University of Groningen

Scope of epidemiology and daily practice in children with type 1 diabetes in the NetherlandsHummelink, Engelina

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CHAPTEr 1

introducti on

9

Introduction

wHAT THis THEsis is ABouT

Job,asevenyearoldboy,wasreferredtotheemergencydepartmentofourhospital.Sinceafewdayshismothernoticedthathehadbeendrinkingalotandhadbeencomplainingofbeingverythirsty.Healsohadtopeefrequently.Jobwettedhisbedoccasionally,butinre-centweekshisbedwasalreadycompletelywetwhenhisparentswenttosleep.Hehadnoteatenwelllastweek,buthedideatalotofyoghurt.Accordingtohisparents,Jobseemedtohavelostsomeweight.Thefamilyhistorydidnotshowanyrelevantdetails.Thewholefamilyhadhadgastroenteritistwoweeksearlier.Onphysicalexamination,wesawaverythin,skinnyboywithsunkeneyes.Nofurtherphysicalorbehaviouralabnormalitieswerenoticed.Theclinicalsuspicionoftype1diabetesmellitus(basedontheclassicalsymptomsofpolyuriaandpolydipsia)wassupportedbylaboratorytestresultswhichshowedaveryhighbloodglucoselevel(48mmol/L)withoutacidosis(bloodthatisacidified).TheHbA1cvalue(ameasurethatreflectsthebloodglucoseconcentrationofthepreceding2-3months)wasclearlyelevated(83mmol/mol).Glucosewasalsofoundinlargequantitiesintheurine.Afewweeks later,confirmationofthesuspicionofautoimmunediabetescamefromtheresultsofautoantibodytesting,whichwaspositiveforantibodiesagainst theLangerhansisletsinthepancreaswhichareresponsiblefortheproductionofinsulininthehumanbody.TheinevitableconclusionofallthisinformationisthatJobhasnewlyonsettype1diabetes

mellitus.Fromnowonhislifeandthatofhisfamilywillchangedramatically,withdailybloodglucosemeasurements,insulininjections,concernsabouttheglucosevalues,fearandrealthreatofhypoglycaemicepisodesandtheriskoflong-termcomplicationsincludingeyeandkidneyproblems.

definition:diabetes mellitus(dM),commonlyreferredtoasdiabetes,isagroupofmetabolicdisorderscharacterisedbyhighbloodglucoselevelsoveraprolongedperiodoftime.Type1diabetesmellitus(T1DM)isthetypeofdiabetesmellitusinwhichinsufficientandeventuallynoinsulinisproduced.T1DMisoneofthemostcommonchronicdiseasesinchildhood.Theincidencediffersconsiderablybetweencountries,withthehighestrecordedincidenceinFinlandwith64.2per100,000person-yearsin2005(1).T1DMhasamajorimpactonqualityoflifeanddailyfunctioningfortheaffectedchildrenandtheirfamily.Themanagementofthisdiseaseposessubstantialdemandsonthechildrenandfamily,leadingtoworkrestrictions,negativefinancialimpact,anxietyandworries(2).

HistoryBetween 1914 and 1916, the Romanian physiologist Nicolas Paulescu first extracted apancreatic antidiabetic agent that he used to treat dogs, but his experiments remainedunnoticedtothescientificworld.Hismethodtopreparepancreaticextractwassimilarto

Chapter1

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theproceduredescribedin1919bytheAmericanscientistIsraelKleiner(3).Thediscoveryof insulinin1921byBantingandBestwasalifesaver,allowingforthefirsttimeapropertreatment for peoplewith T1DM. These Canadian researcherswere awarded the NobelPrizeforMedicineandPhysiology in1923(4). InJanuary1922,a14-yearoldboynamedLeonardThompsonreceivedthefirstinjectionofisletin,asthepancreasextractcontaininginsulinwasinitiallynamed.Hesufferedasevereallergicreaction,whichonhindsightwasnotentirelyunexpectedduetotheratherpoorpurificationoftheinjectedsubstance.Thesecondinjection12dayslaterwassuccessful(5).Untilthattime,T1DMwasafataldisease,whichitstillisinareasoftheworldwhereinsulinisunavailable.

