糖尿病專業(yè)知識宣貫

DiabetesMellitusRenmingHuM.D,PhD

DepartmentofEndocrinologyHuashanHospitalInstituteofEndocrinologyandDiabetesatFudanUniversity第1頁Classificationofdiabetes(ADA-1997)Type1

(beta-celldestruction,usuallyleadingtoabsoluteinsulindeficiency)

AutoimmuneIdiopathicType2

(mayrangefrompredominantlyinsulinresistancewithrelativeinsulindeficiencytoapredominantlysecretorydefectwithorwithoutinsulinresistance)

Otherspecifictypes

Gestationaldiabetes**第2頁Otherspecifictypes

Geneticdefectsofbeta-cellfunctionGeneticdefectsininsulinactionDiseasesoftheexocrinepancreasEndocrinopathiesDrug-orchemical-inducedInfectionsUncommonformsofimmune-mediateddiabetesOthergeneticsyndromessometimesassociatedwithdiabetes第3頁P(yáng)athogenesis

第4頁P(yáng)athologyType1DM：inflammationofpancreasType2DM：amyloidosisofpancreasLargevessel：atherosclerosisKidney：diffuseornodularglomerularsclerosisRetina：arteriolarsclerosis、microaneurysm、exudates、newvesselformationNerve：axondegeneration、myelinolysis第5頁P(yáng)athophysiology

第6頁AbnormalitiesinmetabolismCarbohydrate：anabolism

，catabolism、utilizationLipid：anabolism

，catabolism

，ketoplasiaprotein：anabolism

，catabolism

，glyconeogenesis第7頁Insulinsecretioncurve:normalanddiabetics第8頁ClinicalPresentation

第9頁Naturalhistoryoftype2DMAfterthediagnosisoftype2diabetes:IRconstantlyexistsInsulinsecretionabilitygraduallydeclines:WhenFPGreachsthediagnosticcriteria，insulinsecretionabilityhasalreadydeclinedby50%WhenFPG≥7.0mmol/L，-cellinsulinsecretionabilityWhenFPG≥1011.0mmol/L，-Cinsulinsecretionabilityhasalreadynearedabsolutedeficiency第10頁Modelsoftheonsetoftwophrasesoftype2DMNGTIGR(IFG、IGT)

DMcellexhaustionInsulinresistanceInsulinresistance第11頁WHOplasmaglucoseguidelineIGTIFGNGTDM75gOGTT2hPG

(mmol/L)FPG(mmol/L)7.06.1FPG7.811.1IGT第12頁Comparisonoftype1andtype2DM

type1DMtype2DMUsualageofonset<30years>40yearsModeofonsetacutechronicweightnormaloverweightorobesityorweightlosssymptomspolyuria,polydipsia,similarbutusuallyweightlosslessseverepresentationAcutecomplicationsoftenfewChroniccomplicationsLargevesseldiseaselessthentype2DMleadingcauseofdeathRenaldiseaseleadingcauseofdeath5%10%Insulinandc-peptideloworlackpeakvaluedelayed,highordeficiencyImmunemarkerusually+usually-Therapyinsulindependenceoralantidiabeticagentsareavailable第13頁ChroniccomplicationsMacrovasculardiseaseMicroangiopathyDiabeticretinopathyDiabeticrenaldiseaseDiabeticneuropathyDiabeticdermatopathyInfection第14頁MechanismofcomplicationsActivationofpolyol（orsorbitol）pathway

Formationofnon-enzymesaccharificationproductsChangeofhemodynamicsActivationofPKCMicroangiopathytheory第15頁HyperglycemiaistheessentialreasonfordiabeticcomplicationsDCCT

DiabetesControlandComplicationsTrialUKPDSUnitedKingdomProspectiveDiabetesStudy第16頁UKPTS：resultsHbA1c0.9%，（intensivetherapyvsroutinetherapy）

Intensivetherapygroup:diabetisassociatedcomplications12%，andthefatalnessofmicrovascularcomplications25%。Itcannotevidentlyreducetheincidenceofgreatvesseldisease,suchasmiocardialinfarctionandstrock.Moststimulatingfindings：Biguanidescanpreventorslowtheonsetand/orprogressionofdiabeticcomplicationsinoverweightpatientsTightcontrolofhypertensioncanpreventorslowtheonsetand/orprogressionofdiabeticcomplicationsby24%（144/82mmHgvs154/87mmHg），strokeby44%，microvascularcomplicationsby37%。第17頁Epidemiologyofdiabetes

