心内科医生应掌握的糖尿病知识课件

1、 心内科医生应该了解的糖尿病知识 北京大学人民医院 纪立农心内科医生应掌握的糖尿病知识1 心内科医生应该了解的糖尿病知识 北京大学3020100789101112123456789A.M.P.M.早餐午餐晚餐7550250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 心内科医生应掌握的糖尿病知识23020100789101112123456789A.M.P-细胞的胰岛素分泌调节Transport andphosphorylationGlucose-6-PGlucoseGlycolysisATP (ATP/ADP)Mitochondrialmetabolis

2、mGranule formationand traffickingDepolarizationCa2+InsulinKATPchannelGLUT2SulfonylureasSulfonylureareceptorGenetranscription心内科医生应掌握的糖尿病知识3-细胞的胰岛素分泌调节Transport andGluco 葡萄糖在体内的代谢心内科医生应掌握的糖尿病知识4 葡萄糖在体内的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

3、然病程微血管大血管心内科医生应掌握的糖尿病知识5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I2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心内科医生应掌握的糖尿病知识62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 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 心内科医生应掌握的糖尿病知识7血糖紊乱与心血管

4、病变 Reaven GM et al. Diabetologia. 1977;13:201-206.P.8r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)01/2123400360320280240200160120801997 PPS心内科医生应掌握的糖尿病知识8Reaven GM et al. Diabetologia.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 心

5、内科医生应掌握的糖尿病知识9血糖紊乱与心血管病变 7.06.17.8 11.1FPG mmol/l2hr PPG mmol/lIGRDMNomenclature and description term defined by FPG and 2hr PPG心内科医生应掌握的糖尿病知识107.06.17.8 11.1FPGNomenclature and description term defined by FPG and 2hr PPGIFGIFG+IGTIGTFPG mmol/l2hr PPG mmol/l7.06.17.8 11.1DM心内科医生应掌握的糖尿病知识11Nomenclatu

6、re and description tNomenclature and description term defined by FPG and 2hr PPGIFHCHIFGIFG+IGTIPHIGTFPG mmol/l2hr PPG mmol/l7.06.17.8 11.1Shaw 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心内科医生应掌握的糖尿病知识12Nomen

7、clature and description t空腹和餐后血糖增高的临床表现 IGR(impaired glucose regulation) (impaired glucose homeostasis) (pre-diabetes)DM(diabetes mellitus)Isolated FPG IFG（少见）(impaired fasting glucose) IFH （罕见）(isolated fasting hyperglycemia)Isolated PPGIGT(impaired glucose tolerance)IPH (isolated post-challenge hy

8、perglycemia) (diabetic OGTT)FPG &PPG IFG+IGT (combined IGT)CH (combined hyperglycemia) 心内科医生应掌握的糖尿病知识13空腹和餐后血糖增高的临床表现 IGRDMIsolated 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 心内科医生应掌握的糖尿病知识14血糖紊乱与心血管病变 Impaired glucose tolerance is a cardiovascular risk factor (Fu

9、nagata Study)Tominaga M et al. Diabetes Care 1999Cumulative cardiovascular survival1.000.980.960.940.9201234567YearSurvival rates cardiovascular diseaseNormalIFG (FPG 6.16.9mmo/L)Diabetes (FPG 7.0mmol/L)01.000.990.980.970.960.950.941234567YearSurvival rates cardiovascular diseaseNormalIGT (2h PG 7.8

10、11.0mmol/L)Diabetes (2h PG 11.1mmol/L)心内科医生应掌握的糖尿病知识15Impaired glucose tolerance is Paris Prospective Study 10-year follow-upEschwege E et al. Horm Metab Res 1985p0.001Coronary heart disease mortality(incidence rate/1,000)Glucose7.8mmol/L543210IGTGlucose11.1mmol/L(newly diagnosed diabetes)Knowndiabe

11、tes(n=6,055)(n=690)(n=158)(n=135)Impaired glucose tolerance progressively increases risk of coronary heart disease mortality心内科医生应掌握的糖尿病知识16Paris Prospective Study 10-yea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 DECODE4321043210患者人数 (x1,000)02468101214162-hour plasma glucose (mmol/L)相

