胡仁明-糖尿病課件

Classificationofdiabetes(ADA-1997)Type1

(beta-celldestruction,usuallyleadingtoabsoluteinsulindeficiency)

AutoimmuneIdiopathicType2

(mayrangefrompredominantlyinsulinresistancewithrelativeinsulindeficiencytoapredominantlysecretorydefectwithorwithoutinsulinresistance)

Otherspecifictypes

Gestationaldiabetes**第一頁第二頁，共104頁。Otherspecifictypes

Geneticdefectsofbeta-cellfunctionGeneticdefectsininsulinactionDiseasesoftheexocrinepancreasEndocrinopathiesDrug-orchemical-inducedInfectionsUncommonformsofimmune-mediateddiabetesOthergeneticsyndromessometimesassociatedwithdiabetes第二頁第三頁，共104頁。Pathogenesis

第三頁第四頁，共104頁。PathologyType1DM：inflammationofpancreasType2DM：amyloidosisofpancreasLargevessel：atherosclerosisKidney：diffuseornodularglomerularsclerosisRetina：arteriolarsclerosis、microaneurysm、exudates、newvesselformationNerve：axondegeneration、myelinolysis第四頁第五頁，共104頁。Pathophysiology

第五頁第六頁，共104頁。AbnormalitiesinmetabolismCarbohydrate：anabolism

，catabolism

、utilizationLipid：anabolism

，catabolism

，ketoplasiaprotein：anabolism

，catabolism

，glyconeogenesis第六頁第七頁，共104頁。Insulinsecretioncurve:normalanddiabetics第七頁第八頁，共104頁。ClinicalPresentation

第八頁第九頁，共104頁。Naturalhistoryoftype2DMAfterthediagnosisoftype2diabetes:IRconstantlyexistsInsulinsecretionabilitygraduallydeclines:WhenFPGreachsthediagnosticcriteria，insulinsecretionabilityhasalreadydeclinedby50%WhenFPG≥7.0mmol/L，-cellinsulinsecretionabilityWhenFPG≥1011.0mmol/L，-Cinsulinsecretionabilityhasalreadynearedabsolutedeficiency第九頁第十頁，共104頁。Modelsoftheonsetoftwophrasesoftype2DMNGTIGR(IFG、IGT)

DM

cellexhaustionInsulinresistanceInsulinresistance第十頁第十一頁，共104頁。WHOplasmaglucoseguidelineIGTIFGNGTDM75gOGTT2hPG

(mmol/L)FPG(mmol/L)7.06.1FPG7.811.1IGT第十一頁第十二頁，共104頁。Comparisonoftype1andtype2DM

type1DMtype2DMUsualageofonset<30years>40yearsModeofonsetacutechronicweightnormaloverweightorobesityorweightlosssymptomspolyuria,polydipsia,similarbutusuallyweightlosslessseverepresentationAcutecomplicationsoftenfewChroniccomplicationsLargevesseldiseaselessthentype2DMleadingcauseofdeathRenaldiseaseleadingcauseofdeath5%

10%Insulinandc-peptideloworlackpeakvaluedelayed,highordeficiencyImmunemarkerusually+usually-Therapyinsulindependenceoralantidiabeticagentsareavailable第十二頁第十三頁，共104頁。ChroniccomplicationsMacrovasculardiseaseMicroangiopathyDiabeticretinopathyDiabeticrenaldiseaseDiabeticneuropathyDiabeticdermatopathyInfection第十三頁第十四頁，共104頁。MechanismofcomplicationsActivationofpolyol（orsorbitol）pathway

Formationofnon-enzymesaccharificationproductsChangeofhemodynamicsActivationofPKCMicroangiopathytheory第十四頁第十五頁，共104頁。HyperglycemiaistheessentialreasonfordiabeticcomplicationsDCCT

DiabetesControlandComplicationsTrialUKPDSUnitedKingdomProspectiveDiabetesStudy第十五頁第十六頁，共104頁。UKPTS：resultsHbA1c0.9%，（intensivetherapyvsroutinetherapy）Intensivetherapygroup:diabetisassociatedcomplications12%，andthefatalnessofmicrovascularcomplications25%。Itcannotevidentlyreducetheincidenceofgreatvesseldisease,suchasmiocardialinfarctionandstrock.Moststimulatingfindings：Biguanidescanpreventorslowtheonsetand/orprogressionofdiabeticcomplicationsinoverweightpatientsTightcontrolofhypertensioncanpreventorslowtheonsetand/orprogressionofdiabeticcomplicationsby24%（144/82mmHgvs154/87mmHg），strokeby44%，microvascularcomplicationsby37%。第十六頁第十七頁，共104頁。Epidemiologyofdiabetes

