglycan, a stimulant of other matrix molecules in the vessel
wall, to the diabetic basement membrane. As for the role of lipids, glycated low-density
lipoprotein (LDL) reduces nitric oxide (NO) production and suppresses uptake and clearance
of LDL through its receptor on endothelial cells.
Schematic representation of the formation of some common advanced glycation end products
(AGEs).
It must also be kept in mind that AGEs can be absorbed through diet.8 In this regard, foods
high in protein and fat, such as meat, cheese, and egg yolk, are rich in AGEs, whereas those
high in carbohydrates have the lowest amount of AGEs. In addition, increased cooking
temperatures, through broiling and frying, and increased cooking times lead to an increased
amount of AGEs. A diet heavy in AGEs results in proportional elevations in serum AGE
levels and increased cross-linking in patients with diabetes, whereas, conversely, dietary AGE
restriction causes a marked reduction in serum AGEs in healthy subjects.9-11
together, these findings indicate that the AGE-RAGE interaction elicits and potentiates
inflammatory responses through the enhanced generation of reactive oxygen species,
proinflammatory adhesion molecules, and cytokines, causing continued amplification of
inflammatory events.
diabetes during a follow-up period of 18 years.24 AGE level remained a strong predictor of
survival even after adjustment for confounding factors, including C-reactive protein.
At a pathological level,25,26 when atherosclerotic plaques retrieved from human subjects
were studied, it was found that, compared to nondiabetics, plaques from diabetic subjects had
increased RAGE expression, especially in smooth muscle cells and in macrophages within
the lesion (Figure 5).27 In a prospective study, type 2 diabetic patients were randomized to
treatment with diet alone or with diet plus the addition of a statin for four months before
carotid endarterectomy.28 The expression of AGEs and RAGEs as well as myeloperoxidase,
NFB, cyclooxygenase 2, and metalloproteinases 2 and 9 was significantly lower in the
plaques of statin-treated patients. Fewer macrophages, T cells, and HLA-DRexpressing cells
were noted in the lesions of these subjects. Notably, the ex- pression of RAGE in statintreated, plaque-derived macrophages can be restored by in vitro incubation with AGEs.
Additional findings from plaques retrieved from type 2 diabetic patients include larger
necrotic cores and a correlation between RAGE expression on macrophages and apoptotic
smooth muscle cells.25-29 Altogether, the findings indicate that the AGE-RAGE axis may
compromise cell survival and, thereby, promote mechanisms linked to plaque destabilization.
diminished 24-hour urinary proteinuria and progression of retinopathy, but it did not attenuate
the time-to-doubling of serum creatinine.
A molecule which is being actively studied is 4,5-dimethyl-3- phenacylthiozolium chloride
(ALT-711, or alagebrium), a compound that breaks the crosslinks of AGEs.46 Diabetic rats
treated for 4 months with ALT-711 showed reduced collagen III, increased collagen solubility,
and reduced RAGE mRNA expression compared with placebo. In addition, ALT-711 has been
shown to improve left ventricular function, to reduce ventricular collagen, and to lengthen
survival in diabetic animals. Interestingly, in patients with isolated systolic hypertension,
ALT-711 has been reported to enhance peripheral artery endothelial function and improve
overall impedance matching,48 and, in another study, the molecule improved total arterial
compliance in old people with vascular stiffening.49 Pyridoxamine, the natural form of
vitamin B6, and benfotiamine, a lipid-soluble thiamine derivative, inhibit AGE formation
and/or its effects by several mechanisms, which are not fully understood. In phase 2 trials
involving diabetic patients with overt nephropathy,50 pyridoxamine significantly reduced the
change in serum creatinine from baseline, with no differences in urinary albumin excretion.
On the other hand, benfotiamine was shown to prevent macro- and microvascular endothelial
dysfunction and oxidative stress following a meal rich in AGEs in individuals with type 2
diabetes.51 Finally, benfotiamine plus alpha-lipoic acid normalized increased AGE formation
and prevented an increase in monocyte hexosamine- modified proteins in type 1 diabetic
patients.52
Strategies to directly target RAGEs are being developed as well, based on the observation
that chronic administration of anti-RAGE antibodies to mice with diabetes suppressed
nephropathy without apparent adverse effects.53 Further studies have shown that blockade of
RAGEs by neutralizing antibodies reduced atherosclerosis in uremic mice.54 Clinical phase 2
trials are being conceived to assess the potential of RAGE blockade in humans.
Conclusions
Accelerated chemical modification of proteins and lipids during hyperglycemia leads to the
formation of AGEs. AGEs contribute to the development and progression of diabetic vascular
complications through a number of mechanisms, including interaction with their receptors,
RAGEs. A cascade of dramatic events follows this interaction, which include oxidative stress
and activation of inflammatory pathways that all cause proatherosclerotic changes and induce
vessel damage. Reduction of blood glucose levels and correction of additional classic risk
factors for cardiovascular disease remain the most appropriate ways to reduce vascular
complications and prolong life expectancy in diabetic patients. More targeted therapeutic
approaches aimed at preventing the deleterious effects of the AGE-RAGE interaction have
remarkable potential, and initial studies in humans show encouraging results.