PrevalenceTheestimatedworldwideprevalenceofT1DMinchildrenyoungerthan15yearsofagewasalmost500,000in2013(6).TheaverageannualincreaseofincidenceofT1DMworldwidewas2.8%peryearduringtheperiod1990-1999,withupto79,000newcasesworldwideperyearinchildrenaged0-15years(7).IntheUSA,theincidencerateincreasedby1.4%perannum(19.5casesper100,000youthayear in2002-2003to21.7casesper100,000person-yearsin2011-2012)(8,9).

Asmentioned,thehighestrecordedincidencerateofT1DMinchildrenwasinFinland(64.2per100,000person-years(2005))(10).Bycontrast,theincidenceinChinaandVenezuelaisonlyaround0.1casesofT1DMper100,000person-years(7,11).RecentstudiesshowedastabilizationoftheincidencerateinFinlandintheperiod2005-2011(1);similartrendswerefoundinNorwayandSweden(12).Mostwell-designedandlargerincidencestudiesarefromtheUSAandScandinavia.Un-

fortunately,reliableinformationislackingconcerningtheprevalenceandincidenceinmanydevelopingcountries.The InternationalDiabetesFederationatlasestimatesofworldwideprevalenceofT1DMinchildrenyoungerthan15yearsofagearepresentedinFigure1.DatafromtheNetherlandswereavailableinthreetimeperiods,themostrecentbeingfrom1996to1999 (6).Table1:Theestimatedprevalence in1978–1980and1996-1999was70per100,000person-years(13)and80per100,000person-years,respectively(14).AlthoughallpaediatricianscaringforchildrenwithT1DMintheNetherlandshavetheclinicalexperiencethattheincidenceofthediseasehascontinuedtoincreasesince1999,recentincidenceandprevalencedataonT1DMprevalenceinchildrenareunavailable.

11

Introduction

figure 1: Type1diabetesmellitusinchildrenandadolescents>>numberofnewcasesoftype1diabetesmellitusper100.000childrenandadolescents(0-14)peryear(2017)http://www.diabetesatlas.org/across-the-globe.html

Table 1: Incidence(95%CI)ofT1DMintheNetherlands1978–1980 1978–1980 1996–1999

0–4years 6.8(6.6–7.1) 6.4(6.2–6.7) 12.9(12.0–13.9)

5–9years 10.9(10.3–11.6) 12.4(12.0–12.7) 19.3(18.0–20.7)

10–14years 14.3(13.4–15.3) 18.1(17.6–18.6) 24.2(21.9–26.6)

Total(0–14years) 11.1(10.5–11.7) 12.4(12.0–12.8) Nodata

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Pathogenesis of T1dMIn thepathogenesisofT1DM,a lossofpancreatic isletβcells leads toaprogressiveandeventuallycomplete lossof insulinproducingcapacity in the individual (15).Theautoim-munemechanismsleadingtoinitiationofdamageandcompletedestructionofβcellsareonlypartlyunderstood.Thepathogenesisofthisdiseaseiscomplexandinfluencedbymanyfactors(figure2).

2

Figuur 2

Figuur 3

figure 2: Thenaturalhistoryoftype1diabetes–a25-year-oldconceptrevisedAre-creationofthemodeloftype1diabetes,originallyproposedin1986,isshowninblack.Additionsandconjecturesbasedonrecentknowledgegainsareshowninpurple.www.lancet.comVol383January4,2014

Most childrenpresentingwithT1DMhaveautoantibodies againstpancreaticβ cellsorautoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma-associatedautoantigen(IA2A)andzinctransporter8(ZnT8A)(16,17).TheseautoantibodiesareoftenalreadypresentyearsbeforetheclinicalonsetofT1DM(17).SomegeneticfactorsassociatedwithanincreasedsusceptibilitytodevelopT1DMhave

beenidentified.IndividualswithhaplotypesHLA-DR3-DQ2orHLA-DR4-DQ8aremorepronetodevelopβcellautoimmunity(18).Whateventuallytriggersthisautoimmunityisonlypar-tiallyknown;geneticsusceptibilityisadefinitefactor,bothinitself,butalsobyinfluencingtheseverityofresponsetoenvironmentaltriggers(19).Atthemoment,itisgenerallyacceptedthatanenvironmentaltriggerisneededtoactivate

