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1、,30,20,10,0,7,8,9,10,11,12,1,2,3,4,5,6,7,8,9,A.M.,P.M.,早餐,午餐,晚餐,75,50,25,0,基础胰岛素,基础血糖,胰岛素(U/mL),血糖(mg/dL),时 间,健康人胰岛素和血糖曲线,-细胞的胰岛素分泌调节,Transport andphosphorylation,Glucose-6-P,Glucose,Glycolysis,ATP(ATP/ADP),Mitochondrialmetabolism,Granule formationand trafficking,Depolarization,Ca2+,Insulin,KATPchan
2、nel,GLUT2,Sulfonylureas,Sulfonylureareceptor,Genetranscription,葡萄糖在体内的代谢,胰岛素抵抗,肝糖生成,内源性胰岛素,餐后血糖,空腹血糖,内源性胰岛素,IGT,4 7 年,“诊断糖尿病”,Clinical Diabetes Volume 18,Number 2,2000,显性糖尿病,糖尿病的自然病程,微血管,大血管,2型糖尿病的自然病程与血糖变化相关的其它异常,糖尿病前期,糖尿病发生 并发症出现,并发症发展,残废,死亡,胰岛素抵抗,失明,肾衰,心血管病,截肢,正常血糖,糖 尿 病,病理基础：,其它异常：,血脂紊乱高血压凝血功能异常
3、炎症,血糖紊乱与心血管病变 高血糖的分类 高血糖与心血管病变 血糖调节紊乱与心血管病变 糖尿病心血管病变 应激性高血糖与心血管病变血糖外的因素与心血管病变,内 容,Reaven GM et al.Diabetologia.1977;13:201-206.,P.7r,不同糖耐量状态个体在OGTT试验中的血糖曲线,IGT,空腹血糖 150 mg/dL,正常上限,空腹血糖110-150 mg/dL,正常,Time(hr),血糖(mg/dL),0,1/2,1,2,3,400,360,320,280,240,200,160,120,80,1997 PPS,血糖紊乱与心血管病变 高血糖的分类 高血糖与心血
4、管病变 血糖调节紊乱与心血管病变 糖尿病心血管病变 应激性高血糖与心血管病变血糖外的因素与心血管病变,内 容,FPG mmol/l,2hr PPG mmol/l,IGR,DM,Nomenclature and description term defined by FPG and 2hr PPG,Nomenclature and description term defined by FPG and 2hr PPG,IFG,IFG+IGT,IGT,FPG mmol/l,2hr PPG mmol/l,DM,Nomenclature and description term defined by
5、FPG and 2hr PPG,IFH,CH,IFG,IFG+IGT,IPH,IGT,FPG mmol/l,2hr PPG mmol/l,7.0,6.1,7.8 11.1,Shaw JE,et al.Diabetologia 42:1050,1999Resnick HE,et al.Diabetes Care 23:176,2000Barrett-Conner E,et al.Diabetes Care 21:1236,1998,5.6,空腹和餐后血糖增高的临床表现,血糖紊乱与心血管病变 高血糖的分类 高血糖与心血管病变 血糖调节紊乱与心血管病变 糖尿病心血管病变 应激性高血糖与心血管病变血糖
6、外的因素与心血管病变,内 容,Impaired glucose tolerance is a cardiovascular risk factor(Funagata Study),Tominaga M et al.Diabetes Care 1999,Cumulative cardiovascular survival,0,1.00,0.99,0.98,0.97,0.96,0.95,0.94,1,2,3,4,5,6,7,Year,Survival rates cardiovascular disease,NormalIGT(2h PG 7.811.0mmol/L)Diabetes(2h PG
7、11.1mmol/L),Paris Prospective Study 10-year follow-up,Eschwege E et al.Horm Metab Res 1985,Impaired glucose tolerance progressively increases risk of coronary heart disease mortality,心血管死亡率与餐后高血糖具有线性正相关关系,Tuomilehto J.Unpublished data from DECODE,Cumulative hazard curves for WHO 2 h glucose criteria
8、 adjusted by age,sex,and study centre,The DECODE study group THE LANCET Vol 354 August 21,1999 619,IGT,normal,diabetes,研究设计,安慰剂 t.i.d.(n=715),阿卡波糖 100mg t.i.d.(n=714),1,0,36,6,12,18,24,30,时间（月）,1,2,3,4,5,6,7,8,9,10,11,12,13,14,就医（次）,安慰剂n=1,429,Placebo,60,末次就医,3 个月安慰剂,首次心血管事件的发生,危险下降(%),p,阿卡波糖(n=682)
9、,安慰剂(n=686),患者例数,有利于阿卡波糖,有利于安慰剂,冠心病心梗 11291心绞痛 51255血管重建 112039心血管死亡 1 245充血性心衰脑血管意外/卒中 2 444外周血管病变 1 1 任何预先指定的心血管事件153249,0.02260.13440.18060.6298 0.50610.92550.0326,心血管事件,累计发生率(%),随机化后时间（年）,阿卡波糖,安慰剂,5,4,3,2,1,0,心血管事件发生率(仅指首次事件),血糖紊乱与心血管病变 高血糖的分类 高血糖与心血管病变 血糖调节紊乱与心血管病变 糖尿病心血管病变 应激性高血糖与心血管病变血糖外的因素与心
10、血管病变,内 容,糖尿病对心血管死亡率的影响,美国第一次营养调查和二次营养调查冠心病死亡率的比较,糖尿病是冠心病的等位症,0,1,2,3,4,5,6,7,8,0,20,40,60,80,100,No diabetes and no previous MI(n=1,304)Diabetes and no previous MI(n=890)No diabetes and previous MI(n=69)Diabetes and previous MI(n=169),Survival(%),Year,Haffner SM,et al.N Engl J Med 1998;339:229234.,M
