Duodenal Motility.docx
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Duodenal Motility.docx
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DuodenalMotility
EffectsofPhysiologicalHyperglycemiaonDuodenalMotilityandFlowEvents,GlucoseAbsorption,andIncretinSecretioninHealthyHumans
1.PaulKuo,
2.JudithM.Wishart,
3.MaxBellon,
4.AndréJ.Smout,
5.RichardH.Holloway,
6.RobertJ.L.Fraser,
7.MichaelHorowitz,
8.KarenL.Jonesand
9.ChristopherK.Rayner
-AuthorAffiliations
1.DisciplineofMedicine(P.K.,J.M.W.,R.J.L.F.,M.H.,K.L.J.,C.K.R.),UniversityofAdelaide,RoyalAdelaideHospital,AdelaideSA5000,Australia;DepartmentofNuclearMedicine,PositronEmissionTomography,andBoneDensitometry(M.B.),RoyalAdelaideHospital,AdelaideSA5000,Australia;GastrointestinalResearchUnit(A.J.S.),UniversityMedicalCenterUtrecht,3584CXUtrecht,TheNetherlands;andDepartmentofGastroenterologyandHepatology(R.H.H.,C.K.R.),RoyalAdelaideHospital,AdelaideSA5000,Australia
1.Addressallcorrespondenceandrequestsforreprintsto:
AssociateProfessorChrisRayner,DisciplineofMedicine,UniversityofAdelaide,Level6,EleanorHarraldBuilding,RoyalAdelaideHospital,Adelaide,Australia.E-mail:
chris.rayner@adelaide.edu.au.
NextSection
Abstract
Context:
Acutehyperglycemiaslowsgastricemptying,butitseffectsonsmallintestinalmotoractivityandglucoseabsorptionareunknown.Intype2diabetes,thepostprandialsecretionofglucose-dependentinsulinotropicpolypeptide(GIP)ispreserved,butthatofglucagon-likepeptide-1(GLP-1)ispossiblyreduced;whetherthelatterissecondarytohyperglycemiaordiabetesperseisunknown.
Aim:
Theaimwastoinvestigatetheeffectsofacutehyperglycemiaonduodenalmotilityandflowevents,glucoseabsorption,andincretinhormonesecretion.
Methods:
Ninehealthyvolunteerswerestudiedontwooccasions.Acombinedmanometry/impedancecatheterwaspositionedintheduodenum.Bloodglucosewasclampedateither9mmol/liter(hyperglycemia)or5mmol/liter(euglycemia)throughoutthestudy.ManometryandimpedancerecordingscontinuedbetweenT=−10minandT=180min.BetweenT=0and60min,anintraduodenalglucoseinfusionwasgiven(∼3kcal/min),togetherwith14C-labeled3-O-methylglucose(3-OMG)toevaluateglucoseabsorption.
Results:
Hyperglycemiahadnoeffectonduodenalpressurewavesorfloweventsduringthe60minofintraduodenalglucoseinfusion,whencomparedtoeuglycemia.Duringhyperglycemia,therewasanincreaseinplasmaGIP(P<0.05)and14C-3-OMG(P<0.05)butnoeffectonGLP-1concentrationsinresponsetotheintraduodenalinfusion,comparedtoeuglycemia.
Conclusion:
AcutehyperglycemiainthephysiologicalrangehasnoeffectonduodenalpressurewavesandfloweventsbutisassociatedwithincreasedGIPsecretionandrateofglucoseabsorptioninresponsetointraduodenalglucose.
Althoughitiswellrecognizedthatstrictglycemiccontrolisassociatedwithreductionsinthemicro-andmacrovascularcomplicationsoftype1andtype2diabetes,thecontributionofpostprandialglycemiatooverallbloodglucosecontrolisoftenunderrecognized.Differencesingastricemptyingaccountforaboutonethirdofthevariationintheinitialriseinpostprandialglycemia.Smallintestinalfactors,suchasduodenalmotility
(1)andflowevents
(2)andtheactivityoftheglucosetransporters(sodium-dependentglucosecotransporter-1andGLUT-2)(3),arealsopotentialdeterminantsofglucoseabsorptionandmay,therefore,alsoinfluencepostprandialglycemia.
Videofluoroscopyisconsideredthe“goldstandard”techniqueformeasuringsmallintestinalchymemovement,butitinvolvesexposuretoionizingradiation.Manometryallowsmeasurementoflumen-occlusivecontractionsbutisunabletodetectnonlumenocclusiveevents,whicharealsoimportantinfacilitatingthemovementofchyme.Monitoringofelectricalimpedancehas,inrecentyears,beenusedinthesmallintestinetomeasuretheflowofchyme.Ourgrouphasrecentlyusedacombinedmanometry/impedancecathetertoassessduodenalmotoractivity,underthepharmacologicalinfluenceofhyoscinebutylbromide
(2)andmetoclopramide(4),andidentifiedduodenalfloweventsasbeingamoreimportantdeterminantofglucoseabsorptionthanthenumberofduodenalpressurewavesorpropagatedwavesequences.Informationregardingtheeffectofhyperglycemiaonduodenalmotoractivityislimitedandinconsistent.Currently,thereisnoinformationonhowsmallintestinalfloweventsareinfluencedbyhyperglycemia.
Theincretinhormones,glucagon-likepeptide-1(GLP-1)andglucose-dependentinsulinotropicpolypeptide(GIP),arereleasedfromintestinalLandKcells,respectively,inresponsetoluminalnutrients.Bothhormonesenhancethereleaseofinsulinfromthepancreas,theso-called“incretineffect.”Atpresent,thereisonlylimitedinformationregardingtheeffectofhyperglycemiaonincretinhormonesecretion.
