European Journal of Applied Sciences 4 (1): 01-05, 2012

ISSN 2079-2077
IDOSI Publications, 2012

Mechanism Linking Cognitive Impairment and Diabetes mellitus

T.M. Vijayakumar, G.B.N. Sirisha, M.D. Farzana Begam and M.D. Dhanaraju
Department of Pharmacy Practice, GIET School of Pharmacy, Nh-5,
Chaitanya Nagar, Rajahmundry-533296 Andhra Pradesh, India

Abstract: Diabetes mellitus is an important risk factor for mild cognitive impairment (MCI) and subsequent
Alzheimers disease (AD). Severe diabetes is more likely to be associated with poorly controlled blood sugar,
which can damage nerve cells in the brain and lead to cognitive impairment. In addition, impairment in verbal
memory was found to be associated with history and duration of Type 2 diabetes. The purpose of this article is to
present a comprehensive review of the literature regarding the subject of cognitive dysfunction in diabetes
mellitus. Hyperglycemia alters function through a variety of mechanisms including polyol pathway activation,
increased formation of advanced glycation end products (AGEs), diacylglycerol activation of protein kinase C
and increased glucose shunting in the hexosamine pathway. The same mechanisms may be operative in the brain
and induce the changes in cognitive function that have been detected in patients with diabetes. The pathogenesis
of cognitive dysfunction is only partially understood. Although many studies suggested that changes in cerebral
structure and function in diabetes are related to hyperglycemia -induced end organ damage, macrovascular
disease, hypoglycemia, insulin resistance and amyloid lesions may play a role in some patients. As new
knowledge is gained and can be applied to develop a new and improved ways to prevent and treat all of the
hyperglycemia-related complications of diabetes.
Key words: Cognition

Alzheimers disease Insulin Resistance

especially
in
the
levels of oxidative stress.
hippocampal region of the
The brain is one of the
INTRODUCTION
brain which involves in
organs
systems
most
learning
and
memory
[9].
susceptible
to
damage
by
Diabetes mellitus is a complex metabolic disease
Insulin
is
transported
free
radicals
because
of
its
that can have devastating effects on organs in the body
across
the
blood-brain
high
oxygen
consumption
[1-3]. Diabetes mellitus is associated with slowly
via
specific
rate, its abundance of
progressive end-organ damage in the brain. Mild to barrier
easily per oxidized lipid
moderate impairments of cognitive functioning has been receptors. It may inhibit
membranes
[12].
reported both in type I DM and in patients with type II synaptic activity in the
brain.
Insulin
has
been
Moreover,
brain
tissue
DM [4-5]. Abnormalities in cognitive function mediated
which has relatively little
by frontal lobe (executive functions), including a number found to reversibly reduce
cholinergic
activity
of
antioxidant protection also
of complex behaviors such as problem solving, planning,
straital
neuronal
cultures
contains high levels of
organization, insight, reasoning and attention are noted in
and
to
accelerate
turnover
polyunsaturated fatty acids
patients with diabetes [6]. Glucose is the primary
(PUFA) making it more
substrate for brain energy metabolism [7]. Neurons in of monoamines in the brain
vulnerable to oxidative
brain are unable to store or synthesize glucose and [10]. Increased insulin
concentrations
also
appear
insult [13]. In diabetes
therefore, the needed glucose is obtained from systemic
to
boost
the
levels
of
betacondition, elevated levels
circulation and subsequently transported across the blood
amyloid,
a
protein
involved
of blood glucose and
brain barrier [8]. When diabetes strikes and insulins
in
the
formation
of
senile
insulin may provide a prosignal is ignored by cells, the brain may not get the large
plaques
that
can
lead
to
oxidant
environment.
amount of glucose energy it needs especially for memory.
Alzheimers [11]. Certain
Glucose reacts with oxygen
Loss of brain cells and memory function result
organ
systems
are
to generate a range of
predisposed to greater
reactive
Corresponding Author: T.M.

