Effects of the Non-Nutritive Sweeteners on Glucose Metabolism and Appetite Regulating Hormones

17 Pages·2016·0.28 MB·English

RESEARCHARTICLE
Effects of the Non-Nutritive Sweeteners on
Glucose Metabolism and Appetite Regulating
Hormones: Systematic Review of
Observational Prospective Studies and
Clinical Trials
AlonsoRomo-Romo1,CarlosA.Aguilar-Salinas1,GriseldaX.Brito-Córdova1,Rita
A.GómezDíaz2,DavidVilchisValentín1,PalomaAlmeda-Valdes1*
1 InstitutoNacionaldeCienciasMédicasyNutriciónSalvadorZubirán,DepartmentofEndocrinologyand
Metabolism,MéxicoCity,México,2 MedicalResearchUnitinClinicalEpidemiology,UMAEHospitalde
a11111
Especialidades,CentroMédicoNacionalSigloXXI,InstitutoMexicanodelSeguroSocial(IMSS),México
City,México
*[email protected]
Abstract
OPENACCESS
Citation:Romo-RomoA,Aguilar-SalinasCA,Brito-
CórdovaGX,GómezDíazRA,VilchisValentínD,
Background
Almeda-ValdesP(2016)EffectsoftheNon-Nutritive
SweetenersonGlucoseMetabolismandAppetite Theeffectsofnon-nutritivesweeteners(NNS)onglucosemetabolismandappetiteregulat-
RegulatingHormones:SystematicReviewof inghormonesarenotclear.ThereisanongoingdebateconcerningNNSuseanddeleteri-
ObservationalProspectiveStudiesandClinicalTrials.
ouschangesinmetabolism.
PLoSONE11(8):e0161264.doi:10.1371/journal.
pone.0161264
Editor:ChristianHolscher,UniversityofLancaster, Objectives
UNITEDKINGDOM
Theaimofthisreviewistoanalyzethescientificavailableevidenceregardingtheeffectsof
Received:May12,2016
NNSonglucosemetabolismandappetiteregulatinghormones.
Accepted:August2,2016
Published:August18,2016 DataSourcesandStudyEligibilityCriteria
Copyright:©2016Romo-Romoetal.Thisisan
WeidentifiedhumanobservationalstudiesevaluatingtherelationbetweenNNSconsump-
openaccessarticledistributedunderthetermsofthe
tionandobesity,diabetes,andmetabolicsyndrome,inadditiontoclinicaltrialsevaluating
CreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninany theeffectsofNNSinglucosemetabolismandappetiteregulatinghormones.
medium,providedtheoriginalauthorandsourceare
credited.
Results
DataAvailabilityStatement:Allrelevantdataare
withinthepaperanditsSupportingInformationfile. FourteenobservationalstudiesevaluatingtheassociationbetweenNNSconsumptionand
thedevelopmentofmetabolicdiseasesandtwenty-eightclinicaltrialsstudyingtheeffects
Funding:Theauthorshavenosupportorfundingto
report. ofNNSonmetabolismwereincluded.Finally,twometa-analysesevaluatingtheassociation
betweentheconsumptionofNNS-containingbeveragesandthedevelopmentoftype2dia-
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. beteswereidentified.
PLOSONE|DOI:10.1371/journal.pone.0161264 August18,2016 1/17
Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
Conclusions
SomeobservationalstudiessuggestanassociationbetweenNNSconsumptionanddevel-
opmentofmetabolicdiseases;however,adiposityisaconfounderfrequentlyfoundin
observationalstudies.TheeffectsoftheNNSonglucosemetabolismarenotclear.The
resultsoftheidentifiedclinicaltrialsarecontradictoryandarenotcomparablebecauseof
themajorexistingdifferencesbetweenthem.StudiesevaluatingspecificNNS,withanade-
quatesamplesize,includingahomogeneousstudygroup,identifyingsignificantcomorbidi-
ties,withanappropriatecontrolgroup,withanappropriateexposuretime,andconsidering
adjustmentforconfoundervariablessuchasadiposityareneeded.
Introduction
Theprevalenceofobesityhasmorethandoubledsince1980;inparallelin2014,theestimated
numberofpatientswithdiabetesintheworldwas385millionwithaprojectiontoincreaseto
592millionby2035.Oneofthecontributingfactorsattributedtotheincreaseinobesity,type2
diabetesandothermetabolicdiseasesistheconsumptionofahighsugar/highfatdiet[1].To
avoidthenegativehealthconditionsassociatedwiththeexcessivesugarintake,therehasbeen
anupsurgeintheconsumptionofnonnutritivesweeteners(NNS)asanalternative[2].Atthis
timesixNNS,sucralose,aspartame,saccharin,acesulfame-K,neotame,andadvantame,are
approvedtobeusedassweetenersinfood,andtwonaturallyderivedNNS,steviolglycosides
andLuohanguoextract,aregenerallyrecognizedassafeandendorsedforuseinfoodbythe
USFoodDrugAdministration(FDA)andtheEuropeanFoodSafetyAuthority(EFSA)[3,4].
Nowadays,theyaregloballyusedandtheyarefoundinseveralproducts.
Recently,theEFSAconductedare-evaluationofaspartamesafety,andconcludedthat
aspartameanditsbreakdownproductsaresafeforthegeneralpopulation(includinginfants,
childrenandpregnantwomen)[4].BeforetheFDAapprovedNNSconsumption,aseriesof
toxicologicalandclinicalstudiesinanumberofspecies,includinghumans,wereconductedto
demonstratethattheyaregenerallysafeandwell-tolerated[5].Thereisanongoingdebateover
whetherNNSusemaybeassociatedtodeleteriousmetabolicchangesinhumans[6].Thisarti-
cleaimstocollecttheinformationregardingtheeffectsofNNSconsumptiononmetabolicdis-
eases,basedonasystematicreviewofthescientificliterature.