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ketoses), ultimately result in the formation of AGEs. AGEs in humans have been
predominantly chemically characterized by the detection of pentosidine and N-carboxymethyl lysine (CML). Both pentosidine and CML have been found to accumulate in skin and
lens collagen matrix at accelerated rates in diabetic patients. Indications are that collagen in
IDDM patients undergoes widespread chemical alterations that result in decreased solubility,
alter binding affinities to enzymes, increased stability, accelerated cross-linking and increased
browning. Accumulation of AGEs with structural alterations result in altered tissue properties
that contribute to the reduced susceptibility to catabolism and to the aging of tissues. Also,
when accelerated by hyperglycemia, AGE accumulation is believed to contribute to the
gradual development of diabetic complications. Pentosidine concentrations in the skin of
IDDM patients are often elevated and correlate to the severity of complications. It has also
been suggested that pentosidine is not just a subset of diabetic complications but rather a
general diagnostic feature of the disease process.
Introduction
AGEs alters the structural properties of tissue proteins and reduces their susceptibility to
catabolism (7, 23). It has been shown that the process of AGE formation is accelerated by
hyperglycemia (4, 7, 16). Some of the protein alterations observed in diabetic patients
resemble those in much older, non-diabetic patients, suggesting diabetes induced early aging'
(20).
The chemical nature of AGEs in vivo is largely unknown, but there is a growing population of
structurally-defined AGE adducts such as pyrraline, pentosidine, N-carboxy-methyl lysine
(CML) and crossline that are found to be elevated in diabetic tissues (7, 15, 21). The best
found chemically characterized AGEs in humans are pentosidine and CML (see Figures 1, 2)
(16, 23). Some of the highest levels of pentosidine have been detected in individuals afflicted
with DM (19). Evidence has shown that elevated skin pentosidine levels in individuals with
DM correlate with the severity of the complications (19). Initial investigations have shown
that pentosidine can be detected in smaller levels in various tissues of noncollagenous origin,
including the blood and the human lens (19).
Protein glycation and AGE formation are accompanied by increased free radical activity that
contributes to the bimolecular damage in diabetes (1, 13, 23). AGEs act as mediators and can
initiate a wide range of abnormal responses in cells and tissues such as the inappropriate
expression of growth factors, alterations in growth dynamics, accumulation of extra-cellular
matrix and initiation of cell death (21, 23), through decreased solubility, elasticity and
enzymatic affinities in long-living proteins such as collagen (8, 15).
A number of these chemical and physical skin changes occur in human skin collagen with age
and appear to be accelerated in diabetes (12, 13). AGE cross-linking reactions in collagen
contributes to diabetic circulatory complications such as vascular stiffening and myocardial
dysfunction (22, 23). Although the mechanisms underlying the development of the
complications of diabetes are not fully understood, there is now a consensus that
hyperglycemia does play an important role in the development of retinopathy, nephropathy,
neuropathy and joint stiffness (10, 13). For example, increased serum and tissue levels of
AGEs due to a reduced removal by the kidneys have been evident in end-stage renal failure
(23). In vitro and in vivo studies have shown that AGEs result in irreversible cross-links in
long living matrix structural proteins such as type IV collagen, laminin and fibronectin (23).
Biochemistry of AGEs
AGEs form via a non-enzymatic condensation reaction between reducing sugars and -amino
group or N-terminal groups (7, 10, 15, 16, 21-23) via a neucleophilic addition with
formation of a Schiff base (1, 4). The Schiff base rapidly reaches an equilibrium level in vivo,
reflecting the surrounding glucose concentration.
The chemically unstable Schiff bases form relatively fast and are highly reversible (4, 21, 22).
Over a period of weeks, a slow chemical rearrangement of the Schiff base occurs, resulting in
the formation of stable yet highly reversible ketoamine (Amadori product), an initial reaction
product and intermediate in the formation of AGEs (1-5, 21, 22). Amadori adduct formation
is slower but much faster than the reverse reaction, leading to accumulation of Amadori
glycation products on various proteins (4, 21, 22). Reactive AGE-forming intermediates can
arise from oxidative reactions ("glycoxidation") of free sugar or from initial Schiff base
condensation products with protein amino groups, rather than just from the "classical"
Amadori rearrangement (3). The presence of AGE cross-links in collagen is suggested to
contribute to the severity of diabetic complications (1, 6, 12) although the degree to how
much these relate is unknown.
Adducts of Glycation
The chemical nature of important AGEs as they occur in vivo is largely unknown due to their
heterogeneous and unstable nature; however, there is a growing population of structurally
defined AGE adducts such as pyrraline, pentosidine and CML, all of which have been found
at elevated levels in diabetics (1, 4, 21). The two most commonly measured AGEs are CML
and pentosidine, which are glycoxidation products, formed by sequential glycation and
oxidation reactions (3). The adduct formed by glycation of lysine residues in protein is
termed fructoselysine (FL) (see Figure 3), and levels of FL in hemoglobin, plasma proteins,
collagen, hair, lens and numerous other proteins in the body are also known to increase in
proportion to the degree of hyperglycemia in diabetes (8).