Dementia

B-Amyloid

Vijayakumar,
Department of

Pharmacy Practice,
GIET

School of
Pharmacy,

NH-5,
Chaitanya
Nagar,
Rajahmundry -

533
296,
India.
Tel:

+91
88324844
44,

6577444,
Fax: +91
8832484739.

Europ. J. Appl. Sci., 4 (1): 01-05, 2012

ate unless
oxygen we actively
species counteract
(notably [14].
super Oxidative
oxides, stress has
hydroxy been shown
to
cause
l
radicals cell
damage
and
hydroge and
neuronal
n
in
peroxid death
e) thatanimal
models and
can
damage cell culture
[15]. The
the
constitu association
ents ofof diabetes
cells. mellitus
with
The
higher impaired
cognitive
the
glucose function
levels suggests
that
the
greater diabetes
mellitus
the
damage. may
Thus contribute
people to
Alzheimer
with
disease
poor
glucose (AD)
regulati [16].The
on arepurpose of
exposin this article
to
g theiris
systems present a
comprehen
to
potentia sive review
of
the
lly
harmful literature
oxidativ regarding
e stressthe subject
and alsoof
as agecognitive
increase dysfunction
s,
thein diabetes
harm mellitus.
continue
s
toRelation
accumul Between
Insulin

and
Cognitive
Function:
Insulin
resistance
is
a
condition
that impairs
insulin
function.
AD
has
been called
type
3
diabetes
because a
defect
in
insulin
signaling is
associated
with
the
accumulati
on
of
pathological
betaamyloid
peptide (A
)
and
hyperphosp
horylated
tau protein.
IDE
(insulindegrading
enzyme) is
a protease
involved in
the
degradation
of A and
insulin and
A
may
compete
for
degradation
.
IDE
expression
found
in
the
postmortem
hippocamp
us of AD
patients
who
expressed

the
type
2
APOE diabetes
typically
4
allele have
elevated
was
reduced circulating
by 50%plasma
compare insulin
concentrati
d with
ons
4 in AD
because of
patients
peripheral
and
insulin
controls
resistance,
[17].
which is in
Oxidati
turn related
ve stress
to central
and
obesity.
microinf
Insulin
lammati
receptors
on
are found
mediate
in
high
insulin
concentrati
resistan
ons within
ce in the
the
brain
through
the
pathway
of
docosah
exaenoi
c acid
(DHA)
and,
thus,
omega3 fatty
acids
may
also be
protecti
ve [18].
Individu
als with
prediabetic
states
(e.g.
impaire
d
glucose
toleranc
e
or
fasting
hypergl
ycemia)
or early

limbic
system of
the brain;
in
epidemiolo
gical
studies of
nondiabetic
adults,
hyperinsuli
naemia has
been
associated
with poorer
cognitive
performanc
e and an
increased
risk of AD.
Linkage
Between
Acute
Hyperglyc
emia and
Cognitive
Impairme
nt:
Hyperglyce
mia
has
also been
proposed to
cause end
organ
damage
through
increases in
reactive
oxygen
species, in
particular
superoxide,
which
could then
lead
to
increased
polyol
pathway
activation,
increased
formation
of AGEs,
activation

of
sms may be
protein operative in
kinase Cthe
brain
and
and induce
increase the changes
d
in cognitive
glucose function
shunting that have
in thebeen
hexosa detected in
mine patients
pathway with
[19].
diabetes
Hypergl (Fig. 1).
ycaemia
is
theDiabetic
hallmar Complicati
and
k of allons
types ofCognitive
diabetes Decline:
The
first
and
degree
could
cause relatives of
cognitiv non-insulin
dependent
e
decreme diabetes
nts bymellitus
several patients are
different at the risk
mechani of
accelerated
sms.
Acute atheroscler
and
changes osis
in bloodmicro
glucose vascular
disease
are
known [20]. The
to alterrecognized
regional association
cerebral between
2
blood type
diabetes
flow
and macro
and
could and
microvascu
also
cause lar disease
osmotic is pertinent
the
changes to
pathogenesi
in
of
cerebral s
dementia.
neurons.
These The former
same could cause
mechani cognitive

