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(医学课件)GLP-1及利拉鲁肽整体介绍

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(医学课件)GLP-1及利拉鲁肽整体介绍GLP-1类似物——应对2型糖尿病治疗面对的挑战**2型糖尿病的治疗面临多方面的挑战糖尿病诊断2型糖尿病进展的附加因素碳水化合物代谢参数时间糖尿病前期糖尿病有更有效的解决办法吗?理想的治疗药物应从多方面干预2型糖尿病主要内容GLP-1的发现及生理作用 利拉鲁肽—更出色的GLP-1类似物 -利拉鲁肽的临床特点 -利拉鲁肽与传统药物对比(LEAD3) -基于肠促胰素的治疗的比较*肠促胰素(incretin)的发现 1932年,拉贝尔(LaBarre): 肠道中存在一种可以影响血糖的激...

(医学课件)GLP-1及利拉鲁肽整体介绍
GLP-1类似物——应对2型糖尿病治疗面对的挑战**2型糖尿病的治疗面临多方面的挑战糖尿病诊断2型糖尿病进展的附加因素碳水化合物代谢参数时间糖尿病前期糖尿病有更有效的解决办法吗?理想的治疗药物应从多方面干预2型糖尿病主要内容GLP-1的发现及生理作用 利拉鲁肽—更出色的GLP-1类似物 -利拉鲁肽的临床特点 -利拉鲁肽与传统药物对比(LEAD3) -基于肠促胰素的治疗的比较*肠促胰素(incretin)的发现 1932年,拉贝尔(LaBarre): 肠道中存在一种可以影响血糖的激素,并为之命名为肠促胰素(incretins)。 1967年,佩雷(Perley)和奇普尼斯(Kipnis): 发 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 于《临床研究杂志》(JournalofClinicalInvestigation):肠促胰素效应(IncretinEffect)*血浆葡萄糖(mmol/L)–10–56012018010时间(分)5015血浆葡萄糖900180270肠促胰素在正常胰岛素应答反应中至关重要 尽管血浆葡萄糖浓度相似,口服葡萄糖后的胰岛素应答反应要强于静脉输注葡萄糖Naucketal.Diabetologia1986;29:46–52,健康志愿者(n=8)**β细胞的胰岛素脉冲式分泌和时相分泌共同维持着人体正常血糖水平,同时也受到血糖、血脂、β细胞凋亡与再生、细胞量及胰升血糖素样肽1(GLP-1)等诸多因素的影响。TheincretinhormonesplayacrucialroleinahealthyinsulinresponseTheeffectofincretinsoninsulinsecretionisclearlyindicatedinthisstudy.Healthyvolunteers(n=8)fastedovernightbeforetheyreceivedanoralglucoseloadof50g/400mloranisoglycaemicintravenousglucoseinfusionfor180minutes.Ascanbeseenintheleftfigure,venousplasmaglucoseconcentrationwassimilarwithbothglucoseinterventions.However,insulinconcentrationwasgreaterfollowingoralglucoseingestionthanfollowingintravenousglucoseinfusion,demonstratingthecontributionofincretinsoninsulinsecretion.ReferenceNaucketal.Diabetologia1986;29:46–52*SlideNo.*••2型糖尿病中肠促胰素作用减弱020406080胰岛素(mU/L)0306090120150180时间(min)0204060800306090120150180时间(min)2型糖尿病患者正常人静脉注射葡萄糖口服葡萄糖*与口服后的相应值相比p≤.05NauckMA,etal.Diabetologia.1986;29:46-52.*在糖尿病患者中,肠促胰素的效应与健康人群有所不同。左图是正常人口服葡萄糖或静脉推注葡萄糖得到的胰岛素反应。这右图所示的2型糖尿病患者中的情况有明显不同。我们都很清楚,如果我们口服葡萄糖之后,糖尿病患者得到的早相远远低于正常人,而后相有一个高代偿。在静脉推注葡萄糖时患者与正常人的胰岛素分泌情况也不一样。那么,糖尿病患者中的GLP-1和GIP分泌情况是怎样的呢?Reducedincretineffectintype2(non-insulin-dependent)diabetes.Integratedincrementalimmunoreactiveinsulinandconnectingpeptideresponsestoanoralglucoseloadof50gandan"isoglycaemic"intravenousglucoseinfusion,respectively,weremeasuredin14Type2(non-insulin-dependent)diabeticpatientsand8age-andweight-matchedmetabolicallyhealthycontrolsubjects.Differencesbetweenresponsestooralandintravenousglucoseadministrationareattributedtofactorsotherthanglucoseitself(incretineffect).Despitehigherglucoseincreases,immunoreactiveinsulinandconnectingpeptideresponsesafteroralglucoseweredelayedindiabeticpatients.Integratedresponseswerenotsignificantlydifferentbetweenbothgroups.However,during"isoglycaemic"intravenousinfusion,insulinandconnectingpeptideresponsesweregreaterindiabeticpatientsthanincontrolsubjectsasaconsequenceofthehigherglycaemicstimulus.Thecontributionofincretinfactorstototalinsulinresponseswas72.8+/-6.9%(100%=responsetooralload)incontrolsubjectsand36.0+/-8.8%indiabeticpatients(plessthanorequalto0.05).Thecontributiontoconnectingpeptideresponseswas58.4+/-7.6%incontrolsubjectsand7.6+/-14.5%(plessthanorequalto0.05)indiabeticpatients.Ratiosofintegratedinsulintoconnectingpeptideresponsessuggestareduced(hepatic)insulinextractionincontrolsubjectsafteroralascomparedtointravenousglucose.Thiswasnotthecaseindiabeticpatients.Immunoreactivegastricinhibitorypolypeptideresponseswerenotdifferentbetweencontrolsubjectsanddiabeticpatients.肠促胰素:GLP-1及GIP 胰高糖素样肽1(GLP-1:Glucagon-likepeptide-1) 主要由位于回肠和结肠的L细胞合成和分泌 作用于体内多个部位:胰腺β细胞和α细胞、胃肠道、中枢神经系统及心脏等 其作用是通过特异受体介导的 葡萄糖依赖的促胰岛素多肽(GIP:glucose-dependentinsulinotropicpolypeptide) 主要由位于十二指肠和空肠的K细胞合成和分泌的 作用部位:主要作用于胰腺β细胞;也可作用于脂肪细胞、神经前体细胞及成骨细胞等 其作用是通过特异受体介导的DruckerDJ.DiabetesCare.2003;26:2929-2940;ThorensB.DiabetesMetab.1995;21:311-318;BaggioLL,DruckerDJ.Gastroenterology.2007;132:2131-2157;NybergJ,etal.JNeurosci.2005;25:1816-1825.*讨论葡萄糖依赖的促胰岛素多肽(GIP)和胰高糖素样肽1(GLP-1)是两种肽类激素,负责营养素刺激下胰岛素分泌的绝大部分。GLP-1引起大部分的肠促胰素效应,而GIP负责β细胞功能肠促胰素效应的约20%-30%。GLP-1主要由位于回肠和结肠的L细胞和合成和释放,少部分在十二指肠和空肠合成和释放。GIP由肠道K细胞合成和释放,这种细胞主要位于十二指肠和近端空肠。背景虽然肠促胰素效应最早于1960年代就得到了证实,但大约过了15-20年后,才鉴定出GIP和GLP-1这两种成分。GIP和GLP-1是胰高糖素肽超家族的成员,具有相当多的相同氨基酸成分。进餐后分泌有两种GLP-1形式,GLP-1(7-37)和GLP-1(7-36)酰胺,这两种成分只有1个氨基酸的差别。这两种肽是等效的,血浆半衰期相同,生物活性也相同,都作用于相同的受体;但是血液循环中有活性的GLP-1的绝大部分(80%)似乎是GLP-1(7-36)酰胺。GLP-1与GIP的生理作用不尽相同神经保护食欲心脏保护心输出量胃排空胰高血糖素分泌胰岛素分泌胰岛素合成β细胞增殖β细胞凋亡葡萄糖生成葡萄糖利用脂肪生成骨质生成*SlideNo.*••Toft-Nielsenetal.JClinEndocrinolMetab(2001)进餐进餐时间(min)时间(min)T2DM患者的肠促胰素缺陷主要为GLP-1分泌受损而非GIP*PlasmaConcentrationsofGlucagon,PancreaticPolypeptide,andGIPinPatientsWithType2DiabetesandNormalSubjects1Aclinicalstudyinvestigatedthemeal-stimulatedGLP-1,GIP,andglucagonresponsesinpatientswithtype2diabetes(n=54)vsmatchedcontrolsubjectswithnormalglucosetolerance(NGT)(n=33)andunmatchedsubjectswithimpairedglucosetolerance(IGT)(n=15).Afteranovernightfastfollowing3dayswithoutantidiabeticmedication,subjectsconsumedamixedmealandunderwentbloodsamplingperiodicallyfor4hours.thefastingGIPlevelintheT2DMwasinsignificantlyhigherthanthoseintheNGTandIGTgroup.TheGIPmealresponse(Table2andFig.2)wasslightly,butsignificantly(P0.047),decreasedintheT2DMcomparedwiththeNGTgroup,butthisdifferencewasabsentintheBMIandgender-correctedANOVAanalysisforallthreegroups.Peakvaluesweresimilarinallgroups.FastingGLP-1concentrationsweresignificantlyhigherinT2DMthaninNGT(Table1),buttherewasnodifferencebetweenthethreegroupsuponANOVA,andnosignificantcovariateswerefound.PostprandialGLP-1levels(Fig.3)andAUCweresignificantlydecreasedinT2DMcomparedwithNGT(Table2),and,uponANOVAanalysiscorrectingforBMIandgender,theywerealsodecreasedcomparedwithIGTvalues.TheGLP-1AUCoftheIGTgrouprangedbetweenthoseofT2DMandNGT.TheGLP-1AUCwaslowerinmalesanddecreasedwithincreasingBMI.BMI-andgender-correctedGLP-1AUCmeanswere2464(T2DM),2907(IGT),and3066(NGT)pmol/liter240min(PNSforNGTvs.IGTgroup).TheincrementalGLP-1responseintheT2DMgroupwasevenmoreimpaired(Table2),andherealsoIGTlevelsrangedbetweenT2DMandNGTvalues.GLP-1与GIP T2DM患者GLP-1的缺乏大于GIP; GLP-1比GIP的促胰岛素分泌能力更强; T2DM患者中,GIP不抑制胰高糖素分泌*GLP-1更有研发价值 一种由31个氨基酸组成的肽链 由胃肠道L-细胞分泌 通过进食反应分泌(直接腔内刺激和间接神经刺激)**WhatisGlucagon-LikePeptide-1?Glucagon-likepeptide-1(GLP-1)isa30aminoacidpeptide.ItisanincretinhormonethatissecretedfromL-cellsinthegastrointestinalsysteminresponsetocalorieintake,causingtheglucosedependentsecretionofinsulin.Incretinsarechemicalexcitantsthatpromotepancreaticsections(glucose-dependentinsulinotropicpolypeptide[GIP]isanotherexample).SlideNo.*••胰腺胃心脏大脑肝脏GLP-1具有更多针对T2DM病理生理的作用AdaptedfromBaggio&Drucker.Gastroenterol2007;132;2131–57Intestine心脏保护心功能饱腹感胃排空葡萄糖输出葡萄糖依赖胰岛素分泌胰岛素合成葡萄糖依赖胰高糖素分泌*GLP-1对人体生理具有多种直接和间接影响,靶向作用于胰腺、肝脏、心脏、胃肠系统、肾脏、脂肪细胞、肌肉和中枢神经系统。**PCPslidekitPost-ParisDraft1SlideNo.*••GLP-1控制血糖具有葡萄糖浓度依赖性Mean(SE);*p<0.05;2型糖尿病患者(n=10)Naucketal.Diabetologia1993;36:741–46*GLP-1increasesinsulin,andreducesglucagon,loweringglucoselevelsNaucketal.Diabetologia1993;36:741–4ABSTRACT:Glucagon-likepeptide1(GLP-1)(7-36amide)isaphysiologicalincretinhormonethatisreleasedafternutrientintakefromthelowergutandstimulatesinsulinsecretionatelevatedplasmaglucoseconcentrations.PreviousworkhasshownthateveninType2(non-insulin-dependent)diabeticpatientsGLP-1(7-36amide)retainsmuchofitsinsulinotropicaction.However,itisnotknownwhetherthemagnitudeofthisresponseissufficienttonormalizeplasmaglucoseinType2diabeticpatientswithpoormetaboliccontrol.Therefore,in10Type2diabeticpatientswithunsatisfactorymetaboliccontrol(HbA1c11.6+/-1.7%)ondietandsulphonylureatherapy(insomepatientssupplementedbymetforminoracarbose),1.2pmolxkg-1xmin-1GLP-1(7-36amide)orplacebowasinfusedintravenouslyinthefastingstate(plasmaglucose13.1+/-0.6mmol/l).Inallpatients,insulin(by17.4+/-4.7nmolx1-1xmin;p=0.0157)andC-peptide(by228.0+/-39.1nmolx1-1xmin;p=0.0019)increasedsignificantlyoverbasallevels,glucagonwasreduced(by-1418+/-308pmolx1-1xmin)andplasmaglucosereachednormalfastingconcentrations(4.9+/-0.3mmol/l)within4hofGLP-1(7-36amide)administration,butnotwithplacebo.WhennormalfastingplasmaglucoseconcentrationswerereachedinsulinreturnedtowardsbasallevelsandplasmaglucoseconcentrationsremainedstabledespitetheongoinginfusionofGLP-1(7-36amide).Therefore,exogenousGLP-1(7-36amide)isaneffectivemeansofnormalizingfastingplasmaglucoseconcentrationsinpoorly-controlledType2diabeticpatients.(ABSTRACTTRUNCATEDAT250WORDS)TenType2diabeticpatientswerestudied(Table1).Theywereallbeingtreatedwithdietandsulphonylureacompounds,andsomewerealsoreceivingmetforminoracarbosetreatment.Multiplefastingplasmaglucoseconcentrations(fromhospitalcharts)were13.1+2.0mmolfl(236+36mg/dl),postprandialglucoseconcentrationswere15.1+2.7mmol/1(272+49mg/dl).Becauseofunsatisfactorymetaboliccontrol,eightofthesetenpatientswereassignedtoinsulintreatmentimmediatelyafterthestudy.Thepatientswerestudiedontwooccasions.Allanti-diabeticmedicationwascontinueduntilthemorningbeforethestudies.静脉注射GLP-1(15nmol/L)DPP-4水解失活2型糖尿病患者(n=6)健康个体(n=6)有效GLP-1(pmol/L)时间(分)–5515354505001000257379LysHisAlaThrThrSerPheGluGlyAspValSerSerTyrLeuGluGlyAlaAlaGlnLysPheGluIleAlaTrpLeuGlyValGlyArg酶降解高效清除(4–9L/min)t½=1.5–2.1min(静脉注射2.5–25.0nmol/L)由于半衰期短,人GLP-1临床价值十分有限AdaptedfromVilsbølletal.JClinEndocrinolMetab2003;88:220–4**NativeGLP-1haslimitedclinicalvaluebecauseofitsshorthalf-lifeTherapiddegradationofGLP-1intoitsinactiveformbyDPP-4meansthatwhenadministeredasani.v.bolus,ithasahalf-lifeofjust1.5–2.1minutes.Combinedwithrapidclearance,thismeansthattheactionofGLP-1hasaverylimitedtimespan.ReferencesVilsbølletal.JClinEndocrinolMetab2003;88:220–22424h葡萄糖控制需要24hGLP-1注射血糖(mmol/L)时间(h)5102025150412000408162016hGLP-1注射24hGLP-1注射12000408162004510201525血糖特征:Larsenetal.DiabetesCare2001;24:1416–21(n=8) **24-hourGLP-1presenceisrequiredfor24-hourcontrolBecauseofitsshorthalf-life,continuousadministrationofGLP-1isrequiredtoobtainoptimal,sustainedglycaemiccontrol.Thiswaswell-demonstratedinarandomised,double-blind,placebo-controlledstudyof40hospitalisedtype2diabetespatientswhoreceivedinfusionofGLP-1(4or8ng/kg/min)for16or24hourseverydayfor7days.InpatientsreceivingGLP-1for16hours,phosphate-bufferedsalinesolutionwasinfusedfortheremaining8hoursofthe24-hourperiod.