内科学教学课件：Diabetes Mellitus

DiabetesMellitusDefinition,Epidemiology,Classification,DiagnosticcriteriaEtiologyandpathogenesisPathophysiologyClinicalpresentationLabtestTreatmentDKAandNHDCStageI:descriptionofthesignsofdiabetesrecognition

diabetesmellitus:polyuria,urineissweetStageII:diabetesisassociatedwithpancreas----findofinsulinJan.1922Dr.BantingextracttheinsulinfrompigpancreasandappliedforthediabeticpatientsFatherofinsulin14thNovemberWorldDiabetesDayStageIII:defectsininsulinaction----insulinresistance“agroupofmetabolicdiseasecharacterizedbyhyperglycemiaresultingfrom

defectsininsulinsecretion,

insulinactionorboth.Thechronichyperglycemiaisassociatedwithlong-termdamage,dysfunctionandfailureofvariousorgans,especiallytheeyes,kidney,nerves,heartandbloodvessels.”StageIV:diabetescaninvolvetheeyes,kidneys,nervesandbloodvesselsDiabeticretinopathyDiabeticnephropathyDiabeticfootmicroangiopathymacroangiopathyCerebralvesselCoronalvesselPeripheralvesselWorldHealthOrganization/InternationalDiabetesFederation,1999.DiabetesCare2001;24(Suppl1):S5–S20.Definition

Diabetesmellitusisaheterogeneousprimarydisorderofcarbohydratemetabolismwithmultipleetiologicfactorsthatgenerallyinvolveabsoluteorrelativeinsulindeficiencyorboth.Allcausesofdiabetesultimatelyleadtohyperglycemia,anditcancausesthelatecomplicationsinvolvingtheeyes,kidneys,nervesandbloodvessels.Environmental-GeneticinteractionsAbsoluteorrelativeinsulindeficiencyDisorderofcarbohydrate,proteinandfatmetabolismhyperglycemiaComplicationsinvolvingtheeyes,kidneys,nervesandbloodvessels病因发病机制病理生理共同特征最终结局EpidemiologyGlobalprevalenceofdiabetes

12345678910Total印度中国美国俄联邦日本巴西印度尼西亚巴基斯坦墨西哥Ukraine所有其他国家19.416.0

13.98.96.34.94.54.33.83.649.7135.3印度中国美国巴基斯坦印度尼西亚俄联邦墨西哥巴西埃及日本所有其他国家57.2

37.621.914.512.412.211.711.68.88.5103.6300.0糖尿病患者前10位的国家排名国家国家1995

(百万)2025

(百万)KingH,etal.DiabetesCare1998;21:1414–31.Epidemiology《新英格兰医学杂志》2010;12;1090-101

IDFDiabetesAtlas..中国正在面临糖尿病的巨大挑战中国城市糖尿病患病率：每10年翻倍12.023.21510.5%9200万糖尿病患者1.48亿糖尿病前期患者ClassificationEtiologicclassificationofdiabetesmellitus(1997ADA1999WHO)Type1diabetes(T1DM)OtherspecifictypesType2diabetes(T2DM)Gestationdiabetesmellitus(GDM)Bcelldestruction,usually

leadingtoabsoluteinsulindeficiencyTwo

groups,three

subgroupsA.Immunemediated1)beingrapid,mainlyininfantsandchildren

2)beingslow,mainlyinadults-----latentautoimmunediabetesinadults,LADA（成人晚发性自身免疫性糖尿病）B.Idiopathic一.Type1diabetes(T1DM)mayrangefrompredominantlyinsulinresistancewithrelativeinsulindeficiencytoapredominantlysecretorydefectwithinsulinresistanceTheriskofdevelopingthisformofdiabetesincreaseswithage,obesityandlackofphysicalactivityItisoftenassociatedwithastronggeneticpredisposition,morethanisthetype1diabeteshigherprevalence二.Type2diabetes(T2DM)三.OtherspecifictypesDividedinto8subgroupsaccordingtotheetiology

andpathogenesis,includingallthesecondarydiabetesandspecificetiologicdiabetesGeneticdefectsofBcellfunctionMaturity-onsetdiabetesoftheyoung(MODY)青年发病的成年型糖尿病

1).Chromosome20,HNF-4a(MODY1)2).Chromosome7p,glucokinase(MODY2)

3).Chromosome12,HNF-1a(MODY3)4).Insulinpromoterfactor1,IPF-1((MODY4)5).HNF-1ß(MODY5)6).NEUROD4(MODY6)

7)MitochondrialDNA8).Others

Otherspecifictypes四.Gestationdiabetesmellitus(GDM)DiabetesandIGRbediagnosedduringthegestationScreeningtheGDMduringgestation24—28weeksthroughOGTT6weeksafterparturition,OGTTbegivenagainDiagnosticcriteria(1999,WHO)Plasmaglucose(mmol/L)FPGRPGOGTT2hNormalrange