11、I:myocardial infarctionError bars indicate 95%CI,All other causes,2型糖尿病的死因分析(Verona Diabetes Study;De Marco et al,Diabetes Care 22:756,1999),27.3,7.4,Malignancies,N=7148,10-yr follow-up(1986-1995),Norhammar A et al.Lancet 2002,急性心肌梗塞患者的糖代谢状态,因急性心肌梗塞而入住CCU的181例瑞典患者,出院后3个月糖耐量减退和未被诊断糖尿病的比例保持不变,35%有糖耐量减
12、退（IGT）31%有未被诊断的糖尿病,平均年龄 63.5岁此前未诊断糖尿病血糖 11.1mmol/L,糖尿病是心血管疾病,A.H.A.Scientific Statement(Circulation 1999;100:1134-1146),大血管病变的独立危险因子（UKPDS),UKPDS研究中心梗与不同治疗间的关系,C v G v Ip=0.66,血糖紊乱与心血管病变 高血糖的分类 高血糖与心血管病变 血糖调节紊乱与心血管病变 糖尿病心血管病变 应激性高血糖与心血管病变血糖外的因素与心血管病变,内 容,Survival rate in women by plasma glucose quar
13、tiles 12 and 34(P=0.03).,5.4 0.5,7.5 1.5,Diabetes Care 24:1634-1639,2001,Admission Plasma Glucose is An independent risk factor in nondiabetic women after coronary artery bypass grafting,DIGAMI Study(Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction),Subject 620 patients with
14、 diabetes mellitus and acute myocardial infarction Intensive treatment:Standard treatment plus insulin-glucose infusion for at least 24 hours followed by multidose insulin treatment(306 patients)Control:Standard treatment(314 patients),Study Design,Insulin Treatment,Insulin treatment:Intensive Contr
15、ol pAt discharge 266(87%)135(43%)0.00013 month 245(80%)141(45%)0.0001One year 220(72%)141(49%)0.0001 Other treatment:no difference,Intensive Control PGlucose at(mmol/l)Baseline 15.7(4.2)15.4(4.1)0.4 24 h after randomisation 11.7(4.1)9.6(3.3)0.0001 Glucose at hospital discharge 9.0(3.0)8.2(3.1)0.01Ha
16、emoglobin A1c(%)Baseline 8.0(2.0)8.2(1.9)0.2 3 month 1.1(1.6)0.4(1.5)0.0001)12 months 0.9(1.9)0.4(1.8)0.01,Metabolic control,Actuarial mortality curves during long term follow up,Absolute reduction in risk was 11%;relative risk 0.72(0.55 to 0.92);P=0.011,Key messages Diabetes mellitus is common amon
17、g patients with acute myocardial infarction Diabetic patients with myocardial infarction have a poor short and long term prognosis Poor metabolic control is common among diabetic patients with myocardial infarction Improved metabolic control by means of acute insulin-glucose infusion followed by lon
18、g term intensive insulin treatment improves long term prognosis among these patients,Introduction,30%of patients in surgical ICUs need 5 days intensive care(long-stay patients)Long-stay ICU patients 20%risk of death in ICUHigh morbidity due to specific complications Sepsis and inflammation Multiple
19、organ failureWasting,polyneuropathy,weaknessConsume large fraction of scarce ICU resources,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Hyperglycaemia in ICU,Current practice:Hyperglycaemia is commonCaused by insulin resistanceAdaptive?Only treated when blood glucose 215 mg/dL(12 mmol/L)Ke
20、y hypothesis:Hyperglycaemia(110 mg/dL,6.1 mmol/L)predisposes to specific ICU complications,prolonged intensive care dependency,and death,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Prospective,randomised,controlled trial,All mechanically ventilated patients admitted to ICUConsent from clo
