Advanced glycation end products (AGEs)

and their receptors (RAGEs) in diabetic

vascular disease
by P. Marchetti, Italy

Piero MARCHETTI, MD, PhD

Department of Endocrinology
and Metabolism
University of Pisa
Pisa, ITALY

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.

Advanced glycation end products (AGEs)

Advanced glycation end products (AGEs) are modifications of proteins or lipids that become
nonenzymatically glycated and oxidized after contact with aldose sugars. In other words, they
are the result of a chain of chemical reactions which follow an initial glycation reaction. The
intermediate products are known as Schiff base, Amadori, and Maillard products, after the
researchers who first described them. Initially, glycation involves covalent reactions between
free amino groups of amino acids, such as lysine, arginine, or protein terminal amino acids
and sugars (glucose, fructose, ribose, etc), to create, first, the Schiff base and then Amadori
products, of which the best known are HbA1c (Figure 1) and fructosamine (fructoselysine).
Additional reactions occur successively.

Figure 1. Formation of glycated hemoglobin A1c (HbA1c). HbA1c is an Amadori product

and is formed through the intermediate Schiff base step.
AGE formation from fructoselysine involves the nonoxidative dissociation of fructoselysine
to form new reactive intermediates that again modify proteins to form AGEs of various
different chemical structures (Figure 2). Alternatively, fructoselysine decays and releases its
carbohydrate moiety either as glucose or as the more reactive hexoses, such as 3deoxyglucosone, which themselves may modify proteins. In addition, it has recently been

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

Receptor for AGEs (RAGE)

RAGE is a member of the immunoglobulin superfamily of receptors. The human RAGE gene
is on chromosome 6 in the major histocompatibility complex between genes for class II and
class III. It is composed of 11 exons and a 3_UTR region, and common variants have been
described.12 For example, the Gly82Ser polymorphism in exon 3 is located in the ligandbinding V-domain of RAGE (see below), and has been studied to assess its role in subjects
with vascular disease. It was found that cells bearing the Ser82 isoform displayed higher
ligand affinity resulting in increased activation of the proinflammatory proteins TNF-, IL-6,
and MMP-9.13 In contrast, the 374T/A polymorphism in the promoter region of the RAGE
gene has been shown to exert protective effects. In diabetic patients with the mutation, there
was a lower incidence of coronary heart disease, acute myocardial infarction, and peripheral
vascular disease, and, in nondiabetic individuals, the presence of the polymorphism was
associated with a reduced risk of coronary artery disease.6,14
At the protein level, RAGE is an approximately 45-kDa protein. It has an extracellular
component, consisting of two Ctype (constant) domains preceded by one V-type (variable)
immunoglobulin-like domain (Figure 3). RAGE has a single transmembrane domain
followed by a cytosolic tail. The V domain in the N-terminus is important in ligand binding,
and the cytosolic tail is critical for RAGE-induced intracellular signaling. In addition to fulllength RAGE, truncated forms have also been described (due to mRNA splice variants). In
particular, one variant protein (N-truncated type) lacks the V-type immunoglobulin domain,
but it is otherwise identical to full-length RAGE and is retained in the plasma membrane.

Figure 3. products (RAGE). Adapted from reference 6: Basta G. Atherosclerosis.

2008;196:9-21. Copyright 2008, Elsevier, Ltd.
However, since the V-type immunoglobulin domain is deleted, this RAGE form shows
impaired ability to bind ligands. In addition, forms of RAGE lacking both the cytosolic and
the transmembrane domains have been described. These forms of RAGE are, therefore,
secreted extracellularly, can be detected in circulating blood, and are called soluble receptors
for advanced glycation end products (sRAGEs).5-7 This is of importance since sRAGEs can
bind their ligands in the circulation, thus preventing the adverse intracellular events of the
AGE-RAGE axis (see below).
It has to be kept in mind, however, that RAGEs also bind ligands other than AGEs.5-7 Shortly
after its discovery, structural analysis of the ligand- RAGE interaction revealed that the
receptor recognized three-dimensional structures, such as sheets and fibrils, rather than
specific amino acid sequences (ie, primary structures). As a matter of fact,RAGEs bind
amyloid- peptide (which accumulates in Alzheimers disease) and amyloid A (which
accumulates in systemic amyloidosis). Further ligands of RAGE are S100/calgranulins, a
family of closely related calcium-binding polypeptides that accumulate extracellularly at sites
of chronic inflammation. An additional proinflammatory ligand of RAGE is the DNAbinding protein HMGB1 (amphoterin), which is released by cells undergoing necrosis.
Finally, RAGEs also interact with surface molecules on bacteria and leukocytes. Thus,
RAGEs have a large repertoire of ligands, making this receptor crucial at the crossroad
between diabetes, inflammation, and vascular disease.