impairment
because of
the
increased
incidence
of embolic
stroke [21].
Many
of
the clinical
complicatio
ns
of
diabetes are
caused by
small and
large vessel
pathology
[22].
In
particular
peripheral

microvascu
lar
complicatio
ns
of
diabetes
arising
outside the
brain
appear to
be
correlated
with
correspondi
ng
microvascu
lar changes
in
the
brain. For
example,
diabetic
retinopathy
and retinal
microvascu
lar
abnormaliti
es
were
associated
with
various
MRI signs
such
as
small focal
white
matter

Fig. 1: to cognitive
Possib decline in
le
diabetes
mecha mellitus
nisms patients
related
2

Europ. J. Appl. Sci., 4 (1): 01-05, 2012

hyperin
tensitie
s and
lesions.
Likewi
se, the
presenc
e
of
micro
albumi
nuria
in the
general
populat
ion has
been
associa
ted
with
signific
antly
lower
cogniti
ve
functio
n score
[23].
Investi
gations
and
subseq
uent
clinical
diagno
sis of
microv
ascular
compli
cations
such as
nephro
pathy,
retinop
athy
and
neurop
athy
are
regular
ly
made
in

patients
with
diabetes.
However,
early
investigati
ons
of
potential
cognitive
impairment
at
specialist
memory
clinics are
not
routinely
undertaken
in patients
who do not
show
obvious
signs
of
dementia.
The early
identificati
on
of
clinically
relevant
cognitive
impairment
in diabetic
patients is
essential
because of
available
symptomat
ic
treatment,
the need to
educate
patients
and cares
and
the
need
to
instate
required
supportive
measures.
Role
of
Amyloid
and Insulin
Resistance
in

Cognitive
Dysfunctio
n:
The
mechanisms
through
which
insulin
resistance
might alter
cognitive
function
remain
uncertain,
but effects
on
neurotrans
mission and
memory
formation
have been
hypothesize
d
[24].
Patients
with
Alzheimers
disease
have
a
decrease in
cerebral
spinal fluid
insulin
levels,
suggesting
that there
may
be
impaired
insulin
transport
across the
blood brain
barrier or
increased
insulin
catabolism
that
accounts for
the
impaired
central
insulin
action [25].
Another
potential
mechanism
through

which neurons, by
insulin the enzymes
resistan - and ce may
secretase.
indirectl
-Amyloid is
y
eventually
contribu
degraded by
te
to
the insulincognitiv
degrading
e
enzyme. In
dysfunct
addition,
ion is by
there is a
promoti
growing
ng the
body
of
formatio
evidence
n
of
that insulin
senile
and insulin
plaques
resistance
found in
can affect
Alzheim
the
ers
metabolism
disease.
of APP and
Intracell
-amyloid,
ular
thus
neurofib
rillary potentially
tangles increasing
the burden
and
extracell of cerebral
senile
ular
senile plaques
The
plaques [27].
pathophysio
compos
logical
ed of mechanisms
amyloid
(Fig.
2)
are the
suggest how
patholo
diabetesgical
related
hallmar
factors and
ks
of
comorbid
Alzheim
conditions
ers
can affect
disease
the
brain.
[26]. -Vascular
Amyloi disease and
d
isalterations
formed in glucose,
from theinsulin and
cleavag amyloid
e
ofmetabolism
amyloid seem to be
precurso important
r proteinfactors and
(APP), could
be
produce potentially
d
inmodifiable.

