Type 2 diabetes mellitus and Alzheimer’s disease:from physiopathology to treatment implications

Rodrigo O. Moreira1,2*Stella C. Campos1,2

Ana L. Soldera1,2

1Instituto Estadual de Diabetes eEndocrinologia (IEDE), Rio deJaneiro, Brazil2Pontifícia Universidade Católica doRio de Janeiro (PUC-RJ), Rio deJaneiro, Brazil

* Correspondence to:Rodrigo O. Moreira, InstitutoEstadual de Diabetes eEndocrinologia, Rua Moncorvo Filho90, CEP 20211–340, Rio de Janeiro,Brazil.E-mail: rom_br@yahoo.com

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Type2 diabetesmellitus (T2DM) is a disease characterized by insulin resistance (IR) andprogressive β-cell failure, and affected individuals are at increased risk to developseveral forms of cognitive dysfunction, including AD. Different mechanisms havealready been identified linking visceral obesity, IR and AD. IR is associated witha decrease in glucose uptake by neurons, an increase in amyloid β productionand secretion, in the formation of senile plaques, and also in tau protein phosphor-ylation. Othermechanisms also include a decrease in insulin-degrading enzyme ac-tivity and an increase in oxidative stress secondary to hyperglycemia. Takentogether, these mechanisms suggest that drugs used to ameliorate hyperglycemiaand IR may also have beneficial effects in diabetic patients with AD. Indeed,manuscripts investigating the effects of metformin, thiazolidinedione, leptin,GLP-1 therapies, insulin and bariatric surgery in cognition, and AD have beenpublishedwith very promising results, whichmay indicate an alternative approachfor these patients. Copyright © 2013 John Wiley & Sons, Ltd.

Keywords Cognition; Alzheimer´s Disease; Diabetes Mellitus

Introduction

Alzheimer’s disease (AD) is themost common cause of dementia, and it is currentlyresponsible for up to 4 million cases worldwide. The risk of AD increases exponen-tially with age and doubles every 5 years after 65 years old. Nowadays, AD can befound in up to 50% of the population older than 85 years old [1,2]. The conceptthat dementia is a common and an unpreventable consequence of ageing is widelydisseminated. However, this is not always true. The diagnosis and treatment areusually inadequate because most of the times symptoms are recognized neitherby the physicians nor by the patients (or their families). Recent data suggest thatless than 50% of the patients with dementia receive a formal diagnosis, and thenumber of individuals who receive adequate treatment is even lower [3].

Type 2 diabetes mellitus (T2DM) is a disease characterized by insulinresistance (IR) and progressive β-cell failure. IR is defined as an inadequateresponse by insulin target tissues, such as skeletal muscle, liver and adiposetissue, to the physiological effects of circulating insulin. In the early stages ofT2DM, there is a compensatory increase in insulin levels (hyperinsulinemia)in response to IR [4]. As the disease progress, insulin levels begin to dropand diabetic patients, particularly those with long-term disease, have very

REVIEW ARTICLE

Received: 06 August 2012Revised: 14 February 2013Accepted: 03 June 2013

Copyright © 2013 John Wiley & Sons, Ltd.

DIABETES/METABOLISM RESEARCH AND REVIEWSDiabetes Metab Res Rev 2013.Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2442

low levels of circulating insulin. Recent studies haveindicated that elderly people with T2DM have a higherrisk of cognitive dysfunction and dementia [5], includingthe clinical diagnosis of AD-type dementia [6]. The aimof this review is to discuss the possible mechanismslinking T2DM to AD and also to discuss the effects ofanti-diabetic medication in cognitive function.

Basic concepts in AD – Aβ depositionand tau protein phosphorylation

Alzheimer’s disease is a neurodegenerative diseasecharacterizedbyaprogressivedestructionofneurons.Severalmechanismshave alreadybeen implied in thedevelopmentofAD, and two of the most important are amyloid β (Aβ)depositionand tauproteinhyperphosphorylation.

