內(nèi)科學(xué)教學(xué)課件：43 Diabetes Mellitus (DM)

DiabetesMellitus(DM)ThemeaningofdiabetesmellitusDiabetes:ExtremelyThirst&Polyuria

+Mellitus:Mel(honey)ObjectivesTomasterthediagnosis,classification,clinicalmanifestations,Anti-diabetesmedicineandtherapeuticprincipleofDMTobefamiliarwiththecomplications,pathophysiologyandpathogenesisofDMContentsDefinition&ClassificationEpidemiologyDiagnosisPathogenesisandPathophysiologyAcutediabeticcomplications:DKA&HHSChronicdiabeticcomplicationsManagementDefinition

Diabetesmellitus(DM)comprisesagroupofcommonmetabolicdisordersthatresultsinhyperglycemiaduetoreducedinsulinsecretion,decreasedglucoseutilization,orincreasedglucoseproduction.ClassificationType1diabetes:duetoβ-celldestruction,usuallyleadingtoabsoluteinsulindeficiencyImmune-mediated:LADA(Latentautoimmunediabetesinadult) Immunoautoantibodies(+):ICA(isletcellautoantibody),IAA(autoantibodytoinsulin),GADA(autoantibodytoglutamicaciddecarboxylase),IA-2andIA-2β(autoantibodiestotyrosinephosphatases),ZnT8(autoantibodiestozinctransporter8)Idiopathic:lackimmunologicmarkersType2diabetesduetoaprogressiveinsulinsecretorydefectonthebackgroundofinsulinSpecifictypesofdiabetesduetoothercausesGestationaldiabetesmellitus(GDM):diabetesdiagnosedinthesecondorthirdtrimesterofpregnancythatisnotclearlyovertdiabetesADAguideline2015Specifictypesofdiabetesduetoothercauses

中國(guó)2型糖尿病防治指南草案。2010WenyingYangetal.NEnglJMed2010:362:1090-1101中國(guó)2型糖尿病防治指南。中華內(nèi)分泌與代謝雜志.2008;24(2)中國(guó)14省市糖尿病和代謝綜合征得患病率調(diào)查中華醫(yī)學(xué)會(huì)糖尿病學(xué)分會(huì)網(wǎng)站GuangNinetal.JAMASeptember4,2013Volume310,Number9Epidemiology

——Prevalenceofdiabetesareincreasing,especiallytype2DMYear198019861994200220082010Prevalence(%)EpidemiologyWenyingYang.NEJM.2010,march,25:1090-1101EpidemiologyGuangNinetal.JAMASeptember4,2013Volume310,Number9Epidemiology

——geographicvariation

"Type1Diabetes",bookeditedbyAlanP.EscherandAliceLi,ISBN978-953-51-1017-0,Published:February27,2013Epidemiology

——geographicvariationIDF2009PathogenesisandPathophysiologyInsulinBiosynthesis,Secretion&ActionPathogenesisofT1DM&T2DMPathophysiologyofT1DM&T2DM

InsulinBiosynthesisMechanismofinsulinsecretionInsulinAction——ThemostimportantregulatorofglucosehomeostasisNormalinsulinsecretioncurve-30030609012015018021020016012080400PlasmaInsulin(U/ml)FirstPhaseSecondPhaseTime(Minutes)NaturalhistoryofT2DMObesity

IGT DM

Years-10-505101520253035030025020015010050250200150100500InsulinresistanceRelativeβ-cellfunction

(%)Insulinβ-celldysfunctionFPG2hPGPG(mg/dl)DiagnosisClinicalfeatureHyperglycemiawithoutcontrolMicrovasculardiseaseMacrovasculardiseasePathophysiology

