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NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.

DeGrootLJ,BeckPeccozP,ChrousosG,etal.,editors.Endotext[Internet].SouthDartmouth(MA):MDText.com,Inc.2000.

InsulinPharmacology,TypesofRegimens,andAdjustments
LisaKroon,PharmD,CDE
ProfessorandExecutiveViceChair,DepartmentofClinicalPharmacy,SchoolofPharmacy,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA
kroonl@pharmacy.ucsf.edu

IraD.Goldfine,M.D.
ProfessorofMedicine,DepartmentofMedicine,DiabetesandEndocrineResearch,UniversityofCaliforniaSanFrancisco/Mt.ZionMedicalCenter,San
Francisco,CA
ira.goldfine@ucsf.edu

SinanTanyolac,M.D.
VisitingScientist,DepartmentofMedicine,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA
stanyolac@gmail.com
LastUpdate:October1,2010.

INTRODUCTION
Withtheintroductionofseveralnewinsulinssince1996,insulintherapyoptionsfortype1andtype2diabeticshave
expanded.Insulintherapiesarenowabletomorecloselymimicphysiologicinsulinsecretionandthusachievebetter
glycemiccontrolinpatientswithdiabetes.Thischapterreviewsthepharmacologyofinsulins(usingacomparative
approach),typesofinsulinregimensandtherapeuticadjustmentofthem,andprovidesanoverviewofinsulinpump
therapy.
PHARMACOLOGY
In1922,Canadianresearcherswerethefirsttodemonstrateaphysiologicresponsetoinjectedanimalinsulininapatient
withtype1diabetes.In1955,insulinwasthefirstproteintobefullysequenced.Theinsulinmoleculeconsistsof51
aminoacidsarrangedintwochains,anAchain(21aminoacids)andBchain(30aminoacids)thatarelinkedbytwo
disulfidebonds[1] (Figure1).ProinsulinistheinsulinprecursorthatistransportedtotheGolgiapparatusofthebeta
cellwhereitisprocessedandpackagedintogranules.Proinsulin,asinglechain86aminoacidpeptide,iscleavedinto
insulinandCpeptide(aconnectingpeptide)botharesecretedinequimolarportionsfromthebetacelluponstimulation
fromglucoseandotherinsulinsecretagogues.WhileCpeptidehasnoknownphysiologicfunction,itcanbemeasured
andifpresent,indicatesapersonhasfunctioningbetacells.

Figure1

InsulinStructure

Insulinexertsitseffectonglucosemetabolismbybindingtoinsulinreceptorsthroughoutthebody.Uponbinding,
insulinpromotesthecellularuptakeofglucoseintofatandskeletalmuscleandinhibitshepaticglucoseoutput,thus
loweringthebloodglucose.(seeInsulinsignalingandaction:glucose,lipids,protein)
Commerciallyavailableinsulinsareusedforallpatientswithtype1diabetesinwhominsulinisrequiredforsurvival,
andforpatientswithtype2diabeteswhendiet/exercise,oralagentsandotherinjectablehypoglycemicagents(i.e.,
incretinemimeticagents/GLP1analogs)nolongerprovideadequateglucosecontrol.
SourcesofInsulin

WiththeavailabilityofhumaninsulinbyrecombinantDNAtechnologyinthe1980s,useofanimalinsulindeclined
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dramatically.Beefinsulin,beefporkandporkinsulinarenolongercommerciallyavailable.TheFDAmayallowfor
personalimportationofbeefinsulinfromaforeigncountryifapatientcannotbetreatedwithhumaninsulin[2] .Beef
insulindiffersfromhumaninsulinby3aminoacidsandporkinsulindiffersbyoneaminoacid[3] .
Currently,intheUSA,mostinsulinsusedareeitherhumaninsulinand/oranalogsofhumaninsulin.Therecombinant
DNAtechniqueforhumaninsulininvolvesinsertionofthehumanproinsulingeneintoeitherSaccharomycescerevisiae
(bakersyeast)oranonpathogeniclaboratorystrainofEscherichiacoli(Ecoli)whichserveastheproduction
organism.Humaninsulinisthenisolatedandpurified[4] [5] [6] [7] [8] [9] [10] [11] .
InsulinAnalogs

RecombinantDNAtechnologyhasallowedforthedevelopmentandproductionofanalogstohumaninsulin.With
analogs,theinsulinmoleculestructureismodifiedslightlytoalterthepharmacokineticspropertiesoftheinsulin,
primarilyaffectingtheabsorptionofthedrugfromthesubcutaneoustissue.TheB26B30regionoftheinsulinmolecule
isnotcriticalforinsulinreceptorrecognitionanditisinthisregionthataminoacidsaregenerallysubstituted[12] .
Thus,theinsulinanalogsarestillrecognizedbyandbindtotheinsulinreceptor.Thestructuresofthreeinsulinanalogs
areshowninFigure2(insulinaspart,lisproandglulisine)andFigure3(insulinglargineanddetemir).

Figure2

InsulinAspart,GlulisineandLisproStructures

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InsulinGlargineandDetemirStructures

Becauseinsulinanalogsaremodifiedhumaninsulin,thesafetyandefficacyprofilesoftheseinsulinshavebeen
comparedtohumaninsulin[13] .InsulinandIGF1receptorbindingaffinities(IGFinsulinlikegrowthfactor),
metabolicandmitogenicpotenciesofinsulinlispro,insulinaspart,insulinglargineandinsulindetemirrelativetohuman
insulinhasbeenassessed.Insulinlisproandaspartaresimilartohumaninsulinonalloftheaboveparameters,except
insulinlisprowasfoundtobe1.5foldmorepotentinbindingtotheIGF1receptorcomparedtohumaninsulin.Insulin
glarginewasfoundtohavea6to8foldincreaseinmitogenicpotencyandIGF1receptoraffinitycomparedtohuman
insulin.Insulindetemirwasfoundtotobemorethan5foldlesspotentthanhumaninsulininbiningtoIGF1.Whilethe
clinicalsignificanceofthesedifferencesisnotknown,theylikelydonotrepresentanysignificantconcern[14] .
Immunogenicity

