Low- vs. high-glycemic load diet: effects on postprandial ...
Transcript of Low- vs. high-glycemic load diet: effects on postprandial ...
Low-vs.high-glycemicloaddiet:effectsonpostprandialplasmafreefattyacidlevels
SarahYanez
Athesis
Submittedinpartialfulfillmentofthe
requirementsforthedegreeof
MasterofScience
UniversityofWashington
2016
Committee:
MichaelRosenfeld
MichelleAverill
ProgramAuthorizedtoofferdegree:
NutritionalSciences
UniversityofWashington
Abstract
Low-vs.high-glycemicloaddiet:effectsonpostprandialplasmafreefattyacids
SarahMichelleYanez
Co-chairsofthesupervisorycommittee:MichaelRosenfeld,PhDSchoolofPublicHealth
MichelleAverill,PhD
NutritionalSciencesProgramandDepartmentofEnvironmentalandOccupationalHealth
Introduction:Low-glycemicloaddietsarecommonlyprescribedforbloodglucosemanagement.Currently,however,itisnotclearastowhetherthediethasanyimplications,positiveornegative,oncardiovascularhealthinhealthyindividuals.Methods:UsingdatacollectedfromtheCarbohydratesandRelatedBiomarkers(CARB)Study,conductedattheFredHutchinsonCancerResearchCenter,weanalyzedtheeffectsofahigh-vs.low-glycemicloaddietonfastinglipidsandpostprandialplasmafreefattyacidlevelsinhealthy,non-insulinresistant,adults.Participantswererandomizedtocompleteeitherahigh-orlow-glycemicloaddietfor28days,followedbyawashoutperiodof28days,andthencompletetheoppositedietfor28days.Results:Wefoundthatahigh-vs.low-glycemicloaddietdidnothaveanysignificanteffectonplasmafreefattyacidlevelsintheeighthourtimeperiodfollowingatestbreakfast.Conclusions:Glycemicloaddoesnotappeartoaffectcardiovascularhealthintheshort-term,however,furtherresearchisneededtodetermineanylong-termimplications.Basedonourfindings,wecannotsupportarecommendationthatalow-GLdietisprotectiveagainstcardiovasculardiseaseinhealthyindividuals.
INTRODUCTIONANDBACKGROUND
GLYCEMICINDEXANDGLYCEMICLOAD
GLYCEMICINDEX
Theconceptofglycemicindex(GI)wasfirstintroducedasamethodtoclassify
carbohydrate-containingfoodsbytheirabilitytoraisebloodglucoselevels.29,62GIis
calculatedasthechangeinbloodglucoseafteracarbohydrate-containingfooditem
iseaten,dividedbythechangeinbloodglucoseafteranequalmassofbreadis
eaten,multipliedby100.6,30GIhasbeenstandardizedtobethecomparisonofthe2-
hourpost-prandialglucoseresponseof50gofacarbohydratefoodwiththatof50g
ofwhitebreadorglucose,andisrepresentedbytheareaundertheglucose
responsecurve.32,53Thus,GIisanindicatoroftheintestinalabsorptionof
carbohydrates;low-GIfoodsareabsorbedmoreslowlyandinduceaslower
glycemicresponsethanhigh-GIfoods,whicharerapidlyabsorbedinthe
intestines.10,23,32Whencarbohydrate-containingfoodsofdifferingGIaremixed
togetherinameal,theGIofthemealisarelativemedianoftheindividual
carbohydratefoodGIs.65
GLYCEMICLOAD
Glycemicload,aconceptrelatedtoGI,isarepresentationofboththequantityand
thequalityofcarbohydrateconsumed.GLiscalculatedastheproductofthefood’s
carbohydratecontentanditsGIvalue.39,64GLisawaytosummarizethecombined
effectsoftotalcarbohydrateintakeandoveralldietaryGI.38Alow-GLdietdoesnot
necessarilymeanthatlow-GIfoodswereconsumed.38SinceGLisdependentupon
boththeamountofcarbohydrateandtheGIofthefoodsconsumed,either
decreasedconsumptionoftotalcarbohydrateorimprovedqualityofcarbohydrate,
GI,canlowerGLofthediet.68Thus,thelong-termhealthimplicationsofareduced
GLdietmaybedifferentdependingonwhetherthelowerGLisduetoreduced
carbohydrateintake,reducedGI,oracombinationofthetwo.
BIOLOGICALRESPONSESTOGI/GL
Traditionally,lowGIfoodsorlowGLdietshavebeenrecommendedinthesettingof
glycemiccontrol,aslowGIfoodconsumptionisthoughttoresultinlowerandmore
stablebloodglucoseandinsulinlevels.16TotalmealGLhasbeenshownto,
moderatelywell,predictserumglucoseandinsulinresponsespostprandially.24A
positiveassociationbetweenmealGLlevelsandserumglucoseandinsulin
responseshasbeendemonstrated,indicatingthat,forfoodswithequalGIs,asthe
amountofcarbohydrateincreases,therewillbeaproportionallyconstantincrease
inthebloodglucoseandinsulinresponses.24
However,currentevidencesupportingalinkbetweendyslipidemiaandGLis
lacking.SomestudieshavefoundthatGLhasnoeffectonplasmalipidlevels,16,24,32,64
somehavefoundaninverserelationshipbetweenGLandcirculatingplasma
lipids,53,60andsomehavefoundimprovedlipidstatuswithlowGLdiets.13,39,40,56
INSULIN
EFFECTSOFGI/GL
Thereisepidemiologicalandclinicalevidencesupportingthatdietsignificantly
influencesinsulinsensitivityinobeseand/orinsulinresistantindividuals;23
specifically,thatalowGLdietincreasesinsulinsensitivity.15Otherpreviousstudies
havefoundsimilarresults,andfurtherconcludedthathighGLdiets,overtime,
contributeastateofpancreaticβ-celldysfunctionandadefectiveinsulin
response.10,60,68Adietwithahighcompositionofcarbohydratefoodsinduces
compensatoryhyperinsulinemia.64,72However,ifaheightenedinsulinresponseis
requiredoveranextendedperiodoftime,theabilityofβ-cellstoproduceand
secreteinsulindeclines.Chronicallyhighglucoseintake,pairedwithdecreasing
insulinsecretion,ultimatelyresultsinβ-celldeathandreducedpancreaticcellmass.
