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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719

95-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;28:3

25-353.3.LaBarreJ.BullAcadR.MedBelg.1932;120:620-634.4.McIntyreNetal.Lancet.1964;41:20-21.5.ElrickHetal.JClinEndocr.1964;2

4:1076-1082.6.Hopsu-HavuVK,GlennerGG.Histochemle.1966;7(3):197-201.7.NauckMetal.Diabetologia.1986;29:46-52.8.Kreyma

nnBetal.Lancet.1987;2:1300-1304.9.KiefferTJetal.Endocrinology.1995;136;3385-3596.10.DeaconCFetal.JClinEndocrin

olMetab.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;*P0.05;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)RoleofIncretinSysteminGlucoseHomeostasisNormoglycaemiaGlucoseuptakebyperipheraltissueAda

ptedfromDruckerDJ.CellMetab.2006;3:153-65.¯HepaticglucoseproductionGlucose-dependentinsulin(GLP-1&GIP)Glucose-dependent¯

glucagon(GLP-1)Pancreas-cells-cellsReleaseofactiveincretinsGLP-1&GIPDPP-4inactivatesGLP-1&GIPGItractIngestionoffo

odGLP-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β细胞增殖是是促进胰岛素生物合成是是DruckerDJ.DiabetesCare.2003;26:2929-2940.TheIncretinEffectisReducedinType2Dia

betesAdaptedfromNauckM,etal.Diabetologia.1986;29:46-52.Oralglucose(50g)IVglucose(variable)Responsestoanor

alglucoseloadof50gandintravenousglucoseinfusionweremeasuredin14type2diabeticpatientsand8healthycontrolsubjects.Respons

estoglucoseloadintype2diabeticsandhealthysubjectsControlsubjects(N=8)Type2diabeticpatients(N=14)Oralglucose(50g

)IVglucose(variable)Venousplasmaglucose(mmol/l)Time(min)Time(min)010151201800160051015512018001600202Venousimmunorea

ctiveinsulin(mU/l)(nmol/l)020406080020406080000.10.30.40.60.50.20.10.30.40.60.50.2**********Venousplasmaglu

cose(mmol/l)*P≤0.05totherespectivevalueaftertheoralloadTime(min)Time(min)120180601201806002020101(nmol/l)Venousimmunoreactiveinsulin(mU/l)Incr

etinhormonechanges•Inpatientswithtype2diabetes,levelsofGLP-1releasedinresponsetoglucosearereducedandGIPactivityisdecrease

dContinuousInfusionofGLP-1DecreasesFastingGlucoseaswellasHbA1cAdaptedfromZanderM,etal.Lancet.2002;359(930

9):824-30.Comparedtosaline,patientstreatedwithGLP-1showedfastingand8-hourmeanplasmaglucosethatwasdecr

easedby4.3mmol/land5.5mmol/l(P<0.0001),andHbA1cthatwasdecreasedby1.3%(P=0.003)Patientsassignedsaline(

N=9)PatientsassignedGLP-1(N=10)Glucoseconcentrationinplasma(mmol/L)008246082462520151050252015105Week0Week1Week6Time(hr)Time(hr)Gluco

seconcentrationinplasma(mmol/L)ExogenousGlucose–DependentInsulinotropicPolypeptideWorsensPostprandialHyperglycaemiainType2DiabetesAdaptedfromC

hiaCW,etal.Diabetes.2009;58(6):1342-9.Time(min)GIPPlacebo455256528018038080-20Insulin(mg/mL)Glucose(mg/dL)45525656040200Time(min)19011015023028

018038080-201401902406040200Whencomparedwithplacebo,exogenousGIPinfusionnotonlydidnotlowerpostprandialglucosebutfurtherworsenedhyperglycaemiaduri

nglatepostprandialperiod(120–360min)inpatientswithtype2diabetes(N=22)ChangesininsulinChangesinglucose********P<0.05vsplacebo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.JClinInvest1993,91:301-307SitesofActionofGLP-1BrainGlucoseproductionNeuroprotectionAppetiteLiver