MacrovasculardiseaseDiabeticsareeasytogetatherosclerosisMonckeberg’ssclerosis41.5％Intimalarteriosteogenesis29.3％Coronaryheartdisease、cerebrovasculardisease：24timesRiskofmiocardialinfarction：10timesRiskofstroke:3.8times，especiallyinwomenRiskoflowerlimbamputation：15times，fatalness第18頁HypertensioninDMMorbidityratediabetes:20%40%DiabetesinEU(35-54years):30%50%DiabetesinChina:29.2%pathogenesisaortosclerosisArteriolaresistanceHypertensionassociatedwithDNRenalhypertensioncausedbystenosisofrenalartery第19頁Diabeticretinopathy－leadingcourseofnewcasesofblindnessPathogeny：stateofillness、courseofdisease、ageofonset<5years：eyegrounddiseaseisnotcommon<10years：50％eyegrounddisease<20years：8090％eyegrounddisease

DiabeticRetinopathy第20頁Classifications(China)BackgroundretinopathyⅠmicroaneurysms、dotsofhemorrhagesⅡyellowandwhitehardexudates,haemorrhagesⅢwhitesoftexudates,haemorrhagesspotsProliferativeretinopathyⅣnewvesselformation、haemorrhageintothevitreousⅤnewvesselformationandfibrosisⅥretinaldetachment第21頁DiabeticnephropathyDNistheleadingcauseofESRD(end-stagerenaldisease)Almost40％ofType1DMdiedofuremiaIncidenceofDNintype2DMisabout20％InEU，DNaccountsfor1/3ofdialysisandkidneytransplantationcasesInChina,DNalsoaccountsforquitealotofdialysesandkidneytransplantations第22頁Stagesofdiabeticnephropathy(1)stageIincreasedkidneyDMalreadyfiltrationdiagnosisedGFR↑↑enlargedkidneys(B-ultrasonic)GFR>130ml/minStageIIclinicallysilentphaseDM25yearGFR↑2040％renalenlargement，

withcontinuedglomerularhypertrophy,hyperfiltrationandhypertrophyexpansionofthemesangialmatrix thickeningoftheglomerularbasementmembraneresultinginglomerulosclerosis

StageIIIconcealedDNmicroalbuminuriaDM510yearmicroalbuminuria1/5patientswithhypertension(20-200μg/minretinopothy↑,or30300mg/24h)proteinuria0.150.5g/24hGFR>or=normal第23頁Stagesofdiabeticnephropathy(2)StageIVOvertNephropathy

DM1025yearalbuminuria>300mg/d6070％patientsproteinuria>0.5g/d，withhypertentioGFR↓(whenUAER=100andedemamg/24h,GERbegintodecrease，

about1ml/min/month)retinopathy↑↑

StageVend-stagerenaldisease,ESRDDM1530yearalbuminuriaazotemic→uremiaGFR<1/3ofnormal第24頁Classificationofdiabetesneuropathy（1）Peripheralneuropathy

symmetricmultipleperipheralneuropathysensibilitymultipleneuropathynumbnesstype

paintypenumbness-paintypesensomotormultipleneuropathyacuteorsub-acutemotormultipleneuropathyasymmetricsingleormultipleperiphearalneuropathymemberortorsomononeuralcranialnervesdiseaseradiculopathyproximalmotorneuropathyautonomicneuropathyAutonomicneuropathydiabeticmyelopathydiabeticspinalataxiaspinalmuscularatrophyCerebropathyHypoglycemiacerebropathydiabeticcomacerebrovasculardisease第25頁DiabeticsensabilitymultipleneuropathymorecommoninfemaleAverageageofonsetis58.7yearCourseofDM>15yearsSymptomsofsenseNumbnesstype：largemedullatedfibersPaintype：littlemedullatedfibersandnonmedullatedfibersNumbness-paintype第26頁