Thelong-termconsequenceisglucoseintoleranceanddiabetes.28TheFAO/WHO
hasmadearecommendation,basedonevidencesupportingtheefficacyofalowGI
orGLdietinimprovingglycemiccontrol,10toreducedietaryGIfortheprevention
andmanagementofmetabolicdisease.19However,somestudieshavenotfound
conclusiveevidencethatdifferencesinGIconsumptionleadtodifferencesininsulin
response.16,32IthasbeensuggestedthatGI/GLmaybemostusefulinitsabilityto
regulateglucoseresponsespostprandially,notnecessarilytheassociatedinsulin
response.16
INCRETINEFFECT
Theincretineffectisaphenomenoninwhichoralglucoseadministrationhasbeen
demonstratedtoelicitagreaterinsulinresponsethanintravenousglucose
administration.48Thishasrecentlybeenexplainedbytheactivityofinsulin-
mediatingmoleculessecretedbythegut.
Incretinsarepeptidehormonesthatareproducedentero-endocrinecellsinthe
smallintestinalmucosa.48Theincretinsglucose-independentinsulinotropic
polypeptide(GIP)andglucagon-likepeptide(GLP-1)aresecretedinresponseto
nutrientingestionandactonpancreaticβ-cellsforinsulinsecretion.2,28GIPand
GLP-1havelowbasalplasmaconcentrationsandhaveaninsulinsecretoryresponse
onlyatlevelsthatcorrelatetoacertainlevelofhyperglycemia;theyarethus
ineffectiveatelicitinganinsulinresponsewithlowamountsofdietaryglucose.48
Thisultimatelyservestomaintainacertainbloodglucoseleveldespiteingestionof
awiderangeofcarbohydrateloads.2Theinsulinresponsetothesehormones
accountsforapproximately70%ofpostprandialinsulinsecretion.28Thissuggests
thattheeffectofGIoninsulinresponsesisadditionaltotheeffectofincretins;the
postprandialinsulinresponseisnotentirelydependentupontheGIofthefood
consumed.
Theincretineffecthasbeendemonstratedtobedefectorcompletelyabsentin
individualswithimpairedglucosetolerance,hyperglycemia,anddiabetes.48Inone
study,plasmalevelsofincretinsdonotappeartodifferbetweenhealthyand
diabeticpersons,implyingthatadefectorabsenceoftheincretineffectisamarker
ofbetacelldysfunctionandthereducedsecretionofinsulin.2Thishypothesishas
beenconfirmedbyotherrecentinvestigations.28,49Oneofthesestudies,however,
hasalsoconcludedthatobesesubjectswithnormalglucosetolerancealsohavean
impairedincretineffect,likelyduetoreducedGLP-1secretioninthegut.28This
supportscurrentliteraturethatobesitycontributestoinsulinresistance,butwith
additionaldataregardingthemechanisms.
SHORT-TERMBIOLOGICALEFFECTS:SERUMFREEFATTYACIDS
Itiswellknownthatinsulinhasasignificanteffectontheactivitiesoflipasesthat
regulateFFAavailability:lipoproteinlipasefoundinadiposetissue,hormone-
sensitivelipase,andadiposetriglyceridelipase.60Inthepresenceofhighlevelsof
insulin,whenlipoproteinlipaseactivityisincreasedandhormone-sensitivelipase
andadiposetriglyceridelipaseactivitiesaresuppressed,thecombinedeffectis
improvedclearanceofFFAsfromthebloodstream.31
Lipoproteinlipasehydrolyzestriglyceridesfromcirculatinglipoproteins,either
chylomicronsfromtheintestinesorverylow-densitylipoproteins(VLDL)fromthe
liver.Thisresultsintheproductionoffattyacids.Inadiposetissue,insulinincreases
lipoproteinlipaseactivityandthusincreasestheproductionoffattyacids,whichare
eitheroxidizedforenergyorrepackagedastriglyceridesforstorage.26Conversely,
insulinasaninhibitoryeffectonthelipoproteinlipasefoundinskeletalmuscle,
servingtodirectfattyacidstoadiposetissueforstorage.Thehormoneglucagon,
releasedduringtimesoflowavailablebloodglucoseforenergy,isresponsiblefor
increasinglipoproteinlipaseactivityinmuscletissue.20Theresultistheincreased
abilityofmuscletissuetomobilizefattyacidsforenergyproductionwhenthe
preferredsubstrate,glucose,isunavailable.Theultimateeffectofincreased
lipoproteinlipaseactivityisfavorableuptakeofFFAsfromthecirculation.60
Hormone-sensitivelipaseandadiposetriglyceridelipasearefoundinadiposetissue
andbothservetohydrolyzestoredtriglyceridesintoFFAforreleaseintothe
circulation.35,72Whileitwasthoughtforquitesometimethathormone-sensitive
lipasewastheprimaryenzymeinthehydrolysisoftriglyceridesinadiposetissue,it
hasbeendiscoveredthatadiposetriglyceridelipaseisinfactthecatalystforthe
reactionandhasthemoresignificanteffectontheoverallrateoffattyacid
production.65Adiposetriglyceridelipaseishighlyexpressedinadiposetissueand
highlyspecificfortriglycerides.Itremovesthefirstfattyacidfromatriglyceride
molecule,initiatingitscatabolism.73Insulinsuppressestheactivitiesofthese
molecules,althoughthroughtwodifferentmechanisms.Adiposetriglyceridelipase
isregulatedbyinsulinatthetranscriptionallevel;highlevelsofinsulinreducethe
productionofthelipase.33Insulindoesnot,however,haltproductionofhormone-
sensitivelipase,itsimplydecreasesitslevelofactivity.63Increasedlevelsofinsulin
causethecombinedeffectsofhormone-sensitivelipaseandadiposetriglyceride
lipase:reductionoftriglyceridehydrolysisanddecreasedliberationofFFAintothe
circulation.