Becauseporkandbeefinsulindifferfromhumaninsulinby1and3aminoacidsrespectively,theyaremore
immunogenicthanexogenoushumaninsulin.Olderformulationsofinsulinwerelesspure,containingisletcellpeptides,
proinsulin,Cpeptide,pancreaticpolypeptides,glucagons,andsomastostatin,whichcontributedtoimmunogenicityof
insulin[15] .Componentsofinsulinpreparations(e.g.,zinc,protamine)andsubcutaneousinsulinaggregatesarealso
thoughttocontributetoantibodyformation[16] .Commerciallyavailablehumaninsulinsarenowvirtuallyfreeof
contaminantsandcontain<1ppmofproinsulin(alsoreferredtoaspurified)[17] .Insulinsideeffectssuchas
localorsystemichypersensitivity,lipodystrophy,andantibodyproductioncausinginsulinresistance,arenowrarely
seenwithexogenoushumaninsulin[18] .Becauseoftheavailabilityofhumaninsulinandtheincreasedpotentialfor
animalsourceinsulintobeimmunogenic,animalsourceinsulinsarenowrarelyusedandpeoplewithdiabetesshouldbe
initiatedonhumaninsulin.
Therarehypersensitivityresponsestoinsulincanbeimmediatetype,localorsystemicIgEmediatedreactions[19] .
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Patientswhoexperienceatrueallergicreactiontoinsulinoftenhavereceivedinsulininthepast,andexperiencethe
allergicreactionafterinsulinisrestarted.Anotherallergicreactionseenwithanimalinsulinswasadelayedlocalreaction
thatwasIgGmediated[20] .InsulintherapycanalsoresultintheproductionofinsulinantibodiesoftheIgGclass,
whichneutralizeinsulin.AnimmunologicalinsulinresistancecanoccurinpatientswithveryhightitersofIgG
antibodies.
Lipodystrophyseenwithinsulinreferstotwoconditions:lipoatrophyandlipohypertrophy.Lipoatrophyisanimmune
mediatedconditioninwhichthereislossoffatattheinsulininjectionsites[21] .Lipoatrophyoccursmuchless
frequentlywithpurifiedhumaninsulins.Treatmentforpatientswhowereonananimalinsulinwasinjectionwithhuman
insulinattheatrophiedsite.Lipohypertrophyisanonimmunologicalsideeffectofinsulinresultingfromrepeated
administrationofinsulinatthesameinjectionsite.
Concentration

IntheUnitedStates,allinsulinsareavailableintheconcentrationof100units/ml(denotedasU100).Insulinsyringes
aredesignedtoaccommodatethisconcentrationofinsulin.Regularhumaninsulin(HumulinR,Lilly)isavailableina
moreconcentratedinsulin,U500(500units/ml),howeverthispreparationisusedprimarilyinaspecializedinstitutional
settingorforrarecasesofextremeinsulinresistance,whereverylargedosesofinsulin(generally>200unitsperday)
arerequired.SpecificsyringesforU500insulinarenotavailableandextremecautionmustbetakenaseachmarked
unitonaU100syringewillactuallydeliver5unitsofinsulin.
OutsidetheUnitedStates,alessconcentratedinsulinpreparation,U40,(40units/ml)isstillavailableandsometimes
used.SpecificU40syringesareusedwiththisinsulin.Itisimportantthatpatientstravelingfromonecountrytothe
next,beawareoftheconcentrationofinsulintheyuse,andthattheappropriatesyringeisused.
PhysicalandChemicalProperties

Regularhumaninsuliniscrystallinezincinsulindissolvedinaclearsolution.Itmaybeadministeredbyanyparenteral
route:subcutaneous,intramuscular,orintravenous.Insulinaspart,glulisineandlisproarealsosolublecrystallinezinc
insulin,butareintendedforsubcutaneous(subQ)injection.NPH,orneutralprotamineHagedorn,isasuspensionof
regularinsulincomplexedwithprotaminethatdelaysitsabsorption.Insulinsuspensionsshouldnotbeadministered
intravenously.Allinsulins,exceptinsulinglargine,areformulatedtoaneutralpH.
LongactingInsulinglargineisasoluble,clearinsulin,andhasapHof4.0.ItsacidicpHiscriticalforitssubQ
absorptioncharacteristicsandwillbediscussedfurtherunderpharmacokinetics.Insulinglargineshouldnotbemixed
withotherinsulins,andshouldonlybeadministeredsubcutaneously[22] .
InsulindetemirisalongactinginsulinanalogthathasafattyacidcoupledtoitsothatitbindstoalbumininthesubQ
tissueresultingindelayedabsorption,proloningitsdurationofaction.Likeinsulinglargine,insulindetemirshouldnot
bemixedwithotherinsulins,andshouldbeinjectedsubcutaneously.
Pharmacokinetics
Absorption

