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1
EvaluatingeffectivenessofaContinuousGlucoseMonitoringSystem(CGMS)indiabeticdogsandcats
KatieLott
MasterofVeterinaryScience
December2018
MelbourneVeterinarySchool
TheUniversityofMelbourne
2
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.
3
DECLARATION
Thisistocertifythat
i. Thethesiscomprisesonlymyoriginalworktowardsthemasters
ii. Dueacknowledgementhasbeenmadeinthetexttoallothermaterialused
iii. Thethesisis11826wordsinlength,exclusiveoftablesandappendices
4
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.
5
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
6
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
7
Table23.CGMversusFructosaminestatisticalcomparison–Clinician2,Felineonly
Table24.Interobserveragreement
8
LISTOFFIGURES
Figure1-5DemonstrationofattachmentofCGMdevicetoadog
Figure6-46.CGMtracesfromanimalsinstudy
Figure47-87.Serialbloodglucosecurves
9
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
10
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.
11
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.
12
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
13
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
14
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
15
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
16
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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