Brain
Structural
Abnormal
ities:
In
autopsy
series,
macroscop
ic
brain
infarcts are
more
common in
people
with
diabetes
than
in
people
without the
disorder
[28].
Additional
ly, diabetes
is
associated
with
pathologic
al changes
in
the
cerebral
microvasc
ulature,
including

is of
Cog
nitiv
e
imp
airm
ent

Fig.

amyloid
angiopathy
and
capillary
basement
membrane
thickening
2:
[29].
R
Several
ostudies have
l also
eexamined
the
oincidence of
Alzheimers
f
type
pathology in
i the brains of
npeople with
sdiabetes.
the
uThus,
main
l
anatomical
i
alterations
n
related
to
diabetes
i appear to be
nthe
consequenc
of
te
helevated
blood
e
glucose and
changes due
pto cerebral
ainfarcts are
to
t linked
hhyperinsulin
oaemia as a
vascular
g
risk factor.
eHowever, in
ncontradictio
en to these
sstatements,

hippocampa
l
volume
was
positively
associated
with
the
metabolic
syndrome
and
with
visceral fat
volume in
particular,
in a group
of
48
middleaged
to
elderly nondementia
patients
with
diabetes
[30].
Among
these
subjects, the
metabolic
syndrome
was
not
associated
with
any
cognitive
alterations.
Recurrent
Episodes of
Hypoglyce
mia:
Glucose is
the
predominan
t
fuel
utilized by
the central
nervous
system.
Because the
brain
cannot
synthesize
glucose nor
store more
than a few
minutes
'
supply as
glycogen,

the
functional
brain disturbances
requires [31].
a
Repetitive
continu episodes of
ous
moderate to
supply severe
of
hypoglycem
glucose ia have been
from theimplicated
circulati as
one
on.
possible
Therefo etiology of
re,
cognitive
disrupti dysfunction
on
ofin diabetes.
the
This
is
supply significant
of
because the
exogeno risk
of
us
hypoglycem
glucose ia increases
will
as efforts to
rapidly achieve the
cause level
of
3

glycaemia
necessary to
minimize
the risk of
developing
the micro
vascular
complicatio
ns
of
diabetes are
intensified
[32].
During
acute
hypoglycem
ia episodes,
it has been
shown that
performanc
e
on
immediate
verbal
memory,
immediate

Europ. J. Appl. Sci., 4 (1): 01-05, 2012

have
complicatio
ns
of
visual included
diabetes,
memory subjects
with
along with
,
retinopathy,
working diabetes
neuropathy,
memory onset
earlier in
nephropath
,
y
and
delayed life.
cardiovascu
memory Patients
lar disease.
; visual-with type I
In
the
motor diabetes
clinical
skills, diagnosed
approach to
visual- at less than
individual
spatial 5 year of
may
patients
skills age
have more
with
and
diabetes
global severe and
that present
cognitiv frequent
hypoglyce
with
e
complaints
dysfunct mia
of
ion areepisodes
than those
cognitive
all
disturbance
impaire diagnosed
ages
s a number
d [33-at
older than 5
of
basic
34].
year, these
principles
One
are
possible younger
important:
reason patients
have been
first,
that
to
diabetes
some found
should be
studies have worse
regarded as
found cognitive
dysfunction
a
risk
an
factor
associati .
rather than
on
CONCL
as
the
between
USION
cause of
frequent
cognitive
hypogly
In
decline.
cemia
conclusion,
Therefore,
and
the
cognitiv Evidence
from
diagnostic
e
evaluation
dysfunct neurocognit
should be
ion andive testing
suggests
identical to
others
that
in
did notthat
other
is thatcognitive
dysfunction
patients
the
should
be
with
positive
as
cognitive
investig listed
complaints.
ations one of the
many
may

ACKAnnua
NOWl Data
LEDG
Report
EME
, 2003.
NT
Atlas
of
Aut
endhors
stage
would
renal
like to
diseas
thanks
e
in
KIMS
the
medical
United
college,
States.
Amalap
Bethes
uram
da,
and
MD:
Nation
Pradeep
al
Diabetic
Institu
Care
tes of
hospital,
Health
Rajahm
,
undry
Nation
for their
al
kind
Institu
support
te of
and
Diabet
providin
es and
g
Digest
necessar
ive
y
and
guidanc
Kidne
e
for
y
manuscr
Diseas
ipt
es.
preparat 2. Hossie
ion.
n,

1.