<6.1and<7.8Diabetesmellitus

≥7.0or≥11.1or≥11.1

IGR

IFG

≥6.1---<7.0

IGT

≥7.8---<11.11.Classicsymptompluscasualplasmaglucose≥11.1mmol/L,casualisdefinedasanytimeofdaywithoutregardtotimesincelasttimeor2.Anovernightfastingglucose(FPG)≥7.0mmol/L,Fastingisdefinedasnocaloricintakeforatleast8hoursor3.2hPG≥11.1mmol/LduringanOGTT.Ifwithoutclassicsymptoms,eachmustbeconfirmed,onasubsequentday,byanyoneofthethreemethodsgivenasaboveThediagnosticcriteriafordiabetesmellitusEtiologyandpathogenesisType1DMPronetoketoacidosisAbsoluteinsulindeficiency(ID)(LowC-peptidelevel)B-celldestructionidiopathyGeneticsusceptibilityEnviromentalfactorsinitiateGAD,IAA,ICAIA2HLAautoimmuneVirusinfection,chemical,diet淋巴细胞介导的，以免疫性胰岛炎和选择性胰岛B细胞损伤为特征的自身免疫性疾病Type2DMGeneticsusceptibilityEnviromentalfactors(Riskfactors:obese,richdietphysicalactivity,old)Insulindeficiency(ID)Insulinresistance(IR)IGR(IGT,IFG)T2DMLowbornweightPathophysiologyofDMInsulindeficiencyIRCharacterizedbyhyperglycemiaAccompaniedbydisruptionofprotein,lipid,waterandelectrocytes

metabolismGlucogensynthesisGlucoseoxidationGlucogencatabolismHepaticglucoseproductionAdipocytesuptakeTGLipidsynthesisLipidmobilization-ketoneClinicalfeature

ofDMInsulindeficiency

Insulinresistancehyperglycemiadisruptionofprotein,lipid,waterandelectrolytesmetabolism

Chronicimpairment:Macrovascular(CHD,CVD,PVD)Microvascular(kidney,reticular,nerve)osmoticdiuresispolyuria,thirst,polydipsiaPolyphagiaWeightlossBlurredvisionVulvovagitisandpruritusChroniccomplication

Macrovascular(CHD,CVD,PVD)

-metabolicsyndrome-IRMicrovascular(kidney,reticular,nerve)-thickeningofthecapillarybasementmembraneDiabeticretinopathyNon-proliferationproliferationDiabeticRetinopathy

（China：1984）background I microaneurysmsand/ordothemorrhages II hardexudatesand/ordothemorrhages III softexudatesand/ordothemorrhagesproliferative I growthofabnormalbloodvesselsand/or vitreoushemorrhages II growthofabnormalbloodvesselsand fibroustissue III growthofabnormalbloodvesselsand fibroustissue,detaqchmentoftheretinabackgroundDiabeticRetinopathyHardexdatesDot

hemorrhages

proliferativeDiabeticRetinopathy

DiabeticnephropathyI:hypertrophy,hyperfiltrationII:microalbuminuraafterexerciseIII:microalbuminura(UAER:20-200ug/min)IV:macroalbuminura(UAER>200ug/min)V:ESRDDiabeticneuropathyPeripheralpolyneuropathyMononeuropathyAutonomicneuropathy

Skin infectionAcutecomplicationDiabeticKetoneacidosis(DKA)non-ketonediabetic-hyperosmalcoma(NHDC)Insulindeficiency

InsulinresistancehyperglycemiaOGTT+C-peptide/insulinUrineglucose(formonitoring)bloodglucose(fordiagnosisandmonitoring)HbA1c(formonitoring)Urine/bloodketoneLabtesthypoinsulinemiahyperinsulinemiatreatmentEarly,longterm,integrated,individualizedDietcontrolPhysicalactivityDrugtherapyeducationSelf-monitoringTarget

ideal

acceptable

badFVPG

<6.1mmol/L<7.0mmol/L>7mmol/L2hVPG<8.0mmol/L<10mmol/L>10mmol/LHbA1c<6.2%<7%>8%TG<1.5mmol/L<2.2mmol/L>2.2mmol/LTC<4.5mmol/L>4.5mmol/L>6.0mmol/LLDL-C<2.5mmol/L<4.4mmol/L>4.4mmol/LHDL-C>1.1mmol/L>0.9mmol/L<0.9mmol/LBP<130/80mmHgdietTotalcaloriecontrol(idealbodyweight)CHO(50-60%)Protein(15-20%)Lipid(20-25%)Distribution(eg.1/5,2/5,2/5)生活方式干预生活方式干预----eatless,walkmore30minutes,moderateexercise,5/7daysHealthdietWeightlossLifestylemodification(Finland)Weightloss2.4kgin5years,T2DMdecreased58%DPPWeightloss4.3kgin3years,T2DMdecreased58%OralhypoglycemicagentsSulfonylureas——glyburide,glipizide,glimeperide

