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1、糖尿病與發炎指標糖尿病與發炎指標CRPCRP吳達仁 醫師成大醫學院附設醫院內科部內分泌新陳代謝科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. Phosphochlorin
2、e 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-compou
3、nd 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 microgr
4、aph 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 phos
5、phocholine 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.Amor
6、esensitivelatexparticle-enhancedimmunoturbidimetricassay(“highsensitivityhs-CRPassay”)hasbeendevelopedthathasalowerlimitofdetection(orsensitivity)ofabout0.15mg/l.Itisusedtoassessforcardiovascularrisk.Theriskfactorsbyhs-CRPlevels(CDC,AHA):CRP1mg/lislowCVDriskCRP1to3mg/lismoderateCVDriskCRP3to10mg/lis
7、highCVDriskCRPlevels10mg/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 Fro
8、m 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 & base
9、line 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 Wisse
10、n 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
11、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 CRPHigh
12、er CRPHypertensionHyperglycemiaLow HDL/ high TGSmokingObesityMetabolic syndromeEstrogen/progesterone useChronic infectionLower CRPIncrease exerciseAlcohol consumptionWeight lossMedication:StatinFibrateHypertension and Dyslipidaemia Are Major Risk Factors for CHDKannel W. In: Hypertension: Pathophysi
13、ology 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
14、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 DMA
15、rchives 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反應蛋白反應蛋白 (CRP) (CRP)可加強可加強 TC/HDL TC/HD
16、L比比值值預估首度預估首度心肌梗塞發生之風險心肌梗塞發生之風險RidkorPM.Circulation1996;97:2007-11.冠冠心心病病風風險險TC/HDL 比比值值CRPC-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 C反應蛋白反應蛋白 (CRP) (CRP)與與代謝異常數目代謝異常數目Insuli
17、n 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 ra
18、dioimmunoassay 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 sensi
19、tivity 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 -
20、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 Lipi
21、ds, 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)0.050.2910.080.090Trigl
22、ycerides (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 (
23、ng/ml)5.790.75219.120.304The correlation matrix among changes of lipid profile and The correlation matrix among changes of lipid profile and studied cardiovascular risk factors at the end of 12-week studied cardiovascular risk factors at the end of 12-week fenofibrate treatmentfenofibrate treatment
24、(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 TXBegfo
25、re 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 F
26、actors 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 Fcg
27、amma 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
28、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 internaliza
29、tion 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