——InsulinsecretioncurvesofdifferentpopulationsPathogenesisT1DMEnvironmental&immunologicfactorsGeneticfactorsβ-celldestructionT1DMImmunologicMarkers:ICAsGADInsulinIA-2/ICA-512IsletGangliosideDevelopmentofT1DMHarrisonprinciplesofinternalmedicine16theditionPathogenesisT2DMGeneticfactors&IntrauterinemalnutritionEnvironmentalfactorsβ-celldestructionInsulinresistance2hPG↑IGTT2DMClinicalmanifestationPolyuriaPolyphagiaPolydipsiaWeightlossSyMPTOMSOthers:Fatigue,weaknessblurryvisionfrequentsuperficialinfectionsslowhealingofskinlesionsafterminortraumaDiagnosticcriteriaofDM(WHO1999)DiagnosticcriteriaofDM(ADA2015)A1CisnotcurrentlyrecommendedinChinaDiabetesCare,January2015DiagnosticcriteriaofDM(ADA2015)DiabetesCare,January2015DiagnosticcriteriaofDMNGTIFGIGTIFG+IGT5.67.0FPG(mmol/L)7.811.1OGTT2hPG(mmol/L)DiagnosticcriteriaofDM(China2013)Screeningtestfortype2DMFPG,2-hOGTT(China)A1CarealsorecommendedforADAScreeningage

>45yearsoldIndividualswithriskfactorsatanearlierage,suchasoverweightorobese(BMI≥25kg/m2)Diagnosis

——screeningScreeningDMasymptomaticadultindividuals(ADA2015)DiabetesCare,January2015ScreeningDMasymptomaticadultindividuals(China2013)(1)年齡≥40歲(2)有糖調(diào)節(jié)受損史(3)超重(BMI≥24kg/m2)或肥胖(BMI>28kg/m2)和(或)中心型肥胖(男性腰圍>90cm，女性腰圍≥85cm)(4)靜坐生活方式(5)一級(jí)親屬中有2型糖尿病家族史(6)有巨大兒(出生體重≥4kg)生產(chǎn)史或妊娠糖尿病史的婦女(7)高血壓[收縮壓≥140mmHg和(或)舒張壓≥90mmHg]，或正在接受降壓治療(8)血脂異常[高密度脂蛋白膽固醇(HDL—C)≤0．91mmoL／L(≤35mg／dL)、甘油三酯≥2．22mmol／L(≥200mg／dL)]，或正在接受調(diào)脂治療(9)動(dòng)脈粥樣硬化性心腦血管疾病患者(10)有一過(guò)性類固醇糖尿病病史者(11)多囊卵巢綜合征(PCOS)患者(12)長(zhǎng)期接受抗精神病藥物和(或)抗抑郁藥物治療的患者DifferentialdiagnosisT1DMT2DMUsualageofonset<25years>40yearsModeofonsetAcuteChronicWeightNormalorweightlossOverweightorobesitySymptomsPolyuria,polydipsia,weightlossSimilarbutusuallylessseverepresentationAcutecomplicationsMoreDKAinT1DMMoreHHSinolddiabeticsChroniccomplicationsLargevesseldiseaseLessthanT2DMLeadingcauseofdeathRenaldiseaseLeadingcauseofdeath20%Insulinandc-peptidereleasetestLoworlackPeakvaluedelayed,ordeficiencyImmunologicmarkerusually+usually-TherapywithinsulinInsulindependenceInsulinindependenceInsulinresistanceLADA(Latentautoimmunediabetesofadults)Aformof

type1diabetesmellitusthatoccursinadultsDiagnosticcriteria:Onsetafter20yearsoldwithovertpolydipsia,polyphagia,polyuriaandweightloss,BMI≤25kg/m2,FPG≥16.5mmol/LFastingplasmaC-peptide≤0.4nmol/L,1hor2hC-peptideafterOGTT≤0.8nmol/LGADA(+)NonAsphomozygoteatHLA-DQ-B571+2or3or4LADADiagnosticcriteriaofGDM(ADA2015)DiabetesCare,January2015DiagnosticcriteriaofGDM(ADA2015)DiabetesCare,January2015ManagementofDMDiabeteseducationNutritionPhysicalActivityBloodglucosemonitoringMedicineGoalsGoodmetaboliccontrolRelievesymptomsKeepinggoodphysiologicstateandasociallifeGoodqualityoflivePreventthedevelopmentofacutecomplicationsofdiabetesPreventingthedevelopmentordelayingtheprogressionofthechroniccomplicationsofdiabetesEducation,Education,Education…Diet:mealplanningwithfamilymembersExerciseImportanceofadherencetomedicationregimeInsulininjectionSMBG(self-monitoringofbloodglucose)Recognition,self-treatment,andpreventionofhyperglycemiaandhypoglycemiaAppropriatefootwearfordiabetes,footcareandeyecareKnowwhenneedtoseekformedicalattentionPurchaseandwearthediabetesmedicalbraceletGoodDiabetesManagement

