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Pulido U2fd
Pulido U2fd
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)
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
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
Cognition
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].
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
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].
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
[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.
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as
a
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