12、对危险心内科医生应掌握的糖尿病知识17心血管死亡率与餐后高血糖具有线性正相关关系44患者人数 (xCumulative hazard curves for WHO 2 h glucose criteria adjusted by age, sex, and study centre The DECODE study group THE LANCET Vol 354 August 21, 1999 619IGTnormaldiabetes心内科医生应掌握的糖尿病知识18 研究设计安慰剂 t.i.d. (n=715)阿卡波糖 100mg t.i.d. (n=714)1036612182430时间（

13、月）1234567891011121314就医（次）安慰剂n=1,429Placebo60末次就医3 个月安慰剂心内科医生应掌握的糖尿病知识19研究设计安慰剂 t.i.d. (n=715)阿卡波糖 100首次心血管事件的发生危险下降(%) p阿卡波糖(n=682)安慰剂(n=686)患者例数有利于阿卡波糖有利于安慰剂00.51.01.52.0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 0.50610.9255

14、0.0326心血管事件心内科医生应掌握的糖尿病知识20首次心血管事件的发生危险下降(%) p阿卡波糖安慰剂患者例ITT累计发生率 (%)043215随机化后时间（年）阿卡波糖安慰剂543210心血管事件发生率(仅指首次事件)心内科医生应掌握的糖尿病知识21ITT累计发生率 (%)043215随机化后时间（年）阿卡波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 心内科医生应掌握的糖尿病知识22血糖紊乱与心血管病变 糖尿病对心血管死亡率的影响心内科医生应掌握的糖尿病知识23 糖尿病对心血

15、管死亡率的影响心内科医生应掌握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心内科医生应掌握的糖尿病知识24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心内科医生糖尿病是冠心病的等位症012345678020406080100No 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(%)YearHaffner SM, et al.

16、 N Engl J Med 1998; 339:229234.MI: myocardial infarctionError bars indicate 95% CI心内科医生应掌握的糖尿病知识25糖尿病是冠心病的等位症0123456780204060801 All other causes2型糖尿病的死因分析(Verona Diabetes Study; De Marco et al, Diabetes Care 22:756, 1999) 27.3Digestivediseases8.3Respiratorydiseases4.47.4Cardiovasculardiseases39.8Ma

17、lignanciesDiabetes12.7N=7148, 10-yr follow-up (1986-1995)心内科医生应掌握的糖尿病知识26 All other causes2型糖尿病的死因分析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心内科医生应掌握的糖尿病知识27Norhammar A et al. Lancet 2002糖尿

18、病是心血管疾病A.H.A. Scientific Statement(Circulation 1999; 100: 1134-1146)心内科医生应掌握的糖尿病知识28糖尿病是心血管疾病A.H.A. Scientific Sta 大血管病变的独立危险因子（UKPDS)心内科医生应掌握的糖尿病知识29 大血管病变的独立危险因子（UKPDS)心内科医UKPDS研究中心梗与不同治疗间的关系C v G v Ip = 0.66心内科医生应掌握的糖尿病知识30UKPDS研究中心梗与不同治疗间的关系C v G v Ip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

19、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 心内科医生应掌握的糖尿病知识31血糖紊乱与心血管病变 Survival rate in women by plasma glucose quartiles 12 and 34 (P = 0.03).5.4 0.57.5 1.5Diabetes Care 24:1634-1639, 2001 Admission Plasma Glucose is An independent risk factor in nondiabetic women after coronary artery bypass grafting 心内科医生应

20、掌握的糖尿病知识32Survival rate in women by plasDIGAMI Study (Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction)心内科医生应掌握的糖尿病知识33DIGAMI Study (Diabetes MellituSubject 620 patients with diabetes mellitus and acute myocardial infarction Intensive treatment: Standard treatment plus insul

21、in-glucose infusion for at least 24 hours followed by multidose insulin treatment (306 patients) Control: Standard treatment (314 patients)Study Design心内科医生应掌握的糖尿病知识34Study Design心内科医生应掌握的糖尿病知识34 Insulin TreatmentInsulin treatment: Intensive Control pAt discharge 266 (87%) 135 (43%) 0.00013 month 24

22、5 (80%) 141 (45%) 0.0001One year 220 (72%) 141 (49%) 0.0001 Other treatment: no difference心内科医生应掌握的糖尿病知识35 Insulin Treat 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.