StomachGastricemptyingGItractInsulinbiosynthesis-cellproliferation-cellapoptosisInsulinsecretionGlucagonsecretionMuscleHeartCardioprotect

ionCardiacoutputInsulinsensitivityAdaptedfromDruckerDJ.CellMetab.2006;3:153-65.PancreasGLP-1在人体的作用促进饱腹感，降低食欲α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β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.β细胞工作负荷β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.M

olEndocrinol.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β细胞数量•-刺激新生β细胞的形成•-抑制细胞凋亡◆GLP-1通过

其受体（GLP-1R）发挥作用➢GLP-1R在胰岛β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.-30060120180240270

180900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/L)20100****GLP

-1安慰剂-30060120180240胰高血糖素(pmol/L)时间(分钟)平均值(SE);*P<0.05GLP-1以葡萄糖依赖性方式增加胰岛素的分泌T2DM中胰岛α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18–29岁NGT*(n=8)T2DM(n=8)180-150-120-90-60-30-0100200300400500600700AGRarg(pg/mL)

血糖水平(mg/dL)PG50WardWK,etal.JClinInvest.1984;74:1318–1328.DunningB,etal.Diabetologia.2005;48:1700–1713糖尿病前期胰高糖素异常JJHol

st,Diabetologia(2009)52:1714–1723BoAhren,EuropeanJournalofEndocrinology(1997)137127–131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70010001600200024000.02

.55.07.510.0***********TimeofDayBloodGlucose(mM)GR-/-GR+/+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MüllerWA,etal.NEnglJMed.1970;283:109–115碳水化合物膳食胰高糖素时间(分钟)75100125150–60060120180240pg/mL胰岛素050100150μU/mL0

血糖100200300400mg/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;19:58

0-6.********GLP-1P<.001PlaceboGLP-1orPlaceboPlaceboGLP-1P<.001*******GLP-1orPlaceboGLP-1抑制胰高糖素分泌并非由胰岛素介导◆GLP-1抑制胰岛β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):84–116GLP-1在体内快速降解12330

GLP-1Des-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12330DPP-4提高GLP-1作用的治疗方法:1)模拟GLP-1作用的药物(肠促胰岛素类似物)2)DPP-4酶抑制剂Mentleinetal.

EurJBiochem.1993;Gallwitzetal.EurJBiochem.1994DPP4抑制剂作用机理食物摄入胃胃肠道肠增加和延长GLP-1对α细胞的影响:α细胞：胰腺胰岛素释放净效应：血糖β细胞:增加和延长GLP-1和GIP对β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

-100-80-60-40-2002004812162024Timepost-dose(h)PlasmaDPP4activity(%changefrombaseline).Placebo(n=7)2.5mg(n=6)5mg(n=5)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;10:14-20b-CellStimulationbySaxagliptininPatientswithT

2DStudyschemaSAXA:saxagliptin;PBO,placebo;BMI:bodymassindex;T2D:type2diabetes.n=156n=46SAXA5mgPBOScreeningSingle-blindlead-in2weeksD

ouble-blindtreatment12weeksInclusion▪Treatmentnaïve▪T2D▪18-70yearsold▪HbA1c6-8%▪BMI£40kg/m2▪FastingC-peptide³1ng/mLDie

t&exerciseplaceboSubjectswereprovidedwith:▪Meterstomonitorglucose▪Bloodglucoseself-monitoringinstructionn=20n=16RandomisationA

daptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austria.422HQ09NP101入选标准◆2型糖尿病病人◆筛选访视时，

糖化血红蛋白≥6.0%和≤8.0%◆空腹C-肽浓度≥1.0ng/mL◆未服用药物的患者◆BMI≤40kg/m2◆男性和女性,≥18和≤70岁.女性必须是不在哺乳期和妊娠期Source:CV181041–3.3.1研

