胰岛素类似物:设计和临床应用1型糖尿病发病胰岛素缺乏2型糖尿病发病胰岛素分泌减少+胰岛素作用异常2型糖尿病发病胰岛素分 泌减少+胰岛素作用异常肝糖输出增加2型糖尿病发病胰岛素分泌减少+胰岛素作用异常外周组织对葡萄糖异常2型糖尿 病的病理生理学:餐时胰岛素分泌不足早期胰岛素释放不足造成餐后高血糖12-小时血糖状态餐后血糖与心血管病变风险提示餐后 血糖与心血管疾病相关的研究WhitehallStudyHelsinkiPolicemenStudyParisPro spectiveSurveyTecumsehStudyHonoluluHeartProgram研究结果表明与空腹血 糖及HbA1c相比,餐后血糖对于心血管疾病的风险预测有更好的相关性糖尿病干预研究(DIS)DECODEDECODE: 在未诊断糖尿病的人群中多变量校正的总体死亡危险度胰岛素治疗的里程碑动物胰岛素单组分动物胰岛素人胰岛素胰岛素类似物 人胰岛素应用的局限性皮下注射后胰岛素的扩散天门冬胰岛素类似物1型糖尿病患者实验餐后胰岛素状态1型糖尿病患者实验餐后葡萄糖状 态1型糖尿病-餐后血糖餐后血糖控制—1型糖尿病(儿童)24小时胰岛素模式—1型糖尿病24小时控制—1型糖尿病 治疗12个月后HbA1c状态2型糖尿病实验餐后的胰岛素状态2型糖尿病实验餐后的血糖状态2型糖尿病-餐后血糖控制低血糖 —主要的问题DCCT证实在不增加低血糖风险的情况下,对血糖进行良好控制是非常困难的有30%以上的1型糖尿病患者曾经历过需 第三者帮助的严重夜间低血糖严重夜间低血糖的风险NovoRapid?改善长期血糖控制减少严重夜间低血糖风险改善用药便利性 和灵活性双时效Insulinaspart30NovoMix3030%insulinaspart70%鱼精蛋白 insulinaspartNovoMix?30与BHI30交叉对照:吸收更快,胰岛素峰值水平更高于2型糖尿病, 用药后改善餐后血糖控制用药后使餐时血糖波动显著降低总结NovoMix?30vs.BHI30:起效快速,降血糖 作用更强餐后血糖的变化较小更少发生严重低血糖事件长期血糖控制及安全性相当NovoRapid?vsSHI,临床疗效比较 起效迅速,并迅速回复至正常ANA/DCD/046/NL,UK时间080100402018:006022:00 08:0018:00血清胰岛素(mU/l)13:00NovoMix?30BHI30dinnerbreakfas tlunchp<0.05JacobsenLetal.Diabetes200049(Suppl1 ):A112ANA/DCD/046/NL,UK时间dinnerbreakfastlunch01711818: 001422:0008:0018:00血清葡萄糖(mmol/l)13:00NovoMix?30BHI30 p<0.05(favoursNovoMix?30)p<0.05(favoursBHI30) JacobsenLetal.Diabetes200049(Suppl1):A112ANA/DCD/04 6/NL,UKNovoMix?300510152025晚餐后早餐后BHI30餐后4小时内平均血糖浓度( mmol.h.l-1)44%p=0.00134%p=0.037JacobsenLet al.Diabetes200049(Suppl1):A112有效降低餐后血糖水平维持平稳的24-小时血糖控制显著降 低严重夜间低血糖的风险在不增加低血糖风险的情况下,显著改善长期血糖控制可在餐前即刻注射速度控制方便性Slide14: 24hourinsulinprofilesintype1diabetesInpatientswithty pe1diabetes,NovoRapidisabsorbedmorerapidlyandhasahighe rpeakconcentrationafterallthreemealsthansolublehumanins ulin1.Reference1.HomePD,LindholmA,HyllebergB,etal.Imp rovedglycemiccontrolwithinsulinaspart:amulticenterrandomi zeddouble-blindcrossovertrialintype1diabeticpatients.Dia betesCare1998;21:1904–1909.Slide15:24hourinsulinprofile sintype1diabetesNovoRapidimprovespost-prandialglucoseco ntrolcomparedwithhumaninsulin,thereforeeffectingsmoother2 4hourglycaemiccontrol.PlasmaglucoseconcentrationswithNovo Rapidweresignificantlylowerafterbreakfast(p<0.0001)andlun ch(p<0.0001),buthigheratnight(p<0.01)thanwithsolublehum aninsulin.ThisdemonstratesthatNovoRapidiseffectiveincont rollingglucosepeaksfollowingameal,andtreatmentwithNovoRa pidleadstosmoother24hourglycaemiccontrol,comparedtosolu blehumaninsulin1.Reference1.HomePD,LindholmA,Hylleberg B,etal.Improvedglycemiccontrolwithinsulinaspart:amultic enterrandomizeddouble-blindcrossovertrialintype1diabetic patients.DiabetesCare1998;21:1904–1909.Thenaturalhistory ofType2diabetesisinevitabledeteriorationinbeta-cellfunc tion,ofteninassociationwithinsulinresistance,renderingit arelentlesslyprogressivedisorder.Earlyphaseinsulinsecretio nbecomesprogressivelyreducedinamplitudeasbeta-cellfunctio