RegularBloodGlucoseMonitoring

HealthyNutrition

RegularExercise

PrinciplesofmedicalnutritiontherapyGoal：KeepidealbodyweightLoseweightforobesepatientGainweightforleanpatientBMI(bodymassindex)=bodyweight(kg)/height2(m)Overweight:BMI>=24Obesity:BMI>=28Standardbodyweight＝height（cm）－105Male:(height－100)×0.9female:(height－100)×0.85Energysupply(kcal/kgstandardweight·d)BodilyformWorkintensionInbedLightphysicallaborMiddlephysicallaborHeavyphysicallaborLean20-253540>40Normal15-20303540Obesity1520-253035Thedistributionof*totalcaloricvalue：carbohydrate55%

60%fat20%

25%1/5~

2/5~

2/5protein15%

20%

*Totalcaloricvalue=standardbodyweight×energysupplyExercisetherapyBenefitsGlycaemiccontrolIncreaseinsulinsensitivityReducebloodlipidWeightreductionPhysicalActivityIntensityIncreaseHRmoderatelyto50-70%ofHRmax(220-age)Adjustment:patient’scardiovascularfitnessDurationAtleast150minutes/weekFrequencyspreadoveratleast3days/weekwithnomorethan2consecutivedayswithoutexerciseIndicationsofphysicalactivityT2DMpatientswithBG≤16.7mmol/L,especiallyobeseindividualsT1DMpatientswhoareinstableconditionContraindicationsofphysicalactivityT1DMpatientswhoareinunstableconditionorwithseverechronicdiabeticcomplicationsPatientswithseverenephropathyPatientswithseverehypertensionorischemicheartdiseasePatientswithproliferativeretinopathyPatientswithdiabeticfootPatientswithcerebralarteriosclerosis,severeosteoporosisorbalancedisordersMonitoringSelf-monitoringofbloodglucoseconcentrationMonitoringContinuousglucosemonitoringPharmacologicaltherapyOral

antiglycemicagents(OADs)SulfonylureasNonsulfonylureasecretagogues（Meglitinides）BiguanidesThiazolidinedionesa-GlucosidaseinhibitorsInsulinIncretin-RelatedTherapiesGLP-1receptoragonists

DPP-IVinhibitorsSGLT2inhibitorsOADstherapiesinT2DMWilliam’sTextbookofEndocrinology12thTreatmentwithinsulinororalmedicationamongadultswithdiagnoseddiabetes,UnitedStates,2004-2006Source:2004–2006NationalHealthInterviewSurveyInsulinsecretagogues SulfonylureasMeglitinidesFunction:stimulateendogenousinsulinreleasefromβ-cellsRequirement:asufficientnumberoffunctionalβ-cells50insinsinsNateglinideRepaglinide(36kD)Kir6.2SUreceptorSUreceptorATP

Glimepiride(65kD）Glyburide(40kD）DepolarizationCharacteristicsofinsulinsecretagoguesGenericnameApproveddailydosagerange(mg)Durationofaction(hour)ClearanceSulfonylurea-firstgenerationChlorpropamide100-500>48RenalTolazamide100-100012-24Hepatic,RenalTolbutamide（D860）500-30006-12HepaticSulfonylurea-secondgenerationGlimepiride1-824Hepatic,RenalGlipizide2.5-4012-18HepaticGlipzide(extendedrelease)5-1024HepaticGlyburide1.25-2012-24Hepatic,RenalGlyburide(micronized)0.75-1212-24Hepatic,RenalNonsulfonylureasRepaglinide0.5-162-6HepaticNateglinide180-3602-4RenalSulfonylureasIndicationsPoorcontrolofT2DMbyweightcontrolandphysicalactivityPoorcontrolofT2DMbybiguanidesand