Weaimedtodeterminetheeffectsof“physiological”hyperglycemia(9mmol/liter),comparedwitheuglycemia(5mmol/liter),onduodenalmotilityandflowevents,glucoseabsorption,andincretinhormonereleaseinhealthyhumansinresponsetoanintraduodenalglucoseload.
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SubjectsandMethods
Subjects
Ninehealthyvolunteers(fourmales;meanage,31.7±3.7yr;meanbodymassindex,24.7±1.4kg/m2)wererecruitedbyadvertisement.Nosubjectwastakingmedicationknowntoaffectgastrointestinalfunction.ThestudyprotocolwasapprovedbytheResearchEthicsCommitteeoftheRoyalAdelaideHospital.Written,informedconsentwasobtainedfromeachparticipant.StudieswerecarriedoutinaccordancewiththeDeclarationofHelsinki.
Protocol
Eachsubjectunderwenttwostudies,separatedbyatleast3d,insingle-blinded,randomizedorder.Subjectsattendedthelaboratoryat0830hafteranovernightfast(12hforsolids,10hforliquids).Acombinedmanometryandimpedancecatheterwasinsertedtransnasallyintothestomachandallowedtopassintotheduodenumbyperistalsis.Theassemblyconsistedofamultilumensiliconemanometriccatheter(externaldiameter,4mm;sixduodenalchannelsspacedat3-cmintervals,withanextrasideholeforintraduodenalinfusionsituatedimmediatelydistaltothemostproximalduodenalchannel)(DentsleeveInternationalLtd.,Mississauga,Ontario,Canada),andanimpedancecatheter(externaldiameter,2mm;eightelectrodesspacedat2-cmintervals)(SandhillScientific,HighlandRanch,CO),boundinparallelwithparaffintapesothatthemanometrysideholesandimpedanceelectrodesspannedthesameregionoftheduodenum.Thepositionofthecatheterwasdeterminedbymonitoringtransmucosalpotentialdifference(TMPD),usingestablishedcriteria(antralTMPD,<−20mV;duodenalTMPD,>−15mV;difference,>15mV)(5).
Uponcorrectpositioningofthecombinedmanometry/impedancecatheter,aninsulin/glucoseclampwasstartedtoachievethedesiredglycemictargets(6).Thisinvolvedadministeringa50-mlivbolusofdextrose(BaxterViaflex25%glucose;BaxterHealthcare,OldToongabbie,NSW,Australia)onthehyperglycemicday,orsaline(BaxterViaflex0.9%sodiumchloride;BaxterHealthcare)ontheeuglycemicday,eachinfusedover1min,followedbyaconstantinfusionofthesamesolutionstartingat150ml/handadjustedaccordingtobloodglucoseconcentrationsonthehyperglycemicday,orremainingat150ml/hfortherestofthestudyontheeuglycemicday.Ontheeuglycemicday,subjectswerealsoadministered25%dextroseiviftheirbloodglucoseconcentrationsfellbelow5mmol/liter.Inaddition,100IUofinsulin(ActrapidPenfill,100IU/ml;NovoNordisk,BaulkhamHills,NSW,Australia),madeupto500mlwithsuccinylatedgelatinsolution4%(Gelofusine;B.BraunAustralia,BellaVista,NSW,Australia),wasinfusedivatratesaccordingtoaslidingscale.Abloodsample(0.5ml)wastakenevery5minthroughouttheentireglycemicclampperiodfordeterminationofbloodglucoseconcentrationsusingaportableglucometer(MedisenseOptium;MedisenseInc.,Waltham,MA).
Oncebloodglucoseconcentrationswerestabilizedfor30min(9±1mmol/literonthehyperglycemicday,5±1mmol/literontheeuglycemicday)andduodenalphaseIIactivitywasobserved,manometryandimpedancerecordingscommenced(T=−10min).AtT=0min,anintraduodenalinfusioncontaining45gglucoseand111kBqof14C-labeled3-O-methylglucose(3-OMG),madeupto200mlwithwater,wasadministeredviatheduodenalinfusionchannelinthemanometriccatheterover60min(∼3kcal/min).Thecombinedmanometry/impedancometryrecordingcontinueduntilT=180min.
Venousbloodwassampledevery10minfromT=−10toT=60min,andthenatT=75,90,120,150,and180min,forsubsequentmeasurementofbloodglucose,plasmainsulin,GLP-1,andGIPconcentrations,andplasma14C-3-OMGactivity.
Measurements
Boththemanometricandimpedancesignalswererecordedatasamplingrateof30Hz(Insightstationarysystem;SandhillScientific)andstoredonaharddiscforsubsequentanalysis.
Manometricanalysis
Manometricdatawereanalyzedinanautomatedfashionusingestablishedsoftware
(2).Thenumberofduodenalwaveswithamplitudesofatleast10mmHg(totalnumberinallsixduodenalchannelsper10min)andpropagatedsequencesofduodenalwaves(totalnumberinallsixduodenalchannelsper10min)wereanalyzed,assumingapropagationvelocitybetween0.9and16cm/sec.Themeanamplitudesofthesewaveswerecalculatedastheaverageper10minacrossallsixchannels.
Impedanceanalysis
Impedancerecordingswereanalyzedbytwoindependentobservers(P.K.andC.K.R.)whowereblindedtothestudyconditions.Afloweventwasdefinedasatransientdecreaseinimpedanceofatleast12%frombaselineinatleastt
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