ndeclines,andthelatephaseisbothbluntedanddelayedinons et.Incontrasttothephysiologicalinsulinresponseinwhichin sulinpeaksjust30minutesafterfood,theinsulinpeakinType 2diabetesisnotreacheduntil90-120minutesafterthemeal.In individualswithfastingglucoselevels>18mmol/l,theprandia linsulinresponseisnegligible.Lossoftheearlyphaseinsulin responseresultsinexcessiveexposuretopostprandialglucose. Thishasbeenshowntohavetoxiceffectswithbothshortandlon g-termconsequences.20Ifreducingthepostprandialglucosepea kbyappropriateinsulinreplacementisthekeytorecreatingthe physiologicalprofileandreducingcardiovascularrisk,itisim portanttoclarifytheoptimaltimingformeal-timeinsulinrepla cement.Bruceandcolleagueshaveshownthatthemosteffectivew aytolimitthepostprandialglucosepeakistoprovideinsulinw ithinthefirsthalfhourafterameal.Whenreplacementisdelay eduntil30-60minutesafterthemealorprolongedforup-to3ho ursafterthemeal,thepostprandialglucoseexcursionissubopti mallycontrolled.Slide13:Post-prandialglucosecontrolintype 1diabeticchildrenNovoRapiddemonstratessuperiorpost-prandia lglucosecontrolcomparedwithsolublehumaninsulininjectedju stbeforebreakfastinchildren(6–17years)withtype1diabetes .Themaximumglucoseconcentrationwassignificantlylowerwith NovoRapidcomparedwithsolublehumaninsulin(p<0.05)1.Refer ence1.Dataonfile,NovoNordisk(StudyANA/DCD/043).Slide 24:Type2diabetesThisstudyshowedthatglucoseexcursion,0–3 60minutesafteratestmeal,wassignificantlylowerforNovoRap idthanforsolublehumaninsulindosedatmeal-time(p=0.01)and wascomparablewithsolublehumaninsulindosed30minutesbefor ethemeal1.Reference1.RosenfalckAM,ThorsbyP,KjemsL,et al.Effectsoftherapid-actinganalogueinsulinaspartonpost-p randialglycaemicexcursionscomparedtohumansolubleinsulinAc trapidgivenimmediatelyor30minutesbeforeamealininsulint reatedtype2diabetespatients.Diabetes1999;48:(Suppl1):A1 16.Slide7:NovoRapid–anewflexibleandconvenientinsulin NovoRapidisanewrapid-actinginsulinanalogue,thatcanhelpm eetthemajorchallengeofachievingeffectiveglycaemiccontrol withoutincreasingtheriskofhypoglycaemia,whilstalsoimprovi ngpatientflexibilityandconvenience.Thegreaterimportanceof acuteprandialglucosepeakscomparedwithfastinghyperglycaemi aasadeterminateofriskwasparticularlywellillustratedbyt herecentDECODEstudy(DiabetesEpidemiology:Collaborativeanal ysisOfDiagnosticCriteriainEurope).Aretrospectivemeta-anal ysisofdatafrommorethan25,000individualsfoundthatwhenst ratifiedbyleveloffastingbloodglucose,patients’mortalityr iskincreasedwithincreasingbloodglucoselevels2-hoursafter anoralglucosechallenge.Conversely,whenpatientswerestratif iedby2-hourbloodglucoselevelstherewasnotrendforincreas ingmortalityriskwithincreasingfastingbloodglucoselevels. Thus,themajordeterminateofriskwaspost-challengebloodgluc oselevelandnotfastingbloodglucose.Thiswastruefornon-di