-glucosidaseinhibitorsContraindicationsT1DMAcuteorchronicdiabeticcomplicationsEmergencyDysfunctionofliverorkidneyPregnantorbreast-feedwomenPrimaryandsecondaryfailuretosulfonylureasFailuretosulfonylureasprimaryfailureAbout5%ofpeoplewillimmediatelyfailtocontroltheirbloodglucoselevelsadequatelyonthehighestrecommendeddosesecondaryfailureRoughly5%to10%ofpeoplewhoinitiallyrespondtosulfonylureatherapywillsubsequentlyfaileachyearSulfonylureasthemselvestendtooverworkthepancreasuntiliteventually“burnsout”andisunabletosecreteanadequateamountofinsulinSideeffectsofSUHypoglycemia,

mostcommoninOldpatientsLong-termpharmaceuticsSymptomsofdigestivetractWeightgainLiverdysfunctionTetterMeglitinides:NateglinideandRepaglinideStimulatepancreaticinsulinsecretion(similarwithSU)StimulatingthefirstphasesecretionofinsulinAction:rapidonset,shortduration,suppressingpostprandialhyperglycemiaquicklyTakenwithorwithin15minbeforeeachmealSitesofexcretion:kidney8%，fecal92%IncidenceofhypoglycemiaislowMeglitinides:NateglinideandRepaglinideContraindications:Type1diabetesDiabeticketoacidosis,withorwithoutcomaKnownhypersensitivitytothedrugSideeffects:Hypoglycemia(lessthanSU)WeightgainBiguanidesMetforminDecreasegluconeogenesis:reducingglucoseoutputDecreaseintestinalabsorptionofglucoseImproveinsulinsensitivity:increasingperipheralglucoseuptake&utilizationinperipheraltissues57MetforminIndications:first-lineagentfortype2diabetes(monotherapy/combination)Contraindications:RenaldiseaseorrenaldysfunctionKnownhypersensitivitytothedrugAcuteorchronicmetabolicacidosis,includingDKA,withorwithoutcomaSideeffects:Lacticacidosis:<1/10000diarrhea,nausea,vomitingandflatulenceThiazolidinediones(TZDs)RosiglitazonePioglitazoneImprovesensitivitytoinsulininmuscleandadiposetissueInhibithepaticgluconeogenesisReducehyperinsulinemiaPioglitazonedecreasesTG,andraisesHDLlevelWithoutinsulin,itcannotreducehyperglycemia59Thiazolidinediones(TZDs)Indicationsadjunctstodiet,exerciseandotherOADstoimproveglycemiccontrolinpatientswithT2DMOnlyPioglitazonecanbecombinedwithinsulinContraindications:NYHAClassIIIorIV,SymptomaticCHFKnownhypersensitivityT1DMDiabeticketoacidosisActiveliverdiseaseThiazolidinediones(TZDs)SideeffectsCardiovascularischemiaOsteoporosisandbonefractureWeightgainEdemaα-glucosidaseinhibitorsAcarboseMiglitolDelayentryofcarbohydratesfromtheGItractNotstimulatingthesecretionofInsulin62IndicationsLightcasesUsingdrugseparatelyorcombinedIGTintervention,securitySideeffects:Abdominalpain,diarrheaandflatulenceα-glucosidaseinhibitorsContraindications:AllergicreactionsSeveregastroenteropathyDysfunctionofrenalandliver,Scr>180umol/L(2.0mg/dl)AcutecomplicationsEmergencyPregnantandbreastfeedingwomenα-glucosidaseinhibitorsInsulinTherapyPharmacokineticsofinsulinpreparationsHarrisonprinciplesofinternalmedicine16theditionPharmacokineticsofinsulinpreparations02

