Glucagon-like peptide-1, diabetes, and cognitive decline: possible pathophysiological links and therapeutic opportunities.

Abstract

Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline.

Full text

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Hindawi Publishing Corporation
ExperimentalDiabetes Research
Volume 2011, Article ID 281674, 6 pages
doi:10.1155/2011/281674
Review Article
Glucagon-LikePeptide-1, Diabetes,
andCognitiveDecline: Possible Pathophysiological Links
andTherapeutic Opportunities
EnricoMossello, ElenaBallini, Marta Boncinelli, Matteo Monami,
GiuseppeLonetto,Anna MariaMello, Francesca Tarantini,SamueleBaldasseroni,
EdoardoMannucci, and Niccol` oMarchionni
Unit of Gerontology and Geriatric Medicine, Department of Critical Care Medicine and Surgery, University of Florence
and Careggi Teaching Hospital, 50121 Florence, Italy
Correspondence should be addressed to Enrico Mossello, enrico.mossello@unifi.it
Received 25 February 2011; Accepted 5 April 2011
Academic Editor: Giovanni Di Pasquale
Copyright © 2011 Enrico Mossello et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and
neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide
1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including
cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might
be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1
activity hold out hope for treatment and prevention of Alzheimer’s disease (AD) and cognitive decline.
1.InsulinResistanceand CognitiveDecline
During the last years, Alzheimer’s disease (AD) and clinical
syndromes associated to insulin resistance have shown an
ever-increasing prevalence in Western countries. These con-
ditions pose a great threat to present and future population’s
health and represent two of the main causes of disability and
health expenditures. Several research lines during the last
decade have suggested an association among Type 2 diabetes
mellitus (T2DM), insulin resistance, and cognitive decline,
both in cross-sectional and in longitudinal studies.
Cross-sectional studies have found that older subjects
with T2DMon averageshow a poorercognitiveperformance
than age-matched controls [1]. This association seems
independent of other vascular risk factors and is attributable
not only to a greater extent of white matter lesions but also
to a more severe cortical atrophy [2], especially in temporo-
mesial areas (hippocampus,amygdala) [3].Moreoverinsulin
resistance is associated to a worse cognitive performance
in nondiabetic subjects too [4]. On the other hand cross-
sectional studies have observed a significant association of
dementia, AD in particular, with T2DM [5] and insulin
resistance [6].
Alsoseverallongitudinalstudieshaveobservedan associ-
ation of T2DM with dementia risk over years [7]. Moreover
it has been observed that older nondiabetic subjects with
metabolic syndrome and increased level of inflammatory
markers have an increased risk of subsequent cognitive
decline [8]. Recently published data have shown that, among
nondiabetic nondemented older subjects, insulin resistance
is associated with AD incidence after a few years [9].
In keeping with this observation, insulin resistance has
been associated recently with a greater extent of AD-like
neuropathologyatautopsy[10].Thereforeitisplausiblethat,
among older subjects with asymptomatic AD, a coexistent

