心內科醫(yī)生應掌握的糖尿病知識

1、心內科醫(yī)生應該了解的糖尿病知識,北京大學人民醫(yī)院 紀立農,,,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,,,,,基礎胰島素,基礎血糖,胰島素(U/mL),血糖(mg/dL),時 間,,健康人胰島素和血糖曲線,?-細胞的胰島素分泌調節(jié),Transport andphosphorylation,Glucose-6

2、-P,Glucose,,,Glycolysis,ATP (ATP/ADP),Mitochondrialmetabolism,Granule formationand trafficking,,,Depolarization,,Ca2+,,Insulin,KATPchannel,,,GLUT2,Sulfonylureas,Sulfonylureareceptor,,Genetranscription,,,,葡萄糖在體內的代謝,,

3、,,,,,,胰島素抵抗,肝糖生成,內源性胰島素,餐后血糖,空腹血糖,內源性胰島素,IGT,? 4 —7 年 ?,“診斷糖尿病”,,,,,,Clinical Diabetes Volume 18, Number 2, 2000,顯性糖尿病,,糖尿病的自然病程,,,微血管,大血管,,,,,,,2型糖尿病的自然病程－與血糖變化相關的其它異常,,糖尿病前期,,,,,糖尿病發(fā)生 并發(fā)癥出現(xiàn),,,并發(fā)癥發(fā)展,,,殘廢,,,死亡,,胰島素抵抗,

4、,,,,失明,腎衰,心血管病,截肢,,,正常血糖,糖 尿 病,,病理基礎：,其它異常：,血脂紊亂高血壓凝血功能異常炎癥,,,血糖紊亂與心血管病變 高血糖的分類 高血糖與心血管病變 血糖調節(jié)紊亂與心血管病變 糖尿病心血管病變 應激性高血糖與心

5、血管病變血糖外的因素與心血管病變,內 容,Reaven GM et al. Diabetologia. 1977;13:201-206.,P.8r,不同糖耐量狀態(tài)個體在OGTT試驗中的血糖曲線,,,,,,,,,,,,,,,,,,,,,,,,,,,,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,

6、320,280,240,200,160,120,80,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,©1997 PPS,血糖紊亂與心血管病變 高血糖的分類 高血糖與心血管病變 血糖調節(jié)紊亂與心血管病變 糖尿病心血管病變

7、 應激性高血糖與心血管病變血糖外的因素與心血管病變,內 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

8、,IGT,,FPG mmol/l,2hr PPG mmol/l,,DM,Nomenclature and description term defined by 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 42:1050,1

9、999Resnick 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臨床表現(xiàn),,,,血糖紊亂與心血管病變 高血糖的分類 高血糖與心血管病變 血糖調節(jié)紊亂與心血管病變 糖尿病

10、心血管病變 應激性高血糖與心血管病變血糖外的因素與心血管病變,內 容,Impaired glucose tolerance is a cardiovascular risk factor (Funagata Study),Tominaga M et al. Diabetes Care 1999,Cumulative cardiovascular survival,,,,,,,,,,,,,,,

11、,,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 7.8–11.0mmol/L)Diabetes (2h PG ³11.1mmol/L),,,,Paris Prospective Study 10-year follow-up,Esch

12、wege E et al. Horm Metab Res 1985,Impaired glucose tolerance progressively increases risk of coronary heart disease mortality,,心血管死亡率與餐后高血糖具有線性正相關關系,Tuomilehto J. Unpublished data from DECODE,Cumulative hazard curves fo

13、r WHO 2 h glucose criteria adjusted by age, sex, and study centre,The DECODE study group THE LANCET ? Vol 354 ? August 21, 1999 619,IGT,normal,diabetes,,研究設計,,,,安慰劑 t.i.d. (n=715),阿卡波糖 100mg t.i.d. (n=714),–1,0,36,6,12

14、,18,24,30,,,,,,時間（月）,1,2,3,4,5,6,7,8,9,10,11,12,13,14,就醫(yī)（次）,安慰劑n=1,429,Placebo,,,,60,,末次就醫(yī),,3 個月安慰劑,首次心血管事件的發(fā)生,,,,危險下降(%),p,阿卡波糖(n=682),安慰劑(n=686),患者例數(shù),有利于阿卡波糖,有利于安慰劑,,,,冠心病心梗 11291心絞痛 51255血管重建 112039