究041有效性终点◆主要有效性终点➢主要有效性终点是在肠内给糖的高糖钳夹试验中[静脉-口服高糖钳夹试验，180-480分钟]，胰岛素分泌率曲线下面积在12周时自基线变化的百分比。如果没有12周的测量值，将采用12周前基线后的最后一次测量值。◆次要有效性终点➢次要有效

性终点是在静脉高糖钳夹试验中（120-180分钟），胰岛素分泌率曲线下面积在12周时自基线变化的百分比。如果没有12周的测量值，将采用12周前基线后的最后一次测量值。Source:CV181041–3.5.1.1研究041b-CellStimulationbySaxagliptin

inPatientswithT2DMethodsSAXA:saxagliptin;PBO:placebo;IV:intravenous.*Glucoseinfusiontoachieveandmaintainhyperglycaemia

=280mg/dLfrom0-480min.At480min,infusionadjustedtomaintainhyperglycaemia=450mg/dL.†Arginine5g(10%solution,50mLIVover30sec)ad

ministeredat505min.‡Samplesdrawnatprotocol-specifiedintervals.SequentialIV-OralhyperglycaemicclampandargininestimulationtestPlasmaglucose(mg/dL

)400100505†2004503002804805151801200-30Time(min)75goralglucosechallengeStartglucoseinfusion*SAXAorPBOIVhyperglyca

emicclampIV-OralhyperglycaemicclampArgininestimulationtestSamples‡GlucoseInsulinGlucagonGLP-1GIP0AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep2

7-Oct1,2009.Vienna,Austria.T2D:type2diabetes422HQ09NP101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:CV181

041–Figure7.1(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:CV181041–Table7.1研究041有效性终点(12周)沙格列汀

5mgn=20安慰剂n=16静脉-口服钳夹试验中胰岛素分泌(pmol/kg)(180-480分钟)病例数1615基线平均值(SE)2817.73687.012周LOCF平均值3303.13564.3校正后自基线的几何平均值的变化%a15.9-2.2校正后与安慰剂的差异%b18.5与

安慰剂对照的P-值*0.0350*静脉钳夹试验中胰岛素分泌(pmol/kg)(120-180分钟)病例数1815基线几何平均值446.3593.524周LOCF几何平均值552.1563.1校正后自基线的几何平均值的变化%a22.6-4.1校正后与安慰剂的区别%b27

.9与安慰剂对照的P-值*0.0204*a估值=100*[exp(校正后自基线的自然对数平均值的变化)-1]b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-CellStimu

lationbySaxagliptininPatientswithT2DInsulinsecretionratesinthepostprandialstateSAXA5mg(n=16)PBO(n=15)30-101020Geometricmean%changefrombase

line-200-----*Valuesaregeometricmeans;†Adjusted%changefrombaseline,geometricmeanand95%CI(representedbybar)SAXA:sa

xagliptin;PBO:placebo;T2D:type2diabetes;LOCF,lastobservationcarriedforward.-2.2†-12.49.315.9†4.229.0InsulinsecretionrateduringIV-O

ralhyperglycaemicclamp:adjusted%changefrombaselineatWeek12(LOCF)Insulinsecretionrate(pmol/kg)*Baseline28183687Week12(LOCF)3303

3564Adjusted%differencePBO(95%CI):18.5(1.3,38.7)P=0.035AdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vienna,Austr

ia.422HQ09NP101b-CellStimulationbySaxagliptininPatientswithT2DInsulinsecretionratesinthefastingstate40-101020-200-----*Valuesaregeometricmeans;†

Adjusted%changefrombaseline,geometricmeanand95%CI(representedbybar)SAXA:saxagliptin;PBO:placebo;T2D:type2diabetes;LOCF,lastobservationcarriedforward

.-4.1†-17.411.222.6†7.240.4InsulinsecretionrateduringIVhyperglycaemicclamp:adjusted%changefrombaselineatWeek12(L

OCF)Insulinsecretionrate(pmol/kg)*Baseline446594Week12(LOCF)552563Adjusted%differencePBO(95%CI):27.9(4.2,57.1)P=0.02030-SAXA5mg(n=18)PBO

