Anthony

Pulido
3/17/15
ENGW3307
Musselman
ACS
Unit 1 Final Draft
Word count: 2244
Connecting Advanced Glycation End Products to Diabetes and Alzheimers Disease
Abstract
Advanced glycation end products (AGEs) are formed by the presence of
glycotoxins. Glycotoxins have been shown to produce AGEs by interacting with the
amino group of proteins. Increased AGE levels have been shown to contribute to the
pathogenesis of diabetes. In nondiabetic humans and mice, the presence of AGE in
serum affects the metabolism and encourages proinflammation, both characteristics
of diabetic pathogenesis. Increased AGE levels have been proven to cause cognitive
decline. With research correlating Alzheimers disease (AD) to diabetes mellitus and
insulin resistance, the pathological effects of AGES in diabetes mellitus and dementia
may be important physiological factors in the pathology and connection of diabetes
and AD.

Introduction

Recent research has tested the advanced glycation end products (AGEs)

relation to physiological effects. AGE formation is caused by toxic AGE precursors, or

glycotoxins, including glyoxal, methylglyoxal, and 3-deoxyglucosone [1]. Protein
glycation occurs through a series of reactions between the carbonyl group of a sugar
and the amino group of a protein, commonly occurring in foodstuffs, characterized
by the browning [1]. First, the reducing sugar reacts with the free amino group to
form a Schiff base, which then forms a ketoamine. In the propogation steps, the
ketoamine reacts with other amino acids to form N-carboxymethyl-lysine (CML),
and irreversible AGE [1]. The major cause of cytotoxicity is the reactive carbonyl
series of the AGEs [1] [3].

The glycotoxin, methyl glyoxal (MG), induces protein glycation, leading to the
formation of advanced glycation end products (AGEs) [1] [2] [3] [4] [5]. In mouse studies
to determine the impact of MG, researchers gave an experimental group a diet
without MG and with low AGE, another with MG and with low AGE, and a control
group given regular chow. Results showed that increased MG caused increased
prevalence of AGEs, as well as other adverse physiological effects, including negative
cognitive effects [3]. AGEs cause pro-oxidative and pro-inflammatory stress,
impacting protein structure and function [2] [4] [5]. Research shows that AGEs
contribute to the pathology of Type 1 Diabetes Mellitus (T1DM) [6] and Type 2
Diabetes Mellitus (T2DM) [7], and impact many of the same pathways to diabetes
mellitus (DM), including metabolism, the immune system mechanisms, and
cognitive function [1] [2] [3] [4] [5] [6] [7]. As in diabetic patients, increased MG levels have
been correlated to changes in insulin sensitivity, showing a decrease in insulin
sensitivity in older humans [3]. Studies have been shown to correlating diabetes to
Alzheimers disease (AD) [8] [9], so with AGE correlation to diabetes, research may
support diabetes and AD correlation further.

Metabolism

In diabetes, with the increase in blood glucose, the prevalence of carbonyls

leads to an increase in protein glycation [1] [2] [5] [6], causing an evident increase in MG
and AGEs in diabetic patients over nondiabetic subjects [5]. Two major metabolic
variables differ in diabetic patients compared to nondiabetic patients, including
LDL-cholesterol levels and triglyceride levels [1] [5]. Some AGEs, such as CML, are
proteins and lipids, so increased LDL-cholesterol and triglyceride levels are
commonly correlated with high MG, AGE, and CML levels [1] [3] [6]. In mice fed MG-rich
diets, the mice had a greater body weight and a greater amount of visceral fat
modified by AGEs [3]. In a study comparing 83 diabetic patients with 20 healthy,
nondiabetic patients, Zdenka Turk and her team used a DELFIA immunoassay on
serum and urine samples to show a significant increase in MG and AGEs [5]. Turks
team tested blood samples for LDL-cholesterol and triglycerides levels to prove a

positive correlation in LDL-cholesterol and triglyceride levels to MG and AGE

concentrations [5].

Immune Effects

Researchers have proven a significant correlation in immune system changes

in diabetics, particularly including the presence of autoantibodies. Genes may cause