InsulinadministeredviaSCinjectionisabsorbeddirectlyintothebloodstream,withthelymphaticsystemplayinga
minorroleintransport[23] .TheabsorptionofhumaninsulinaftersubQabsorptionistheratelimitingstepofinsulin
activity.ThisabsorptionisinconsistentwiththecoefficientsofvariationofT50%(timefor50%oftheinsulindosetobe
absorbed)varying~25%withinanindividualandupto50%betweenpatients[24] [25] .Mostofthisvariabilityof
insulinabsorptioniscorrelatedtobloodflowdifferencesatthevarioussitesofinjection(abdomen,deltoid,gluteus,and
thigh)[26] .Forregularinsulin,theimpactofthisisa~2timesfasterrateofabsorptionfromtheabdomenthanother
subcutaneoussites[27] .Theclinicalsignificanceofthisisthatpatientsshouldavoidrandomuseofdifferentbody
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regionsfortheirinjections.Forexample,ifapatientpreferstousetheirthighforanoontimeinjection,thissiteshouldbe
usedconsistentlyforthisinjection.Forsimplicity,however,theabdomenisoftenrecommendedasthepreferredsiteof
injectionbecauseitistheleastsusceptibletofactorsaffectinginsulinabsorption(seeTable1).Insulinaspart,glulisine
andlisproappeartohavelessdaytodayvariationinabsorptionratesandalsolessabsorptionvariationfromthe
differentbodyregions[28] [29] [30] [31] .Insulinglarginespharmacokineticprofileissimilarafterabdominal,
deltoidorthighSCadministration[32] .
AgeneralprincipleforfactorsthatcanalterinsulinabsorptionisthatwhenlocalbloodflowinthesubQtissueis
changed,theabsorptionrateofinsulinwillalsobeaffected.AfactorthatincreasessubQbloodflowwillincreasethe
absorptionrateandviceversa.SeeTable1forfactorsthataffectinsulinabsorption.
Table1

FactorsAffectingInsulinAbsorption([33][34][35])

Factor

Comment

Exerciseofinjectedarea

Strenuousexerciseofalimbwithin1hourofinjection.Clinicallysignificantforregular
humaninsulin.

Localmassage

WhileitisOKtopressontheinjectionsitetopreventseepage,thesiteshouldnotbe
rubbedvigorouslyormassaged.

Temperature

Heatcan
increaseabsorptionrate.Avoidthesauna,shower,hotbathsoonafterinjection.
Coldhastheoppositeeffect.

Siteofinjection

Insulinisabsorbedfasterfromtheabdomen.Lessclinicallyrelevantwithrapidacting
insulins,insulinglargineandinsulindetemir.

Lipohypertrophy

Injectionintohypertrophiedareasdelaysinsulinabsorption.

Jetinjectors

Increase

absorptionrate.

Insulinmixtures

Absorptionratesareunpredictablewhensuspensioninsulinsarenotmixedadequately(i.e.,
theyneedtoberesuspended).

Insulindose

Largerdoseshavedelayinactionand
increasedduration.

Physicalstatus(solublevs. Suspensioninsulinsmustbesufficientlyresuspendedpriortoinjectiontoreducevariability.
suspension)
Distribution

CirculatinginsulinisdistributedinequilibriumbetweenfreeinsulinandinsulinboundtoIgGantibodies[36] .The
presenceofinsulinantibodiescandelaytheonsetofinsulinactivity,reducethepeakconcentrationoffreeinsulin,and
prolongthebiologichalflifeofinsulin[37] .
Elimination

Thekidneysandliveraccountforthemajorityofinsulindegradation.Normally,theliverdegrades~60%ofinsulin
releasedbythepancreas(insulindeliveredthroughportalveinbloodflow)andthekidneys~3545%[38] .When
insulinisinjectedexogenously,thedegradationprofileisalteredsinceinsulinisnolongerdelivereddirectlytotheportal
vein.ThekidneyhasagreaterroleininsulindegradationwithsubQinsulin(~60%),withtheliverdegrading~3040%[
39] .
Becausethekidneysareinvolvedinthedegradationofinsulin,renaldysfunctionwillreducetheclearanceofinsulinand
prolongitseffect.Thisdecreasedclearanceisseenwithbothendogenousinsulinproduction(eithernormalproduction
orthatstimulatedbyoralagents)andexogenousinsulinadministration.Renalfunctiongenerallyneedstobegreatly
diminishedbeforethisbecomesclinicallysignificant[40] .
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Pharmacodynamics

Theonset,peak,anddurationofeffectarethemostclinicallysignificantdifferencesamongtheinsulins.Insulin
pharmacodynamicsreferstothemetaboliceffectofinsulin.Commerciallyavailableinsulinscanbecategorizedasrapid
acting,shortacting,intermediateacting,andlongacting.ThecurrentinsulinsavailableintheUnitedStatesarelistedin
Table2.Insulinpharmacodynamics(i.e.,onset,peakandduration)ofthevariousinsulins)areshowninTable3.Itis
importanttonotethatrangesarelistedfortheonset,peakandduration,accountingforintra/interpatientvariability.
Eachpatientwillhaveanindividualpatternofresponse.Byhavingthepatientselfmonitortheirbloodglucose
frequently,thepatientspecifictimeactionprofileofthespecificinsulincanbebetterappreciated.Figures4a4c[41] [
42] [43] [44]

graphicallyshowthetimeactivityprofilesforthevariousinsulins.
Table2I

nsulinsCommerciallyAvailableintheUS

Category/Nameof
Insulin

Source

BrandName(manufacturer)

Preparation(s)

RapidActing
InsulinLispro
InsulinAspart
InsulinGlulisine

Recombinant
DNARecombinant
DNA
RecombinantDNA

Humalog(Lilly)Novolog(Novo vial,cartridge,disposablepenvial,
Nordisk)
cartridge,disposablepen
Apidra(sanofiaventis)
vial,disposablepen

ShortActing
Regular
Human

RecombinantDNA

HumulinR(Lilly)NovolinR
(NovoNordisk)

vialvial

IntermediateActing RecombinantDNA
NPH
Human

HumulinN(Lilly)NovolinN
(NovoNordisk)

vial,disposablepenvial

LongActing
InsulinDetemir
InsulinGlargine

Recombinant
DNARecombinant
DNA

Levemir(NovoNordisk
)Lantus(sanofiaventis)

vial,disposablepenvial,cartridge,
disposablepen

InsulinMixtures
NPH/Regular
(70%/30%)
Human
Lispro
Protamine/Lispro
(50%/50%)
Lispro
Protamine/Lispro
(75%/25%)
Aspart
Protamine/Aspart
(70%/30%)