Amyloid β is a small fragment derived from Aβ precursorprotein (AβPP), an important compound for the mainte-nance of integrity and synaptic regulation. It is an insolubleprotein that slowly accumulates in the extracellular space.In vitro studies have already demonstrated that Aβ is toxicfor neurons synapses, capable of destroying synapticmembranes and, eventually, leading to cell death [7]. Aβexcess is associated with the formation of plaques, whichare not sufficient to cause dementia. It may also be foundin normal individuals as a consequence of ageing(Figure 1A). However, further increases in plaques numberassociated with changes in their contents may turn these

physiologic plaques into senile plaques, which are consid-ered to be pathological (Figure 1B). These senile plaqueshave their cores formed by Aβ and are surrounded by ahigher content of inflammatory proteins, activated glialcells and also other components [8,9].

Another typical pathologic finding of AD is the forma-tion of neurofibrillary tangles (NFTs). The progression ofthese lesions correlates anatomically with the evolutionof the disease and their number and distribution have adirect relationship with the severity of the disease. NFTsare formed in the interior of neurons through phosphory-lation of tau protein and are necessary for the mainte-nance of the cytoskeleton structure of the cells(Figure 2A). In AD, by mechanisms that will be explainedin the succeeding text, there is a hyperphosphorylation oftau protein. This pathologic process leads to a dissociationof the NFTs and the formation of paired helical filaments,compromising the cytoskeleton structure of neurons andinducing their collapse [10,11].

Insulin, IR and AD

The concept that neurons located in the central nervoussystem (CNS) do not require insulin to mediate glucoseuptake has been extensively revised in the last years.Indeed, the localization of insulin receptors in hippocampusand medial temporal cortex is consistent with evidence thatinsulin does influence memory [12]. Insulin is readily

Figure 1. Amyloid β (Aβ) and cognition in Alzheimer disease and insulin resistance. In physiologic conditions, Aβ is produced by neuronsderived from Aβ precursor protein. In healthy individuals, Aβ forms plaques in the extracellular matrix, with no pathological meaning (A). Inpatients with Alzheimer’s disease, by mechanisms not yet completely understood, there is either an increase in the production or a decrease in deg-radation of Aβ, leading to the formation of senile plaques and cell death (B). In patients with insulin resistance, there is both an increase in Aβ pro-duction as well as a decrease in Aβ catabolism, leading to an increased formation of senile plaques. In such individuals, the decrease in Aβdegradation is associated with a decrease in insulin-degrading enzyme action, secondary to hyperinsulinemia and free fatty acids (C).

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transported into the CNS across the blood brain barrier(BBB) by a saturable, receptor-mediated process. It isnecessary to mediate glucose uptake in several typeof neurons. Specific regional effects of insulin on glu-cose metabolism via insulin-sensitive glucose trans-porters 4 and 8 may impact brain function [13].

Several mechanisms have been identified linking insulinand IR to AD. Basic research suggests that insulinaccelerates AD-related pathology through its effects on Aβmetabolism and tau protein phosphorylation. Firstly, insulininfluences AβPP metabolism by accelerating its traffickingto the plasma membrane from the trans-Golgi network,where it is generated [14]. Therefore, insulin, and conse-quently hyperinsulinemia, promotes the secretion of AβPPand the formation of Aβ. A second insulin effect in Aβseems to be mediated by insulin-degrading enzyme (IDE).IDE was identified as an enzyme responsible not only forthe degradation of insulin but also Aβ. In patients withIR, compensatory hyperinsulinemia may lead to a decreasein Aβ degradation by IDE, enhancing its deposition in neu-ron cells [15] (Figure 1C). Moreover, AβPP-Aβ exerts ad-verse/neurodegenerative effects because it can alsofunction as a neurotoxin [7].

Insulin also seems to be an important determinant of tauprotein phosphorylation. Different mechanisms to explainthesefindingshave also been identified. Insulin supports neu-ronal cytoskeletal functions via Akt phosphorylation [16],which is required for cytoskeleton assembly and stabilization.Impairedinsulinsignallingcanresultinhyperphosphorylationof taudueto inhibitionofPI3K/Aktandincreasedactivationofglycogen synthase kinase-3β (GSK-3β) [17]. The activation ofGSK-3β leads to the enhanced phosphorylation of tau proteinand the formation of NFTs [15]. It is important to notice thatthe impaired activation of insulin receptors may be a directconsequence of decreased insulin levels in patients withT2DM and also indirectly related to Aβ production. AβPP-Aβ

can adversely affect insulin signalling by competing withand inhibiting insulin binding or reducing the affinity of insu-lin binding to its own receptor [18]. Finally, GSK-3β can beactivated by oxidative stress [19] (Figure 2B), which is amajor product of hyperglycemia and one of the most impor-tant determinants of microvascular diabetic complications,especially neuropathy [20].

