糖尿病與腦血管疾病

1、糖尿病與心血管病變,復(fù)旦大學(xué)華山醫(yī)院 內(nèi)分泌糖尿病研究所 糖尿病防治研究中心 朱 禧 星,T2-DM命名和定義的發(fā)展,Diabetes Mellitus: 集中于糖代謝Diabesity: 多數(shù)伴有肥胖Diabetes Mellipidtus: 發(fā)展為糖、脂病,,T2-DM是代謝綜合征的主要成員（WHO）T2-DM≈CHD 等同病 （

2、ATP-Ⅲ）,Story of,TITANIC & Iceberg,BHCZXQ:,,,,,,HEALTH,Life Style Diseases,T2-DMIGT,,Hypertension,Dyslipidemia,Obesity,Microalbuminuria,,,etc,HYPERINSULINEMIA,Isomaa et al. Diabetes Care 2001.,CVD morbidity & mor

3、tality & the Metabolic Syndrome (Botnia study: 35–70 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 = 16

4、97)3-fold increase risk for CHD & 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),Ma

5、gnitude of the Atherosclerotic Burden in T2DM Asymptomatic Diabetics Have Significant CV disease,Diabetes is diagnosed late: 50% of newly diagnosed T2DM have CV diseaseType 2 diabetics have a 2-fold increas

6、e 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

7、. NIH, 1995; Harris, D. Care 1998;Haffner, NEJM 1998; Bonora, Diabetologia 2000; Schugrin, D. Care 2001,,,T2-DM中動脈硬化負(fù)擔(dān)的程度,DM患CV病2-4倍于非DM者估計在T2-DM中死亡原因的75%為CV病;在美國,用于DM的醫(yī)保費用,每年約9000億美元總費用中的75%用于CV病kannel,Ahu,

8、1990;ZIEGLLER,Daib Metab Rev 1994;NDOG,Diabetes 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 I

9、nfarction,Survival(%) 100

10、 80 60 40 no Diabetes and no Previous MI ( n=1304) Diabetes and no Previous MI ( n=890)

11、 no Diabetes and Previous MI (n=69 ) 20 Diabetes and Previous MI (n=169 ) 0 0 1

12、 2 3 4 5 6 7 8Haffner SM, et al. N Engl J Med. 1998;339;229--234.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

13、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,DECODE研究,( Diabetes Epidemiology : Collaborative analysis of Diagnosis criteria in Europe)歐洲13個中心25, 364人

14、 ----1, 275人有糖尿病史共跟蹤10年 (平均7.3年)包括13個有關(guān)男性的研究 ( 132, 785人年) 和6個有關(guān)女性的研究

15、 (48, 900人年)DECODE Study Group . Lancet 1999; 354; 617-621,Decode研究的結(jié)果,餐后2小時血糖比空腹血糖更有力的預(yù)測死亡; 2h blood glucose is more powerful at predictingpremature death from all causes than

16、 fasting bloodglucose levels無論空腹血糖水平怎樣, 餐后血糖水平的提高都會增加死亡的危險;For any level of fasting glucose , the risk of premature death increased with increasing 2-hglucose Source: DECO

17、OE Study Group . Br J Med 1994: 317: 371 - 375,餐后血漿葡萄糖水平與死亡的危險,(mmol/ L)

18、 DECODE 研究小組 ( Lance 1999, 35. 617-21 ),DECODE: 結(jié)論,餐后2小時血糖 (2H-PG) 是糖尿病死亡的獨立危險因素.DECODE Study Group

19、 . Lancet 1999; 354: 617-621,HbA1c As a Predictor of Coronary Artery Disease in T2DM,P<0.01 vs lowest tertilep<0.05 vs lowest terile

20、 CHD Mor AII CHD Events 25 20

21、 15 Incidencein 3.5 years 10 ( % ) 5

22、 <6% 6%-7.9% 7.9% 6% 6%-7.9% 7.9%

23、 HbA1c Tertile HbA1c Tertile Kuuslsto J.at alDiabetes. 1994:43:960-967,,,,,,,,,,,,,,,,,,,血漿葡萄糖時相與動脈硬化關(guān)系,比較FPG,OGTT服糖

24、后PG ( 30m 60m 90m 120m ) PGS(高峰) , OGTT時糖面積和 HbA1c 與頸動脈IMT之間關(guān)系;PG和PGS與IMT關(guān)系較FPG和 HbA1c更相關(guān)PGS中以 120m 最相關(guān), 30m 無相關(guān) Diab care 2000;23:1830,餐后

