糖尿病与发炎指标CRP

糖尿病与发炎指标糖尿病与发炎指标CRPCRPCRP: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.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.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/lgenerallyindicatesbacterialinfectionDemographic and Descriptive Characteristics of the Demographic and Descriptive Characteristics of the US Population Without a Previous Diagnosis ofUS Population Without a Previous Diagnosis of Hypertension From NHANES III Hypertension From NHANES IIIMatthiasB.etal.DiabetesCare2004;27:1680-1687.140 140 180 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;97:1440-45The 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-44.9-14.0-40.1-19.7Influence 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.Factors Associated with Increased or Decreased CRPHigher CRPHypertensionHyperglycemiaLow HDL/high TGSmokingObesityMetabolic syndromeEstrogen/progesterone useChronic infectionLower CRPIncrease exerciseAlcohol consumptionWeight lossMedication:StatinFibrateHypertension 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 menConcomitant 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 HgHypertension and High Cholesterol are Twice as Prevalent in Adults with DM Compared to those without DMArchives of Internal Medicine 2002;162:427-433*P0.001Hypertension and Dyslipidemia Commonly Hypertension and Dyslipidemia Commonly Occurs in Diabetes in TaiwanOccurs in Diabetes in TaiwanTADE 2002Prevalence(%)High uric acidDyslipidemiaObesityHypertension C C反应蛋白反应蛋白 (CRP)(CRP)可加强可加强 TC/HDLTC/HDL比值预估首度心比值预估首度心肌梗塞发生之风险肌梗塞发生之风险RidkorPM.Circulation1996;97:2007-11.冠冠心心病病风风险险TC/HDL 比值比值CRPC-RP(mg/L)0 1 2 3 40 1 2 3 4N=1,008代谢异常数目代谢异常数目代谢异常数目代谢异常数目代谢异常包括：代谢异常包括：代谢异常包括：代谢异常包括：肥胖肥胖高血压高血压高三酸甘油脂症高三酸甘油脂症低低HDL-C高胰岛素血症高胰岛素血症Festaetal.Circulation2000;102:42-7.C C反应蛋白反应蛋白 (CRP)(CRP)与与代谢异常数目代谢异常数目Insulin Resistance Atherosclerosis StudyInsulin Resistance Atherosclerosis Study54321P0.001Albert MA,et al.Circulation.2003;107:443 Alcohol Consumption and Plasma C-RPMany 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-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)Relationship Between Adiponectin and Glycemic Control,Blood Relationship Between Adiponectin and Glycemic Control,Blood Lipids,and Inflammatory Markers in Men With Type 2 DiabetesLipids,and Inflammatory 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)5.790.75219.120.304The correlation matrix among changes of lipid pro studied The correlation matrix among changes of lipid pro 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 Chol0.23550.37050.27841 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-0.2591-0.1355-0.02470.06200.0155Begfore 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 Changes of the Studied Risk Factors at the End of 12-week Fenofibrate Treatment (n=39)12-week Fenofibrate Treatment (n=39)Binding and Internalization of C-reactive Protein by Binding and Internalization of C-reactive Protein by Fcgamma Receptors on Human Aortic Endothelial Fcgamma Receptors on Human Aortic Endothelial Cells(HAEC)Mediates Biological Effects 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(P0.01).Preincubation with anti-CD32 and CD64 antibodies significantly inhibited maximal binding of CRP to HAECs 64%and 30%,respectively,whereas antibodies to CD16 had no effect.Internalization of CRP,as determined by loss of surface expression,was 50%.Binding and internalization of biotinylated CRP was confirmed by confocal microscopy and CRP colocalized with CD32 and CD64.Most importantly,the increase in interleukin-8,intercellular adhesion molecule 1,and vascular cell adhesion molecule-1 and the decrease in eNOS and prostacyclin induced by CRP was abrogated with antibodies to CD32 and CD64.CONCLUSIONS:We demonstrate that CRP mediates its biological effects on HAECs via binding and internalization through Fcgamma receptors,CD32 and CD64.DevarajS,etal.ArteriosclerThrombVascBiol.2005;25:1359-63