23、01Haemoglobin 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) 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 organ failu

24、reWasting, polyneuropathy, weaknessConsume large fraction of scarce ICU resourcesVan den Berghe G et al. N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识40Introduction 30% of patients Hyperglycaemia in ICUCurrent practice: Hyperglycaemia is commonCaused by insulin resistanceAdaptive? Only treated when

25、blood glucose 215 mg/dL (12 mmol/L)Key hypothesis: Hyperglycaemia (110 mg/dL, 6.1 mmol/L) predisposes to specific ICU complications, prolonged intensive care dependency, and deathVan den Berghe G et al. N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识41Hyperglycaemia in ICUCurrent pProspective, randomi

26、sed, controlled trialAll mechanically ventilated patients admitted to ICUConsent from closest 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 t

27、reatmentGlucose 215 mg/dL, maintain at 180 200心内科医生应掌握的糖尿病知识42Prospective, randomised, contrStudy designProtocolStandard feeding regimen 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 st

28、udy physician not involved in clinical decision makingPrimary outcome measureDeath from any cause in ICU(cause of death confirmed by autopsy-blinded pathologist)Secondary outcome measuresIn-hospital mortality Van den Berghe G et al. N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识43Study designProtocol

29、 Study designSecondary outcome measures: morbidityBloodstream infections*Inflammation*Acute renal failure and need for dialysis/haemofiltration*Anaemia and need for red-cell transfusions*Hyperbilirubinaemia*Critical illness polyneuropathy by weekly EMG screening*Prolonged (14 days) mechanical ventil

30、ation and ICU stayCosts (cumulative TISS)*By blinded investigators. Van den Berghe G et al. N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识44Study designSecondary outcome Data analysisIntention-to-treat analysisThree monthly interim analyses of primary outcome (deaths during intensive care)Study termi

31、nated 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心内科医生应掌握的糖尿病知识45Data analysisIntention-to-treaStudy population at baseline0.9Male71%71% 0.08Age (y)62146314First 24 h APACHE II score9 (713)9 (713)0.4First 24 h TI

32、SS score43 (3647)43 (3746)0.7Malignancy15%16%0.70.1BMI (kg/m2)25.84.726.24.40.9Pre-admission diabetes13%13%On-admission glycaemia 200 mg/dL12%11%0.2Conventional(n=783)Intensive(n=765)P valueInsulin treatmentNoncardiac surgery type of illness 37%38%0.8Van den Berghe G et al. N Engl J Med 2001:345:135

33、9-1367心内科医生应掌握的糖尿病知识46Study population at baseline0.Blood glucose controlConventionalIntensiveP value(n=783)(n=765)Patients receiving insulin39%99%0.0001Mean daily insulin dose, when given (IU/d)33710.0001Duration of insulin requirement (% ICU stay)671000.0001Insulin treatmentVan den Berghe G et al.

34、 N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识47Blood glucose controlConventioBlood glucose controlConventionalIntensiveDays in ICUBlood glucose (mg/dL)P 0.0001M SEMVan den Berghe G et al. Crit Care Med 2002: In press501001502000011234567891011121314152229心内科医生应掌握的糖尿病知识48Blood glucose controlConvent

35、ioInsulin administeredConventionalIntensive024600.10.20.30.40.50.6Units / hUnits / h per Cal / kg Days in ICUAll P 14 days*Mechanical ventilation 14 days*Dialysis / haemofiltration*Bloodstream infections*Antibiotics 10 days*Critical illness polyneuropathy46283517412944437222723* P 0.01 P 0.0001Error

36、 bars: 95% confidence intervalsVan den Berghe G et al. N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识54MorbidityRRR (%)020406002040NNInsulin dose or glycaemic control?Multivariate logistic regression analysis of effect on ICU mortality: (corrected for all univariate determinants of outcome) OR 95% CI

37、 P-valueDaily insulin dose : 1.006 1.0021.000 0.005(per added unit)Mean blood glucose level : 1.015 1.0091.021 150 mg/dL 5 days (N = 451)Van den Berghe G et al. Crit Care Med 2002: In press心内科医生应掌握的糖尿病知识56Is strict normoglycaemia essen548990125126161162197198232Blood glucose level (mg/dL)21846810121

38、416Risk of critical illness polyneuropathy (%)Rho = 1.0P 0.0001Is 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心内科医生应掌握的糖尿病知识575489901251261611621971982Results summaryStrict glycaemic control 110 mg/dL w

39、ith 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 prolonged ventilator dependencyProl

40、onged ICU stayVan den Berghe G et al. N Engl J Med 2001:345:1359-1367心内科医生应掌握的糖尿病知识58Results summaryStrict glycaemi “ 超越高血糖”2000年ADA president Speech:心内科医生应掌握的糖尿病知识59 “ 超越高血糖”2000年ADA pr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 心内科医生应掌握的糖尿病知识60血糖紊乱与心血管病变 糖尿病因肥胖而始

41、并因肥胖而终 E.P. JOSLIN，1927心内科医生应掌握的糖尿病知识61糖尿病因肥胖而始并因肥胖而终心内科医生应掌握的糖尿病知识61 大血管病变的独立危险因子（UKPDS)心内科医生应掌握的糖尿病知识62 大血管病变的独立危险因子（UKPDS)心内科医各种代谢紊乱与糖尿病并发症的相关性Am J Cardiol 2001;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）血脂血压心内科医生应掌握的糖尿病知识63各种代谢紊乱与糖尿病并发症的相关性Am J Cardiol 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

42、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心内科医生应掌握的糖尿病知识642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 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0.9mmol/L（35mg/dl）,女性0.90，女性0.85及/或BMI30kg/m2微量白蛋白尿20微克/分或白蛋白/肌

43、肝30mg/g 心内科医生应掌握的糖尿病知识65 WHO （1999）关于代谢综合征的工作定 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40mg/dl, 女性102cm，女性88cm 心内科医生应掌握的糖尿病知识66 NCEP-ATPIII确定代谢综合Cardiovascular Disease Mortality02810124605101520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

44、2002; 288: 2709-2716All-Cause Mortality02810124605101520CumulativeHazard (%)RR indicates relative risk; CI, confidence interval. Median follow-up (range) for survivors was 11.6 (9.1-19.7) yearsNo. at RiskMetabolicSyndromeYes866852834292No288279234100Yes866852834292No288279234100Follow-up, gFollow-up

45、, gRR (85% CI)2.13 (1.64-3.61)RR (85% CI)3.55 (1.96-6.43)Metabolic SyndromeYesNoMetabolic SyndromeYesNo心内科医生应掌握的糖尿病知识67Cardiovascular Disease Mortali死亡四重奏 “Deadly Quartet”的影响搭桥手术后随访Sprecher, et al JACC 2000; 36: 1159-1165No. ofRiskFactorsMaleFemaleYears1.0Survival0.90.80.70.60.501234567891001234No.

46、ofRiskFactorsYears1.0Survival0.90.80.70.60.501234567891001234Deadly Quartet Risk Factors = obesity, diabetes, hypertension, hypertriglyceridemia心内科医生应掌握的糖尿病知识68死亡四重奏 “Deadly Quartet”的影响搭桥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高血压高血糖血脂异常凝血功能障碍吸烟 ARB2002心内科医生应掌握的糖尿病知识69糖尿病并发症的病因和危险因素和微血管病变大血管病变

47、足高血压高Steno-2研究：2型糖尿病患者多因素干预与心血管疾病研究心内科医生应掌握的糖尿病知识70Steno-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心内科医生应掌握的糖尿病知识71Steno-2 研究目的对有微量白蛋白尿的2型糖尿病患者进行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6.5%, 使用口服药当口服药使用至极量而HbA1c7.0%，开始使用胰岛素心内科医生应掌握的糖尿病知识76强化治疗组的干预措施饮食干预：脂肪摄入量小于总热量的30；强化治疗组降糖药物治疗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岛素治疗HbA1c7%HbA1c7%HbA1c7%HbA1c7%睡前NPH80U 或血糖控制不满意心内科医生应掌握