theautoimmunedestructionofpancreaticβcells(21).Severalenvironmentalfactorshave

13

Introduction

beenproposedinstudies,includinginfections,especiallyviralinfectionswithe.g.retrovirusandenterovirus(17).StudiesexaminingtheincidenceofT1DMinrelationtoseasonofbirthandseasonofdiseaseonsetmayhelptosupportassociationswithsuchenvironmentalfac-tors(20,21).Anassociationwithseasonofonsetwouldpointtowardsseasonalenvironmen-talfactorstriggeringtheimmuneresponseleadingtoT1DM.TheEurodiabstudydescribedseasonalitywithpeakincidenceinthewinterin21ofthe23participatingEuropeancountries(22).AstheNetherlandshasnotbeenparticipatinginthisregistersince1999,seasonalitypatternsindiagnosisofT1DMintheNetherlandsareunknown.

Additional autoimmune diseases in T1dMPatientshavingT1DMaremorepronetodevelopotherautoimmunediseases,themostcom-monbeingautoimmunethyroiddiseaseandcoeliacdisease.Lesscommonareautoimmunegastric disease, Addison’s disease, autoimmune hepatitis, myasthenia gravis, perniciousanaemia,vitiligo,non-organspecificautoimmunediseaseandmultipleautoimmunediseases(suchasjuvenileidiopathicarthritis,Sjögrensyndrome,psoriasisandsarcoidosis)(24).The prevalence of autoimmune thyroid disease (AITD) in a combined population of

childrenandadultsinEuropeisestimatedtobe3%forhypothyroidismand0.75%forhy-perthyroidism(23).InchildrenwithT1DM,detectableantithyroidantibodieswerereportedin15%-19%ofpatients(25,26).Unfortunately,itisatpresentunknownwhatproportionofchildrenwiththyroidautoantibodieswilldevelopAITD,withestimatesrangingfrom3%to60%(24–26).TheprevalenceofovertthyroiddiseaseinchildrenintheNetherlandswithandwithoutT1DMisunknown.

Clinical presentationAlthoughT1DMcanhaveitsdébutinadulthood,thepeakincidenceageisinchildhoodandadolescence(27).Classicalclinicalfeaturesincludepolydipsia,polyuria,weightlossduetohyperglycaemiaandsometimespolyphagiaandblurredvision(28).

Othertypesofdiabetesinchildrenandadolescentsincludetype2diabetesmellitus(T2DM),maturityonsetdiabetesof theyoung (MODY),Kir6.2diabetes,diabetesassociatedwithcysticfibrosisandsteroidinduceddiabetes.

T2DMischaracterizedbyincreasinginsulindemandcausedbyincreasedinsulinresistanceresultinginarelativeinsulinshortage(insteadoftheabsoluteshortageinT1DM).However,thisrelativeshortageoccursmostly inadults(29,30).MostT2DMcasesbecomemanifestwhenβcellsareincapableofmeetingthisincreaseddemand.Acombinationofhereditary,social,behaviouralandenvironmentalfactorsplayaroleintheaetiologyofthisdisease(31).It isestimatedthat8-45%ofchildrenwithdiabetes intheUSAhaveT2DM,comparedtoapproximately2%intheNetherlands.ThishigherprevalenceofT2DMintheUSAislargely

Chapter1

14

explainedbythemuchhigherprevalenceofoverweightandobesityintheUSAcomparedtotheNetherlands,especiallyinminoritypopulations(32).

MODYisamonogeneticautosomaldominantdefectinβcellfunctionrepresenting1-2%ofchildrenwithdiabetes.MODYischaracterizedbyhyperglycaemiastartingatanagebelow25causedbyimpairedinsulinsecretionwithminimalornodefectsininsulinaction(33).Finally,anyprocessthatdiffuselyinjuresthepancreascanleadtodiabetes,suchaspancre-

atitisandtrauma,endocrinopathies,drugorchemicallyinducedglucosemetabolismdisorders,infection,geneticsyndromessuchascysticfibrosis,andgeneticdefectsininsulinaction(32).Inthisthesis,onlychildrenwithT1DMwillbestudied.