StudySearchandSelection
WeidentifiedhumanstudiesevaluatingtheeffectsofNNSconsumptioninmetaboliccondi-
tionsthroughsystematicsearchesandhandsearchesonApril8,2015(updatedonMarch25,
2016)inthreeelectronicdatabases:PubMed,TheCochraneLibrary,andTripDatabase.We
conductedthesearchforobservationalstudiestoanswerthefollowingresearchquestion:Is
therearelationbetweenNNSconsumptionandthedevelopmentofmetabolicchronicdiseases
inadults?Forclinicaltrials,wedirectedthesearchtoanswerthenextresearchquestion:Is
thereaneffectofNNSonglucosemetabolismandappetiteregulatinghormonescomparedto
waterorothersweetenersinadults?Thetermsusedinthesystematicsearchwerethoserelated
toNNSandartificiallysweetenedbeveragesincludingthenextMedicalSubjectHeadings
(MeSH)terms:artificialsweeteners/non-nutritivesweeteners/carbonatedbeverages/sucra-
lose/aspartame/stevia/saccharin/acesulfamepotassium/dietsoda/diabetesmellitus/obe-
sity/metabolicsyndrome.Tocomplementthesearch,wealsoperformedahand-searching
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Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
strategythroughcertainjournalsandreferencesinotherarticles.Timeandlanguageofpubli-
cationwerenotrestricted.Inclusioncriteriaconsistedinoriginalstudiesofprospectivedesign
conductedinadulthumans.Forcohortstudies,weconsideredthosethatevaluatetheassocia-
tionbetweenNNSconsumptionandthedevelopmentofdiabetes,metabolicsyndromeorobe-
sity,withafollowupofatleastthreeyears.Forclinicaltrialsweincludedthosethatevaluate
theeffectsofanyNNSonoutcomesrelatedtoglucosemetabolismandappetiteregulatinghor-
mones(S1File).Oneresearcher(AR)screenedthearticlestitlesandabstractstoremovethose
thateasilyweredetectedtobenotrelatedtotheobjectiveofthisreview,andthreeresearchers
(AR,PA,andGB)readthearticlesthatcouldbeeligibleinthesystematicreviewandselect
thosethatfinallyareincluded.ArticlesevaluatingtheeffectsofNNSinotherconditionsor
evaluatingotheroutcomesnotrelatedwereexcluded.
Results
Literaturesearch
Weidentify1569studiesthroughdatabasesearching;inaddition,376werefoundbythehand
searchingstrategy.Afterduplicatesremovalandinitialscreening,72studieswerereviewed.
Finally,44studieswereincludedaftertheexclusionof28thatdidnotfulfilltheinclusioncrite-
ria.Fig1showstheflowchartdescribingtheprocessofthesystematicsearch.
Observationalstudies
WeincludedfourteenobservationalstudiesevaluatingtheassociationbetweenNNSconsump-
tionandthedevelopmentofmetabolicdiseasesincludingtype2diabetes,obesity,andmetabolic
Fig1.Flowdiagramofthesystematicsearch.
doi:10.1371/journal.pone.0161264.g001
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Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
syndrome.AllofthesestudieshaveconsideredNNSconsumptioninbeveragesandmostof
theminsoftdrinks.
Summarizingtheresults,themajorityofthesestudieshavefoundsignificantassociations
betweentheingestionofNNSandthedevelopmentofmetabolicdiseases.Amongthesestudies
therearetworeportsderivedfromtheNurses’HealthStudy(NHSIandII)thatincluded
morethan70,000and90,000women,withanaveragefollow-upof24and8yearsforthefirst
andthesecondstudies,respectively.Thefirstofthesestudiesfoundasignificantassociation
betweencaffeinatedartificiallysweetenedbeveragesconsumptionanddevelopmentoftype2
diabetes(RR1.35,95%CI1.24–1.47).However,thisassociationwaslostaftertheadjustment
forbodymassindex(BMI)andenergyintake(RR1.01,95%CI0.93–1.10)[7].IntheNHSII
noassociationwasfound[8].
Anotherlargecohortstudythatevaluatedtheeffectofartificiallysweetenedbeveragescon-
sumptionandthedevelopmentoftype2diabetesistheHealthProfessionalsFollow-UpStudy.
Thisincludedapproximately40,000malehealthprofessionalsfollowedover20years.This
studyfoundasignificantassociationbetweenNNSconsumptionandtype2diabetesdevelop-
ment,evenaftermultivariableadjustment(HR1.40,95%CI1.26–1.56).However,thisassocia-
tionwaslostaftertheadjustmentforBMI(HR1.09,95%CI0.98–1.21)[9].
TheEuropeanProspectiveInvestigationintoCancerandNutrition(EPIC)Study,per-
formedineightEuropeancountries,included340,234menandwomen.Thisstudyreporteda
significantassociationbetweenartificiallysweetenedsoftdrinksingestionandtype2diabetes
development(HR1.93,95%CI1.47–2.54).Thisassociationwasattenuatedaftermultivariable
adjustment(HR1.88,95%CI1.44–2.45),andloststatisticalsignificanceafterfurtheradjust-
mentforBMIandenergyintake(HR1.13,95%CI0.85–1.52)[10].
Table1showsasummaryoftheresultsoftheincludedcohortstudies.OnTable2thecrude
andadjustedrisksreportedinthesestudiesarecontrasted.
Clinicaltrials
Twenty-eightclinicaltrialsstudyingdifferenteffectsofNNSwereidentified.Ofthesestudies,
10foundsignificanteffectsonsomeorallthestudiedvariables.Allofthesestudieshaveana-
lyzedglucoseandmostofthemhavemeasuredinsulinconcentrations,11quantifiedGLP-1
concentrations.However,onlyonestudyhasmeasuredinsulinsensitivityandpancreatic
response,andanothersinglestudyhasevaluatedthechangesintheintestinalmicrobiome.The
majorityoftheclinicaltrialshaveevaluatedtheeffectsofaspartame(14trials),followedby
sucralose(11studies),andsaccharin,acesulfame-K,andstevia(5studiesforsaccharin,5for
acesulfame-K,and4forstevia).Mostofthesestudieshaveperformedanacutesingleexposure
totheNNS(n=20)andtheremaining(n=8)haveevaluatedalongerexposurethatvaries
betweensevendaysto18weeks.Thirteenstudiesincludedindividualswithdiabetes.