Recombinant
DNARecombinant
DNA
RecombinantDNA
RecombinantDNA

Humulin70/30(Lilly)Novolin
70/30(NovoNordisk)
HumalogMix50/50(Lilly)
HumalogMix75/25(Lilly)
NovologMix70/30(Novo
Nordisk

vial,disposablepenvial
vial,disposablepen
vial,disposablepen
vial,disposablepen

Note:Allinsulinanalogsareavailablebyprescriptiononly.OnAugust17,2009,NovoNordiskannouncedthe
NovolinInnoletR,N,and70/30devicesandtheNovolinR,Nand70/30PenFillcartridgeswouldnolongerbe
availableafterDecember31,2009.
Table3I

nsulinPharmacodynamics([45][46][47][48][49][50][51][52][53][54][55][56][57])

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Insulin

Onset(hr)

Peak(hr)

Duration(hr) Appearance

InsulinLispro

within15min 1

35

Clear

InsulinAspart

within15min 13

35

Clear

InsulinGlulisine .25.5

.51

Clear

Regular

24

58

Clear

NPH

12

410

14+

Cloudy

InsulinDetemir

34

68(thoughrelativelyflat) upto2024

Clear

InsulinGlargine

1.5

flat

24

Clear

LisproMix50/50 .25.5

.53

1424

Cloudy

LisproMix75/25 .255

.52.5

1424

Cloudy

AspartMix70/30 .1.2

14

1824

Cloudy

Note:Patientspecificonset,peak,durationmayvaryfromtimeslistedintable,
Peakanddurationareoftenverydosedependentwithshorterdurationofactionswith
smallerdosesandviceversa.

Figure4a

PharmacodynamicProfilesofaRapidInsulinAnalog(insulinlispro)andRegularInsulin.

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Figure4b

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PharmacodynamicProfilesofLongActingandIntermediateActing

BasalInsulins.

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Figure4c

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PharmacodynamicProfile:LisproNPLinComparisonwithNPH

DoseDependentEffect

ThepharmacodynamicsofregularandNPHareparticularlyaffectedbythesizeofthedose[58] .Largerdosescan
causeadelayinthepeakandincreasethedurationofaction.Forexample,injecting4unitsofNPHwillhavea
significantlydifferenttimeactionprofilecomparedto30unitsofNPH.
RapidActingInsulins
InsulinLispro(Humalog)

Insulinlispro[Lys(B28),Pro(B29)]isaninsulinanalogthatwasapprovedin1996(Humalog).TheB28(proline),B29
(lysine)aminoacidsequenceoftheinsulinmoleculeisreversedtobelysineprolineresultinginarapidabsorption,
within15minutes.Becauseitisabsorbedmorerapidly,itsonsetandpeakaresooner(anddurationshorter)comparedto
regularinsulin.Insulinlisproisalsoapprovedforinjectionimmediatelyafterameal.Becauseinsulinlisprocanbe
injectedjustbefore(orafter)themealversuswaiting30minuteswithregularinsulin,patientsmayfinditprovidesthem
withmoreflexibilityandconveniencefortheirmealtimeinsulininjection.Insulinlisprocanbemoreeffectivein
loweringpostprandialbloodglucoselevelsandhasareducedriskofhypoglycemiacomparedtoregularinsulin[59] [
60] [61]

.Thereasoninsulinlisproisassociatedwithlesshypoglycemiaisduetobettermatchingofinsulineffectand
foodabsorption[62] .Insulinlisprohasbeenstudiedforuseininsulinpumpsand,FDAapprovedforthisindicationin
2004.[63] [64] [65] .Intherarecaseofseverehumaninsulinallergy,insulinlisprohasbeenshowntobeless
immunogenic[66] .
InsulinAspart(Novolog)
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InsulinaspartisahumaninsulinanalogapprovedJune7,2000(Novolog).TheB28aminoacidprolineissubstituted
withasparticacidresultinginarapidonsetofactivity.Insulinaspartshouldbeinjected510minutesbeforethemeal.
Advantageslistedaboveforinsulinlisproarethesameforinsulinaspart[67] .TheinsulinaspartisFDAapprovedfor
useininsulinpumps[68] [69] .
Whileonamolarbasisinsulinaspartandlisprohaveidenticalinvivopotencycomparedtoregularhumaninsulin,
higherpeakconcentrationsareachievedwiththerapidactinginsulins[70] .Thus,whilea1:1conversionisoftenused
fortheinitialswitchfromregularinsulintoinsulinaspart,glulisineorlispro,overtime,apatientsrapidacting
insulindosemayneedtobeadjusted,oftenreduced.Thisdosingchangeisalsoduetothebettermatchingofthepeakof
theinsulinwiththemeal,thusachievingbetterpostprandialcontrol.
InsulinGlulisine(Apidra)

Insulinglulisineisarapidactinginsulinanaloguethatdiffersfromhumaninsulininthattheaminoacidasparagineat
positionB3isreplacedbylysineandthelysineinpositionB29isreplacedbyglutamicacid.Chemically,itis3Blysine
29Bglutamicacidhumaninsulin.Wheninjectedsubcutaneously,itsonsetofactionismorerapidandachieveshigher
concentrationscomparedtohumaninsulinonaunitperunitbasis.Whenusedasamealtimeinsulin,thedoseshouldbe
givenwithin15minutesbeforeamealorwithin20minutesafterstartingameal.Insulinglulisinealsoisbeingusedin
insulinpumps[71] .InsulinglulisinehasbeenavailableinUSAsince2007andFDAapprovedin2004.
ShortActingInsulin(Regular)

Regularinsulinhasanonsetofactionof3060minutes.Itshouldbeinjectedapproximately30minutesbeforethemeal.
Adherencetothisschedulecanbeinconvenientanddifficultforsomepatients.
IntermediateActingInsulins(NPH)