Cellular effects of the AGE-RAGE interaction

RAGE is expressed in many tissues and is most abundant in the heart, lung, skeletal muscle,
and vessel wall. In addition, it is present in monocytes/macrophages and lymphocytes. In
vessels, it is located in the endothelium and in smooth muscle cells. Physiologically, the

receptor might play a role in developmental processes, at least as shown in a few

experimental models. For example, RAGE activation contributes to axonal sprouting that
accompanies neuronal development, while reduction of functional regeneration of the sciatic
nerve occurs after blockade of RAGE.15,16 However, RAGE-/- mice demonstrate neither
obvious neuronal deficits nor overt behavior abnormalities, indicating that RAGE may
contribute to neuronal development, but that there are redundant systems that substitute for
this receptor in its absence.16
Intriguingly, it has been demonstrated that activation of RAGE can promote cell survival
through increased expression of the antiapoptotic protein Bcl-2.15 However, whereas
nanomolar concentrations of ligand induced trophic effects in RAGE-expressing cells,
micromolar concentrations caused apoptosis in a manner that appeared to depend on
oxidative stress.15 For both of these outcomes, the cytoplasmic domain of RAGE was
required, as cells lacking the cytosolic tail were unresponsive. After being highly expressed
during embryonic development, RAGE is downregulated in most organs during normal life.
With aging, RAGE expression increases again, possibly due to the accumulation of RAGE
ligands, which upregulate receptor expression. In the cases of diabetes, inflammation, and
atherosclerosis, there is marked induction of RAGE due to the action of its ligands and to
several mediators from activated inflammatory cells.5-7,16,17 In turn, the binding of ligands to
RAGE induces further upregulation of the receptor (positive feedback), leading to a vicious
circle. Unsurprisingly, one of the locations where RAGE expression is enhanced is in the
diabetic atherosclerotic plaque (particularly at the vulnerable regions of the plaque and in
macrophages), where it colocalizes with cyclooxygenase 2, microsomal prostaglandin E2,
and metalloproteases.
The most important pathological consequence of RAGE interaction with its ligands is the
activation of several intracellular pathways, leading to the induction of oxidative stress and a
broad spectrum of signaling mechanisms, schematically represented in Figure 4. The
interactions lead to prolonged inflammation, mainly as a result of the RAGE-dependent
expression of proinflammatory cytokines and chemokines. In the vasculature, the first
pathological consequence of RAGE interaction with its ligands is the induction of increased
intracellular reactive oxygen species (ROS), the generation of which is linked, at least in part,
to the activation of the NAD(P)H-oxidase system. In addition, in endothelial cells,
mitochondrial sources of ROS are also involved, following the AGE-RAGE interaction.
Experimental evidence demonstrates that RAGE dependent modulation of gene expression
and cellular properties depends upon signal transduction. Based on the intensity and duration
of stimulation, diverse signaling pathwaysmay be triggered (Figure 4), including p21ras,
erk1/2, mitogen-activated protein kinases (MAPKs), p38 and SAPK/JNK MAPKs, PI3K, and
the JAK/STAT pathway. The downstream consequence of these changes is the activation of
key transcription factors (nuclear factor-B [NFB], in particular), which in turn cause
induction of molecules with damaging actions on the cells (Figure 4). In human endothelial
cells, RAGE activation enhances the expression of adhesion molecules, including VCAM-1,
ICAM-1, and E-selectin. AGE bound to RAGE on the endothelium also determines
alterations to the surface antithrombotic properties of flowing blood, as shown by a reduction
in thrombomodulin expression and the concomitant induction of tissue factor expression that
confers procoagulant properties. The interaction of AGEs with RAGEs in monocytes induces
their activation to macrophages, which manifests with the induction of platelet-derived
growth factor, insulin-like growth factor 1, and proinflammatory cytokines, such as IL-1 and
TNF-. In addition to all this, AGE-RAGE interaction promotes monocyte chemotaxis and, at
the level of smooth muscle cells, is associated with increased cellular proliferation. Viewed