Glinides——retaglinide，nateglinide

Biguanides——metforminglucosidaseinhibitor——

acarbose,miglitol

Thiazolidiones——

rosiglitazone,pioglitazoneDPP-4inhibitor

——

gliptins

Mechanismofaction-SUnategliniderepaglinide(36kD)SURdepolarizationATPglimipiride（65kD）glyburide（140kD）Kir6.2SURMechanismofaction-MF↓Insulinsecretionburden↓Hepaticoutput控制血糖↑GlucoseuptakemusclepancreaseliverAmericanDiabetesAssociation.MedicalManagementofNon-Insulin-Dependent(Type2)Diabetes.3rdet.Alexandria,VA:AmericanDiabetesAssociation:1994Mechanismofaction-acarboseAcarboseOligosaccharideAcarboseSmallintestine

mucosaReversibleinhibitionofoligosaccharidebreakdownby-glucosidasesMechanismofaction-TZDAgonistsofPPARγ(peroxisomeproliferatoractivatedreceptorγ,)Mechanismofaction---DPP-4抑制剂活性的

GLP-1和GIP肠促胰岛素释放控制血糖稳定胃肠道进食GLP-1和GIP通过调控胰岛功能维持血糖稳态

胰岛α-细胞β-细胞肌肉和脂肪组织对葡萄糖的摄入和储存葡萄糖依赖性β-细胞胰岛素分泌(GLP-1和GIP)葡萄糖依赖性α-细胞胰升糖素分泌(GLP-1)肝脏向血液中释放的葡萄糖BrubakerPL,DruckerDJ.Endocrinology.2004;145:2653–2659;ZanderMetal.Lancet.2002;359:824–830;AhrénB.CurrDiabRep.2003;3:365–372;HolstJJ.DiabetesMetabResRev.2002;18:430–441;HolzGG,ChepurnyOG.CurrMedChem.2003;10:2471–2483;CreutzfeldtWOCetal.DiabetesCare.1996;19:580–586;DruckerDJ.DiabetesCare.2003;26:2929–2940.以肠促胰岛激素为基础的治疗:作用机制DPP-IV=dipeptidylpeptidaseIVAdaptedfromDruckerDJExpertOpinInvestDrugs2003;12(1):87–100;AhrénBCurrDiabRep2003;3:365–372.肠道GLP-1释放无活性GLP-1(9-36)进餐活性GLP-1(7-36)DPP-4酶抑制剂DPP-4酶

GLP-1类似物口服糖尿病药物总结DPP–4抑制剂DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):S24-40胰岛素抵抗胰高糖素抑制不足细胞功能失调胃肠道吸收葡萄糖慢性β细胞功能衰竭胰岛素分泌不足β细胞功能异常二甲双胍格列酮类磺脲类格列奈类α-糖苷酶抑制剂IndicationofinsulintherapyT1DMT2DM:Acutecomplication:NHDC,DKA,LAEndstageofchroniccomplicationStressPregnancySUFailureSevereweightlossCortisoltherapyInsulintherapyFastinghyperglycemiainsulindeficiency(waningofcirculatinginsulinlevels)SomogyiphenomenaDawnphenomenaSTEP-WISESTRATIGEMatthaeiS,etal.EndocrRev21:585,2000EDUCATIONDIETEXERCISEMFTZDSUinsulin80120160200FPG(mg/dl)100806040200meaninsulinduringOGTT(mU/l)T2DM（obese）Lifestylechange:diet,exercise,weightloss↓Biguanides/-glucosidaseinhibitorALONE↓AddSU↓OHA+NPH10pm.iH↓MultipleinsulininjectionsIRT2DM（non-obese）Lifestylechange:diet,exercise,weightloss↓SUaloneoraddBiguanides/-glucosidaseinhibitor↓Add↓OHA+NPH10pm.iH↓MultipleinsulininjectionspregnancyDietExerciseInsulintherapyInsulindeficiencyRapidmobilizationofenergyfromstoresinmuscleandfatdepots.KetoneproductionInsulin-antagonistichormoneUtilizationisreducedKetoneisaccumulatedacidosisDisturbanceofelectrocyteNauseavomitingRapidanddeeprespirationosmoticdiuresisHyperglycemiapolyuriaDKAdepletionofintravascularvolumePrecipitatingfactors:infection,diet,surgery,trauma,pregnancyPrecipitatingfactorsMostcommon:infectionCerebrovascularaccidentAlcoholabusePancreatitisMyocardialinfarctionTraumaDrugs(corticosteroids,thiazides,sympathomimeticagents)InsulindeficiencyRapidmobilizationofenergyfromstoresinmuscleandfatdepotsKetoneisaccumulatedInsulin-antagonistichormoneacidosisDisturbanceofelectrolytesHyperglycemiaLabtestdepletionofintravascularvolumeacetoacetate,B-hydroxybutyrate,acetoneHCO3-

,PHK,Na,ClBunCrPrecipitatingfactors:bloodcount,X-ray,ECGInsulindeficiencyInsulin-antagonistichormoneKetoneisaccumulatedacidosisDisturbanceofelect