MacrovasculardiseaseDiabeticsareeasytogetatherosclerosisMonckeberg’ssclerosis41.5％Intimalarteriosteogenesis29.3％Coronaryheartdisease、cerebrovasculardisease：24timesRiskofmiocardialinfarction：10timesRiskofstroke:3.8times，especiallyinwomenRiskoflowerlimbamputation：15times，fatalness第十七頁第十八頁，共104頁。HypertensioninDMMorbidityratediabetes:20%

40%DiabetesinEU(35-54years):30%

50%DiabetesinChina:29.2%pathogenesisaortosclerosisArteriolaresistanceHypertensionassociatedwithDNRenalhypertensioncausedbystenosisofrenalartery第十八頁第十九頁，共104頁。Diabeticretinopathy－leadingcourseofnewcasesofblindnessPathogeny：stateofillness、courseofdisease、ageofonset<5years：eyegrounddiseaseisnotcommon<10years：50％eyegrounddisease<20years：80

90％eyegrounddisease

DiabeticRetinopathy第十九頁第二十頁，共104頁。Classifications(China)BackgroundretinopathyⅠmicroaneurysms、dotsofhemorrhagesⅡyellowandwhitehardexudates,haemorrhagesⅢwhitesoftexudates,haemorrhagesspotsProliferativeretinopathyⅣnewvesselformation、haemorrhageintothevitreousⅤnewvesselformationandfibrosisⅥretinaldetachment第二十頁第二十一頁，共104頁。DiabeticnephropathyDNistheleadingcauseofESRD(end-stagerenaldisease)Almost40％ofType1DMdiedofuremiaIncidenceofDNintype2DMisabout20％InEU，DNaccountsfor1/3ofdialysisandkidneytransplantationcasesInChina,DNalsoaccountsforquitealotofdialysesandkidneytransplantations第二十一頁第二十二頁，共104頁。Stagesofdiabeticnephropathy(1)stageIincreasedkidneyDMalreadyfiltrationdiagnosisedGFR↑↑enlargedkidneys(B-ultrasonic)GFR>130ml/minStageIIclinicallysilentphaseDM2

5yearGFR↑20

40％renalenlargement， withcontinuedglomerularhypertrophy,hyperfiltrationandhypertrophyexpansionofthemesangialmatrix thickeningoftheglomerularbasementmembraneresultinginglomerulosclerosis

StageIIIconcealedDNmicroalbuminuriaDM5

10yearmicroalbuminuria1/5patientswithhypertension(20-200μg/minretinopothy↑,or30

300mg/24h)proteinuria0.15

0.5g/24hGFR>or=normal第二十二頁第二十三頁，共104頁。Stagesofdiabeticnephropathy(2)StageIVOvertNephropathy

DM10

25yearalbuminuria>300mg/d60

70％patientsproteinuria>0.5g/d，withhypertentioGFR↓(whenUAER=100andedemamg/24h,GERbegintodecrease，about1ml/min/month)retinopathy↑↑

StageVend-stagerenaldisease,ESRDDM15

30yearalbuminuriaazotemic→uremiaGFR<1/3ofnormal第二十三頁第二十四頁，共104頁。Classificationofdiabetesneuropathy（1）Peripheralneuropathy

symmetricmultipleperipheralneuropathysensibilitymultipleneuropathynumbnesstype

paintypenumbness-paintypesensomotormultipleneuropathyacuteorsub-acutemotormultipleneuropathyasymmetricsingleormultipleperiphearalneuropathymemberortorsomononeuralcranialnervesdiseaseradiculopathyproximalmotorneuropathyautonomicneuropathyAutonomicneuropathydiabeticmyelopathydiabeticspinalataxiaspinalmuscularatrophyCerebropathyHypoglycemiacerebropathydiabeticcomacerebrovasculardisease第二十四頁第二十五頁，共104頁。DiabeticsensabilitymultipleneuropathymorecommoninfemaleAverageageofonsetis58.7yearCourseofDM>15yearsSymptomsofsenseNumbnesstype：largemedullatedfibersPaintype：littlemedullatedfibersandnonmedullatedfibersNumbness-paintype第二十五頁第二十六頁，共104頁。