ThestudiesbyPepino[20]andSuez[21]demonstrateadeleteriouseffectincreasingglucose
concentrationsafteranacuteanda7-dayexposuretosucraloseandsaccharin,respectively.
Pepino,alsoreportedadecreaseininsulinsensitivityalongwithincreasedinsulinandC-pep-
tideconcentrations.Remarkably,thisstudyincludedsubjectswithahighdegreeofobesity
(averageBMI42kg/m2).InthestudyofSuezafteraseven-dayperiodofsacchariningestion,
infourofsevensubjectsglucoseconcentrationsshowedasignificantincrement.Subsequently,
afecestransplantfromsomeoftheindividualswiththeglucoseincreaseaftersaccharinexpo-
suretomicewasperformed.Afterthetransplant,glucoseconcentrationsalsoincreasedin
thesemice,suggestingthatNNSconsumptionmodifyintestinalmicrobiomeindetrimentof
glucosetolerance.ThemicrobiomeshowedasignificantimbalancewithanincreaseintheBac-
teroidesgenusandClostridialesorder[21].
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Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
Table1. Observationalstudiesevaluatingtheassociationbetweenartificiallysweetenedbeveragesconsumptionandtheriskfordevelopmentof
metabolicdiseases.
Author,year,cohort,andcountry Follow-up Population(Number Results
time andage)
(cid:129) SchulzeMB,etal. 8years (cid:129)91,249women (cid:129)741incidentcasesofT2D
(cid:129) 2004 (cid:129)24–44years (cid:129)Nosignificantassociationbetweentheconsumptionofoneormore
(cid:129) TheNurses’HealthStudy(NHSII) dietsoftdrinksperdayanddevelopmentofT2Dafteradjustmentfor
(cid:129) USA[8] baselineBMI(RR:1.21;95%CI:0.97–1.50;P=0.12)
(cid:129) DhingraR,etal. 4years (cid:129)6,039adults (cid:129)1,239incidentcasesofmetabolicsyndrome
(cid:129) 2007 (cid:129)Meanage52.9 (cid:129)Associationbetweentheconsumptionofoneormoredietsoftdrinks
(cid:129) TheFraminghamHeartStudy years perdayandthedevelopmentofmetabolicsyndromeafter
(cid:129) USA[11] multivariableadjustment(OR:1.53;95%CI:1.10–2.15)comparedwith
theconsumptionoflessthanonesoftdrinkperweek.However,the
adjustmentdidnotincludeBMIorwaistcircumference
(cid:129) LutseyPL,etal. 9years (cid:129)9,514adults (cid:129)3,782incidentcasesofmetabolicsyndrome
(cid:129) 2008 (cid:129)45–64years (cid:129)Consumptionofartificiallysweetenedbeverages(thirdtertile)
(cid:129) TheAtherosclerosisRiskin associatedwithincidentmetabolicsyndromeaftermultivariable
Communities(ARIC)Study adjustmentwithoutconsiderationofadiposity(HR:1.34;95%CI:1.24–
(cid:129) USA[12] 1.44;P<0.001)
(cid:129) FowlerSP,etal. 7–8years (cid:129)3,682adults (cid:129)1,250incidentcasesofoverweightorobesity(BMI(cid:1)25kg/m2)in
(cid:129) 2008 (cid:129)25–64years peoplewithnormalweightatthebeginningofthestudy(BMI<25kg/
(cid:129) TheSanAntonioHeartStudy(SAHS) m2)
(cid:129) USA[13] (cid:129)Significantassociationbetweentheconsumptionofartificially
sweetenedbeverages(fourthquartile)andtheincidenceofobesity
(OR:2.03;95%CI:1.36–3.03;P<0.001)
(cid:129)Positivedose-responserelationshipwiththechangesinBMIduring
thestudy(OR:1.78;95%CI:1.51–2.06;P<0.0001)
(cid:129) PalmerJR,etal. 4years (cid:129)43,960women (cid:129)906incidentcasesofT2D
(cid:129) 2008 (cid:129)21–69years (cid:129)Norelationshipbetweentheconsumptionofoneormoredietsoft
(cid:129) TheBlacksWomen’sHealthStudy drinksperdayandtheriskofT2D(RR:1.06;95%CI:0.83–1.36)
(BWHS) comparedwiththeconsumptionoflessthanonedietsoftdrinkper
(cid:129) USA[14] month
(cid:129) NettletonJA,etal. 7years (cid:129)5,011adults (cid:129)871incidentcasesofmetabolicsyndromeand413ofT2D
(cid:129) 2009 (cid:129)45–84years (cid:129)Intakeofoneormoreservingsperdayofdietsodawaspositively
(cid:129) TheMulti-EthnicStudyof associatedwithincidentmetabolicsyndrome(HR:1.36;95%CI:1.11–
Atherosclerosis(MESA) 1.66;P<0.001).However,afteradjustmentbyadiposity(BMIandwaist
(cid:129) USA[15] circumference)theassociationwasnotsignificant(HR:1.17;95CI:
0.96–1.44;P=0.06)
(cid:129)Intakeofoneormoreservingsperdayofdietsodawaspositively
associatedwithincidentT2D(HR:1.67;95%CI:1.27–2.20;P<0.001).
