胰高血糖素样肽_1受体激动剂治疗2型糖尿病的研究进展

Mar.2010Vol.7No.3-1212317300002730046312DiabetesmellitusDM－/、。41、2、、。290%。。2T2DM。。ADOPT、HbA1c6.5%。、2。———IDMPS84312232.7%HbA1c＜7%2HbA1c。。HbA1c7%22。(、、)、、、2。UKPDSβ[1]。β。：。、、、。E-mail:1060323977qq.com【】90%2。1(GLP-1)2。GLP-1(97%)GLP-1。-1。【】2-1-13β。。。。-1Glucagon-likepeptide-1GLP-1(incretin)β2T2DM[2-3]。2-1(GLP-1)2。1979。-1(GLP-1)(GIP)。-1(GLP-1)(GIP)。、。β()。GLP-1GLP-1β、GLP-1[2-5]。GLP-1αL(PC1)GLP-1。GLP-12GLP-1(7-37)GLP-1(7-36)GLP-180%GLP-1(7-36)[6]。GLP-12.1GLP-1βGLP-12ββ2。2.2GLP-1GLP-1。。GLP-1。2.3GLP-1GLP-1。GLP-1()。2.4GLP-1GLP-1、。GLP-1。(DPP-)1~2。GLP-1。GLP-1GLP-1。1GLP-1[5-12]。3GLP-1-1(GLP-1)2。GLP-1GLP-1(GLP-1)。GLP-1。GLP-1。3.1GLP-1GLP-1(Exenatide/Byetta)LillyAmylin4Mar.2010Vol.7No.339-1(GLP-1)β[13-14]。20054FDA。、2。20098GLP-1———2。GLP-1LiraglutideGLP-1(97%)GLP-1。404000LEADLiraglutideEffectandActioninDiabetesββ。β2、、“”、。。“”。GLP-1GLP-1。20096302010120。200912SFDA。4762010。3.1.1，11GLP-1GLP-1GLP-116GLP-1。DDP-12~141[15-16]。3.1.2GLP-1LEAD(Liraglu-tideEffectandActioninDiabetes)40400026、。2、。3.1.3β，LEAD1-42β。(HOMA)β1.8mgβ。/。ββ2。[17-20]。3.1.4LEAD1-4(HbA1c)HbA1cHbA1c。3.1.4.152LEAD-3(8.0mg/d)(1.2mg/d1.8mg/d)HbA1c(0.84%、1.14%vs0.51%)5(HbA1c≤6.5%)(28%、38%vs16%)。HbA1c(1.8mg/d1.60%vs0.71%)。。3.1.4.2LEAD-22。LEAD-12[18]。3.1.4.3LEAD-4++。3.1.5，。LEAD-3(1.8mg/d)(8.0mg/d)(0.25/vs1.96/P＜0.05)。GLP-1。LEAD。GLP-1。3.1.63.1.6.1。LEAD1-3(BMI)2。BMIBMI(≥35kg/m2)。CTX(DEXA)。2。。3.1.6.2LEAD326()22.7~4.5mmHg。5.6mmHg18%。。GLP-1GLP-1———GLP-12[21-25]。3.2GLP-1《》3.1。“”。GLP-1(Preproglucagon)L-GLP-1(7-36)GLP-1“”[rhGLP-1(7-36)]GLP-1(7-36)。2“”“”。2。。-1。GLP-1。GLP-1。、。80GLP-1GLP-1R[-1Glucagonlikepeptide-1receptorGLP-1R]。GLP-1R20036Mar.2010Vol.7No.3。48000。-1。Boc5。2Boc5。Boc5、、。10。4、、72[26]。4。2.520253.8398020255930。90%2GLP-1R。20122205。8%。20022208。Pharmacor2-1GLP-1PPAR。2006-2012GLP-1PPAR2。PPAR。GLP-1。：[1][2][3][4][5][6][7][8][9][10][11][12][13][14]UKProspectiveDiabetesStudy(UKPDS)Group.Intensiveblood-glucosecontrolwithsulphonylureasorinsulincomparedwithconventionltreatmentandriskofcomplicationsinpatientswithtype2diabetes(UKPDS33)[J].Lancet,1998,352(9131):837-853.VaidyaHB,GoyalRK.Glucagon-likepeptides-1modulatorsasnewertargetfordiabetes[J].CurrDrugTargerts2008,9(10):911-920.GautierJF,ChoukemSP,GirardJ.Physiologyofincretins(GIPandGLP-1)andabnormalitiesintype2diabetes[J].DiabetesMetab,2008,34(Suppl2):65-72.HolstJJ,DeaconCF,Vilsb覬llT,etal.Glucagon-likepeptide-1,glucosehomeostasisanddiabetes[J].TrendsMolMed,2008,14(4):161-168.ZhouJ,EganJM.SNAP-25isphosphorylatedbyglucoseandGLP-1inRIN1046-38cells[J].BiochemBiophysResCommun,1997