Treatment opti ons for glycaemic controlThemainstayofT1DMtreatmentistheexogenousreplacementof insulintocompensateforthelossofendogenousinsulinproduction.Achievinggoodglycaemiccontrol(withbloodglucoseconcentrationsbetween4.5and9mmol/l) remainsamajorchallenge inand formostpatients,however.Ideally,insulinreplacementtherapyshouldmimicthephysiologi-cal insulinsecretionresponseasmuchaspossible. Indailypractice,however,findingandmaintainingthebalancebetweenshort-termcomplications(i.e.hypoglycaemicevents,therisk ofwhich increaseswith strict insulinmanagement) and long-term adverse sequelae(microvascularcomplicationssuchasretinopathy,renalfailureandneuropathy,whichareless likelywithstrictglucosemanagement) isastruggle forpatientsandtheir families.Avarietyoftreatmentmethodsandschemeshavebeendevelopedtoimproveandmaintainoptimalglycaemiccontrol,mostlybysubcutaneousinsulinadministration.The twomost commonly used treatment strategies aremultiple daily injections (MDI)

(Figure3),combiningalongactinginsulincoveringabasalneedduringthedaywithshortacting insulin injectionsadministeredbeforethemeals,andcontinuoussubcutaneous in-sulininfusion(CSII)(26).CSIIinvolveswearingadevice(comprisinganinsulinpumpandaninfusionset,includingacannulaforsubcutaneousinsertionandatubingsystemtoconnecttheinsulinreservoirtothecannula)whichprovidesasteadyflowofshortactinginsulinintothebody.The“basalflow”deliversinsulinbetweenthemealsandatnight,andbolusdosesareadministeredtocoverthefoodeatenandcorrecthighbloodglucoselevels.

B L D BSfigure 3: principleofmultipledailyinjections(MDI):thebasalflow(greyhorizontalbar)coverstheinsulinrequirementovernightandbetweenmeals,theboluses(yellowhumps)representtheextrainsulinrequiredtoprocessglucoseintakeduringbreakfast(B),lunch(L)anddinner(D).Beforesleep(BS)

15

Introduction

Strivingforoptimalglycaemiccontrolrequiresrepeatedorongoingmeasurementofbloodglucose levels, either by using a blood glucosemeter (self-monitoring of blood glucose,SMBG)orwithareal-timecontinuousglucosemonitoringsensorsubcutaneously(rtCGM).Technological advances aimed at progressive integration of CSII and rtCGM are being

made,especiallyindevelopedcountries.Sensor-augmentedpumpsystemsarealreadybe-ingusedinclinicalpractice,allowingautomatedstopsofinsulindeliverywhenglucoselevelsdropbelowaspecifiedcut-offpoint(34).Anevenmoresophisticatedclosedloopsystemwithbothloweringorstoppingofinsulindeliveryincaseofhypoglycaemiaandincreasedinsulin delivery in case of hyperglycaemia (thus increasinglymimicking the physiologicalfunctionofthepancreasautomatically)isexpectedwithinthenextfewyears(35).Besidesthesetechnicaldevelopments,thereisthepossibilityofislet-celltransplantationor

pancreatictransplantation,forexampleinpatientswithsevere,lifethreatinghypoglycaemia,severeglycaemicvariabilityandprogressivediabeticcomplications.Improvementsoftrans-plantproceduresandimmunosuppressiveregimenshaveledtobetterlong-termresults.Inse-lectedcentresofpancreas-alonetransplantation,five-yearinsulinindependenceratesofmorethan50%havebeendescribed(36).Remainingchallengesforlargerscaleimplementationofthistreatmentincludetheshortageofhumandonorpancreases,theneedforimmunosuppres-sionandtheinadequacyoftheisletisolationprocess(37).IntheNetherlands,allchildrenwithT1DMarebeingtreatedwithinsulinusingCSIIorMDIsothisthesisfocusedonthistreatment.

Treatment goals in children with T1dMAccordingtothe InternationalSocietyofPaediatricandAdolescentDiabetes (ISPAD), themaingoalsoftreatmentofchildrenwithT1DMaretonormalizegrowthanddevelopmentandtoreducetherisksofshort-andlong-termcomplicationsbyoptimalglycaemiccontrol(table2)(38).Thelong-termmicrovascularcomplicationsofT1DMarerelatedtothedegreeoflong-termmetabolicdysregulation:thehighertheHbA1coveralongperiodoftime,thehigherthemicrovascularcomplicationrisk.T1DMisalsoassociatedwithanincreasedriskofmacrovascularcomplications.Thisisonlypartlydependentonthedegreeoflong-termmetaboliccontrol(38,39).