Themaximalbloodglucoseloweringeffectwasreportedinpatientsreceivingcontinuous24-hourinfusionof8ng/kg/minGLP-1;theaveragedecreasefrombaselinetoday7in24-hourglucoseareaunderthecurve(AUC)wassignificantlygreaterinthisgroupthanintheothergroups(p<0.05).Inpatientsreceiving16hoursofGLP-1infusion,fastingandnocturnalplasmaglucose(04.00hours)atday7weresignificantlyhigherthaninthosereceiving24hoursofGLP-1infusion(p<0.05).ThisstudythereforedemonstratesthatglucosecontrolcanonlybemaintainedwithGLP-1duringcontinuousinfusion.ReferenceLarsenetal.DiabetesCare2001;24:1416–21*小结 GLP-1是一种由进食反应刺激分泌的31个氨基酸组成的肽链 GLP-1有多重生理作用 GLP-1葡萄糖浓度依赖性调节胰岛素和胰高糖素的分泌,降低血糖 人GLP-1被DPP-4迅速降解,必须持续存在以达到治疗效果**References:主要内容 GLP-1的发现及生理作用 利拉鲁肽—更出色的GLP-1类似物 -利拉鲁肽的基本介绍 -利拉鲁肽与传统药物对比(LEAD3) -基于肠促胰素的治疗的比较*如何使GLP-1的治疗成为现实? 抵抗DPP-IV降解的GLP-1类似物(GLP-1受体激动剂,Incretin类似物) 抑制DPP-IV活性 (DPP-IV抑制剂)*基于肠促胰素的治疗的研发思路Wick&Newlin.JAmAcadNursePract2009;21:623–30;White.JAmPharmAssoc2009;49(Suppl.1):S30–40人GLP-1类似物:利拉鲁肽利拉鲁肽是每日注射1次的人GLP-1类似物Knudsenetal.JMedChem2000;43:1664–9;Degnetal.Diabetes2004;53:1187–94*利拉鲁肽的多肽前体,通过一种工艺过程生产其中包括在酿酒酵母(Saccharomycescerevisiae)重组DNA的表达,已被工程化,与在34位赖氨酸被精氨酸取代的天然人GLP-1是97%同源。通过附着一个C-16脂肪酸(棕榈酸palmiticacid)与一个谷氨酸连接物(spacer)连接在多肽前体26位处遗留的赖氨酸残基上制成利拉鲁肽。利拉鲁肽的分子式为C172H265N43O51而相对分子质量是3751.2。利拉鲁肽具有更多针对T2DM病理生理的作用*动物实验利拉鲁肽在低血糖水平时不诱导胰岛素分泌对应的血糖平台水平mmol/L(mg/dL)安慰剂数据为平均±SEM;2型糖尿病患者(n=11)Naucketal.Diabetes2003;52(Suppl.1):A128***LiraglutidedoesnotinduceinsulinsecretionatlowglucoselevelsThelowriskofhypoglycaemiaduringliraglutidetreatmentislikelytoresultfromitsglucose-dependentinsulinotropicaction.Supportforthisproposalcomesfromthisstudyof11patientswithtype2diabetes.Patientsunderwentclampexperimentsduringwhichaconstantconcentrationofinsulinandvaryingconcentrationsofglucosewereinfusedintravenouslytomaintainconsecutiveglucoseplateausof4.3,3.7,3.0,and2.3mmol/l(77,67,54,and41mg/dl).Eachplateauwasmaintainedfor60minutes.Severalhoursbeforetheclampwasinitiated,patientsreceivedasubcutaneousinjectionofliraglutide(7.5µgperkgbodyweight)orplacebo.Duringtheclampexperiments,insulinsecretionwashigherwithliraglutidethanplacebo(p=0.0034).However,atthetwolowestglucoseplateaus,therewasnodifferenceininsulinsecretionbetweenliraglutideandplacebo;insulinsecretionratesat3.0mmol/lglucosewere0.26±0.05and0.19±0.04pmol/kg/minforliraglutideandplacebo,respectively(p = 0.065).Thecorrespondingvaluesfor2.3mmol/lglucosewere0.21±0.04vs.0.15±0.03pmol/kg/min(p = 