沙格列汀的作用机制课件.ppt

沙格列汀的作用机制,肠促胰岛激素简史,1902-首次观察到藏到对胰岛分泌的影响1,2,1932-首次确定肠促胰岛素3,1964-证实仓促胰岛素效应1,4,5,1966-首次描述DPP-46,1973-GIP被确定为一种人类长促胰岛素1,1986-证实了长促胰岛素在2型糖尿病患者中的作用7,1995-DPP-4被确定为一种灭活GIP和GLP-1的酶9,10,1987-GLP-1被确定为一种人类长促胰岛素,CreutzfeldtW.RegulPept.2005;128:87-91.BaylissWMetal.JPhystol.1902;28:325-353.LaBarreJ.BullAcadR.MedBelg.1932;120:620-634.McIntyreNetal.Lancet.1964;41:20-21.ElrickHetal.JClinEndocr.1964;24:1076-1082.Hopsu-HavuVK,GlennerGG.Histochemle.1966;7(3):197-201.NauckMetal.Diabetologia.1986;29:46-52.KreymannBetal.Lancet.1987;2:1300-1304.KiefferTJetal.Endocrinology.1995;136;3385-3596.DeaconCFetal.JClinEndocrinolMetab.1995;80:952-957.,静脉血浆葡萄糖(mmol/L),时间(分钟),C-肽(nmol/L),0.0,0.5,1.0,1.5,2.0,时间(分钟),口服葡萄糖静脉注射葡萄糖,平均值SE;n=6;*P0.05;01-02=葡萄糖输注时间,肠促胰素效应的发现与静脉注射葡萄糖相比，口服葡萄糖增强了-细胞反应,NauckJ.ClinEndocrinolMetab.1986;63:492-8.,检测8名健康对照受试者口服葡萄糖（50g）和静脉注射葡萄糖的反应,与静脉注射葡萄糖相比，口服葡萄糖后，患者的血清C肽水平更高，由此证实了肠促胰素效应,肠促胰素效应,Naucketal.Diabetologia.1986,2型糖尿病患者肠促胰岛素效应减弱,Time(min),Insulin(mU/l),80,60,40,20,0,180,60,120,0,Time(min),Insulin(mU/l),180,60,120,0,非糖尿病组(n=8),2型糖尿病组(n=14),RoleofIncretinSysteminGlucoseHomeostasis,Normoglycaemia,Glucoseuptakebyperipheraltissue,AdaptedfromDruckerDJ.CellMetab.2006;3:153-65.,Hepaticglucoseproduction,Glucose-dependentinsulin(GLP-126:2929-2940.,TheIncretinEffectisReducedinType2Diabetes,AdaptedfromNauckM,etal.Diabetologia.1986;29:46-52.,Responsestoanoralglucoseloadof50gandintravenousglucoseinfusionweremeasuredin14type2diabeticpatientsand8healthycontrolsubjects.,Responsestoglucoseloadintype2diabeticsandhealthysubjects,Controlsubjects(N=8),Type2diabeticpatients(N=14),Venousplasmaglucose(mmol/l),Time(min),Time(min),0,10,15,120,180,01,60,0,5,10,15,5,120,180,01,60,02,02,Venousimmunoreactiveinsulin(mU/l),(nmol/l),0,20,40,60,80,0,20,40,60,80,0,0,0.1,0.3,0.4,0.6,0.5,0.2,0.1,0.3,0.4,0.6,0.5,0.2,*,*,*,*,*,*,*,*,*,*,Venousplasmaglucose(mmol/l),*P0.05totherespectivevalueaftertheoralload,Time(min),Time(min),120,180,60,120,180,60,02,02,01,01,(nmol/l),Venousimmunoreactiveinsulin(mU/l),Incretinhormonechanges,Inpatientswithtype2diabetes,levelsofGLP-1releasedinresponsetoglucosearereducedandGIPactivityisdecreased,ContinuousInfusionofGLP-1DecreasesFastingGlucoseaswellasHbA1c,AdaptedfromZanderM,etal.Lancet.2002;359(9309):824-30.,Comparedtosaline,patientstreatedwithGLP-1showedfastingand8-hourmeanplasmaglucosethatwasdecreasedby4.3mmol/land5.5mmol/l(P0.0001),andHbA1cthatwasdecreasedby1.3%(P=0.003),Patientsassignedsaline(N=9),PatientsassignedGLP-1(N=10),Glucoseconcentrationinplasma(mmol/L),0,0,Week0,Week1,Week6,Time(hr),Time(hr),Glucoseconcentrationinplasma(mmol/L),ExogenousGlucoseDependentInsulinotropicPolypeptideWorsensPostprandialHyperglycaemiainType2Diabetes,AdaptedfromChiaCW,etal.Diabetes.2009;58(6):1342-9.,GIPgivenatsupraphysiologicallevelsstillhasanearly,short-livedinsulinotropiceffectintype2diabetes,Time(min),Insulin(mg/mL),Glucose(mg/dL),Time(min),140,190,240,60,40,20,0,Whencomparedwithplacebo,exogenousGIPinfusionnotonlydidnotlowerpostprandialglucosebutfurtherworsenedhyperglycaemiaduringlatepostprandialperiod(120360min)inpatientswithtype2diabetes(N=22),Changesininsulin,Changesinglucose,*,*,*,*,*,*,*,*P0.05vsplacebo,在2型糖尿病的治疗中，针对GLP-1的药物更有价值,肠促胰岛素的效应在2型糖尿病患者中减弱在2型糖尿病患者中GIP水平正常甚至略微升高，但其作用很小-GIP抵抗GIP的促胰岛素分泌作用的减弱可能是遗传因素和环境因素共同作用引起的2型糖尿病患者中，GLP-1水平降低，但其作用未受损开发提高GLP-1水平的药物具有重要的临床意义,Nauck.MAetal.JClinInvest1993,91:301-307,SitesofActionofGLP-1,Brain,Glucoseproduction,NeuroprotectionAppetite,Liver,Stomach,Gastricemptying,GItract,Insulinbiosynthesis-cellproliferation-cellapoptosis,InsulinsecretionGlucagonsecretion,Muscle,Heart,CardioprotectionCardiacoutput,Insulinsensitivity,AdaptedfromDruckerDJ.CellMetab.2006;3:153-65.,Pancreas,GLP-1在人体的作用,促进饱腹感，降低食欲,胃:有助于调节胃排空,细胞:促进血糖依赖性胰岛素分泌,进食后，小肠开始分泌GLP-1,Adaptedfrom:FlintA,etal.JClinInvest.1998;101:515-20.HolstJJ.TEM.2005;10:229-35.LovshinJA,DruckerDJ.NatRevEndocrinol.2009;5:262-9.,胰高血糖素样肽-1(GLP-1),进食后由肠道L细胞分泌GLP-1在进食后数分钟内开始分泌，对食物中脂类和碳水化合物的反应最为明显,KiefferTJ,etal.EndocrRev.1999;20:876-913DruckerDJ.CurrPharmDes.2001;7:1399-412.DruckerDJ.MolEndocrinol.2003;17:161-71.,GLP-1通过其受体（GLP-1R）发挥作用GLP-1R在胰岛细胞上表达，受刺激后，可激活cAMP，以及蛋白激酶A依赖性或非依赖性的作用,Glucose-DependentEffectsofGLP-1,2型糖尿病(n=10),Adaptedfrom:NauckMA,etal.Diabetologia.1993;36:741-4.,-30,0,60,120,180,240,270,180,90,0,安慰剂,*,*,*,*,*,*,*,GLP-1,葡萄糖(mg/dL),安慰剂,GLP-1,300,200,100,0,*,*,*,*,*,*,*,*,GLP-1,安慰剂,-30,0,60,120,180,240,胰岛素(pmol/L),20,10,0,GLP-1,安慰剂,-30,0,60,120,180,240,胰高血糖素(pmol/L),时间(分钟),平均值(SE);*P0.05,GLP-1以葡萄糖依赖性方式增加胰岛素的分泌,T2DM中胰岛细胞对葡萄糖的敏感性降低,AGRarg=2-5分钟对精氨酸的平均急性胰高糖素反应；PG50=对AGRarg的抑制达最大值的一半时所需的血糖水平T2DM=2型糖尿病;*健康者平均年龄1829岁,WardWK,etal.JClinInvest.1984;74:13181328.DunningB,etal.Diabetologia.2005;48:17001713,糖尿病前期胰高糖素异常,JJHolst,Diabetologia(2009)52:17141723BoAhren,EuropeanJournalofEndocrinology(1997)137127131,糖尿病前期状态的病理生理学,胰高血糖素受体敲除小鼠血糖水平降低,RWGellingetal.PNAS100:1438-1443,2003,血糖(随意饲养),血糖,时间(天),T2DM是胰岛素分泌不足和胰高糖素分泌增加致高血糖,MllerWA,etal.NEnglJMed.1970;283:109115,碳水化合物膳食,胰高糖素,时间(分钟),75,100,125,150,60,0,60,120,180,240,pg/mL,胰岛素,0,50,100,150,U/mL,0,血糖,100,200,300,400,mg/dL,正常葡萄糖耐量,2型糖尿病,正常葡萄糖耐量,2型糖尿病,GLP-1降低1型糖尿病患者的胰高糖素和血糖水平,CreutzfeldtWO,etal.DiabetesCare.1996;19:580-6.,GLP-1抑制胰高糖素分泌并非由胰岛素介导,GLP-1抑制胰岛细胞功能无残留的1型糖尿病患者的胰高血糖素分泌在2型糖尿病中，在不足以导致可测出胰岛素分泌的血糖水平下，GLP-1能抑制胰高血糖素的分泌没有证据显示其他非肠促胰素类降糖药物对人胰高糖素分泌起作用,JesperGromadaEndocrineReviews28(1):84116,GLP-1在体内快速降解,123,30,GLP-1,Des-HA-GLP-1(失活),GLP-1被二肽基肽酶-4（DPP-4）降解失活半衰期1-2分钟,12,330,DPP-4,提高GLP-1作用的治疗方法:模拟GLP-1作用的药物(肠促胰岛素类似物)DPP-4酶抑制剂,Mentleinetal.EurJBiochem.1993;Gallwitzetal.EurJBiochem.1994,DPP4抑制剂作用机理,食物摄入,胃,胃肠道,肠,增加和延长GLP-1对细胞的影响:,细胞：,胰腺,胰岛素释放,净效应：血糖,细胞:,增加和延长GLP-1和GIP对细胞的作用：,DPP4抑制剂,胰高血糖素分泌,Drucker和Nauck,2006;Idris和Donnelly,2007;Barnett,2006,肠促胰岛素,临床药效学:稳定状态下，血浆中不同剂量的DPP-4活性,CV181002(MADinT2DM),dataaremeans,血浆DPP4活性(自基线的变化%),DPP-4抑制剂沙格列汀具有双重作用机制,DPP-4抑制剂沙格列汀,BrJDiabetesVaseDis2010;10:14-20,b-CellStimulationbySaxagliptininPatientswithT2DStudyschema,SAXA:saxagliptin;PBO,placebo;BMI:bodymassindex;T2D:type2diabetes.,n=156,n=46,SAXA5mg,PBO,Screening,Single-blindlead-in2weeks,Double-blindtreatment12weeks,InclusionTreatmentnaveT2D18-70yearsoldHbA1c6-8%BMI40kg/m2FastingC-peptide1ng/mL,DietPBO:placebo;IV:intravenous.*Glucoseinfusiontoachieveandmaintainhyperglycaemia=280mg/dLfrom0-480min.At480min,infusionadjustedtomaintainhyperglycaemia=450mg/dL.Arginine5g(10%solution,50mLIVover30sec)administeredat505min.Samplesdrawnatprotocol-specifiedintervals.,SequentialIV-Oralhyperglycaemicclampandargininestimulationtest,Plasmaglucose(mg/dL),400,100,505,200,450,300,280,480,515,180,120,0,-30,Time(min),75goralglucosechallenge,Startglucoseinfusion*,SAXAorPBO,IVhyperglycaemicclamp,IV-Oralhyperglycaemicclamp,Argininestimulationtest,0,AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