However,afteradjustmentforadiposity(BMIandwaistcircumference)
theassociationwasattenuatedremainingstatisticallysignificant(HR:
1.38;95CI:1.04–1.82;P=0.01)
(cid:129) deKoningL,etal. 20years (cid:129)40,389men (cid:129)2,680incidentcasesofT2D
(cid:129) 2011 (cid:129)40–75years (cid:129)Associationofartificiallysweetenedbeveragesconsumption(fourth
(cid:129) TheHealthProfessionalsFollow-Up quartile,medianconsumptionof6.5servingsperweek)andthe
Study(HPFS) developmentofT2D(HR:1.91;95%CI:1.72–2.11;P<0.01).However,
(cid:129) USA[9] inthemultivariatemodeltheassociationwasnotconserved(HR:1.09;
95%CI:0.98–1.21;P=0.13)
(cid:129) DuffeyKJ,etal. 20years (cid:129)3,728adults (cid:129)Thenon-consumersofdietbeverageshadlowerriskfordeveloping
(cid:129) 2012 (cid:129)18–30years metabolicsyndromecomparedtoconsumers(HR:0.81;95%CI:
(cid:129) TheCoronaryArteryRiskDevelopment 0.69–0.95;P<0.05)
inYoungAdults(CARDIA)Study
(cid:129) USA[16]
(Continued)
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Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
Table1. (Continued)
Author,year,cohort,andcountry Follow-up Population(Number Results
time andage)
(cid:129) BhupathirajuSN,et.al. 24years (cid:129)74,749women (cid:129)7,370incidentcasesofT2D
(cid:129) 2013 (cid:129)30–55years (cid:129)Noassociationbetweentheconsumptionofoneormoreservingsper
(cid:129) TheNurses’HealthStudyI(NHSI) dayofcaffeinatedartificiallysweetenedbeveragesandthe
(cid:129) USA[7] developmentofT2Daftermultivariableadjustment,includingBMIand
energyintake(RR:1.01;95%CI:0.93–1.10;P=0.99)
(cid:129)Theconsumptionofcaffeine-freeartificiallysweetenedbeverageswas
associatedwithhigherriskofT2Daftermultivariableadjustmentfor
BMIandenergyintake(RR:1.09;95%CI:1.00–1.18;P=0.02)
(cid:129) BhupathirajuSN,et.al. 22years (cid:129)39,059men (cid:129)2,865incidentcasesofT2D
(cid:129) 2013 (cid:129)40–75years (cid:129)Noassociationbetweentheconsumptionofoneormoreservingsper
(cid:129) TheHealthProfessionalsFollow-Up dayofcaffeinatedartificiallysweetenedbeveragesandthe
Study(HPFS) developmentofT2DaftermultivariableadjustmentincludingBMIand
(cid:129) USA[7] energyintake(RR:1.06;95%CI:0.93–1.22;P=0.55);andalsofor
caffeine-freeartificiallysweetenedbeverages(RR:1.15;95%CI:
0.99–1.33;P=0.06)
(cid:129) TheInterActConsortium 16years (cid:129)340,234adults (cid:129)11,684incidentcasesofT2D
(cid:129) 2013 (cid:129)39–69years (cid:129)Significantassociationbetweentheconsumptionofoneormore
(cid:129) TheEuropeanProspectiveInvestigation servingsperdayofartificiallysweetenedsoftdrinksandthe
intoCancerandNutrition(EPIC)Study developmentofT2D(HR:1.84;95%CI:1.52–2.23;P<0.0001).
(cid:129) EightEuropeancountries[10] However,aftermultivariableadjustmentincludingBMIandenergy
intake,theassociationdidnotremainedstatisticallysignificant(HR:
1.13;95%CI:0.85–1.52;P=0.24)
(cid:129) FagherazziG,etal. 14years (cid:129)66,118women (cid:129)1,369incidentcasesofT2D
(cid:129) 2013 (cid:129)Meanage52.6 (cid:129)Consumptionofmorethan603mLperweekofartificiallysweetened
(cid:129) EpidemiologicstudyofFrenchfemale years beveragesassociatedwithincidentT2Daftermultivariableadjustment
teachers(E3N)intheEPICStudy includingBMI(HR:1.68;95%CI:1.19–2.39;P=0.0057)
(cid:129) France[17]
(cid:129) SakuraiM,etal. 7years (cid:129)2,037men (cid:129)170incidentcasesofT2D
(cid:129) 2014 (cid:129)35–55years (cid:129)Consumptionofoneormoreservingsperweekofdietsoda
(cid:129) Employeehealthexaminationsofa associatedwithincreaseddiabetesriskaftermultivariableadjustment
factoryinJapan (HR:1.70;95%CI:1.13–2.55;P=0.013)comparedtonon-consumers
(cid:129) Japan[18] ofdietsoda.
(cid:129) O’ConnorL,etal. 10.8years (cid:129)24,653adults (cid:129)847incidentcasesofT2D
(cid:129) 2015 (cid:129)40–79years (cid:129)Oneservingperday(336g)ofartificiallysweetenedbeverageswas
(cid:129) TheEPIC-NorfolkStudy associatedtodevelopmentofT2Daftermultivariableadjustment(HR:
(cid:129) UK[19] 1.22;95%CI:1.11–1.33;P<0.001).
(cid:129)Afterasecondadjustmentconsideringadiposity(BMIandwaist
circumference)theassociationdidnotremainedsignificant(HR:1.06;
95%CI:0.93–1.20;P=0.124)
T2D:type2diabetes,BMI:bodymassindex,RR:relativerisk,CI:confidenceinterval,HR:hazardratio,OR:oddsratio.
doi:10.1371/journal.pone.0161264.t001
GLP-1concentrations,measuredinelevenstudies,havebeenshowntobedecreasedinone
reportafteraspartameingestion[22]andincreasedintwostudiesaftersucralose+acesulfame-
Kandsucraloseexposure[23,24].Concentrationsofappetite-regulatinghormones,including
cholecystokinin,ghrelin,andpeptideYY,haveonlybeenstudiedinthreestudies.Innoneof
themchangesintheconcentrationsofthesevariableswerefound.Inaddition,nochangein
thesubjectiveappetiteratingsoronthequantityoffoodconsumedafterNNSexposurehas
beenfound.
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Table2. Crudeandadjustedassociationsbetweentheconsumptionofartificiallysweetenedbeveragesandthedevelopmentofmetabolicdis-
easesinobservationalprospectivestudies.