INSULINSIGNALINGANDLIPIDMETABOLISM
Figure1.Normallipidmetabolism(black)vs.lipidmetabolisminastateofinsulinresistance(red).Insulinhasinhibitory(-)andenhancing(+)effectsonmanystagesoflipidmetabolism.Insulinplaysanimportantroleinnutrientuptakeinthepostprandialperiod.
Dietarycarbohydratesareabsorbedintheintestinesandtransportedthroughthe
bloodstreamasglucose.Whileglucoseuptakebytheliverisindependentofinsulin
action,theconversionofglucosetofattyacidsisinsulin-dependent.Glucoseis
convertedtopyruvatethroughglycolysis,andthentoacetyl-coAthroughthe
insulin-stimulatedactionofpyruvatedehydrogenase.18Acetyl-coAisthenconverted
intofattyacids,inwhichtheenzymefattyacidsynthaseisupregulatedbyinsulin.
Fattyacidsaresubsequentlyesterifiedintotriglyceridesandpackagedintovery
low-densitylipoprotein(VLDL)fortransportthroughthecirculationsystem.18VLDL
iscarriedtoadiposetissuefordepositionoffattyacidsviatheinsulin-stimulated
actionoflipoproteinlipase(LPL).6ExtractionofthefattyacidsleavesaVLDL
remnant,whichthenbecomesanintermediate-densitylipoprotein(IDL).TheseIDL
moleculeslosetriglyceridesinthebloodstreamandformlow-densitylipoproteins
(LDL).44Therate-limitingstepofLDLsynthesisisindirectlyregulatedbyinsulin.3-
hydroxy-3-methylglutaryl-coAreductaseistheresponsibleenzymeandismost
activewhenbloodglucoselevelsarehigh.48Increasedinsulinclearanceofblood
glucosedecreasestheenzyme’sactivityandthuscholesterolproduction.
Dietaryfats,ontheotherhand,areemulsifiedintheintestinesforabsorption,and
thenpackagedintochylomicronsfortransportthroughthecirculationbeforebeing
depositedinadiposetissue.AgainthroughtheactionsofLPL,stimulatedbyinsulin,
triglyceridesareextractedfromthechylomicrons.6Inadiposetissue,deposited
triglyceridesarehydrolyzedintofreefattyacids,aprocessinhibitedbytheactionof
insulin.Additionally,thefattyacid-triglyceridecycleensuresconservationof
triglyceridestorageinadiposetissuethroughtheconsistentre-esterificationoffree
fattyacidstotriglycerides.6,69
Inastateofinsulinresistance,serumlipidlevelsarenegativelyaltered.HSLactivity
isincreasedinadipocytes,increasingtriglyceridehydrolysisandbuild-upoffree
fattyacids.6Thesearethentransportedtotheliver,wheretheincreasedavailability
offattyacidsfortriglyceridesynthesisincreasestheproductionandsecretionof
VLDL.WhenthethresholdforserumVLDLisreached,formationofHDLbytheliver
decreaseswhileformationofLDLincreases.Theendresultisdyslipidemia.69
FREEFATTYACIDS
RELATIONSHIPTOGI/GL
Asdemonstratedinthefigureabove,FFAsenterthecirculationthroughthe
hydrolysisofbothtriglyceridesinadiposetissueandglucoseintheliver.However,
highcirculatinglevelsofFFAshaveyettobedefinitivelylinkedtoadiethighin
carbohydratesorglycemicload.Thecurrentevidencedescribingarelationship
betweenGIorGLandFFAlevelsvarieswidely.Somestudiesdeterminingthat
plasmaFFAlevelswereincreasedbyalowGLdiet,13,35somehavefoundnoeffectof
GIorGLonFFAlevels,16,24andstillothershavefoundthatFFAconcentrationsare
suppressedbyhighGImeals.41,53
Asdiscussedpreviously,insulinactstobothincreaselipoproteinlipaseactivityfor
theuptakeofFFAtoadiposefromthecirculationanddecreasetheactivitiesof
hormone-sensitivelipaseandadiposetriglyceridelipaseforthereductionofFFA
liberationfromadiposetissueintothecirculation.Throughtheseactions,an
increasedinsulinresponseduetoahighglycemicloadmealcouldlikelymediatethe
FFAresponsesothatthereiseithernodifferenceinplasmalevelsorverylittle
differencepostprandially.56However,inthelatepostprandialperiod
(approximatelyfourtosixhoursafterthemeal),lowbloodglucoselevelstriggera
counter-regulatoryresponseandglucagonisreleased.Glucagonstimulates
gluconeogenicandglycogenolyticpathwaysinordertoproduceglucoseandrestore
normalbloodlevels,concurrentlyelevatingFFAlevels.41Inthisway,ahigh-GLmeal
mayactuallycauseFFAlevelstoriseversusthemoreattenuatedhormoneresponse
elicitedbyalow-GLmeal.Again,thisresultwouldonlybeseeninthelaterhours
afteratestmeal.
