糖尿病与脑血管疾病课件

1、 糖尿病与心血管病变 复旦大学华山医院 内分泌糖尿病研究所 糖尿病防治研究中心 朱 禧 星 T2-DM命名和定义的发展Diabetes Mellitus: 集中于糖代谢Diabesity: 多数伴有肥胖Diabetes Mellipidtus: 发展为糖、脂病T2-DM是代谢综合征的主要成员（WHO）T2-DMCHD 等同病 （ATP-）Story ofTITANIC & IcebergBHCZXQ:HEALTHLife Style DiseasesT2-DMIGTHypertensionDyslipidemiaObesityMicroalbuminuriaetcHYPERINSULINEMI

2、AIsomaa et al. Diabetes Care 2001.CVD morbidity & mortality & the Metabolic Syndrome (Botnia study: 3570 years)Metabolic Syndrome seen in:10% females & 15% males with NGT (n = 1988)42% & 64% with IFG/IGT (n = 798)78% & 84% with Type 2 diabetes (n = 1697)3-fold increase risk for CHD & stroke in peopl

3、e with Metabolic Syndrome (P 0.001)CVD mortality markedly increased in subjects with the Metabolic Syndrome in 6.9 year follow-up (12% v 2.2%, P 0.001) T2-DM中动脉硬化负担的程度DM患CV病2-4倍于非DM者估计在T2-DM中死亡原因的75%为CV病;在美国,用于DM的医保费用,每年约9000亿美元总费用中的75%用于CV病kannel,Ahu,1990;ZIEGLLER,Daib Metab Rev 1994;NDOG,Diabetes

4、in America,2nd ed.NIH,1995;Harris, D. Care 1998; Lowell, Diabetologla, 2000 Death From CHD in Type 2 Diabetic PatientsWith or Without Previous Myocardial InfarctionSurvival(%) 100 80 60 40 no Diabetes and no Previous MI ( n=1304) Diabetes and no Previous MI ( n=890) no Diabetes and Previous MI (n=69

5、 ) 20 Diabetes and Previous MI (n=169 ) 0 0 1 2 3 4 5 6 7 8Haffner SM, et al. N Engl J Med. 1998;339;229-234. Decode研究的结果餐后2小时血糖比空腹血糖更有力的预测死亡; 2h blood glucose is more powerful at predictingpremature death from all causes than fasting bloodglucose levels无论空腹血糖水平怎样, 餐后血糖水平的提高都会增加死亡的危险;For any level o

6、f fasting glucose , the risk of premature death increased with increasing 2-hglucose Source: DECOOE Study Group . Br J Med 1994: 317: 371 - 375餐后血浆葡萄糖水平与死亡的危险 (mmol/ L) DECODE 研究小组 ( Lance 1999, 35. 617-21 ) DECODE: 结论餐后2小时血糖 (2H-PG) 是糖尿病死亡的独立危险因素.DECODE Study Group . Lancet 1999; 354: 617-621 血浆葡萄糖

7、时相与动脉硬化关系比较FPG,OGTT服糖后PG ( 30m 60m 90m 120m ) PGS(高峰) , OGTT时糖面积和 HbA1c 与颈动脉IMT之间关系;PG和PGS与IMT关系较FPG和 HbA1c更相关PGS中以 120m 最相关, 30m 无相关 Diab care 2000;23:1830 餐后血浆葡萄糖 (PPG)许多因素可影响PPG曲线, 如CHO吸收,胰岛素和胰升血糖素分泌状态等;进餐开始10分钟后, 血糖开始 , 吸收持续5-6小时PGS (高峰) 的时间和大小取决与进餐计时,进餐量及其成份;DM的餐后血糖高峰在2小时, 在GDM则为1-h. Diab care

8、2001;24:775 FPG 和 2h-PG 均需重现 (二)三.1998年 ADA/WHO DM 诊断标 FPG 为 126mg/dl, FPG 和 2h-PG 相当性较好, IGT 心血管危险性与DM相似 , 需加强随访 IDF -WPR T2-DM 诊疗指南, 要求FPG 和 2h-PG 以及HbA1C都须达标 大 动 脉內膜: 內皮细胞, 內皮下间隙, 內弹力层中膜: 平滑肌细胞(SMC), 细胞外基质(ECM), 外弹力层等外膜: 也可有SMC, 胶元, 弹性蛋白, 血管滋养血管等DM血管病变的病理生理基础内皮细胞生理功能紊乱血管平滑肌细胞功能紊乱泡沫细胞和脂条、斑块形成代谢综合征

9、：高糖，高血压，血脂紊乱 etc.ROS(高糖引出)，氧化应激血小板功能紊乱及凝血功能异常炎症反应和粘附分子参与抽烟: 尼古丁HbCO缺氧內皮损伤 內皮功能障碍和病变內皮细胞（EC）在生理或病理时可分泌ACE， 因子，tPA, PAI-1，NO，PGI2，TXA2, ET, LPL 等 DM 时，因子、PAI-1、ET和ACE, NO，促进血凝，內皮损伤，进而促进炎症反应炎症细胞因子如TNF-和MCP-1(单核细胞趋化蛋白-1)等在多种因素联合作用下，使mono移行至內皮下层并分化成巨噬细胞，吞噬氧化或/和糖化LDL-C成为foam cell，并可分泌基质金属蛋白酶，降解斑块帽基质，泡沫细胞在