B.M.
REFEREN
and
CES
A.M.
Afkha
U.
mi,
S.
2008.
Re
Effect
nal
of
Dat
Educat
a
ion on
Sys
Impro
te
vemen
m
t
of
(U
Qualit
SR
y of
DS
Life
)

by SF20 in
Type 2
Diabet
ic
Patient
s,
Middl
e-East
J.
Scienti
fic
Res.,
3: 6772.
3.

Singh,
V., M.
Singh,
S.
Shukla
,
S.
Singh,
M.H.
Manso
ori
and
M.L.
Kori,
2011.
Antidi
abetic
Effect
of
Flacou
rtia
indica
Merr
in
Strept
ozotoc
in
Induce
d
Diabet
ic
Rats.,
5:
147152.

4.

5.

lle,
Bie
J.L.,
ssel
R.H.
s,
Heine,
G.J
J.M.
.
Dekke
r, G.
and
Nijpels
L.J.
,
Ka
R.P.C.
ppe
Kessel
lle,
s, R.J.
200
Biessel
5.
s
et
Inc
al.,
rea
2008.
sed
risk
Cognit
of
ive
Alz
Functi
hei
oning
mer
in
s
Elderl
dis
y
eas
Person
e in
s with
Typ
Type 2
e II
Diabet
dia
es and
bet
Metab
es:
olic
ins
Syndr
ulin
ome:
Ind
the
uce
Hoorn
d
Study.
pat
hol
Demen
ogy
tia and
?
Geriatr
Bio
ic
che
Cognit
mic
ive
al
Disord
Soc
ers,
iety
26:
Tra
261-9.
nsa
ctio 6. Munshi,
n,
M., L.
33:
Grand
104
e, M.
1Hayes,
4.
D.
Ka
Ayres,
ppe
S.

Emmy
,
R.
Capels
on, L.
Susan
et al.,
2006.
Cognit
ive
Dysfu
nction
Is
Associ
ated
with
Poor
Diabet
es
Contro
l
in
Older
Adults
.
Diabet
es
Care,

29:17
94
99
.

7.

Fellow
s, L.K.
and
M.G.
Boutel
le,
1993.
Rapid
change
s
in
extrace
llular
glucos
e
levels
and
blood
flow in
the
striatu
m of
the
freely
movin

g
rat.
Bra
in
Res
.,
604
:
225
231
.

8.

Mc
Nei
ll,
G.,
A.
Av
ene
ll,
M.
K.
Ca
mp
bell
, 9.
J.A
.
Co
ok,
P.C
.
Ha
nna
for
d,
M.
M.
Kil
onz
o,
M.
Ma
ry
et
al.,
200
7.
Is
Ant
ioxi
dan
t
The

rapy a
Viable
Altern
ative
for
Mild
Cognit
ive
Impair
ment?
Exami
nation
of the
Eviden
ce.
Demen
tia and
Geriatr
ic
Cognit
ive
Disord
ers,
24: 119.
Mende
lsohn,
A.B.,
S.H.
Belle,
M.
Gangu
li and
G.P.
Stoehr
, 1998.
Use of
Antiox
idant
Supple
ments
and Its
Associ
ation
with
Cognit
ive
Functi
on in a
Rural
Elderl
y
Cohort
.

Ameri
can J.
Epide
miol.,

148:
38-44.

10. Russo,
V.C.,
P.D.
Gluck
man,
E.L.
Feldm
an and
G.A.
Werthe
r,
2005.
The
insulin
-like
growth
factor
system
and its
pleiotr
opic
functio
ns in
brain.
Endocr
. Rev.,
26:
916943.

11. Marde
r, E.E.,
T.J.
Carew
and
D.V.
Essen,
2008.
Diabet
es, the
Brain
and
Cognit
ion.
Societ
y for
Neuros
cience,
pp: 1-

2.