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50R024681012141618202224（小時(shí)）Aspart25Onset:0.5hourMaximumeffect:2-8hoursDuration:24hoursOnset:10-20minMaximumeffect:1-4hoursDuration:24hoursOnset:0.5hourMaximumeffect:2-8hoursDuration:24hoursPharmacokineticsofinsulinpreparations早餐午餐晚餐睡前（12：00）早餐上午下午夜間30R30RRepresentativeinsulinregimensRepresentativeinsulinregimensHarrisonprinciplesofinternalmedicine16theditionTheinjectionoftwoshotsofintermediate-actinginsulin(NPHorlente)andshort-actinginsulin(lispro,insulinaspart,orregular)OneshotofglargineatbedtimetoprovidebasalinsulincoverageandthreeshotsoflisproorinsulinasparttoprovideglycemiccoverageforeachmealInsulinadministrationbyinsulininfusiondeviceisshownwiththebasalinsulinandabolusinjectionateachmealIndicationsofinsulinType1DMType2DMPoorcontrolbyOADsAcutecomplications:DKA,HHSSeverechroniccomplicationsofdiabetesEmergencySeveredysfunctionofliverorkidneyGestationandbreast-breedwomenWithouttoleranceOHA,

curativeeffectofOHA↓,SUinvalidationDistinctleanWithdiseasestreatedbyglucocorticoidSomespecifictypesofDM：secondarypancreasdisease,endocrinopathies,geneticdiabetesSideeffectsofinsulinHypoglycemiaEdemaBlurredvisionWeightgainAnaphylaxis:localreaction:itching,urticaria,lipiddystrophiasystemicreaction:urticaria,angioneuroticedema,anaphylacticshockInsulindrugresistanceAneedfor200ormoreunitsofinsulinperdayin3consecutivedayswithoutDKAorothercounterregulatoryfactorsMethodsofdeliveryinsulinIntravenous(IV)Syringes(SC)JetinjectorsPensInsulinpumpsSiteSelection:

WherecanIgivetheInjections?4majorareas:Arms-posteriorsurfaceAbdomen-avoid1inchareaaroundnavelThighs-anteriorsurfaceHipsNote:Systematicrotationofinjectionsiteswithinananatomicareatopreventlipodystrophy.Administeringeachinjection0.5-1inchawayfromthepreviousinjection.StoringandHandlingInsulinStoredatthetemperature:2–8℃Ifstoredinarefrigerator,unopenedbottlesaregooduntiltheexpirationdateprintedonthebottleOpenedbottlesthatarestoredinarefrigeratorshouldbeusedwithinonemonthofbeingopenedProtectyourinsulin(bottles,pens,andcartridges)fromextremesofhotandcoldNeverstoreyourinsulininthefreezer-onceinsulinisfrozen,itlosesitspotencyDawnPhenomenonAnearly-morning(usuallybetween5a.m.and8a.m.)increasein

bloodglucoseOccurinbothdiabeticpatientsandnon-diabeticindividuals,butmorecommonindiabeticpatientsCausedbythereleaseof

counterregulatoryhormones

suchas

growthhormone,

cortisol,

glucagon,or

epinephrine,allofwhichcansignalthe

liver

torelease

glucoseSomogyieffectAreboundinghighbloodsugarthatisaresponseto

lowbloodsugarDifferentialDiagnosis:Measurebloodglucosebetween0AM-4AMfor2-3times19701950201019301990有關(guān)腸促胰素的關(guān)鍵研究KimWetal.PharmacolRev.2008;60(4):470-512.NauckMetal.Diabetologia.1986;29(1):46-52.Deaconetal.AmJPhysiolEndocrinolMetab.2002;282(4):E873-E879.Nikolaidisetal.AmJPhysiolHeartCircPhysiol.2005;289(6):H2401-H2408.1992-1994：研究發(fā)現(xiàn)外源性GIP不降低2型糖尿病患者的血糖，但外源性GLP-1反之11985：發(fā)現(xiàn)第2種腸促胰素：GLP-112005：更多研究表明GLP-1的非葡萄糖依賴性41932：第1次使用“腸促胰素”的概念：來(lái)自腸道的一種可以調(diào)節(jié)進(jìn)食后胰島素分泌的物質(zhì)11971：分離出第1種腸促胰素：GIP2002:發(fā)現(xiàn)曾經(jīng)被認(rèn)為是無(wú)活性的GLP-1