Obesity, visceral fat, inflammationand AD

Visceral fat is one of the most important determinants of IRin individuals with metabolic syndrome and T2DMpatients. This effect is partially mediated by an excess infree fatty acids, currently named lipotoxicity [21]. Is has al-ready been demonstrated that free fatty acids may exert aninhibitory effect in IDE, contributing to a further decrease inAβ degradation and an increase in Aβ deposition [22](Figure 1C). Another important link between visceral fatand AD is inflammation. Tumour necrosis factor α, whichis over-expressed in the adipose tissue of IR individuals, isan adipokine that has been linked to IR, lipotoxicity and βcell failure. Neutralization of tumour necrosis factor αincreases insulin sensitivity and decreases plasma free fattyacids levels [23]. Tumour necrosis factor α is elevated in thebrains and cerebrospinal fluid of patients with AD and inadults with mild cognitive impairment [24,25], andinhibits Aβ transport from brain to periphery [26].

Other mechanisms linking DM and AD

Another important characteristic of IR and T2DM is athero-genic dyslipidemia. The coexistence of low high-density

Figure 2. Tau protein phosphorylation in Alzheimer’s disease and insulin resistance. In healthy individuals, insulin binds to its receptor,activates Akt phosphorylation and inhibits glycogen synthase kinase-3β activation. This leads to tau protein phosphorylation and formation ofneurofibrillary tangles, which are essential for the maintenance of the cytoskeleton structure of the neurons (A). In individuals with insulinresistance, there is a decrease in Akt phosphorylation and an increase in glycogen synthase kinase-3β activation (also induced by reactiveoxygen species), leading to an overexpression of neurofibrillary tangle and a significant impairment in neurons cytoskeleton structure. In thesepatients, there is also a decrease in insulin binding to its receptor induced by amyloid β (B).

Type 2 Diabetes and Alzheimer’s Disease

Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev (2013).DOI: 10.1002/dmrr

lipoprotein cholesterol with increased levels of triglycer-ides, and small and dense low-density lipoprotein choles-terol is often associated with both subclinical and clinicalatherosclerosis, including cerebrovascular disease [4].Recent studies have suggested that these modifications inthe vascular wall may also influence cognitive status,including the development of AD. It has been hypothesizedthat even small increases in carotid intima media thicknessmay produce diffuse hypoperfusion with chronic hypoxia,which might ultimately trigger neurodegenerative changes[27]. An altered cerebral hemodynamic might also favourthe cognitive decline by producing a detrimental effect onthe neurovascular unit. A deregulation of the neurovascularunitwould reduce the clearance of products of inflammation,oxidative stress and of Aβ promoting neurodegeneration[28]. In line with this hypotheses, Silvestrini et al. demon-strated that the progression of subclinical carotid disease(measured through intima media thickness) is directlyassociated with the decline in cognitive function (measuredwith mini-mental state examination) after 1 year of followup in patients previously diagnosed with dementia [29].

Is there a role for anti-diabeticmedication in Alzheimer’s treatment?

The relationship among IR, T2DM and AD seemsundoubtedly. However, it still needs to be determinedwhether the use of anti-diabetic medications, particularlyinsulin sensitizers and insulin, could have any beneficialeffects in cognition and memory. Although there is onlya few manuscript published in this topic, results suggesta promising effect of insulin sensitizers and intranasalleptin, among others, in the treatment of AD.

Insulin sensitizer – metformin

The effects of metformin in cognition and AD have beenstudied both in vitro and in animal models. Gupta et al.studied metformin effects on neuronal IR andAD-associated characteristics in an in vitro model of ‘type3 diabetes’ by differentiating neuronal cell line Neuro-2aunder prolonged presence of insulin. A time-coursedanalysis with 100 nM insulin revealed an attenuation ofinsulin-stimulated phosphorylation of the key insulinsignalling protein Akt (Table 1). It should be noticed thata decrease in Akt phosphorylation is associated with anincrease in tau protein phosphorylation. They alsoobserved a marked reduction in insulin-stimulated tyro-sine phosphorylation of IRß in cells under prolongedpresence of insulin. The results from this study thussuggest that metformin could effectively ameliorate theimpaired glucose uptake in insulin-resistant neuronal

cells. Treatment with metformin did not affect cellmorphology, growth rates or caused cell death. Finally,metformin effect on adenosine monophosphate-dependentkinase (AMPK) activation was tested and an enhancementin AMPK phosphorylation, as compared with respectiveuntreated controls, was demonstrated. These results suggestthat the use of insulin sensitizer drugmetformin, well-knownfor its action in peripheral tissues, could also directly sensitizethe impaired insulin action in neuronal IR [30].