15、心血管死亡 1 245充血性心衰腦血管意外/卒中 2 444外周血管病變 1 1 –任何預先指定的心血管事件153249,0.02260.13440.18060.6298 –0.50610.92550.0326,心血管事件,,累計發(fā)生率 (%),,,,,,,隨機化后時間（年）,阿卡波糖,安慰劑,,,,,,,5,4,3,2,1,0,,,心血管事件發(fā)生率

16、(僅指首次事件),血糖紊亂與心血管病變 高血糖的分類 高血糖與心血管病變 血糖調節(jié)紊亂與心血管病變 糖尿病心血管病變 應激性高血糖與心血管病變血糖外的因素與心血管病變,內 容,糖尿病對心血管死亡率的影響,美國第一次營養(yǎng)調查和二次營養(yǎng)調查冠心病死亡率的比較,糖尿病是冠心病的等位癥,,,,,,

17、,,,,,,,,,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,

18、,,,Haffner SM, et al. N Engl J Med 1998; 339:229–234.,MI: 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),,,,,,

19、,,,,,,,,,,,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謝狀態(tài),因急性心肌梗塞而入住CCU的181例瑞典患者,出院后3個月糖耐量減退和未被診斷糖尿病的比例保持不變,,,,,35% 有糖耐量減退（IGT）31% 有未被診斷的糖尿病,平均年齡 63.5歲此前

20、未診斷糖尿病血糖 <11.1mmol/L,糖尿病是心血管疾病,A.H.A. Scientific Statement(Circulation 1999; 100: 1134-1146),大血管病變的獨立危險因子（UKPDS),,UKPDS研究中心梗與不同治療間的關系,C v G v Ip = 0.66,血糖紊亂與心血管病變 高血糖的分類 高血糖與心血管病變

21、 血糖調節(jié)紊亂與心血管病變 糖尿病心血管病變 應激性高血糖與心血管病變血糖外的因素與心血管病變,內 容,Survival rate in women by plasma glucose quartiles 1–2 and 3–4 (P = 0.03).,5.4 ± 0.5,7.5 ± 1.5,Diabetes Care 24:1634-1

22、639, 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 Infar

23、ction),Subject 620 patients with diabetes mellitus and acute myocardial infarction Intensive treatment: Standard treatment plus insulin-glucose infusion for at least 24 hours followed by

24、 multidose insulin treatment (306 patients) Control: Standard treatment (314 patients),,Study Design,Insulin Treatment,Insulin treatment: Intensive Control

25、 pAt discharge 266 (87%) 135 (43%) <0.00013 month 245 (80%) 141 (45%) <0.0001One year 220 (72%) 141 (49%) &l

26、t;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 randomisat

27、ion 11.7 (4.1) 9.6 (3.3) <0.0001 Glucose at hospital discharge 9.0 (3.0) 8.2 (3.1) <0.01Haemoglobin A1c (%) Baseline 8.0 (2.0)

28、 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 c

29、ontrol,,,,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 among patients with acute myocardia

30、l 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 mea

31、ns of acute insulin-glucose infusion followed by long term intensive insulin treatment improves long term prognosis among these patients,Introduction,± 30% of patients in surgical ICUs need >5 days intensive care

32、 (long-stay patients)Long-stay ICU patients 20% risk of death in ICUHigh morbidity due to specific complications Sepsis and inflammation Multiple organ failureWasting, polyneuropathy, weaknessConsume large

33、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 g

34、lucose >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 death,Van den Berghe G et al. N

35、 Engl J Med 2001:345:1359-1367,Prospective, randomised, controlled trial,All mechanically ventilated patients admitted to ICUConsent from closest family memberStratified for on-admission diagnosis and randomised to:,

36、,,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,

37、ProtocolStandard 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 study physician not i

38、nvolved 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.

39、 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 transfusi

40、ons*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

41、Engl J Med 2001:345:1359-1367,Data analysis,Intention-to-treat analysisThree monthly interim analyses of primary outcome (deaths during intensive care)Study terminated for ethical reasons: significantly reduced ICU

42、 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),62±14,63±14,First 24 h APACHE II score,9 (7–13),9 (7–13),0.4,Firs

43、t 24 h TISS score,43 (36–47),43 (37–46),0.7,Malignancy,15%,16%,0.7,0.1,BMI (kg/m2),25.8±4.7,26.2±4.4,0.9,Pre-admission diabetes,13%,13%,On-admission glycaemia ≥200 mg/dL,12%,11%,0.2,Conventional(n=783),Intensi

44、ve(n=765),P value,Insulin treatment,,Noncardiac surgery type of illness,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 r