Cohort Pathology Follow-up n Cruderisk Multivariableadjustment Adiposityadjustment
NHSI[7] T2D 24years 74,749 1.59(1.47–1.71) 1.35(1.24–1.47) 1.01(0.93–1.10)
NHSII[8] T2D 8years 91,249 1.21(0.97–1.50) ---- ----
FraminghamHeartStudy[11] MS 4years 6,039 1.42(1.10–1.84) 1.53(1.10–2.15) ----
ARIC[12] MS 9years 9,514 1.20(1.11–1.29) 1.34(1.24–1.44) ----
BWHS[14] T2D 4years 43,960 1.06(0.83–1.36) ---- ----
MESA[15] MS 7years 5,011 1.31(1.07–1.60) 1.36(1.11–1.66) 1.17(0.96–1.44)
MESA[15] T2D 7years 5,011 1.63(1.24–2.13) 1.67(1.27–2.20) 1.38(1.04–1.82)
HPFS[7] T2D 22years 39,059 1.87(1.65–2.12) 1.32(1.15–1.51) 1.06(0.93–1.22)
HPFS–2[9] T2D 20years 40,389 1.91(1.72–2.11) 1.40(1.26–1.56) 1.09(0.98–1.21)
CARDIAa[16] MS 20years 3,728 0.81(0.69–0.95) ---- ----
SAHS[13] OB 7–8years 3,682 2.03(1.36–3.03) ---- ----
EPIC[10] T2D 16years 340,234 1.93(1.47–2.54) 1.88(1.44–2.45) 1.13(0.85–1.52)
EPIC-France[17] T2D 14years 66,118 3.50(2.49–4.93) 2.21(1.56–3.14) 1.68(1.19–2.39)
EPIC-Norfolk[19] T2D 10.8years 24,653 1.70(1.35–2.14) 1.67(1.33–2.11) 1.17(0.93–1.48)
EmployeeFactoryJapan[18] T2D 7years 2,037 1.99(1.33–2.98) 1.82(1.22–2.71) 1.70(1.13–2.55)
NHS:Nurses’HealthStudy,ARIC:theAtherosclerosisRiskinCommunitiesstudy,BWHS:theBlacksWomen’sHealthStudy,MESA:theMulti-EthnicStudy
ofAtherosclerosis,HPFS:theHealthProfessionalsFollow-UpStudy,CARDIA:theCoronaryArteryRiskDevelopmentinYoungAdultsstudy,SAHS:the
SanAntonioHeartStudy,EPIC:theEuropeanProspectiveInvestigationintoCancerandNutritionstudy,T2D:type2diabetes,MS:metabolicsyndrome,
OB:obesity,n:individualsincludedinthestudies.Associationsbetweenthehighestrangeofartificiallysweetenedbeveragesconsumptionandthe
incidenceofthespecificmetabolicdiseasestudied,expressedinrelativerisks,oddsratiosorhazardratioswith95%confidenceintervals(95%CI).
aTheCARDIAstudyevaluatestheriskofthenon-consumersofdietbeveragestodevelopmetabolicsyndromecomparedtotheconsumers.
doi:10.1371/journal.pone.0161264.t002
OnTable3thedescriptionandresultsofthesestudiesareshown.Asareference,one12oz
diet-cokecontainsapproximately140mgofaspartameandacesulfameKmix,one12ozdiet-
Dr.Peppercancontainsapproximately65and22mgofsucraloseandacesulfame,respectively,
andone12-ozCoca-ColaLifecancontains27mgofstevia.SomeoftheNNSavailableasindi-
vidualpacketsincludeSweetandLow,containing34mgofsaccharin,andSplendacontaining
12mgofsucralose.OnTable4asummaryofthestudiesindicatingthemethodologyused,
studiedvariables,andtheNNSevaluatedarepresented.
Meta-analysis
Twometa-analyseshavebeenpublishedtoevaluatetheassociationbetweentheconsumption
ofNNS-containingbeveragesandthedevelopmentoftype2diabetestoclarifyifthisrelation
isclearlylinkedtotheconsumptionoftheseproductsorrelatedtootherlifestylefactors.Both
meta-analysesevaluatedtheassociationbetweenNNSconsumption,withoutspecifyingof
stratifyingforthespecificNNSingested.Whilebothstudiesexcludedcohortsincludingindi-
vidualswithaknowndiagnosisofdiabetes,thearticlebyGrenwoodonlyincludedfourstudies.
Thismaybeduetotheselectioncriteriathatspecifythatonlystudiesincludingindividuals
“fromagenerallyhealthypopulation”wereconsidered[48].Incontrast,thestudybyImamura
evaluatedtenstudiesestimatingtheriskoftype2diabetesassociatedtoconsumptionofNNS-
containingbeverages[49].Noneofthestudiesdisclosedsignificantcompetinginterests.
Inthefirstmeta-analysisthatincluded4observationalprospectivestudies,thepooledesti-
matedrelativerisk(RR)was1.13(95%CI:1.02–1.25;P=0.02)fortheconsumptionof330ml
perdayofartificiallysweetenedbeveragesandthedevelopmentoftype2diabetes.Therewas
PLOSONE|DOI:10.1371/journal.pone.0161264 August18,2016 7/17
Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
Table3. Clinicaltrialsevaluatingtheeffectofnon-nutritivesweetenersconsumptiononglucosemetabolismandappetiteregulatinghormones.
No. Authorandyear Population Methodology Variables Results
1 (cid:129)NehrlingJK, 62subjectswithdiabetes(31insulin- (cid:129)Randomized,double-blindstudy (cid:129)Glucose NochangesinplasmaglucoseorHbA1c
etal. dependentand31non-insulin- (cid:129)29participantsconsumed2.7gof (cid:129)HbA1c levelsduringthetreatment.