the presence of autoantibodies, particularly islet cell antibodies (ICAs), which target
insulin-producing cells in the pancreas, and these ICAs characterize T1DM. Although
T1DM is often associated with genetic factors, outside factors may be significant
biomarkers for T1DM, including proinflammation. [6] AGE concentrations are greater
in diabetics, and one common AGE, N-carboxymethyl-lysine (CML), is particularly
common in T1DM [6] with its causal effect on proinflammation [1] [4] [6].
Researchers used indirect fluorescence to select 115 European children of
German descent between 1989 and 2008 who were ICA-positive. Researchers then
tested the 115 ICA+ children for diabetes development and serum CML using an
ELISA assay. Of the 115 children with ICA, only 33 developed T1DM, and every child
that developed T1DM had increased CML levels. When using CML concentration and
ICA presence as T1DM risk factor predictors, the accuracy of predictive values for
T1DM increased. [6]
Research was also done on caffeic acid (CA) and other phenolic acids to
determine its effects on the protein glycation assisted by MG in fetal bovine serum
(FBS). Wus research team found the adverse effects of these glycated FBS proteins,
including pro-oxidation, proinflammation and chemotactic migration [] caused by
the proglycation activity of CA on FBS were verified using cell models []. The
presence of MG and CA caused proinflammatory protein tumor necrosis factor
expression and secretion increase in macrophages, and interleukin-1 expression
and secretion increase in monocytes. The proinflammatory effects of MG and CA
also caused increased migration of monocytes, further showing how AGEs induce an
immune response. However, with the addition of aminoguanidine, which inhibits
AGES, the immune responses, tumor necrosis factor and interleukin-1 expression
and secretion and monocyte migration, decreased. [2]

Cognition

Glycotoxins have been shown to decrease cognitive function in mice and

humans [3] [4]. AGEs have been shown to promote neurotoxicity, a major
characteristic of AD [3] [4]. In the study on the effects of MG rich diets on the
metabolism and physiology of mice, the cognitive function of the mice was also
studied. Results showed brain physiology changes in multiple different pathways
with the presence of MG in the diet [3]. With an MG-positive diet, results showed
reduced levels of sirtuin 1 by reduced neocortical expression (SIRT1), which has
been linked to dementia or AD [3]. SIRT1 regulates ADAM10, which regulates the
production of amyloid precursor proteins, so with reduced levels of SIRT1, ADAM10
regulation can lead to the formation of amyloid plaques [3]. MG-positive mouse
neurons also suppressed ADAM10 directly, and both suppression of ADAM10 and
SIRT1 lead to a greater concentration of reactive oxygen species, which are highly
oxidative [3]. The MG-positive mice also showed impaired learning, motor
coordination, and memory, compared to MG-negative mice [3].

In humans, increased glycotoxin levels also showed increased cognitive

decline in humans [3] [4]. Researchers used the Mini Mental State Examination
(MMSE) to determine any change in cognitive function in older individuals [3] [4].
With higher MG levels, results showed higher AGE levels and SIRT1 suppression [3],
and in turn, showed a decline in MMSE [4]. For every 1 nmol/mL of serum MG, the
annual decline of MMSE increased by 0.36 MMSE points [4]. AGE concentrations
were about double in AD patients, and due to the increased AGE concentration in
diabetics, it is suggested that antidiabetic drugs may counteract the relationship
between serum MG and diabetes [4] [7] or maintain the relationship while preventing
the MG effects on cognitive function [4].

Treatments for AGEs, Diabetes, and Alzheimers

Multiple mechanisms of anti-glycation have been proposed to prevent AGE

formation. The introduction of hydroxyl radicals and super oxide radicals can
counteract the oxidative stress from the production Schiff base, inhibiting glycation.
Blocking of the carbonyl groups of the reducing sugars, Schiff bases, or ketoamines

can inhibit glycation. Metal ion chelation has been suggested to inhibit AGE
formation as well [1].
AGE association with diabetes has encouraged research in MG inhibition.
Black tea brew has been shown as an herbal, indigenous remedy for some diabetes
complication, so Ratnasooriya and a team of researchers tested the effects of black
tea brew (BTB) for inhibition of glycation [7]. Evidence proved, with increased BTB
concentrations, antiglycation effects increased, and the antiglycation effects were
proven stronger than those of the antiglycation drug, rutin [7].

Research shows MG and AGEs contribute to the pathogenesis of diabetes by

the concentrations of the glycotoxins, as well as the impacts on metabolism and the
immune system that reflect diabetic pathology. MG and AGE also correlates to
dementia and AD, which reflects recent trends in the correlation between diabetes
and AD with recent references to AD as Type 3 diabetes mellitus due to evidence
proving declining insulin resistance in AD patients [8] [9] BTB has been shown to
counteract diabetic pathology as an inhibitor of glycation, so as Beeri notes,
antidiabetic drugs could counteract MGs effects on cognitive decline and AD.
Multiple forms of treatment for diabetes have been shown to treat some of the
effects of Alzheimers. Intranasal insulin has been shown to have an attenuating
affect at multiple steps in the pathology of insulin [8]. The introduction of intranasal
insulin works to impede insulin resistance in the central nervous system. The
intranasal insulin also prevents the decrease of brain insulin expression, insulin
levels in the cerebrospinal fluid, and brain insulin receptor expression. In turn,
intranasal insulin decreases neurotoxicity and synapse loss, which lead to cognitive
impairment and neurodegeneration, the major characteristics of Alzheimers
disease [8]. When testing the antidiabetic drugs, Metformin, Metformin with
Sulphonylureas, Metformin with Rosiglitazone, and Rosiglitazone on separate
patients, some patients showed decreased risk of dementia, less impairment of
brain metabolism, and improvement of working memory [9]. Meanwhile, intranasal
insulin gave the most evident improved cognition in the patients tested [9].
Research proves antidiabetic treatments can counteract cognitive decline
and AD pathology [8] [9]. However, there is a need for published research directly

testing the effects of antidiabetic drugs on MG and AGE levels in serum and
cerebrospinal fluid, to determine if the antidiabetic drugs affect the AGE
concentrations or counteract AGE interactions with brain physiology. Research in
antiglycation chemicals, such as BTB, which affect MG levels, should be tested for a
direct relationship to diabetes and AD to determine if there is attenuation of
diabetes and AD pathogenesis.
Discussion