21、sest family memberStratified for on-admission diagnosis and randomised to:,Intensive insulin treatmentGlucose 110 mg/dL,maintain at 80 110(at ICU discharge:conventional approach 200 mg/dL),Conventional insulin treatmentGlucose 215 mg/dL,maintain at 180 200,Study design,ProtocolStandard feeding regim
22、en started on admission Insulin by continuous i.v.infusion(syringe pump)Whole blood glucose monitored every 1 to 4 hoursInsulin dose adjusted by ICU nurses and a study physician not involved in clinical decision makingPrimary outcome measureDeath from any cause in ICU(cause of death confirmed by aut
23、opsy-blinded pathologist)Secondary outcome measuresIn-hospital mortality,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Study design,Secondary outcome measures:morbidityBloodstream infections*Inflammation*Acute renal failure and need for dialysis/haemofiltration*Anaemia and need for red-cell
24、 transfusions*Hyperbilirubinaemia*Critical illness polyneuropathy by weekly EMG screening*Prolonged(14 days)mechanical ventilation and ICU stayCosts(cumulative TISS),*By blinded investigators.,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Data analysis,Intention-to-treat analysisThree month
25、ly interim analyses of primary outcome(deaths during intensive care)Study terminated for ethical reasons:significantly reduced ICU mortality at 1 year(N=1548),Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Study population at baseline,0.9,Male,71%,71%,0.08,Age(y),6214,6314,First 24 h APACHE
26、II score,9(713),9(713),0.4,First 24 h TISS score,43(3647),43(3746),0.7,Malignancy,15%,16%,0.7,0.1,BMI(kg/m2),25.84.7,26.24.4,0.9,Pre-admission diabetes,13%,13%,On-admission glycaemia 200 mg/dL,12%,11%,0.2,Conventional(n=783),Intensive(n=765),P value,Insulin treatment,Noncardiac surgery type of illne
27、ss,37%,38%,0.8,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Blood glucose control,Conventional,Intensive,P value,(n=783),(n=765),Patients receiving insulin,39%,99%,0.0001,Mean daily insulin dose,when given(IU/d),33,71,0.0001,Duration of insulin requirement(%ICU stay),67,100,0.0001,Insulin
28、treatment,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Blood glucose control,Conventional,Intensive,Days in ICU,Blood glucose(mg/dL),P 0.0001,M SEM,Van den Berghe G et al.Crit Care Med 2002:In press,5,0,1,0,0,1,5,0,2,0,0,0,0,1,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,22,29,Insulin administered,
29、Conventional,Intensive,0,2,4,6,0,0.1,0.2,0.3,0.4,0.5,0.6,Units/h,Units/h per Cal/kg,Days in ICU,All P 0.0001,M SEM,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,22,29,Van den Berghe G et al.Crit Care Med 2002:In press,Mortality,Conventional,Intensive,P value,(n=783),(n=765),Insulin treatment,*After correction
30、 for multiple interim analysis,adjusted P=0.036.,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Deaths by severity of illness strata,No.of ICU deaths,No.of ICU deaths,First 24 h APACHE II score,First 24 h TISS score,0,5,10,15,20,25,30,0,3,6,9,12,15,18,21,24,0,8,16,24,32,40,48,16,24,32,40,48,