0.11;2.3mmol/lglucose).Theseresultsindicatethat,asplasmaglucosefelltohypoglycaemiclevels,insulinsecretionintheliraglutidegroupdidnotdifferfromnormal.Thus,theinsulinotropicactionofliraglutideisglucosedependent.ReferenceStudy1224.Naucketal.Diabetes2003;52(Suppl1):A128利拉鲁肽在低血糖时不抑制胰高糖素分泌Adaptedfrom:1.Naucketal.Diabetes2003;52(Suppl1):A128.Dataaremean±SEM 利拉鲁肽不抑制低血糖诱导的胰高糖素分泌1 利拉鲁肽葡萄糖输注率与安慰剂相同1 不影响总体低血糖反调节应答胰高糖素(pq/ml)分钟对应的血糖平台水平mmol/l(mg/dl)利拉鲁肽(体重7.5µg/kg)(n=11)安慰剂(n=11)06012018024040801201604.3(77)3.7(67)3.0(54)2.3(41)**LiraglutidedoesnotsuppressglucagonsecretionduringhypoglycaemiaThesuppressionofglucagonsecretion(asoccursfollowingliraglutideadministration)couldpotentiallyinterferewithhypoglycaemiacounter-regulation.However,asthisstudyshows,hypoglycaemiacounter-regulationisunaffectedbyliraglutide.In11patientswithtype2diabetes,capillaryglucoseconcentrationsweremaintainedat4.3,3.7,3.0,and2.3mmol/l(77,67,54,41mg/dl)for60minuteseach(hypoglycaemicclampusingi.v.insulininfusion).Glucagonsecretionincreasedtoasimilarextentwithliraglutideandplaceboasthehypoglycaemiaplateauwasreduced.Furthermore,theglucoseinfusionrequiredtomaintainthespecifiedglycaemiaplateaudidnotdifferduringtreatmentwithplaceboandliraglutide.Astheglucoseplateauwaslowered,therewasasimilarincreaseincortisolandcatecholamineswithbothtreatments.Growthhormonealsoincreasedinbothgroupsalthoughthisincreasewasslightlybutsignificantlylowerduringliraglutidetreatment(p=0.034).Similarfindingswerefoundinastudyinvestigatingthehypoglycaemiacounter-regulatoryresponseduringGLP-1treatment(Naucketal.2002):areductioningrowthhormoneisconsistentwiththedocumentedeffectofGLP-1onpituitaryactions.ReferencesStudy1224.Naucketal.Diabetes2003;52(Suppl1):A128Naucketal.JClinEndocrinolMetab2002;87:1239–1246利拉鲁肽对β细胞有多重积极作用分泌能力胰岛素原/胰岛素第一时相胰岛素分泌β细胞功能(HOMA)β细胞量2型糖尿病患者动物实验体外研究β细胞凋亡β细胞的葡萄敏感性(胰岛素分泌率)β细胞Madsbadetal.Diabetologia2006;49(Suppl.1):A004;Sturisetal.BrJPharmacol2003;140:123–32.Rolinetal.AmJPhysiolEndocrinolMetab2002;283:E745–52;Bregenholtetal.Diabetologia2001;44(Suppl.1):A19;Bregenholtetal.Diabetes2001:50(Suppl.2):A31;Degnetal.Diabetes2004;53:1187–94;Changetal.Diabetes2003;52:1786–91*利拉鲁肽可改善第一时相胰岛素分泌和β细胞最大胰岛素分泌能力DegnKB,etal.Diabetes2004;53:1187–9417.** 下面我们来看一下,利拉鲁肽对第一时相胰岛素分泌的影响,这个研究在前15分钟,放大图中可以看到应用利拉鲁肽后胰岛素早相的分泌增加明显,利拉鲁肽不仅增加第一时相的分泌,还可以增加最大β细胞分泌能力,用钳夹试验使胰岛素水平处于高水平,与安慰剂相比,β细胞分泌能力得到显著提高。