Advanced glycation end products show significant correlation to T1DM,

T1DM, and AD in pathogenesis. At a physiological level, the presence of AGEs

correlates with higher LDL-cholesterol and triglyceride levels, proinflammation,
peroxidation, and cognitive decline, all of which correlate to diabetes; cognitive
decline is the main characteristic of AD. Along with the correlation of AGEs to
diabetes and dementia, research has shown a connection between diabetes and AD,
connecting AD to decreased insulin sensitivity.
Glycation inhibitors, such as BTB have been shown to reduce AGE production
which influences diabetes, while antidiabetic drugs have been shown to attenuate
AD symptoms. While diabetes and AD have been correlated as well, AGE correlation
to AD has not been extensively proven. If MG levels are tested in relation to mice and
humans given antidiabetic drugs, research may show changes in MG levels. With
research on antiglycation, further tests on the effects of glycation inhibition on the
symptoms of diabetics and AD patients may be promising.

Works Cited
[1] Wu, C.H., Huang, S. M., Lin, J. A., and Yen, G. C. (2011) Inhibition of advanced
glycation endproduct formation by foodstuffs. Food & Function 2. 224.

[2] Wu, C.H., Huang, H. W., Lin, J. A., Huang, S. M., and Yen, G. C. (2011) The
proglycation effect of caffeic acid leads to the elevation of oxidative stress and
inflammation in monocytes, macrophages and vascular endothelial cells. The Journal
of Nutritional Biochemistry 22. 585-594.

[3] Cai, W., Uribarri, J., Zhu, L., Chen, X., Swamy, S., Zhao, Z., Grosjean, F., Simonaro, C.,
Kuchel, G. A., Schnaider-Beeri, M., Woodward, M., Striker, G. E., and Vlassara, H.
(2014) Oral glycotoxins are a modifiable cause of dementia and the metabolic
syndrome in mice and humans. PNAS 111.

[4] Beeri, M.S ., Moshier, E., Schmeidler, J., Godbold, J., Uribarri, J., Reddy, S., Sano, M.,
Grossman, H. T., Cai, W., Vlassara, H., and Silverman, J. M. (2011) Serum
concentration of an inflammatory glycotoxin, methylglyoxal, is associated with
increased cognitive decline in elderly individuals. Mechanisms of Ageing and
Development 132, 583-587.

[5] Turk, Z., Cavlovic-Naglic, M., and Turk, N. (September 2011) Relationship of
methylglyoxal-adduct biogenesis to LDL and triglyceride levels in diabetics. Life
Sciences 89. 485-490.

[6] Beyan, H., Riese, H., Hawa, M. I., Beretta, G., Davidson, H. W., Hutton, J. C., Burger,
H., Schlosser, M., Snieder, H., Boehm, B. O., and Leslie, R. D. (May 2012) Glycotoxin
and Autoantibodies Are Additive Environmentally Determined Predictors of Type 1
Diabetes. Diabetes 61.

[7] Ratnasooriya, W. D., Abeysekera, W. K. S. M., Muthunayake, T. B. S., and
Ratnasooriya, C. D. T. (2014) In Vitro Antiglycation and Cross-Link Breaking
Activities of Sri Lankan Low-Grown Orthodox Orange Pekoe Grade Black Tea
(Camellia sinensis L). Trop J Pharm Res 13(4).

[8] Freiherr, J., Hallschmid, M., Frey, W. H., Brnner, Y. F., Chapman, C. D., Hlscher,
C., Craft, S., De Felice, F. G., and Benedict, C. (2013) Intranasal Insulin as a Treatment
for Alzheimers Disease: A Review of Basic Research and Clinical Evidence. CNS
Drugs 27. 505-514.

[9] Alagiakrishnan, K. (2013) Antidiabetic Drugs and Their Potential Role in

Treating Mild Cognitive Impairment and Alzheimers Disease. Discovery Medicine.

Acknowledgements
Thank you to Ian Doxsee and Dan Humphrey for peer reviewing my paper. Thank
you to Jamaica Siwak for going over my paper as a biologist. Thank you to Professor
Musselman for her patience in the writing process, including topic changes and
multiple meetings and discussions.