abeticindividuals,thosewithimpairedglucosetoleranceandpat ientswithdiabetes.0204060801000306090Time(mins) 第一时相第二时相时间(分钟)血浆胰岛素mU/L静脉注射葡萄糖后胰岛素的分泌FPG<8mmol/lFPG<12 mmol/lFPG12–15mmol/lFPG>18mmol/l正常人0.401.000.800.60胰 岛素平均浓度(nmol/l)0.200–300306090120150180210240时间(分钟) CoatesPAetal.DiabetesResClinPract1994;26:1772型糖尿病人pmol /lMitrakouAetal.Diabetes1990;39:1381mmol/lfmol/l–60060 120180240300糖摄入后时间(分钟)603045血浆胰高糖素0120240360–6006 0120180240300血浆胰岛素–60060120180240300糖摄入后时间(分钟)510 1520血浆血糖μmol/kg/min–600601201802403008内源性葡萄糖生成4122 型糖尿病正常人fmol/l–60060120180240300葡萄糖摄入后时间(分钟)603045血浆 胰高糖素–60060120180240300血浆胰岛素01202402型糖尿病人正常人早期胰岛素释放不 足造成餐后高血糖–600601201802403008内生葡萄糖412–600601201802 40300葡萄糖摄入后时间(分钟)5101520血浆血糖正常人2型糖尿病人早期胰岛素释放不足造成餐后高血糖1 00246808:3010:3012:3014:3016:3018:30时间血糖mmol/L饮食正 常双胍优降糖DECODEStudyGroup.Lancet1999;354:617经年龄,性别,胆固醇,BMI,收 缩压,吸烟等因素校正FPG(mmol/l)1.01.52.02.5<6.16.1-7.07.1-7.7?7.8 相对危险度<7.87.8-11.0?11.1餐后2h血浆血糖(mmol/l)Bruceetal.Diabe tes1988;37:736.外源性胰岛素替代治疗餐时用药是最有效060120180543210-11 .8U胰岛素0-30分钟1.8U胰岛素30-60分钟1.8U胰岛素0-180分钟对照Δ血糖(mm ol/l)时间(分钟)吸收较慢作用时间长注射时间不方便餐后高血糖低血糖危险增加皮下组织Mol/l弥散毛 细血管壁10-310-410-510-8Brangeetal.DiabetesCare1990;13:92 3-954.ThrLysAspThrTyrPhePheGlyArgGluGlyGluCysValLe uTyrLeuAlaValLeuHisSerGlyCysLeuHisGlnAsnValPheB1 AsnCysTyrAsnGluLeuGlnTyrLeuSerCysIleSerThrCysCysG lnGluValIleGlyA21A1B28B30AspPro血清胰岛素时间(小时)Insulin Asp,t=0min可溶性人胰岛素,t=0min可溶性人胰岛素,t=-30min(0.15U/k g)0(pmol/l)0(mU/l)100502575AdaptedfromLindholmetal. 1999血清葡萄糖(mmol/l)时间(小时)InsulinAsp,t=0min可溶性人胰岛素,t= 0min可溶性人胰岛素,t=-30min(0.15U/kg)AdaptedfromLindholmeta l.19990血糖波动,0–240min4001200800(mmol/l′ml)Lindholmet al1999p<0.001p<0.02NovoRapid?t=0min可溶性人胰岛素t=0min可 溶性人胰岛素t=-30minDataonfile,NovoNordisk(StudyANA/DCD/043 ).NovoRapid?可溶性人胰岛素(0.15U/kg)早餐0246810-3003060 90120150180210240270300时间(分钟)血清血糖变化(mmol/l)晚餐Insul atard早餐午餐p<0.05NovoRapid?可溶性人胰岛素Homeetal.DiabetesCare1 998;21:1904-1909.血清胰岛素时间(mU/l)(pmol/l)6003000100200 40050002040608010006001200180024000600晚餐Insulatard 早餐中餐p<0.0001p<0.0001p<0.01NovoRapid?可溶性人胰岛素Homeetal.Dia betesCare1998;21:1904-1909.时间血浆血糖(mmol/l)6810121416 1806001200180024000600HbA1c(%)时间(月)NovoRapid?可溶性人胰岛素p <0.058.58.07.50036129NovoRapid?-vs-solublehumaninsu lin,12monthsbasal-bolus0102030405060708090-30030 6090120150180210240270300330360NovoRapid?,t=0min可溶性人胰岛素,t=0min可溶性人胰岛素,t=-30min(0.15U/kg)时间(分钟)总血清胰岛素0(pmol/l)(mU/l)100600300150450时间(分钟)-300306090120150180210240270300330360681012140血清血糖(mmol/l)NovoRapid?,t=0min可溶性人胰岛素,t=0min可溶性人胰岛素,t=-30min(0.15U/kg)Rosenfalcketal.Diabetes1999,48(Suppl1):A116p=0.01120010008006004002000InsulinAspt=0可溶性人胰岛素t=0可溶性人胰岛素t=-30平均血糖波动,0.360min(mmol/lxmin)DCCTResearchGroup.Diabetes1997;46:271–286.Wardetal.NZMedJ1990;103:339-341.0268104InsulinAsp可溶性人胰岛素百分比50%P<0.02Comparedtosolublehumaninsulin |
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