31、56,64,Conventional,Intensive,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Kaplan-Meier plots for survival,0,10,20,Hospital survival(%),0,4,8,1,0,ICU survival(%),80,90,100,80,90,100,70,All patients,P=0.005,All patients,P=0.01,Long-stay patients,P=0.007,Long-stay patients,P=0.02,100,90,80,10
32、0,90,80,70,Days after inclusion,Days after inclusion,0,20,40,60,80,100,120,0,50,100,150,200,Intensive,Conventional,Intensive,Conventional,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Causes of death,Multiple-organ failure,with septic focus,33,8,Multiple-organ failure,no septic focus,18,14,
33、Severe brain damage,5,3,Acute cardiovascular collapse,7,10,Conventional,Intensive,(n=783),(n=765),Insulin treatment,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Morbidity,RRR(%),0,20,40,60,0,20,40,NNT,ICU stay 14 days,*,Mechanical ventilation 14 days,*,Dialysis/haemofiltration,*,Bloodstrea
34、m infections,*,Antibiotics 10 days,*,Critical illness polyneuropathy,46,28,35,17,41,29,44,4,37,22,27,23,*P 0.01 P 0.0001Error bars:95%confidence intervals,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,Insulin dose or glycaemic control?,Multivariate logistic regression analysis of effect on
35、ICU mortality:(corrected for all univariate determinants of outcome)OR 95%CI P-valueDaily insulin dose:1.006 1.0021.000 0.005(per added unit)Mean blood glucose level:1.015 1.0091.021 0.0001(per added mg/dL),Van den Berghe G et al.N Engl J Med 2002;346:1586-1588.Van den Berghe G et al.Crit Care Med 2
36、002:In press,Is strict normoglycaemia essential?,0,5,10,15,20,25,30,35,40,45,0,50,100,150,200,250,150 mg/dL,110 mg/dL,110150 mg/dL,P=0.0259,P=0.0009,Days after inclusion,Cumulative hazard(%)(in-hospital death),Patients in ICU for 5 days(N=451),Van den Berghe G et al.Crit Care Med 2002:In press,5489,
37、90125,126161,162197,198232,Blood glucose level(mg/dL),2,18,4,6,8,10,12,14,16,Risk of critical illness polyneuropathy(%),Rho=1.0P 0.0001,Is strict normoglycaemia essential?,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367.Van den Berghe G et al.Crit Care Med 2002:In press,Results summary,Strict
38、 glycaemic control 110 mg/dL with exogenous insulinReduced ICU and hospital mortality of surgical ICU patientsReduced ICU morbidity:Severe infections and inflammationAcute renal failure and need for dialysisAnaemia and need for transfusionHyperbilirubinaemiaCritical illness polyneuropathy and prolon
39、ged ventilator dependencyProlonged ICU stay,Van den Berghe G et al.N Engl J Med 2001:345:1359-1367,“超越高血糖”,2000年ADA president Speech:,血糖紊乱与心血管病变 高血糖的分类 高血糖与心血管病变 血糖调节紊乱与心血管病变 糖尿病心血管病变 应激性高血糖与心血管病变血糖外的因素与心血管病变,内 容,糖尿病因肥胖而始并因肥胖而终 E.P.JOSLIN，1927,大血管病变的独立危险因子（UKPDS),各种代谢紊乱与糖尿病并发症的相关性,Am J Cardiol 2001;
40、88(suppl):16H19H,胰岛素抵抗综合症,大血管病变,微血管病变,高血糖（细胞）,血脂,血压,2型糖尿病的自然病程与血糖变化相关的其它异常,糖尿病前期,糖尿病发生 并发症出现,并发症发展,残废,死亡,胰岛素抵抗,失明,肾衰,心血管病,截肢,正常血糖,糖 尿 病,病理基础：,其它异常：,血脂紊乱高血压凝血功能异常炎症,WHO（1999）关于代谢综合征的工作定义,基本要求：l 糖调节受损或糖尿病及/或l 胰岛素抵抗（背景人群钳夹试验中葡萄糖摄取率下四分位数以下）尚有下列2个或更多成份：l 动脉压增高140/90mmHgl 血浆甘油三酯增高1.7mmol/L及/或l 低HDL-C，男性0.