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2Experimental Diabetes Research
impairment of insulin metabolism can hasten symptoms
expression.
This association might be linked to different biological
mechanisms, first of all the presence of brain insulin
resistance. In fact brain insulin receptor activity might
have several neuroprotective effects, via PI3K (phosphatidyl-
inositol-3-kinase)/Akt and ERK1/2 signalling pathways [11,
12]:decreased inflammation andapoptosis, increased synap-
tic plasticity, and inhibition of glycogen synthase kinase-
(GSK-)3, with subsequent decreased tau phosphorylation,
whichisahallmarkofADneuropathology.Ithasbeenshown
in vitro that insulin receptor activation is able to decrease
synapticbindingsitesthroughwhich amyloid oligomerspro-
ducetheirtoxicactivity, with resulting reduction ofoxidative
stress and dendritic spines loss [13]. Moreover postmortem
analyses of AD patients brain have shown an impairment
of insulin and IGF-1 receptors signalling, especially evident
in neurons with neurofibrillary tangles, suggesting that
degenerating neurons are resistant to insulin/IGF-1 action
[14]. Some authors have even proposed the existence of a
“Type 3 diabetes mellitus”, limited to central nervous system
(CNS), as a cause for AD, as they were able to produce
an AD-like neurodegeneration in a mouse model after
intracerebroventricular injection of streptozotocin, inducing
a depletion of CSF insulin without any change in peripheral
insulin metabolism [15]. This hypothesis is supported by
a pilot study, which has shown a significant cognitive
improvement after intranasal insulin, without change of
peripheral glucose metabolism [16].
On the other hand, experimental data have associated
peripheral insulin resistance with reduced insulin activity
insidetheCNS,duetoareducedhormonetransport through
the blood-brain barrier [17], and with increased brain
Aβ production in murine models of AD [18]. Moreover
in studies of normal subjects with euglycemic clamp, the
infusion of high insulin doses, mimicking insulin resistance,
raises Aβ-42 levels, probably due to a reduced catabolism,
and CNS inflammatory markers [19].
2.Metabolic EffectsofGLP-1,T2DM,
and the“Gut-to-Brain”Axis
Glucagon-like peptide-1 (GLP-1), a member of the incretins
family, is a 30-aminoacid peptide, which is derived from pre-
proglucagonmoleculeand issecreted by intestinal endocrine
epithelial L-cells. It is the most potent stimulator of oral
glucose-induced insulin secretion, it is released in response
to meal intake and is rapidly metabolized and inactivated by
dipeptidyl-peptidase-4 [20]. GLP-1 transmembrane receptor
(GLP-1R) is a G-protein-coupled receptor and is expressed
not only in pancreatic islets, butalso in gastrointestinal tract,
kidney, lung, vascular system, heart, and brain [21].
GLP-1R activation stimulates adenylate cyclase, with
formation of cyclic adenosine monophosphate (cAMP) and
subsequentphosphorylation ofproteinkinase A;moreoverit
activates PI3-kinase pathway, with downstream activation of
Akt kinase, MAP-kinases, and src-kinases [22, 23]. Via these
pathways, GLP-1 stimulates pancreatic β-cells, activating
insulin secretion and inducing insulin gene expression [21];
moreover it has been shown that GLP-1 stimulates pro-
liferation and differentiation, and reduces apoptosis of β-
cells [23]. It seems interesting that, at least in pancreatic
islets, GLP-1 activity seems synergic with insulin action in
promoting β-cell survival [24].
Beyond its main activity, GLP-1 reduces plasma gluca-
gon, inhibits gastrointestinal motility, and promotes satiety,
reducing food intake [21]. Moreover it has a wide range of
functions on glucose metabolism and cardiovascular system.
In fact it improves insulin sensitivity, reduces appetite, mod-
ulates heart rate and blood pressure, reduces vascular tone,
ameliorates endothelial function, and increases myocardial
contractility, with preliminary data suggesting clinical bene-
fit in heart failure [25].
It has been known for many years that T2DM is charac-
terized by a severely reduced incretin effect, defined as the
difference between insulin responses to oral and intravenous
glucoseadministration [26].ReducedGLP-1 levelshavebeen
observed after a mixed meal in Type 2 diabetes compared
with controls [27], with a marked reduction especially of
the late-phase response [28]. Moreover an altered GLP-1
response both to mixed meal [29] and to oral glucose load
[30] has been observed in insulin resistance.
It has been proven that at least part of the metabolic
effect of GLP-1 is mediated by CNS [31]. In fact brain GLP-
1R are partly responsible not only for food intake control,
but also for control of glucose homeostasis, with coordinate
actions on pancreas and liver [32]. It has been observed in
micethatGLP-1 secretedintothehepatoportalveinincreases
the firing rate of the vagus nerve, sending signals to the
brainstem nucleus of the tractus solitarius, which on the
otherhandreleasesGLP-1inhypothalamicregions,inducing
reflex insulin secretion and muscle glycogen synthesis [33].
Thesedatasupporttheexistenceofa“gut-to-brainaxis”,with
a central role of GLP-1 released both by intestinal cells and
by neurons, involved in the regulation of systemic glucose
metabolism, whose activity seems to be blunted in high-fat
fed, insulin-resistant mice [33].
On the other hand, it has been hypothesized that GLP-
1 can influence brain metabolism. In fact a small human
study with FDG-PET (positron emission tomography with
18-fluorodeoxyglucose)has shown a possible effectof GLP-1
on brainglucosemetabolism. In thisstudyGLP-1 infusion in
normoglycemic conditions reduced glucose transport across
blood-brain barrier in specific brain areas while a trend of
decrease of cerebral metabolic rate was also observed, thus
maintaining brain glucose concentration unchanged. This
observation leads the authors to hypothesize that GLP-1
may exert a neuroprotective effect by limiting intracerebral
glucose fluctuation in postprandial periods, when plasma
glucose is increased [34].
3.GLP-1,Neuroprotection,
and Alzheimer’s Disease
Beyond its metabolic role, several studies have clarified a
role of GLP-1 in CNS function. Experimental studies have
identified a widespread expression of GLP-1R across a
large number of rat brain regions, not directly involved