NPH,whichstandsforNeutralProtamineHagedorn,wascreatedin1936byHansChristianHagedornandB.Norman
Jensen.Thesescientistsdiscoveredthattheeffectsofsubcutaneouslyinjectedinsulincouldbeprolongedbytheaddition
ofprotamine,aproteinthattheyobtainedfromthe"milt"orsemenofrivertrout.NPHinsuliniscategorizedasan
intermediateactinginsulin,whoseonsetofactionisapproximately2hours,peakeffectat614hours,anddurationof
actionupto24hours(dependingonthesizeofthedose).Intermediateactinginsulinscanserveabasalinsulinand/or
prandialinsulindependingontimeofadministration.NPHinsulinisavailableinvariouscombinationswitheither
regularinsulinorshortactinginsulins(Table2).
LongActingInsulins

Longactinginsulinsservetoprovideabasal(orbaseline)levelofinsulin.
InsulinGlargine(Lantus)

Insulinglargine(21AGly30BaLArg30BbLArghumaninsulin)isaninsulinanalogapprovedApril20,2000
(Lantus).Itconsistsoftwomodificationstohumaninsulin.TwoargininesareaddedtotheCterminusoftheBchain
shiftingtheisoelectricpointoftheinsulinfromapHor5.4to6.7[72] .Thischangemakestheinsulinmoresolubleat
anacidicpHandinsulinglargineisformulatedatapHof4.0[73] .ThesecondmodificationisattheA21position,
whereasparagineisreplacedbyglycine.Thissubstitutionpreventsdeamidationanddimerisationthatwouldoccurwith
acidsensitiveasparagine.Wheninsulinglargineisinjectedintosubcutaneoustissue,whichisatphysiologicpH,the
acidicsolutionisneutralized.Microprecipitatesofinsulinglargineareformed,fromwhichsmallamountsofinsulinare
releasedthroughouta24hourperiod,resultinginalowlevelofinsulinthroughouttheday[74] .Thebiologicalactivity
ofinsulinglargineisduetoitsabsorptionkineticsandnotadifferentpharmacodynamicactivity(e.g.,stimulationof
peripheralglucoseuptake)[75] .
Itiscriticalthatinsulinglarginenotbemixedinthesamesyringewithanyanotherinsulinorsolutionbecausethiswill
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alteritspHandthusaffectitsabsorptionprofile.Lantusmaybegivenatanytimeofday.Insulinglarginehasbeen
showntohavelessnocturnalhypoglycemiawhenusedatbedtimecomparedwithNPHinsulin[76] [77] .
InsulinDetemir(Levemir)

Insulindetemirisalongactinghumaninsulinanalogformaintainingthebasallevelofinsulinitstradenameis
Levemir.ItisaninsulinanaloginwhichtheB30aminoacidisomittedandaC14fattyacidchain(myristicacid)is
boundtotheB29lysineaminoacid.Insulindetemirisslowlyabsorbedduetoitsstrongassociationwithalbumininthe
subQtissueandwhenitreachesthebloodstreamitagainbindstoalbumindelayingitsdistributiontotheperipheral
tissues.
Storage

Allinsulinshaveanexpirationdatewhichislabeledondirectlyontheproduct(vials,cartridges,disposablepensand
otherdeliverydevices)applieswhentheyareunopenedandrefrigerated.Unopened(i.e.,insulinnotcurrentlyinuse)
insulinshouldbestoredintherefrigeratorat36F46F(2C8C).Insulinshouldneverbefrozenorstoredinan
ambienttemperaturegreaterthan86F(30C).Aninsulinvialinusemaybekeptatroomtemperature,below86
F,or30C(insulinglulisineandNovoNordiskhumaninsulins,N,Rand70/30,shouldbestoredupto77F
only),for28days,orabout1month(exceptforinsulindetemirandNovoNordiskhumaninsulins,whichcanbekept
forupto42days).Insulincartridges,disposablepensandotherdeliverydevicescanhavedifferentstorage
recommendationsforroomtemperature.Onceopened,insulincartridgesandpensshouldnotberefrigerated.
AdverseEffects

