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 of,TITANIC & Iceberg,BHCZXQ:,HEALTH,Life Style Diseases,T2-DMIGT,Hypertension,Dyslipidemia,Obesity,Microalbuminuria,etc,HY
2、PERINSULINEMIA,Isomaa 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 &
3、 stroke in people 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),Magnitude of the Atherosclerotic Burden in T2DM Asymptomatic Diabetics Have Significant CV disease,Diabetes is diagnosed late: 50% o
4、f newly diagnosed T2DM have CV diseaseType 2 diabetics have a 2-fold increase in silent ischemia and unrecognized myocardial infarctionAsymptomatic T2DM patiants have marked atherosclerosis by carotid sonography (IMT) or electron beam CTKannel, AHJ, 1990; NDDG, Diabetes in America. 2nd ed. NIH, 1995
5、; Harris, D. Care 1998;Haffner, NEJM 1998; Bonora, Diabetologia 2000; Schugrin, D. Care 2001,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 in America,2nd ed.NIH,1995;Harris, D. Care 1998; Lowell, D
6、iabetologla, 2000,Death From CHD in Type 2 Diabetic PatientsWith or Without Previous Myocardial Infarction,Survival(%) 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 ) 20 Diabetes and Previous MI (n=169 ) 0 0 1 2 3 4 5 6 7
7、 8Haffner SM, et al. N Engl J Med. 1998;339;229-234.,DECODE研究,( Diabetes Epidemiology : Collaborative analysis of Diagnosis criteria in Europe)欧洲13个中心25, 364人 -1, 275人有糖尿病史共跟踪10年 (平均7.3年)包括13个有关男性的研究 ( 132, 785人年) 和6个有关女性的研究 (48, 900人年)DECODE Study Group . Lancet 1999; 354; 617-621,Decode研究的结果,餐后2小时
8、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 of fasting glucose , the risk of premature death increased with increasing 2-hglucose Source: DECOOE Study Group . Br J Med 199
9、4: 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,HbA1c As a Predictor of Coronary Artery Disease in T2DM,P0.01 vs lowest tertilep0.05 vs lowest terile CHD Mor AII CHD Events 25 2
10、0 15 Incidencein 3.5 years 10 ( % ) 5 6% 6%-7.9% 7.9% 6% 6%-7.9% 7.9% HbA1c Tertile HbA1c Tertile Kuuslsto J.at alDiabetes. 1994:43:960-967,血浆葡萄糖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;23:18
11、30,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 2001;24:775,FPG 和 2h-PG 均需重视 (一),一. 19851998 因 1985 WHO DM诊断标准 中 FPG和2h-PG并不相当, 渐发现筛查和早 期诊断有遗漏, 控制达标不佳 渐渐重 视和 强调2h-PG水平. 二. FPG代表基础水平，2h-PG反映负荷后水平， 有不同的临
12、床意义,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：高糖，
13、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VCA
14、M 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,内皮素-1的生理功能,肾脏钠、水潴留增加血管张力刺激肾素-血管紧张素系统血管平滑肌增生,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,Type of Immu
15、ne Systems, Innate immune syst(IIS) inflammation specially related-1st line defense agnt noxious stimuli* an ancient inherited defense system using germ line-encoded protein to recognize pathogen and trigger elimination; takes 1-2 days,Types of Immune System(contd),Adaptive(acquired) immune system(A
16、IS)* only in vertebrates,* more sophisticated immune response mediated by B takes several days or more,Innate Immune System,Phagocytic cells: monocytes & macrophagesacute phase reactants cytokines complementsacute phase reactants,Mono-macrophages,On the lst line defense of IIS,Arise from procursor w
17、ithin marrow,Tissue monocytes migrating from circulation secrete factors: IL-1,2,6, TNF-, central to Ag-specific activation of T & B cells,Mono-macrophages(contd),Mediate innate immune effector functions: destruction of Ab-coated bacteria, tumor cells or even normal hematopoitic cellsMediate Ag-nons
18、pecific lytic activity and eliminate cell types like tumor cells without Ab,Acute 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),Complements,An important soluble component of IIS: regulat
19、ory proteins for cell lysis,C3 when bound to foreign antigen surfaces opsonization for phagocytosis,Cytokines,Soluble proteins from various cell types critical for both IIS IL-6 , TNF-, resistin and adiponectin are examples of potent adipose cytokines,Expression perturbed in most immune, inflammator
20、y and infectious diseases,Proinflammatory 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-1，1（monocyte inflammatory proteins）等也可作用于mono/phagocyte生成炎症细胞因子,Inflammatory Markers,coagulation factors, PAI-1Factor , leucocytesplateletshaptog
21、lobinC 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
22、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,Cardiovascular Health StudyDiabetes 2001;50:2384-89,4481 non-dm subjects,65y, followed 3-4ybaseline CRP, WBC, platelet, albumin, fibrinogen and F
23、actor 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 2.03 : 1baseline CRP level predicted incident DM,West Scotland Coronary Prevention Study(WOSCOPS) Diabetes 2002;51:1596-00,5245 middle aged me
24、n, 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 quintile(CRP4.18mg/l) was 3-fold risk to develop DMCRP(very stable in serum) is to better predict develop of T2-dm,Inflammatory markers and ri
25、sk of T2-DM: Role of AdiponectinADA 2002,A 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, sICAM-1, sVCAM-1 & adiponectin measured,Risk of T2-DM and Adiponcetin (contd),CRP adipocectin( )ly correla
26、ted with CRP,sE-seletin(p0.05). Only adiponectin signif different in DM than in control(p0.003)adiponectin -protective for develop of DM(HRR0.61, p0.01), remained signific after adjustment for other makerslow adiponectin predicted T2-DM develop,Summary,Inflammation is known one of the important factors in the formation of atherosclerosisInflammation may also play a possible role in diabetogenesis,DM和心血管病治疗原则,2型糖尿病的治疗观念从单纯强调控制血糖转变为提倡全方位多因素干预，严格纠正各种异常，包括生活方式，高血糖, 高血压、血脂紊乱、高凝状态等,据UKPDS的结果, 同时严控血压对CHD的益处较单独严控血糖更大，,欢 迎 讨 论,谢 谢 大 家!,