Another important study suggests that metforminactivates a kinase implicated in tau protein phosphoryla-tion [31]. The enzyme named protein phosphatase 2A(PP2A) seems to be the major tau phosphatase, andefficiently dephosphorylates tau in vitro and in vivo[31,32]. The authors demonstrated that metformin has adirect effect on the association between PP2Ac, theregulatory subunit of PP2A-α4, and the ubiquitin ligaseMID1, which targets microtubule-associated PP2A fordegradation via the proteasome. The study demonstrateda significant insulin-independent influence of metforminon the phosphorylation pattern of the AD-related tau pro-tein. It also suggests a potential beneficial effect of long-term metformin treatment and raises the expectation thatmetformin would have a neuroprotective and prophylacticeffect in patients with the predisposition for AD [31].

Insulin Sensitizer – PPAR-γ Agonists

Thiazolidinedione (TZD) activate peroxisome proliferator-activated receptor gamma (PPAR-γ) and are used toimprove peripheral insulin sensitivity in T2DM. PPAR-γmay offer some therapeutic relief for AD by loweringperipheral insulin and enhancing insulin sensitivity,including in substantia nigra pars compacta neurons. Inaddition, PPAR-γ agonists have been shown to inhibitinflammatory gene expression [33], alter Aß and exhibitneuroprotective effects [34]. A few mechanisms have al-ready been proposed to explain these neuroprotectiveeffects. As shown in Table 1, TZDs may directly decreaseAβ deposition and tau protein hyperphosphorylation[35], or act indirectly through an Aβ-clearing effect [36].

As ageing is a common risk factor for both AD andT2DM, Blalock et al. investigated whether pioglitazonecould alter brain ageing under non-pathological condi-tions. Male rats were treated for 4–5 months with eithera control or a pioglitazone-containing diet and a reductionin the Ca2+�dependent afterhyperpolarization was seenin aged animals, with no significant change in long-termpotentiation maintenance or learning and memory perfor-mance. Finally, a combination of microarray analyses ofhippocampal tissue and serum-based multiplex cytokineassays revealed that age-dependent inflammatory increases

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Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev (2013).DOI: 10.1002/dmrr

Table

1.Mainstudieswithinsu

linsensitize

rsan

dco

gnition

Study

Model

Med

ication

Mainco

nclusions

Gup

taet

al.[30

]Expe

rimen

tal

Metform

inIn

thepresen

ceof

high

conc

entrations

ofinsulin

,ne

uron

alcelllin

eNeu

ro-2arevealed

anattenu

ationof

insulin

-stimulated

phosph

orylationof

theinsulin

sign

allin

gproteinAkt.

Incells

trea

tedwithbo

thinsulin

andmetform

in,

metform

incaused

anincrea

sein

gluc

oseup

take

inthesecells.

Kicksteinet

al.[31

]Expe

rimen

tal

Metform

inMetform

inindu

cesPP

2Aactivity,

which

decrea

sestauproteinph

osph

orylation,

before

andat

lower

levelsthan

AMPK

activity

Moo

net

al.[36

]Expe

rimen

tal

Rosiglitazon

eRO

SIde

mon

stratedan

amyloidβ(Aβ)-clearingeffect

byincrea

sing

LRP1

,an

Aβou

twardtran

sporterin

thebloo

d–brainba

rrier.

Babloc

ket

al.[37

]Animal

mod

elPiog

litazon

eLo

ng-term

PIO

trea

tmen

twas

able

toblun

tseveralind

ices

ofag

eing

butap

parently

affected

neithe

rag

e-relatedco

gnitivede

clineno

rpe

riph

eral/cen

tral

age-relatedincrea

sesin

inflam

matorysign

allin

gSe

arcy

etal.[35

]Animal

mod

elPiog

litazon

ePIO-treated

anim

alswithADshow

edim

prov

edlearning

ontheactive

avoida

ncetask,

decrea

sedhipp

ocam

pala

myloid-βan

dtaude

posits,a

nden

hanc

edshort-an

dlong

-term

plasticity.