Pentosidine has been detected and measured in tissue proteins by chemical and
chromatographic methods (2, 17, 19). Pentosidine is unique in that it can be formed by the
reaction of lysine and arginine, forming a fluorescent crosslink with any of several
carbohydrate precursors including glucose, ribose, ascorbic acid, and 3-deoxyglucosone (see
Figure 2) (7, 22). The development of increased fluorescence of proteins in diabetes and
aging is enhanced by oxidation reactions and carbohydrate or lipid-dependent processes (7).
It has been proposed that AGEs such as pentosidine are in fact active intermediates in the
cross-linking of proteins and formation of reactive oxygen species (2).
Pentosdine has been found in a variety of tissues of human origin including skin, tracheal
cartilage, cortical bone, aorta, cardiac muscle, lung, liver, kidney, lens, red blood cells, and
blood proteins (19). Pentosidine has been found to accumulate in the skin and lens at
accelerated rates in diabetics (11, 15). Overall, correlations between skin pentosidine levels
and the severity of long-term complications indicate that pentosidine parallels severity (19).
Formation of elevated skin pentosidine levels in IDDM patients with severe complications,
although unclear, has been associated to poorer metabolic control compared to those with less
severe complications (19). Therefore, skin pentosidine would be formed primarily from
glycated skin collagen and should reflect cumulative glycohemoglobin AIC values which are
now a chemically accepted indicator of glycemic control (4, 7).
Preventative Measures
Poor metabolic control and other characteristics of IDDM result in diabetic nephropathy,
neuropathy, retinopathy, atherosclerosis and difficulty in healing wounds (1). Preventative
measures for clinical problems that may be the result of accelerated AGE production with
IDDM include improvement of glycemic control (4, 10). Recent studies have shown that
when the quality of patient control is good (for example, patients who maintain a normal
blood-glucose level) the concentrations of the AGE-products, CML and pentosidine, are
typically lower (18). However, recent clinical trials suggest that when complications are
already present, improvement of glycemic control alone may not be sufficient to prevent the
continued progression of these pathologic processes, potentially due to the irreversibility of
AGE formation as well as poor clearance mechanisms.
Due to detrimental effects of AGEs, researchers attempt to find inhibitors of the advanced
glycation process (6).Brownlee et al. suggest that optimal future therapies to minimize tissue
damage may require pharmacologic agents that directly interfere with the self-perpetuating
component of hyperglycemia-initiated tissue damage (4). Aminoguanadine (AG) (see Figure
4), an inhibitor of advanced glycation reactions in vitro, has been found to inhibit the
development of diabetic complications in animal models of diabetes. (4, 12). Booth et al.
suggest that these inhibitors can potentially react as a hydrazine with carbonyls of Amadori
intermediates or can hunt for reactive dicarbonyls through its guanidinium moiety. However,
the mechanism of AGE formation is only partially understood, making it difficult to identify
the precise chemical products responsible for in vivo damage and thus impede the
development of specific inhibitors.
Summary
that can be used to decrease or predict the occurrence of long term complications of AGE
formation to improve the quality and length of life for IDDM patients.
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receptors and diabetic angiopathy. Diabetes Metabolism 27, 535-542.
Aging
The Maillard reaction over your lifetime
Aging
There are many scientists who believe that the human body may be
viewed as a low temperature oven, indeed viewing the body as a 'slowcooker' with a relatively long cooking time of 75 years or more [your
lifetime] where the Maillard reaction occurs on a daily basis progressively
damaging proteins such as collagen, elastin etc.
Diabetics are known to age must faster. The authors of one study stated
the following:
'These results support the description of diabetes as a disease
characterized by accelerated chemical aging of long-lived tissue
proteins81.'
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From Schiff Bases to Amdori products to AGEs
This Schiff base in the human body is a reversible reaction which stabilizes
[reaches equilibrium] within several hours of the complex forming.
The increased risk with eating high glycemic index carbohydrates was
largely seen in individuals with a body mass index [BMI] over 23 2. To
calculate your BMI to see if you are at risk with high glycemic index foods
click on this link: BodyCalculator
So every meal counts. Keeping your glucose spikes low and keeping insulin
levels low should be the goal of any individual who wants to avoid
diabetes, premature aging, dementia, heart disease and numerous other
chronic illnesses including cancer.
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AGEs and RAGEs
RAGEs which are receptors for AGEs, are autocatalytic. In other words
once an AGE binds to a RAGE, more RAGEs are formed to bind to even
more AGEs --- a positive feedback loop.
AGEs binding to their RAGEs are associated with numerous disease states
including: inflammatory diseases such as atherosclerosis, asthma,
arthritis, myocardial infarction, peripheral vascular disease, nephropathy,
retinopathy , cataracts, neuropathy, Alzheimers disease