12. Mo
rris
,
M.
C.,
D.
A.
Eva
ns, 13.
J.L.
Bie
nia
s,
C.
C.
Tan
gne
y
and
R.S
.
Wil
son
,
200
2.
Vit
ami
n E
and
Co
gnit
ive
De
clin
e in
Old
er
Per
son
s.
4

Archiv
es of
Neurol
.,

59:11
25
32
.
Ortega
, R.M.,
A.M.
Requej
o,
A.M.
LopezSobale
r,
P.Andr
es, B.
Navia,
J.M.
Perea
and F.
Robles
, 2002.
Cognit
ive
Functi
on in
Elderl
y
People
Is
Influen
ced by
Vitami
n
E
Status.
The J.
Nutriti
on,

132:
206568.

14. Arvani
takis,
Z.,
R.S.
Wilson
,
L.
Yan,
N.T.
Aggar
wal
and
D.A.
Bennet
t,
2006.
Diabet
es and
Functi
on in
Differe
nt
Cognit
ive
Syste
ms in
Older
Individ
uals
withou
t
Demen
tia.
Diabet
es
Care,
29:
560-5.

Europ. J. Appl. Sci., 4 (1): 01-05, 2012

d
J.J.
Kulsta
adults.
15. Pea
d,
Public
coc
19.Eri
Health
k,
cksen,
Nutriti
M.J
R.A.
on, 3:
.,
Roth,
337A.
et al.,
43.
R.
Fol 16.
so
m,
D.S
.
Kn
op
ma
n,
T.H
.
Mo
sle
y,
D.
C.
Gof
f
and
M.
Szk
lo,
200
0.
Die
tary
anti
oxi
dan
t
inta
ke
and
cog
niti
ve
per
for
ma 17.
nce
in
mid
dleage

Ryan,
C.M.,
M.O.
Geckl
e and
T.J.
Orchar
d,
2003.
Cognit
ive
efficie
ncy
declin
es
over
time
in
adults
with
type 1
diabet
es:
effects
of
microand
macro
vascul
ar
compli
cation
s.
Diabet
ologia,
46:
940948.
Cook,
D.G.,
J.B.
Levere
nz, P.J.
McMil
lan,

2003.
Reduc
ed
hippoc
ampal
insulin
degrad
ing
enzym
e
in
lateonset
Alzhei
mers
diseas
e
is
associ
ated
with
the
apolip
oprote
in Eepsilo
n4
Allele.
Am. J.
Pathol.
, 162:
313319.

18.

Cole,
G.M.
and
S.A.
Frauts
chy,
2007.
The
role of
insulin
and
neurot

rop
hic
fac
-tor
sig
nal
ing
in
bra
in
agi
ng
and
Alz
hei
me
rs
Dis
eas
e.
Ex
p.
Ge
ron
20.
tol.
,
42:
1021.

19.

brain
structu
re in
type- 1
diabet
es:
relatio
n
to
microa
ngiopa
thy
and
preced
ing
severe
hypogl
ycemi
a.
Diabet
es, 52:
149156.

d
G.J.
Bies
sels,
200
6.
Brai
n
ima
ging
in

patient
s with
diabet
es. A
system
atic
review
.
Diabet
es
Care,
29:
25392548.
Huber,
J.D.,
2008.
Diabet
es,
cogniti
ve
functi
on and
the
bloodbrain
barrier
. Curr.
Pharm
. Des.,
14:
15941600.

Va
n
Ha
rte
n,
B.,
F.E
.
De
Le
eu
w,
H.
C.
We
inst
ein,21. Fergus
on,
16
S.C.,
. S
A.
c
Blane
h
and P.
e
l
Perros
t
, 2003.
e
Cognit
n
ive
s
a
ability
n
and

22.

Wenk,
G.L.,
2006.
Neuro
pathol
ogic
chang
es in
Alzhei
mers
diseas
e:
potenti
al
targets
for
treatm
ent.
J. Clin
Psychi
atry,
67: 37.