(cid:129)1985[25] dependent)aged18–65years aspartameperdayincapsulesand33
participantsconsumedplacebocapsules
(cornstarch)during18weeks
(cid:129)Fastingand2-hourafterbreakfast
samplescollectedinweeks0,9,17,18
2 (cid:129)OkunoG, (cid:129)Firststudy:7healthycontrolsand (cid:129)Firststudy:crossoverdesign,2visits, (cid:129)Glucose (cid:129)Smallbutsignificantdecreaseinblood
etal. 22untreatedsubjectswithdiabetes consumptionof100gglucoseor500mg (cid:129)Insulin glucose2hand3hafteraspartame
(cid:129)1986[26] (cid:129)Sdaigeaecbdoent1ed8s–sa6tug4deyyde:3a98rss–u8b1jeycetsarwsi(th5 (cid:129)aSmsegpcaaorsntpadamsrtteaumodnye:fdaoasvteiliynrg2cowneseukmsp,OtioGnToTf1(5205 (cid:129)(cid:129)GTrliugclyacgeornides (cid:129)Nafirdosmtositnhtuiesdtrryca(htpiao<nn0gc.e0os5m)wpearreedobtosegrlvuecdosinein
treatedwithinsulin) gglucose)beforeandafterintervention (cid:129)Totalcholesterol bothstudiesaftertheconsumptionof
(cid:129)HDL-cholesterol aspartame
3 (cid:129)HorwitzDL, 12normalsubjectsand10subjects (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Nosignificanteffectsofsweetenersat
etal. withnon-insulin-dependentdiabetes 3visits:consumptionofaflavored (cid:129)Insulin anytimepointinglucose,insulinor
(cid:129)1988[27] aged18–65years beverageunsweetenedorwith135mg (cid:129)Glucagon glucagon
saccharinor400mgaspartame (cid:129)Innormalsubjects,highermeanAUC
(cid:129)Samplescollectedover3hafter insulinlevelsafteraspartame
consumingthetestbeverage comparedwithsaccharinor
unsweetenedbeverage(p<0.05)
4 (cid:129)CooperPL, 17subjectswithnon-insulin- (cid:129)Crossoverstudy (cid:129)Glucose Nochangesonglucose,insulinor
etal. dependentdiabetes,aged62.2±14.0 (cid:129)Dailyintakeof28gsucroseor30g (cid:129)Insulin triglycerideswerefoundwiththe
(cid:129)1988[28] years,andBMI26.0±3.0kg/m2 starch+saccharinduring6weeks (cid:129)Triglycerides sacchariningestion
(cid:129)Samplescollectedover3hoursatthe
beginningofthestudyandattheendof
eachinterventionperiod
5 (cid:129)ColagiuriS, 9subjectswithnon-insulin-dependent (cid:129)Crossoverstudy (cid:129)Glucose Aspartameingestiondidnotgenerate
etal. diabetes,aged66±5years,andBMI (cid:129)Dailyintakeof45gsucroseor162mg (cid:129)HbA1c changesonanyofthevariables
(cid:129)1989[29] 26.4±2.1kg/m2 aspartameduring6weeks (cid:129)Weight measured
(cid:129)Samplescollectedonfastingatthe (cid:129)Totalcholesterol
beginningofthestudyandattheendof (cid:129)HDL-cholesterol
eachinterventionperiod
(cid:129)Triglycerides
6 (cid:129)RodinJ 12overweightand12normal-weight (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Aspartameconsumptionhadnot
(cid:129)1990[30] subjects,aged22–50years (cid:129)4visits:500mlwaterorwater+50g (cid:129)Insulin effectsonglucose,insulin,glucagon
glucoseor50gfructoseor250mg (cid:129)Glucagon andfreefattyacidsconcentrations
aspartame (cid:129)Freefattyacids (cid:129)Theaspartameloaddidnotstimulate
(cid:129)Slaatemr,psleusbjceocltlsecctoendsouvmeerd48amluinncuhteusn;til (cid:129)Caloricintake fwoaotderin(tcaoknetrboel)yondtheconsumptionof
theyfeltsatiated
7 (cid:129)HärtelB,etal. 14healthysubjectsaged19–52years (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)LowerinsulinlevelsaftertheNNS
(cid:129)1993[31] withnormalglucosetolerance (cid:129)6visits:330mlwateronlyorwater+33 (cid:129)Insulin ingestioncomparedtosucrose
gsucroseor165mgaspartameor165 (p<0.001)
mgacesulfame-Kor800mgcyclamate (cid:129)Lowerglucoselevelsinsometimes
or75mgsaccharin afteraspartameorsacchariningestion
(cid:129)BloodSamplescollectedover120 comparedtowater(p<0.05),this
minutes changeswerenotphysiologically
meaningful
8 (cid:129)MezitisNH, 13subjectswithT1Dand13subjects (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Sucraloseingestionhadnoeffectson
etal. withT2D(HbA1c<10%) 2visits:administrationofonecapsule (cid:129)C-peptide glucoseandC-peptideconcentrations
(cid:129)1996[32] with1000mgsucraloseorplacebo comparedtoplacebo
(cellulose),followedbyastandardized (cid:129)Hypoglycemiaoccurredineachof
360-Kcalliquidbreakfast threeT1Dparticipantswiththe
(cid:129)Bloodsamplesobtainedduring4hours sucraloseingestion;however,
sucralosewasnotconsideredthe
cause
9 (cid:129)MelansonKJ, 10healthynon-smorkersmen,aged (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)In40%oftheparticipants,blood
etal. 19–31years,BMI23.4±1.9kg/m2 3visits:consumptionofsimple (cid:129)Caloricintake glucosedeclinedafteraspartame
(cid:129)1999[33] carbohydrateorhigh-fatoraspartame- ingestion,whilein20%increasedand
containingdrinks in40%remainedstable
(cid:129)Later,subjectsconsumedfoodad (cid:129)Nostatisticallysignificantdifferences
libitum betweengroupsoncaloricintake
(Continued)
PLOSONE|DOI:10.1371/journal.pone.0161264 August18,2016 8/17
Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
Table3. (Continued)
No. Authorandyear Population Methodology Variables Results
10 (cid:129)GrotzVL,etal. 128subjectswithT2D,aged31–70 (cid:129)2randomizedassignedgroups:daily (cid:129)Glucose Noeffectswerefoundonglucose,C-
(cid:129)2003[34] years,andHbA1clevels(cid:3)10% consumptionoftwocapsuleswith (cid:129)C-peptide peptideorchangesinHbA1cafter
sucralose(667mgperday)ortwo (cid:129)HbA1c sucraloseconsumption
capsulesofplacebo(cellulose)during13
weeks
11 (cid:129)HallWL,etal. 6subjectsaged24–31yearsandBMI (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)LowerplasmaGLP-1concentrations
(cid:129)2003[22] <25kg/m2 (cid:129)3visits:ingestionofcapsuleswith400 (cid:129)Insulin afteraspartameandaminoacids
mgaspartameor176mgasparticacid (cid:129)GLP-1 ingestion(p<0.05).