41、90，女性0.85及/或BMI30kg/m2微量白蛋白尿20微克/分或白蛋白/肌肝30mg/g,NCEP-ATPIII确定代谢综合征的指标,具备下列3个或更多指标l 空腹血糖110mg/dll 血压130/85mmHgl 甘油三酯150mg/dll HDL-C 男性102cm，女性88cm,Cardiovascular Disease Mortality,代谢综合症:总死亡率和心血管病死亡率 Kuopio Heart Study,Lokka,H-M,et al JAMA 2002;288:2709-2716,All-Cause Mortality,CumulativeHazard(%),RR
42、indicates relative risk;CI,confidence interval.Median follow-up(range)for survivors was 11.6(9.1-19.7)years,No.at RiskMetabolicSyndrome,Yes866852834292No288279234100,Yes866852834292No288279234100,Follow-up,g,Follow-up,g,RR(85%CI)2.13(1.64-3.61),RR(85%CI)3.55(1.96-6.43),Metabolic Syndrome,Yes,No,Meta
43、bolic Syndrome,Yes,No,死亡四重奏“Deadly Quartet”的影响搭桥手术后随访,Sprecher,et al JACC 2000;36:1159-1165,No.ofRiskFactors,Male,Female,Years,1.0,Survival,0.9,0.8,0.7,0.6,0.5,0,1,2,3,4,5,6,7,8,9,10,0,1,2,3,4,No.ofRiskFactors,Years,1.0,Survival,0.9,0.8,0.7,0.6,0.5,0,1,2,3,4,5,6,7,8,9,10,0,1,2,3,4,Deadly Quartet Ris
44、k Factors=obesity,diabetes,hypertension,hypertriglyceridemia,糖尿病并发症的病因和危险因素和,微血管病变眼睛肾脏神经,大血管病变缺血性心脏病中风周围血管病变,足,吸烟,ARB,2002,Steno-2研究：2型糖尿病患者多因素干预与心血管疾病研究,Steno-2 研究,目的,对有微量白蛋白尿的2型糖尿病患者进行8年多的研究，比较包括行为和药物干预在内的强化多因素达标治疗与常规治疗对心血管疾病的影响,Steno-2研究,169位有微量白蛋白尿的2型糖尿病患者,9名患者因C肽600而退出,160位患者随机分组,80位患者接受常规治疗,80
45、位患者接受强化治疗,15例死亡7例发生CVD5例癌症3例其他原因,12例死亡7例发生CVD2例癌症3例其他原因,2例自动退出,1例自动退出,63例完成研究,67例完成研究,Steno-2 研究,试验设计,开放性对照平行试验，有160例有微量白蛋白尿的2型白人糖尿病患者参与患者随机分组，接受全科医师的常规治疗或Steno糖尿病中心的强化治疗,160,Steno-2 研究,初级终点:所有心血管疾病心血管死亡非致死性心梗冠脉搭桥非致死性中风血管重建截肢 次级终点:微血管疾病肾病的进展视网膜病变的进展神经病变的进展,8年后的终点事件,Steno-2 研究,基线特征,强化治疗组的干预措施,饮食干预：脂肪