Geldm

ache

ret

al.[38

]Hum

an(25individu

alswithAD)

Piog

litazon

eNosign

ificant

trea

tmen

teffect

was

observed

onco

gnition,

activities

ofda

ilyliving,

neurop

sych

iatric

symptom

s,an

dglob

alfunc

tion

Sato

etal.[33

]42

individu

alswithT2

DM

andAD

(n=21

,PIO

grou

pan

dn=21

,con

trol

grou

p)Piog

litazon

ePIO-treated

T2DM

individu

alsshow

edan

improv

emen

tof

cerebral

bloo

dflow

intherigh

tan

dleft

parietal

lobe

,toge

ther

withco

gnitivean

dfunc

tion

alim

prov

emen

ts

PP2A

=protein

phosph

atase;

PIO=piog

litazon

e;RO

SI=rosiglitazon

e;AMPK

=ad

enosine

mon

opho

spha

te-dep

ende

ntkina

se;AD=Alzhe

imer’s

disease;

T2DM

=type

2diab

etes

mellitus;L

RP1=LD

Lreceptor-related

protein1.

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Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev (2013).DOI: 10.1002/dmrr

were not reversed by the PPAR-γ [37]. Conclusions for thisstudy are presented in Table 1.

The beneficial effects of TZD in cognition have alreadybeen demonstrated in humans. However, results are stillcontradictory. For instance, Sato et al. decided to test theeffects of pioglitazone on cognition, regional cerebralblood flow and plasma levels of Aß40 and Aß42. To reachthis goal, a controlled trial in T2DM patients with mild ADwas performed. The pioglitazone group showed animprovement of regional cerebral blood flow in the rightand left parietal lobe and some regions of the frontal lobe.In contrast, the control group showed no improvement ofregional cerebral blood flow in any brain regions. Animprovement in insulin action in the brain was alsodemonstrated, resulting in cognitive improvement [33].On the other hand, Geldmacher et al. failed to demon-strate any significant effect of pioglitazone on cognition,activities of daily living, neuropsychiatric symptoms andglobal function of patients with AD [38].

Leptin

Leptin is a protein that was originally discovered as anadipocyte-derived hormone that controls feeding behaviourthrough receptors in the hypothalamus [39]. It has beenshown that it has some important physiological roles in thecontrol of fat storage and mobilization, the reproductivesystem, the immune system, bone homeostasis, insulinsensitivity, and neuronal activity and protection.

Leptin receptors have been identified in peripheral tissues,and in neurons in the brain, including the hippocampus,which is particularly vulnerable in AD [16,40–42]. Leptinhas been shown to reduce the amount of extracellular Aβ,both in vitro and in vivo models of AD, as well as to reducetau protein phosphorylation in neuronal cells. One of themost important activities of leptin is the control of AMPK.In addition to maintaining lipid levels, AMPK may also beof great relevance to AD, because its activation may directlydecrease tau protein phosphorylation, at least in vitro. Asecond mechanism attributed to leptin involves theAMPK-mediated down regulation of GSK-3β, which is an im-portant activator of tau hyperphosphorylation. Importantly,chronic administration of leptin resulted in a significantimprovement in the cognitive performance of transgenicanimal models of AD.

On the basis of the available data, select neuronalpopulations may have a deficient/defective AMPK systemfor one or more of the following reasons: low leptin/insu-lin levels, low leptin/insulin sensitivity, abnormal choles-terol and fatty acid membrane composition, and lowglucose uptake. These pathways can then lead to changesin synaptic properties, to an increase in Aβ deposition, to

an increase in tau protein phosphorylation and finallydeath. These intriguing biological activities of leptin holda promise for long-term therapeutic benefit for ADpatients. Its unique mode of action in the CNS canpositively sway disease pathways and may be used as adesirable complementation to other strategies [19].

Insulin

Insulin has a profound effect in the CNS where it entersthrough the BBB. It is responsible for many key processesin the brain, such as food intake, energy homeostasis, repro-ductive endocrinology, synaptic activity, peripheral insulinactions, learning andmemory. It also regulates neural prolif-eration, apoptosis and synaptic transmission [43,44].