10、VCAM 和WBC的参与下，粘附于內膜，逐渐形成斑块 斑块不稳定型斑块： 含大量炎症细胞和脂质，纤维帽较薄，易破，稳定型斑块： 纤维帽较厚，炎症细胞和脂质较少。NO的生理功能抑制血小板的激活血管扩张抑制管壁炎性反应抑制平滑肌细胞的增殖、移行 平滑肌细胞病理时（如DM），SMC在PDGF（血小板源生长因子）和TNF-，IL-1，TGF-等细胞因子的作用下移行至內膜并增生SMC可合成ECM，如胶质，葡糖氨基多糖，使血管基质增生炎症反应与动脉硬化和T2-DM形成有关炎症反应与免疫相关Types of Immune System(contd)Adaptive(acquired) immune syst

11、em(AIS)* only in vertebrates,* more sophisticated immune response mediated by B & T lymphocytes and Igs; takes several days or moreInnate Immune SystemPhagocytic cells: monocytes & macrophagesacute phase reactants cytokines complementsacute phase reactants Mono-macrophagesOn the lst line defense of

12、IIS,Arise from procursor within marrow,Tissue monocytes migrating from circulation secrete factors: IL-1,2,6, TNF-, central to Ag-specific activation of T & B cellsMono-macrophages(contd)Mediate innate immune effector functions: destruction of Ab-coated bacteria, tumor cells or even normal hematopoi

13、tic cellsMediate Ag-nonspecific lytic activity and eliminate cell types like tumor cells without AbAcute Phase Reactants(Proteins)Inc or Dec in amount in response to inflammation by hepatocytesIncrement as little as 50%(complement), or as large as 1,000-fold(CRP)ComplementsAn important soluble compo

14、nent of IIS: regulatory proteins for cell lysis,C3 when bound to foreign antigen surfaces opsonization for phagocytosis CytokinesSoluble proteins from various cell types critical for both IIS & AIS,Chief stimulators of the acute phase protein changes,activated macrophages, monocytes & adipocytes are

15、 important sources; IL-6 , TNF-, resistin and adiponectin are examples of potent adipose cytokines,Expression perturbed in most immune, inflammatory and infectious diseasesProinflammatory Cytokines由mono/phagocyte按应激要求而生成如IL-6，TNF-等化学因子（chemokines）家属如IL-8，MCP-1，2，3（monocyte chemotactic proteins）,MIP-

16、1，1（monocyte inflammatory proteins）等也可作用于mono/phagocyte生成炎症细胞因子Inflammatory Markerscoagulation factors, PAI-1Factor , leucocytesplateletshaptoglobinC Reactive Protein(CRP), IL-6 dependent hepatic biosynthesized Adiponectin(脂联素,ADN)（Clin Chim Acta 04;344:1-12; Am J Phy End Met 03;285:E527-33）ADN系由脂肪细

17、胞分泌的cytokine, 具有促胰岛素敏感性、抗炎作用从而有抗动脉硬化作用,血ADN水平在T2DM和冠心病，均有预测意义，且与血CRP呈负相关, Adiponectin(contd) （B B Res Com 04;314:415-9）在脂细胞中ADN与TNF-或IL-6相互抑制其表达；ADN增加肌肉对FFA的氧化，肥者血ADN较瘦者低53%，减肥后ADN51%,ADN可抑制resistin介导的粘附分子VCAM-1、ICAM-1的表达，减少对內皮细胞的不良影响 C反应蛋白（CRP）由肝脏合成的炎症急性反应蛋白血CRP可预测冠心病、心梗，与脂联素呈负相关血CRP可预测T2-DM发生Cardi

18、ovascular Health StudyDiabetes 2001;50:2384-894481 non-dm subjects,65y, followed 3-4ybaseline CRP, WBC, platelet, albumin, fibrinogen and Factor measuredafter adjustment for subclinical CVD, BMI and other inflammation, elevated CRP(75% percentile, 2.86mg/l)gp VS lower(25% percentile, 0.82mg/l)gp 2.0

19、3 : 1baseline CRP level predicted incident DM West Scotland Coronary Prevention Study(WOSCOPS) Diabetes 2002;51:1596-005245 middle aged men, baseline CRP measured, followed 5 ys, 127 transited from NGTDMCRP still a DM predictor indepentent of baseline BMI, BG & F-TG(multivariate ana)The highest quin

20、tile(CRP4.18mg/l) was 3-fold risk to develop DMCRP(very stable in serum) is to better predict develop of T2-dmInflammatory markers and risk of T2-DM: Role of AdiponectinADA 2002A study in NGT Pima Indians, followed 4.6 yrs85(61F/24M) develop DM ; controls matched at baseline for age, BMI & genderbaseline CRP, IL-6, sE-selectin, sICA