ThrglyTyrPhePheGlyArgGluGlyValLeuTyrLeuAlaGluValLeuHisSerGlyCysLeuHisGlnAsnValPheB1A21B29A1AspTyrAsnGluLeuGlnTyrLeuSerIleSerThrCysGlnGluValIleCysCysCysCysB28LysProProLysB30Karsholm&Ludvigsen.Receptor1995;5:1-8.des-threonineB30myristilated=detemirThrglyTyrPhePheGlyArgGluGlyValLeuTyrLeuAlaGluValLeuHisSerGlyCysLeuHisGlnAsnValPheB1A21B29A1AsnTyrAsnGluLeuGlnTyrLeuSerIleSerThrCysGlnGluValIleCysCysCysCysB28ThrLysProB30Karsholm&Ludvigsen.Receptor1995;5:1-8.IGF-1受体结合866066783162718地特胰岛素8110192门冬胰岛素641100100100人胰岛素胰岛素受体亲和力代谢作用强度IGF-I受体亲和力甘精胰岛素8284赖脯胰岛素110.9580.97.51001IGF-IR/IR亲和力比值促有丝分裂作用强度1.9156KurtzhalsPInternationalJournalofObesity2004;28,Suppl2,S23–S28Capillarymembrane6聚体的稳定性双6聚体的形成白蛋白的结合稀释Capillaryblood皮下组织中性澄清液PH=7.42聚体10–5M6聚体10–3M单体10–8M地特胰岛素在血液中血浆白蛋白结合计算60分钟双倍吸收速率对组织中人胰岛素和地特胰岛素浓度的影响吸收速率Kurtzhals.IntJObesRelatMetabDisord2004;28(Suppl.2):S23–8血浆浓度人血清白蛋白600µM游离脂肪酸300µM地特胰岛素0.01µM不是所有的研究均显示平坦无峰HeiseT,PieberTR.DiabesMetab2007;9:648-659HeiseT,PieberTR.DiabesMetab2007;9:648-65902468101214161820222400.51.01.52.02.53.0葡萄糖输注率(mg/kg/min)时间(小时)KleinOetal.DiabetesObesMetab2007;9:290-299胰岛素注射甘精胰岛素地特胰岛素血糖(mg/dl)平均剂量:地特,26.3U/天;甘精,26.6U/天KingA.Diabetologia2008;51(Suppl.1):S401(P-993)A.Philis-Tsimikasetal.ClinTher2006;28:1569-1581MatthewC.Riddleetal.DiabetesCare200326:3080–3086(95%CI)–0.12(–0.25,0.01)–0.08(–0.26,0.09)–0.16(0.35,0.02)0.00(–0.11,0.11)0.09(–0.12,0.29)0.07(–0.09,0.23)0.16(0.00,0.31)0.56(0.33,0.78)0.13(–0.00,0.25)0.10(–0.08,0.29)0.07(–0.07,0.21)地特胰岛素优势NPH优势–0.5–0.100.10.50.8Type1&2HbA1cdifferenceRussell-Jonesetal2004Pieberetal2005Homeetal2004Kølendorfetal2006Robertsonetal2007Tajimaetal2006Haaketal2005NN304-1337Hermansenetal2006Philis-Tsimikasetal2006Kobayashietal2006Overall0.06(–0.03,0.15)–4–101Russell-Jonesetal2004–1.16(–1.84,0.48)Pieberetal2005–2.00(–2.90,–1.00)Homeetal2004–2.30(–3.30,–1.30)Robertsonetal2007–1.14(–2.11,–0.16)Tajimaetal2006–0.54(–0.97,–0.10)Haaketal20050.11(–0.40,0.63)NN304-1337–0.00(–0.69,0.48)Hermansenetal20060.32(–0.02,0.66)Philis-Tsimikasetal2006–0.46(–1.05,0.13)Kobayashietal20060.11(–0.22,0.45)Overall–0.59(–1.04,–0.14)地特胰岛素优势NPH优势FPGdifferenceType1&2(95%CI)‘糖尿病患者的血糖和尿糖即使在进餐碳水化合物及胰岛素注射剂量未改变的情况下,也会经常出现很大的波动。’