1、Ward WK et al.Diabetes Care 1984;7:491502正常人正常人2型糖尿病人型糖尿病人20g 葡萄糖葡萄糖300306090 120120100806040200时间(分钟)Plasma insulin(U/ml)20g葡萄糖葡萄糖3003060 90 120时间(分钟)120100806040200Plasma insulin(U/ml)Polonsky KS et.al N.Engl.J.Med.19882 2型糖尿病型糖尿病-健康对照健康对照IRIU/ml6040200-601005分钟分钟精氨酸精氨酸 2.5g2.5g葡萄糖葡萄糖 20g20g-60100
2、5Polonsky KS et.al N.Engl.J.Med.1988 2 2型糖尿病患者型糖尿病患者(n=16)(n=16)8008006am6am时时 间间 10am10am2pm2pm6pm6pm10pm10pm2am2am6am6am700700600600500500400400300300200200100100 健康对照者健康对照者(n=14)(n=14)胰胰岛岛素素分分泌泌速速率率pmol/min100806040HOMA,diet-treatedn=376时间时间(年年)100-细胞细胞功功 能能(%)806040200每年下降每年下降4%Holman RR.Diabete
3、s Res Clin Pract 1998;40(Suppl):S215.10 9 8 7 6 5 4 3 2 11234560诊断时诊断时-细胞的功能细胞的功能胰岛素分泌波动小而不规则胰岛素分泌波动小而不规则 缺乏进餐后第一时相胰岛素分泌应答缺乏进餐后第一时相胰岛素分泌应答 餐后胰岛素第二时相分泌缓慢上升，峰值降低餐后胰岛素第二时相分泌缓慢上升，峰值降低 两餐间不能恢复到基础状态两餐间不能恢复到基础状态 胰岛素原分泌在早期增加胰岛素原分泌在早期增加 晚期胰岛素的分泌缺乏晚期胰岛素的分泌缺乏1920193019401950196019701980199020001923 动物胰岛素1973 单
4、组分胰岛素1987 人胰岛素1996 胰岛素类似物1938 NPH insulin1953 长效胰岛素时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用246810121416182022240中性可溶性人胰岛素中性可溶性人胰岛素无色澄清溶液无色澄清溶液可以皮下注射、肌肉注射、静脉点滴可以皮下注射、肌肉注射、静脉点滴起始作用时间起始作用时间:0.5:0.5至至1 1小时小时最大作用时间最大作用时间:1:1至至3 3小时小时作用维持时间作用维持时间:8:8至至1010小时小时GLy LIe Val Glu GLn CysThr Ser Lle Cys Ser Leu Tyr Gln Leu G
5、lu Asn Tyr Cys Asn15101521Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Lau TyrCysLeu ValCysGlyGluArgGlyPhePheTyrThrProLysThr151015202530SSSS达峰时间2-4 hr时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用246810121416182022240门冬氨酸胰岛素、赖脯胰岛素门冬氨酸胰岛素、赖脯胰岛素无色澄清溶液无色澄清溶液可以皮下注射、肌肉注射、静脉点滴可以皮下注射、肌肉注射、静脉点滴起始作用时间起始作用时间:5:5分钟分钟最大
6、作用时间最大作用时间:1:1小时小时作用维持时间作用维持时间:4:4小时小时达峰时间1 hr时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用246810121416182022240始作用时间：始作用时间：1.5小时小时最大作起用时间：最大作起用时间：4至至12小时小时作用维持时间：作用维持时间：24小时小时低精蛋白锌人胰岛素低精蛋白锌人胰岛素白色混悬溶液白色混悬溶液皮下注射皮下注射时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用246810121416182022240始作用时间：始作用时间：0.5小时小时最大作起用时间：最大作起用时间：4至至12小时小时作用维持时间：作用维持时间：
7、24小时小时双时相低精蛋白锌人胰岛素双时相低精蛋白锌人胰岛素白色混悬溶液白色混悬溶液皮下注射皮下注射时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用246810121416182022240始作用时间：始作用时间：0.5小时小时最大作起用时间：最大作起用时间：1至至12小时小时作用维持时间：作用维持时间：24小时小时双时相胰岛素类似物双时相胰岛素类似物白色混悬溶液白色混悬溶液皮下注射皮下注射时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用246810121416182022240胰岛素类似物胰岛素类似物无色澄清溶液无色澄清溶液皮下注射皮下注射始作用时间：始作用时间：2小时小时最大作起用
8、时间：作用平稳最大作起用时间：作用平稳作用维持时间：作用维持时间：24小时小时控制良好控制良好7.5%ISIS Therapy Monitor Phase VI,2002(ex-Avandia)Asia-Pacific Type 2 Diabetes Policy Group.Type 2 Diabetes Practical Targets and Treatments.2002.平均平均HbA1C(%)n=2729控制佳控制佳4.4 6.1 mmol/L9.027.968.458.538.748.24METSU-GlucobayMET+SUMET+-GlucobaySU+-Glucobay
9、7.06.1控制一般控制一般7.0 mmol/L控制差控制差7.0 mmol/LISIS Therapy Monitor Phase VI,2002(ex-Avandia)Asia-Pacific Type 2 Diabetes Policy Group.Type 2 Diabetes Practical Targets and Treatments.2002.平均平均FPG(mmol/L)n=2729InitiaInitial lA1C%A1C%Achieve ACEAchieve ACEGlycemic GoalsGlycemic Goals(FPG,PPG,and A1C)(FPG,PP