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.

Figure 5. RAGE (receptor for advanced glycation end products)

expression is higher in plaques from type 2 diabetic patients. Adapted from reference 27:
Cipollone F, Iezzi A, Fazia M, et al. Circulation. 2003; 108:1070-1077. Copyright 2003,
American Heart Association, Inc.

AGE, RAGE, and diabetes

It has long been recognized that increased HbA1c (a precursor of AGEs) levels are associated
with a higher incidence of vascular complications and reduced life expectancy in diabetic
patients. In addition, intervention studies to reduce HbA1c lead to lower micro- and
macrovascular lesions and a reduced death rate over several years.18,19
Serum levels of AGEs in patients with type 2 diabetes and coronary heart disease are higher
than those in patients without heart disease and correlate with the severity of the coronary
syndrome.3,4,20 Furthermore, AGE levels are higher in type 2 diabetic patients with
peripheral artery occlusive disease compared with those without it. Serum levels of AGE in
type 1 diabetic patients are associated with decreased isovolumetric relaxation time of the left
ventricle, a marker of left ventricular diastolic dysfunction.21 AGEs are also related to other
other features of cardiovascular disease, such as carotid stenosis, peripheral artery occlusive
disease, increased pulse pressure, and a low ankle-brachial index.3,4,22 Unsurprisingly, other
studies have demonstrated that serum AGE level is a predictor for heart failure and new
cardiac events.3,4 In addition, work has shown that high AGE levels correlate with poor
outcomes, as demonstrated by adverse cardiac events in patients after cardiac surgery,
prolonged ventilation times, and longer stays in intensive care units.3,4 Finally, in diabetic
patients receiving cardiac stents, an elevated level of serum AGEs appears to be an
independent risk factor for the development of angiographic restenosis.23
In terms of relationship with life expectancy, it has been reported that increased serum levels
of AGE predicted increased total cardiovascular and coronary mortality in women with type 2

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.

Figure 6. NF B activation by AGEs is reduced by the presence

of gliclazide. *P<0.05 vs the other groups.
Abbreviations: AGE, advanced glycation end product; NF B, nuclear factor-B. Adapted
from reference 43: Mamputu JC, Renier G. Diabetes Obes Metab. 2004;6:95-103. Copyright
2004, Blackwell Publishing, Ltd.
Obviously, direct intervention on the AGE-RAGE system might lead to new and more
targeted therapeutic approaches. Molecules under investigation for possible clinical use can
be roughly subdivided into two main groups: those that prevent the formation of AGEs and
those that degrade existing AGEs. For example, aminoguanidine is a hydrazine compound
that prevents AGE formation by interacting with derivatives of early glycation products that
are not bound to proteins. In animal models of diabetes, aminoguanidine treatment increased
arterial elasticity, decreased vascular AGE accumulation as well as the severity of
atherosclerotic plaques, and, in addition, reduced accumulation of fibronectin and laminin in
the extracellular membrane of streptozotocin-induced diabetic rats with diabetic
nephropathy.46 In a placebo-controlled, randomized trial in patients with type 1 diabetes
mellitus,47 aminoguanidine caused a slower reduction in glomerular filtration rate,

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.