NervoussymptomexaminationparasthesiaLowerlimbspallestheticdisturbanceordissapearTendonreflexlowordissappearSensorystaxiaParatrophysymptomsCharcotarthropathy、ischemicgangrenosisandfootulcer第二十六頁第二十七頁，共104頁。DiabeticautonomicneuropathyPupildiseaseCardiovascularparafunctionFixedheartratePosturalhypertensionSuddencardiacdeathGestrophageal,diarrheaNeuropathicbladder,erectilefailureAbnormalsweating第二十七頁第二十八頁，共104頁。Glucosuria：associatedwithrenalthresholdofsugar(onlyforclue)KetonuriaBloodsugar：plasmaglucose，PODHBA1c：2

3monthsbloodsugarlevelFructosamine：2

3weeksbloodsugarlevelOGTT：2hourspecimenInsulinandC-peptidereleasetestLaboratorytests第二十八頁第二十九頁，共104頁。Diagnosis第二十九頁第三十頁，共104頁。CriteriafordiagnosingdiabetesFPGRandomOGTTplasmaglucose2hPGmmol/Lmmol/Lmmol/LDM≥7.0≥11.1≥11.1IGRIFG6.1≤FPG<7.0IGT7.8≤FPG<11.1Normal<6.1<7.8第三十頁第三十一頁，共104頁。CharacteristicsofnewdiabeticdiagnosticcriteriaFPG<6.1mmol/Lisnormalfastingglucose，OGTT2hPG<7.8mmol/Lisnormalglucosetolerance；Impairedfastingglucosecorrespondingwithimpairedglucosetolerance(IFG)：6.1mmol/L≤FPG<7.0mmol/L；ThecutoffvalueofFPGdeclinefrom7.8mmol/Lto7.0mol/L.thecutoffvaluesofOGTT2hrPGandrandomplasmaglucoselevelarestill11.1mmol/L；FPGistheinitialscreeningtestofdiabetes，OGTTisnotrecommendedforroutinediagnosticuse.ThediagnosesofGestationaldiabetesisnotchanged第三十一頁第三十二頁，共104頁。PracticalproblemsindiagnosisSymptoms＋randomplasmaglucose≥11.1mmol/LFPG：≥7.0mmol/LOGTT：2hPG≥11.1mmol/LAsymtomaticpersonstestsshouldberepeatedtheonce第三十二頁第三十三頁，共104頁。latentautoimmunediabetesmellitusinadults（LADA）AdultonsetSymptomsareevidentSecretionfunctionofcellislowGADApositiveHLA-DQBchainisnonaspartatehomozygote第三十三頁第三十四頁，共104頁。Management第三十四頁第三十五頁，共104頁。GoalsGoodmetabolismcontrol（bloodsugar、bloodlipid、HBA1Cetc）RelievesymptomsKeepinggoodphysiologicstateandasociallifeGoodqualityoflivePreventthedevelopmentofacutecomplicationsofdiabetes（hypoglycemia、DKA、hyperosmolarnonketoticsyndrome、lacticacidosis）Preventingthedevelopmentordelayingtheprogressionofthechroniccomplicationsofdiabetes第三十五頁第三十六頁，共104頁。PrincipleoftreatmentEarlyLife-longsynthesisindividual第三十六頁第三十七頁，共104頁。Goalsofcontrol

goodaveragebad

PBG(mmol/L) fasting4.4-6.1

7.0>7.0non-fasting4.4-8.0

10.0>10.0HBA1c(％) <6.56.5-7.5>7.5 BP(mmHg)<130/80>130/80-<140/90 >140/90 BMI(Kg/m2)M<25M<27

27 F<24F<26F

26TC

(mmol/L)

<4.5

4.5

6.0 HDL-c(mmol/L)

>1.11.1-0.9<0.9 TG

(mmol/L)