(9-36)的代謝產(chǎn)物，，具有一定的生物學(xué)活性3FPO1986：發(fā)現(xiàn)T2DM患者的腸促胰素效應(yīng)21964-1967：口服葡萄糖較靜脈滴注葡萄糖引起的胰島素分泌更多。這種差異被稱為“腸促胰素效應(yīng)”胰島素(mmol/L)腸促胰素效應(yīng)的發(fā)現(xiàn)口服葡萄糖較靜脈給予葡萄糖引起血漿胰島素增加的程度更高1該現(xiàn)象被稱為腸促胰素效應(yīng)，且約占口服葡萄糖后總胰島素釋放的50-70%1

口服葡萄糖(50g/400mL)靜脈葡萄糖* P≤0.05口服葡萄糖與靜脈葡萄糖相比。

IR：免疫反應(yīng);IV=i靜脈注射.BaggioLLetal.Gastroenterology.2007;132(6):2131-2157.Naucketal.JClinEndocrinolMetab.1986;63(2):492-498.0100200靜脈血糖(mg/dL)時(shí)間（分）20160120180020102601201800.00.20.40.60.8******腸促胰素效應(yīng)2時(shí)間（分）2腸促胰素的種類GIP和GLP-1的分泌及代謝SeinoY,FukushimaM,YabeD.GIPandGLP-1,thetwoincretinhormones:Similaritiesanddifferences.JDiabetesInvest.2010;1(1/2):8-23小腸營(yíng)養(yǎng)物質(zhì)K細(xì)胞L細(xì)胞分泌腸促胰素效應(yīng)腸促胰素效應(yīng)失活腎排泄腸促胰素在血糖穩(wěn)態(tài)中的作用DPP=dipeptidylpeptidase;GLP=glucagon-likepeptide;GIP=gastricinhibitorypeptide;GI=gastrointestinal.DruckerDJetal.Lancet.2006;368(9548):1696-1705.β

細(xì)胞α

細(xì)胞腸促胰素釋放增加+-血糖穩(wěn)態(tài)食物攝取腸促胰素的作用胰島素釋放增加胰高血糖素降低胰島LiverMuscleDPP-4酶迅速降解腸促胰素胃腸道腸促胰素（GIP和GLP-1）持續(xù)分泌肝臟肌肉肌肉攝取葡萄糖增加肝糖輸出減少GLP-1通過(guò)DPP-4代謝 GLP：胰高血糖素樣肽；DPP：二肽基肽酶TomasEetal.TrendsEndocrinolMetab.2010;21(2):59-67.NauckMA.EurJInternMed.2009;20(2):S303-308.BaggioLLetal.Gastroenterology.2007;132(6):2131-2157.(胰島素釋放)1(非胰島素模擬)1,2HisAlaGluGlyThrPheThrSerAspValSerSerTyrLeuGluGlyGlnArgGlyLysValLeuTrpAlaHePheGlulysAlaAlaAlaHisGluGlyThrPheThrSerAspValSerSerTyrLeuGluGlyGlnArgGlyLysValLeuTrpAlaHePheGlulysAlaAla失活GLP-1(9-36)2活性GLP-1(7-36)DPP-41,2DPP-4將

寡肽的氨基末端或第2個(gè)氨基酸為丙氨酸或脯氨酸的蛋白氨基末端剪切去2個(gè)，抑制其活性3GLP-1的氨基末端第2個(gè)氨基酸為丙氨酸

，是DPP-4的作用底物，GLP-1被迅速剪切成短的GLP-1(9-37)orGLP-1(9-36)NH23

GLP-1迅速(t1/2=1–2分鐘)被DPP-4裂解失活，導(dǎo)致氨基末端肽縮短為GLP-1(9-37)andGLP-1(9-36)NH23抑制DPP-4可以升高活性GLP-1水平GLP-1被滅活(>80%)活性GLP-1進(jìn)餐DPP-4腸道分泌GLP-1GLP-1t?=1–2分鐘DPP-4抑制劑RothenbergP,etal.Diabetes.2000;49(Suppl1):A39.Abstract160-OR.