EFFECTSONCARDIOVASCULARHEALTH
ThereareseveralmechanismsbywhichhighFFAlevelsmightimpact
cardiovascularhealth.AnincreasedamountofFFAisavailabletotheliverfor
increasedtriglycerideproductionandVLDLsecretion.39,60,70Highserumtriglyceride
levelasbeendiscoveredtobeanindependentriskfactorforcoronaryheartdisease
(CHD),afteradjustmentforLDLandHDLcholesterollevels,age,bloodpressure,
smoking,diabetes,familyhistoryofmyocardialinfarction,andanginapectoris.1,12,42
Whileitisnotnecessarilythetriglycerideitselfthatleadstoheartdisease,high
levelsoftriglyceridesindicatehighlevelsofhighcholesterol-containingremnant
lipoproteinsthatthendepositthatcholesterolintoarterialwalls.51,75
HighlevelsofFFAsarealsobelievedtocontributetoinsulinresistance.55FFAlevels
surpassingstoragecapacityinadiposetissuearedepositedinothertissues,like
skeletalmuscleandliver,35,58throughtheinhibitionofinsulinsignaling.FFAs
completewithglucoseasanenergysubstrateinskeletalmuscle,alteringthe
partitioningoffatbetweenadipocytesandmuscle.58Theexactmechanismbywhich
FFAsaffectglucosetransportandutilizationhasyettobeclearlyidentified.8Insulin
resistanceitselfisassociatedwithhighratesofcholesterolsynthesis.54
Lastly,highlevelsofFFAsmaythemselvespredictcardiovascularmortality.55The
myocardiumappearstobenegativelyaffectedbyhighlevelsofFFAs,asincreased
useasametabolicsubstrateappearstohaveunfavorablealterationsatthecellular
level,resultingininefficientglucosemetabolism.47Thishasbeendemonstratedto
haveproarrhythmiceffects,increaseischemicdamage,andcontributetothe
developmentofheartfailure.27,52
GLYCEMICLOADANDCARDIOVASCULARHEALTH
CURRENTEVIDENCE
Asofyet,theliteratureisunabletodeterminewhateffects,ifany,glycemicloadhas
oncardiovascularhealth.Whilelow-GIdietsarefrequentlyrecommendedto
diabeticpatientswiththeintentofimprovingglycemiccontrolandinsulin
sensitivity,thereislittleevidencetosupportimprovementoflipidprofiles.Thereis
evenfewerdatatodescribetheeffectsofthisdietonnon-diabeticindividuals.9
SomestudieshavefoundthatGLhasnoeffectonplasmalipidlevels,13,24,32,64some
havefoundaninverserelationshipbetweenGLandcirculatingplasmalipids,50,57
andsomehavefoundimprovedlipidstatuswithlowGLdiets.13,40,42,62
Studyresultshavevariedbasedupongender,nationality,age,andBMI
classification.Inmiddle-agedandolderSwedish,dietaryGI/GLhadnosignificant
associationwithcardiovascularillness.67AnotherstudydoneinItalywith
overweight,oldermenandwomenfoundapositiveassociationbetweendietaryGI
andincidenceofmyocardialinfarction,butnoassociationbetweendietaryGI/GL
andincidenceofcardiovasculardiseaseoritsriskfactors.37Ameta-analysis
evaluatedstudiesoftheassociationsofGIandGLwithcoronaryheartdisease
eventsandfounddiscrepanciesbetweennationalitiesandsex;DanishandBlack
AmericanmendemonstratedpositivebenefitswithconsumptionoflowerGIfoods,
andoverallonlywomen,notmen,showedanincreaseinrelativeriskofcoronary
heartdiseasewiththeconsumptionofhighGIfoods/ahighGLdiet.66
However,therehavebeenstudiesshowingasignificantpositiveassociation
betweendietaryGLandtheriskofcardiovasculardisease.Variousstudieshave
shownthatlow-GIdietsresultinlowertriglycerideandlipoproteincholesterol
levels,aswellasalowerratiooftotalcholesteroltohigh-densitylipoproteinlevels,
indicatorsofcardiovascularhealth.41OneofthefirststudiesregardingGIindicated
thatitmighthaveabeneficialimpactonbloodlipids.30IncreaseddietaryGLwas
showntobeassociatedwithandincreaseinthecardiovasculardiseaseriskfactor
high-densitylipoprotein(HDL)inBrazilianmiddle-agedmen.16InUSwomen,GI
wasfoundtobeastrongindicatorofcoronaryheartdiseaserisk,independentof
carbohydratecomplexity.40
ACochranereviewassessingtheprescriptionoflowGIdietsforcardiovascular
healthdidnotfindanyevidencefromrandomizedcontrolledtrialstoshowaneffect
oflowGIdietsoncoronaryheartdisease.Someweakevidenceforminoreffectson
someCHDriskfactorswasfound;therewassomeevidenceofareductionintotal
cholesterolwithlowGIdietsandborderlinesupportforadecreaseinLDLwithlow
GIdiets.32Obesitywasidentifiedasaknownriskfactorforcoronaryheartdisease,
thereforeenergy-restricteddietsbasedonlowGIfoodsmightproducethegreatest
weightlossandthusthegreatestcardiovascularprotection.Thesedietsalsomay
improveinsulinsensitivityinobeseindividuals,therebyimprovingcholesterol
profiles.46
