Low-vs.high-glycemicloaddiet:effectsonpostprandialplasmafreefattyacidlevels

SarahYanez

Athesis

Submittedinpartialfulfillmentofthe

requirementsforthedegreeof

MasterofScience

UniversityofWashington

2016

Committee:

MichaelRosenfeld

MichelleAverill

ProgramAuthorizedtoofferdegree:

NutritionalSciences

©Copyright2016SarahYanez

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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