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6/10/2016 EffectsofglucoseonthebrainAssociateddisordersDiapedia,TheLivingTextbookofDiabetes

Effectsofglucoseonthebrain
Creators:ShamikMukherji,AlanJacobson
Thoughthereisagreatamountofattentiongiventotheeffectsofdiabetesontheperipheralnervoussystem,itisimportant
nottooverlookthediseaseseffectsonourbrains.Whileotherorgansinthebodymayrelyonalternativesourcesofenergy,
suchasfattyacids,thebrainreliesalmostsolelyonglucose,usingketonesasalastresort.Forthisreason,thebloodbrain
barrierisrichinGlut1activeglucosetransporters,andover99%oftheglucosethatpassesitisusedbyneuronsandglia.
Thus,themetabolicefficiencyandcontinuousdemandsofthebrainrenderituniquelysusceptibletofluctuationsinglucose
concentrationinthebody.

Aswediscussinthischapter,hyperglycemiaandhypoglycemiabothcanhavedetrimentaleffectsoncognitionaswellas
mood.TheseeffectsareevidentinpeoplewithType1andType2diabetes.Themostcommonmanifestationsofcognitive
deficitareneuralslowing,attentiondeficit,andexecutivefunctioning.Patientswithtype2diabetesinparticulardomorepoorly

inmeasuresoflearningandmemory[1].

Itisimportanttonotethatinahospitalsettingpatientswithoutdiabetescanbecomehyperglycemic,andthesepatientshave

anincreasedmortalityrisk[2].Stressinducedhyperglycemiainpatientswithoutdiabetescanoccurduringperiodsofacute

illnessandmaybeduetohormonalcascades,particularlyincreasesinepinephrine,cortisol,growthhormoneandglucagon[3].
Patientsmayhaveprediabetes,ormayhavefrankdiabetesthatisundiagnosed.Amonghyperglycemicpatientsingeneral
medicinewards,onestudyfoundthat12%wereundiagnosed,andthattheyhad18.3timesthemortalityrateoftheir
normoglycemicpeers.Thesepatientsalsohadlongerhospitalstays,wereadmittedtotheICUmoreoften,andlargelyhad

theirhyperglycemiauntreatedthroughoutthecourseoftheirstay[4].Similarly,inpatientsbothwithandwithoutdiabetes,

hypoglycemiaisassociatedwithincreasedinpatientmortalityandincreasedhospitallengthofstay[5][6].

Aclinicalawarenessofapatientsglycemicstate,especiallyifthepersonhasdiabetes,iskeytoprotectinghigherneurological
functioning,suchasmoodandcognition,aswellasmitigatingtheriskofmortality.Inthischapter,wewillfurtherdiscussthe
acuteandchroniceffectsofbothhypoglycemiaandhyperglycemiaonthebrain.

AcuteHyperglycemia
Theeffectsofacutehyperglycemiaonmoodandcognitioninpeoplewithdiabetesarecontroversial.Onestudyshowedthat
peoplewithtype2diabetesmaynotexhibitchangesincognitionormoodinshortperiodsofmildhyperglycemia.Interestingly,

patientsmayreportfeelingsofwellbeingandlessangerduringperiodsofbriefmildhyperglycemia[7].Otherresearch
contradictsthis,reportingincreasedirritabilityanddecreasedfeelingsofwellbeinginpeoplewithtype1andtype2diabetes

whoareacutelyhyperglycemic[8][9].Itappearsthatglucoselevelandnotvariabilityisthedeterminantofmoodvariation[9].
Patientswithlowerpostprandialglucose,however,dobetterthanthosewithhigherpostprandialglucoseincognitivetesting
[10].

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Inpragmaticstudiesinvolvingpeoplewithdiabeteswhosedrivingabilitiesareassessed,acutehyperglycemiacanleadto

tirednessanddecreasedvisualacuity.Thiscanthencauseincorrecttreatmentadjustmentprecipitatinghypoglycemia[11].
Peoplewithtype1diabeteshavebeenshowntohavelowerverbalandoverallIQscoresduringperiodsofacute
hyperglycemia[12].BothpeoplewithType1andType2diabeteshaveexhibitedlowercognitivescoreswhenbloodglucose

increasespast15mmol/l[13].Thus,acutehyperglycemiaappearstohavedetrimentaleffectsthatmayperturbdaytoday
functionsofbothpeoplewithType1andType2diabetes.

