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EvaluatingeffectivenessofaContinuousGlucoseMonitoringSystem(CGMS)indiabeticdogsandcats

KatieLott

MasterofVeterinaryScience

December2018

MelbourneVeterinarySchool

TheUniversityofMelbourne

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ABSTRACT

Real-time continuous glucose monitoring systems (CGMS) measure interstitial glucose

concentrations,andhavebeenusedinthemanagementofdiabetesmellitusinpeople,dogs

andcats.Thedevicesareusedforupto72hours,andprovideglucosemeasurementsevery

5minutes,with288datapointsprovidedina24-hourperiod.Thisprovisionofadetailed

insight into glycaemic control over a longer period of time than traditional methods of

monitoringholdsthepotentialforimprovedmanagementofdiabetesmellitus.Theprimary

aimofthisstudywastodetermineifCGMS(usingtheGuardian™system)resultedindifferent

clinical decisionmaking comparedwithmonitoring serial blood glucose curves and serum

fructosamineconcentrationindiabeticdogsandcats.Secondaryaimsweretodeterminethe

incidenceofnocturnalhypoglycaemiaandreboundhyperglycaemiaindiabeticdogsandcats.

Continuous glucosemonitoring and fructosaminemeasurementwere performed in client-

owned dogs and cats, both newly and previously diagnosed with diabetes mellitus. A

retrospective serial glucose curve was plotted with glucosemeasurements every 2 hours

obtainedfromtheCGMsdata.Resultsofthethreemonitoringmodalitiesalongwithhistorical

data(i.e.appetite,thirst, insulindosage)werecollatedandablindedreviewperformedby

twoboardcertifiedsmallanimal internalmedicineclinicians. Statisticalanalysis showeda

differenceinclinicaltreatmentrecommendationsforthemanagementofdiabeticdogsand

catswhenusingCGMsversusbothserialglucosecurvesandserumfructosamine.Nocturnal

hypoglycaemiawasseenin14.6%ofdiabeticdogsandcatsandthe9.8%hadepisodesofthe

Somogyieffect.

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DECLARATION

Thisistocertifythat

i. Thethesiscomprisesonlymyoriginalworktowardsthemasters

ii. Dueacknowledgementhasbeenmadeinthetexttoallothermaterialused

iii. Thethesisis11826wordsinlength,exclusiveoftablesandappendices

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ACKNOWLEDGEMENTS

ThankyoutoDrCarolineMansfieldforsupervisingmymastersresearchproject.Herhelpwith

developingtheideafortheproject,makingsureitkepttoscheduleandthenassistingwith

thepreparationofthisthesisismuchappreciated.

ThankyoutoDrLindaFleeman,whohelpedrecruitdiabeticanimalsintothisstudy.

ThankyoutoDrErinBellandDrJulianDandrieuxwhobothanalysedthedataofthethree

monitoringmethods applied to the diabetic animals enrolled in the study, providing their

clinicalrecommendationsasabasisforanalysis.

ThankyoutoDrGarryAndersonforhishelpwithstatisticalanalysis inthefirstpartofthe

project and to Rachel Sore who helped with statistical analysis of the data collected

throughoutthestudy.

Andthankyoutoalltheownersoftheanimalsenrolledwhoallowedtheirpetstobeincluded

inthisstudy.

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TableofContents

ABSTRACT..........................................................................................................................2

DECLARATION....................................................................................................................3

ACKNOWLEDGEMENTS.......................................................................................................4

LISTOFTABLES...................................................................................................................6

LISTOFFIGURES.................................................................................................................8

CHAPTERONE:BACKGROUNDANDREVIEWOFTHELITERATURE.......................................91.1ThePancreas.........................................................................................................................91.2Diabetesmellitus...................................................................................................................91.3.Diabetesmellitusincats.....................................................................................................11

1.3.1Pathogenesis........................................................................................................................111.3.2DiabeticRemission..............................................................................................................14

1.4.Diabetesmellitusindogs....................................................................................................151.5Diabeticmonitoring.............................................................................................................18

1.5.1BloodGlucoseCurve............................................................................................................191.5.2SerumFructosamine............................................................................................................20

1.6NocturnalhypoglycaemiaandSomogyi...............................................................................221.7Continuousglucosemonitoring...........................................................................................23

CHAPTER2:CLINICALRECOMMENDATIONSBASEDONMETHODSOFMONITORINGDIABETESMELLITUS.........................................................................................................27

2.1Introduction........................................................................................................................272.2Materialsandmethods........................................................................................................28

2.2.1Animalsenrolledinthestudy..............................................................................................282.2.2Datacollection.....................................................................................................................292.2.3DataReview.........................................................................................................................302.2.4StatisticalAnalysis................................................................................................................312.2.4.5.1Canineonly....................................................................................................................322.2.4.5.2Felineonly.....................................................................................................................33

2.3Results.................................................................................................................................332.3.1Studypopulation.................................................................................................................332.3.2CGMversusserialbloodglucose.........................................................................................332.3.3CGMversusfructosamine...................................................................................................342.3.4Serialbloodglucoseversusfructosamine...........................................................................342.3.5Interobserveragreement....................................................................................................342.3.6Speciesvariation..................................................................................................................342.3.7NocturnalhypoglycaemiaandSomogyi..............................................................................35

2.4Discussionofresults............................................................................................................352.4.1CGMversusserialbloodglucose.........................................................................................352.4.2CGMversusfructosamine...................................................................................................362.4.3Serialbloodglucoseversusfructosamine...........................................................................362.4.5Speciesvariation..................................................................................................................37

2.5Conclusion...........................................................................................................................38

SUMMARY.......................................................................................................................39

REFERENCES.....................................................................................................................41

APPENDIX.........................................................................................................................50

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LISTOFTABLES

Table1.CGMSversusserialbloodglucosecurvestatisticalcomparison–Clinician1

Table2.CGMSversusserialbloodglucosecurvestatisticalcomparison–Clinician2

Table3.CGMSversusFructosaminestatisticalcomparison–Clinician1

Table4.CGMSversusFructosaminestatisticalcomparison–Clinician2

Table5.SerialbloodglucoseversusFructosaminestatisticalcomparison–Clinician1

Table6.SerialbloodglucoseversusFructosaminestatisticalcomparison–Clinician2

Table7.Signalmentofcases

Table8.Treatmentrecommendationtable

Table9.Treatmentrecommendations:CGMversusSerialbloodglucosecurve

Table10.Serumfructosamineresults

Table11.Treatmentrecommendations:CGMversusFructosamine

Table12.Treatmentrecommendations:Serialbloodglucosecurveversusserumfructosamine

Table13.Inter-observeragreementstatisticalcomparison–CGM

Table14.Inter-observeragreementstatisticalcomparison–SerialBloodGlucoseCurve

Table15.Inter-observeragreementstatisticalcomparison–SerumFructosamine

Table16.CGMversusSerialbloodglucosecurvestatisticalcomparison–Clinician1,Canineonly

Table17.CGMversusSerialbloodglucosecurvestatisticalcomparison–Clinician2,Canineonly

Table18.CGMversusFructosaminestatisticalcomparison–Clinician1,Canineonly

Table19.CGMversusFructosaminestatisticalcomparison–Clinician2,Canineonly

Table20.CGMversusSerialbloodglucosecurvestatisticalcomparison–Clinician1,Felineonly

Table21.CGMversusSerialbloodglucosecurvestatisticalcomparison–Clinician2,Felineonly

Table22.CGMversusFructosaminestatisticalcomparison–Clinician1,Felineonly

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Table23.CGMversusFructosaminestatisticalcomparison–Clinician2,Felineonly

Table24.Interobserveragreement

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LISTOFFIGURES

Figure1-5DemonstrationofattachmentofCGMdevicetoadog

Figure6-46.CGMtracesfromanimalsinstudy

Figure47-87.Serialbloodglucosecurves

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CHAPTERONE:BACKGROUNDANDREVIEWOFTHELITERATURE

1.1ThePancreas

Thepancreasisaglandcontainingexocrineandendocrineelements,whichservetoregulatedigestion

andmetabolism,respectively.1Throughoutthepancreaticparenchymathereareisolatedclustersof

cellsformingtheisletsofLangerhans.2Theisletscontainendocrinecellsthatsynthesiseandsecrete

hormones including glucagon (alpha cells), insulin (beta cells), somatostatin (delta cells), and

pancreaticpolypeptide(pancreaticpolypeptidecells).

Thebloodsupplytothepancreasoriginatesfromthecoeliacandcranialmesentericarteries.5,6The

nervoussupplyoriginatesfromthevagusandsplanchnicnerves,whichtravelalongsidethecoeliac

and caudal mesenteric arteries.5,6 The neurogenic supply, which forms a large web of nerves

throughouttheparenchyma,isintrinsicallyinvolvedintheendocrinefunctionofthepancreas.

After ingestionofameal,chemicals includingglucose,aminoacidsandcertaindigestivehormones

(such as secretin, gastrin and the incretin hormones glucagon like peptide-1 and gastric inhibitory

peptide),stimulatethebeta(β)cellsofthepancreastoreleaseinsulin.2 Insulinthenpromotesthe

storageofglucoseandtheuptakeofaminoacids,increasesproteinandlipidsynthesis,andinhibits

lipolysisandgluconeogenesis. Neighbouringalpha (α) cells secreteglucagon into theblood in the

oppositemanner; there is increasedsecretionwhenbloodglucose is low,anddecreasedsecretion

whenbloodglucose is high. Glucagon therefore is the counter regulatoryhormone for lowblood

glucose, acting exclusively on the liver to activate glycogenolysis and gluconeogenesis almost

instantaneously.Thesecretionofinsulinandglucagonintothebloodinresponsetothebloodglucose

concentrationistheprimarymechanismforkeepingglucoseconcentrationsintheextracellularfluids

withinnarrowphysiologicallimits.Dysfunctionoftheβ-cellsresultinginreducedproductionofinsulin

contributestothedevelopmentofthemostcommondisorderoftheendocrinepancreas,diabetes

mellitus.

1.2Diabetesmellitus

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Diabetes mellitus is the result of relative or absolute insulin deficiency leading to persistent

hyperglycaemia.5 Insulin is exclusively produced by theβ cells of the islets of Langerhans in the

pancreas,andinsulindeficiencyoccurswithinsufficientfunctionordestructionoftheβcells.Relative

insulin deficiency refers to insulin resistance, where the effectiveness of a given concentration of

insulintodecreasebloodglucoseisreduced,necessitatingthesecretionofmoreinsulintomaintain

glucoseconcentrations.5,6

Inhumandiabetes,thepathogenesisoftheβcellfailureisusedtoclassifydiabetesastype1,type2,

gestationaldiabetes,andotherspecifictypesofdiabetes.5Type1diabetesiscausedbyautoimmune

damagetopancreaticβcellsandappearstobethemostcommonformofdiabetesindogs.5,6Type2

diabetesischaracterisedbyinsulinresistancewithconcurrentβcellfailure,whichisthemostcommon

form of diabetes in cats.5,6 Other types of diabetes in people include diseases that damage the

pancreas (such as pancreatitis, pancreatic carcinoma, and pancreatectomy), toxic causes ofβ cell

damage (including the antineoplastic drug streptozotocin), genetic causes of diabetes, gestational

diabetes and diabetes associated with other endocrine diseases (such as hyperadrenocorticism,

acromegaly,andglucogonoma).5 Thedogandcatalsodevelopdiabetessecondarytoanumberof

theseconditions,thoughtodifferentdegrees.

Clinicalsignsofdiabetesmellitusincludepolydipsia,polyuriaandweightlossdespitepolyphagia.2If

clinical signs of uncomplicated diabetes are not observed by the owner or the onset of disease is

associatedwithotherseveredisease,thediabeticdogorcatmaydevelopsystemicsignsofillness(i.e.,

lethargy, anorexia, vomiting, and weakness) as progressive ketonaemia and metabolic acidosis

develop.Thisseverestateistermeddiabetesketoacidosis(DKA).Complicationsofdiabetesasseenin

people are rare in dogs and cats, with the exception of the development of diabetes-associated

cataracts.Diabeticcataracts,rarelyseenincats,developinapproximately50%ofdogswithdiabetes

mellituswithin5to6monthsofdiagnosisand in75%within12monthsofdiagnosis.7Thisspecies

differenceisrelatedtothepathogenesisofdiabeticcataractformation.8Aldosereductase,anenzyme

thatreducesglucoseandgalactosetotheirrespectivesugaralcoholssorbitolandgalactitol,isfound

in much higher concentrations in the lenses of dogs compared with age-matched cats. The

accumulationofsugaralcoholsinlenscellscanleadtoanintracellularincreaseinfluidsthatresultsin

lenscellswelling.Thisswellingisassociatedwithincreasedmembranepermeabilityandaseriesof

complexbiochemicalchangesthatareassociatedwithcataractformation.

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1.3.Diabetesmellitusincats

1.3.1Pathogenesis

Diabetesmellitusisacommonhormonalconditionofcats,withreportedincidencebetween1in50

to1in400,dependingonthepopulationstudied.6Diabetesmellitusinthecatcloselyresemblestype

2diabetesmellitusinpeople,causing80–95%ofdiabetesmellitusincats.5,6,12Theremaining15–

20%ofspecifictypesofdiabetesincatsarecausedbyavarietyofdiseasesthateitherdecreaseβ-cell

mass or cause peripheral insulin resistance.6 Pancreatic adenocarcinoma and pancreatitis causing

fibrosisaretwosuchdiseasesthatcanproducediabetesbydecreasingβ-cellnumbers.9Acromegaly,

adisordercausedbyexcessivesecretionofgrowthhormonebyafunctionaladenomaofthepituitary

gland,producesmarkedperipheralinsulinresistance.10Moremoderateinsulinresistanceresultsfrom

hyperadrenocorticismandhyperthyroidism.6

The most common form of diabetes mellitus in cats is similar to human type 2 diabetes, a

heterogeneousdiseaseattributabletoacombinationofimpairedinsulinactioninliver,muscle,and

adipose tissue (insulin resistance), andβ cell failure.11Development of of these defects involves a

complexaetiologycausedbyacombinationofgeneticfactors,environmentalinteractions(including

obesity)andanincreasedriskwithaging.5Inpeople,type2diabetesusuallydevelopsinmiddleage,

whilediabetesmellitustypicallydevelops incatsgreaterthan6yearsofagewithapeak incidence

between9and13yearsofage.Susceptibilitytotype2diabetesinpeopleisinherited,andpreliminary

datasupportageneticinfluenceincats.6Itislikelythatdiabetesinthecatisapolygenicdiseaseand

thatmanygeneswillbeassociatedwithanincreasedriskforthedisease.11Whilethegeneticfactors

predisposingcatstodiabetesareunknown,themostconvincingevidenceofageneticbasiscomes

fromstudies in theBurmesecat. Inbreeding lines fromAustralia,NewZealand13,14and theUnited

Kingdom15thefrequencyofdiabetesinBurmesecatsisapproximatelyfourtimesthefrequencyof

diabetesindomesticcatsinAustralia(1in50Burmesecomparedwith<1in200domesticcats).15In

arecentstudyonobesityinBurmesecats,leanBurmeseshowedgeneexpressionpatternssimilarto

those of age-matched and gender-matched obese domestic cats for the majority of the genes

examined.16Thepossibilityofaninheritedsusceptibilitytolipiddysregulationasapossiblecauseof

increasedincidenceofdiabetesinthisbreedwarrantsfurtherinvestigation.