austria.,T2D:type2diabetes,422HQ09NP101,基线和12周(LOCF)时，高糖钳夹试验中，在空腹（0-180分钟）和OGTT后（180-480分钟）状态的胰岛素分泌率,Source:CV181041Figure7.1(App.5.3.4),研究041,胰岛素分泌率平均值(pmol/kg*min),分钟,胰岛素分泌率平均值(pmol/kg*min),分钟,10,沙格列汀5mg,安慰剂,10,主要和次要有效性终点,Source:CV181041Table7.1,研究041,a估值=100*exp(校正后自基线的自然对数平均值的变化)-1b估值=100*exp(校正后沙格列汀5mg和安慰剂间自然对数平均值变化的差异)-1*在alpha=0.05水平有意义时，比较沙格列汀5mg和安慰剂,b-CellStimulationbySaxagliptininPatientswithT2DInsulinsecretionratesinthepostprandialstate,SAXA5mg(n=16),PBO(n=15),30,-10,10,20,Geometricmean%changefrombaseline,-20,0,-,-,-,-,-,*Valuesaregeometricmeans;Adjusted%changefrombaseline,geometricmeanand95%CI(representedbybar)SAXA:saxagliptin;PBO:placebo;T2D:type2diabetes;LOCF,lastobservationcarriedforward.,-2.2,-12.4,9.3,15.9,4.2,29.0,InsulinsecretionrateduringIV-Oralhyperglycaemicclamp:adjusted%changefrombaselineatWeek12(LOCF),Adjusted%differencePBO(95%CI):18.5(1.3,38.7)P=0.035,AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austria.,422HQ09NP101,b-CellStimulationbySaxagliptininPatientswithT2DInsulinsecretionratesinthefastingstate,40,-10,10,20,-20,0,-,-,-,-,-,*Valuesaregeometricmeans;Adjusted%changefrombaseline,geometricmeanand95%CI(representedbybar)SAXA:saxagliptin;PBO:placebo;T2D:type2diabetes;LOCF,lastobservationcarriedforward.,-4.1,-17.4,11.2,22.6,7.2,40.4,InsulinsecretionrateduringIVhyperglycaemicclamp:adjusted%changefrombaselineatWeek12(LOCF),Adjusted%differencePBO(95%CI):27.9(4.2,57.1)P=0.020,30,-,SAXA5mg(n=18),PBO(n=15),Geometricmean%changefrombaseline,AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austria.,422HQ09NP101,b-CellStimulationbySaxagliptininPatientswithT2DInsulinsecretionfollowingIVarginine,*LOCF:lastobservationcarriedforward.PvaluevsPBO=0.074(Kruskal-Wallistest)SAXA:saxagliptin;PBO:placebo;IV,intravenous;T2D:type2diabetes.,AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austria.,InsulinsecretionfollowingIVarginine:changesfrombaselineatWeek12,422HQ09NP101,静脉-口服高糖钳夹试验中，胰高糖素曲线下面积12周(LOCF)时自基线的变化,Source:CV181041Section7.4.3.1(App.5.6.3),研究041,a沙格列汀5mg与安慰剂自基线变化的差异b估值=沙格列汀5mg校正后平均值变化安慰剂校正后平均值变化,Henryetal.Diabetes,ObesityandMetabolism2011;13:850-858.,沙格列汀单剂治疗降低胰高糖素水平,沙格列汀降低胰高糖素水平达15.4%,SAXA:saxagliptin;PBO:placebo;T2D:type2diabetes.,b-CellStimula