25、血漿葡萄糖 (PPG),許多因素可影響PPG曲線, 如CHO吸收,胰島素和胰升血糖素分泌狀態(tài)等;進餐開始10分鐘后, 血糖開始 , 吸收持續(xù)5-6小時PGS (高峰) 的時間和大小取決與進餐計時,進餐量及其成份;DM的餐后血糖高峰在2小時, 在GDM則為1-h. Diab care

26、2001;24:775,,FPG 和 2h-PG 均需重視 (一),一. 1985~1998 因 1985 WHO DM診斷標(biāo)準(zhǔn) 中 FPG和2h-PG并不相當(dāng), 漸發(fā)現(xiàn)篩查和早 期診斷有遺漏, 控制達標(biāo)不佳 漸漸重 視和 強調(diào)2h-PG水平. 二. FPG代表基礎(chǔ)水平，2h-PG反映負(fù)荷后水平， 有不同的臨床意義,,

27、FPG 和 2h-PG 均需重現(xiàn) (二),三.1998年 ADA/WHO DM 診斷標(biāo) FPG 為 ≥126mg/dl, FPG 和 2h-PG 相當(dāng)性較好, IGT 心血管危險性與DM相似 , 需加強隨訪 IDF -WPR T2-DM 診療指南, 要求FPG 和 2h-PG 以及HbA1C都須達標(biāo),,,,,,,,,大 動 脈,內(nèi)膜: 內(nèi)皮細胞, 內(nèi)皮下間隙

28、, 內(nèi)彈力層中膜: 平滑肌細胞(SMC), 細胞外基質(zhì)(ECM), 外彈力層等外膜: 也可有SMC, 膠元, 彈性蛋白, 血管滋養(yǎng)血管等,DM血管病變的病理生理基礎(chǔ),內(nèi)皮細胞生理功能紊亂血管平滑肌細胞功能紊亂泡沫細胞和脂條、斑塊形成代謝綜合征：高糖，高血壓，血脂紊亂 etc.ROS↑(高糖引出)，氧化應(yīng)激↑血小板功能紊亂及凝血功能異常炎癥反應(yīng)和粘附分子參與抽煙: 尼古丁→HbCO↑→缺氧→內(nèi)皮損傷,內(nèi)皮功能障礙和病

29、變,內(nèi)皮細胞（EC）在生理或病理時可分泌ACE， Ⅷ因子，tPA, PAI-1，NO，PGI2，TXA2, ET, LPL 等 DM 時，Ⅷ因子、PAI-1、ET和ACE↑, NO↓，促進血凝，內(nèi)皮損傷，進而促進炎癥反應(yīng)炎癥細胞因子如TNF-α和MCP-1(單核細胞趨化蛋白-1)等在多種因素聯(lián)合作用下，使mono移行至內(nèi)皮下層并分化成巨噬細胞，吞噬氧化或/和糖化LDL-C成為foam cell，并可分泌基質(zhì)金屬蛋白酶，降解斑塊帽基質(zhì)

30、，泡沫細胞在VCAM 和WBC的參與下，粘附于內(nèi)膜，逐漸形成斑塊,斑塊,不穩(wěn)定型斑塊： 含大量炎癥細胞和脂質(zhì)，纖維帽較薄，易破，穩(wěn)定型斑塊： 纖維帽較厚，炎癥細胞和脂質(zhì)較少。,NO的生理功能,抑制血小板的激活血管擴張抑制管壁炎性反應(yīng)抑制平滑肌細胞的增殖、移行,內(nèi)皮素-1的生理功能,腎臟鈉、水潴留增加血管張力刺激腎素-血管緊張素系統(tǒng)血管平滑肌增生,平滑肌細胞,病理時（如DM），SMC在PDGF（血小板源生長因子）和TNF

31、-α，IL-1，TGF-β等細胞因子的作用下移行至內(nèi)膜并增生SMC可合成ECM，如膠質(zhì)，葡糖氨基多糖，使血管基質(zhì)增生,△炎癥反應(yīng)與動脈硬化和T2-DM形成有關(guān)△炎癥反應(yīng)與免疫相關(guān),,Type of Immune Systems,◆ Innate immune syst(IIS) inflammation specially related---1st line defense agnt noxious stimul

32、i* an ancient inherited defense system using germ line-encoded protein to recognize pathogen and trigger elimination; takes 1-2 days,Types of Immune System(cont’d),◆Adaptive(acquired) immune system(AIS)* only in v

33、ertebrates,* more sophisticated immune response mediated by B & T lymphocytes and Igs; takes several days or more,Innate Immune System,Phagocytic cells: monocytes & macrophagesacute phase rea