ChronicHyperglycemia
Theeffectsofchronichyperglycemiaaremorepronouncedthanthoseofacutehyperglycemia.Longtermhyperglycemiaas
seeninpeoplewithdiabetesappearstoresultinsignificantchangesintheirmoodandcognitivestate.Forinstance,type2

diabetesisbidirectionallyassociatedwithdepression[14].Indeed,peoplewithtype2diabeteswhohaveahemoglobinHbA1c

withinthenormalnondiabeticrangeexhibitfewersymptomsofdepressionthanthosewithhighHbA1c[15].

Peoplewithtype1diabetesperformsignificantlyworsethantheirnondiabeticpeersinattention,psychomotorefficiency,

cognitiveflexibility,andgeneralintelligence[16].Theetiologyoftheseeffectsisunclear,andisthesourceofmuchresearch.
StudieshavefoundthathighHbA1clevelspredictcognitivedeficitanditsdevelopmentovertimeinpatientswithandwithout

diabetes[17].Hyperglycemiaandadiposityareassociatedwithpoorcognitivefunctioninginmiddleagedpeoplewithout
diabetesaswell,whichshowsthatthesefactorsindependentlyaffectcognitivefunctioningoutsideoftheusualcomplications

ofdiabetes[18].Childrenwithtype1diabetesmayhavepoorerworkingmemoryasaresultofhyperglycemia.Childrenwith
multipleriskfactors,ofwhichhyperglycemiawasone,appearedtodoworseintestsofverbalabilities,workingmemory,and
mentalefficiency.Childrenwithotherriskfactors,suchasearlieronsetdiabetesandhypoglycemia,inconjunctionwith
hyperglycemia,didworsethanpeersinthesametests.Chronichyperglycemiaincreasestheriskofcognitivedeclineinthose
withdiabetesby60100%.ThisisprimarilyduetoahigherriskofvasculardementiaratherthanthatofAlzheimersdisease
[19].TheriskofAlzheimersdiseaseinpeoplewithdiabetes,however,iselevatedaswell[20].Thereisa50100%increased

riskofstrokeinpeoplewithdiabetesversusanormalpopulation,withastrokerelativeriskof1.15(95%CI1.081.23)for

every1%(11mmol/mol)riseinHbA1c[21].Theetiologyofthisisunderstudy.Endocrineabnormalities,suchaschangesin
insulinandamyloidmetabolism,andincreasedoxidativestressmaybeatfault.Inflammatoryphenomena,evidencedbyan

increaseinCRP,IL6,andTNfconcentration,havebeenstudiedinrelationtothisphenomenonaswell[22].

ArterialspinlabelingMRIstudieshaveshownthatcerebralbloodflowispoorerinpeoplewithdiabetes,andthatthesepeople

exhibitsignsofcorticalandsubcorticalatrophy[23].Lacunarinfarctsoccurmorefrequentlyinpeoplewithdiabetes,andthereis

asignificantassociationbetweencognitivedysfunction,lacunarinfarcts,andtheirprevalenceindiabetes[24].Hippocampal
atrophymaybeanothercauseofcognitivedysfunction,asitsdegreeispredictedbyHbA1c.A1015%lossinhippocampal

volumehasbeendocumentedintheelderlywithprediabetes,andisassociatedwithmemoryimpairments[25].The
hippocampusishighlyvulnerabletohypoglycemicdamage,aswouldbeexpectedinpeoplewithType1diabetes,however,
studiesshowthatcorticalatrophyinthehippocampusismorepronouncedinthosewithType2diabetes.Thismaybebecause

peoplewithType2diabetesareolderonaveragethanpeoplewithType1diabetes[26][27].Thereasonsfortheincreasedrisk
ofdementiaand/orcognitivedeficitinthosewithdiabetesmayultimatelybemultifactorial.

AcuteHypoglycemia
Despitetheconflictingevidenceregardingtheeffectsofrecurrentepisodesofhypoglycemiaonthebrain,itisgenerally

acceptedthathypoglycemiacausesneuronalinjuryandimpairmentsinmoodandcognition[28][29].Moderateepisodesof

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hypoglycemiahavebeenshowntocauseshorttermcognitivedeficits,whichincreasetheriskofmotorvehicleaccidents[29].
InavehicledrivingstudyonpeoplewithType1diabetes,cognitionwasshowntoreturntobaselineuponreturntoeuglycemia
[30].Thelengthoftimeittakesforonetorecovercognitivelyfromhypoglycemicepisodeisamatterofdebateandmaybe

relatedtotheseverityofthehypoglycemia.Cognitiverecoverymaytakeseveraldaysinthosewhohaveexperiencedsevere

hypoglycemia[31][32].Inhealthypeoplewithoutdiabetes,acuteepisodesofhypoglycemiacausefeelingsoftirednessand

increasedtension[33].InpeoplewithType1diabetes,acutehypoglycemiacausesdeficitsincognitivetaskcompletion,

increasedanxiety,anddecreasedenergy[34].