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Obesityistheleadingacquiredcauseofinsulinresistanceisbothcatsandpeople.5,17It has been shown

that obese cats are 3.9 times more likely to develop diabetes mellitus compared with cats with an optimal

body weight.18 Obesitycausesinsulinresistancethroughavarietyofmechanisms,includingchangesin

adipose-secreted hormones (adipokines), and through systemic inflammatory mediators.19,20

Adipokinesthatarepotentially involvedinthepathogenesisofdiabetes incats includeadiponectin

and leptin.21,22 Adiponectin secretion is decreased with obesity. Decreased adiponectin has been

showntobeassociatedwithdiminishedinsulinsensitivity,however,causationhasnotbeproven.21

Leptin concentrations are increased in obese cats,23,24 and are independently associated with

decreasedinsulinsensitivity.22Othermediatorssecretedinincreasingconcentrationswithobesityin

bothpeopleandcatsincludeinflammatorycytokines,suchasinterleukin-6(IL-6)andtumournecrosis

factor-α (TNF-α).20,25,26 In combination, these hormones andmediators decrease the intracellular

effects of insulin by increasing phosphorylation of insulin receptor substrate, whichmediates the

effectsofinsulinafteritbindstoinsulinreceptors.

Other risk factors for the development of diabetes in cats include gender (males higher risk than

females),physicalinactivity,indoorconfinement,increasingage,theadministrationofglucocorticoids

andprogestinsandahighcarbohydratediet.27,28,29,30,31AstudybyFarrowetal.showedthatcatsfed

high-carbohydratedietshadsignificantlyhighermeanandpeakglucoseconcentrations,andtended

tohavehigherinsulinconcentrationsthancatsfedeitherhigh-proteinorhigh-fatdiets.Inaddition,

diabetic cats fed a very low-carbohydrate, high-protein diet have been shown to have reduced

hyperglycaemia, reduced requirement for exogenous insulin and increased rate of diabetic

remission.32

Inhealthypeople,insulinsecretionisincreasedinresponsetodecreasedinsulinsensitivity.33However

people34andcats6withtype2diabeteshaveadegreeofpre-existingβcellinsufficiency.Thus,insulin

resistanceitselfdoesnotcausediabetesmellitus,butrathercontributestodiseasedevelopmentin

individualswithearlystagesofβcellfailurebyincreasingthedemandforinsulin.6Previously,βcell

exhaustionsecondarytochronichyperfunctionhasbeenproposedasapossiblecauseofβcellfailure

ininsulinresistantanimals,however,manyindividualcatswithinsulinresistancedonotprogressto

diabetes. Inaddition,type2diabetesisnotreportedinotherspeciessuchasdogs,despitesimilar

conditionscausinginsulinresistance.35

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One hypothesis on the cause ofβ cell failure in cats is the damage to pancreatic islets caused by

amyloid deposition.36 Islet amyloid polypeptide (amylin) is an endocrine peptide hormone that

aggregatelymisfoldstoformamyloiddeposits inandaroundthepancreatic isletβ-cells.37,38Amylin

and insulinare co-secretedby thepancreas, and thereforean increase in secretionof insulinwith

insulinresistanceleadstoanincreaseinsecretionofamylin.Amyloidsinduceβ-celldeaththroughthe

formation of reactive oxygen species, mitochondrial dysfunction, chromatin condensation, and

apoptoticmechanisms, though the preciseway bywhich amyloidogenesis contributes to diabetes

remainstobeestablished.

Isletamyloidhasalsobeendocumentedinnon-diabeticcats.39Thefactthatisletamyloidcanbefound

insomecatswithoutdiabetesandthatthedepositionswerenotpronouncedinalldiabeticpancreata,

ledsomeresearcherstoconcludethatisletamyloidisofnomajorimportance.40However,thelocation

ofamyloid,intra-versusextracellular,aswellasdiabeticrelatedconditionsthatcouldinitiateamyloid

inducedmembranedamagehavebeenproposedasexplanationsforthesefindings.40,41Forexample,

analteredratioofinsulintoamylin,asobservedindiabeticpatients,couldleadtoadecreaseofthe

inhibitoryeffectofinsulinonamyloidfibrilformation.Ontheotherhand,achanginglipidcomposition

oftheβ-cells,couldalsotriggeranincreaseinamyloid-membraneinteractions.Invitrostudiesshow

thatnegativelychargedlipidsincreasetherateofamyloidfibrilformationandalsoenhanceamyloid-

inducedmembranedamage.

Chronic hyperglycaemia (glucose toxicity) and hyperlipidaemia contribute to changes in the

microenvironmentoftheendoplasmicreticulumoftheβcells,whichalsocanleadtoβcelldeath.42

Proteins are assembled, modified and folded in the endoplasmic reticulum and if the number of

proteinsthathavefoldedorassembledproperlyrisestoohigh,theunfoldedproteinresponsetriggers

βcelldeath. Damagetoβcellsbyreactiveoxygenspecies isanothermechanismforβcell failure,

wherebyreactiveoxygenspeciesaregeneratedwhenthereisexcessfuel(suchasglucose)inthecell.43

Pancreatitiscanalsoleadtodiabetesthroughdestructionofβcells.44Postmortemexaminationof

diabeticcatsfoundlesionsconsistentwithpancreatitisinapproximatelyhalfofdiabeticanimals,with

chronicpancreatitispresentinthemajority(46%)andacutepancreatitisin5%.45Theprevalenceof

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chronicpancreatitisinthisdiabeticpopulation,however,issimilartoreportedprevalenceinhealthy

catsatpostmortem(45%).46Whilethisraisesquestionsoverthesignificanceofpancreatitisinthe

pathogenesis of diabetes in cats, pancreatitis may certainly contribute to the development of

pancreatitisinsomeindividuals.5,44

Currenttreatmentrecommendationsarethecombineduseoflong-actinginsulin,lowcarbohydrate

dietandregularmonitoringofglycaemiccontrol.47Theprimarygoaloftreatingdiabetesmellitusin

catsittoeliminatetheclinicalsignsofdiabeteswhilepreventingcomplications,suchashypoglycaemia

anddiabetic ketoacidosis, therebyenablinga goodqualityof life.2A secondarygoal is theaim for

diabetic remission throughgoodglycaemiccontrol in recentlydiagnoseddiabeticcats,allowing for

fasterresolutionofβcelldysfunctionandthroughaddressinganyothercausesofinsulinresistance.42

1.3.2DiabeticRemission

Duetotherebeingpotentiallysomeresidualβcell function innewlydiagnoseddiabeticcats,early

glycaemiccontrolmaypotentiallyallowfordiabeticremission.48Thehighestremissionrates(>80%)

havebeenachievedwiththeuseoflongactinginsulincombinedwithalowcarbohydratediet(less

than or equal to approximately 6% of metabolisable energy from carbohydrates) and intensive

monitoringprotocolsasmentionedabove.47,49,50Diabeticremissionoccurstypicallyafter1-3months

afterinitiatinginsulintherapywhenanintensiveprotocolisfollowed.51Glargineisalong-actinginsulin

thatiswellsuitedtoachievingeuglycaemiabecauseitsdurationofactionismorethan12hours;this

preventsmarkedhyperglycaemiafromoccurringaroundthetimeofthenextinjection.47Aprospective

studywhereallcatswerefedthesamelowcarbohydrate,highproteindiet,lookedatthedifference

inremissionratesbetween3differenttypesofinsulin(8catspergroup).49Onehundredpercentof

thecatstreatedwithglargineachievedremission,comparedwith25%ofcatsreceivingLenteand38%

ofcatsreceivingprotaminezincinsulin(PZI).Thiscorrespondedtoasignificanteffectofinsulintype

(P=0.014)onprobabilityof remission. Aretrospectivestudy involving90cats treatedwitheither

glargineorPZIincombinationwithalowcarbohydratedietshowedremissionratesof72%forglargine

and56%forPZI.39Whetherthisdifferencewassignificantwasnotinvestigated.

Astudyinvolvinganintensiveglargineinsulindosingprotocolutilisinghomebloodglucosemonitoring

andalowcarbohydratedietdemonstratedfastertimetoremissioniftreatmentwasinstitutedearly.47

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Theprotocolinvolvedownersperforminganaverageof5±2bloodglucosemeasurementsperday

withstrictguidelinesforadjustmentoninsulindosagebasedonbloodglucoseresults.Theeventual

aimwastomaintainmostbloodglucoseconcentrationsbetween2.8and5.5mmol/L(usinghuman

blood glucosemeters). In this study, cats started with the intensive programwithin 6months of

diagnosisofdiabeteshadaremissionrateof84%(n=46),comparedwitharemissionrateof35%for

catsstartedontheprogramlongerthan6monthspostdiagnosis(n=19).Thiswashighlysignificant(P

< 0.001). These findings aremirrored in a study involving intensive control of blood glucose using

anotherlongactinginsulin,detemir,inassociationwithhomemonitroing.50Eighty-onepercentof

catsstartingthisprogramwithin6monthsofdiagnosis(n=9)achievedremission,comparedwith42%

ofcatsstartingafter6months(n=3).

Diabeticremission,however,doesnotoccurorisnotpermanentinallcats.48,50Bydefinition,βcell

functionisabnormalincatsthathavedevelopeddiabetes,andtherefore,evenifremissionisachieved,

these cats have permanent reduced β cell functional capacity.51 These cats can therefore be

consideredas‘pre-diabetic’,withahigherriskofdevelopingdiabetesthanthegeneralpopulation.In

one study, 29%of cats (n=13) that achieveddiabetic remission relapsed, requiring reinstitution of

insulintherapy;noneofthesecatsachievedremissionforasecondtime.23However,inanotherstudy,

where26%of(n=9)catsthatachievedremissionrelapsed,22%(2outof9cats),wereabletoachieve

remissionforasecondtime.47

1.4.Diabetesmellitusindogs

Diabetesmellitusisoneofthemostfrequentendocrinediseasesaffectingmiddleagedtoolderdogs,

withaprevalenceof58per10,000dogsreported.6Incontrasttocats,diabetesindogsisanalogous

totype1diabetesinpeople;andischaracterisedbypancreaticβcelldestructionleadingtoabsolute

insulindeficiency.53Type1diabetesinpeopleoccursprimarilyinadolescenceandearlyadulthood,

howevermostdogswithdiabetesmellitusaremiddleagedorolderatthetimeofdiagnosis(usually

greaterthan7years).14Ithasrecentlybeenproposedthatcaninediabetesmoretypicallyresembles

humanadultonsetautoimmune type1diabetes,or latentautoimmunediabetesofadults (LADA),

ratherthanthejuvenile-onsetform.54

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Latentautoimmunediabetesofadults(LADA)developswhencellmediatedautoimmuneprocesses

cause β cell destruction in association with multiple genetic predispositions and poorly defined

environmentalfactors.55Theunderlyingcauseofpancreaticβcellfailureindogsremainstobefully

established,thoughtheaetiologyisthoughttobemultifactorial.Geneticpredispositions,alongwith

exocrinepancreatic disease and/or immunemediatedmechanisms, environmental factors, insulin-

antagonisticdiseasesanddrugsareallthoughttobeinvolved.54

Geneticpredispositionsincaninediabeteshavebeensuggestedduetofamilialassociations,pedigree

analysisofKeeshonds, andgenomic studies aimedat identificationof susceptibility andprotective

major histocompatibility complex haplotypes.56,57,58 The major genetic susceptibility in humans is

linkedtomajorhistocompatibilitycomplex(MHC)allelesonchromosome6p.59Preliminarysequence

analysis of the dogMHC alleles in a heterogenous population of diabetic dogs identified that one

haplotype is overrepresented; this haplotype has sequence similarities to human major

histocompatibilitycomplexallelesassociatedwithsusceptibilitytotype1diabetes.57

Inflammatorycellinfiltrationofpancreaticisletsoccursin46%ofdiabeticdogs60andapproximately

50% of diabetic dogs have circulating antibodies against β cells.61,62 Immune- mediated insulitis

characterisedbyinfiltrationoflymphocytesintoisletcellshasbeendescribedandantibodiesdirected

against islet cells, insulin, proinsulin, intracellular glutamic acid decarboxylase 65 (GAD65), and

insulinomaantigen2(IA2)havebeenidentifiedindiabeticdogs.61,63,64,65

Multiple environmental factors likely initiateβ cell autoimmunity in genetically susceptible dogs.6

Seasonalityisaproposedenvironmentalinfluence,withtype1diabetesdiagnosedmorefrequentlyin

people during American autumn and winter and diabetes in dogs diagnosed more frequently in

winter.66Whileobesity isanimportantenvironmentalfactorintype2diabetesinpeopleandcats,

obesityhasnotbeenshowntobeariskfactorforcaninediabetes.12However,despitetheabsenceof

progressiontoovertdiabetesmellitus,insulinresistanceandimpairedglycaemiccontroldoesoccurin

obese dogs, and may add to progression in the presence of other predisposing factors, such as

dioestrusandpancreatitis.12,54

17

Extensivepancreaticdamagefromchronicpancreatitisisresponsibleforthedevelopmentofdiabetes

inupto28%ofdiabeticdogs.60Thegutimmunesystemlikelyplaysacentralroleinthepathogenesis

of type 1 diabetes, because accumulating evidence suggests that affected people have aberrant

regulationofgut immunity.67,68 Thegutandpancreasare immunologicallyandanatomically linked

andinfluencedbythesameenvironmentalfactorssuchasintestinalmicroflora,infectionsanddietary

factors.67Whilealterationsinthegutmicrobiota(dysbiosis)havebeendemonstratedinpeoplewith

diabetes,nocausalityhasyetbeendemonstrated.69Inaddition,astudyonthefaecalmicrobiotaof

catswithdiabetesmellitusshowednodifferencebetweenthefaecalmicrobiotaofdiabeticandnon-

diabeticcats.70However,largerstudiesarerequiredindogsandcatsbeforeanycausalityorlinkcan

beclearlydisproven.

Anothercauseofdiabetes inbothpeopleanddogs isgestationaldiabetes.5 Inwomen,gestational

diabetesisdefinedasanydegreeofglucoseintolerancethathasitsonsetorfirstrecognitionduring

pregnancy.71Indogs,reducedinsulinsensitivityoccursinhealthybitchesbyday30–35ofgestation

and becomes more severe during late pregnancy.72 This is due to increased concentration

progesterone during this phase of pregnancy stimulating themammary gland to produce growth

hormone,apotentinducerofinsulinresistance.73Aswithhumangestationaldiabetes,diabetescan

eitherpersist,or resolveafterpregnancy indogs. Ina studyof13dogswithgestationaldiabetes,

diabetesresolvedin7outof13dogswithin21daysfollowingpregnancy.74Whilethemajorityofdogs

inthisstudyhadreversiblediabetessuggestingtransitoryinsulinresistanceastheunderlyingcause,5

dogs did have permanent diabetes. Thismay be secondary to irreversible damage to the β cells

throughglucotoxicity,orthattheseindividualdogshadanothercauseofdiabetessuchasautoimmune

diabetesorpancreatitisthatmayhavecoincidedwithpregnancy.

Otherformsofinsulinresistanceindogsincludechronicglucocorticoidtherapy,hyperadrenocorticsm,

acromegalyandobesity.73,75,76,77Aswithgestationaldiabetes,mostdogsdonotdevelopovertdiabetes

in the presence of insulin resistance, and therefore development of diabetes may also require

underlyingreducedβcellfunctionfromotherprocesses.