Themostsignificantadverseeffectofinsulinishypoglycemia.IntheDCCT(DiabetesControlandComplications
Trial),intensiveinsulintherapywasassociatedwitha23foldincreaseinseverehypoglycemia(i.e.,apersonrequiring
assistance)[78] .Likewise,intheUKPDS(UnitedKingdomProspectiveDiabetesStudy),insulintherapyinthe
intensivelytreatedgroupresultedin1.8%rateofmajorhypoglycemicepisodescomparedto0.7%intheconventional
group[79] .Allpatientsreceivinginsulinshouldbeawareofthesymptomsofhypoglycemiaandhowtotreatit.
Weightgainisanothersignificantsideeffectofinsulintherapy.Inpart,theweightgaincanbearesultoffrequent
hypoglycemicepisodesinwhichpatientsoftenovertreat/overeatinresponsetohunger.Insulin,beingananabolic
hormone,alsopromotestheuptakeoffattyacidsintoadiposetissue.TheamountofweightgainintheDCCTand
UKPDSassociatedwithinsulintherapywas4.6kgand4.0kgrespectively[80] [81] .However,lessweightgainis
encounteredwithlongactinginsulinanalogs[82] [83] .
Trueallergicreactionsandcutaneousreactionsarerare(seeImmunogenicity).Toavoidlipohypertrophy,patientsshould
beinstructedtorotatetheirinsulininjectionsites,preferablyrotatingwithinonearea(e.g.,abdomenavoid2inchradius
aroundnavel)andnotreusingforoneweek[84] .
InJune2009,4retrospective,epidemiologicstudiesassessingtheriskofcancerfrominsulinuse,glargineinparticular,
werepublishedonlineattheEuropeanAssociationfortheStudyofDiabetes'journalwebsite3oftheseEuropean
studiesreportedanincreasedriskofcancerwithinsulinglargine.IntheGermanystudy,acorrelationbetweeninsulin
doseandcancerriskwasfoundforallinsulintypes(humaninsulin,aspart,lisproorglargine)howeverafteradjusting
fordose,insulinglarginewasfoundtohaveadosedependentincreasedriskofcancercomparedtohumaninsulin(e.g.,
HR1.09,1.19and1.31foratotaldailydosesof10units,30unitsand50unitsrespectively).[85] Themedianfollow
uptimewasonly1.63years(1.31yearsforinsulinglargine)andbodymassindexwasnotaccountedfor.TheSwedish
studyfoundastatisticallysignificantincreasedriskofbreastcanceronlyinwomenwhousedinsulinglarginealone(RR
1.99),butnotinthoseoninsulinglargineplusotherinsulins.[86] TheScotlandstudydemonstratedaincreasedriskof
cancer(HR1.55)forpatientsoninsulinglarginealone,whilethoseoninsulinglargineplusotherinsulinshadaslightly
lowerincidenceofcancer(HR0.81)comparedtohumaninsulinonlyuserswhichwasnotstatisticallysignificant.[87]
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Finally,intheUKstudy,nolinkbetweeninsulinglargineandcancerwasfound.[88] Theseobservationalstudies
assessedlargepatientdatabasesandhavesignificant,inherentlimitationstogeneralizetheirconclusions,suchasthe
potentialfordifferentpretreatmentcharacteristicsofthegroups,selectionbias,thesmallnumbersofcancercasesfound,
andshortdurationoffollowup.Also,type2diabetesitselfisassociatedwithanincreasedriskofcolon,pancreasand
breastcancer.Furthermore,inarandomised,5year,openlabeltrialcomparingtheprogressionofretinopathyofNPH
andinsulinglargineusers,noincreasedriskofcancerwasfoundinthe1017patientsample.[89] Lastly,inananalysis
of31randomizedcontrolledtrialsfromthesanofiaventissafetydatabase(phase2,3,and4studies),insulinglargine
wasnotassociatedwithanincreasedriskofcancer,includingbreastcancer.[90] Ofnote,themainstudyaffectingthese
findingsistheRosenstocketalstudycomparingglarginetoNPHthathadanapproximate5yearduration,whereas19
ofthestudiesincludedhadveryshortdurations(approximately6months).OnJuly1,2009,theFDAissuedanearly
communicationaboutthesafetyofLantusandisworkingwiththemanufacturertoreviewthecollectivedataand
determinewhetheradditionalstudiesneedtobeperformed.Atthistime,thesedatadonotprovideconclusiveevidence
ofanincreasedriskofcancerassociatedwithinsulinglargine.
TYPESOFREGIMENS
GeneralPrinciples
Type1Diabetes

Withdecreasingbetacellfunctionresultingindecreasedinsulinproduction,peoplewithtype1diabetesmayrequire
insulinforsurvival.Ingeneral,insulinopenictype1diabeticsgenerallyrequire0.51.0unitsperkgofbodyweightper
dayofinsulin[91] .Insulintherapyisofteninitiatedat0.50.75units/kg/day[92] .Duringtheearlystagesoftype1
diabetes,patientswillrequirelessinsulinbecausethebetacellsarestillproducingsomeinsulininsulinrequirementscan
beintherangeof0.10.6unitsperkgperday[93] [94] .Intensiveinsulintherapy(definedas3insulininjections
daily)isindicatedforpeoplewithtype1diabetesasthishasbeenshowntoprovidebetterglycemiccontrolthan1or2
dailyinjectionsandreducethedevelopmentandprogressionofmicrovascularcomplications[95] .
Type2Diabetes

Manypatientswithtype2diabeteswilleventuallyrequireinsulintherapy.Sincetype2diabetesisassociatedwith
insulinresistance,insulinrequirementscanexceed1unit/kg/day.IntheUKPDS,by9yearslessthan25%ofpatients
treatedwithasulfonylureaasmonotherapywereabletomaintainA1Clevels<7.0%themajorityofpatientsrequired
insulintherapywithin9yearsofdiagnosis[96] .Wheninitiatinginsulintherapyinpatientswithtype2diabetes,insulin
isoftenusedincombinationwiththeoralmedicationsapatientistaking.Oftenanintermediatetolongactinginsulin
(e.g.,NPH,insulinglargine,orinsulindetemir)isaddedatbedtimeor70/30insulinbeforedinner[97] .Therationaleis
thatinsulin,bysuppressinghepaticglucoseoutputduringthenight,willcontrolthefastingbloodglucose(FPG),while
theoralmedication(s)continuestocontrolprandialglucoselevelsandglucosethroughouttheday[98] .Typically,a
startingdoseof10unitsisutilized,or~0.10.2units/kg[99] .Theintermediatetolongactinginsulinistitratedto
achievetheFPGtarget(seeAdjustmentsbelow).Ifthepatienthaspoorglycemiccontrolduringtheday,daytimeinsulin
caninitiatedtwicedailyregimenofinsulinormultipledailyinjectionscanbeused.Atthispoint,thepatientis
experiencingbetacellfailure.Ifthepatientistakinganinsulinsecretagogue(e.g.,glyburide,repaglinide,etc),itshould
bediscontinued,asinsulinwillnowbereplacedexogenously.However,theinsulinsensitizingoralagents(e.g.,
metforminshouldbecontinued)Anotheroptionistodiscontinuetheinsulinsecretagoguewheninsulintherapyisstarted
tosimplifythemedicationregimenandtoavoidpotentialhypoglycemia.[100] .
GoalsofTherapy

