1、Macleod and ClowesBanting and Best SSA A链链B B链链GLyLIeValGluGLnCysThrSerLleCysSerLeuTyrGlnLeuGluAsnTyrCysAsn15101521PheValAsnGlnHisLeuCysGlySerHisLeuValGluAlaLauTyrCysLeuValCysGlyGluArgGlyPhePheTyrThrProLysThr151015202530SSSS翻译翻译储存在同一个分泌颗粒中，储存在同一个分泌颗粒中，总储存量为总储存量为300U300U胰岛素胰岛素结构基因结构基因mRNAmRNA前前胰岛素原胰岛
2、素原核糖体核糖体胰岛素原胰岛素原(86(86个氨基酸个氨基酸)内质网内质网折叠折叠锌锌-胰岛胰岛素素原六聚体原六聚体锌锌-胰岛素六聚体胰岛素六聚体C C肽肽(31(31个氨基酸个氨基酸)酶酶高尔基体高尔基体酶酶葡萄糖葡萄糖葡萄糖转运蛋白葡萄糖转运蛋白葡萄糖葡萄糖葡萄糖激酶葡萄糖激酶G-6-PG-6-P代谢代谢信号信号ATPATPADPADPK K+ATPATP去极化去极化钙内流钙内流胰岛素分泌胰岛素分泌分泌颗粒分泌颗粒钙内流钙内流时间时间(分钟分钟)血浆胰岛素血浆胰岛素 U/LU/L0 020204040606080801001000 0303060609090第一时相第一时相第二时相第二时相
3、静脉注射葡萄糖后胰岛素的分泌静脉注射葡萄糖后胰岛素的分泌 20 100102030Adapted from International Diabetes Center(IDC).Minneapolis,Minnesota.糖尿病病程相对 细胞功能血浆葡萄糖胰岛素抵抗胰岛素分泌126 mg/dL空腹餐后020406080100 10 9 8 7 6 5 4 3 2 10123456年限-细胞的功能(%)Adapted from UK Prospective Diabetes Study(UKPDS)Group.Diabetes.1995;44:1249-1258.胰岛素胰岛素 敏感性敏感性 胰岛
4、素胰岛素 分泌分泌大血管病变大血管病变 30%50%50%50%70%-100%40%70%150%10%100%100%2型型 糖尿病糖尿病 糖耐量低减糖耐量低减 出现胰岛出现胰岛 素抵抗素抵抗 正常糖代谢正常糖代谢 Leslie RDG等，等，糖尿病发病的分子机制糖尿病发病的分子机制第第22章，章，131156页，页，1997）Adapted from UK Prospective Diabetes Study(UKPDS)Group.Lancet.1998;352:837-853.9876正常范围ADA控制目标ADA 建议行动目标00369随机化后的年限1218常规治疗强化治疗强化治疗7
5、.4%6.6%8.4%7.5%8.7%8.1%Median HbA1c(%)UK Prospective Diabetes Study(UKPDS)Group.Lancet.1998;352:837-853.Ohkubo Y,Kishichikawa H,Araki E,et al.Diabetes Res Clin Pract 1995;28:103-117.RegularNPHBSLHS胰岛素的作用BHenry,et al.Diabetes Care.1993;16:21-31.20040010030000200600100040080006000600180024001200060006
6、00180024001200单独饮食控制每天二次胰岛素治疗6个月血浆葡萄糖BLSmg/dLpmol/LBLS预混胰岛素血胰岛素水平预混胰岛素Lindstrm,et al.Diabetes Care.1992;15:27-34.0300250200150100500800 1200 1600 2000 2400 0400 08000800 1200 1600 2000 2400 0400 0800血浆葡萄糖血胰岛素水平RNRR0300200100正常对照OHA治疗三短一中胰岛素治疗8周mg/dLpmol/LBLSBLSRNRRHSHSGlyThrGluPheTyrProLysThrGlyThrG
7、luPheTyrAspLysThr23 24 25 26 27 28 29 30InsulinAspartGlyThrGluPheTyrLysProThrLispro23 24 25 26 27 28 29 30常规人胰岛素常规人胰岛素胰岛素类似物胰岛素类似物Aspart，Lispro峰值时间峰值时间=80120 分分峰值时间峰值时间=4050 分分毛细血管壁毛细血管壁皮下组织皮下组织ThrGluLysValPheAsnGluLeuGlnTyrLeuSerCysIleSerCysCysGlnGluValIleGlyTyrCysAsnLysProThrTyrPhePheArgGlyGluGlyC
8、ysValLeuTyrLeuAlaValLeuHisSerGlyCysAsnGlnLeuHisB1A21A1B29C14 脂肪酸链脂肪酸链(Myristic acid)Thr4:0025507516:0020:00 24:004:00BreakfastLunchDinnerPlasma Insulin U/ml)8:0012:008:00TimeOHABIDS 06001200180024000600Holman,et al.Diabet Med.1987;4:457-462.磺脲类降糖药正常对照 磺脲类降糖药睡前胰岛素血浆葡萄糖水平(mg/dL)360270180900BLSJohnson
9、JL,et al.Arch Intern Med.1996;156:259-264.*P 0.05 vs.baseline value1.4-0.6-0.250.8-2.5*-1.1*-3-2-1012Fasting Serum GlucoseHbA1c(%)Weight(kg)Change From Baseline ValuesSulfonylurea+InsulinInsulin OnlyBergenstal,et al.Diabetes.1998;47(suppl 1):A89.Abstract 347.HbA1c(%)Insulin+metforminInsulin+placebo8
10、.68.48.28.07.87.67.47.27.06.86.6026Treatment(mo)Combination TherapyInsulinBergenstal,et al.Diabetes.1998;47(suppl 1):A89.Abstract 347.Insulin(U/kg)PInsulin+metforminInsulin+placebo1.31.2.0011.11.00.90.80.7026Treatment(mo)Combination TherapyInsulinIns+Placebo15 mg QD30 mg QD 0.3 1.0 1.3Placebo-adjust
11、ed at 30 mg 1.0%Placebo-adjusted at 4 mg BID 1.3%Insulin+PioglitazoneInsulin+RosiglitazoneChange of Mean HbA1c(%)Rubin,et al.Diabetes.1999;48(suppl 1):A110;Raskin,et al.Diabetes.1999;48(suppl 1):A95.Ins+Placebo2 mg BID4 mg BIDChange of Mean HbA1c(%)10 1 210 1 2 0.1 0.6 1.2Effects on Plasma Glucose*T
12、roglitazone was the glitazone used in this study,but is no longer FDA-approved for clinical use.Yu,et al.Diabetes.1999;48:2414-2421.08001200160024000800MetforminContinuous insulin infusion10006004002000GlitazonePlasma Glucose(mg/dL)80010006004002000Plasma Glucose(mg/dL)80008001200160024000800Continu
13、ous insulin infusion plus metforminContinuous insulin infusionContinuous insulin infusion plus glitazoneTime of DayTime of DayYki-Jrvinen,et al.Ann Intern Med.1999;130:389-396.021 1.93.90.93.64.624203653 2.5 2.1 2.0(2/24)8(5/24)21(1/24)4(0/24)0435 3 2 1002040600515102520睡前 NPH+:优降糖二甲双胍优降糖+二甲双胍 早晨 NPHHbA1c (%)体重(kg)退出率(%)胰岛素剂量(U)谢谢大家NoImage