References
1. Stirban AO, Tschoepe D. Cardiovascular complications in diabetes: targets and interventions. Diabetes Care. 2008;31(suppl 2):S215-221.
2. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation.
2006; 114:597-605.
3. Meerwaldt R, Links T, Zeebregts C, Tio R, Hillebrands JL, Smit A. The clinical relevance of assessing advanced glycation endproducts accumulation in
diabetes. Cardiovasc Diabetol. 2008;7:29.
4. Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res. 2004;53:131-142.
5. Yan SF, Yan SD, Herold K, Ramsamy R, Schmidt AM. Receptor for advanced glycation end products and the cardiovascular complications of diabetes and
beyond: lessons from AGEing. Endocrinol Metab Clin North Am. 2006;35: 511-524.
6. Basta G. Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications. Atherosclerosis. 2008;196: 9-21.
7. Yan SF, DAgati V, Schmidt AM, Ramasamy R. Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the
cardiovascular complications of diabetes & aging. Curr Mol Med. 2007;7:699-710.

8. Xanthis A, Hatzitolios A, Koliakos G, Tatola V. Advanced glycosylation end products and nutritiona possible relation with diabetic atherosclerosis and how
to prevent it. J Food Sci. 2007;72:R125-R129.
9. Koschinsky T, He CJ, Mitsuhashi T, et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy.
Proc Natl Acad Sci U S A. 1997;94:6474-6479.
10. Goldberg T, Cai W, Peppa M, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004;104:1287-1291.
11. Uribarri J, Cai W, Sandu O, Peppa M, Goldberg T, Vlassara H. Diet-derived advanced glycation end products are major contributors to the bodys AGE pool
and induce inflammation in healthy subjects. Ann N Y Acad Sci. 2005;1043: 461-466.
12. Hudson BI, Stickland MH, Grant PJ. Identification of polymorphisms in the receptor for advanced glycation end products (RAGE) gene: prevalence in type
2 diabetes and ethnic groups. Diabetes. 1998;47:1155-1157.
13. Hofmann MA, Drury S, Hudson BI, et al. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun. 2002;3:123135.
14. Pettersson-Fernholm K, Forsblom C, Hudson BI, et al. The functional -374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular
disease in type 1 diabetic patients. Diabetes. 2003;52:891-894.
15. Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H. Coregulation of neurite outgrowth and cell survival by amphoterin and S100
proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem. 2000;275:40096-40105.
16. Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med. 2005;83:876-886.
17. Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H. Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular
injury. J Pharmacol Sci. 2005;97:305-311.
18. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;
353:2643-2653.
19. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:15771589.
20. Kiuchi K, Nejima J, Takano T, Ohta M, Hashimoto H. Increased serum concentrations of advanced glycation end products: a marker of coronary artery
disease activity in type 2 diabetic patients. Heart. 2001;85:87-91.
21. Berg TJ, Snorgaard O, Faber J, et al. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with
type 1 diabetes. Diabetes Care. 1999;22:1186-1190.
22. Lapolla A, Piarulli F, Sartore G, et al. Advanced glycation end products and antioxidant status in type 2 diabetic patients with and without peripheral artery
disease. Diabetes Care. 2007;30:670-676.
23. Choi EY, Kwon HM, Ahn CW, et al. Serum levels of advanced glycation end products are associated with in-stent restenosis in diabetic patients. Yonsei Med
J. 2005;46:78-85.
24.Kilhovd BK, Juutilainen A, Lehto S, et al. Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in
women with type 2 diabetes: a population-based 18 year follow-up study. Diabetologia. 2007;50:1409-1417.
25. Schalkwijk CG, Baidoshvili A, Stehouwer CD, van Hinsbergh VW, Niessen HW. Increased accumulation of the glycoxidation product Nepsilon(carboxymethyl) lysine in hearts of diabetic patients: generation and characterisation of a monoclonal anti-CML antibody. Biochim Biophys Acta.
2004;1636:82-89.
26. Sakata N, Meng J, Jimi S, Takebayashi S. Nonenzymatic glycation and extractability of collagen in human atherosclerotic plaques. Atherosclerosis. 1995;
116:63-75.
27. Cipollone F, Iezzi A, Fazia M, et al. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response
in human atherosclerotic plaques: role of glycemic control. Circulation. 2003;108: 1070-1077.