Theprimaryaimsof therapy fordiabeticdogsare resolutionof clinical signs, avoidanceof insulin-

induced hypoglycaemia and resumption of usual lifestyle activity.78 These are achieved through a

combinationof insulintherapy,dietarymanagementandregularmonitoring. Dietarymanagement

18

involves feeding a palatable diet with sufficient calories to achieve and maintain optimal body

condition.78 Thecurrent recommendeddiet fordogswithdiabetes is a lowcarbodyrdratediet.79,80

Either lente,NPH,orpremixedcombinationsofregularandNPHinsulinadministeredtwicedaily is

favouredforlongtermmanagementofdiabetes.LongeractinginsulinssuchasglargineandPZItend

tobelesspredictablebecausetheirpeakactionismorevariableindogsthanincats.78Aconservative

approachto insulindosing isusedtoreducetheriskofhypoglycaemia,apotential life threatening

complication, rather than aim for very tight glycaemic control. This approach is feasible with the

morbidity and mortality associated with late complications of diabetes (including retinopathy,

nephropathyandneuropathy)inpeoplebeinguncommonindogs.81Themainexplanationforthisis

the timeelapsedbefore clinicalmanifestationsof these syndromes in people,whichusually occur

manyyearsaftertheonsetofdiabetes.Smallanimals,especiallythedog,havearelativelyshortlife

span (2-5 years) after the diagnosis of diabetes, putting them at a lower risk for developing late

complicationsofdiabetes.Anexception to this isdiabetic cataracts,which isa common long-term

complicationofdiabetesindogs.Cataractsdevelopwithin5-6monthsofdiagnosisinmostdiabetic

dogs,and,by16months,approximately80%ofdogshavesignificantcataractformation.82,83

1.5Diabeticmonitoring

Traditionally, diabetic dogs and cats have been monitored via history taking, clinical examination

findings,urineglucosemonitoringathome,serialbloodglucosecurves inhospitalorathomeand

serum fructosamine concentration.84 Successful management of diabetes is characterised by

maintenance of a stable body weight, mitigation of clinical signs such as polydipsia, polyuria and

polyphagia,aswellastheavoidanceofketosisorhypoglycaemia.85Achievingeuglycaemiaisnotthe

primarygoalofinsulintherapyindogsorcatsduetotheriskoflife-threateninghypoglycaemiaand

theabsenceof the longtermcomplicationsofhyperglycaemiaseen inpeoplesuchas retinopathy,

vasculardisease,andrenalinjury.85

Frequencyofdiabeticmonitoringisvariableanddependentontheclinicalstatusoftheanimal,the

goal of therapy and client expectations.85 Newly diagnosed animals are usually monitored more

frequently,oftenevery7-14days,whiledeterminingtheoptimalinsulintypeanddose.Itisgenerally

recommendedthatsomeformofclinicalevaluationtakeplaceevery4-12weeksforwellcontrolled

diabetic dogs and cats, particularly in the first year of diagnosis. Owners should be educated on

19

parameterstomonitorathome,includingthirst,appetite,weight,activitylevels,changesinbehaviour;

andareadvisedtocontacttheveterinarianwithanyconcerns.Decisionsaboutmonitoringareoften

influencedbytheowner’sfinancialsituation,levelofmotivation,andoverallexpectationswithregard

totheirpets.85Recentstudiesevaluatingthequalityoflifeofdiabeticdogsandcatsasperceivedby

theirowners identified thatowner’s rankedworryabout theirpet’sdiabetesandworryabout the

incidenceofhypoglycaemiainthetop5outof29issuesaddressed.86,87

Duetoinnatedeficienciesinthedirectmonitoringofglycaemiccontrol(discussedfurtherinfollowing

sections)viabloodglucosecurvesandserumfructosaminelevels,ownerimpressionregardingquality

of lifeandseverityofclinicalsigns,alongwithanimalbodyweightarekeypartsoftheassessment

process.85

1.5.1BloodGlucoseCurve

Standardbloodglucosecurvesmeasureserumglucoseconcentrationsevery1-2hoursovera12-24-

hour period.88 The most common curve performed in practice is over an 8-12-hour period, with

measurements performedevery 2 hours. The length of the intervals in samplingmeans there is a

windowwherethelowestglucoseconcentration(nadir)canbemissed,creatingthepotentialtolead

to flawed and possibly harmful treatment recommendations. Cats subjected to repeated blood

samplinginaforeignenvironment,suchasaveterinaryhospital,canhavestresshyperglycaemia(an

elevatedbloodglucoseconcentrationduetothestressofhandlingandsampling)thatcandramatically

interfere with interpretation of blood glucose curves.84 Blood glucose concentrations of 16 – 22

mmol/Lhavebeenreportedinhealthycatsstressedbyvisitstoveterinaryhospitals.89Astudylooking

asstresshyperglycaemiain20healthyadultcatsshowedpeakbloodglucoseconcentrationsranging

from5.2-15.8mmol/L.90Glucoseconcentrationsnormalisedwithin90minutesinmorethanhalfthe

catsinthestudy.

Measurement of blood glucose at home by owners using portable blood glucose monitors is

sometimestechnicallychallengingandrequiresahighlevelofinstructionandveterinarysupport.47,91

Theaccuracyofportablebloodglucosemonitors(PBGM),usedbothinthehomeandclinicalsetting,

canvarybetweenmonitors.Studieshavebeenperformedinbothdogsandcatsassessingtheaccuracy

of 5 PBGM including the Glucometer Elite™ (Elite), Glucometer DEX™ (DEX), SureStep™, Precision

20

QID™,andAccu-ChekSimplicity™.92,93BothstudiesshowedthatthelargestdifferencesbetweenPBGM

readingandreferencevalueswereinthehighglycaemicrange,withdifferencesbeingsmallerinthe

lowand reference glycaemic range. In cats, theAccu-Chek™andElite™appeared tobe themost

accurate.However,bothstudiesconcludedthatallPBGMwereacceptableforclinicaluseindogsand

cats.

In humanmedicine, numerous factors can influence the accuracy ofmeasurements obtainedwith

PBGM.Thetwoaforementionedstudieslookedattheeffectofanticoagulants,bloodsamplesizeand

haematocritonglucosereadingsinanexvivomodel.Inboththedogandcat,useofsmallerblood

dropsthanrequiredcouldleadtoerroneousresults,resultswerenotaffectedbyanticoagulants,and

bloodglucoseconcentrationstendedtobeover-estimatedinanaemicanimals.

Markeddaytodayvariabilityinglucosecurveshasbeendocumentedwithbothdogsandcats,thereby

makingdecisionsbasedonan isolated12hourwindowpotentially inaccurate, leading to incorrect

adjustmentsininsulindosage.94Astudylookingat30pairedglucosecurvesperformedover12hours

on2consecutivedaysfrom10diabeticdogsdemonstratedalargeday-to-dayvariationinserialblood

glucosecurves.95Measuredparameters(includingbloodglucoseconcentrationsbeforemorningand

evening insulin injection,maximum andminimum blood glucose concentrations and time to peak

effect,differencebetweenmorningbloodglucoseandnadir,areaunderthebloodglucosecurve,mean

bloodglucoseover12-hourperiod,standarddeviationofthebloodglucosemeasurements,andtheJ

index,whicharithmeticallycombinesthemeanandSDintoasinglevalue)weresignificantinindicating

day to day variability. In addition, evaluation of the paired curves led to an opposite treatment

recommendationon27%ofoccasions.

Asimilarstudywasperformedin7diabeticcats.96Eachcathadthree12-hourbloodglucosecurves

performed,2athomeon2consecutivedays,andathirdwasperformedintheclinicaminimumof4

weeksafterhomeglucosemonitoring.Differencesbetweenhomecurvevariableswerenotsmaller

thanthosebetweenhomeandcliniccurves,indicatinglargedaytodayvariabilityinbothhomeand

cliniccurves.Evaluationofhomeandcliniccurvesledtothesametreatmentrecommendationon14

of28occasions

1.5.2SerumFructosamine

21

Fructosamines are glycosylated serum proteins, formed by a non-enzymatic reaction known as

glycosylation.25Glycosylation, the linkageofalbuminandotherplasmaproteins toa sugar (usually

glucose),isanirreversibleprocess.84,97Therefore,serumfructosamineconcentrationsareproportional

tothebloodglucoseconcentrationoverthelifespanoftheglycatedproteinbeingmeasured.Thelife

spanofalbuminincatsisunknown,butisassumedtobesimilartothatindogs,i.e.1-2weeks.84The

measurementofserumfructosamineisconsequentlyanevaluationoflongtermglycaemiccontroland

is not thought to be affected by acute changes in glucose concentrations, such as stress induced

hyperglycaemia.84,97,98

Studiesintheusefulnessoffructosamineasameasureofdiagnosisandcontrolindiabetesmellitusin

dogsandcatsinitiallyshowedpromisingresults.Inastudylookingathealthydogs(n=48)andcats(n

= 32) in comparison to dogs (n = 32) and cats (n = 9)with diabetesmellitus and catswith stress

hyperglycaemia (n = 8), newly diagnosed diabetic dogs and cats that had not undergone previous

insulin therapyhadsignificantlyhigher fructosamineconcentrations thannon-diabeticanimals (p<

0.05).99The8catswithtransientstresshyperglycaemiawereabletobedifferentiatedfromhealthy

cats and cats with diabetes mellitus. Transient hyperglycaemia was confirmed with these cats

requiring tohavehadaminimumof3check-upsconductedafter theunderlyingdiseasehadbeen

curedtorevealbloodglucoseconcentrationswithinthereferenceinterval.

Anotherstudyshowedserumfructosamineconcentrationswerenotaltered in17clinicallyhealthy

catssubjectedtotransientstresshyperglycaemiaviatheadministrationofglucoseintravenously.100A

furtherstudyincatscomparedhealthycatswithcatsdisplayingstresshyperglycaemiaresultingfrom

non-diabeticdisease,catswithuntreateddiabetesmellitusandcatswithtreateddiabetesmellitus.98

Allofthehealthycats(26/26)and86%ofthecats(12/14)withstresshyperglycaemiahadfructosamine

concentrationswithinthereferenceinterval(175to400µmol/L).Thisisincomparisonto93%ofthe

untreateddiabetics(28/30)havingfructosamineconcentrationsabovethereferenceinterval.The30

cats treated for diabetes that were considered to have had a good response to therapy had a

significantlylowerserumfructosamineconcentrationscomparedtothoseconsideredtohavefairor

poorresponsetotreatment.98

Limitations of serum fructosamine as a diagnostic andmonitoring aid in diabetesmellitus include

conditionsthatwillalterserumfructosaminevalues.Astudyevaluatingfructosamineindogsandcats

withhypo-orhyperproteinaemia,azotaemia,hyperlipidaemiaandhyperbilirubinaemiafoundvarious

22

conditionscanalterfructosamineresults.101Bothdogsandcatswithhypoproteinaemiawerefoundto

havesignificantly lower fructosaminevaluesthancontrolanimals. Dogsalonewere foundtohave

significantlyreducedfructosaminevaluesinthepresenceofhyperlipidaemiaandazotaemiacompared

to the control group.101 Additionally, serum fructosamine is limited by the inability to provide

information about glucose nadirs or acute change in glucose concentration in response to insulin

administration.97Anotherfactorlimitingtheusefulnessofthistestisthedelayinobtainingresults,as

itisgenerallymeasuredinspecialistveterinarypathologylaboratories.

1.6NocturnalhypoglycaemiaandSomogyi

Nocturnalhypoglycaemiaisawell-recognisedoccurrenceinhumanmedicine.102,103Ratesofnocturnal

hypoglycaemiabetween29and65%havebeendocumentedinpeoplereceivingtwicedailyinsulin.103

Thetypeofinsulintherapyhasbeenshowntoaffecttheincidenceofnocturnalhypoglycaemia.Lente

insulin,suchasNPH,hasashortdurationofactionwithapronouncedpeakofmetabolicactivity3-7

hourspostsubcutaneousinjection.104Thispeakactivityoccursduringthenightatatimewheninsulin

requirementisatitslowest.Incontrast,glargineisalongactinginsulinwithoutapronouncedpeak,

allowingimprovednocturnalbloodglucosecontrolandreducednocturnalhypoglycaemia.104Asmost

diabeticdogsaretreatedwithlenteinsulin(Caninsulin™)andmostcatswithglargine(Lantus™),itcan

behypothesisedthatdogswouldbemoresusceptibletonocturnalhypoglycaemiathancats.

In 1959,Michael Somogyi theorised that nocturnal hypoglycaemia led to a rebound highmorning

fastingbloodglucoseduetothereleaseofcounterregulatoryhormones,includinggrowthhormone,

cortisolandcatecholamines.Thistheoryhasbeentermedthe‘Somogyieffect’withmuchdebateas

toitsvalidityandresearchbothsupportingandcontradictingitsexistence.102,105

Anexperimentlookingattheresponseofinsulin-antagonistichormonestohypoglycaemiaprovides

supportfortheSomogyieffect.106Thestudyinvolvedtwogroupsoftype1diabeticandnon-diabetic

children(n=29pergroup).Thisstudyshowedasmallincreaseofplasmagrowthhormoneandarise

ofplasmaadrenalineduringnightlyhypoglycaemiacompared toanightwithouthypoglycaemia.106

Another study showed that fasting and post breakfast plasma glucose concentrations were

significantlyhigherafternocturnalhypoglycaemiathanwhenhypoglycaemiawasprevented.107

23

AstudyusingMedtronicMiniMed™CGMS in126adult type1diabeticpeopleovera6-dayperiod

offeredamorethoroughevaluationoftheoccurrenceofnocturnalhypoglycaemia.105Most(86%)of

thepatientsweremanagedwithbasalbolustreatmentwithneutralprotamineHagedorn(NPH,also

knownasHumulin™).‘Hypoglycaemicnights’weredefinedasCGMSglucosereadingsoflessthan2.2

mmol/Llastingforatleast10minutes,with‘possible’hypoglycaemicnightsdefinedasCGMSglucose

readingsof2.3–3.5mmol/L.Thisstudyshowedthatfastingmorningbloodglucosewassignificantly

lowerafterhypoglycaemic(139nights)andpossiblyhypoglycaemicnights(96nights)whencompared

to non-hypoglycaemic nights (359 nights).105 This seemed to disprove the Somoygi phenomenon,

however,thisisonlystudytodoso.

Aretrospectivestudylookingattheincidenceofreboundhyperglycemiaincatsfoundthatdespitethe

frequentoccurrenceofbiochemicalhypoglycaemia, reboundhyperglycaemia is rare incats treated

withglargine.108Thestudyevaluated10767bloodglucosecurvesof55catstreatedwithglarginewith

amedianoffivebloodglucosemeasurementsperday.Whilebiochemicalhypoglycaemiaoccurred

frequently,bloodglucosecurvesconsistentwithreboundhyperglycaemiawithinsulinresistancewas

confinedtofoursingleeventsinfourdifferentcats.In14/55cats(25%),amedianof1.5%(range0.32–

7.7%) of blood glucose curves were consistent with rebound hyperglycaemia without an insulin

resistancecomponent.

1.7Continuousglucosemonitoring

Continuous glucose monitoring was developed to address some of the limitations of traditional

monitoring techniques in diabetes mellitus and ultimately to allow tighter glycaemic control.