<1.5 <2.2

2.2 LDL-C

(mmol/L)<2.5 2.6-4.40 >4.0第三十七頁第三十八頁，共104頁。ControlactualityofDMinChina26centers、3965patients28％patientsmeasureHbA1c：8.12.6%，52％>7.5％FPG：9.23.7mmol/L，55%>7.8mmol/LDetermingrateofmicroalbumininurine：20％第三十八頁第三十九頁，共104頁。DiabetesManagementPlanPatienteducationHealthnutritiontherapyExercisetherapyDrugtherapyMonitoringofbloodglucose第三十九頁第四十頁，共104頁。PhasestherapyofDMEarlyreactionPatienttherapyMedicalnutritiontherapyExercisetherapySingledrugtherapydeclineofcurativeeffectCombineddrugtherapySecondaryfailure、distinctinsufficiencyofinsulinInsulintherapy第四十頁第四十一頁，共104頁。PrinciplesofmedicalnutritiontheraphyrationalcontroloftotalcalorificvalueGoal：KeepidealbodyweightLossweightforobesepatientAddweightforleanpatientStandardbodyweight＝height（cm）－105male：（height－100）×0.9female：（height－100）×0.85Bodymassindex（BMI）：weight（kg）/height2（m2）第四十一頁第四十二頁，共104頁。Adult-onsetdiabetesthermalenergysupplyperday（therm/kgstandardweight）

workintension Bodilyform

inbedlightphysicalmiddleheavylaborphysicalphysicallaborlaborlean20

253540>40normal15

20303540obesity1520

253035第四十二頁第四十三頁，共104頁。

Nutritionprinciplesofdiabetics

ModerateweightcontrolThedistributionoftotalcalorficvalue：carbohydrate55%

60%fat20%

25%1/5、2/5、2/5protein15%

20%DrinklimitationAvoiding‘diabetic’foods(whichcontainsorbitolorfrucotose)Aspartameisanacceptablecalorie-freesweetenersalt<10g/d，(<3g/dayifhypertensive)第四十三頁第四十四頁，共104頁。Calculationprotein：0.81.2/kgstandardweightfat：0.61.0/kgstandardweightcarbohydrate：totalcalorificvalue－caloriesofproteinandfat第四十四頁第四十五頁，共104頁。ExercisetherapyBenefitsGlycaemiccontrolIncreaseβcellsensitivitytoglucoseBloodlipidWeightreductionEstimationofquantityofexercise：heartrate<170－age(year)第四十五頁第四十六頁，共104頁。DrugtherapySulfonylureasBiguanidesα-glucosidaseinhibitorsTniazolidinedionesMeglitinidesInsulinDry-combinationtherapy第四十六頁第四十七頁，共104頁。Sulfonylureas:modeofactionTheprincipalactionofthesedrugsistostimulateendogenousinsulinsecretionfromthepancreaticβ-cellsNottoincreasesynthesisofinsulinAlsotoincreaseβ-cellssensitivitytoglucoseandexertsomeinfluenceindiminishinginsulinresistance.第四十七頁第四十八頁，共104頁。Sulfonylureas（SU）：firstchoiceofnon-obesityT2DM

GeneralnamedurationofactionpotencymeritsmainsiteofexcretionTolbutamide(D860)shortweakcheaprenalGlyburide(micronase)longstrongaffirmedhypoglycemiaeffectsinloweringbloodglucoselevels cheaprenalGliclazide(diamicvon)mediumstrongpreventandrenalglipizide(minidiab)shotstrongaffirmedeffectsrenalGliquidone(glurenorm)shotweeknotrenal(only5%)Glipizide(tonbac)longstronggoodcompliancelowincidenceofhypoglycemia第四十八頁第四十九頁，共104頁。TherapeuticeffectsofSUPrimaryfailuretorespondtoSUoccursin20%to25%ofpatientsFPGand2hPGHbA1c1%

2％Astheperiodoftreatmentprogresses,effectsdecline：Secondaryfailureoccursattherateof10%to15%peryearAfter5years，onlyhalfofthepatientscankeepidealbloodglucosecontrol. UKPDS：firstyear:bloodglucose，insulinthen:bloodglucoseinsulinthe6thyear:returnedtothestatebeforetherapy第四十九頁第五十頁，共104頁。IndicationsandcontraindicationsofSUIndicationsPoorcontrolofT2DMbyweightcontrolandphysicalactivityPoorcontrolofT2DMbybiguanidesand

-CombinedwithinsulinContraindicationsT1DMAcuteorchronicdiabeticcomplicationsEmergencyDysfunctionofliverorkidneyPregnantorbleedingwomen第五十頁第五十一頁，共104頁。SideeffectsofSUHypoglycemia，mostcommoninOldpatientsLong-termpharmaceuticsSymptomsofdigestivetractLiverdysfunctionTetterChangeofhematology第五十一頁第五十二頁，共104頁。Biguanides：firstchoiceofobesitytype2DM