28. Cuccurullo C, Iezzi A, Fazia ML, et al. Suppression of RAGE as a basis of simvastatin- dependent plaque stabilization in type 2 diabetes. Arterioscler
Thromb Vasc Biol. 2006;26:2716-2723.
29. Burke AP, Kolodgie FD, Zieske A, et al. Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler Thromb
Vasc Biol. 2004;24:1266-1271.
30. Falcone C, Emanuele E, DAngelo A, et al. Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic
men. Arterioscler Thromb Vasc Biol. 2005;25:1032-1037.
31. Katakami N, Matsuhisa M, Kaneto H, et al. Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible
association with diabetic vascular complications. Diabetes Care. 2005; 28:2716-2721.
32. Koyama H, Shoji T, Yokoyama H, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and
atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:2587-2593.
33. Koyama H, Shoji T, Fukumoto S, et al. Low circulating endogenous secretory receptor for AGEs predicts cardiovascular mortality in patients with end-stage
renal disease. Arterioscler Thromb Vasc Biol. 2007;27:147-153.
34. Basta G, Sironi AM, Lazzerini G, et al. Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and
S100A12 protein. J Clin Endocrinol Metab. 2006;91:4628-4634.
35. Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association between serum levels of soluble receptor for advanced glycation end products
and circulating advanced glycation end products in type 2 diabetes. Diabetologia. 2006;49:2756-2762.
36. Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus
conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen
Ancillary Study Group. Diabetes Control and Complications Trial. Diabetes. 1999;48: 870-880.
37. Schurman L, McCarthy AD, Sedlinsky C, et al. Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Exp
Clin Endocrinol Diabetes. 2008;116:333-340.
38. Ota K, Nakamura J, Li W, et al. Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells. Biochem Biophys Res Commun. 2007;
357:270-275.
39. Ouslimani N, Mahrouf M, Peynet J, et al. Metformin reduces endothelial cell expression of both the receptor for advanced glycation end products and lectinlike oxidized receptor 1. Metabolism. 2007;56:308-313.
40. Diamanti-Kandarakis E, Alexandraki K, Piperi C, et al. Effect of metformin administration on plasma advanced glycation end product levels in women with
polycystic ovary syndrome. Metabolism. 2007;56:129-134.
41. Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are
ameliorated by metformin. J Clin Endocrinol Metab. 2004;89:5535-5541.
42. Mamputu JC, Renier G. Advanced glycation end products increase, through a protein kinase C-dependent pathway, vascular endothelial growth factor
expression in retinal endothelial cells. Inhibitory effect of gliclazide. J Diabetes Complications. 2002;16:284-293.
43. Mamputu JC, Renier G. Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect
of gliclazide. Diabetes Obes Metab. 2004;6:95-103.
44. Li W, Ota K, Nakamura J, et al. Antiglycation effect of gliclazide on in vitro AGE formation from glucose and methylglyoxal. Exp Biol Med. 2008;233:176179.
45. Del Guerra S, Grupillo M, Masini M, et al. Gliclazide protects human islet betacells from apoptosis induced by intermittent high glucose. Diabetes Metab
Res Rev. 2007;23:234-238.
46. Desai K, Wu L. Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? Recent Pat Cardiovasc Drug Discov. 2007;2:89-99.
47. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am
J Nephrol. 2004;24:32-40.
48. Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients
with isolated systolic hypertension. J Hypertens. 2007;25:577-583.
49. Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation.
2001;104: 1464-1470.
50. Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill JB. Effects of pyridoxamine in combined phase 2 studies of patients with
type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol. 2007;27: 605-614.
51. Stirban A, Negrean M, Stratmann B, et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal

rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care. 2006;29:2064-2071.
52. Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia. 2008;
51:1930-1932.
53. Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association between serum levels of soluble receptor for advanced glycation end products
and circulating advanced glycation end products in type 2 diabetes. Diabetologia. 2006;49:2756-2762.
54. Bro S, Flyvbjerg A, Binder CJ, et al. A neutralizing antibody against receptor for advanced glycation end products (RAGE) reduces atherosclerosis in uremic
mice. Atherosclerosis. 2008;201:274-280.