,238(2):297-300.ChiaCW,EganJM.Incretin-basedtherapiesintype2diabetesmellitus[J].ClinEndocrinolMetab,2008,93(10):3703-3716.NauckMA,KleineN,OrskovC,etal.Normalizationoffastinghyperglycemiabyexogenousglucagonlikepeptide1(7-36amide)intype2(noninsulindependent)diabeticpatients[J].Diabetologia,1993,36(8):741-744.DruckerD,NauckM.Theincretinsystem:glucagon-likepeptide-1receptoragonistsanddipeptidylpeptidase-4inhibitorsintype2diabetes[J].Lancet,2006,368(9548):1696-1705.GiorginoF,NatalicchioA,LeonardiniA,etal.ExploitingthepleiotropicactionsofGLP-1forthemanagementoftype2diabetesmellitusanditscomplications[J].DiabResClinPract,2007,78(Suppl1):59-67.DruckerDJ.Enhancingincretinactionforthetreatmentoftype2diabetes[J].DiabetesCare,2003,26(10):2929-2940.NauckMA,WollschlagerD,WernerJ,etal.Effectsofsubcutaneousglucagon-likepeptide-1inpatientswithNIDDM[J].Diabetologia,1996,39(12):1546-1553.UrusovaIA,FarillaL,HuHX,etal.GLP-1inhibitionofpancreaticisletcellapoptosis[J].TrendsinEndocrinolMetab,2004,15(1):27-33.DefronzoRA,RatnerRE,HanJ,etal.Effectsofexenatide(exendin-4)onglycemiccontrolandweightover30weeksinmetformin-treatedpatientswithtype2diabetes[J].DiabetesCare,2005,28(5):1092-1100.BuseJB,HenryRR,HanJ,etal.Effectsofexenatide(exendin-4)onglycemiccontrolover30weeksinsulfonylurea-treatedpatienmtswithtype2diabetes[J].DiabetesCare,2004,27(11):2628-2635.7Russell-JonesD.Molecular.Pharmacologicalandclinicalaspectsofliraglutide,aoncedailyhumanGLP-1analogue[J].MolCellEndocrinol,2009,297(1-2):137-140.SteensgaardDB,ThomsenJK,OlsenHB,etal.Themolecularbasisforthedelayedabsorptionoftheonce-dailyhumanGLP-1analogue,liraglutide[J].Diabetes,2008,57(Suppl1):A164.MarreM,ShawJ,BrandleM,etal.Liraglutide,aonce-dailyhumanGLP-1analog,addedtoasulfonylurea(SU)offerssignificantlybetterglycemiccontrolandfavourableweightchangecomparedwithrosiglitazoneandSUcombinationtherapyinsubjectswithtype2diabetes[J].Diabetes,2008,57(Suppl.1):A4.NauckM,FridA,HermansenK,etal.Efficacyandsafetycomparisonofliraglutide,glimepiride,andplacebo,allincombinationwithmetforminintype2diabetes[J].DiabetesCare,2009,32(1):84-90.GarberA,HenryR,RatnerR,etal.Liraglutideversusglimepiridemonotherapyfortype2diabetes(LEAD3Mono):arandomised,52week,phaseIII,doubleblind,paralleltreatmenttrial[J].Lancet2009,373(9662):473-481.ZinmanB,GerichJ,BuseJ,etal.EffectoftheGLP-1analogliraglutideonglycemiccontrolandweightreductioninpatientsonmetforminandrosiglitazone:arandomizeddouble-blindplacebocontrolledtrial[J].CanJDiab,2008,32(Suppl.):A107.MadsbadS,SchmitzO,RanstamJ,