学术讨论—糖尿病与发炎指标CRP..ppt

糖尿病與發炎指標糖尿病與發炎指標CRP吳達仁 醫師成大醫學院附設醫院內科部內分泌(fnm)新陳代謝科第一页，共二十六页。CRP:From Acute Phase Protein to Cardiovascular disease CRP is a symmetrical ring molecule that consists of 5 noncovalent but associate protomers.Each protomer has 2 calcium ions responsible for the specific binding of phosphochlorine.Phosphochlorine is a common constituent of many bacterial and fungal polysaccharides and most biologic cell membranes,such as the phosphochlorine residues of C(or capsular)-polysaccharide of Streptococcus pneumoniae.The protein was named“C-reactive”because of this reaction.A stable pentameric protein-compound with a half-life of 19 hours,without diurnal variation,CRP is a pathogenic marker and a nonspecific marker of inflammation.CRP is synthesized in response to the acute phase of a bacterial or fungal infection.第二页，共二十六页。Molecular Structure and Morphology of Human CRP(a)Negatively stained electron micrograph showing the typical pentameric disc-like structure face-on and side-on(arrows).(b)Ribbon diagram of the crystal structure,showing the lectin fold and the two calcium atoms(spheres)in the ligand-binding site of each protomer.(c)Space-filling model of the CRP molecule,showing a single phosphocholine molecule located in the ligand-binding site of each protomer).PepysMB,etal.ClinInvest2003;111:1805-1812.第三页，共二十六页。Assays of CRP and Reference RangesDuringtheacutephaseofinfection,serumCRPlevelsweremeasuredbyratenephelometry(“serumCRPassay”).Theseassayshavealowerlimitofdetectionofonly6to10mg/l.Amoresensitivelatexparticle-enhancedimmunoturbidimetricassay(“highsensitivityhs-CRPassay”)hasbeendevelopedthathasalowerlimitofdetection(orsensitivity)ofabout0.15mg/l.Itisusedtoassessforcardiovascularrisk.Theriskfactorsbyhs-CRPlevels(CDC,AHA):CRP1mg/lislowCVDriskCRP1to3mg/lismoderateCVDriskCRP3to10mg/lishighCVDriskCRPlevels10mg/lgenerallyindicatesbacterialinfection第四页，共二十六页。Demographic and Descriptive Characteristics of the US Population Without a Previous Diagnosis of Hypertension From NHANES III Hypertension From NHANES IIIMatthiasB.etal.DiabetesCare2004;27:1680-1687.第五页，共二十六页。140 140 180 180mg/dLWOSCOPS:Overlap AnalysisFrequency per 100Frequency per 100On treatment LDLOn treatment LDL n Events1120 1081071 67PlaceboPravastatinRR on Pravastatin =0.65Log rank p=0.002Adjust for on-treatment LDL,HDL,VLDL,TG&baseline covariates.RR on Pravastatin=0.64,p=0.0147777155155116116194194232232mg/dLmg/dLWOSCOPS Group.Circulation.1998;97:1440-45第六页，共二十六页。第七页，共二十六页。The Effects of Atorvastatin versus Simvastatin on Atherosclerosis Progression Study(ASAP)Atorvastatin reduced CRP levels to a greater extent than simvastatinvan Wissen S,et al.Atherosclerosis.2002;165:361-366.*P0.001 for difference between groups;*P=0.02 for difference between groups*-50-45-40-35-30-25-20-15-10-501 Year2 YearsAtorvastatinSimvastatinPercent change in hs-CRP-44.9-14.0-40.1-19.7第八页，共二十六页。Influence of Baseline BMI on Ability of Atorvastatin to Modify CV Risk Factors(REVERSAL Study)P0.01P0.01P30)Thrombogenic/hemostatic stateAtherogenic dietNon-modifiableAgeMale sexFamily history of premature CHDNational Cholesterol Education Program Adult Treatment Panel III.2002.NIH Publication No.02-5215.第十一页，共二十六页。Factors Associated with Increased or Decreased CRPHigher CRPHypertensionHyperglycemiaLow HDL/high TGSmokingObesityMetabolic syndromeEstrogen/progesterone useChronic infectionLower CRPIncrease exerciseAlcohol consumptionWeight lossMedication:StatinFibrate第十二页，共二十六页。Hypertension and Dyslipidaemia Are Major Risk Factors for CHDKannel W.In:Hypertension:Pathophysiology and Treatment.New York:McGraw-Hill,Inc.;1977:888-909;Castelli WP.Am J Med.1984;76:4-12.CHD incidence/1000Probability of CVD/1000Age40506070Framingham studySBP(mm Hg)in menTC(mg/dL)in men第十三页，共二十六页。Concomitant Hypertension and Dyslipidemia Increase the Risk of Developing Fatal CVDAdapted from De Backer G et al.Eur J Cardiovasc Prev Rehabil.2003;10(suppl 1):S1-S78.DyslipidemiaHypertensionDyslipidemia/HypertensionTC 271 mg/dL(7 mmol/L)SBP 180 mm HgTC 271 mg/dL(7 mmol/L)SBP 180 mm Hg第十四页，共二十六页。