+flo2u2r4amscgopnhtreonlylalanineor400mgcorn (cid:129)GIP (cid:129)Aefsfepcatrstaomnethceonosthuemrpvtaiorinabhlaedsnot
(cid:129)Samplescollectedover120minutes (cid:129)CCK
(cid:129)VAStomeasuresubjectiveappetite (cid:129)Gastricemptying
Desiretoeat
ratings
Hunger
Fullness
12 (cid:129)GregersenS, 12subjectswithT2D,BMI25–32kg/ (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Steviosidereducedtheglycemic
etal. m2,andHbA1clevels<10% 2visits:412kcalbreakfastconsumption (cid:129)Insulin responsein18±5%(p=0.013)
(cid:129)2004[35] +supplement(1gsteviosideor1g (cid:129)GLP-1 (cid:129)Insulinogenicindexincreasedby
(cid:129)mSaamizpelesstacrcohlleacstecdonotvroelr)240minutes (cid:129)GIP acopnpsrouxmimptaiotenly(p4<00%.0a0f1te)rstevioside
(cid:129)Glucagon (cid:129)Nootherstatisticallysignificanteffects
(cid:129)Insulinogenic werefoundoninsulin,glucagon,GLP-1
index andGIP
13 (cid:129)Barriocanal (cid:129)76subjectsdividedin3groups:30 (cid:129)Randomizedassignmenttoconsume (cid:129)Glucose Steviolglycosidesdidnotgenerate
LA,etal. withT2D,16withT1D,and30 250mgsteviolglycosidesorplacebo (cid:129)Insulin changesonanyofthestudiedvariables
(cid:129)2008[36] healthysubjects (cid:129)Participantswerefollowed-upfor3 (cid:129)HbA1c
(cid:129)Eachgroupwassubdividedto months
receivetheactivetreatmentor
placebo
14 (cid:129)MakiKC,etal. 122subjectswithdiabetesaged33– (cid:129)Randomizeddouble-blindstudy (cid:129)HbA1c TheconsumptionofrebaudiosideAover
(cid:129)2008[37] 75years (cid:129)60subjectsconsumed1000mg (cid:129)Glucose 16weeksdidnotshowneffectsinany
rebaudiosideAcapsulesand62 (cid:129)Insulin variable
subjectsconsumedplacebocapsules (cid:129)C-peptide
(cellulose)during16weeks
(cid:129)Subjectswereaskedtomaintainastable (cid:129)Bodyweight
dietduringthestudy (cid:129)Bloodpressure
(cid:129)Triglycerides
(cid:129)Totalcholesterol
(cid:129)HDL-cholesterol
(cid:129)LDL-cholesterol
15 (cid:129)MaJ,etal. 7healthysubjectswithBMI21.6±1.2 (cid:129)Crossoverstudy (cid:129)Glucose Sucralosedidnotshowedeffectsatany
(cid:129)2009[38] kg/m2,age24±2years,non-smokers, 4visits:intragastricinfusionof50g (cid:129)Insulin doseonglucose,insulin,GLP-1,GIP,and
andalcoholconsumption<20gper sucrose,80mgsucralose,800mg (cid:129)GLP-1 gastricemptyingcomparedtosaline
day sucraloseor500mlsalinein3minutes
(cid:129)Sampleswereobtainedduring240 (cid:129)GIP
minutes (cid:129)Gastricemptying
16 (cid:129)AntonSD, (cid:129)Subjectsaged18–49yearsand (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Lowerplasmaglucoseandinsulin
etal. non-smokers. (cid:129)3visits:consumptionofteasweetened (cid:129)Insulin concentrationswithsteviaconsumption
(cid:129)2010[39] (cid:129)1192swuitbhjeocbtesswitiyth(wnaoirsmtaclirwcuemigfhetraenndce w(qiuthansutitcyronsoetsoprescteifiveiad)oprraesvpioaurtsamtoethe (cid:129)Iinndsuelxinogenic gcolumcopsaereadntdops<u0c.r0o5sefo(rpi<n0s.u0l1in)for
atleast90cmforfemalesand100 consumptionofabuffetadlibitum (cid:129)Hunger (cid:129)Greaterinsulinogenicindexwith
cmformales) (cid:129)VraAtiSngtsomeasuresubjectiveappetite (cid:129)Satiety a(ps<p0a.r0ta5m)econsumptionat60minutes
(cid:129)Fullness (cid:129)Energyintakedidnotincreasewith
(cid:129)Organoleptic NNSconsumptionandnoeffectswere
characteristics foundonappetiteparameters
17 (cid:129)MaJ,etal. 10healthysubjects,withBMI23.4±0.8 (cid:129)Crossoverstudy (cid:129)Glucose Noeffectsonglucoseintestinal
(cid:129)2010[40] kg/m2,andage27±2years (cid:129)2visits:intraduodenalinfusionof (cid:129)GLP-1 absorptionorGLP-1secretionwere
sucralose(960mg)insalinecompared observedwithsucraloseconsumption
toonlysalineinfusionduring150
minutes
(Continued)
PLOSONE|DOI:10.1371/journal.pone.0161264 August18,2016 9/17
Non-NutritiveSweeteners,GlucoseMetabolism,andAppetiteHormones
Table3. (Continued)
No. Authorandyear Population Methodology Variables Results
18 (cid:129)FordHE,etal. 8healthysubjectsaged22–27years, (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Sucralosedidnotstimulatecephalic