Table 2: complicationsofT1DMshorttermcomplications - hypoglycaemia

- hyperglycaemia- ketoacidosis

LongtermcomplicationsMicrovascular

- retinopathy- nephropathy- peripheralneuropathy- autonomicneuropathy

LongtermcomplicationsMacrovascular

- cardiovasculardisease- peripheralarterialdisease- cerebrovasculardiseases

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AnothergoalofT1DMtreatmentistofacilitatethepatientinleadingalifeasnormallyaspossiblewithoutlimitations,orasfewaspossible,indailyactivity.GoodglycaemiccontrolallowschildrentogotoschoolwithoutinterruptionsintheireducationduetotheirT1DM,andtoparticipateinsportsandothersocialactivitiestothesameextentaschildrenwithoutT1DM.

Achieving good glycaemic control requires properly developed self-management skills,including a correct use of insulinwithMDI or CSII, and frequent daily SMBG or rtCGM.Developingthesecomplexandsophisticatedself-managementskillsrequiresextensiveandongoing education, and amutually trusting relationship between patients, parents, andmedicalteam.Diabetesself-managementwillofcoursehavetotakeintoaccountdifferencesbetweenchildrenofvariousagesanddifferencesinunderstandingand(coping)possibilitiesofbothpatientsandcaregivers(32).DespitethecriticalimportanceofteachingandlearningproperT1DMself-managementskills for long-termglycaemiccontrol, there ishardlyanyevidenceonthekeyfactorsrelatedtosuccessfulself-managementeducationindiabetes.

Unfortunately, in daily practice, it is hard to achieve and maintain treatment goals asrecommendedintheISPADguidelines,especiallyduringpuberty(40).AdministeringinsulinbolusesandperformingSMBGjustbeforeorduringmealsisparticularlychallenginginado-lescents.AdolescentsusuallymanagetheirT1DMincreasinglyindependently,withwaningsupervision fromtheirparentsorcaregivers.However,manyadolescents lack thecopingand problem-solving skills to adequately self-manage their disease, and poor adherenceto insulin treatment is particularly common in this age range (42,43).Most childrenandadolescentswithT1DMdonotreachtheirHbA1ctargets,especiallyadolescentgirlswithlongstandingdisease (44–46).Although it isgenerallyassumed thatadherence to insulinmanagementisofkeyimportancefortheshort-andlong-termcomplicationriskinT1DMand thatpooradherence to insulinmanagement is common in thepaediatricage range,particularlyinadolescents,theliteratureontheimpactandthedeterminantsofpooradher-enceinT1DMinchildrenissurprisinglyscant.Inthefewshort-termstudiesavailable,insulinbolusfrequencyandSMBGfrequencyweredeterminantsofHbA1clevels(47).

ThemanagementofT1DMisintensiveandcomplex.Overthepastdecades,managementofthisdiseasehasevolvedfroma‘one-sizefitsall’MDIapproachtoapatient-specificmulti-disciplinaryteamapproachwithmanydifferentinsulinpreparationsforMDI,CSII,combinedwitheitherSMBGorCGM.Withthiscomplex,intensiveandmultidisciplinarycare,thecostsoftreatmentperchildhaveincreasedsignificantly(41).TogetherwiththeincreasedT1DMprevalenceinchildren,thiswillhaveconsiderableimpactonthenationalhealthcarebudgetneededtodeliverappropriatecareforthesepatients.

17

Introduction

From a societal point of view, helping children and their parents to cope with T1DMself-management,willhelpto lessenthe individualandfamilyburden.Dependingontheinsurancesystemofacountry,thecostsinvolvedinpropermanagementandtreatmentofT1DMwillbeincurredbythecommunitythoughhealthinsurance,bythefamilyitself,oracombinationofthesetwo.IntheNetherlands,T1DMtreatmentcostsaremainlybornebythecommunitythroughuniversalhealthinsurance.EffortstoclearlydemonstratethefinancialimpactofT1DMmanagementinacountryare

quiteoftenhamperedbytherestrictedavailabilityofdataoncostsandtheneedtoobtainsuchinformationfromasometimesoverwhelmingarrayofdatasources.IntheNetherlands,informationofhealthreimbursementdataisconcentratedinthena-

tionalhealthcareinformationcentreVektis(48).Vektiswassetupbyhealthinsurerstosup-portclaimsreimbursementandenablethemainstakeholdersinDutchhealthcaretobasetheirdecision-makingandpolicyexecutiononreliable,essentialandtimelydata(48).ThisallowstheassessmentofinformationwithregardstothemajorityofcostsinchildrenandadolescentswithT1DMintheNetherlands.Informationonpersonalandfamilyexpensesinrelationtodiabetesismoredifficulttoobtain.