Somogyi,AmJMed1959不可预知性:即使小心准备,也可能被抓住注射部位的因素•注射部位•注射深度•脂营养不良•血流改变:例如:温度,运动,低血糖,酮症酸中毒胰岛素准备•剂量(浓度和体积)•物理状态(溶液或混悬液)延长作用机制•自我聚集•沉淀•与白蛋白结合T.Heiseetal.Diabetes2004;53:1614-1620GIR(mg/kg/min)Elapsedtime(h)NPHIGlarIDetp0.001forallcomparisonsofAUCN=54T1DM68%48%27%HeiseTetal.Diabetes2004;53:1614–20.*p0.001vs.地特胰岛素010203040506070NPH甘精胰岛素地特胰岛素CVinGIR-AUC0-12h[%]59%46%27%**T.Heiseetal.Diabetes2004;53:1614-16207.607.667.778.027.558.307.887.367.497.637.647.737.947.937.558.418.117.587.517.48HbA1c胰岛素作用变异少的临床意义是什么?0102030405060708090020406080Within-patientvariability(CV)offastingbloodglucose(FBG)Hypoglycaemia(episodes/person/year)HellerSetal.Diabetologia2004;47(Suppl.1):A303空腹血糖的个体内变异(变异系数)低血糖(事件/人/年)7.887.607.537.677.657.757.788.007.558.307.887.367.467.607.787.647.597.737.948.007.558.418.117.587.527.50IDetNPH*********p0.05地特vs.NPH地特胰岛素vs.NPH胰岛素HbA1c(%)†IDet(am+pre-dinner);‡IDet(am+bed);#IDet(12hourly);##IDet(am+bed)*地特胰岛素与NPH比较发生低血糖的相对危险度HellerS,KimH.Diabetes2005;54(Suppl.1):A120.MuggeoMetal.DiabetesCare2000;23:45–50.ItertileIItertileIIItertile生存率1.00.70.60.500246810时间(年)0.80.91.00.70.60.500246810时间(年)0.80.9p=0.005p0.001平均FPG平均CVFPG•胰岛素相关的体重增长似乎具有累积作用体重改变每季度测量一次理想体重来自于1983年的人寿保险规范DCCT.DiabetesCare1988;11:567-73UKPDS33.Lancet1998;352(9131):837-53强化治疗常规治疗100102104106108110036912时间(月)理想体重的百分比-2.502.557.53691215随机研究的时间(年)平均体重改变(kg)体重变化(kg)*****–1.0–0.50.00.51.01.52.02.53.03.54.0Hermansenetal.(2006)Philis-Tsimikasetal.(2006)Raslovaetal.(2004)Haaketal.(2005)Rosenstocketal.(2008)*p0.05,**p0.01地特胰岛素NPH胰岛素甘精胰岛素1年研究**K.Hermansenetal.DiabetesCare2006;29(6):1269-74基线BMI-0.52525-2727-2929-3131平均体重变化(kg)353634395537425069760.00.51.01.52.02.53.03.5IDetNPHn=每个BMI类别中的患者数量•胰岛素以可饱和的转运机制通过血脑屏障•胰岛素受体在嗅球、下丘脑和海马处浓度最高•健康人中,胰岛素具有和瘦素一样传导饱感信号的作用•大脑除了葡萄糖易感还有胰岛素易感•大脑的胰岛素大部分来自于外周胰岛素Banks.EurJPharmacology2004;490(1–3):5–12;Schwartz,Porte.Science2005;307(5708):375–9门脉循环胰腺葡萄糖胰岛素外周组织食物体循环门脉循环胰腺葡萄糖外周组织食物Systemiccirculation相对的增加:•抑制脂肪分解•外周葡萄糖摄取•脂肪合成胰岛素相对的减少:•抑制内源性葡萄糖产生胰岛素皮下注射结合白蛋白的IDet肝脏外周肝窦小孔无小孔内皮HordernV.etal.Diabetologia2005;48:420-6一天一次方便使用减少个体内变异有效安全控制血糖减少低血糖减少体重增加