The importance of insulin in the pathogenesis of AD seemsto be a paradox. In the early stages of IR, hyperinsulinemiaassociated with an impaired transport of insulin throughthe BBB leads to an impaired activation of insulin receptorin neurons, to an increase in tau protein phosphorylationand in Aβ deposition. As disease progress, insulin levels beginto fall. It should be noted that T2DM is characterized by lowinsulin levels, particularly in those patients with long-termdisease. Consequently, insulin levels in the CNS should alsobe low. Therefore, although insulin excess may contributeto the development of AD in the early stages of disease,insulin deficient seems to aggravate cognitive impairmentin patients with long-term disease. This hypothesis suggeststhat insulin replacement may be of some benefit in specificpopulations of diabetic patients with AD.

Plastino et al. developed a study to evaluate cognitiveimpairment patients with AD and T2DM with either oralanti-diabetic drugs or combination of insulin with othermedications. Medications for AD were kept unchanged. Atthe end of the study, authors evaluated cognitive functionand memory ability in 104 patients. A significant slowingin cognitive decline was demonstrated in the group ofpatients treated with a combination of insulin and oralanti-diabetic medications (group B) in comparison withthe group treated only with oral medications (group A).Among group B patients, more than 76.8% were found tobe stabilized over 12 months on mini-mental state scores[45]. Another important study, the Honolulu–Asia AgingStudy, demonstrated that the effect of high levels of insulinon the risk of dementia was independent of diabetes andblood glucose level [46]. Conversely, some studies supportedthat intranasal insulin improves memory and cognitiveabilities in patients with early AD [47].

Insulin therapy could have an independent effect on cog-nitive performance, and this could be explained throughdifferent mechanisms. For instance, insulin promotes cellmembrane expression of N-Methyl-D-aspartate receptors,

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which increases neuronal Ca2+ influx [48]. Ca2+ influxpresumably activates Ca2+-dependent enzymes, includingα-dependent enzymes and, strengthens neuronal synapticassociation [49]. Low doses of exogenous insulin mayincrease cerebral glucose metabolism, and then modulateselective brain functions, such as memory [50], and alsoneurotransmitter synthesis and secretion, reversing theamnestic effects of cholinergic blockade [51]. However,these studies did not take into account glycemic controland the overall effects of hyperglycemia in cognition.

Intranasal insulin

Intranasal delivery is a non-invasive mean of bypassingthe BBB and introduces this hormone to the brain withouta significant rise in its circulating levels. Shemesh et al.systematically reviewed and analysed existing clinicaltrials that assessed the potential beneficial effects of intra-nasal insulin administration on cognitive functions. Eightstudies (328 participants) were analysed. In healthypeople, Cohen’s effect size calculations suggest that only160 IU/d intranasal insulin induced potential beneficialeffects [52]. Among cognitively impaired patients, onlylower doses of insulin were assessed, and 20 IU revealedpotential beneficial effects on cognitive function. Thiswas significant in a single study assessing long-termintranasal insulin administration, whereas acute adminis-tration of 20 IU intranasal insulin tended to show abeneficial effect on immediate recall in APOE ε 4(�),but not APOE ε 4(+) patients [53]. The current limitedclinical experience suggests potential benefit on cognitiveeffects of intranasal insulin but more analyses should beprovided for clinical considerations for the future.

Incretins hormones

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have very simi-lar properties in protecting neurons from toxic effects, andare capable of reversing the detrimental effects that Aβ frag-ments have on synaptic plasticity. GLP-1 is an endogenous30-amino acid peptide hormone, which is released by intesti-nal L-cells and binds to the GLP-1 receptor (GLP-1R) coupledto the cyclic AMP second messenger pathway [54]. GLP-1Rstimulation enhances β -cell proliferation, glucose-dependentinsulin secretion and lowers blood glucose in T2DM patients[55]. GLP-1R is found in neurons in brains of rodents andhumans [56]. Moreover, GLP-1 and exendin-4, a more stableanalogue of GLP-1, have been shown to reduce endogenouslevels of Aβ in the mouse brain and AβPP in neurons [57].GIP is also a gastrointestinal hormone that is secreted in

response to food intake. It has modulating effects on bloodsugar levels similar to GLP-1 or insulin [58,59]. Recently, ithas been found that GIP receptors are also expressed in neu-rons in the CNS [60]. Furthermore, GIP receptors are foundin neuronal progenitor cells [61]. These two hormones havea half-time of minutes in the blood stream and for thetreatment of T2DM, long-lasting analogues have been devel-oped not to be broken down by the endogenous proteasedipeptidyl peptidase-4.