46、摄入量小于总热量的30；饱和脂肪酸小于总热量的10运动干预：30分钟轻中度运动，每周5次鼓励患者及家属戒烟所有患者使用相当于50mg bid开博通剂量的ACEI或相当于50mg bid 络沙坦剂量的ARB所有患者使用阿司匹林（除非有禁忌证）当HbA1c6.5%,使用口服药当口服药使用至极量而HbA1c7.0%，开始使用胰岛素,强化治疗组降糖药物治疗,BMI25,BMI25,开始使用二甲双胍（极量1g bid),开始使用格列奇特(极量160mg bid),格列奇特二甲双胍,二甲双胍格列奇特,强化组患者经饮食运动后HbA1c6.5,加用睡前NPH停二甲双胍,加用睡前NPH停格列奇特,使用每日多次胰
47、岛素治疗,HbA1c7%,HbA1c7%,HbA1c7%,HbA1c7%,睡前NPH80U 或血糖控制不满意,Steno-2 研究,治疗目标,降糖治疗,对照治疗组强化治疗组P值（N63）（N67)饮食治疗（人数）4 10.15口服药治疗（人数）38 500.14胰岛素治疗（人数）34 380.91两种治疗联合（人数）13 220.14胰岛素剂量（单位）0.91中位数 64 62区间 12-360 12-260,降压治疗,人数对照治疗组强化治疗组P值（N63）（N67)ACEI 32 530.002ARB 12 310.002 ACEI+ARB 0 190.001 利尿剂 39 380.42 钙
48、通道拮抗剂 18 240.45 B受体阻滞剂 13 100.35,调脂治疗及其他,人数对照治疗组强化治疗组P值（N63）（N67)降脂药物他丁类 14 570.001倍特类 3 10.27两者联合 0 11.00阿司匹林 35 580.001维生素及微量元素 0 420.001,8年后达到治疗目标的患者,脂肪摄入30%E,饱和脂肪10%E,非吸烟者,运动150 分钟/周,强化组 常规组,p=0.09,p=0.02,p=0.58,p=0.13,Steno-2 研究,达到的治疗目标,强化组 常规组,强化组 常规组,强化组 常规组,第8年生化危险因素,糖化血红蛋白(分别为9.0和 7.9%)收缩压(
49、分别为146和 131 mm Hg)舒张压(分别为78和 73 mm Hg)总胆固醇(分别为5.6和 4.1 mmol/l)LDL胆固醇(分别为3.3和 2.1 mmol/l)甘油三酯(分别为3.0和 1.7 mmol/l)尿白蛋白(分别为126和 26 mg/24h),Steno-2 研究,随访期间的危险因素,%糖化血红蛋白,mm Hg收缩压,mmol/l 空腹血清总胆固醇,mm Hg舒张压,达到的治疗目标,糖化血红蛋白6.5%,胆固醇4.5 mmol/l,甘油三酯1.7 mmol/l,收缩压130 mmHg,舒张压80 mmHg,8年后达到治疗目标的患者,%,p=0.06,p0.0001,
50、p=0.19,p=0.001,p=0.21,Steno-2 研究,强化组 常规组,强化组 常规组,强化组 常规组,强化组 常规组,强化组 常规组,初级心血管终点事件,常规治疗组有35例发生85起心血管事件(44%)，而强化治疗组19例患者发生33起心血管事件(24%),微血管并发症,肾病,视网膜病变,自主神经病变,周围神经病变,比数比,0.39,0.42,0.37,1.09,强化治疗较好,常规治疗较好,8年累计发病率,总结,Steno-2 研究,对于有微量白蛋白尿的患者，经过8年以多因素达标为靶目标的阶梯强化治疗（包括生活方式干预和多种药物治疗）使发生心血管事件的绝对危险性降低了20强化治疗第