Traditional serial blood glucosemeasurementsmaymiss substantial fluctuations in glucose levels,

particularlyepisodesofnocturnalhypoglycaemia. Incontrast,CGMusingtheGuardianREAL-time,

provides 288 data points over 24 hours, providing detailed insight into daily changes in glycaemic

control.Thesubcutaneoussiteasasiteforcontinuousglucosemeasurementwaschosendueitsease

ofuseandsafeaccessibility.Multiplesubsequentstudieshavevalidatedsubcutaneousinterstitialfluid

(ISF)glucoseasshowinggoodcorrelationwithbloodglucose.109,110

24

TherearemanydifferenttypesofCGMS,includingGlucoDay,FreestyleNavigator,DexComSEVENPlus,

Medtronic iPro2 and Guardian Real-Time.111 The Guardian REAL-Time CGMS (Medtronic, Dublin,

Ireland)systemconsistsofadisposablesensor,atransmitterandamonitor.Thesensorishousedin

flexible 1.5cm tubing with a membrane-covered side window that allows the active electrode to

interactwiththeISF.Thesensorisplacedinthesubcutaneoustissuebymeansofa22Gretractable

needle.GlucoseintheISFundergoesanelectrochemicalreactionontheglucoseoxidase-containing

electrode that generates a small electric current.; this will subsequently be converted to glucose

concentration(mmol/L).Thesensoriswirelesslyconnectedtoatransmitterthattransmitsdataover

amaximaldistanceof3mtoapagersizedmonitor.Dataarecollectedevery10secondsandamean

valuecomputedevery5minutes.Thesensorcanbeusedforupto72hours(seefigures1–5).88

BenefitsofCGMestablished throughhumanmedicine studies include real timealarms concerning

bloodglucoseconcentrations(toohighortoolow),datastorageforreviewtodetectglucosetrends

allowingimprovedglycaemiccontrol,reductioninnumberofcapillarymeasurements,largenumber

ofglucosemeasurementsallowingbetterevaluationoffastingandpostprandialbloodglucoselevels

forbetteradjustmentofinsulindosage;theeffectofexerciseonglucoselevels;andthedetectionof

unrecognised hypoglycaemia or periods of sustained hyperglycaemia.112 There are, however, a

number of limitations to the use of CGMS in dogs and cats. Use in the home environment is

complicatedbytheneedforrepeatedcalibrationsandproximityofthemonitortotheanimal.Useof

CGM equipment outside of the hospital setting poses a risk of damage to the equipment, with

replacementbeingcostly.However,performingCGMinthehospitalsettingcanaltertheglycaemic

controlthoughachangeinactivitylevels,appetite,andtheintroductionofstress.Technicaldifficulties

with the CGM include dislodgement of the interstitial probe, an inability to perform calibration in

animalswithserumglucosereadingsaboveallowablecalibration(22.2mmol/LforGuardianRealTime)

andlossofconnectionofthesensortothemonitoriftheanimalismovedmorethan3metersfrom

themonitor (branddependent). Inthe incidenceof lossofconnection,recalibration isrequiredto

startatthebeginning,creatinga2-hourgapindatacollection.

TheuseofCGMShasbeenevaluatedinbothdogsandcats,initiallytodetermineifthesensorlocation

affectedmeasurement. A 2010 pilot study by Affenzeller et alof 6 clinically healthy beagle dogs

evaluated both the interscapular region (IR) and thoracic region (TR) as sites for attachment of

CGMS.113Alldogsconcurrentlyhadplasmaglucoseconcentrationsmeasuredhourlyoveraperiodof

72hoursviaacentralvenouscatheter in the jugularvein. Thesevalueswerecompared tovalues

25

collectedviatheCGMS.Withrespecttotheperiodofrecording,meanabsoluteandrelativedifference,

andspecificityandsensitivityofhypoglycaemiadetection,thedatacollectedfromtheinterscapular

regionseemedtobemoreaccurate (notsignificant). However, the incidenceof fibredamagewas

higher in the IR group than the TR group.113 Another study involving 18 diabetic cats evaluated

placementofCGMSatthreelocations;thelateralchestwall,dorsalneckandkneefold.114Initialisation

wassuccessfulin15outof20lateralchestwallsensors,9outof10necksensorsand3outof10knee

foldsensors.Comparedwithareferenceportablebloodglucosemeter,0.8%ofmeasurementsfrom

lateralchestwallsensors,0.7%fromkneefoldsensorsand0%fromnecksensorswouldhaveresulted

inerroneoustreatment.Whilethenumbersinthisstudyaresmall,theresultssuggestthatdorsalneck

placementmaybesuperiortolateralchestwallandkneefoldplacementinthecat.114

Initial studies into theuseofCGMSformonitoringdiabetesmellitus incatshaveshownpromising

results. Astudyof14diabeticcatsmonitoredforupto72hourswiththeMiniMedCGMSshowed

goodcorrelationbetweenbloodglucoseandISFglucosemeasurements(r=0.862).94Inaddition,the

useoftheCGMSovera3-dayperiodhighlightedtheday-to-dayvariabilityofglycaemiccontrol.This

underscoresthepotential forclinicaldecisionsbasedonserialbloodglucosecurves involvingsmall

windows of time leading to possible detrimental changes in clinical mangement.94 Another study

including 39 cats; 32with diabetesmellitus, 2 with suspected insulinoma and 5 healthy cats also

showedgoodcorrelationbetweenbloodglucoseandISFglucose.88Thisprospectivestudycompared

pairedCGMSandbloodglucose readingsandnormal,high,and lowbloodglucoseconcentrations,

demonstratingthatresultscorrelatingsignificantly;r=0.95,P<0.0001,withaconcordanceof95.7%.

TheGCGMSwas100,96.1and91.0%accurateatnormal,high,andlowbloodglucoseconcentrations

whencomparedtopairedbloodglucosemeasurements.Astudycomparingclinicalrecommendations

based on serial blood glucose measurements (SBGM) versus CGMS (Guardian REAL-Time) in 13

diabetic cats failed to identify a significant difference in recommendations between the two

systems.110However, theoccurrenceof lownadirs recordedwith theCGMS shows that thedevice

detectedperiodsofhypoglycaemianotidentifiedduringSBGM.110

Similarly, promising results have been seen with preliminary studies into the use of CGMS for

monitoringdiabeticdogs.ASpearman’srankcorrelationcoefficientof0.81wasfoundbetweenISF

andbloodglucose inastudyof10clinicallyunstablediabeticdogs.111EachdogworetheMiniMed

CGMSforupto48hours,whileconcurrentlyundergoingserialbloodglucosemeasurementevery1-3

hours.Thisdatawasevaluatedseparatelybytwoboardcertifiedveterinaryinterniststodetermine

26

any difference in clinical decisions between the two methods. In the majority of cases, similar

recommendationsweremade,thoughnostatisticalanalysiswasperformed.Inaddition,thisresultis

biased by the lownumbers of cases and the non-uniformity of the serial blood glucose datawith

variable sampling times.111 Another study involving 10 clinically stable diabetic dogs using the

GlucoDayCGMSshowedthatthedevicewasabletoprovidedataonthedog’sbloodglucoseinthe

homeenvironment.115Hypoglycaemicepisodesrangingfrom15to2157minutesweredetectedin3

dogs,withreboundhyperglycaemiaidentifiedinone.Unfortunately,therewasnofollowupclinical

dataon thesedogsandnocomparisonwasmadebetween serialbloodglucosemonitoring in this

study.115

Continuous glucose monitoring systems are a developing technology in the field of diabetes

management.ClinicaltrialsinhumanmedicinehaveshowntheclosermonitoringprovidedbyCGMS

hasallowedchangesinmanagementthatleadtotheloweringofhaemoglobinA1c(HbA1c,glycated

haemoglobin) significantly, particularly in adults with type 1 diabetes.112 A recent meta-analysis

reviewing11randomisedcontrolledtrialsconcludedthatrealtimeCGMintype1diabetesmellitusis

associatedwithasignificantreductioninHbA1c(-0.276;95%confidenceintervals-0.465to-0.087),

primarilyinindividualsover15yearsofage.116ClinicaldataonwhetherCGMhastheabilitytochange

clinicaldecisionmakingindiabetesmellitusindogsandcatsislimited.

27

CHAPTER2:CLINICALRECOMMENDATIONSBASEDONMETHODSOF

MONITORINGDIABETESMELLITUS

2.1Introduction

CGMShavethepotentialtoofferasuperiormethodformonitoringdiabeticcatsanddogsandcould

replacemoretraditionalmethods.Thestrengthsoftheserialbloodglucosecurve:identifyingblood

glucose variability and identifying the nadir and degree of fluctuation; can also be some of its

limitations.Thebloodglucosevariabilityestablishedthroughaserialglucosecurvemaynotshowthe

extentofvariationthroughoutthedayinastandard8–10-hourcurve,inaddition,glucosevariesfrom

daytoday.Thetruenadirmaybemissedthroughtheserialbloodglucosecurve,fallingbetweenthe

interval of glucose measurements. Lastly substantial fluctuations in glucose levels, particularly

episodes of nocturnal hypoglycaemia, will be missed by traditional serial glucose curves. These

limitationscanallbeaddressedthroughtheuseofCGM.Inaddition,catsaresubjectedtolessstress

throughminimisedhandlingandlessfrequentbloodsampling.Thepotentialtousethesesystemsin

thehomeenvironmentwouldallowforanimalstomaintaintheirnormalactivitiesandfoodintakein

a stress free environment and allow the measurement of pre-insulin glucose without fear of

inappetenceinthehospitalsetting.

Similarly, the limitations of fructosamine can also bemanaged through CGM. CGM provides the

informationlackingthroughmonitoringofserumfructosamine,includingtheglucosenadirandacute

changesinglucoseconcentrationinresponsetoinsulinadministrationinbothatimeefficientmanner

andwithoutthelimitationsinherentwithserialglucosecurves.CGMalsoaddressesthemajorstrength

ofserumfructosaminemeasurementthroughreducedstressinobtainingglucosemeasurements.

Whilethepotentialforimprovedmonitoringofdiabeticcatsanddogsseemsapparent,todate,the

clinicalutilityofCGMShasnotbeenproperlydetermined.Initialstudieshavefocusedonestablishing

the correlation between blood glucose and interstitial fluid glucose in dogs and cats in order to

evaluate the utility of the device in monitoring of diabetic dogs and cats.88,94,97 Preliminary

investigationofpotentialdifferenceinclinicaldecisionmakingwithCGMhasbeenevaluatedinone

studyinvolving13diabeticcats,andasecondstudyof10diabeticdog.114,109Bothstudiescontained

low case numbers and failed to identify any difference in clinical decisionmaking. However, the

28

potentialforadisparityinclinicaldecisionmakingwasevident,withonestudyhighlightingtheday-

to-day variability of glycemic control, and another identifying episodes of hypoglycemia and

Somogyi.94,13

Nocturnal hypoglycaemia and the Somogyi effect is assumed to occur to some extent in diabetic

animals,butthetrueincidenceisnotknown.Thisislikelytobeinpartduetoserialbloodglucose

curvesandserumfructosaminebeingunlikelyorunabletodemonstratetheiroccurrence.Serialblood

glucosecurvesaretypicallyperformedinhouseandoveraperiodof8to12hoursthroughouttheday,

eliminatingthepossibilityofdetectingnocturnalhypoglycaemia.TheSomogyieffectispurportedto

be more likely to occur after nocturnal hypoglycaemia in humans, with rebound hyperglycaemia

occurring throughout the following day secondary to release of counter-regulatory hormones.

Therefore,thelikelihoodofdetectingtheSomogyieffectonadaytimeserialbloodglucosecurve,with

atotalof4to6bloodglucosemeasurements,isunlikely.Serumfructosamine,asasingledatapoint

reviewingbloodglucoselevelsoveraperiodoftwoweeks,isunabletodemonstratetheoccurrence

ofeithernocturnalhypoglycaemiaortheSomogyieffect.

The aimof this studywas primarily to determine if CGMSusing theGuardian system (Medtronic)

resulted indifferentclinicaldecisionmakingcomparedwithmonitoringserialbloodglucosecurves

andserumfructosamineconcentrationindiabeticdogsandcats.Secondaryaimsweretodetermine

theincidenceofnocturnalhypoglycaemiaandtheSomogyieffectindiabeticdogs.

2.2Materialsandmethods

2.2.1Animalsenrolledinthestudy

ClientowneddiabeticdogsandcatspresentingtotheUniversityofMelbourneVeterinaryHospitalor

AnimalDiabetesAustraliawerereviewedforrecruitmenttothestudy.Thestudywasapprovedbythe

AnimalEthicsCommitteeoftheUniversityofMelbourne(AEC#1212474).Animalswereidentifiedas

diabeticbasedonpresentingclinicalsigns,includingacombinationofpolyuria,polydipsia,polyphagia

and weight loss; and confirmed with clinical pathology findings of persistent hyperglycemia and

glucosuria.Bothnewlydiagnosedandlong-termdiabeticanimalswereconsideredforinclusioninthe

29

study,however,diabeticketoacidoticanimalsthatwerecriticallyunwellwereexcluded.Alldiabetic

animalswerebeingtreatedwithexogenousinsulin.

Ownersofdiabeticanimalsthatfulfilledthestudycriteriawereapproachedandaskediftheywould

enroltheiranimalinthestudy.Ahandoutwasprovidedtotheownersoutliningthepurposeofthe

studyandwhatwasinvolvedfortheiranimal.Uponelectingtoparticipateinthestudytheowners

wereprovidedwithanadmissionform.Theadmissionformcontainedasectionwheretheowners

coulddetailcurrentdiet,insulinandselectedhealthparameters,andrequiredasignaturetoafford

consenttoenrolinthestudy.

2.2.2Datacollection

Animalswereadmittedtohospital inthemorningafterreceivingtheirmorningmealandinsulinat

home.Atthetimeofadmissiontheownerwasaskedtocompleteanadmissionform(seeAppendix

A).Ontheformtheownerrecordedtheiranimal’scurrentweight,diet,insulintypeanddose,timeof

lastmealand insulinadministration inadditionto informationoftheanimal’sthirst,activity levels,

demeanourandanypotentialsignsofconcurrentillness.Informationonappetite,thirst,activitylevels

anddemeanourwereobtainedthrougharankingsystemof1to5,with1being‘notatall’,and5being

‘extremelyso’.Theownerprovidedtheiranimal’sinsulinandusualeveningandmorningmealtobe

fedwhileinhospital.Theanimalswerehousedinhospitalcagesduringtheirstay,andgivenfoodand

insulinasnormallygivenathome.Afterobtaininga24hourCGMtrace,theanimalsweredischarged

totheirownersthefollowingafternoon.

TheGuardianREAL-TimeCGMSwasinsertedfollowingadmissiontotheclinic,withthesensorplaced

inthesubcutaneoustissueofthedorsalneck(seeFigures1-5).Afteratwo-hourperiodofinitialisation

a2ml sampleofwholebloodwascollected. Adropofbloodwasused toprovidean initialblood

glucose measurement, with the remainder of the sample used for measurement of serum

fructosamine.Allserumglucosemeasurementswereobtainedusingaportablebloodglucosemeter

(PBGM).TheinitialbloodglucosemeasurementwasenteredintotheCGMdeviceasareferencevalue

forcalibration.TheCGMSwasthenre-calibratedwithinthefirst6hoursofinitialcalibration,witha

thirdcalibrationperformedwithinthenext12hours.Asmalldropofbloodwascollectedfromeither

theeartiporfootpadforprovisionofthesecondandthirdcalibration.Ifaperipheralbloodglucose

30

concentrationgreaterthan22mmol/Lwasobtained,validationwasnotperformed,andanotherblood

glucosemeasurementwasacquiredonehourlater.Ifcalibrationcouldnotbeperformedwithinthe

requiredtimeframe,theanimalwasdischargedtotheownerandanotherappointmentwasmadefor

continuousglucosemonitoring.