Beforestartingapatientoninsulin,oradjustingtheircurrentinsulintherapy,itisimportanttoestablishglycemicgoals
tailoredtothepatient.TheAmericanDiabetesAssociationcurrentlyrecommendsthefollowingglycemicgoals[101] :
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Preprandialplasmaglucose70130mg/dl
Postprandialplasmaglucose<180mg/dl
A1C<7%
Forexample,ifapatientspreprandialbloodglucoselevelshavebeeninthehigh200s,aninitialgoalmightbe
tolowerthemto150mg/dl.Uponachievingthis,alowergoalcanbeset(e.g.,90130mg/dl).IntheDCCT,
retinopathyinitiallyworsenedduringthefirstyearinpatients(withtype1diabetes)whoreceivedintensivetherapy[102
]
.Thisisthoughttobeduetorapidloweringofglucoselevels.Thusinpatientswithproliferativeretinopathyorthose
withhighA1C(e.g,>10%),slowerloweringofglucoseiswarranted[103] .Anotherexampleofindividualizing
glycemicgoalsisapatientwithhypoglycemicunawarenessglycemicgoalsshouldbelessaggressiveasglucoselevels
shouldnotborderaround70mg/dltooclosely.
ReplacementStrategies
PhysiologicInsulinReplacement

Afunctioningpancreasreleasesinsulincontinuously,tosupplyabasalamounttosuppresshepaticglucoseoutput
betweenmealsandovernight,andalsoreleasesabolusofinsulinprandiallytopromoteglucoseutilizationaftereating[
104]
.Replacinginsulininamannerthatattemptstomimicphysiologicinsulinreleaseisoftenreferredtoasthe
basal/bolusconcept.Thisphysiologicreplacementrequiresmultipledailyinjections(3ormore)oruseofaninsulin
pump.Basalinsulinrequirementsareapproximately50%ofthetotaldailyamount.Prandialinsulinis~1020%ofthe
totaldailyinsulinrequirementateachmeal[105] .Providingbasalbolusinsulinregimensallowpatientstohave
flexibilityintheirmealtimesandachievebetterglycemiccontrol.
NonPhysiologicInsulinReplacement

Wheninsulinisgivenonceortwicedaily,insulinlevelsdonotmimicphysiologicinsulinreleasepatterns.Forpeople
withtype2diabetes,inwhombasalinsulinreplacementisnotascritical,onceortwicedailyregimenscanstillwork
satisfactorilywithreasonableglycemiccontrolachieved.
ExamplesofRegimens
OnceDailyInsulinRegimen(forpatientswithtype2diabetesonoralagents)

NPH(Figure5a),insulinglargine(Figure5b),orinsulindetemiraremostoftengivenatbedtime(howeverinsulin
glarginecanbeadministeredanytimeoftheday)orforpatientwhoeatlargeamountsofcarbohydratesatdinner,an
insulinmixture,regularandNPHoraprexmixedinsulin,canbegivenpriortodinner(Figure5c).

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Figure5a.

Figure5b.

Figure5c.
TwicedailyInsulinRegimen(SplitMixedandPreMixedRegimens)

Twothirdsoftheinsulindoseisgiveninthemorningbeforebreakfastandonethirdisgivenbeforedinner.Premixed
insulinscanbeusedoramixtureofashortactinginsulin(e.g.,regular,insulinaspart/glulisine/lispro)andan
intermediateactinginsulin(e.g.,NPH)(Figure6a)[106] .
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Figure6a.

2/3totaldailydoseatbreakfast:givenas2/3NPHand1/3Regular(orinsulinaspart/glulisine/lispro)
1/3totaldailydoseatdinner:dividedinequalamountsofNPHandRegular(orinsulinaspart/glulisine/lispro)
ForpatientswhoexperiencenocturnalhypoglycemiawhenNPHisadministeredatdinnerwithashortactinginsulin,
movingtheNPHdosetobedtimehelpsreducetheriskfornocturnalhypoglycemia[107] .Conversely,NPHatdinner
canresultinfastinghyperglycemiaduetodissipationofinsulinactivityandthedawnphenomenon.MovingtheNPH
dosetobedtimecanhelpresolvethisproblem[108] (Figure6b).Anobviouslimitationtousingpremixedinsulinis
reducedflexibilityindosingifthedoseisadjusted,bothtypesofinsulininthemixtureareadjusted.

Figure6b.
MultipleDailyInsulinInjectionRegimen:BasalplusPrandialInsulin

Manydifferenttypesofregimensarepossiblewithmultipledailyinjections.Regular,insulinaspart,glulisineandlispro
areusedtoprovideprandialinsulin.NPH,insulinglargine,andinsulindetemirareusedtoprovidebasalinsulin.
Regular,insulinaspart/glulisine/lisprobeforemealsandNPH,insulinglargineorinsulindetemiratbedtime
(Figure7a,7b).
Insulinaspart/glulisine/lisprobeforemealsandNPHtwicedaily(breakfastandbedtime)(Figure8).

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Figure7a.

Figure7b.

Figure8.
InsulinPumps

Insulinpumporcontinuoussubcutaneousinsulininfusion(CSII)therapyisanotheroptionforintensiveinsulintherapy.
Whilepumptherapyusedtobereservedforprimarilytype1diabetes,patientswithtype2diabetesarenowusing
insulinpumps[109] .Patientsinitiatedoninsulinpumptherapyneedtobeveryknowledgeableaboutdiabetes
managementandbepracticingselfmanagement.Patientsalreadyknowhowtocountcarbohydratesandadjusttheir
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insulindoses.Potentialadvantagesofinsulinpumpsincludelessweightgain,lesshypoglycemia,andbettercontrolof
fastinghyperglycemiaduetothedawnphenomenoncomparedtomultipledailyinjections[110] [111] [112] [113] .
TimingofPrandialInsulinInjection

Thelagtimefrominjectingregularinsulinandeatingisapproximately30minuteswhileinsulinaspart/glulisine/lispro
canbeinjectedwithin15minutesofeating.Dependingonthelevelofhyperglycemiabeforemeals,thelagtimecanbe
increased.Rapidactinginsulinsallowpatientstoadjustinsulintomatchtheirlifestyleratherthanhavingtoadaptthe
timingofmealstoamorefixedinsulinregimen[114] .
Adjustments