Thereisaneedforwell-designed,adequatelypowered,randomizedcontrolledtrials
ofsignificantdurationtobetterunderstandthefulleffectsofGIorGLonlipid
profilesandcardiovascularhealth.Currently,thereisinsufficientevidencethat
healthcareprovidersshouldrecommendalow-GLdietoverothertherapeuticdiets
forthepreventionofheartdiseaseinhealthy,non-insulinresistantindividuals
METHODS
STUDYPOPULATION
ParticipantsintheCarbohydratesandRelatedBiomarkers(CARB)study,conducted
attheFredHutchinsonCancerResearchCenter,(FHCRC)includedhealthy,non-
smokingmenandwomenbetweentheagesof18and45yearsoldfromtheSeattle
area.SpecialrecruitmenteffortsweregivenforAfricanAmericanandHispanic
populations.Priortoenrollment,potentialparticipantsweregivenaneligibility
questionnaire,excludingthosewho:(1)hadphysician-diagnoseddiseasesrequiring
dietaryrestrictionsormodifications;(2)hadaBMIbetween25and28,inorderto
demonstrateanysignificantdifferencesinoutcomesbetweenhealthyweightand
obeseindividuals;(3)werecurrentlypregnantorlactating,orhadplanstobecome
pregnant;(4)regularlytookhormones,anti-inflammatorymedications,orother
medicationsthatmightinterferewithoutcomemeasures;(5)usedtobaccoor
consumed>2drinksperday;(6)restrictedtheireatingorhadfoodallergies;and
(7)hadimpairedfastingglucose,definedasfastingbloodglucoselevels≥5.6
mmol/L.Enrolledparticipantswerealsoaskedtodiscontinuetheuseofanydietary
supplements.ApprovalwasobtainedfromtheInstitutionalReviewBoardandthe
ClinicalTrialsOfficeoftheFHCRCandallparticipantsprovidedwritten,informed
consent.50
RESEARCHDESIGN
89participantswereenrolledinthestudybetweenJune2006andJuly2009.
ParticipantswereblockrandomizedbytheBMIgroup(18.5-24.9kg/m2or28.0-
40.0kg/m2)andsextotheorderofexperimentaldiets.61Participantswereassigned
tobothalow-andhigh-GLdiet,inacross-overdesign,for28consecutivedayseach,
witha28daywashoutperiodinbetweendietsduringwhichparticipantsconsumed
theirhabitualdiets(Figure2).62AsubsetofCARBstudyparticipantswaschosento
participateinapostprandialstudy(CARB-PPL).Thisincluded20participantswho
consumedastandardizedtestbreakfastandremainedatthefacilityforpost-
prandialtesting.61ItistheCARB-PPLsamplesthatwereusedinthisanalysis.
Participantswereinstructedtoconsumeonlythefoodandbeveragesprovided
duringthefeedingperiods;coffeeandtea(creamersandsweetenerswereprovided
bythestudy)werepermittedatstablecontinuouslevels.61Participantsateonemeal
eachday,MondaythroughFriday,attheHumanNutritionLabatFHCRCunder
supervisionbystudystaff.Aftertheeveningmeal,participantswereprovidedwith
breakfast,lunch,andsnackforthefollowingday.Followingtheeveningmealon
Friday,participantswereprovidedwithallfoodtobeconsumedovertheweekend
aswellasMonday’sbreakfastandlunch.Allfoodthatremainedunconsumedwas
returnedtothelabwherestaffweighedandrecordedit.Participantsalsocompleted
adailychecklistconfirmingconsumptionoftheday’sfoods,alongwithconsumption
ofnon-studyfoods.60
STUDYDIETS
Bothhigh-andlow-GLdietsweredesignedtobeweight-maintaining.3-daydiet
recordswereobtainedfromparticipantsinordertoestimatehabitualenergy
intake.ThisdatawasusedinconjunctionwiththeMifflinequationtoestimate
energyneeds.50A7-daymenurotationforeachdietwasgeneratedusingProNutra
(Version3.2,Viocare).Macronutrientcontentwasidenticalbetweeneachdiet,with
15%ofdailyenergycomingfromprotein,30%ofdailyenergycomingfromfat,and
55%ofdailyenergycomingfromcarbohydrates.Fibercontentdifferedbetweenthe
twodietswith55g/dayinthelowGLdietversus28g/dayinthehighGLdiet.The
lowGLdietwasdefinedatGL125,andhighwas250.61Participantweightswere
takenthreetimesperweekandenergyadjustmentsweremadein200kcal
incrementsasnecessarytomaintainbaselineweight.62Thetestbreakfastsforthe
postprandialstudywerealsodesignedtobesimilartothe28-daydietsinoverall
macronutrientcontentandmatchtheGLprofileofthediettreatment.61
Figure2.Cross-overdesignofstudydiets.
SAMPLECOLLECTIONANDANALYSIS
Samplecollectionsweredoneinthemorningsofthefirstandlastdaysofthediet
periods.50Ondayonea12-hourfastingblooddrawwastakenandonday28,from
the20postprandialstudyparticipants,apostprandialblooddrawwascollected
followingbreakfast,at0,30,60,120,180,240,270,300,330,360,420,and480
minutesafterthestartofthemeal(Figure3).Afterbeingallowedtoclotfor
approximately30-45minutes,bothserumandplasmawerespunandaliquoted.