Blood samples for themeasurementof fructosaminewere centrifuged,with serum separated and

storedatminuseightydegreesCelsius. Frozenserumsamplesweresubmitted inbatchestoASAP

Laboratory inMelbourne, Victoria. A retrospective serial glucose curvewas plotted,with glucose

measurementsevery2hoursobtainedfromCGMtrace.The glucose curve measurements were

obtained from the CGM to minimise stress of handling and repeated phlebotomy. Avoidance

of repeated blood sampling is one of the benefits of CGM, and obtaining blood glucose

measurements while the CGM was in place would have negated the impact of this benefit in

the outcome of CGM results. Interstitial fluid glucose has been demonstrated to have good

correlation with blood glucose, however, an exact comparison would require glucose

measurement performed on blood.

2.2.3DataReview

Resultsofeachof the3monitoringmodalitieswerecollated into three informationpackets. Each

informationpacket contained the resultsof1of the3monitoring techniquesandacorresponding

information sheet on the animal fromwhich the datawas collected. The information sheet (see

AppendixB)containedsignalment,whentheanimalwasdiagnosed, insulin type,doseandtimeof

administration,dietfedandchangeinweightalongwithanownerquestionnaire(obtainedfromthe

admissionform)onthirst,appetite,demeanour,energylevelsandanyconcurrentclinicalsigns.

Inordertominimisebiasthefollowingmeasuresweretaken;(1)the3roundsofinformationpackets

werereviewedbytwoboardcertifiedsmallanimalinternistsnotinvolvedincasemanagementofthe

diabeticanimals;(2)eachanimalwasassignedarandomisedcasenumber,allocatedbydrawingnames

fromajar(3)newcasenumbersweredrawnfortheanimalsforeachofthe3monitoringtechniques

(4)breedwasnotspecifiedontheanimal’sinformationsheettominimisefamiliaritywithindividual

casesbetweeninformationpackets(5)evaluationofeachroundofinformationpacketswasseparated

by1week.

31

Thecliniciansweresuppliedwithaform(seeAppendixC)torecordtheirtreatmentrecommendations

basedontheinformationpacketstheywereprovidedwith.Theformrequiredtheclinicianstorecord

whether,basedontheinformationtheywereprovided,theywouldrecommendincreasing,decreasing

ormaintainingthesameinsulindose,discontinuinginsulinorswitchingtoanewtypeofinsulin.When

recommending an increase or decrease, the recommended dosewas to be recorded. When all 3

roundswerecompletedthedatawascollatedontoanexcelspreadsheetinpreparationforstatistical

analysis.

The continuous glucose curves were evaluated for evidence of nocturnal hypoglycaemia and the

Somogyi effect, defined as an episode of hypoglycaemia followed by a period of rebound

hyperglycemia. These animals were included in the calculations for incidence of the nocturnal

hypoglycaemiaandSomogyi.

2.2.4StatisticalAnalysis

Cohen’skappa(κ)wasusedtomeasurelevelofagreementbetweenevaluationofdiabeticmonitoring

methods for each clinician. Kappa was also used to assess interobserver reliability and species

variationwithintheindividualmonitoringtechniques.CohenhassuggestedthattheKapparesultcan

beinterpretedasfollows:values≤0asindicatingnoagreementand0.01-0.20asnonetoslight,0.21-

0.40asfair,0.41-0.6asmoderate,0.61-0.80assubstantial,and0.81-1.0asalmostperfectagreement.

2.2.4.1CGMversusserialbloodglucose

Thekappavaluesforbothclinicianswhencomparingcontinuousglucosemonitoringwithserialblood

glucosecurveshadafairtomoderatelevelofagreement.Clinician1hadmoderateagreement(κ=

0.57,seeTable1),andclinician2hadfairagreement(κ=0.26,seeTable2).

The was fair disagreement between the two monitoring methods for clinician 1 (κ = 0.29; 95%

confidenceinterval0.16–0.46)andmoderatedisagreementforclinician2(κ=0.51;95%confidence

interval0.35-0.67).

32

2.2.4.2CGMversusfructosamine

Both clinicians showed a fair agreement when comparing continuous glucose monitoring with

fructosamine (clinician1κ=0.26, seeTable3;clinician2κ=0.4, seeTable4). Theproportionof

disagreementbetweenthetwomonitoringmethodswasmoderateforbothclinicians(κ=0.52;95%

confidenceinterval0.34–0.69).

2.2.4.3Serialbloodglucoseversusfructosamine

Clinician 1 showed no to slight agreement when comparing serial blood glucose curves with

fructosamine (κ = 0.16, see Table 5). Clinician 2 had fair agreement (κ = 0.25, see Table 6). The

proportionofdisagreementbetweenthetwomonitoringmethodswasmoderateforbothclinicians

(clinician1κ=0.58,95%confidenceinterval0.39–0.75;clinician2κ=0.52,95%confidenceinterval

0.34-0.69).

2.2.4.4Interobserveragreement

AsubstantiallevelofagreementwasfoundbetweenthetwoclinicianswhenassessingbothCGMand

fructosamine (CGM κ = 0.67, see Table 13; fructosmaine κ = 0.71, see Table 14). Treatment

recommendationsbasedonserumfructosamineshowedonly‘fairagreement’betweenclinicians(κ=

0.39).

2.2.4.5Speciesvariation

2.2.4.5.1Canineonly

When comparingCGMwith serial blood glucose curves, the level of agreementwasmoderate for

clinician1(κ=0.46,seeTable16)andnonetoslightagreementforclinician2(κ=13,seeTable17).

ThelevelofagreementbetweenclinicianswhencomparingCGMversusfructosamine,bothclinicians

hadafairagreement(clinician1κ=0.31,seeTable18;clinicianκ=0.29,seeTable19).

33

2.2.4.5.2Felineonly

When comparing felineCGMwith serial blood glucose curves, the level of agreementwas fair for

clinician2(κ=0.46,seeTable20).However,clinician1showedasubstantiallevelofagreement(κ=

0.79, see Table 21). When comparingCGMwith fructosamine, both clinicianshad lower levels of

agreement,withclinician1havingnotoslightagreement(κ=0.15,seeTable22)andclinician2having

fairagreement(κ=0.34,seeTable23).

2.3Results

2.3.1Studypopulation

Fourty-onediabeticanimalswereenrolledinthestudy,including27dogsand14cats. Signalment,

insulintypeanddosearesummarisedinTable7.Therewere20breedsofdogswithinthegroupand

9breedsofcats(withtheDSHover-representedat8/14).Themedianageoftheanimalsinthestudy

was10years,witharangeof6-15years(caninemedianage10,range6-13years;felinemedianage

12,range6-15years).

2.3.2CGMversusserialbloodglucose

Continuousglucosemonitoringwasperformedonall41animalsinthestudy(seeFigures6-47).Serial

bloodglucosecurveswereextrapolatedfromtheCGMtracesforallanimalsaspreviouslydiscussed

(seeFigures48-89). EachofthetwoboardcertifiedSmallAnimalMedicinecliniciansreviewedthe

randomised CGM curves and serial blood glucose curves along with the associated randomised

informationsheetandrecordedtheirtreatmentrecommendationsforeachcase(seeTable8).

AsdemonstratedthroughCohen’sKappaabove,thelevelofagreementbetweenthetwomonitoring

modalitieswas below theminimum acceptable level of agreement for both clinicians. Treatment

recommendationsweredifferentfor13outof41cases(32%)forclinician1and20outof41cases

(49%)forclinician2(seeTable9).

34

2.3.3CGMversusfructosamine

Serumfructosaminewasperformedfor33outofthe41cases(23/27diabeticdogs,and10/14diabetic

cats) (see Table 10). Treatment recommendationsmade by the two board certified Small Animal

Medicinecliniciansfortheserumfructosaminevalueswerecomparedtotreatmentrecommendations

fortheCGMcurves.Similarly,theKappavaluedemonstratedthelevelofagreementbetweenCGM

and fructosamine was below the minimum acceptable level of agreement for both clinicians.

Treatmentrecommendationsweredifferentfor18outof33cases(55%)forclinician1and16outof

33cases(48%)forclinician2(seeTable11).

2.3.4Serialbloodglucoseversusfructosamine

Treatment recommendations based on the 33 serum fructosamine results were compared to the

corresponding serial blood glucose curves. As with the above comparisons, the Kappa value

demonstrated the level of agreement between serial blood glucoses curves and fructosaminewas

belowtheminimumacceptablelevelofagreementforbothclinicians.Treatmentrecommendations

weredifferentfor19outof33cases(58%)forclinician1and16outof33cases(48%)forclinician2

(seeTable12).

2.3.5Interobserveragreement

Thetwoboardcertifiedsmallanimalclinicianshadasubstantiallevelofagreementwithregardsto

reviewingCGMandserialbloodglucosecurves. Forthefourty-oneCGMcurvesreviewed,thetwo

cliniciansmadethesametreatmentrecommendationinthirty-twocases(78%,seeTable24).Forthe

fourty-one serial blood glucose curves reviewed, the two clinicians made the same treatment

recommendationinthirty-fourcases(83%,seeTable24).Therewas,however,asignificantdifference

in treatment recommendations based on review of serum fructosamine results between the two

clinicians,withthesametreatmentrecommendationbeingmadeforonlythirteenoutofthirty-three

cases(40%).

2.3.6Speciesvariation

35

Thedatawasreviewedtoassesswhetherthedifferencesindiabetesbetweendogsandcatsimpacted

theoutcomeonlevelofagreementbetweentreatmentrecommendations.Forthereviewofcanine

CGMversusofserialbloodglucosecurves,clinician1haddifferenttreatmentrecommendationsfor

10outof27cases(37%)andclinician2haddifferentrecommendationsfor16outof27cases(59%,

see Table 24). This high level of discrepancy between CGM and serial glucose curveswas not as

apparentwithfelinediabetics,withclinician1makingadifferenttreatmentrecommendationin3out

of14cases(21%),andclinician2in4outof14cases(29%).

A significant difference in treatment recommendation was made regardless of species when

comparingCGMwithserumfructosamine.Clinician1madedifferenttreatmentrecommendationsfor

6outof10cases(60%),andclinician2for5outof10cases(50%,seeTable24).

2.3.7NocturnalhypoglycaemiaandSomogyi

Nocturnalhypoglycaemia(bloodglucose<3.9mmol/L)occurredinsixoutoffourty-oneanimalsinour

study(14.6%).Fiveofthese6animalsweredogs(18.5%),andonewasacat(seefigures8,11,12,16,

20,and38).Somogyi(reboundhyperglycemiapostahypoglycemicevent)wasidentifiedinfourout

offorty-oneanimals(9.8%),occurringinthreedogs(11.1%)andonecat(7.1%)(seefigures11,16,20,

and38).

2.4Discussionofresults

ThispaperevaluatestheutilityofCGMasamethodofmonitoringcanineandfelinediabetes.Itsutility

is in part assessed by whether the analysis of CGM curves results in a different treatment

recommendationwhencomparedtoothertraditionalmonitoringmodalities.Theabilitytoresultina

different treatment recommendation highlights that CGM provides different clinical data to serial

bloodglucosecurvesandserumfructosamine. Thisdifferenceistheprovisionofadditionalclinical

dataallowingforamorethoroughanalysisoftheanimal’sdiabeticcontrol.

2.4.1CGMversusserialbloodglucose

36

Intermsoftraditionaldiabeticmonitoring,CGMismostsimilartoserialbloodglucosecurves.They

bothprovideaplotofthepatient’sbloodglucoseovertime,withbothbeinganalysedtoassessthe

variabilityofbloodglucose,thenadirandincidenceofhypoglycemia.CGM,however,addressesmany

ofthelimitationsofserialglucosemonitoringasdiscussedabove,therebyhavingthepotentialtogive

asuperiorpictureofdiabeticcontrolandthusresultinadifferenttreatmentrecommendation.

Wherepreliminarystudieswithlowcasenumberswereunabletodemonstrateasignificantdifference

inclinicaldecisionmakingbetweenCGMandserialbloodglucosecurves,thisstudydemonstrateda

clear difference.50,55 This difference underscores the potential for CGM to provide a unique

perspectiveontheclinicalcontrolofadiabeticdogandcat,thusopeningupthepotentialforenhanced

diseasecontrol.

2.4.2CGMversusfructosamine

CGM,aspreviouslydiscussed,providesmoreclinicaldatapointsforanalysisofdiabeticcontrolover

serumfructosamine.Thisdifferenceissupportedthroughourstudywhichdemonstratedadistinct

differenceintreatmentrecommendationsmadebybothcliniciansbasedontheirindividualanalysis

ofthesetwodifferentmonitoringmodalities.Similarly,toserialbloodglucosecurves,thisunderscores

thepotentialforenhanceddiseasecontrolthroughmonitoringofCGMoverserumfructosamine.

2.4.3Serialbloodglucoseversusfructosamine

Whethertherewasanydifferenceintreatmentrecommendationsbetweenthetraditionalserialblood

glucose curve versus serum fructosamine was also analysed to demonstrate the difference in

representation of clinical control between these techniques. This study demonstrated a clear

differencebetweentreatmentrecommendationsforthemonitoringmodalities.

2.4.4Interobserveragreement

Theclinicaldatausedtodecideontreatmentrecommendationsformanagementofdiabeticdogsand

cats is not explicitly objective. Appropriate treatment recommendations cannot be based on the

37

results of a monitoring tool alone, but must take into account the animal’s clinical picture. This

includes, as previously discussed, change in weight, thirst level and appetite, clinical signs of

hypoglcemiaandpresenceorabsenceofketosis.Theseparametersarecombinedwithareviewof

glycemiccontrolthroughthemeasurementofserumfructosamineand/orserialbloodglucosecurves,

and/orCGM.Thiscombinationofclinicaldataisthenappliedtomakeajudgementondiabeticcontrol

and themostappropriate recommendation for change, if any, in the treatmentplan formanaging

diabetes.

Giventhesubjectivenatureofdiabeticmonitoringreview,itisimportanttoanalysetheinterobserver

reliabilityofanypotentialmonitoringtechnique. Inourstudy,thetwocliniciansthatreviewedthe

data showeda substantial level of agreementbetween their recommendations for bothCGMand

serial glucose curves. A fair level of agreement only was found between clinicians whenmaking

treatment decisions based on fructosamine. This is proposed to be due to the limitations of

fructosamineasamonitoringmodality,particularlyintheprovisionofasingledatapointforreviewof

diabeticcontrol.

The interobserver variability in decision making affects the key outcome variable of the study of

whetherthedifferentmonitoringtechniquesresultedindifferentclinicaldecisionmaking.Alimitation

of the study, is therefore, the lack of a standardised decision algorithm in the interpretation and

decision making process of the two clinicians. The reasoning for not providing a standardised

algorithmwastomimicthedecisionmakinginpracticewherecliniciansrarelyfollowanalgorithm,but

ratherinterpretresultsandclinicalsignsbasedontheirknowledgeofthediseaseprocess.Inorderto

minimisebiaswithouttheuseofadecisionalgorithmanincreasednumberofcliniciansprovidingtheir

clinicalrecommendationsonthestudydatawouldhavebeenvaluable.

