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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