糖尿病與腦血管疾病課件

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-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(fèi)用,每年約9000億美元總費(fèi)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 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 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餐后血漿葡萄糖水平與死亡的危險 (mmol/ L) 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(dú)立危險因素.DECODE Study Group . Lancet 1999; 354: 617-621 血漿葡萄糖

7、時相與動脈硬化關(guān)系比較FPG,OGTT服糖后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(jìn)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(jìn)餐計時,進(jìn)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

8、2001;24:775 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(qiáng)隨訪 IDF -WPR T2-DM 診療指南, 要求FPG 和 2h-PG 以及HbA1C都須達(dá)標(biāo) 大 動 脈內(nèi)膜: 內(nèi)皮細(xì)胞, 內(nèi)皮下間隙, 內(nèi)彈力層中膜: 平滑肌細(xì)胞(SMC), 細(xì)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(xì)胞生理功能紊亂血管平滑肌細(xì)胞功能紊亂泡沫細(xì)胞和脂條、斑塊形成代謝綜合征

9、：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)皮功能障礙和病變內(nèi)皮細(xì)胞（EC）在生理或病理時可分泌ACE， 因子，tPA, PAI-1，NO，PGI2，TXA2, ET, LPL 等 DM 時，因子、PAI-1、ET和ACE, NO，促進(jìn)血凝，內(nèi)皮損傷，進(jìn)而促進(jìn)炎癥反應(yīng)炎癥細(xì)胞因子如TNF-和MCP-1(單核細(xì)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(xì)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)，泡沫細(xì)胞在

10、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(xì)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(xì)胞和脂質(zhì)較少。NO的生理功能抑制血小板的激活血管擴(kuò)張抑制管壁炎性反應(yīng)抑制平滑肌細(xì)胞的增殖、移行 平滑肌細(xì)胞病理時（如DM），SMC在PDGF（血小板源生長因子）和TNF-，IL-1，TGF-等細(xì)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)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按應(yīng)激要求而生成如IL-6，TNF-等化學(xué)因子（chemokines）家屬如IL-8，MCP-1，2，3（monocyte chemotactic proteins）,MIP-

16、1，1（monocyte inflammatory proteins）等也可作用于mono/phagocyte生成炎癥細(xì)胞因子Inflammatory Markerscoagulation factors, PAI-1Factor , leucocytesplateletshaptoglobinC Reactive Protein(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(xì)

17、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), Adiponectin(contd) （B B Res Com 04;314:415-9）在脂細(xì)胞中ADN與TNF-或IL-6相互抑制其表達(dá)；ADN增加肌肉對FFA的氧化，肥者血ADN較瘦者低53%，減肥后ADN51%,ADN可抑制resistin介導(dǎo)的粘附分子VCAM-1、ICAM-1的表達(dá)，減少對內(nèi)皮細(xì)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，與脂聯(lián)素呈負(fù)相關(guān)血CRP可預(yù)測T2-DM發(fā)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