The same biochemical mechanisms that control neuro-transmitters release into the synaptic cleft via cyclic AMPlevel regulation are found in neurons [62–64]. Bindingsites for GLP-1Rs have been found in the hypothalamus,striatum, brain stem, substantia nigra and subventricularzone among other structures [65–67]. Moreover, it hasbeen hypothesized that GLP-1 can influence brain metab-olism. In fact, a small human study with positron emissiontomography with 18-fluorodeoxyglucose has shown a pos-sible effect of GLP-1 in brain glucose metabolism. The au-thors hypothesized that GLP-1 may exert a neuroprotectiveeffect by limiting intracerebral glucose fluctuation in post-prandial periods, when plasma glucose is increased [68].GLP-1R expression has also been observed in specific cellularsubtypes, which are crucial for memory and learningfunctions [69]. GLP-1R activation has been shown to reverseneuronal insulin receptor desensitization [70]. An importantadvantage of administering incretins over insulin is the factthat incretins only affect high glucose level triggered insulinrelease but show little effect in normoglycaemic situations.This opens the possibility to administer incretins to peoplewho do not have T2DM [71]. However, further studies arenecessary to confirm these hypotheses.

Bariatric surgery

Ghanim et al. hypothesized that AβPP, expressed inthe peripheral blood mononuclear cells, diminishes af-ter marked caloric restriction and weight loss associ-ated with Roux-en-Y gastric bypass surgery. FifteenT2DM patients with morbid obesity underwent Roux-en-Y gastric bypass, and the expression of inflamma-tory and AD-related genes was examined before andafter 6 months in plasma and in mononuclear cells.The expression of APP mRNA fell by 30%, and thatof protein fell by 36%. In addition, there was a reduc-tion in the expression of other AD-related genesincluding presinilin-2, ADAM-9, GSK-3ß, PICALM,SORL-1 and clusterin. They conclude that obesityand caloric intake modulate the expression of AβPPin mononuclear cells. And it is relevant that cognitivefunction has been shown to improve with weight lossfollowing bariatric surgery [71].

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ConclusionsIn the last years, the importance of insulin in memoryformation, cognition and neuron function has been exten-sively revised. The former concept that neurons do notrequire insulin for glucose transport has been provenwrong, and insulin has been shown to modulate severalother actions in the CNS. Therefore, diseases that compro-mise either insulin levels and/or insulin function may leadto neurological damage, including neurodegenerative dis-eases. In line with this hypothesis, IR and T2DM wereidentified as major pathogenic determinants of AD. Thisrelationship has been demonstrated in vivo, in vitro andalso in epidemiological studies. Moreover, other compo-nents of these diseases, such as atherogenic dyslipidemia,inflammation, micro and macrovascular disease, andoxidative stress may contribute, or even exacerbate,neuron dysfunction.

The concept that IR, T2DM and AD share common patho-physiological features suggests that drugs that improve gly-cemic levels and IR might have additional benefits in T2DMpatients with cognitive dysfunction, including patients with

AD. A few studies have already been performed but resultsare still preliminary and, in some cases, contradictories.Larger, randomized, double-blind trials are necessary toelucidate the effects of some anti-diabetic medications,including metformin, pioglitazone, dipeptidyl peptidase-4inhibitors and GLP-1 analogues/agonists in the preventionand/or progression of cognitive dysfunction, particularly inpatients with T2DM. Because of the impact of AD inmortal-ity and quality of life, treatment should be initiated as soonas possible to prevent the progression of the disease.Therefore, it should be also considered that these studiesshould evaluate the effects of these medications in combi-nation and in early stages of IR, and not only after the diag-nosis of T2DM.

Conflict of interest

Rodrigo O. Moreira received Speaker fees from Novartis,Novo Nordisk, Abbott, Merck Serono, Servier and MSD.Stella C. Campos and Ana L. Soldera have no conflicts ofinterest to declare.

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