NervoussymptomexaminationparasthesiaLowerlimbspallestheticdisturbanceordissapearTendonreflexlowordissappearSensorystaxiaParatrophysymptomsCharcotarthropathy、ischemicgangrenosisandfootulcer第27頁DiabeticautonomicneuropathyPupildiseaseCardiovascularparafunctionFixedheartratePosturalhypertensionSuddencardiacdeathGestrophageal,diarrheaNeuropathicbladder,erectilefailureAbnormalsweating第28頁Glucosuria：associatedwithrenalthresholdofsugar(onlyforclue)KetonuriaBloodsugar：plasmaglucose，PODHBA1c：23monthsbloodsugarlevelFructosamine：23weeksbloodsugarlevelOGTT：2hourspecimenInsulinandC-peptidereleasetestLaboratorytests第29頁Diagnosis第30頁CriteriafordiagnosingdiabetesFPGRandomOGTTplasmaglucose2hPGmmol/Lmmol/Lmmol/LDM≥7.0≥11.1≥11.1IGRIFG6.1≤FPG<7.0IGT7.8≤FPG<11.1Normal<6.1<7.8第31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32頁P(yáng)racticalproblemsindiagnosisSymptoms＋randomplasmaglucose≥11.1mmol/LFPG：≥7.0mmol/LOGTT：2hPG≥11.1mmol/LAsymtomaticpersonstestsshouldberepeatedtheonce第33頁latentautoimmunediabetesmellitusinadults（LADA）AdultonsetSymptomsareevidentSecretionfunctionofcellislowGADApositiveHLA-DQBchainisnonaspartatehomozygote第34頁Management第35頁GoalsGoodmetabolismcontrol（bloodsugar、bloodlipid、HBA1Cetc）RelievesymptomsKeepinggoodphysiologicstateandasociallifeGoodqualityoflivePreventthedevelopmentofacutecomplicationsofdiabetes（hypoglycemia、DKA、hyperosmolarnonketoticsyndrome、lacticacidosis）Preventingthedevelopmentordelayingtheprogressionofthechroniccomplicationsofdiabetes第36頁P(yáng)rincipleoftreatmentEarlyLife-longsynthesisindividual第37頁Goalsofcontrol

goodaveragebad

PBG(mmol/L) fasting4.4-6.17.0>7.0non-fasting4.4-8.010.0>10.0HBA1c(％) <6.56.5-7.5>7.5 BP(mmHg)<130/80>130/80-<140/90 >140/90 BMI(Kg/m2)M<25M<2727 F<24F<26F26TC

(mmol/L)

<4.5 4.56.0 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38頁ControlactualityofDMinChina26centers、3965patients28％patientsmeasureHbA1c：8.12.6%，52％>7.5％FPG：9.23.7mmol/L，55%>7.8mmol/LDetermingrateofmicroalbumininurine：20％

第39頁DiabetesManagementPlanPatienteducationHealthnutritiontherapyExercisetherapyDrugtherapyMonitoringofbloodglucose第40頁P(yáng)hasestherapyofDMEarlyreactionPatienttherapyMedicalnutritiontherapyExercisetherapySingledrugtherapydeclineofcurativeeffectCombineddrugtherapySecondaryfailure、distinctinsufficiencyofinsulinInsulintherapy第41頁P(yáng)rinciplesofmedicalnutritiontheraphyrationalcontroloftotalcalorificvalueGoal：KeepidealbodyweightLossweightforobesepatientAddweightforleanpatientStandardbodyweight＝height（cm）－105male：（height－100）×0.9female：（height－100）×0.85Bodymassindex（BMI）：weight（kg）/height2（m2）第42頁Adult-onsetdiabetesthermalenergysupplyperday（therm/kgstandardweight

）

workintension Bodilyform

inbedlightphysicalmiddleheavylaborphysicalphysicallaborlaborlean20253540>40normal1520303540obesity1520253035第43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44頁Calculationprotein：0.81.2/kgstandardweightfat：0.61.0/kgstandardweightcarbohydrate：totalcalorificvalue－caloriesofproteinandfat第45頁ExercisetherapyBenefitsGlycaemiccontrolIncreaseβcellsensitivitytoglucoseBloodlipidWeightreductionEstimationofquantityofexercise：heartrate<170－age(year)第46頁DrugtherapySulfonylureasBiguanidesα-glucosidaseinhibitorsTniazolidinedionesMeglitinidesInsulinDry-combinationtherapy第47頁Sulfonylureas:modeofactionTheprincipalactionofthesedrugsistostimulateendogenousinsulinsecretionfromthepancreaticβ-cellsNottoincreasesynthesisofinsulinAlsotoincreaseβ-cellssensitivitytoglucoseandexertsomeinfluenceindiminishinginsulinresistance.第48頁Sulfonylureas（SU）：