GenericnamedosagemeritsNB

phenformin<75mg/dcheaplacticacidosis（降糖靈） restrainoxygenicmetabolismlowerenergyofoxygenicmetabolismdimethylbiguanide<1.5g/dlowgastrointestinalside-effectsreaction（降糖片）

第五十二頁第五十三頁，共104頁。MechanismsofactionofbiguanidesIncreasingβcellsensitivitytoglucoseEnhancingglucoseuptakeandutilizationbymuscleReducingHGPbyinhibitinggluconeogenesis.DecreasingintestinalglucoseabsorptionDoNotstimulatingendogenousinsulinsecretionfromβcellDoNotcausinghypoglycemiawhenusedsingly第五十三頁第五十四頁，共104頁。indicationsandcontraindicationsofBiguanidesIndicationsObesityT2DMPoorcontrolbySUPoorcontrolbyinsulin，includingT1DMSimpleobesityPolycysticovarysyndromeContraindicationsAllergicreactionsRenaldysfunction，serumcreatinine>1.4mg/dlAcuteorchronicacidosisHeart、lungdisease：hypoxia、acidosisinclinationHypohepatiaSeveregastroenteropathyPregnancy第五十四頁第五十五頁，共104頁。SideeffectsofBiguanidesDiarrheaAnaphylaxisOvertmacies：commoninelderlypatientsLacticacidosis第五十五頁第五十六頁，共104頁。Inhibiting

-glucosidaseDelayingthedigestionofglucose2hPGNotstimulatingthesecretionofInsulinα-glucosidaseinhibitors:modeofaction第五十六頁第五十七頁，共104頁。TherapeuticeffectsofAcarbose2hPGFPGHbA1cabout1％.WhenusedincombinationwithSU,HbA1c:about2％SeruminsulinslightlydeclinedWeightnotafewpatientsWhenusedasmonotherapy,itdonotcausehypoglycemiaWhenusedincombinationwithotheroralantidiabeticagents,itmaycausehypoglyceiaIfhypoglycemiahappens,patientshouldbetreatedbyglucose.Otherkindsofsugarareineffective第五十七頁第五十八頁，共104頁。Indicationsandcontraindicationsof

α-glucosidaseinhibitorsIndicationsLightcasesusingdrugseparatelyorcombinedIGTintervention，securityContraindicationsAllergicreactionsSeveregastroenteropathyDysfunctionofrenalandliverAcutecomplicationsEmergencyPregnantandbreastfeedingwomen第五十八頁第五十九頁，共104頁。thiazolidinedion（TZD）：insulinsensitizersInsulinsensitizers;agonistattheperoxisomeproliferator-activatedreceptor

（PPAR

）;increaseglucoseutilizationinperipheraltissues.Reducinginsulinresistance，hyperglycemiaandhyperlipaemiaandhypertensioncanbeimprovedatvariesdegreesForT2DM:usedasmonotherapyorincombinationwithSU,insulin.WhenusedincombinationwithSUorinsulin,hyperglycemiaWithoutinsulin，itcannotreducehyperglycemiaLiverfunctionshouldbemonitoredfrequently.Stopusingitincaseliverdysfunctionisfound.Incidenceofedema:4

5%ItmaycauseHbslightly↓第五十九頁第六十頁，共104頁。Meglitinides：repaglinideStimulatePancreaticinsulinsecretion（similarwithSU）：specificcombinitionwith36KDaproteinKpathwaycloseStimulatingthefirstphrasesecretionofinsulinAction:rapidonset，shortduration，suppressingpostloadhyperglycemiaquicklySitesofexcretion:kidney8%，fecal92%Usedasmonotherapyorincombinationwithbiguanides，α-glucosidaseinhibitorsIncidenceofhypoglycemiaislow第六十頁第六十一頁，共104頁。FactorsinchoosingoralantidiabeticagentsageweightBloodglucoselevelFunctionofliverandkidneyCharacteristicofdrugcosts第六十一頁第六十二頁，共104頁。ChooseoforalantihyperglucemicagentsOlderpatients：shorttermSUObesityorhyperinsulinismpatients：biguanidesoracarbose2hPG：α－glucosidaseConcentrationofplasmaglucose：>270