Hypertension and High Cholesterol are Twice as Prevalent in Adults with DM Compared to those without DMArchives of Internal Medicine 2002;162:427-433*P0.001第十五页，共二十六页。Hypertension and Dyslipidemia Commonly Occurs Hypertension and Dyslipidemia Commonly Occurs in Diabetes in Taiwanin Diabetes in TaiwanTADE 2002Prevalence(%)High uric acidDyslipidemiaObesityHypertension 第十六页，共二十六页。C反應蛋白反應蛋白(dnbi)(dnbi)(CRP)可加強可加強 TC/HDL比值預估首度心比值預估首度心肌梗塞發生之風險肌梗塞發生之風險RidkorPM.Circulation1996;97:2007-11.冠冠心心病病風風險險TC/HDL 比值比值(bzh)CRP第十七页，共二十六页。C-RP(mg/L)0 1 2 3 40 1 2 3 4N=1,008代謝異常數目代謝異常數目代謝異常數目代謝異常數目代謝異常包括：代謝異常包括：代謝異常包括：代謝異常包括：肥胖肥胖(fipng)高血壓高血壓高三酸甘油脂症高三酸甘油脂症低低HDL-C高胰島素血症高胰島素血症Festaetal.Circulation2000;102:42-7.C反應蛋白反應蛋白(dnbi)(dnbi)(CRP)與與代謝異常數目代謝異常數目Insulin Resistance Atherosclerosis StudyInsulin Resistance Atherosclerosis Study54321P0.001第十八页，共二十六页。Albert MA,et al.Circulation.2003;107:443 Alcohol Consumption and Plasma C-RP第十九页，共二十六页。Many Assays Developed Before hs-CRP Are More Sensitive Than“hs-CRP Assay”As early as 1981,a solid-phase single-antibody competitive radioimmunoassay with a single rabbit anti-CRP antibody directly immobilized onto a magnetic particle had a sensitivity of 0.05 mg/l.With use of a double-antibody competitive radioimmunoassay,the sensitivity was increased further to 0.003 mg/l.An in-house ELISA CRP assay developed in 1997 has a sensitivity of 0.007 mg/l and was used in 1999 to evaluate the hs-CRP test for clinical use.In 2000,an immunoradiometric assay(IRMA)was developed with polyclonal antibodies of CRP immobilized on microtiter plates and monoclonal antibodies of CRP labeled with 125I.IRMA had a sensitivity of 0.05 mg/l 第二十页，共二十六页。-36.4*Atorvastatin-5.2PravastatinChange in CRP levels from baseline Change(%)*P0.001 vs pravastatin-40-30-20-1001.82.918 Months2.83.0BaselineAtorvastatinPravastatinCRP(mg/L)第二十一页，共二十六页。Relationship Between Adiponectin and Glycemic Control,Blood Lipids,and Relationship Between Adiponectin and Glycemic Control,Blood Lipids,and Inflammatory Markers in Men With Type 2 DiabetesInflammatory Markers in Men With Type 2 DiabetesMatthiasB.etal.DiabetesCare2004;27:1680-1687.BiomarkerAge adjustedMultivariate adjusted*EstimatePEstimatePHbA1c(%)-0.160.009-0.210.001Total cholesterol(mmol/l)0.050.2910.080.090Triglycerides(mmol/l)-0.450.001-0.390.001HDL cholesterol(mmol/l)0.160.0010.130.001LDL cholesterol(mmol/l)0.080.0540.100.020apoB100(g/l)-0.060.001-0.040.001CRP(mg/l)-0.970.001-0.510.003Fibrinogen(mol/l)-0.870.001-0.530.001sTNFR2(pg/ml)52.820.26289.770.071sICAM-1(ng/ml)-7.810.032-7.560.049sVCAM-1(ng/ml)5.790.75219.120.304第二十二页，共二十六页。The correlation matrix among changes of lipid profile and studied The correlation matrix among changes of lipid profile and studied cardiovascular risk factors at the end of 12-week fenofibrate cardiovascular risk factors at the end of 12-week fenofibrate treatmenttreatment (n=39)(n=39)Correlation hs-CRP ESR Fibrinogen Chol TG hs-CRP1 ESR0.7470#1 Fibrinogen0.5449*0.8138#1 Chol0.23550.3705 0.27841 TG-0.0054-0.0077-0.13120.17541 HDL-c0.01000.2480 0.17910.0560-0.3732 Uric acid-0.0107-0.1335-0.1568-0.2308-0.1788 Creatinine-0.2591-0.1355-0.02470.06200.0155第二十三页，共二十六页。Begfore TXBegfore TXAfter TxAfter TxP valueFibrinogen(mg/dl)421 152(403 103)344 81(337 72)P0.001ESR(mm/h)19.1 24.8(16.2 17.0)9.7 8.7(9.4 8.4)P0.01CRP(mg/L)3.3 3.3(3.0 2.6)2.1 1.8(2.0 1.8)P0.01Hb(g/dl)14.0 1.613.9 1.5NSProinsulin(pmol/L)45 1644 15NSWBC(x 103)7.5 1.97.1 1.7NSChanges of the Studied Risk Factors at the End of 12-week Changes of the Studied Risk Factors at the End of 12-week Fenofibrate Treatment (n=39)Fenofibrate Treatment (n=39)第二十四页，共二十六页。Binding and Internalization of C-reactive Protein by Fcgamma Receptors on Human Aortic Endothelial Cells(HAEC)Mediates Biological Effects Several reports showed that CRP binds to Fcgamma receptors on leukocytes.CRP(100 microg/mL)significantly upregulated surface expression of Fcgamma receptors,CD32,as well as CD64 on HAECs(P30)。10(suppl 1):S1-S78.。C反應蛋白(dnbi)(CRP)可加強 TC/HDL比值預估首度心肌梗塞發生之風險。*P0.001 vs pravastatin。HDL cholesterol(mmol/l)。LDL cholesterol(mmol/l)。25:1359-63第二十六页，共二十六页。