(n=15)Geometricmean%changefrombaselineAdaptedfromHenryR,etal.PosterpresentedatEASD.Sep27-Oct1,2009.Vien

na,Austria.422HQ09NP101b-CellStimulationbySaxagliptininPatientswithT2DInsulinsecretionfollowingIVarginineInsulinsecretioninfirs

t5minutesfollowingIVarginineSAXA5mgPBOAcuteinsulinresponse,mU/mL(n=16)(n=14)Baseline,median(Q1,Q3)164(107,203)204(175,268)Week12,median(Q1,

Q3)172(136,228)185(147,208)Changefrombaseline*,median(Q1,Q3)24.0†(-5.8,71.5)-21.7(-52.3,5.3)*LOCF:lastobservationcarriedforward.†Pva

luevsPBO=0.074(Kruskal-Wallistest)SAXA:saxagliptin;PBO:placebo;IV,intravenous;T2D:type2diabetes.Adaptedfrom

HenryR,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:CV181041–Section7.4.3.1(App.5.6.3)研究041单位:pg*min/mL沙格列汀5mgn=20安慰剂n=16统计学结果病例数1714基线平均值(

SE)14279(1228.2)11177(880.2)12周LOCF平均值(SE)11571(1112.7)12965(1272.5)自基线变化的平均值(SE)-2708(864.9)1788(1247.5)校正后自基线的变化平均值(SE)-2191(957.8)1161

(1061.9)95%双侧检验的可信区间[-4153,-229][-1014,3336]与安慰剂的不同a平均值(SE)b-3352(1473.8)95%双侧检验的可信区间[-6371,-333]p-值0.0308a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%胰高血糖素pg/ml75g口服葡萄糖测试沙格列汀5mg

:基线沙格列汀5mg:12周SAXA:saxagliptin;PBO:placebo;T2D:type2diabetes.b-CellStimulationbySaxagliptininPatientswithT2DGLP-1andGIPconcentrationsduringIV-

Oralhyperglycaemicclamp360Time(min)MeanactiveGLP-1concentrations(pmol/L)0270300420480GLP-1SAXA5mg-Week12PBO-Week12PBO-Baseline

SAXA5mg-Baseline5432124021018075goralglucosechallenge360Time(min)MeanactiveGIPconcentrations(pmol/L)0270300420480GIPSAXA

5mg-Week12PBO-Week12PBO-BaselineSAXA5mg-Baseline806040201024021018075goralglucosechallenge305070AdaptedfromHenryR,etal.Posterpr

esentedatEASD.Sep27-Oct1,2009.Vienna,Austria.ActiveGLP-1andGIPconcentrationsduringIV-OralhyperglycemicclampatbaselineandWeek12(LOCF)422HQ09NP

101A1CChangesfromBaselineatWeek12(LOCF)Source:CV181041–Section7.4.4(App.5.7.1)Study041Unit:PercentSAXA5mgn=20PBOn=16SummaryStatisticsn1816B

aselinemean(SE)6.94(0.117)6.59(0.144)Week12LOCFmean(SE)6.77(0.155)6.64(0.167)Meanfrombaseline(SE)-0.1

7(0.133)0.05(0.094)AdjustedfrombaselineMean(SE)-0.14(0.118)0.02(0.125)95%two-sidedCI[-0.38,0.10][-0.23,0.28]FastingPlasm

aGlucose–ChangesfromBaselineatWeek12(LOCF)Source:CV181041–Section7.4.1.5(App.5.7.2)Study041MeanChangefromBaselinewith95%CISAXA5mgPBOn=

1816BaselineMean(mg/dL)133.2124.7GlucoseAUCDuringOGTT–ChangesfromBaselineatWeek12(LOCF)Study041MeanChan

gefromBaselinewith95%CISAXA5mgPBOn=1615BaselineMean(mg•min/dL)5910850473Source:CV181041–Section7.4.1.3(App.5.4.7)