沙格列汀的作用机制.pptx
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沙格列汀的作用机制.pptx
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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1,21932-首次确定肠促胰岛素31964-证实仓促胰岛素效应1,4,51966-首次描述DPP-461973-GIP被确定为一种人类长促胰岛素11986-证实了长促胰岛素在2型糖尿病患者中的作用71995-DPP-4被确定为一种灭活GIP和GLP-1的酶9,101987-GLP-1被确定为一种人类长促胰岛素1.CreutzfeldtW.RegulPept.2005;128:
87-91.2.BaylissWMetal.JPhystol.1902;28:
325-353.3.LaBarreJ.BullAcadR.MedBelg.1932;120:
620-634.4.McIntyreNetal.Lancet.1964;41:
20-21.5.ElrickHetal.JClinEndocr.1964;24:
1076-1082.6.Hopsu-HavuVK,GlennerGG.Histochemle.1966;7(3):
197-201.7.NauckMetal.Diabetologia.1986;29:
46-52.8.KreymannBetal.Lancet.1987;2:
1300-1304.9.KiefferTJetal.Endocrinology.1995;136;3385-3596.10.DeaconCFetal.JClinEndocrinolMetab.1995;80:
952-957.静脉血浆葡萄糖(mmol/L)时间(分钟)C-肽(nmol/L)115.500.00.51.01.52.0时间(分钟)016012018002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016012018002肠促胰素效应Naucketal.Diabetologia.19862型糖尿病患者肠促胰岛素效应减弱口服葡萄糖静脉注射葡萄糖Time(min)Insulin(mU/l)806040200180601200Time(min)Insulin(mU/l)806040200180601200肠促胰岛素效应非糖尿病组(n=8)2型糖尿病组(n=14)RoleofIncretinSysteminGlucoseHomeostasisNormoglycaemiaGlucoseuptakebyperipheraltissueAdaptedfromDruckerDJ.CellMetab.2006;3:
153-65.HepaticglucoseproductionGlucose-dependentinsulin(GLP-1&GIP)Glucose-dependentglucagon(GLP-1)Pancreas-cells-cellsReleaseofactiveincretinsGLP-1&GIPDPP-4inactivatesGLP-1&GIPGItractIngestionoffoodGLP-1和GIP是两类主要的肠促胰素GLP-1(胰高糖素样肽-1)GIP(葡萄糖依赖的促胰岛素释放多肽)主要合成部位L细胞(回肠和结肠)K细胞(十二指肠和空肠)2型糖尿病患者中分泌是否餐后胰高糖素是否食物摄入是否延缓胃排空是否促进细胞增殖是是促进胰岛素生物合成是是DruckerDJ.DiabetesCare.2003;26:
2929-2940.TheIncretinEffectisReducedinType2DiabetesAdaptedfromNauckM,etal.Diabetologia.1986;29:
46-52.Oralglucose(50g)IVglucose(variable)Responsestoanoralglucoseloadof50gandintravenousglucoseinfusionweremeasuredin14type2diabeticpatientsand8healthycontrolsubjects.Responsestoglucoseloadintype2diabeticsandhealthysubjectsControlsubjects(N=8)Type2diabeticpatients(N=14)Oralglucose(50g)IVglucose(variable)Venousplasmaglucose(mmol/l)Time(min)Time(min)010151201800160051015512018001600202Venousimmunoreactiveinsulin(mU/l)(nmol/l)020406080020406080000.10.30.40.60.50.20.10.30.40.60.50.2*Venousplasmaglucose(mmol/l)*P0.05totherespectivevalueaftertheoralloadTime(min)Time(min)120180601201806002020101(nmol/l)Venousimmunoreactiveinsulin(mU/l)IncretinhormonechangesInpatientswithtype2diabetes,levelsofGLP-1releasedinresponsetoglucosearereducedandGIPactivityisdecreasedContinuousInfusionofGLP-1DecreasesFastingGlucoseaswellasHbA1cAdaptedfromZanderM,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)008246082462520151050252015105Week0Week1Week6Time(hr)Time(hr)Glucoseconcentrationinplasma(mmol/L)ExogenousGlucoseDependentInsulinotropicPolypeptideWorsensPostprandialHyperglycaemiainType2DiabetesAdaptedfromChiaCW,etal.Diabetes.2009;58(6):
1342-9.GIPgivenatsupraphysiologicallevelsstillhasanearly,short-livedinsulinotropiceffectintype2diabetesTime(min)GIPPlacebo455256528018038080-20Insulin(mg/mL)Glucose(mg/dL)45525656040200Time(min)19011015023028018038080-201401902406040200Whencomparedwithplacebo,exogenousGIPinfusionnotonlydidnotlowerpostprandialglucosebutfurtherworsenedhyperglycaemiaduringlatepostprandialperiod(120360min)inpatientswithtype2diabetes(N=22)ChangesininsulinChangesinglucose*P0.05vsplacebo在2型糖尿病的治疗中,针对GLP-1的药物更有价值u肠促胰岛素的效应在2型糖尿病患者中减弱u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u2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:
301-307SitesofActionofGLP-1BrainGlucoseproductionNeuroprotectionAppetiteLiverStomachGastricemptyingGItractInsulinbiosynthesis-cellproliferation-cellapoptosisInsulinsecretionGlucagonsecretionMuscleHeartCardioprotectionCardiacoutputInsulinsensitivityAdaptedfromDruckerDJ.CellMetab.2006;3:
153-65.PancreasGLP-1在人体的作用促进饱腹感,降低食欲细胞:
餐后胰高血糖素分泌肝脏:
胰高血糖素减少肝糖输出胃:
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-1Adaptedfrom:
FlintA,etal.JClinInvest.1998;101:
515-20.HolstJJ.TEM.2005;10:
229-35.LovshinJA,DruckerDJ.NatRevEndocrinol.2009;5:
262-9.细胞工作负荷细胞反应胰高血糖素样肽-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1.KiefferTJ,etal.EndocrRev.1999;20:
876-9132.DruckerDJ.CurrPharmDes.2001;7:
1399-412.3.DruckerDJ.MolEndocrinol.2003;17:
161-71.在人体和动物体内在动物体内和体外研究中促进葡萄糖刺激的胰岛素分泌抑制胰高血糖素的释放延缓胃排空减少食物的摄入量增强胰岛素基因的转录可能通过以下途径增加细胞数量-刺激新生细胞的形成-抑制细胞凋亡uGLP-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2型糖尿病(n=10)Adaptedfrom:
NauckMA,etal.Diabetologia.1993;36:
741-4.-30060120180240270180900安慰剂*GLP-1葡萄糖(mg/dL)安慰剂GLP-13002001000*GLP-1安慰剂-30060120180240胰岛素(pmol/
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