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in metabolic control, including hippocampus, thalamus,
striatum, substantia nigra, amygdala, nucleus basalis Meyn-
ert, subventricular zone, and temporal cortex [35]. GLP-1R
expression has been observed in specific cellular subtypes
which are crucial for memory and learning functions,
including pyramidal neurons of CA region and granule cells
of dentate gyrus in hippocampus, and in large neocortical
neurons [36]. Other authors have observed GLP-1R expres-
sion also on glial cells (microglia and astrocytes), proposing
a role for them as modulators of CNS inflammation [37].
TheneurotrophiceffectofGLP-1Rhasbeenstronglysug-
gested by studies of mice knockout (KO) for GLP-1R, which
show an impairment of contextual memory, as assessed
by the passive avoidance test, which measures the ability
of the animal to learn and remember that an instinctive
behavior causes a punishment. Memory impairment of KO
mice was reversible after GLP1-R gene DNA transfer with a
viral vector [38]. These data were confirmed in a subsequent
study of cognitive functions in a GLP-1R KO mouse model:
a reduced recognition memory and spatial memory has
been shown while other behavioural parameters, including
exploration and anxiety, were unchanged. Interestingly a
neurophysiological study of hippocampus CA1 area mice
showed a severe impairment of long-term potentiation,
which is the synaptic process associated to consolidation of
long-term memory [39].
Adding to these observations, it has been demonstrated
that GLP-1 analogues, which have greater metabolic stability
thanthenativemolecule,alsocrossblood-brainbarrierwhen
administered peripherally [40]. As only small amounts of
native GLP-1 reach CNS if peripherally administered, due
to rapid catabolism, much of the pharmacologic research
has focused on analogues of the molecule, which are more
resistant to degradation, while retaining the stimulatory
effect on GLP-1R.
Several experimental evidences have demonstrated a
neuroprotectiverole forGLP-1 and itsanalogues. In cultured
rat pheochromocytoma cells, some authors observed that
GLP-1 and exendin-4, (Ex-4) a long-acting GLP-1 ana-
logue, stimulated neurite outgrowth in a similar fashion to
nerve-growth-factor (NGF). Besides, Ex-4 was able to aug-
ment NGF-induced neuronal differentiation, and apparently
attenuated neural degeneration following NGF withdrawal
[41]. Other authors confirmed these data on cultured neural
cells, finding that GLP-1 exposure protected cells from
death promoted by NGF deprivation, by suppressing the
proapoptotic protein Bim (Bcl-2 interacting mediator of cell
death) [42].
Part of the neuroprotective effect of GLP-1R agonists
is probably related to reduced neuronal damage due to
amyloid metabolism. In fact Ex-4 has been shown to reduce
the synthesis of amyloidogenic Aβ fragment and to protect
cells from β-amyloid toxicity in cultured neural cells [43].
Moreoverintracerebroventricular injection of GLP-1 or Ex-4
has been shown to decrease levels of brain amyloid fragment
in control mice [44].
The efficacy of peripherally administered GLP-1 ana-
logues has been shown also in experimental models. In nor-
mal adult rats Ex-4 improves hippocampus-based cognitive
performance, namely, spatial learning and working memory,
as assessed by the “radial arm maze,” which allows the
measurement of the time necessary for the animal to find
food, placed at the end of several equidistantly spaced arms,
which radiate form a central platform [45]. In the same
paper the repeated administration of Ex-4 was effective in
ameliorating mood and reducing hopelessness, as measured
by the immobility time in the “forced swim test,” during
which animals are forced to swim in a cylinder filled with
water, from which they cannot escape [45].
The previously mentioned behavioural effects are par-
alleled by several histochemical changes observed “ex vivo.”
Intraperitoneal administration of Ex-4 has increased both
the number of proliferating cells and the expression of
neuronal differentiation markers in adult rat hippocampus
and in subventricular zone [45, 46].
A neuroprotective effect of Ex-4 has been observed
recently in experimental models of neurodegeneration. In
the triple transgenic AD-mouse, which is an experimental
model of the human disease, the induction of diabetes with
streptozotocin was associated with an increase of β-amyloid
brain load, consistently with evidence linking T2DM with
AD neuropathology, and subcutaneous administration of
Ex-4 prevented this increase [43]. The results of this study
suggests that Ex-4 may have a therapeutic role in AD,
alone or with T2DM. Moreover in an animal model of
Parkinson’s disease, in which Ex-4 was able to increase
the number of dopaminergic neurons in the substantia
nigra, acontemporary reductionofextrapyramidal signswas
observed [46].
Another long-acting GLP-1 analogue used for T2DM,
liraglutide (Lir), is able to cross the blood-brain barrier
[47], and has shown neuroprotective effects in experimental
models. This is also the case for other GLP-1 mimetics,
Asp(7)GLP-1, N-glyc-GLP-1, and Pro(9)GLP-1, which, like
Lir, are able to increase synaptic plasticity, measured as long-
term potentation in CA1 hippocampal region of rats [47].
Both Ex-4 and Lir were recently tested for their neu-
roprotective effect in mouse models of T2DM. In this
study GLP-1 analogues were injected subcutaneously to
three mouse models of diabetes (ob/ob mice, db/db mice,
and high-fat-diet-fed mice). At the histochemical analysis
a greater number of proliferating neurons in hippocampal
dentate gyrus was found in diabetic mice compared with
nondiabetic controls, and this number was further enhanced
by both drugs [48]. The increased neurogenesis in T2DM
models was interpreted by the authors as a response to
increased brain cell death which is associated with the
disease; this compensatory process would be supported
by GLP-1 mimetics. This interpretation is supported by
another paper published by the same authors, regarding the
cognitive effect of Lir in the mouse model of high-fat-diet-
induced obesity. In parallel with metabolic changes (weight
loss, increased glucose tolerance), mice treated with Lir
subcutaneousinjections showed an improvement oflearning
and memory ability, assessed with “object recognition test.”
The test measures the extent of exploratory activity of a
previously presented object, which is expected to be lower
in comparison with newly presented objects, and is therefore