Insulindosesshouldbeadjustedtoachieveglycemictargets.Itisalwaysbesttoerrontheconservativesidewhen
dosinginsulinatinitiationorwhenadjustingcurrentinsulintherapy.Typicallya1020%increaseordecreaseinan
insulindoseisappropriate.Ifapatientisexperiencinghypoglycemia,adjustmentoftheinsulindosecausingthe
hypoglycemiashouldbeaddressedpreferentiallyoverotherinsulindoseadjustments.Hyperglycemiaisadominoeffect:
ifapatientishyperglycemicinthemorning,chancesaretheyremainhyperglycemicthroughouttheday.Therefore,
adjusttheearliesttimeofhyperglycemiafirst[115] .
AdjustmentofIntermediatetoLongActingInsulin

Whenadoseofintermediateorlongactinginsulinisadjusted,itisrecommendedtowaitatleast25daysbeforefurther
changesinthedosetoassesstheresponse[116] .
AdjustmentofOnceDailyEveningInsulin

TheFPGisusedtoadjusttheintermediatetolongactinginsulingivenintheevening.Acommonweeklytitration
scheduleusedis[117] :
IftheFPGis>140mg/dl:Increaseby4units
IftheFPGis120140mg/dl:Increaseby2units
Forinsulinglargine,thefollowingtitrationschedulehasbeenstudiedandshowntocauselessnocturnalhypoglycemia
comparedtobedtimeNPHinsulin.Inthisstudy,insulinwastitrated,usingaforcedtitrationschedule,totargetaFPGof
100mg/dl[118] .
ForcedTitrationScheduleStartwith10unitsbedtimebasalinsulindoseadjustweekly
FPG(mg/dL)

Increaseinsulindose

100120

120140

140180

180

Decreaseinsulindose(e.g.,24units/day)ifhypoglycemiaoccurs.(modifiedrecommendationfromreference112)
SupplementalInsulinforCorrectionofHyperglycemia

Regularinsulin,insulinaspart/glulisine/lisprocanbeusedtocorrectforhyperglycemia[119] .Ingeneral,12unitsof
insulinwilllowerthebloodglucoseby3050mg/dl.Often1unitforevery50mg/dlabovetheglucosetargetisa
startingsupplementaldose,adjustingforinsulinsensitivity[120] .Anexampleofasupplementalinsulinregimenisas
follows:Forevery50mg/dlabovethepremealglucosetarget(e.g.,150mg/dl),add1unitofinsulin[121] .So,ifa
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personspremealglucosewas250mg/dl,2unitsofinsulinwouldbeaddedtotheusualdoseofpremealinsulin.
Supplementalinsulincanalsobeusedforsnacks[122] .
CarbohydrateCounting

Amoresophisticatedtypeofinsulinregimenisoneinwhichapatientdosestheirprandialinsulinbasedonthenumber
ofcarbohydrateseatenatthemeal.Bylearninghowtocounttheircarbohydrates,anddosingtheirinsulinaccordingly,
patientsareaffordedflexibilityintheirmeals.Astartinginsulintocarbohydraterationoftenusedis1unitofinsulinfor
every15gramsofcarbohydrate[123] .Thisratioisadjustedbasedoninsulinsensitivityandmaybedifferentforeach
meal.Carbohydratecountingistoodifficultforsomepatients.Inthesepatients,mealportionsizesandestimatesof
carbohydrateservings(15grams)areconceptsthatcanbelearned.Medicalnutritiontherapyisacriticalcomponentof
therapyforpatientsoninsulin.
Acomprehensivediabeteseducationclass,thatteachesselfmanagementskills,suchashowtodoseprandialinsulinby
matchingittotheamountofcarbohydrateintakeareanexcellentresourcetofacilitatepatientsinadoptinganintensive
insulintherapyregimen[124] .
AdjustmentsforExercise

Exerciseimprovesinsulinsensitivity.Thus,whenapatientexercises,itisoftennecessarytodecreasetheinsulindose
(andincreasecaloricintake).Formorningexercise,theprebreakfastinsulindoseshouldbereduced(~25%depending
onthedurationandintensityoftheexercise).Forlatemorning/earlyafternoonandeveningexercise,theprelunchand
predinnerinsulindoseshouldbereducedrespectively[125] .Theeffectofexerciseoninsulinsensitivitycanlastfor
manyhourssoseveralinsulindosesmayneedtobeadjusted.
SelfMonitoringofBloodGlucose

Patientswhowerenotselfmonitoringtheirbloodglucose(SMBG)levelspriortoinsulinneedtobeeducatedhowtodo
this,howtointerprettheirglucosereadings,andhowtotreathypoglycemiaifitoccurs.Involvementofdiabetes
educatorisextremelyusefulwheninitiatingpatientsoninsulintoprovidecomprehensiveselfmanagementtraining.The
ADAcurrentlyrecommendthatpeoplewithtype1diabetesSMBGatleast3timesdailyandthosewithtype2diabetes
atleastdaily[126] .Mostglucosemetersarenowplasmareferenced,correlatingbettertotheADAsglycemic
goals.Plasmaglucoseconcentrationsareapproximately1015%higherthanwholebloodglucoseconcentrations[127] .
SICKDAYGUIDELINES
Acommonmisconceptionamongpatientsisthatiftheyaresickenoughthattheydonteatorevenvomit,they
shouldnottaketheirdiabetesmedications,insulinincluded.Patientsshouldbeinstructedtocontinuetheirinsulin
therapy,maintainfluidintake,eatsmallermealsastolerated,andtesttheirglucoselevelsevery14hours(ketonesas
wellforpeoplewithtype1diabetes).Insulintherapyshouldbeadjustedbasedontheglucoselevels.Iftheglucoseis
>240mg/dlwithmoderatetolargeketonuria,patientsshouldcontacttheirproviderimmediately[128] .
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