DeaconCF,etal.Diabetes.1995;44:1126–1131.DPP-4inhibitorsContraindication:historyofaserioushypersensitivityreaction,suchasanaphylaxisorangioedemaSideeffects:UpperrespiratorytractcomplaintsHeadacheItchRashDPP-4抑制劑藥代動(dòng)力學(xué)比較西格列汀利格列汀沙格列汀維格列汀劑量100mgQD5mgQD5mgQD50mgBD半衰期(t1/2),小時(shí)12.412.5–21.12.2–3.81.3–2.4消除腎(大部分未改變)膽汁而不經(jīng)腎(大部分未改變)肝和腎活性代謝物腎>>肝失活代謝物需根據(jù)腎臟調(diào)整劑量是否是輕度腎功能不全不需要;不推薦用于中至重度腎功能不全患者DPP-4的選擇性>2600倍vsDPP-8>10,000倍vsDPP-9>10,000-倍vsDPP-8/9>400倍vsDPP-8>100倍vsDPP-9>90倍vsDPP-8潛在的藥物相互作用低低強(qiáng)CYP3A4/5抑制劑低食物影響無(wú)無(wú)無(wú)無(wú)基于Exendin-4結(jié)構(gòu)的GLP-1RALixisenatide:a44aminoacidpeptidebasedonExendin-4withadeletionofaprolineresidueandadditionofsixlysineresiduesC-terminallyBydureon?：Basicsofpoly-(d,l-lactide-co-glycolide)microspheresExenatide(Byetta?)rH-AlbuminCJC-1134-PCIncretin-RelatedTherapiesIncretin:GLP-1,GIPenhanceinsulinsecretionbyβcellssuppressesglucagonsecretionbyalphacellsSlowinggastricemptyinganddelayingcarbohydrateabsorption,ReducingfoodintakedegradationbyDPP4,1~2minutesinplasmaDrugGLP-1mimeticsDPP-4inhibitors92↑satiety↓foodintakeβcell:

↑glucose-dependentinsulinsecretionliver:

↑storageofglucose↓glucagonfrom

α-cellstomach:

regulate

gastricemptyingFoodintakepromoteGLP-1secretion↓βcellload↑βcellreactionAdaptedfromFlintA,etal.JClinInvest.1998;101:515-520;LarssonH,etal.ActaPhysiolScand.1997;160:413-422;NauckMA,etal.Diabetologia.1996;39:1546-1553;DruckerDJ.Diabetes.

1998;47:159-169.Indications

adjunctive(addon)therapyinpatientswhohavenotachievedadequateglycemiccontrolwith:Metformin,sulfonylurea,orTZDmonotherapyCombinationofmetforminandsulfonylureaCombinationofmetforminandTZDContraindications:KnownhypersensitivitytotheactiveingredientoranyoftheproductcomponentsGastroparesisESRDorsevererenalimpairmentSideeffects:AcutepancreatitisNausea,vomiting,anddiarrheaGLP-1ReceptorAgonistsSGLT2Inhibitors

-Sodium–GlucoseCotransporter2Inhibitors

BlockingglucosereabsorptionintheproximalrenaltubulebyinhibitingSGLT2Insulin-independentglucoseloweringProvidemodestweightlossandbloodpressurereductionDrug-CombinedtherapyReasonabledietandpoorplasmaglucosecontrolbymonotherapySU,biguanides,TZDandα-glucosidaseinhibitors,allcanbeusedincombinationwitheachotherOralagents+insulinDrugsofthesameclasscannotbeusedinacombinedwayDrug-CombinedtherapyInsulinsecretagoguesMetforminTZDsInsulinα-glucosidaseinhibitorsDiabetesCare,2015T2DMtreatmentstrategyHbA1cOADs+basicinsulinOADcombinedtherapyOADs+increasebasicinsulinOAD+basicinsulin+insulinbeforemeals7%DMduration<5yDietOADmonotherapyTargetofHbA1c2013中國(guó)2型糖尿病防治指南《2013版中國(guó)2型糖尿病防治指南》TheassociationofHbA1ClevelswithriskofdiabeticcomplicationsGlycemicTargets(ADA2015)Goalsofcontrol(China2013)ItemGoalBG(mmol/L)Fasting4.4-7.0non-fasting<10.0HbA1C(%)<7.0BP(mmHg)<140/80TC(mmol/L)Male>1.0Female>1.3TG(mmol/L)<1.7LDL-C(mmol/L)withCHD<2.6withoutCHD<1.8BMI(kg/m2)<24.0UrinaryAlb/Cr(mg/g)Male<22.0Female<31.0Urinaryalbuminexcretionrate(mg/d)<30.0Aerobics(min/week)≥150PatientanddiseasefactorsusedtodetermineoptimalA1CtargetsADA2015Pancreasorisletcelltransplantation