Diabetes.2004May;53(5):1187-94.Oneweek'streatmentwiththelong-actingglucagon-likepeptide1derivativeliraglutide(NN2211)markedlyimproves24-hglycemiaandalpha-andbeta-cellfunctionandreducesendogenousglucosereleaseinpatientswithtype2diabetes.DegnKB,JuhlCB,SturisJ,JakobsenG,BrockB,ChandramouliV,RungbyJ,LandauBR,SchmitzO.AbstractGlucagon-likepeptide1(GLP-1)ispotentiallyaveryattractiveagentfortreatingtype2diabetes.Weexploredtheeffectofshort-term(1week)treatmentwithaGLP-1derivative,liraglutide(NN2211),on24-hdynamicsinglycemiaandcirculatingfreefattyacids,isletcellhormoneprofiles,andgastricemptyingduringmealsusingacetaminophen.Furthermore,fastingendogenousglucosereleaseandgluconeogenesis(3-(3)H-glucoseinfusionand(2)H(2)Oingestion,respectively)weredetermined,andaspectsofpancreaticisletcellfunctionwereelucidatedonthesubsequentdayusinghomeostasismodelassessmentandfirst-andsecond-phaseinsulinresponseduringahyperglycemicclamp(plasmaglucoseapproximately16mmol/l),and,finally,ontopofhyperglycemia,anargininestimulationtestwasperformed.Foraccomplishingthis,13patientswithtype2diabeteswereexaminedinadouble-blind,placebo-controlledcrossoverdesign.Liraglutide(6microg/kg)wasadministeredsubcutaneouslyoncedaily.Liraglutidesignificantlyreducedthe24-hareaunderthecurveforglucose(P=0.01)andglucagon(P=0.04),whereastheareaunderthecurveforcirculatingfreefattyacidswasunaltered.Twenty-four-hourinsulinsecretionratesasassessedbydeconvolutionofserumC-peptideconcentrationswereunchanged,indicatingarelativeincrease.Gastricemptyingwasnotinfluencedatthedoseofliraglutideused.Fastingendogenousglucosereleasewasdecreased(P=0.04)asaresultofareducedglycogenolysis(P=0.01),whereasgluconeogenesiswasunaltered.First-phaseinsulinresponseandtheinsulinresponsetoanargininestimulationtestwiththepresenceofhyperglycemiaweremarkedlyincreased(P<0.001),whereastheproinsulin/insulinratiofell(P=0.001).Thedispositionindex(peakinsulinconcentrationafterintravenousbolusofglucosemultipliedbyinsulinsensitivityasassessedbyhomeostasismodelassessment)almostdoubledduringliraglutidetreatment(P<0.01).Bothduringhyperglycemiaperseandafterarginineexposure,theglucagonresponseswerereducedduringliraglutideadministration(P<0.01andP=0.01).Thus,1week'streatmentwithasingledailydoseoftheGLP-1derivativeliraglutide,operatingthroughseveraldifferentmechanismsincludinganamelioratedpancreaticisletcellfunctioninindividualswithtype2diabetes,improvesglycemiccontrolthroughout24hofdailyliving,i.e.,prandialandnocturnalperiods.ThisstudyfurtheremphasizesGLP-1anditsderivativesasapromisingnovelconceptfortreatmentoftype2diabetes.PMID:15111485Effectofliraglutideonfirst-phaseinsulinsecretionandmaximalbeta-cellinsulinsecretorycapacityThisstudyassessedtheeffectofliraglutideonpancreaticB-cellfunction.PatientswithType2diabetes(