firstchoiceofnon-obesityT2DM

GeneralnamedurationofactionpotencymeritsmainsiteofexcretionTolbutamide(D860)shortweakcheaprenalGlyburide(micronase)longstrongaffirmedhypoglycemiaeffectsinloweringbloodglucoselevels cheaprenalGliclazide(diamicvon)mediumstrongpreventandrenalglipizide(minidiab)shotstrongaffirmedeffectsrenalGliquidone(glurenorm)shotweeknotrenal(only5%)Glipizide(tonbac)longstronggoodcompliancelowincidenceofhypoglycemia第49頁TherapeuticeffectsofSUPrimaryfailuretorespondtoSUoccursin20%to25%ofpatientsFPGand2hPGHbA1c1%2％Astheperiodoftreatmentprogresses,effectsdecline：

Secondaryfailureoccursattherateof10%to15%peryearAfter5years，onlyhalfofthepatientscankeepidealbloodglucosecontrol. UKPDS：firstyear:bloodglucose，insulinthen:bloodglucoseinsulinthe6thyear:returnedtothestatebeforetherapy第50頁IndicationsandcontraindicationsofSUIndicationsPoorcontrolofT2DMbyweightcontrolandphysicalactivityPoorcontrolofT2DMbybiguanidesand-CombinedwithinsulinContraindicationsT1DMAcuteorchronicdiabeticcomplicationsEmergencyDysfunctionofliverorkidneyPregnantorbleedingwomen第51頁SideeffectsofSUHypoglycemia，mostcommoninOldpatientsLong-termpharmaceuticsSymptomsofdigestivetractLiverdysfunctionTetterChangeofhematology第52頁Biguanides：firstchoiceofobesitytype2DM

GenericnamedosagemeritsNB

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

第53頁MechanismsofactionofbiguanidesIncreasingβcellsensitivitytoglucoseEnhancingglucoseuptakeandutilizationbymuscleReducingHGPbyinhibitinggluconeogenesis.DecreasingintestinalglucoseabsorptionDoNotstimulatingendogenousinsulinsecretionfromβcellDoNotcausinghypoglycemiawhenusedsingly第54頁indicationsandcontraindicationsofBiguanidesIndicationsObesityT2DMPoorcontrolbySUPoorcontrolbyinsulin，includingT1DMSimpleobesityPolycysticovarysyndromeContraindicationsAllergicreactionsRenaldysfunction，serumcreatinine>1.4mg/dlAcuteorchronicacidosisHeart、lungdisease：hypoxia、acidosisinclinationHypohepatiaSeveregastroenteropathyPregnancy第55頁SideeffectsofBiguanidesDiarrheaAnaphylaxisOvertmacies：commoninelderlypatientsLacticacidosis第56頁Inhibiting-glucosidaseDelayingthedigestionofglucose2hPGNotstimulatingthesecretionofInsulinα-glucosidaseinhibitors:modeofaction第57頁TherapeuticeffectsofAcarbose2hPGFPGHbA1cabout1％.WhenusedincombinationwithSU,HbA1c:about2％SeruminsulinslightlydeclinedWeightnotafewpatientsWhenusedasmonotherapy,itdonotcausehypoglycemiaWhenusedincombinationwithotheroralantidiabeticagents,itmaycausehypoglyceiaIfhypoglycemiahappens,patientshouldbetreatedbyglucose.Otherkindsofsugarareineffective第58頁Indicationsandcontraindicationsof

α-glucosidaseinhibitorsIndicationsLightcasesusingdrugseparatelyorcombinedIGTintervention，securityContraindicationsAllergicreactionsSeveregastroenteropathyDysfunctionofrenalandliverAcutecomplicationsEmergencyPregnantandbreastfeedingwomen第59頁thiazolidinedion（TZD）：insulinsensitizersInsulinsensitizers;agonistattheperoxisomeproliferator-activatedreceptor