Aims of this thesis

Incidence and prevalence of T1DM in Dutch children

Duringthe last25yearstheprevalenceofT1DMincreasedworldwide. InEurope,the in-creaseinincidencerateappearstobe3-4%perannumwithavarietyintherateofincrease(7).BecauserecentdataontheincidenceofT1DMinDutchchildrenwerelacking,theVektisdatabasewasusedtoexaminetheprevalenceandincidenceofT1DMinDutchchildren0-14yearsofageoverseveralyears(Chapter2).

Seasonality of diagnosis in children with type 1 diabetes mellitus

The seasonality ofmany infectiousdiseases has beendescribed in detail (49). Infectiousdiseases,which in part also have a seasonal distribution in their occurrence, are one ofthemost commonlymentionedpossible triggers in thedevelopmentofT1DM.AlthoughseasonalityofT1DMindifferentagegroupshasbeenexamined(43,19),withmoststudiesreportingapeakincidenceintheautumnandwinter(50,51),itisunknownwhetherandtowhatextentthisphenomenonexistsintheNetherlands.Wethereforestudiedtheseasonal-ityofT1DMdiagnosisinDutchchildren(Chapter3).

Thyroid disease and type 1 diabetes mellitus

AlthoughtheincreasedriskofautoimmunethyroiddiseaseinchildrenwithT1DMisuniver-sallyacknowledged,thescientificbasisforthisassociationislargelybasedonthedemon-strationofanti-thyroidantibodiesinthebloodofT1DMpatients.Onlyabouthalfofpatients

Chapter1

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withsuchanti-thyroidantibodieswilldevelopovertautoimmunethyroiddisease,andtheincidenceandprevalenceofovertautoimmunehypo-andhyperthyroidisminchildrenwithT1DMarelargelyunknown.ThiswasthetopicofthestudyinChapter4.

The overall health expenditure of a child with type 1 diabetes mellitus

StudiesoncostsrelatedtoT1DMamongchildrenarescarce(52–54).AlthoughtheavailableliteraturesuggestsanincreaseintheT1DM-relatedcostsoverthelastdecades,nodataareavailableonthecostsofT1DMmanagementfortheDutchhealthcaresystem.In Chapter 5,boththeoverallhealthcarecostsinchildrenwithT1DMandthemorespecificcostsrelatedtothemanagementofT1DMwereinvestigated.

Adherence to mealtime insulin bolusing and glycaemic control in adolescents on insulin pump therapy

Poor self-management contributes to insufficient glycaemic control in adolescents withT1DM.However,studiesexaminingtheimpactofpooradherencetoCSIIonmedium-andlong-termglycaemiccontrolarerareinthepaediatricagerange,specificallyinadolescents.InChapter 6, we investigated the relation between adherence tomealtime boluses andSMBGwithglycaemiccontrolinadolescents.

Factors related to optimal insulin pump management in adolescents with T1DM.In children with a chronic disease such as T1DM, nonadherence is common. Optimal

managementofT1DMimprovesbothshort-termglycaemiccontrolandthepreventionoflong-termadversesequelae.Factorsunderlyingoptimaladherencetoself-managementinCSII are largelyunknown,however. InChapter 7,weanalysed theassociationofoptimaladherence toCSII self-management in relation toage,gender,diabetesdurationand theresultsofanumberofquestionnairesassessingthepsychologicalandsocialconsequencesofT1DMfilledoutbypatientsandparents(includingtheFearofself-testingquestionnaire,Blood glucosemonitoring communicationquestionnaire, the illness perceptionquestion-naire(IPQ),theproblemareasindiabetes(PAID–T)questionnaire,andtheDiabetesfamilyconflictscale).

AgeneraldiscussionofthefindingofthesestudiesareispresentedinChapter 8.

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Introduction

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