Sampleswereimmediatelystoredat-20°C,andplacedforstorageina-80°Cfreezer
bytheendoftheday.ThesamplesprovidedbytheCARB-PPLstudyforthislipid
analysishadnotbeenpreviouslythawed.Plasmasampleswereanalyzedatthe
UniversityofWashington’sNutritionObesityResearchCenteranalyticalcoreand
lipidpanelsweregenerated.
FFAsweremeasuredonaRocheCobasMiraPlusChemistryAnalyzerusingreagent
fromGenzyme/Wako.Afterbeingallowedtothawforapproximately30minutes,
sampleswereanalyzedatroomtemperature.
Figure3.Timesofpostprandialblooddraws.
STATISTICALANALYSIS
Theoverallgoalofthisstudywastotesttheeffectsofa28-daylow-vs.high-GLdiet
interventiononthepostprandialresponsesofserumlipids,specificallyfreefatty
acids.Wecalculatedareaunderthecurve(AUC)ofpost-prandialFFA
measurementsusingtrapezoidalapproximation.In30and60minutetimeperiods,
accordingtowhenblooddrawsweretaken,wecalculatedtheAUCforthe
postprandialperiodsafterbreakfastandafterlunch.WerepeatedtheAUCanalysis
separatelyforeachthenormalweightandoverweight/obesegroupsforthetotal
timeperiod,beforelunch,andafterlunch.Apairedt-testwasdoneforeachofthe
AUCanalysesinordertodetermineifasignificantp-valueexistedbetweenthediet
sets.
Fastinglipidpanelsdrawnonthe28thdayofeachdietperiodwereanalyzedusinga
2-waypairedANOVA.
RESULTS
Table1.Characteristicsofstudyparticipantsn=20 Agerange(y) 19-44Male/Female(n) 10,10BMI(n) 18.5-24.9kg/m2
("Normal"weightgroup)10
28-40kg/m2
("Overweight/obese"weightgroup)10
Ethnicity(self-reported) Non-Hispanicwhite 8Hispanic 7AfricanAmerican 4Asian/PacificIslander/NativeAmerican 1
Blockrandomizationoftheparticipantsensuredthattheparticipantgroupwas
composedofequalpartsmalesandfemalesandnormalweightand
overweight/obeseweightgroups.Therewerefivewomenandfivemencomprising
boththenormalandoverweight/obeseweightgroups.Onaverage,the
overweight/obeseweightgroupwasslightlyolderthanthenormalweightgroup(P
<0.001).Ethnicitydidnotvaryacrossweightgroups.Baseduponself-reporteddata
fromthedailyfoodcheck-offformsandreturnedfood,itappearedthat97%of
participantsconsumedmorethan90%oftheprovidedfoods.Nosignificant
differenceinadherencebystudydietwasdetermined.
Table2.Meanenergyandmacronutrientcontentof2400kcalhigh-andlow-GLreferencedietsa
High-GLdietn=7days
Low-GLdietn=7days
Dietarydescriptor mean±SD mean±SDEnergy(kcal/day)b 2398±8 2396±6Protein(g/day) 90±1 90±0Energyfromprotein(%usingtotalcarb) 15±0.2* 14±0.4*Energyfromprotein(%usingavailablecarb)c 15±0.2 16±0.2Fat(g/day) 80±0 81±1Energyfromfat(using%totalcarb) 30±0.3* 29±0.8*Energyfromfat(using%availablecarb) 31±0.2 31±0.6Totalcarbohydrate(g/day) 341±6* 361±15*Energyfromtotalcarbohydrate(%) 56±0.5* 57±1.1*Energyfromavailablecarbohydrate(%) 54±0.8 53±0.8Dietaryfiber(g/day) 24±5* 49±8*GI/day 78±5* 34±1*GL/day 244±14* 117±3*
aDatafromProNutra:MetabolicDietStudyManagementSystem(ViocareTechnologies)and/ortheNutritionDataSystemforResearch(version2005,NutritionCoordinatingCenter,UniversityofMinnesota)bTotalenergycalculatedassumsof4kcal/gprotein,9kcal/gfat,and4kcal/gtotalcarbohydrate.cTotalenergycalculatedusingavailablecarbohydrate.Asterisk(*)nexttoP-value,0.05forpairedt-testscomparinghigh-andlow-GLdiets.
Table2showstheplanneddailymeanmacronutrientcontent,dietaryGI,dietaryGL,
anddistributionofenergyforbothhigh-andlow-GL2400-kcalreferencediets.All
dietsateachenergylevelweresimilartothereferencedietshown.Fibercontent
washigherinthelow-GLdiet.Increasedfiberintakehasbeenshowntoreducetotal
cholesterolandapoBlevelsrelativetoHDL-cholesterolandApoA1levels,thus
reducingtheriskofcoronaryheartdisease.(29)Thepercentavailablecarbohydrate
doesnotfactorthefibercontentintoenergycalculations,asfiberisonlyavailable
forenergyafterfermentation.AvailablecarbohydrateisrecommendedbytheFAO
asausefulconceptforenergyevaluation.Necessaryenergyadjustmentsforweight
maintenancethroughoutthestudydidnotsignificantlydifferbydiettypeorfeeding
period.Thetestbreakfastconsumedforpostprandialanalysiswasconstructedtobe
composedofmacronutrientratiosconsistentwiththestudydiets.
Table3.Endofdietperiodfastinglipidpanelresults(n=20)
High-GL Low-GL
mg/dL Mean±SD Mean±SDCholesterol 142±29 140±33Triglyceride 84±51 93±73HDL 41±10 40±9LDL 85±23 81±24ApoA1 130±21 130±20ApoB 73±19 73±21Fastingbloodsamplesfrom20participantsweredrawnonday28ofeachdiet
period,beforeconsumptionofthetestbreakfast.TherewasnoeffectofGLon
fastingtotalcholesterol,HDLcholesterol,LDLcholesterol,ApoA1,andApoBlevels.