Keywords: AGE; RAGE; diabetes; vascular disease

REVIEW: Advanced Glycation End-products (AGEs) in Hyperglycemic Patients

by: Julie Hatfield
Institution: Juniata College
Date: October 2005
Abstract

The role of advanced glycation end-products (AGEs) in the development of complications in

individuals with insulin-dependent diabetes mellitus (IDDM) has been explored by previous
studies. However, the relationship between these reactive AGEs and diabetic complications
are still somewhat unknown. Glycation (nonenzymatic glycosylation) processes, also known
as the Maillard reactions, are a series of reactions between carbohydrates and free amino
groups of proteins. The preliminary intermediates, (Amadori products; 1-amino, 1-deoxy, 2-

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

The pathogenesis of diabetic complications continues to be a central issue in current diabetes

research (15). One of the most prevalent metabolic syndromes world-wide, diabetes mellitus
(DM), is characterized by hyperglycemia resulting in short-term metabolic changes in lipid
and protein metabolism and long-term irreversible vascular and connective-tissue changes.
These changes include diabetes-specific complications such as retinopathy, nephropathy and
neuropathy and complications of the macro-vasculature such as atherosclerosis; potentially
resulting in heart disease, stroke and peripheral vascular disease (11). Links between chronic
hyperglycemia and the development of long-term diabetic-specific complications have been
discovered and are yet not completely understood (11, 23).

Figure 1. Structure of fluorophore P (Pentosidine).

Glycation, a chemical modification of proteins with reducing sugars, indicates a possible
explanation for the association (7, 15) between hyperglycemia and the wide variety of tissue
pathologies. Research suggests that reducing sugars can react with the amino groups of longlived proteins to produce non-enzymatic cross-links (19, 23). Formations of these cross-links
occur as end-stage products of the Maillard reaction; they are known as advanced glycation
end-products (AGEs) (7, 20).
AGEs are a class of complex, often unstable, reactive compounds formed in excess during
aging and diabetes mellitus (23). According to the "glycation hypothesis," accumulation of

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).

Figure 2. Structure of carboxyl methyl lysine (CML).

Pentosidine is a fluorescent crosslink with visible wave length fluorescence, making it easy to
detect (15). Methods for synthesizing and detecting AGEs such as pentosidine have been
proposed in various studies (7, 14, 19). Prevention of AGE-mediated cell toxicity has been
proposed as a key strategy in preventing the onset of diabetic complications and some agerelated pathology (21). This review will continue to analyze evidence that AGEs play a
significant role in diabetic complications considering various anti-AGE therapeutic strategies
that appear to reduce the severity and onset of complications (4, 10, 12, 13, 15, 23).
Long-Term Complications Due to AGEs

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

The formation of AGEs is implicated by the pathogenesis of long-term complications of

diabetes (3, 6). There appears to be two general pathophysiologic mechanisms by which
hyperglycemia leads to irreversible tissue damage (4). Intracellular hyperglycemia can result
by increased flux through different metabolic pathways, changing glomerular basement
membrane. Increases in the polyol pathway activity results in metabolic changes too,
consequence of decreasing levels of NADPH, gluthathione and myoinositol (4).
A major consequence of hyperglycemia is excessive nonenzymatic glycosylation of proteins
(3, 4, 10), primarily due to long-term exposure to elevated glucose concentrations (12).
Nonenzymatic glycation may be occurring, although at a much slower rate than that seen
most in IDDM patients (3). Nonenzymatic protein glycation (Mallard Reaction) by glucose is
a complex cascade of condensations, rearrangements, fragmentations and oxidative
modifications (3). Glucose chemically attaches to proteins and nucleic acids without the aid
of enzymes, increasing the formation of AGEs (4). These AGEs form on intra- and
extracellular proteins, lipids, and nucleic acids, leading to the generation of protein
fluorescene and the irreversible cross-links (1, 11, 15). The formation of AGEs requires the
reaction of reducing sugars like glucose, fructose, galactose, mannose and ribose (22).
Interestingly, glucose is among the least reactive of the common sugars, perhaps leading to its
evolutionary selection as the principle free sugar in vivo (1, 22).
For a given protein, the extent of nonenzymatic glycosylation is determined by the sum of
effects of a number of independently acting variables such as pH, temperature, protein
concentration, etc. (4, 9). Glucose concentration and incubation time are the most clinically
relevant variables affecting the extent of nonenzymatic glycosylation (4). Characteristic to
diabetics, increased levels of glucose concentrations cause the level of accumulated Amadori
products on proteins to rise (4).