（PPAR）;increaseglucoseutilizationinperipheraltissues.Reducinginsulinresistance，hyperglycemiaandhyperlipaemiaandhypertensioncanbeimprovedatvariesdegreesForT2DM:usedasmonotherapyorincombinationwithSU,insulin.WhenusedincombinationwithSUorinsulin,hyperglycemiaWithoutinsulin，itcannotreducehyperglycemiaLiverfunctionshouldbemonitoredfrequently.Stopusingitincaseliverdysfunctionisfound.Incidenceofedema:45%ItmaycauseHbslightly↓第60頁Meglitinides：repaglinideStimulatePancreaticinsulinsecretion（similarwithSU）：specificcombinitionwith36KDaproteinKpathwaycloseStimulatingthefirstphrasesecretionofinsulinAction:rapidonset，shortduration，suppressingpostloadhyperglycemiaquicklySitesofexcretion:kidney8%，fecal92%Usedasmonotherapyorincombinationwithbiguanides，α-glucosidaseinhibitorsIncidenceofhypoglycemiaislow第61頁FactorsinchoosingoralantidiabeticagentsageweightBloodglucoselevelFunctionofliverandkidneyCharacteristicofdrugcosts第62頁ChooseoforalantihyperglucemicagentsOlderpatients：shorttermSUObesityorhyperinsulinismpatients：biguanidesoracarbose2hPG：α－glucosidaseConcentrationofplasmaglucose：>270300mg/dl.thesymptomsofhypertensionareevident.InsulintherapyisavailableImpairedliverandkidneyfunction：avoidusingOHALean、fastingandafter-excitationinsulinall：insulin第63頁Drug-CombinedtherapyReasonabledietandpoorplasmaglucosecontrolbymonotherapySU、biguanides、TZDandα-glucosidaseinhibitorsallcanbeusedincombinationwitheachotherSmalldosagecombinedwithofallkindsofdrugs;enhancingeffectsofreduceglucaemia;sideeffectsofsingleagentsOralagentswithinsulinDrugsofthesameclasscannotbeusedinacombinedway.第64頁Insulintherapy第65頁IndicationsofinsulinType1DMType2DMAcutecomplicationsSeverechroniccomplicationsofdiabetesEmergencySeveredysfunctionofliverorkidneyGestationandbleedingwomenWithouttoleranceOHA，curativeeffectofOHA，SUinvalidationDistinctleanWithdiseasestreatedbyglucocorticoidSomespecifictypesofDM：secondarypancreasdisease、endocrinopathies、geneticdiabetes第66頁ObstaclestousingInsinT2DM

oldnotion：NIDDMThedoctorusesOHAonlyanddoesnotseetheneedtouseIns.ThepatientdoesnotwanttouseInforfearofdevelopinginsulindependenceafteruseingit.HyperinsulinismcanleadAStoCVD？hypoglycemia，BW↑第67頁國內(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)短效胰島素一般胰島素(RI)上海生物制藥廠

豬400U/瓶優(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/瓶長效胰島素

PZI上海生物制藥廠

豬400U/瓶第68頁DifferencesbetweenhumanandanimalinsulinDifferenceinpharmacodynamic：CloseactionintensityHumaninsulin:absorptionisfast，timeofonsetofeffectisearlyDifferenceinimmunogenicity:AntigenicitofhumaninsulinisweakerthananimalinsulinAfterusehumaninsulin,antibodytiterofbloodinsulinislowerSynthesizedinsulin：lispro（28proline29proline）Quickabsorption,shorteffecttime第69頁Shot-termintensiveinsulin

therapyforT2DMIndications：monotherapyorcombinationtherapyoforalantihyperglycemiatherapyfailtoachieveglucosetargets，overthyperglycemia，fastingandpostprandialC-peptideMethod：useinsulin2timesperday：

NPH/R70/30prebreakfastandpresupper，adjustthedosagewiththemonitoringresultsofbloodsugar.useinsulin4timesperday：

RIpremeal、NPHbeforesleepPeriodoftreatment：severalweeksormonthes第70頁Shot-termintensiveinsulin

therapyforT2DM

Estimationofinitialdosage：0.20.4U/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71頁SecondaryfailureofOHA:combinationwithinsulinFPGoralanti-hyperglycemiaagents+NPHbeforesleepPPGNPHbeforebreakfast+oralanti-hyperglycemiaagentsFPGPPGoralanti-hyperglycemiaagents+NPHbeforesleepandbeforebreakfastInsulin：adjustper3~4days ，

onephraseeachtime upfor2~4UeverytimeBeforeyouaddinsulin,hypoglyce