Table4.Totalparticipant(n=20)areaunderthecurve,plasmafreefattyacids BeforeLunch
mEq/LAfterlunchmEq/L
TotalTimemEq/L
High-GL 1.00±0.28 1.34±0.41 2.33±0.54Low-GL 1.02±0.36 1.48±0.52* 2.53±0.79
The“beforelunch”timeperiodisdefinedastimepoints0:00through4:00,andthe
“afterlunch”timeperiodastimepoints4:00through8:00.
Atspecifictimeperiods,thehigh-vs.low-GLdietdidnothaveanysignificanteffect
onplasmaFFAlevels.
Figure1.Mean±SDFFAlevels(mEq/L)oftheCARB-PPLparticipantsatthetimeofeachblooddraw.Betweenthehigh-GL(solidblueline)andthelow-GL(solidredline)diets,thereisnotasignificancedifferenceincirculatingFFAlevelsacrosstheeighthourtimeperiod.
00.10.20.30.40.50.60.70.80.91
0:00 0:30 1:00 2:00 3:00 4:00 4:30 5:00 5:30 6:00 7:00 8:00
mEq/L
TimeofBloodDraw
Figure4.EffectsofHigh-vs.Low-GLDietonPlasmaFreeFattyAcidAverage:Total
TimePeriod
High-GL Low-GL
Lunch
Breakfast
Figure2.Mean±SDFFAlevels(mEq/L)oftheCARB-PPLparticipantsatthetimeofeachblooddrawinthetimeperiodbeforealunchmealisconsumed(0:00to4:00).TrapezoidalapproximationsdidnotdeterminesignificanceinthedifferencebetweenFFAlevelsforthetwostudydiets,high-GL(solidblueline)andlow-GL(solidredline).
00.10.20.30.40.50.60.70.80.91
0:00 0:30 1:00 2:00 3:00 4:00
mEq/L
TimeofBloodDraw
Figure5.EffectsofHigh-vs.Low-GLDietonPlasmaFreeFattyAcidAverage:Pre-
LunchTimePeriod
Low-GL High-GL
LunchBreakfast
Figure3.Mean±SDFFAlevels(mEq/L)oftheCARB-PPLparticipantsatthetimeofeachblooddrawinthetimeperiodafteralunchmealisconsumed(4:00to8:00).TrapezoidalapproximationsdidnotidentifysignificanceinthedifferencebetweenFFAlevelsforthetwostudydiets,high-GL(solidblueline)andlow-GL(solidredline)atanyoftheindividualtimepoints.
00.10.20.30.40.50.60.70.80.91
4:00 4:30 5:00 5:30 6:00 7:00 8:00
mEq/L
TimeofBloodDraw
Figure6.EffectsofHigh-vs.Low-GLDietonPlasmaFreeFattyAcidAverage:Post-
LunchTimePeriod
Low-GL High-GL
Lunch
Table5.Areaunderthecurve,FFA:normalvs.overweight/obeseparticipants
n=10 Pre-Lunch(mEq/L)
Post-Lunch(mEq/L)
TotalTimePeriod(mEq/L)
NormalWeightBMI18.5-24.9kg/m2
High-GL 1.31±0.28 2.29±0.92 3.57±1.0Low-GL 1.25±0.37 2.26±1.00 3.51±1.30Overweight/ObeseBMI25-40kg/m2
High-GL 1.40±0.50 1.98±0.50 3.38±0.78Low-GL 1.45±0.57 2.34±0.72 3.29±1.18
WeanalyzedtheFFAresponseofthetwoweightgroups,normaland
overweight/obese,forthetwostudydietsseparatelybecauseofthepotential
impactthatadiposebiologymayhaveonFFAclearance.TherewasnoeffectofGL
onpostprandialFFAlevelsbetweenthetwoweightgroups.
0
0.2
0.4
0.6
0.8
1
0:00 0:30 1:00 2:00 3:00 4:00 4:30 5:00 5:30 6:00 7:00 8:00
mEq/L
TimeofBloodDraw
Figure7.EffectsofHigh-vs.Low-GLDietonPlasmaFreeFattyAcidAverage,Normalvs.Overweight/ObeseWeight
Groups:TotalTimePeriod
Low-GL,Normalweight Low-GL,Overweight/Obese
High-GL,Normalweight High-GL,Overweight/Obese
Lunch
Breakfast
Figure4.Mean±SDFFAlevels(mEq/L)oftheCARB-PPLparticipantsatthetimeofeachblooddrawintheeight-hourperiodfollowingthetestbreakfast.
DISCUSSIONThisrandomized,cross-over,controlledfeedingstudytestedtheeffectofhigh-GLvs.
low-GLexperimentaldietsonpost-prandialplasmaFFAlevels.Theresultsofour
analysisshowedthatahigh-vs.low-GLdietdidnothaveanysignificanteffecton
fastinglipidsorpost-prandialplasmaFFAlevelsintheeighthoursfollowingatest
breakfastmeal.However,thereisacomplexrelationshipbetweendietary
carbohydratesandbloodlipidlevels.WhileGLdoesnotappeartoaffectbloodlipid
levels,andbyextensioncardiovascularhealth,intheshort-term,furtherresearchis
neededtodetermineanylong-termimplications.Thecurrentstateofresearchdoes
notsupporttherecommendationofalow-GLdietforcardiovasculardisease
preventionovertherecommendationofother,proventherapeuticdiets.