Non-enzymatic glycosylaton is a common posttranslational modification of proteins in vivo,

resulting from reactions between glucose and amino groups on proteins, this process is coined
the "Maillard reaction" and results in the formation of AGEs (1, 8, 11, 15, 23).
The Maillard Reaction (Non-enzymatic glycosylation)

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).

Figure 3. Structure formed by glycation of lysine residues in protein, fructoselysine (FL).

Early studies of nonenzymatic glycosylation showed that this process ultimately gives rise to
pigmented, fluorescent and glucose-derived protein crosslinks (4). These pigmented,
fluorescent compounds have been used to study the relationship between AGE formation and
various tissue pathologies (2, 17, 19). Along with the brown color, fluorescence is one of the
qualitative properties of AGEs (22). The fluorescent AGE crosslink pentosidine was first
isolated and identified from dura mater collagen and has been identified in vivo in skin
collagen and plasma proteins of diabetic patients (3, 7, 22).
Pentosidine Formation and Significance

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.

Figure 4. Aminoguanadine (AG), a structurally identified AGE inhibitor.

AGE inhibitors

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

A major consequence of hyperglycemia is excessive non-enzymatic glycosylation of proteins

resulting in various protein-protein cross-links and non-crosslinked structures (4, 10, 22).
AGE products contribute to long term complications of IDDM patients (2, 4, 17, 19). With
the increasing rate of occurrence of IDDM, it is important to increase knowledge about AGEs
and AGE-inhibitors. Through research it may be possible and beneficial to find substances

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.
References

1. Ahmed, N. (2005) Advanced glycation end products,role in pathology of diabetic

complications. Diabetes Research and Clinical Practice 67, 3-21.
2. Baynes J. et al. (1999) Role of oxidative stress in diabetic complications. Diabetes 48, 1-9.
3. Booth A. et al. (1997) In vitro kenetic studies of formation of antigenic advanced glycation
end products (AGEs). Journal of Biological Chemistry 272, 5430-5437.
4. Brownlee, M. et al. (1984). Nonenzymatic glycosylation and the pathogenesis of diabetic
complications. Annals of Internal Medicine 101, 527-537.
5. Chellan P, et al. (2001) Early glycation products produce pentosidine cross-links on native
proteins. Journal of Biological Chemistry 276, 3895-3903.
6. Degenhardt, T. et al. (1999) Aminoguanidine inhibits albuminuria, but not the formation of
advanced glycation end-prodcuts in skin collagen of diabetic rats. Diabetes research and
clinical practice 43, 81-89.
7. Dyer, D.G. (1993) Accumulation of maillard reaction products in skin collagen in diabetes
and aging. Journal of Clinical Investigation 91, 2463-2469.
8. Dunn, J. et al. (1989). Oxidation of glycation proteins: age-dependent accumulation of N(carboxylmethyl)lysine in lens proteins. Biochemistry 28, 9464-9468.
9. Eble, A.S. et al. (1983) Nonenzymatic glucose and glucose-dependent crosslinking or
protein. Journal of Biological Chemistry 10, 9406-9412.
10. Forbes J. M. et al. (2003). Role of advanced glycation end products in diabetic
nephropathy. Journal of American Society of Nephrology 14, S254-S258.
11. Hudson, J. et al. (2002) Glycation and diabetes:The RAGE connection. Current Science
83, 1515-1521.
12. Kochakian, M. (1996) Chronic dosing with aminoguanidine and novel advanced
glycosylation end product-formation inhibitors ameliorates cross-linking of tail tendon
collagen in STZ-induced diabetic rats. Diabetes 45, 1694-1700.
13. Lyons, T. et al. (1991). Decrease in skin collagen glycation with improved glycemic
control in patients with insulin-dependent diabetes mellitus. Journal of Clinical Investigation
87, 1910-1915.