10、G,and A1C)InterventionInterventionContinuousContinuousTitration of RxTitration of Rx(2-3 months)(2-3 months)If 6.5%A1C GoalIf 6.5%A1C GoalNot AchievedNot AchievedAssess FPGAssess FPGandand PPG PPGInitial TherapyInitial TherapyMonitor/adjust Rx Monitor/adjust Rx to maximal effective to maximal effect
11、ive dose to meet ACE dose to meet ACE Glycemic GoalsGlycemic GoalsIntensify Lifestyle Intensify Lifestyle ModificationModificationIntensify or combine RxIntensify or combine Rx including incretin mimeticincluding incretin mimetic*1 1Target:Target:PPGPPGand FPGand FPGMonitor/adjust Rx Monitor/adjust
12、Rx to maximal effective to maximal effective dose to meet ACE dose to meet ACE Glycemic GoalsGlycemic GoalsCombine TherapiesCombine Therapies 6,76,7Intensify Lifestyle Intensify Lifestyle ModificationModificationIntensify or combine Rx,Intensify or combine Rx,including incretin mimetic including inc
13、retin mimetic with SU,TZD,and/or with SU,TZD,and/or metforminmetformin 6-76-77-87-8Lifestyle Lifestyle ModificatioModification nLifestyle Lifestyle ModificatioModification nIf 6.5%A1C GoalIf 6.5%A1C GoalNot AchievedNot AchievedAlternativesAlternatives Glinides Glinides SU(low dose)SU(low dose)Prandi
14、al insulin Prandial insulin5,85,8Preferred:Preferred:Metformin Metformin4 4 TZD TZD10,1110,11 AGI AGI DPP-4 Inhibitor DPP-4 InhibitorAlternativesAlternatives Prandial insulinPrandial insulin5,85,8 Premixed insulinPremixed insulinpreparationspreparations8 8 Basal insulinBasal insulinanaloganalog9 9 M
15、etformin Metformin Glinides Glinides AGI AGI TZD TZD SU SU DPP-4 Inhibitor DPP-4 InhibitorACE/AACE Diabetes Road Map Task ForcePaul S.Jellinger,MD,MACE,Co-ChairJaime A.Davidson,MD,FACE,Co-ChairLawrence Blonde,MD,FACP,FACEDaniel Einhorn,MD,FACP,FACE George Grunberger,MD,FACP,FACEYehuda Handelsman,MD,
16、FACP,FACERichard Hellman,MD,FACP,FACEHarold Lebovitz,MD,FACEPhilip Levy,MD,FACEVictor L.Roberts,MD,MBA,FACP,FACE Endocr Pract.2007;13:260-268Endocr Pract.2007;13:260-268ACE Glycemic Goals 6.5%A1C 110 mg/dL FPG 110 mg/dL Preprandial 140 mg/dL 2-hr PPGAccess Roadmap at:Access Roadmap at: *Available as
17、 exenatide 1Indicated for patients not at goal despite SU and/ormetformin or TZD therapy;incretin mimetic is notindicated for insulin-using patients 4Preferred first agent in most patients 5Rapid-acting insulin analog(available as lispro,aspart and glulisine),inhaled insulin,or regular insulin 6Appr
18、opriate for most patients 72 or more agents may be required 8Analog preparations preferred 9Available as glargine and detemir10A recent report(NEJM;6/14/07)suggests a possible link of rosiglitazone to cardiovascular events that requires further evaluation.11 Cannot be used in NYHA CHF Class 3 or 4 2