ApreviouslypublishedstudyinvestigatingtheeffectsofGLoninsulinresponse
foundthatahigh-GLtestmealresultedinanincreasedinsulinresponseas
comparedtoalow-GLtestmeal(Figure8).61
Figure8.Meanconcentrations(±SD)offastingandpost-prandialplasmainsulininhealthyandoverweight-obeseparticipantswhowerefasting(time0)andthenconsumedahigh-(solidlinewithcloseddiamonds)andlow-(dottedwithopensquares)glycemicloadmeal.TakenfromRuncheyetal,2013.
ItcouldbeexpectedthatahigherinsulinresponsewouldmediatetheFFAresponse;
theFFAresponsetoahigh-GLmealwouldthusbethesameorlowerthanthattoa
low-GLmeal.FFAuptakefromthecirculationintoadiposetissueisinsulin-
dependentthroughtheactionoflipoproteinlipase.25ThestorageofFFAinadipose
tissueastriglyceridesisalsoinsulin-dependentthroughtheactionsofhormone-
sensitivelipaseandadiposetriglyceridelipase.35,72However,whiletheactionof
insulinonhormone-sensitivelipaseisimmediate,itsactiononthemorecrucial
enzyme,adiposetriglyceridelipase,istranscriptive.33Thus,thetrueeffectsof
insulinonplasmaFFAlevelswouldnotbevisibleintheearlypostprandialperiod.
Thefourhourpostprandialtimeperiodmonitoredintheinsulinstudyisinadequate
inindetermininganycarryovereffectofGLoninsulin,alsomakingitimpossibleto
comparetheobservedpost-lunchplasmaFFAlevelsofthisstudytoaninsulin
response.
WealsoexploredthepossibledifferenceinFFAresponsebetweenthenormal
weightandoverweight/obesegroups.WedidnotfindthatGLhadadifferenteffect
onpostprandialplasmaFFAlevelsbetweenthetwoweightgroups.Wecanthen
postulatethatadiposityalonedoesnothaveaneffectonplasmaFFAlevels.The
participantsofthisstudywerenotinsulinresistant,thereforetheirinsulinresponse
wasthesameastheirnormalweightcounterparts.Theinsulinstudysimilarlydid
notobserveeffectsofadiposityoninsulinresponse.59
STRENGTHSANDLIMITATIONS
Thisstudywasacrossoverdesignwithtwo28-daycontrolleddietinterventions
differingsubstantiallyinGL.Itwasalsouniqueinthatthedietswereindividualized
toberealistic,isocaloric,andweigh-maintainingdespitebeinghigh-orlow-GL.
Therewereseveralsignificantlimitationstothisstudy.Therewasasmallsample
sizeforthepostprandialarmofthestudy;thesamplesizewasevensmallerwhen
participantsweredividedbyweightgroup.Participantswerealsosampledfroma
populationgroupthatmetveryspecificenrollmentcriteria.Allparticipantswere
healthyandinsulin-responsive,withnormalglycemiccontrol.Thiswasnota
population-basedparticipantgroup,thusresultsarelikelynotgeneralizable.
Becausevolunteerswithinsulinresistancewerenotincludedinthisstudy,wewere
unabletoexploretheeffectsofGLonbloodlipidsinthoseindividuals.Therewasno
differenceinpancreaticfunctionbetweenourweightgroups,andthereforeno
expected,orobserved,differenceininsulinresponse.Ourparticipantswerealso
limitedtothenormalandveryoverweightorobese.Beingoverweightisthoughtto
beprotectiveagainstmanychronicdiseasesandtheirriskfactors,yetwewere
unabletoexploredifferencesinFFAresponseamongtheseindividualscomparedto
theotherweightgroups.
Thedietlengthof28daysonlyallowedustointerprettheshort-termeffectsofGL
onpostprandialFFAlevels.Insulinresistancedevelopingduetoachronicallyhigh
carbohydrateintakeandstressonthepancreaticβ-cellsisnotdiscernableinafour-
weekspan.AstudyoflongerdurationwouldbeneededtodetermineifGLdirectly
contributestothedevelopmentofinsulinresistance,contributingindirectlyto
unfavorablelipidprofilesandthedevelopmentofcardiovasculardisease.
FUTUREDIRECTIONS
Thereisaneedforarandomizedcontrolledtrialofdurationlongerthan12weeks
todeterminetheeffectsofGLonbloodlipids,specificallyplasmaFFAlevels,andthe
riskofcardiovasculardisease.Thereiscurrentlylittle,ifany,evidencetosupport
thatalow-GLdietcouldbeprotectiveagainstthedevelopmentofcardiovascular
disease.
StudiesexploringtheeffectsofGLonbloodlipidprofilesbetweenindividualswith
insulinresistancearenecessarytodeterminehearthealthimplications.Wecould
thenmoreappropriatelydeterminewhetheralow-GLdietisbeneficialtoboth
insulinresistantandhealthindividuals,oronlytheformer.Wewouldalsobeable
toexploretheeffectsofGLversusanothertherapeuticdietthatperhapsprovides
protectivebenefitsinclusiveofbutnotlimitedtoGL.
CLINICALIMPLICATIONS
Basedonthisstudyandthecurrentstateoftheliterature,itcannotbe
recommendedthathealthcareproviderscounselalow-GLdietforthepreventionof
cardiovasculardiseaseinahealthypatientpopulationoverotherproven
therapeuticdiets.ThisstudydoesnotsupportarecommendationfortheuseofGL
inpreventingcardiovasculardiseaseinhealthyindividualsasneitherlow-norhigh-
GLdietswereshowntobeprotectiveagainstcoronaryheartdiseaseinregardsto
FFA.
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