(cid:129)2011[41] withBMI18.8kg/m2,andnon- (cid:129)3visits:ingestionof50mlwateror (cid:129)Insulin responseandhadnoeffectson
smokers sucraloseormaltodextrin+sucralose (cid:129)GLP-1 glucose,insulin,GLP-1andPYY
(cid:129)Af(esfettiemdriunslgoaltpuiortoinotonocsfooinlragwleacssatievoixntye,cmsuwoteeddeifite-tda-ssteham- (cid:129)(cid:129)PFoYoYdintake (cid:129)cSinouancpcrapelenottsirtaeetidsoiundbsnjeocttsivheorwaetidngdsiffoerrefonocdes
receptors) (cid:129)Hunger intake
(cid:129)Bloodsampleswereobtainedduring2 (cid:129)Desiretoeat
hours (cid:129)Cephalic
response
19 (cid:129)BrownAW, 8femalevolunteerswithBMI22.16 (cid:129)Crossoverstudy (cid:129)Glucose Nosignificantdifferenceswereobserved
etal. ±1.71kg/m2,aged21.75±2.25years, (cid:129)4visits:355mlwaterorwater+50g (cid:129)Insulin inanyofthevariableswiththe
(cid:129)2011[23] non-smokers,withoutdiabetesor sucroseor6ggranularsucraloseor50g (cid:129)Glucagon consumptionofsucralosecomparedto
alcoholconsumption sucroseand6ggranularsucralose (cid:129)Triglycerides water
(cid:129)Breakfast(500kcal)after60minutes (cid:129)Ghrelin
andbloodsamplesoverthenext2hours
(cid:129)VAStomeasureappetite (cid:129)Hunger
(cid:129)Gastrointestinal
comfort
(cid:129)Generalwell-
being
20 (cid:129)SteinertRE, 12healthysubjectsaged23.3±0.7 (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)NoneoftheNNShadeffectson
etal. years,BMI23.0±0.5kg/m2,non- (cid:129)6visits:intragasticinfusion(over2min) (cid:129)Insulin biochemicalvariablescomparedto
(cid:129)2011[42] smokersandwithoutchronicdiseases of250mlwaterorwater+50gglucose (cid:129)GLP-1 water
or25gfructoseor169mgaspartameor (cid:129)PYY (cid:129)Lowerappetitesubjectiveratingswith
220mgacesulfame-Kor62mg NNScomparedtoglucoseand
sucralose (cid:129)Ghrelin fructose;however,thedifferenceswere
(cid:129)Bloodsamplesobtainedduring2hours (cid:129)Hunger notstatisticallysignificant
(cid:129)VAStomeasureappetite (cid:129)Satiety
(cid:129)Fullness
21 (cid:129)MaerskM, (cid:129)24subjectsaged20–50yearswith (cid:129)Crossoverstudy (cid:129)Glucose Aspartame-containingbeveragedidnot
etal. obesity(BMI28–36kg/m2) (cid:129)4visits:500mlsucrose-sweetened (cid:129)Insulin showedeffectsonanyofthevariables
(cid:129)2012[43] (cid:129) Individualswithdiabetesor regularsoda,500mlsemi-skimmedmilk, (cid:129)Ghrelin
pregnancywereexcluded 500mlaspartame-sweeteneddietsoda (cid:129)GLP-1
or500mlbottledstillwater.
(cid:129)Adlibitumfoodconsumptionfroma (cid:129)GIP
buffetafter4hours (cid:129)Hunger
(cid:129)VAStomeasureappetite (cid:129)Satiety
(cid:129)Fullness
(cid:129)Prospective
desiretoeat
(cid:129)ThirstEnergy
intake
22 (cid:129)WuT,etal. 10healthysubjectsaged28.8±4.0 (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)Sucraloseconsumptiondidnotpresent
(cid:129)2012[44] years,andBMI25.5±1.5kg/m2 (cid:129)4visits:ingestionof40gglucose,40g (cid:129)GLP-1 effectsonglucose,insulin,GLP-1and
tagatose/isomaltmixture,40g3-O- (cid:129)GIP GIPconcentrations
methylglucose,or60mgsucralose (cid:129)Insulin (cid:129)Gastricemptyingwaslowerafterthe
(cid:129)Samplescollectedover240minutes (cid:129)Gastricemptying ianngdes3t-iOon-moeftthayglagtlousceo/siesocmomalptamreixdtutroe
sucralose(p=0.033andp=0.012,
respectively)
23 (cid:129)BrownR,etal. (cid:129)Subjectsaged12–25yearsdivided (cid:129)Crossoverstudy (cid:129)Glucose (cid:129)GLP-1AUC43%higherwiththe
(cid:129)2012[45] in3groups:9withT1D,10with (cid:129)3-hOGTTwith75g (cid:129)C-peptide ingestionofdietsodainT1Dsubjects
T2D,and25healthycontrol (cid:129)2visits:atminute-10subjectsdrank240 (cid:129)GLP-1 (p=0.02)
(cid:129)pAallrTtic2iDpawnetsreoverweightorobese mawcaletoesfrudlfieatmseo-dKaowri2th40sumcrlaolfocsaerbaonndated (cid:129)(cid:129)GPYIPY (cid:129)GisnuLgbPejes-1tciotAsnU(poCf=d30i4e.%t0s2oh9di)gahienrhweiathlththye
(cid:129)Nodifferencesonglucose,C-peptide,
GIP,andPYY
(Continued)
PLOSONE|DOI:10.1371/journal.pone.0161264 August18,2016 10/17