19、007 AACE.All rights reserved.No portion of the Roadmap may be altered,reproduced or distributed in any form without the express permission of AACE.胰岛素和OHA联合应用的理论基础u口服药主要和辅助的作用仍然得到发挥u内源胰岛素仍可直接进入肝脏起作用u节省外源性胰岛素u降低医源性高胰岛素血症u减少胰岛素的副作用如体重增加、心血管并发症等u低血糖危险性减低空腹血糖正常化：空腹血糖正常化：治疗达标治疗达标A1C7%的核心的核心Monnier L,et a
20、l,Diabetes Care.2003;26(3):881-5餐后血糖空腹血糖HbA1C贡贡献献率率 10.2 空空 腹腹 血血 糖糖加用加用NPH或或Glargine-TREAT TO TARGETRiddle MC,et al.Diabetes Care 26:3080-3086,2003.Riddle MC,et al.Diabetes Care 26:3080-3086,2003.BG;timeRiddle MC,et al.Diabetes Care 26:3080-3086,2003.Riddle MC,et al.Diabetes Care 26:3080-3086,2003.
21、6.56.966.76.976.26.36.46.56.66.76.86.977.1FPG(mmol/L)HbA1c(%)GlargineNPHNPH或或Glargine与二甲双胍合用与二甲双胍合用-LANMET studyYki-Jarvinen H,et al.Diabetologia 49:442-451,2006.Yki-Jarvinen H,et al.Diabetologia 49:442-451,2006.Yki-Jarvinen H,et al.Diabetologia 49:442-451,2006.Glargine NPHGlargine NPHFPG结果：结果：Glarg
22、ine+MET组(n=16,180)，从11.3mmol/L下降到5.7mmol/L；NPH+MET组(n=13,106)，从11.0mmol/L下降到6.0mmol/L。HbA1c结果：结果：Glargine+MET组，从9.13%下降到7.14%；NPH+MET组，从9.26%下降到7.16%。*Intent-to-treat analysis.OAD=oral anti-diabetic drug.Janka H et al.Diabetes Care.2005;28(2):254-98.83%8.85%7.49%7.2%56789来得时来得时+OAD预混胰岛素预混胰岛素基线基线24周周
23、P0.0005HbA1c (%)时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用810121416182022242466时间（小时）时间（小时）相对胰岛素作用相对胰岛素作用810121416182022242466朱禧星.现代糖尿病学 第一版Polonsky KS et al,N Engl J Med 1996胰岛素胰岛素(mU/L)10203040506070006:0009:0012:0015:0018:0021:0024:0003:0006:00时时 间间正常游离胰岛素正常游离胰岛素(平均平均)进进餐餐进进餐餐进进餐餐Intensive Insulin Therapy in Cri
24、tically Ill PatientsVan den Berghe G,Wouters P,Weekers F,et al.Intensive insulin therapy in critically ill patients.N Engl J Med 2001;345:1359-1367 Intensive Insulin Therapy in the Medical ICUVan den Berghe G,Wilmer A,Hermans G,et al.Intensive insulin therapy in the medical ICU.N Engl J Med 2006;354
25、:449-461.Copyright 1997 BMJ Publishing Group Ltd.Malmberg,K.BMJ 1997;314:1512Fig 1 Actuarial mortality curves during long term follow up in patients receiving insulin-glucose infusion and in control group among total DIGAMI cohort.Absolute reduction in risk was 11%;relative risk 0.72(0.55 to 0.92);P
26、=0.011Copyright restrictions may apply.Malmberg,K.et al.Eur Heart J 2005 26:650-661;doi:10.1093/eurheartj/ehi199Glucose control expressed as fasting blood glucose(A)and HbA1c(B)Copyright restrictions may apply.Malmberg,K.et al.Eur Heart J 2005 26:650-661;doi:10.1093/eurheartj/ehi199Mortality in groups 1,2,and 3(intention to treat analysis)Copyright restrictions may apply.Malmberg,K.et al.Eur Heart J 2005 26:650-661;doi:10.1093/eurheartj/ehi199Time to the secondary endpoints stroke(A)and myocardial reinfarction(B)73 结束语结束语