14. Maurizio, S. et al. (1995). Role of advanced glycation end-products (AGE) in late
diabetic complications. Diabetes Research and Clinical Practice 28, 9-17.
15. McCance, D. et al. (1993) Maillard reaction products and their relation to complications
in insulin-dependent diabetes mellitus. Journal of Clinical Investigators 91, 2470-2478.
16. Price, D. et al. (2001) Chelating activity of adcanced glycation end-product inhibitors.
Journal of Biological Chemistry 276, 48967-48972.
17. Sajithlal, G. et al. (1998) Advanced glycation end products induce crosslinking of
collagen in vitro. Biochimica et biophyisica Acta 1407, 215-224.
18. Schiel, R. et al. (2003) Improvement of the quality of diabetes control and decrease in the
concentration of AGE-products in patients with type 1 and insulin-treated type 2 diabetes
mellitus studied over a period of 10 years (JEVIN). Journal of Diabetes and Its
Complications 17, 90-97.
19. Sell, D. et al. (1991) Pentosidine: a molecular marker for the cumulative damage to
proteins in diabetes, aging, and uremia. Diabetes/Metabolisim Reviews 7, 239-251.
20. Sensi, M. et al. (1995) Role of advanced glycation end-products (AGE) in late diabetic
complications. Diabetes Research and Clinical Practice 28, 9-17.
21. Stitt, A.W. (2001) Advanced glycation: an important pathological even in diabetic and age
related ocular disease. British Journal of Ophthalomol 85, 746-753.
22. Ulrich, P and Cerami A. (2001) Protein glycation, diabetes and aging. Recent Progress in
Hormone Research 56, 1-22.
23. Wautier, J.L. and Guillausseau, P.J (2001) Advanced glycation end products, their
receptors and diabetic angiopathy. Diabetes Metabolism 27, 535-542.

Advanced Glycation Endproducts [AGEs]

Crosslinkages

Aging
The Maillard reaction over your lifetime

Aging

The Maillard reaction is glycation or

crosslinkage occurring rapidly due to excessive
heat acting on the surface of food being cooked.

The heat causes sugar to link to an amino acid

on proteins leading to the browning effect seen
on the surface of cooked meat or the browning seen on toasted bread.

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.

Diabetes and aging

Diabetics suffer from elevated blood glucose levels.

High blood glucose levels result in glucotoxicity where this excess

glucose binds to amino acids in the process called the Maillard reaction

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.'

If you are pre-diabetic [insulin resistance, the Metabolic Syndrome], then

you are at risk of accelerated aging due to an accumulation of AGE's in
your body.

Click to enlarge
From Schiff Bases to Amdori products to AGEs

The Maillard reaction is a familiar one to most people. The cooking of

food creates a brown discolouration due to the reaction of sugar and
protein which is called the Maillard reaction.

The Maillard reaction involves a chemical reaction between a sugar

[usually glucose] with a protein.

The complex caused by the combination of glucose with the protein is

called a Schiff base.

This Schiff base in the human body is a reversible reaction which stabilizes
[reaches equilibrium] within several hours of the complex forming.

If there is continued exposure to the sugar [glucose], the Schiff base

[glucose + protein complex] undergoes rearrangement which is a non-

enzymatic glycosylation resulting in a more stable but much less

reversible compound, known as an Amadori product.

The Amadori product in the human body, stabilizes or reaches equilibrium

over several weeks.

Amadori products undergo further change to irreversible Advanced

Glycation Endproducts [AGEs] also known as Advanced Glycosylation
Endproducts

Every meal counts

1 in 4 individuals in Australia has diabetes or impaired glucose

metabolism.

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.

Click to enlarge
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