Thereisevidencethatanextendedepisodeofseverehypoglycemiacausesdirectneuronalnecrosis[35].Thebrains
metabolismitselfchangesafterrepeatedepisodesofhypoglycemiainashortamountoftime.Hypoglycemicepisodeswithin

1224hofeachotherresultinasuppressionofcounterregulatoryresponsestosubsequenthypoglycemicepisodes[36].Asthis
isfoundinbothtype1andtype2diabetes,itmayalsobeanadaptivemechanismbywhichthebrainbetterresistsfurther

hypoglycemicinsult,andmaybeexpressedevenatthecellularlevel[37][38][39].However,thisincreasesthepatientsriskof
subsequenthypoglycemia.Thepatientsawarenessoftheirownsymptoms,asaresultofthesemechanisms,becomes

impaired[39][40].Poorhypoglycemiaawarenessinpeoplewithdiabetescanbedangerousbecauseaffectedindividualsdonot
realizethattheirbloodglucoseislow,andextremeanduncorrectedhypoglycemiamayleadtounconsciousnessandeven
death.

Inpeoplewithtype1diabetes,pulsedarterialspinlabelingandBOLDfMRIstudieshavedemonstratedincreasedbloodflowin
severalbrainregionssuchasthehypothalamus,brainstem,anteriorcingulatedcortex,uncus,andputamenduringperiodsof

mildhypoglycemia,whichmaysuggestthatthesestructuresareespeciallysensitivetoevensmallbloodglucosechanges[41]
[42].Thus,evensmallacuteglycemicchangesmaybeofclinicalimportance.

ExposuretoRecurrentHypoglycemia
Theeffectsofrecurrenthypoglycemiaoncognitionaresubjecttodebate.Multiplehypoglycemicepisodesmaybeexperienced
inthosewithtype1diabeteswhoundergointensiveinsulintherapy.Repeatedhypoglycemiainbothtype1andtype2diabetes
hasbeenshowntocauseimpairedhypoglycemiaawareness,andanalterationoftheglycemicthresholdsthatthebrainis

usedto[43].Asmentionedearlier,thispoorawarenessofhypoglycemiamayleadtopoortreatmentadjustmentpractices,
whichcouldthenleadtounconsciousnessordeathasthehypoglycemiabecomesmoresevere.

Analysisofthe18yearDCCTtrialshowednosignificantdeclineincognitioninpersonswithtype1diabetes,despitehigh

frequencyofhypoglycemiccomaand/orseizures[44].Theremay,however,beadaptivechangesthatunderliereducedcerebral
efficiencyinpeoplewithType1diabetes.PeoplewithType1diabeteshavebeenshowntohaveincreasedbrainactivationin
severalregions(bilateralfrontalandparietalcortices,insula,thalamus,andcerebellum)duringperiodsofhypoglycemia.Higher
HbA1cwasassociatedwithloweractivationintherightparahippocampalgyrusandamygdalaaswell,whichcouldindicate
compensatoryrecruitment.Thus,whilecognitivedifferencesmaynotbeevidentinthosewithahistoryofhypoglycemia,such
peoplemayrequireahigherlevelofbrainactivationtomaintainthesamelevelofcognitivefunctionastheirpeerswithout

diabetes[45].

Certainnegativeeffectsofrecurrenthypoglycemiahavebeenuncoveredusingneuroimagingtechniques.VoxelBased
Morphometry(VBM)studiessuggestthatahigherselfreportedfrequencyofseverehypoglycemiceventswereassociatedwith

graymatterdensitylosses,particularlyintheleftcerebrellarposteriorlobeandthelimbicunci[46].Thereisevidencethatthe
cerebellumisinvolvedinhigherexecutivefunctioning,language,andaffect.Insulttothisregionmayresponsibleforseveral
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cognitivedeficits[47].

Personswithtype2diabetesdonotundergorepeatedepisodesofhypoglycemiaasfrequentlyasthosewithtype1diabetes
[48].Thereissomedebateastotheeffectsofrecurrenthypoglycemiaonthedevelopmentofcognitivedysfunctionand

dementiainthosewithtype2diabetes.Studiesoffercontradictoryevidenceregardingtherelationshipbetweenhypoglycemic

episodesandlaterdementiadevelopment[49][50][51].Furtherresearchisneededtohelpelucidatethelongtermeffectsof
recurrenthypoglycemicepisodesoncognition,mood,anddementiadevelopment.

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