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considered a measure of recognition memory. Furthermore,
Lir reduced negative effects of high-fat diet on hippocampal
long-term potentation [49].
Another analogue of GLP-1, Val(8)-GLP-1(7-36), was
studied in rats, and its intracerebroventricular injection
reversedtheimpairmentofspatialmemoryinducedbyinjec-
tion of β-amyloid fragment Aβ1–40. Moreover pretreatment
withVal8-glucagon-likepeptide-1preventedtheimpairment
of hippocampal long-term potentiation that is induced by
the presence of Aβ1–40 [50]. These data are consistent with
a different research, performed with the same molecule, on
AD-like mice with a double mutation of amyloid precursor
protein (APP) and presenilin 1 (PS1). A beneficial effect
was observed on long-term potentiation, both in young
(9 months) and in older animals (18 months) while β-
amyloid plaques and inflammatory microglia activation was
unchanged in treated animals [51]. These data support the
hypothesis that GLP-1R agonists might partly prevent toxic
effect of β-amyloid deposition, with obvious interest for
possible AD treatment.
With the backgroundofthepreviouslydiscussed preclin-
ical data, Ex-4 is now being studied as a treatment for AD
and PD in Phase 2 studies (see http://www.clinicaltrials.gov/,
NCT01255163 and NCT01174810). Of notice, the hypo-
glycemic effect of GLP-1 analogues in normoglycemic sub-
jects seems minimal [52, 53] and should not constitute a
major concern for the treatment of nondiabetic subjects.
4.Conclusions
The available evidences strongly support the hypothesis that
the observed association between insulin resistance/T2DM
and cognitive decline/dementiais mediated not only by well-
known vascular changes, but also by direct neurotoxic effect
of glucose metabolism impairment.
Incretin activity, and GLP-1 in particular, which is
reducedininsulinresistanceconditions,representsapossible
pathophysiological link between metabolism disorders and
neurodegeneration. The reduction of GLP-1 levels, charac-
teristicofT2DM,mightbeassociated toareducedneuropro-
tection, which seems particularly relevant for hippocampal
regions [39], where AD neuropathology is most evident. It is
temptingtospeculatethatGLP-1 andinsulinhavesynergistic
activity in promoting neuron survival, as it has been shown
inpancreaticβ-cells, bothfornativeGLP-1[24]andforGLP-
1 synthetic analogues [54, 55]. Human studies evaluating
the association between GLP-1 levels and cognitive function,
controlling for insulin resistance status, are needed to
support the hypothesis of a direct neuroprotective effect of
incretins.
GLP-1 analogues has been shown to enhance cognitive
function in control animals [38, 45], to prevent cognitive
impairment in models of T2DM [48, 49], and to counteract
β-amyloid toxicity in models of AD [43, 51]. These experi-
mental datasupport the effortoftesting such moleculesboth
for the prevention of cognitive decline in T2DM and for
treatment of AD patients in randomized controlled trials.
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