34、ctants cytokines complementsacute phase reactants,,,,Mono-macrophages,On the lst line defense of IIS,Arise from procursor within marrow,Tissue monocytes migrating from circulation secrete factors: IL-1,2

35、,6, TNF-α, central to Ag-specific activation of T & B cells,Mono-macrophages(cont’d),Mediate innate immune effector functions: destruction of Ab-coated bacteria, tumor cells or even normal hematopoitic cellsMediate

36、 Ag-nonspecific 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%(compleme

37、nt), or as large as 1,000-fold(CRP),Complements,An important soluble component of IIS: regulatory proteins for cell lysis,C3 when bound to foreign antigen surfaces →opsonization for phagocytosis,Cytokines,Soluble

38、proteins from various cell types critical for both IIS & AIS,Chief stimulators of the acute phase protein changes,activated macrophages, monocytes & adipocytes are important sources; IL-6 , TNF-α, resistin

39、and adiponectin are examples of potent adipose cytokines,Expression perturbed in most immune, inflammatory and infectious diseases,Proinflammatory Cytokines,由mono/phagocyte按應(yīng)激要求而生成如IL-6，TNF-α等化學(xué)因子（chemokines）家屬如IL-8，

40、MCP-1，2，3（monocyte chemotactic proteins）,MIP-1α，1β（monocyte inflammatory proteins）等也可作用于mono/phagocyte生成炎癥細胞因子,Inflammatory Markers,coagulation factors, PAI-1Factor Ⅶ, ⅧleucocytesplateletshaptoglobinC Reactive Prote

41、in(CRP), IL-6 dependent hepatic biosynthesized,Adiponectin(脂聯(lián)素,ADN)（Clin Chim Acta 04;344:1-12; Am J Phy End Met 03;285:E527-33）,ADN系由脂肪細胞分泌的cytokine, 具有促胰島素敏感性、抗炎作用從而有抗動脈硬化作用,血ADN水平在T2DM和冠心病↓，均有預(yù)測意義，且與血CRP呈負(fù)相關(guān),,Adip

42、onectin(cont’d) （B B Res Com 04;314:415-9）,在脂細胞中ADN與TNF-α或IL-6相互抑制其表達；ADN增加肌肉對FFA的氧化，肥者血ADN較瘦者低53%，減肥后ADN↑51%,ADN可抑制resistin介導(dǎo)的粘附分子VCAM-1、ICAM-1的表達，減少對內(nèi)皮細胞的不良影響,C反應(yīng)蛋白（CRP）,由肝臟合成的炎癥急性反應(yīng)蛋白血CRP↑可預(yù)測冠心病、心梗，與脂

43、聯(lián)素呈負(fù)相關(guān)血CRP↑可預(yù)測T2-DM發(fā)生,Cardiovascular Health StudyDiabetes 2001;50:2384-89,4481 non-dm subjects,＞65y, followed 3-4ybaseline CRP, WBC, platelet, albumin, fibrinogen and Factor Ⅷ measuredafter adjustment for subclinica

44、l 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)

45、 Diabetes 2002;51:1596-00,5245 middle aged men, baseline CRP measured, followed 5 ys, 127 transited from NGT→DMCRP still a DM predictor indepentent of baseline BMI, BG & F-TG(multivariate ana)The h

46、ighest quintile(CRP＞4.18mg/l) was ＞3-fold risk to develop DMCRP(very stable in serum) is to better predict develop of T2-dm,Inflammatory markers and risk of T2-DM: Role of AdiponectinADA 2002,A study in NGT Pima I

47、ndians, 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 Adiponc

48、etin (cont’d),CRP & IL-6 (＋)ly correlated with BMI(p＜0.001); adipocectin( －)ly correlated with CRP,sE-seletin(p＜0.05). Only adiponectin signif different in DM than in control(p＝0.003)adiponectin

49、--protective for develop of DM(HRR＝0.61, p＝0.01), 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

50、 atherosclerosisInflammation may also play a possible role in diabetogenesis,DM和心血管病治療原則,◆2型糖尿病的治療觀念從單純強調(diào)控制血糖轉(zhuǎn)變?yōu)樘岢轿欢嘁蛩馗深A(yù)，嚴(yán)格糾正各種異常，包括生活方式，高血糖, 高血壓、血脂紊亂、高凝狀態(tài)等,◆據(jù)UKPDS的結(jié)果, 同時嚴(yán)控血壓對CHD的益處較單獨嚴(yán)控血糖更大，,,,,,歡 迎