Mostpancreastransplantsaredonetotreattype1diabetesThemajorityofpancreastransplantation(>90%)aresimultaneouspancreas-kidneytransplantationondiabeticpatientsend-stage

renaldiseaseIsletorstemcelltransplatationstillhavelimitationsandmanyobstaclesremainthatcurrentlyprecludeitswidespreadapplicationKeypointsDiagnosticcriteriaofDMThedifferencebetweenT1DMandT2DMThemechanism,indications,contraindicationsandSideeffectsofOADsAcutecomplicationsDiabeticKetoacidosis(DKA)HyperglycemicHyperosmolarState(HHS)ClinicalManifestationsofDKASymptomsNausea/vomitingThirst/polyuriaAbdominalpainShortnessofbreathPhysicalfindingsTachycarida/hypotensionDehydration/Drymucousmembranes/reducedskinturgorTachypnea/kussmaulrespirations/respiratorydistress“ketotic/fruity”odorAbdominaltendernessLethargy/obtundation/cerebraledema/possiblycomaCommonPrecipitatingFactorsofDKAPathophysiologyofDKARelativeorabsoluteinsulindeficiencyInappropriatecounterregulatoryhormone(glucagon,catecholamines,cortisolandGH)excessketonebodysynthesisintheliver

Acidosis,dehydration,electrolyteimbalance,circulatoryfailure,renalfailure,centralnervoussystemdysfunctionKetonebodiesthree

water-soluble

molecules

thatareproducedbythe

liver

from

fattyacids

duringperiodsoflowfoodintake(fasting)orcarbohydraterestrictionforcellsofthebodytouseas

energy

insteadofglucoseAcetone,

acetoaceticacid,beta-hydroxybutyricacid

ConfirmthediagnosisGuidelinesfortheManagementofDiabeticKetoacidosis.JulieAEdge,Oxford,November2009DifferentialdiagnosisofDKA

DKAhypoglycemiaHHSLacticacidosisHistoryDMwithrecipitatingFactorsofDKADMwithlesseating,overactivityelderswithinfection,vomittingordiarrhealiverorrenalfailure,hypovolemicshock,heartfailure,drinking,PhenforminOnsetslowonset,withanorexia,sick,thirsty,polyuria,Drowsinessquickonset,feelhunger,sweating,palpitations,tremorslowonset,drowsiness,hallucination,twitchrelativelyquickonset,anorexia,sick,comatose,symptomsofconcomitantdiseaseSignskindehydration,dryhumid,hyperhidrosisdehydrationdehydration,flushingrespirationdeep,fastnormalfastdeep,fastpulseweakandfaststrongandfastweakandfastweakandfastBPlowornormalnormalorslightlyhighlowlowchemicalexaminationurineglucose++++-or+++++-or+urineketone-～+++--or+-or+bloodglucosehigh,usually16.7-33.3mmol/Llow,<2.5mmol/Lextremelyhigh,usuallyhigherthan33.3mmol/LnormalorhighbloodsodiumlowornormalnormalnormalorsignificantlyhighnormalorhighPHlownormalnormalorslightlylowlowCO2CPlownormalnormalorslightlylowlowlacticacidslightlyhighnormalnormalsignificantlyhighplasmaosmoticpressurenormalorslightlyhighnormalsignificantlyhighnormalManagement—fluidandinsulinManagement—potassiumandbicarbonateHHS(hyperosmolarhyperglycemicstate)Acomplicationof

diabetesmellitus(predominantly

type2)inwhich

highbloodsugars

causesevere

dehydration,increasesinosmolarity

andahighriskofcomplications,

coma

an