23. Craft,
S., E.
Peskin
d,
M.W.
Schwa
rtz,
G.D.
Schell
enberg

,
M.
Ra
ski
nd
and
D.
Por
te 24.
Jr.,
19
98
Cer
ebr
osp
ina
l
flui
d
and
pla
sm
a
ins
uli
n
lev
els
in
Alz
hei
me
rs 25.
dis
eas
e:
rel
ati
ons
hip
to
sev
erit
y
of
de
me
nti
a
and
apo
lip
opr
ote

in E
genoty
pe.
Neurol
.,
50:
164168.
Braak,
H.and
E.
Braak,
1997.
Freque
ncy of
stages
of
Alzhei
merrelated
lesions
in
differe
nt age
catego
ries.
Neuro
biol
Aging,
18:
351357.
Sinha,
S. and
I.
Lieber
burg,
1999.
Cellul
ar
mecha
nisms
of
amyloi
d
produc
tion
and
secreti
on.
Proc.
Natl.
Acad.
Sci.

USA,
96:
1104911053.

26. Ci
me
n,
K., 27.
201
0.
Gly
cox
idat
ive
Str
ess
and
Car
dio
vas
cul
ar
Co
mpl
icat
ion
s in
Ex
peri
me
ntal
lyInd
uce
d
Dia
bet
es:
Eff
ects
of 28.
Ant
ioxi
dan
t
Tre
atm
ent.
The
Op
en
Car
dio
vas
cul
ar
Me
dici

ne J.,
4: 240256.
Peila,
R.,
B.L.
Rodrig
uez
and
L.J.
Launer
, 2002.
Type 2
diabet
es,
APOE
gene
and
the
risk
for
demen
tia and
related
pathol
ogies:
the
Honol
uluAsia
Aging
Study.
Diabet
es, 51:
125662.
Johnso
n, P.C.,
K.
Brene
del
and E.
Meeza
n,
1982.
Thicke
ned
cerebr
al
cortica
l
capilla
ry
basem

ent
membr
anes in
diabeti
cs.
Arch.
Pathol.
Lab.
Med.,

106:
2141
7.

29. Anan,
F., T.
Masak
i,
T.
Shimo
mura,
M.
Fujiki,
Y.
Umen
o, N.
Eshim
a, et
al.,
2010.
Abdo
minal
viscera
l
fat
accum
ulation
is
associa
ted
with
hippoc
ampus
volume in
nondemen
tia
patient
s with
type 2
diabete
s
mellitu
s.
Neuroi
mage,

49:
5762.

30. Raj
es,
Q.,
I.
Ikr
am,
M.
Sek
ara
n,
F.L
.
He
w,
M.
V.
Ku
mut31.
ha,
C.
Kar
uth
an
and
Z.
An
nua
r,
200
6.
Sial
ic
Aci 32.
d
and
Vas
cul
ar
Cel
l
Ad
hes
ion
Mo
lec
ule1
as
Ear
ly
Ma

rkers
in the
First
Degre
e
Relati
ves of
Type 2
Diabet
es
Mellit
us
Patient
s.
J.
Med.
Sci.,

ally
validat
ed
reanal
ysis of
the
Diabet
es
Contro
l and
Compl
ication
s Trial
data.
Diabet
es
Care,

6: 235

22: 12

240
.
Philip,
E.C.,
2008.
The
Barrie
r
of
Hypog
lycemi
a
in
Diabet
es.
Diabet
es, 57:
31693176.
Austin
, E.J.
and
I.J.
Deary,
1999.
Effects
of
repeat
ed
hypogl
ycemi
a on
cogniti
ve
functio
n:
a
psycho
metric

73
12
77.

33.

Somm
erfield
, A.J.,
I.J.
Deary,
V.
McAu
lay
and
B.M.
Frier,
2003.
Shortterm,
delaye
d and
worki
ng
memo
ry are
impair
ed
during
hypogl
ycemi
a
in
indivi
duals
with
type 1
diabet
es.
Diabet

es
Car
e,

26:390
396
.

34. Wi
do
m,
B.
and
D.
C.
Si
mo

nson,
1990.
Glyce
mic
control
and
neurop
sychol
ogical
functio
n
during
hypogl
ycemi
a
in

patient
s with
insulin
depend
ent
diabete
s
mellitu
s. Ann.
Intern
Med.,
112:
904912.
5