2.4.5Speciesvariation

Therewasnosignificantdifferenceintreatmentrecommendationsmadewhenseparatingoutdogs

withregardstoCGMversusserialbloodglucosemonitoringandCGMversusserumfructosaminefor

both clinicians. When looking at cats only, there was no significant difference in treatment

recommendationsbetweenCGMandserumfructosamineforbothclinicians,however,therewasa

differencebetweenCGMversusserialglucosecurvetreatmentrecommendations foroneclinician.

This discrepancymay be due to the lower numbers of cats in this study, the limitations of stress

38

hyperglycemia in the hospital setting, or due to the suspected higher incidence of nocturnal

hypoglycaemiaindogsasoutlinedinchapterone.

2.4.6NocturnalhypoglycaemiaandSomogyi

Therateofnocturnalhypoglycaemiaindogsinthisstudywas18.5%.Thisisincontrasttothereported

rateofnocturnalhypoglycaemiainpeopleofbetween29to65%.39Demonstrationoftheoccurrence

ofnocturnalhypoglycaemiaandtheSomogyieffectwiththeuseofCGMinthisstudyhighlightsthe

potentialimpactofCGMinthemonitoringofdiabeticdogsandcats.Ofthesixepisodesofnocturnal

hypoglycaemiadocumentedthroughCGM,onlyoneoftheseanimalsshoweddaytimehypoglycaemia

ontheserialbloodglucosecurve.NoneoftheincidentsoftheSomogyieffectweredetectablethrough

serialbloodglucosemonitoring.

The resultsof serum fructosamine for theanimalswithnocturnalhypoglycaemiaand theSomogyi

effect showed somediscrepancies in thedepictionof glycaemic control. Of the fivepatientswith

nocturnalhypoglycaemia,twodogshadfructosaminevalueswithinthewell-controlledrange,onedog

hadavalueabovethepoorlycontrolledinterval,twodogshadvalueswithinthehealthydogreference

interval(19and35umol/Lbelowthewell-controlledrange)andonecathadafructosaminevalue10

umol/Lbelowtheexcellentcontrolinterval.ThefouranimalswithSomogyiwerethetwodogswith

valuesinthewell-controlledrange(animal6table10,figure12;animal15tablet10,figure20),the

dogwiththevalueabovethepoorlycontrolledrange(animal11table10,figure16)andthecat(animal

33table10,figure38).

CliniciantreatmentrecommendationsvariedbetweentheanimalswithdocumentedSomogyi.Both

cliniciansrecommendedreducingthedoseofinsulinforallfouranimalswithSomogyiwhenevaluating

CGM. However, when evaluating serial glucose curves, the dose was recommended to remain

unchanged in sevenoutofeight treatment recommendations. Dose reductionwas recommended

onlytwooutofeighttimesbasedonfructosamineresults,withfiverecommendationstoleavethe

doseunchangedandadoseincreaserecommendedbyoneclinician.

2.5Conclusion

39

Inconclusion,ourresultsexhibitedadistinctdifferenceinclinicaltreatmentrecommendationsforthe

managementofdiabeticdogsandcatswhenmonitoringCGMversusbothserialglucosecurvesand

serumfructosamine.Thisdifferencecanbeexplainedbythedifferenceinclinicaldataprovidedon

diabeticcontrolbyCGMascomparedwiththeothertechniques.Thisissupportedbythedifference

demonstratedbetweenallthreemonitoringtechniques.WithCGMprovidingasubstantialincrease

in clinical data points as compared with the other techniques, while simultaneously addressing

inherentlimitationsofthesemethodologies,CGMhasthepotentialtoofferamorecomprehensive

clinicalpicturethatcanbeusedinthedecisionmakingprocessfortreatmentrecommendations.

While theCGMprovidedadditional clinicaldata, it alsowasnotwithout its limitations.During the

study we encountered a number of technical difficulties. These included dislodgement of the

interstitial probe, an inability to perform calibration in some animalswith serumglucose readings

above22.2mmol/L(requiringthemtoreturnonanotherday)andlossofconnectionofthesensorto

themonitoriftheanimalwasremovedfromitscageandthemonitorleftbehind.Intheincidenceof

lossofconnection,recalibrationwasrequiredtostartatthebeginning,creatinga2-hourgapindata

collection.

CGMoffersadistinctadvantageoverbothserialbloodglucosecurvesandserumfructosamineinthe

potential for identifying otherwise unknown events of nocturnal hypoglycaemia and the Somogyi

event. Failingto identifytheoccurrenceoftheseincidencescanleadto incorrect interpretationof

diabeticcontrolandsubsequently inappropriate treatment recommendations. Forexample, in the

eventof theSomogyieffect,documentationofprolongedreboundhyperglycaemiacan leadtothe

recommendation for an increase in insulin. This recommendationwould lead to furthereventsof

potentiallylifethreateninghypoglycaemia.Withourstudydemonstratingarateof14.6%ofdiabetic

dogsandcatshavingepisodesofnocturnalhypoglycaemiaand9.8%havingepisodesoftheSomogyi

effect,thecapacityformisinterpretationandpotentiallygraveoutcomesisapparent.

SUMMARY

The primary aim of the study, to determine if CGMS resulted in different clinical decisionmaking

comparedwithmonitoring serial glucose curvesand serum fructosamine concentration indiabetic

dogs and cats was met, with data indicating a statistical difference in clinical treatment

recommendationsbetweenCGMandbothserialglucosecurvesandserumfructosamine.Secondary

aimsweretodeterminetheincidenceofnocturnalhypoglycaemiaandtheSomogyieffectindiabetic

40

dogsorcats. Ourdatademonstratedarateof14.6%ofdiabeticdogsandcatshavingepisodesof

nocturnal hypoglycaemia and 9.8%having episodes of the Somogyi effect. For diabetic dogs, this

correspondedtoarateof18.5%fornocturnalhypoglycaemiaand11.1%fortheSomogyievent.

Therewereanumberoflimitationstoourstudy.Theseincludedthelackofastandardiseddecision

algorithmforthetwoclinicianstoapplywhenprovidingtreatmentrecommendations,aswellashaving

only two clinicians review the study data. In addition, diabetic monitoring was performed in the

hospital, thereby altering glycaemic control through a change in activity levels, appetite, and the

introductionofstress.ThebrandofglucometerusedforCGMcalibrationwasnotrecorded.TheCGM

wasmonitoredforonly24hours,therebynotaddressingpotentialday-to-dayvariation.Ideally,the

monitorshouldbekeptonforthefull72-hourperiod,however,astheanimalswerekeptinhospital

for the period ofmonitoring, this was not feasible. The serial blood glucosemeasurements were

obtained retrospectively from the CGM data. This was done to minimise stress of handling and

repeatedphlebotomy.Interstitialfluidglucosehasbeendemonstratedtohavegoodcorrelationwith

blood glucose, however, an exact comparisonwould require glucosemeasurement performed on

blood.NewerCGMproductscontinuetocomeontothemarket,andmanyofthesefacilitateglucose

recordingsathome,overanextendedperiodoftime.

Inconclusion,ourresultsdemonstratedthatadifferenceinclinicaltreatmentrecommendationsfor

themanagementofdiabeticdogsandcatsexistswithclinicianassessmentofCGMversusbothserial

glucose curves and serum fructosamine. This difference can be explained by CGM providing a

substantial increase indatapoints as comparedwith theother techniques. In addition, CGMwas

showntoofferanadvantageoverbothserialbloodglucosecurvesandserumfructosamine in the

potentialforidentifyingotherwiseunknowneventsofnocturnalhypoglycaemia.Failingtoidentifythe

occurrence of these incidences can lead to incorrect interpretation of diabetic control and

subsequentlyinappropriatetreatmentrecommendations.

41

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50

APPENDIXAPPENDIXA.StudyAdmissionForm

Date: Timeofadmit:

Weight:__________kg BCS:______/9

CurrentInsulintype:___________________ Timelastinsulin:_________

Currentinsulindose(unitsandtimeperday):_____________________________

Currentdiet:___________________________ Timelastfed:____________

Amountandfrequency:__________________

Pleaserankfrom1(notatall)to5(extremelyso)thefollowing:

Mypet’sappetiteisincreased

1 2 3 4 5

Mypetisdrinkingalot

1 2 3 4 5

Mypetisnotveryactive

1 2 3 4 5

Mypetisverybrightandhappy

1 2 3 4 5

Hasyourpethadanyvomitingordiarrhoea?_____________________________________________

Doyouhaveanyotherconcernsorcomments?_________________________________________________________________

Consent

I ___________________________ consent tomy pet undergoing continuous glucosemonitoring at theUniversityofMelbourneVeterinaryTeachingHospital.Thisinvolvesshavingapatchofhaironthesideofthechestandattachingasmalldevicewhichusesaneedleprickto insertasmallsensorundertheskinwhichwillmeasureglucose.Thestudyinvolvesanovernightstayanddischargeislikelytobethefollowingafternoon/evening. If this is the first study a sample of blood will be collected for two further tests(fructosaminewhichmonitorscontrolofdiabetesandIGF-1totestfor‘acromegaly’aconditionwhichcanmakecontrolofdiabetesdifficult).

___________________________

Signature.UniversityofMelbourneAnimalEthicsApprovalNo.1212474

51

APPENDIXB.InformationSheet

Case:

Signalment:

Diagnosis:

Insulintype:

Insulindose:

Diet:

Weight: Previousweight:

Ownerquestionnaire:

Myanimal’sappetiteisincreased

1 2 3 4 5

Comment:

Myanimalisdrinkingalot

1 2 3 4 5

Comment:

Myanimalisnotveryactive

1 2 3 4 5

Comment:

Myanimalisverybrightandhappy

1 2 3 4 5

Comment:

Otherclinicalsigns:

52

APPENDIXC.ClinicianTreatmentRecommendationForm

Foreachcaseenteratreatmentdecisioninoneofthe3columns

CaseNumber

ChangeInsulinDose/Frequency(Enternewdose)

Nochange Changeinsulintype(Enternewinsulin)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

53

Table1.CGMversusSerialbloodglucosecurvestatisticalcomparison–Clinician1

Rows: CGM Clinician 1

Rows: SBG Clinician 1

0 1 2 3 4 All

0 5 1 0 0 0 6

1 2 13 3 0 0 18

2 5 1 9 0 0 15

3 0 0 0 1 0 1

4 0 0 0 0 1 1

All 12 15 12 1 1 41

Kappa 0.574762

Table2.CGMversusSerialbloodglucosecurvestatisticalcomparison–Clinician2

Rows: CGM Clinician 2

Rows: SBG Clinician 2

0 1 2 All

0 6 3 0 9

1 1 8 3 12

2 8 5 6 19

3 0 0 1 1

All 15 16 10 41

Kappa 0.260309

Table3.CGMversusFructosaminestatisticalcomparison–Clinician1

Rows: CGM Clinician 1

54

Rows: Fructosamine Clinician 1

0 1 2 Missing All

0 3 3 0 0 6

1 5 8 0 5 13

2 5 3 5 2 13

3 0 0 0 1 0

4 1 0 0 0 1

All 14 14 5 * 33

Kappa 0.259894

Table4.CGMversusFructosaminestatisticalcomparison–Clinician2

Rows: CGM Clinician 2

Rows: Fructosamine Clinician 2

0 1 2 Missing All

0 6 2 0 1 8

1 4 4 1 3 9

2 7 2 7 3 16

3 0 0 0 1 0

All 17 8 8 * 33

Kappa 0.298805

55

Table5.SerialbloodglucosecurveversusFructosaminestatisticalcomparison–Clinician1

Rows: SBG Clinician 1

Rows: Fructosamine Clinician 1

0 1 2 Missing All

0 5 4 2 1 11

1 3 6 0 6 9

2 5 4 3 0 12

3 0 0 0 1 0

4 1 0 0 0 1

All 14 14 5 * 33

Kappa 0.162884

Table6.SerialbloodglucosecurveversusFructosaminestatisticalcomparison–Clinician2

Rows: SBG Clinician 2

Rows: Fructosamine Clinician 2

0 1 2 Missing All

0 8 2 3 2 13

1 5 5 1 5 11

2 4 1 4 1 9

All 17 8 8 * 33

Kappa 0.254237

57

Table7.Signalmentofcases

Animal Species Breed Age(years) Sex Weight(kg) Insulintype Morningdose(IU) Eveningdose(IU)

1 Canine Chihuahuax 12 FS 6.4 Caninsulin 3 2

2 Canine ShihTzu 8 FS 10.3 Caninsulin 7 7

3 Canine Labrador 13 MN 36.4 Caninsulin 18 15

4 Canine PoodlexSpaniel 10 FS 5.1 Caninsulin 3 3

5 Canine Labrador 10 MN 43.1 Regular30%Isopohane70%

20 20

6 Canine PoodlexShihTzu 9 MN 7.1 Caninsulin 4 4

7 Canine Maltesex 11 FS 5.2 Caninsulin 2 2

8 Canine IrishSetter 6 M 28.7 Caninsulin 6 6

9 Canine Maltesex 12 F 6.1 Caninsulin 4 3

10 Canine MiniatureDaschund 12 MN 8.3 Regular30%Isopohane70%

5.5 5.5

11 Canine MiniaturePoodle 11 FS 8.4 Regular30%Isopohane70%

8 8

12 Canine MaltesexShihTzu 9 FS 9.4 Caninsulin 4.8 4.8

58

13 Canine CKCS 10 FS 10.4 Regular30%Isopohane70%

16 16

14 Canine GoldenRetriever 7 FS 23.3 Regular30%Isopohane70%

12.5 12.5

15 Canine MaltesexBichonFrise 9 FS 6.7 Caninsulin 6 6

16 Canine SilkyTerrier 13 MN 9.6 Caninsulin 5 5

17 Canine Pomeranian 8 FS 6.4 Caninsulin 6.4 6.4

18 Canine WHWT 9 FS 8.7 Caninsulin 8 8

19 Canine Pug 7 MN 9.9 GlargineU-100

4 4

20 Canine Cattledogx 10 MN 18.5 Regular30%Isopohane70%

0 15

21 Canine Colliex 7 FS 15.35 Caninsulin 4 4

22 Canine WHWT 8 FS 9.5 Regular30%Isopohane70%

6.5 6

23 Canine Labrador 11 MN 43.1 Caninsulin 25 25

24 Canine Kelpiex 11 MN 18 Regular30%Isopohane70%

7.5 7.5

59

25 Canine JRT 10 M 6.7 Caninsulin 3 2

26 Canine BorderCollie 10 F 22.1 Caninsulin 8 8

27 Canine Rottweiler 10 M 42.4 Isophane 27 27

28 Feline DSH 13 FS 6.77 GlargineU-100

1 1

29 Feline DSH 15 FS 6.3 GlargineU-100

2 2

30 Feline DSH 15 MN 6.13 GlargineU-100

1 1

31 Feline DSH 9 MN 6.18 GlargineU-100

1 1

32 Feline DSH 6 FS 2.83 GlargineU-100

1 1

33 Feline Burmesex 12 MN 5.76 GlargineU-100

3 3

34 Feline SpottedMist 13 FS 4 GlargineU-100

2 2

35 Feline Burmese 12 FS 5.2 GlargineU-100

6 6

36 Feline DSH 11 FS 6.35 GlargineU-100

13 13

37 Feline BritishShorthairx 10 MN 6.44 GlargineU-100

1 1

60

38 Feline MaineCoon 14 MN 8.7 GlargineU-100

8 8

39 Feline Birman 9 MN 7.3 GlargineU-100

7 7

40 Feline DSH 13 MN 6.43 GlargineU-100

4 1

41 Feline DSH 10 MN 6.2 GlargineU-100

2 2

Key:CKCSCavalierKingCharlesSpaniel,WHWTWestHighlandWhiteTerrier,JRTJackRussellTerrier,DSHDomesticShorthair,FSFemaleSpayed,MNMale