45、eceiving 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 treatment,Van den Berghe G et al. N Engl J Med 200

46、1:345:1359-1367,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,,,,,,,,,,,,,

47、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,0,1’,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,22,29,Insulin administered,,Conventional,,Intensive,,,,,,,,,,,,,,,,,,,,,,,,0,,,,,2,,,,,4,,6,,,,,,,,,,,,,,,,,,,,,,,

48、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,

49、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,In

50、tensive,P value,(n=783),(n=765),,Insulin treatment,*After correction 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,,,,,,,,

51、,,,,,,,,,,,,,,,,,,,,,,,,No. of ICU deaths,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,No. of ICU deaths,First 24 h APACHE II score,First 24 h TISS score,0,5,10,15,20,25,30,0,3,6,9,12,15,18,21,24,0,8,16,24,32,40,48,16,24,32,40,48,56,64,

52、,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 (%),,,,,,,,,,,,,,

53、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,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=0.02,100,90,80,100,90,80,70,

54、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 failur

55、e, with septic focus,33,8,Multiple-organ failure, no septic focus,18,14,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

56、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,*,,,,,Bloodstream infections,*,,,,,

57、,,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 2001:345:135

58、9-1367,Insulin dose or glycaemic control?,Multivariate logistic regression analysis of effect on ICU mortality: (corrected for all univariate determinants of outcome)

59、 OR 95% CI P-valueDaily insulin dose : 1.006 1.002–1.000 0.005(per added unit)Mean blood glucose level : 1.015 1.009–1.021 <0.0001(per added mg/dL),Van den B

60、erghe G et al. N Engl J Med 2002; 346: 1586-1588. Van den Berghe G et al. Crit Care Med 2002: In press,Is strict normoglycaemia essential?,,,0,,5,,10,,15,,20,,25,,30,,35,,40,,45,,,0,,,50,,,100,,,150,,,200,,250,> 150 m

61、g/dL,,< 110 mg/dL,,110–150 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 Bergh

62、e G et al. Crit Care Med 2002: In press,54–89,90–125,126–161,162–197,198–232,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Blood glucose level (mg/dL),2,18,4,6,8,10,12,14,16,Risk of critical illness polyneuropathy (%),Rho = 1.0P &l

63、t; 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 glycaemic control <110 mg/dL with exo

64、genous insulinReduced ICU and hospital mortality of surgical ICU patientsReduced ICU morbidity: Severe infections and inflammationAcute renal failure and need for dialysisAnaemia and need for transfusionHyperbiliru

65、binaemiaCritical illness polyneuropathy and prolonged 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:,血糖紊亂與心血管病變 高血糖的分類

66、 高血糖與心血管病變 血糖調節(jié)紊亂與心血管病變 糖尿病心血管病變 應激性高血糖與心血管病變血糖外的因素與心血管病變,內 容,糖尿病因肥胖而始并因肥胖而終 －－－E.P. JOSLIN，1927,大血管病變的獨立危險因子（UKPDS),,各種代謝紊亂與糖尿病并發(fā)癥的相關性,Am J

67、Cardiol 2001;88(suppl):16H–19H,,,胰島素抵抗綜合癥,大血管病變,微血管病變,高血糖 （?－細胞）,血脂,,血壓,,,,,,,2型糖尿病的自然病程－與血糖變化相關的其它異常,,糖尿病前期,,,,,糖尿病發(fā)生 并發(fā)癥出現(xiàn),,,并發(fā)癥發(fā)展,,,殘廢,,,死亡,,胰島素抵抗,,,,,失明,腎衰,心血管病,截肢,,,正常血糖,糖 尿 病,,病理基礎：

68、,其它異常：,血脂紊亂高血壓凝血功能異常炎癥,,,WHO （1999）關于代謝綜合征的工作定義,基本要求：l         糖調節(jié)受損或糖尿病及/或l         胰島素抵抗（背景人群鉗夾試驗中葡萄糖攝取率下四分位數(shù)以下）尚有下列2個或更多成份：l 

69、        動脈壓增高≥140/90mmHgl         血漿甘油三酯增高≥1.7mmol/L及/或l         低HDL-C，男性0.90，女性>0.85及/或BMI>30kg

70、/m2微量白蛋白尿≥20微克/分或白蛋白/肌肝≥30mg/g,NCEP-ATPIII確定代謝綜合征的指標,具備下列3個或更多指標l         空腹血糖≥110mg/dll         血壓≥130/85mmHgl    &