n=39)wererandomizedtotreatmentwith0.65,1.25or1.9mg/dayliraglutideorplacebofor14weeks.First-andsecond-phaseinsulinreleaseweremeasuredbymeansoftheinsulin-modifiedfrequentlysampledintravenousglucosetolerancetest.Arginine-stimulatedinsulinsecretionwasmeasuredduringahyperglycaemicclamp(20mmol/l).Glucoseeffectivenessandinsulinsensitivitywereestimatedbymeansoftheinsulin-modifiedfrequentlysampledintravenousglucosetolerancetest.Fourteenweeksoftreatmentwithliraglutideshowedimprovementsinfirst-andsecond-phaseinsulinsecretion,togetherwithimprovementsinarginine-stimulatedinsulinsecretionduringhyperglycaemia.Thetwohighestdosesofliraglutide(1.25and1.9mg/day)significantlyincreasedfirst-phaseinsulinsecretionby118and103%,respectively(P<0.05).Second-phaseinsulinsecretionwassignificantlyincreasedonlyinthe1.25mg/daygroupvs.placebo.Arginine-stimulatedinsulinsecretionincreasedsignificantlyatthetwohighestdoselevelsvs.placeboby114and94%,respectively(P<0.05).LEAD研究在2型糖尿病领域最大,最全面的III期临床试验>4,000例2型糖尿病患者5个随机、对照、双盲研究1个随机、对照、开放研究>40个国家挑战目前对2型糖尿病治疗的预期**可能这些小范围的试验还不能说明问 快递公司问题件快递公司问题件货款处理关于圆的周长面积重点题型关于解方程组的题及答案关于南海问题 。SlideNo.*••LEAD可用于2型糖尿病的序贯治疗利拉鲁肽单药vs.SULEAD3利拉鲁肽+METvs.SU+METLEAD2利拉鲁肽+SUvs.TZD+SULEAD1利拉鲁肽+MET+TZDvs.MET+TZDLEAD4利拉鲁肽+MET+SUvs.甘精胰岛素+MET+SULEAD5利拉鲁肽+MET和/或SUvs.艾塞那肽(Exenatide)+MET和/或SULEAD6LEAD:LiraglutideEffectandActioninDiabetes.Allstudies26weeks’duration(LEAD3=52weeks);allRCT;Marreetal.DiabeticMedicine2009;26:268–78(LEAD-1);Naucketal.DiabetesCare2009;32:84–90(LEAD-2);Garberetal.Lancet2009;373:473–81(LEAD-3);Zinmanetal.DiabetesCare2009;DOI:10.2337/dc08-2124(LEAD-4);Russell-Jonesetal.Diabetes2008;57(Suppl.1):A159(LEAD-5);Buseetal.Lancet2009;inpress(LEAD-6).*LEADcoversthecontinuumofT2Dcare,comparedwithstandardtreatmentsTheLEADstudiesweredesignedtoinvestigatetheefficacyofliraglutideateachstepinthetreatmentcontinuumfrommonotherapytocombinationwithtwoOADs.*LEAD研究:基线资料Marreetal.Diabetes2008;57(Suppl.1):A4(LEAD1);Naucketal,DiabetesCare,publishedonline10.2337/dc08-1355(LEAD2);Garberetal,TheLancet,earlyonlinepublication,25Sept2008(LEAD3);Zinmanetal.Diabetologia2008;51(Suppl.1):Poster898(LEAD4);Russell-Jonesetal.Diabetes2008;57Suppl.1):A159(LEAD5).* LEAD3单药治疗 LEAD2联合二甲双胍 LEAD1联合磺脲类 LEAD4二甲双胍+噻唑烷二酮 LEAD5二甲双胍+磺脲类 随机患者 746 1091 1041 533 581 研究时间(周) 52 26 26 26 26 年龄(岁) 53.0 56.8 56.1 55.1 57.5 糖尿病时间(年) 5.4 7.4 7.9 9.2 9.4 空腹血糖(mM) 9.5 10.0 9.8 10.1 9.2 HbA1c(%) 8.3 8.4 8.4 8.3 8.2 BMI(kg/m2) 33.1 31.0 30.0 33.5 30.5 体重(kg) 98.8 88.6 81.6 9
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