Neutered

Table8.TreatmentRecommendationTable

Animal

OriginalDose CGM

Clinician1

CGM

Clinician2

SBG

Clinician1

SBG

Clinician2

Fructosamine

Clinician1

Fructosamine

Clinician2

AM

dose

PMdose

AM

dose

PMdose

AMdose

PMdose

AMdose

PMdose

AMdose

PMdose

AMdose

PMdose

AMdose

PMdose

1 3 2 3.5 2 2 2 3.5 2.5 2 2 3 2 1.5 1.5

61

2 7 7 7.5 7.5 7 7 7 7 7 7 7.5 7.5 8 8

3 18 15 15 15 10 10 18 15 18 15 16 16 12 12

4 3 3 2 2 1.5 1.5 4 4 3.5 3.5 3.5 3.5 4 4

5 20 20 21 21 20 20 20 20 20 20 22 22 20 20

6 4 4 4 2 2 2 4 4 4 4 4 4 3 3

7 2 2 1 1 1 1 1 1 1 1 1.5 1.5 1 1

8 6 6 7 7 7 7 8 8 8 8 8 8 8 8

9 4 3 4 3 3.5 3.5 4 3 3.5 3.5 4 3 4 3

10 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 6 6 6 6

11 8 8 6 6 4 4 7 6 8 8 9 9 8 8

12 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8

13 16 16 * * 8 8 * * 16 16 16 16 13 13

14 12.5 12.5 12 12 12.5 12.5 13.5 13.5 14 14 14 14 12.5 12.5

15 6 6 4.5 4 2 2 6 6 6 6 5 5 6 6

16 5 5 6 4 6 6 5 5 5 5 5 5 5 5

17 6.4 6.4 7 6.4 6.4 6.4 7 7 7 7 6.4 6.4 6.4 6.4

18 8 8 9 8.5 10 10 9 9 4 4 8 8 6 6

19 4 4 4 0 3 3 4 0 5 5 4 4 4 4

62

20 0 15 0 17 7.5 7.5 0 17 8 8 0 17 10 10

21 4 4 5 5 4 4 4.5 4.5 5 5 ND ND ND ND

22 6.5 6 7 6 7 7 7 5 6 6 7 7 7 7

23 25 25 28 28 28 28 28 28 28 28 ND ND ND ND

24 7.5 7.5 6 6 7 7 6.5 6.5 7 7 8 8 7.5 7.5

25 3 2 3 1 1.5 1.5 3.5 2.5 2.5 2.5 ND ND ND ND

26 8 8 9 9 10 10 9 9 10 10 ND ND ND ND

27 27 27 28 28 29 29 20 20 13 13 27 27 27 27

28 1 1 1.5 1 1.5 1.5 1.5 1.5 1.5 1.5 1 1 1 1

29 2 2 2 0 1 1 2 2 2 2 ND ND ND ND

30 1 1 2 2 1.5 1.5 2 2 1.5 1.5 2 2 1.5 1.5

31 1 1 2 2 1.5 1.5 2 2 1.5 1.5 2 2 1.5 1.5

32 1 1 1.5 1.5 0.5 0.5 2 2 1.5 1.5 ND ND ND ND

33 3 3 2 1 1.5 1.5 3 3 3 3 3 3 3 3

34 2 2 2 1 1 1 2.5 0 2.5 2.5 2.5 0 1 1

35 6 6 4 4 4 4 3 3 4 4 6.5 6.5. 5 5

36 13 13 14 14 14 14 14 14 14 14 ND ND ND ND

37 1 1 0 0 0 0 0 0 0.5 0.5 ND ND ND ND

63

38 8 8 8 8 8 8 8 8 8 8 9 9 8 8

39 7 7 4 4 6 6 4 4 5 5 7 7 7 7

40 4 1 3 0 2 2 2 2 2 2 4 1 1 1

41 2 2 2.5 2.5 3 3 2.5 2.5 2.5 2.5 2.5 2.5 2 2

Key:

*Switchinsulintoglargine

NDNotdone

56

Table7.Signalmentofcases

Animal Species Breed Age(years) Sex Weight(kg) Insulintype Morningdose(IU) Eveningdose(IU)

1 Canine Chihuahuax 12 FS 6.4 Caninsulin 3 2

2 Canine ShihTzu 8 FS 10.3 Caninsulin 7 7

3 Canine Labrador 13 MN 36.4 Caninsulin 18 15

4 Canine PoodlexSpaniel 10 FS 5.1 Caninsulin 3 3

5 Canine Labrador 10 MN 43.1 Regular30%Isopohane70%

20 20

6 Canine PoodlexShihTzu 9 MN 7.1 Caninsulin 4 4

7 Canine Maltesex 11 FS 5.2 Caninsulin 2 2

8 Canine IrishSetter 6 M 28.7 Caninsulin 6 6

9 Canine Maltesex 12 F 6.1 Caninsulin 4 3

10 Canine MiniatureDaschund 12 MN 8.3 Regular30%Isopohane70%

5.5 5.5

11 Canine MiniaturePoodle 11 FS 8.4 Regular30%Isopohane70%

8 8

12 Canine MaltesexShihTzu 9 FS 9.4 Caninsulin 4.8 4.8

57

13 Canine CKCS 10 FS 10.4 Regular30%Isopohane70%

16 16

14 Canine GoldenRetriever 7 FS 23.3 Regular30%Isopohane70%

12.5 12.5

15 Canine MaltesexBichonFrise 9 FS 6.7 Caninsulin 6 6

16 Canine SilkyTerrier 13 MN 9.6 Caninsulin 5 5

17 Canine Pomeranian 8 FS 6.4 Caninsulin 6.4 6.4

18 Canine WHWT 9 FS 8.7 Caninsulin 8 8

19 Canine Pug 7 MN 9.9 GlargineU-100

4 4

20 Canine Cattledogx 10 MN 18.5 Regular30%Isopohane70%

0 15

21 Canine Colliex 7 FS 15.35 Caninsulin 4 4

22 Canine WHWT 8 FS 9.5 Regular30%Isopohane70%

6.5 6

23 Canine Labrador 11 MN 43.1 Caninsulin 25 25

24 Canine Kelpiex 11 MN 18 Regular30%Isopohane70%

7.5 7.5

58

25 Canine JRT 10 M 6.7 Caninsulin 3 2

26 Canine BorderCollie 10 F 22.1 Caninsulin 8 8

27 Canine Rottweiler 10 M 42.4 Isophane 27 27

28 Feline DSH 13 FS 6.77 GlargineU-100

1 1

29 Feline DSH 15 FS 6.3 GlargineU-100

2 2

30 Feline DSH 15 MN 6.13 GlargineU-100

1 1

31 Feline DSH 9 MN 6.18 GlargineU-100

1 1

32 Feline DSH 6 FS 2.83 GlargineU-100

1 1

33 Feline Burmesex 12 MN 5.76 GlargineU-100

3 3

34 Feline SpottedMist 13 FS 4 GlargineU-100

2 2

35 Feline Burmese 12 FS 5.2 GlargineU-100

6 6

36 Feline DSH 11 FS 6.35 GlargineU-100

13 13

37 Feline BritishShorthairx 10 MN 6.44 GlargineU-100

1 1

59

38 Feline MaineCoon 14 MN 8.7 GlargineU-100

8 8

39 Feline Birman 9 MN 7.3 GlargineU-100

7 7

40 Feline DSH 13 MN 6.43 GlargineU-100

4 1

41 Feline DSH 10 MN 6.2 GlargineU-100

2 2

Key:CKCSCavalierKingCharlesSpaniel,WHWTWestHighlandWhiteTerrier,JRTJackRussellTerrier,DSHDomesticShorthair,FSFemaleSpayed,MNMale

Neutered

60

Table8.TreatmentRecommendationTable

Animal

OriginalDose CGM

Clinician1

CGM

Clinician2

SBG

Clinician1

SBG

Clinician2

Fructosamine

Clinician1

Fructosamine

Clinician2

AM

dose

PMdose

AM

dose

PMdose

AMdose

PMdose

AMdose

PMdose

AMdose

PMdose

AMdose

PMdose

AMdose

PMdose

1 3 2 3.5 2 2 2 3.5 2.5 2 2 3 2 1.5 1.5

2 7 7 7.5 7.5 7 7 7 7 7 7 7.5 7.5 8 8

3 18 15 15 15 10 10 18 15 18 15 16 16 12 12

4 3 3 2 2 1.5 1.5 4 4 3.5 3.5 3.5 3.5 4 4

5 20 20 21 21 20 20 20 20 20 20 22 22 20 20

6 4 4 4 2 2 2 4 4 4 4 4 4 3 3

7 2 2 1 1 1 1 1 1 1 1 1.5 1.5 1 1

8 6 6 7 7 7 7 8 8 8 8 8 8 8 8

9 4 3 4 3 3.5 3.5 4 3 3.5 3.5 4 3 4 3

10 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 6 6 6 6

11 8 8 6 6 4 4 7 6 8 8 9 9 8 8

12 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8 4.8

61

13 16 16 * * 8 8 * * 16 16 16 16 13 13

14 12.5 12.5 12 12 12.5 12.5 13.5 13.5 14 14 14 14 12.5 12.5

15 6 6 4.5 4 2 2 6 6 6 6 5 5 6 6

16 5 5 6 4 6 6 5 5 5 5 5 5 5 5

17 6.4 6.4 7 6.4 6.4 6.4 7 7 7 7 6.4 6.4 6.4 6.4

18 8 8 9 8.5 10 10 9 9 4 4 8 8 6 6

19 4 4 4 0 3 3 4 0 5 5 4 4 4 4

20 0 15 0 17 7.5 7.5 0 17 8 8 0 17 10 10

21 4 4 5 5 4 4 4.5 4.5 5 5 ND ND ND ND

22 6.5 6 7 6 7 7 7 5 6 6 7 7 7 7

23 25 25 28 28 28 28 28 28 28 28 ND ND ND ND

24 7.5 7.5 6 6 7 7 6.5 6.5 7 7 8 8 7.5 7.5

25 3 2 3 1 1.5 1.5 3.5 2.5 2.5 2.5 ND ND ND ND

26 8 8 9 9 10 10 9 9 10 10 ND ND ND ND

27 27 27 28 28 29 29 20 20 13 13 27 27 27 27

28 1 1 1.5 1 1.5 1.5 1.5 1.5 1.5 1.5 1 1 1 1

29 2 2 2 0 1 1 2 2 2 2 ND ND ND ND

30 1 1 2 2 1.5 1.5 2 2 1.5 1.5 2 2 1.5 1.5

62

31 1 1 2 2 1.5 1.5 2 2 1.5 1.5 2 2 1.5 1.5

32 1 1 1.5 1.5 0.5 0.5 2 2 1.5 1.5 ND ND ND ND

33 3 3 2 1 1.5 1.5 3 3 3 3 3 3 3 3

34 2 2 2 1 1 1 2.5 0 2.5 2.5 2.5 0 1 1

35 6 6 4 4 4 4 3 3 4 4 6.5 6.5. 5 5

36 13 13 14 14 14 14 14 14 14 14 ND ND ND ND

37 1 1 0 0 0 0 0 0 0.5 0.5 ND ND ND ND

38 8 8 8 8 8 8 8 8 8 8 9 9 8 8

39 7 7 4 4 6 6 4 4 5 5 7 7 7 7

40 4 1 3 0 2 2 2 2 2 2 4 1 1 1

41 2 2 2.5 2.5 3 3 2.5 2.5 2.5 2.5 2.5 2.5 2 2

Key:

*Switchinsulintoglargine

NDNotdone

63

Table9.Treatmentrecommendations:CGMversusSerialbloodglucosecurve

Clinician1 Clinician2

Animal CGM SBG CGM SBG

1 ↑ ↑ ↓ ↓

2 ↑ ↔ ↔ ↔

3 ↓ ↔ ↓ ↔

4 ↓ ↑ ↓ ↑

5 ↑ ↔ ↔ ↔

6 ↓ ↔ ↓ ↔

7 ↓ ↓ ↓ ↓

8 ↑ ↑ ↑ ↑

9 ↔ ↔ ↔ ↔

10 ↔ ↔ ↔ ↔

11 ↓ ↓ ↓ ↔

12 ↔ ↔ ↔ ↔

13 * * ↓ ↔

14 ↓ ↑ ↔ ↑

15 ↓ ↔ ↓ ↔

16 ↔ ↔ ↑ ↔

17 ↑ ↑ ↔ ↑

18 ↑ ↑ ↑ ↓

19 ↓ ↓ ↓ ↑

20 ↑ ↑ ↔ ↑

21 ↑ ↑ ↔ ↑

22 ↑ ↓ ↑ ↓

23 ↑ ↑ ↑ ↑

24 ↓ ↓ ↓ ↓

25 ↓ ↑ ↓ ↔

64

26 ↑ ↑ ↑ ↑

27 ↑ ↓ ↑ ↓

28 ↑ ↑ ↑ ↑

29 ↓ ↔ ↓ ↔

30 ↑ ↑ ↑ ↑

31 ↑ ↑ ↑ ↑

32 ↓ ↑ ↓ ↑

33 ↓ ↔ ↓ ↔

34 ↓ ↓ ↓ ↑

35 ↓ ↓ ↓ ↓

36 ↑ ↑ ↑ ↑

37 STOP STOP STOP STOP

38 ↔ ↔ ↔ ↔

39 ↓ ↓ ↓ ↓

40 ↓ ↓ ↓ ↓

41 ↑ ↑ ↑ ↑

Key

↑ increasedose;↓decreasedose;↔nochange;NDnotdone;*changeinsulintoglargine;STOPstopinsulin

65

Table10.SerumFructosamineresults

Animal SerumFructosamine

Animal SerumFructosamine

1 468 22 997

2 693 23 ND

3 197 24 962

4 587 25 ND

5 891 26 ND

6 239 27 373

7 181 28 386

8 425 29 ND

9 321 30 1068

10 732 31 877

11 2040 32 ND

12 577 33 340

13 381 34 659

14 5423 35 499

15 264 36 ND

16 677 37 ND

17 327 38 800

18 442 39 422

19 495 40 405

20 520 41 651

21 ND

Key:NDnotdone

FructosamineReferenceInterval(umol/L)

Canine(cases1-27)

Healthydogs 187-386

66

Diabeticdogs

Newlydiagnosed 325–834

Wellcontrolled216–474

Poorlycontrolled 382–745

Feline(cases28-41)