300mg/dl.thesymptomsofhypertensionareevident.InsulintherapyisavailableImpairedliverandkidneyfunction：avoidusingOHALean、fastingandafter-excitationinsulinall：insulin第六十二頁第六十三頁，共104頁。Drug-CombinedtherapyReasonabledietandpoorplasmaglucosecontrolbymonotherapySU、biguanides、TZDandα-glucosidaseinhibitorsallcanbeusedincombinationwitheachotherSmalldosagecombinedwithofallkindsofdrugs;enhancingeffectsofreduceglucaemia;sideeffectsofsingleagentsOralagentswithinsulinDrugsofthesameclasscannotbeusedinacombinedway.第六十三頁第六十四頁，共104頁。Insulintherapy第六十四頁第六十五頁，共104頁。IndicationsofinsulinType1DMType2DMAcutecomplicationsSeverechroniccomplicationsofdiabetesEmergencySeveredysfunctionofliverorkidneyGestationandbleedingwomenWithouttoleranceOHA，curativeeffectofOHA，SUinvalidationDistinctleanWithdiseasestreatedbyglucocorticoidSomespecifictypesofDM：secondarypancreasdisease、endocrinopathies、geneticdiabetes第六十五頁第六十六頁，共104頁。ObstaclestousingInsinT2DM

oldnotion：NIDDMThedoctorusesOHAonlyanddoesnotseetheneedtouseIns.ThepatientdoesnotwanttouseInforfearofdevelopinginsulindependenceafteruseingit.HyperinsulinismcanleadAStoCVD？hypoglycemia，BW↑第六十六頁第六十七頁，共104頁。國(guó)內(nèi)常用胰島素一覽表產(chǎn)品名生產(chǎn)廠家種屬來源包裝(U/瓶)短效胰島素普通胰島素(RI)上海生物制藥廠豬400U/瓶?jī)?yōu)泌林R禮來基因重組400U/瓶諾和靈-R諾和諾德基因重組400U/瓶Lispro禮來基因重組400U/瓶中效胰島素優(yōu)泌林N禮來基因重組400U/瓶諾和靈-N諾和諾德基因重組400U/瓶NPH徐州生化制藥廠豬400U/瓶混合胰島素優(yōu)泌林70/30禮來基因重組400U/瓶(人工合成)諾和靈-30R諾和諾德基因重組400U/瓶諾和靈-30R諾和諾德基因重組300U/瓶長(zhǎng)效胰島素PZI上海生物制藥廠豬400U/瓶第六十七頁第六十八頁，共104頁。DifferencesbetweenhumanandanimalinsulinDifferenceinpharmacodynamic：CloseactionintensityHumaninsulin:absorptionisfast，timeofonsetofeffectisearlyDifferenceinimmunogenicity:AntigenicitofhumaninsulinisweakerthananimalinsulinAfterusehumaninsulin,antibodytiterofbloodinsulinislowerSynthesizedinsulin：lispro（28proline29proline）Quickabsorption,shorteffecttime第六十八頁第六十九頁，共104頁。Shot-termintensiveinsulin

therapyforT2DMIndications：monotherapyorcombinationtherapyoforalantihyperglycemiatherapyfailtoachieveglucosetargets，overthyperglycemia，fastingandpostprandialC-peptideMethod：useinsulin2timesperday：NPH/R70/30prebreakfastandpresupper，adjustthedosagewiththemonitoringresultsofbloodsugar.useinsulin4timesperday：RIpremeal、NPHbeforesleepPeriodoftreatment：severalweeksormonthes第六十九頁第七十頁，共104頁。Shot-termintensiveinsulin

therapyforT2DM

Estimationofinitialdosage：0.2

0.4U/KgweightperdayModeoftherapyRIbeforemeals：RI—RI—RI—O，beforebreakfast＞beforesupper＞beforedinerRIbeforethreemeals+RIbeforesupper：RI—RI—RI—RIRIbeforethreemeals+NPHbeforesupper:RI—RI—RI/NPHRIbeforethreemeals+NPHbeforesleep：RI—RI—RI—NPHmixedinsulin（RI/NPH）beforethreemeals（2/3beforebreakfast，1/3beforesupper），theproportion:10R—50RNPH/R70/30beforebreakfastandsupper第七十頁第七十一頁，共104頁。SecondaryfailureofOHA:combinationwithinsulinFPG

oralanti-hyperglycemiaagents+NPHbeforesleepPPG

NPHbeforebreakfast+oralanti-hyperglycemiaagentsFPG

PPG