Excellentcontrol 350–400umol/L

Goodcontrol 400–4500umol/L

Faircontrol 450–500umol/L

Poorcontrol >500umol/L

67

Table11.Treatmentrecommendations:CGMversusserumfructosamine

Clinician1 Clinician2

Animal CGM Fructosamine CGM Fructosamine

1 ↑ ↔ ↓ ↓

2 ↑ ↑ ↔ ↑

3 ↓ ↓ ↓ ↓

4 ↓ ↑ ↓ ↑

5 ↑ ↑ ↔ ↔

6 ↓ ↔ ↓ ↓

7 ↓ ↓ ↓ ↓

8 ↑ ↑ ↑ ↑

9 ↔ ↔ ↔ ↔

10 ↔ ↑ ↔ ↑

11 ↓ ↑ ↓ ↔

12 ↔ ↔ ↔ ↔

13 * ↔ ↓ ↓

14 ↓ ↑ ↔ ↔

15 ↓ ↓ ↓ ↔

16 ↔ ↔ ↑ ↔

17 ↑ ↔ ↔ ↔

18 ↑ ↔ ↑ ↓

19 ↓ ↔ ↓ ↔

20 ↑ ↑ ↔ ↑

21 ↑ ND ↔ ND

22 ↑ ↑ ↑ ↑

23 ↑ ND ↑ ND

24 ↓ ↑ ↓ ↔

25 ↓ ND ↓ ND

68

26 ↑ ND ↑ ND

27 ↑ ↔ ↑ ↔

28 ↑ ↔ ↑ ↔

29 ↓ ND ↓ ND

30 ↑ ↑ ↑ ↑

31 ↑ ↑ ↑ ↑

32 ↓ ND ↓ ND

33 ↓ ↔ ↓ ↔

34 ↓ ↓ ↓ ↓

35 ↓ ↑ ↓ ↓

36 ↑ ND ↑ ND

37 STOP ND STOP ND

38 ↔ ↑ ↔ ↔

39 ↓ ↔ ↓ ↔

40 ↓ ↑ ↓ ↔

41 ↑ ↑ ↑ ↔

Key

↑ increasedose;↓decreasedose;↔nochange;NDnotdone;*changeinsulintoglargine;STOPstopinsulin

69

Table12.Treatmentrecommendations:Serialbloodglucoseversusserumfructosamine

Clinician1 Clinician2

Animal SBG Fructosamine SBG Fructosamine

1 ↑ ↔ ↓ ↓

2 ↔ ↑ ↔ ↑

3 ↔ ↓ ↔ ↓

4 ↑ ↑ ↑ ↑

5 ↔ ↑ ↔ ↔

6 ↔ ↔ ↔ ↓

7 ↓ ↓ ↓ ↓

8 ↑ ↑ ↑ ↑

9 ↔ ↔ ↔ ↔

10 ↔ ↑ ↔ ↑

11 ↓ ↑ ↔ ↔

12 ↔ ↔ ↔ ↔

13 * ↔ ↔ ↓

14 ↑ ↑ ↑ ↔

15 ↔ ↓ ↔ ↔

16 ↔ ↔ ↔ ↔

17 ↑ ↔ ↑ ↔

18 ↑ ↔ ↓ ↓

19 ↓ ↔ ↑ ↔

20 ↑ ↑ ↑ ↑

21 ↑ ND ↑ ND

22 ↓ ↑ ↓ ↑

23 ↑ ND ↑ ND

24 ↓ ↑ ↓ ↔

25 ↑ ND ↔ ND

70

26 ↑ ND ↑ ND

27 ↓ ↔ ↓ ↔

28 ↑ ↔ ↑ ↔

29 ↔ ND ↔ ND

30 ↑ ↑ ↑ ↑

31 ↑ ↑ ↑ ↑

32 ↑ ND ↑ ND

33 ↔ ↔ ↔ ↔

34 ↓ ↓ ↑ ↓

35 ↓ ↑ ↓ ↓

36 ↑ ND ↑ ND

37 STOP ND STOP ND

38 ↔ ↑ ↔ ↔

39 ↓ ↔ ↓ ↔

40 ↓ ↑ ↓ ↔

41 ↑ ↑ ↑ ↔

Key

↑ increasedose;↓decreasedose;↔nochange;NDnotdone;*changeinsulintoglargine;STOPstopinsulin

71

Table13.Inter-observeragreementstatisticalcomparison–CGM

Rows: CGM clinician 1

Columns: CGM clinician 2

0 1 2 3 All

0 5 1 0 0 6

1 4 11 3 0 18

2 0 0 15 0 15

3 0 0 0 1 1

4 0 0 1 0 1

All 9 12 19 1 41

Kappa 0.672

Table14.Inter-observeragreementstatisticalcomparison–SerialBloodGlucoseCurve

Rows: SBG clinician 1

Columns: SBG clinician 2

0 1 2 All

0 12 0 0 12

1 1 13 1 15

2 1 3 8 12

3 0 0 1 1

4 1 0 0 1

All 15 16 10 41

Kappa 0.712533

72

Table15.Inter-observeragreementstatisticalcomparison–SerumFructosamine

Rows: Fructosamine Clinician 1

Columns: Fructosamine Clinician 2

0 1 2 Missing All

0 9 0 5 0 14

1 6 8 0 0 14

2 2 0 3 0 5

Missing 0 0 0 8 *

All 17 8 8 * 33

Table16.CGMversusSerialbloodglucosestatisticalcomparison–Clinician1,Canineonly

Rows: CGM Clinician 1

Rows: SBG Clinician 1

0 1 2 4 All

0 4 1 0 0 5

1 2 7 3 0 12

2 3 1 5 0 9

4 0 0 0 1 1

All 9 9 8 1 27

Kappa 0.463221

73

Table17.CGMversusSerialbloodglucosestatisticalcomparison–Clinician2,Canineonly

Rows: CGM Clinician 2

Rows: SBG Clinician 2

0 1 2 All

0 5 3 0 8

1 1 3 3 7

2 6 3 3 12

All 12 9 6 27

Kappa 0.132530

Table18.CGMversusFructosaminestatisticalcomparison–Clinician1,Canineonly

Rows: CGM Clinician 1

Rows: Fructosamine Clinician 1

0 1 2 Missing All

0 3 2 0 0 5

1 4 5 0 3 9

2 2 2 4 1 8

4 1 0 0 0 1

All 10 9 4 * 23

Kappa 0.308743

74

Table19.CGMversusFructosaminestatisticalcomparison–Clinician2,Canineonly

Rows: CGM Clinician 2

Rows: Fructosamine Clinician 2

0 1 2 Missing All

0 5 2 0 1 7

1 2 2 1 2 5

2 4 2 5 1 11

All 11 6 6 * 23

Kappa 0.289326

Table20.CGMversusSerialbloodglucosestatisticalcomparison–Clinician1,Felineonly

Rows: CGM Clinician 1

Rows: SBG Clinician 1

0 1 2 3 All

0 1 0 0 0 1

1 0 6 0 0 6

2 2 0 4 0 6

3 0 0 0 1 1

All 3 6 4 1 14

Kappa 0.787879

75

Table21.CGMversusSerialbloodglucosestatisticalcomparison–Clinician2,Felineonly

Rows: CGM Clinician 2

Rows: SBG Clinician 2

0 1 2 All

0 1 0 0 1

1 0 5 0 5

2 2 2 3 7

3 0 0 1 1

All 3 7 4 14

Kappa 0.461538

Table22.CGMversusFructosaminestatisticalcomparison–Clinician1,Felineonly

Rows: CGM Clinician 1

Rows: Fructosamine Clinician 1

0 1 2 Missing All

0 0 1 0 0 1

1 1 3 0 2 4

2 3 1 1 1 5

3 0 0 0 1 0

All 4 5 1 * 10

Kappa 0.154930

76

Table23.CGMversusFructosaminestatisticalcomparison–Clinician2,Felineonly

Rows: CGM Clinician 2

Rows: Fructosamine Clinician 2

0 1 2 Missing All

0 1 0 0 0 1

1 2 2 0 1 4

2 3 0 2 2 5

3 0 0 0 1 0

All 6 2 2 * 10

Kappa 0.342105

77

Table24.Inter-observeragreement

CGM SBG Fructosamine

Animal Clinician1 Clinician2 Clinician1 Clinician2 Clinician1 Clinician2

1 ↑ ↓ ↑ ↓ ↔ ↓

2 ↑ ↔ ↔ ↔ ↑ ↑

3 ↓ ↓ ↔ ↔ ↓ ↓

4 ↓ ↓ ↑ ↑ ↑ ↑

5 ↑ ↔ ↔ ↔ ↑ ↔

6 ↓ ↓ ↔ ↔ ↔ ↓

7 ↓ ↓ ↓ ↓ ↓ ↓

8 ↑ ↑ ↑ ↑ ↑ ↑

9 ↔ ↔ ↔ ↔ ↔ ↔

10 ↔ ↔ ↔ ↔ ↑ ↑

11 ↓ ↓ ↓ ↔ ↑ ↔

12 ↔ ↔ ↔ ↔ ↔ ↔

13 * ↓ * ↔ ↔ ↓

14 ↓ ↔ ↑ ↑ ↑ ↔

15 ↓ ↓ ↔ ↔ ↓ ↔

16 ↔ ↑ ↔ ↔ ↔ ↔

17 ↑ ↔ ↑ ↑ ↔ ↔

18 ↑ ↑ ↑ ↓ ↔ ↓

19 ↓ ↓ ↓ ↑ ↔ ↔

20 ↑ ↔ ↑ ↑ ↑ ↑

21 ↑ ↔ ↑ ↑ ND ND

22 ↑ ↑ ↓ ↓ ↑ ↑

23 ↑ ↑ ↑ ↑ ND ND

24 ↓ ↓ ↓ ↓ ↑ ↔

25 ↓ ↓ ↑ ↔ ND ND

78

26 ↑ ↑ ↑ ↑ ND ND

27 ↑ ↑ ↓ ↓ ↔ ↔

28 ↑ ↑ ↑ ↑ ↔ ↔

29 ↓ ↓ ↔ ↔ ND ND

30 ↑ ↑ ↑ ↑ ↑ ↑

31 ↑ ↑ ↑ ↑ ↑ ↑

32 ↓ ↓ ↑ ↑ ND ND

33 ↓ ↓ ↔ ↔ ↔ ↔

34 ↓ ↓ ↓ ↑ ↓ ↓

35 ↓ ↓ ↓ ↓ ↑ ↓

36 ↑ ↑ ↑ ↑ ND ND

37 STOP STOP STOP STOP ND ND

38 ↔ ↔ ↔ ↔ ↑ ↔

39 ↓ ↓ ↓ ↓ ↔ ↔

40 ↓ ↓ ↓ ↓ ↑ ↔

41 ↑ ↑ ↑ ↑ ↑ ↔

Key

↑ increasedose;↓decreasedose;↔nochange;NDnotdone;*changeinsulintoglargine;STOPstopinsulin

79

Figure1.CGMequipment:device Figure2.Attachsensortoclipped

usedtoloadandattachsensor; patchofskinonproximalthoracic

disposablesensor;transmitterattached wall

tocharger;monitoringstoragedevice

Figure3.Attachtransmittertosensor. Figure4.Securethedeviceto

theanimalbyapplyingabandage

Figure5.Attachthetransmitterto

theanimal’scage.

80

Figure6.Continuousglucosecurve:Animal1

Figure7.Continuousglucosecurve:Animal2

Figure8.Continuousglucosecurve:Animal3

Figure9.Continuousglucosecurve:Animal4

81

Figure10.Continuousglucosecurve:Animal5

Figure11.Continuousglucosecurve:Animal6

Figure12.Continuousglucosecurve:Animal7

Figure13.Continuousglucosecurve:Animal8

82

Figure14.Continuousglucosecurve:Animal9

Figure15.Continuousglucosecurve:Animal10

Figure16.Continuousglucosecurve:Animal11

Figure17.Continuousglucosecurve:Animal12

83

Figure18.Continuousglucosecurve:Animal13

Figure19.Continuousglucosecurve:Animal14

Figure20.Continuousglucosecurve:Animal15

Figure21.Continuousglucosecurve:Animal16

84

Figure22.Continuousglucosecurve:Animal17

Figure23.Continuousglucosecurve:Animal18

Figure24.Continuousglucosecurve:Animal19

Figure25.Continuousglucosecurve:Animal20

85

Figure26.Continuousglucosecurve:Animal21

Figure27.Continuousglucosecurve:Animal22

Figure28.Continuousglucosecurve:Animal23

86

Figure29.Continuousglucosecurve:Animal24

Figure30.Continuousglucosecurve:Animal25

Figure31.Continuousglucosecurve:Animal26

Figure32.Continuousglucosecurve:Animal27

87

Figure33.Continuousglucosecurve:Animal28

Figure34.Continuousglucosecurve:Animal29

Figure35.Continuousglucosecurve:Animal30

Figure36.Continuousglucosecurve:Animal31

88

Figure37.Continuousglucosecurve:Animal32

Figure38.Continuousglucosecurve:Animal33

Figure39.Continuousglucosecurve:Animal34

89

Figure40.Continuousglucosecurve:Animal35

Figure41.Continuousglucosecurve:Animal36

Figure42.Continuousglucosecurve:Animal37

90

Figure43.Continuousglucosecurve:Animal38

Figure44.Continuousglucosecurve:Animal39

91

Figure45.Continuousglucosecurve:Animal40

Figure46.Continuousglucosecurve:Animal41

Figure47.Serialglucosecurve:Animal1

92

Figure48.Serialglucosecurve:Animal2

Figure49.Serialglucosecurve:Animal3

93

Figure50.Serialglucosecurve:Animal4

Figure51.Serialglucosecurve:Animal5

Figure52.Serialglucosecurve:Animal6

94

Figure53.Serialglucosecurve:Animal7

Figure54.Serialglucosecurve:Animal8

95

Figure55.Serialglucosecurve:Animal9

Figure56.Serialglucosecurve:Animal10

96

Figure57.Serialglucosecurve:Animal11

Figure58.Serialglucosecurve:Animal12

97

Figure59.Serialglucosecurve:Animal13

Figure60.Serialglucosecurve:Animal14

98

Figure61.Serialglucosecurve:Animal15

Figure62.Serialglucosecurve:Animal16

Figure63.Serialglucosecurve:Animal17

99

Figure64.Serialglucosecurve:Animal18

Figure65.Serialglucosecurve:Animal19

100

Figure66.Serialglucosecurve:Animal20

Figure67.Serialglucosecurve:Animal21

101

Figure68.Serialglucosecurve:Animal22

Figure69.Serialglucosecurve:Animal23

102

Figure70.Serialglucosecurve:Animal24

Figure71.Serialglucosecurve:Animal25

103

Figure72.Serialglucosecurve:Animal26

Figure73.Serialglucosecurve:Animal27

104

Figure74.Serialglucosecurve:Animal28

Figure75.Serialglucosecurve:Animal29

Figure76.Serialglucosecurve:Animal30

105

Figure77.Serialglucosecurve:Animal31

Figure78.Serialglucosecurve:Animal32

106

Figure79.Serialglucosecurve:Animal33

Figure80.Serialglucosecurve:Animal34

107

Figure81.Serialglucosecurve:Animal35

Figure82.Serialglucosecurve:Animal36

Figure83.Serialglucosecurve:Animal37

108

Figure84.Serialglucosecurve:Animal38

Figure85.Serialglucosecurve:Animal39

Figure86.Serialglucosecurve:Animal40

109

Figure87.Serialglucosecurve:Animal41

Minerva Access is the Institutional Repository of The University of Melbourne

Author/s:

Lott, Katie

Title:

Evaluating effectiveness of a Continuous Glucose Monitoring System (CGMS) in diabetic

dogs and cats

Date:

2018

Persistent Link:

http://hdl.handle.net/11343/219700

File Description:

Evaluating effectiveness of a Continuous Glucose Monitoring System (CGMS) in diabetic

dogs and cats

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