罗格列酮对2型糖尿病患者颈动脉硬化多个影响因素的干预研究
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摘要
目的：探讨影响2型糖尿病患者颈动脉硬化的多个影响因素如：LDL-C、TG、Ins、CRP、VCAM-1等，并观察罗格列酮对颈动脉硬化的治疗效果。方法：收集110例2型糖尿病患者（男60例，女50例）采用彩色多普勒超声诊断仪，10MHz高频探头检测患者双侧颈动脉，按超声检查结果分为四组：颈动脉(CAs)正常组20例（颈动脉IMT≤0.8mm）；颈动脉内膜增厚组30例（0.9mm≤IMT≤1.3mm）；稳定斑块组45例（斑块呈强回声伴或不伴声影）；不稳定斑块组15例（斑块呈略低回声，内部或周边有强回声附着）。留取患者空腹血清采用ELISA法测定Ins、PI、sVCAM-1并同时测定HbA1C、UAE、CRP及血脂系列。全部统计资料采用SPSS11.0统计软件进行方差分析。以颈动脉粥样硬化程度评分,颈动脉正常评分为0分，颈动脉内膜增厚者评分为1分，稳定斑块者评分为2分，不稳定斑块者评分为3分。以颈动脉粥样硬化评分为应变量，分别以年龄、TG、TC、 LDL-C、HDL-C、UAE、HbA1C、BMI、Ins、PI、VCAM-1、CRP为自变量做多元逐步回归分析。选取稳定斑块组及不稳定斑块组的30名患者进行药物干预，除常规治疗外加用罗格列酮4mg/d 干预治疗8周，其余30名患者采用常规治疗作为对照组。8周后复查颈动脉超声及各项血清学指标。将罗格列酮干预组的各项指标与对照组的检测指标的均数做均数的单样本t检验。
结果：四组间HbA1C、BMI、UAE、CRP、Ins、PI均无明显差异；而颈动脉内膜增厚组、稳定斑块组、不稳定斑块组的年龄、TG、TC、LDL-C及sVCAM-1明显高于颈动脉正常组，且差异有显著性，P值均＜0.01。多元回归分析结果显示患者的年龄、TG、sVCAM-1、LDL-C进入回归方程，与颈动脉粥样硬化有显著相关性。罗格列酮有效的降低了sVCAM-1、CRP及TG水平,罗格列酮可以部分的改善颈动脉硬化的程度。
结论：已有研究结果表明VCAM-1与糖尿病及其慢性并发症的发生、发展密切相关。本研究发现在2型糖尿病患者中血清sVCAM-1水平与颈动脉粥样硬化程度相关。sVCAM-1水平可能为2型糖尿病患者大血管病变的标志物,及早检测血清中sVCAM-1浓度可以预测糖尿病大血管病变的发生与发展。罗
格列酮抑制了动脉粥样硬化的炎症反应，从而有可能延缓了动脉硬化的进展和斑块破裂的进程，在糖尿病的治疗及预防其大血管并发症中有独特的优势。
Objective To discuss the multiple facters affecting carotid arterial atheroisclerosis in type 2 diabetes mellitus and observe the therapy effect of rosiglitazone.
Methods: Collected 110 cases with type 2 diabetes and examined their arterial wall thickness and local atherosclerosis in the carotid arteries (CAs) by B-mode ultrasonography of the CAs. According to the results of B-mode ultrasonography,the 110 cases were disparted for four groups：carotid arteries normal; carotid arteries incrassation; stabilization plaque and destabilization plaque. The limosis serum insulin，proinsulin，sVCAM-1，HbA1C，TC，TG，LDL-C，HDL-C，CRP and microalbuminuria were determined. The relationship between these factors and the grade of carotid arteries arteriosclerosis was analyzed. 30 cases were choosed in plaque group and these cases were therpyed by rosiglitazone for 8 weeks.
Results: insulin,proinsulin, HbA1C，BMI，CRP and microalbuminuria were not of significant difference among four groups. The level of TC,TG,LDL-C,HDL-C and sVCAM-1were lower in normal group than those in other groups. Multiple linear regression showed that the grade of carotid arteries were correlated with age，TG，LDL-C and sVCAM-1.
Conclusion：the level of sVCAM-1 was likely to be the marker of the diabetes’ complication； rosiglitazone could decrease the level of sVCAM-1 and protect the heart and vascular in diabetes patients.
结果：四组间HbA1C、BMI、UAE、CRP、Ins、PI均无明显差异；而颈动脉内膜增厚组、稳定斑块组、不稳定斑块组的年龄、TG、TC、LDL-C及sVCAM-1明显高于颈动脉正常组，且差异有显著性，P值均＜0.01。多元回归分析结果显示患者的年龄、TG、sVCAM-1、LDL-C进入回归方程，与颈动脉粥样硬化有显著相关性。罗格列酮有效的降低了sVCAM-1、CRP及TG水平,罗格列酮可以部分的改善颈动脉硬化的程度。
结论：已有研究结果表明VCAM-1与糖尿病及其慢性并发症的发生、发展密切相关。本研究发现在2型糖尿病患者中血清sVCAM-1水平与颈动脉粥样硬化程度相关。sVCAM-1水平可能为2型糖尿病患者大血管病变的标志物,及早检测血清中sVCAM-1浓度可以预测糖尿病大血管病变的发生与发展。罗
格列酮抑制了动脉粥样硬化的炎症反应，从而有可能延缓了动脉硬化的进展和斑块破裂的进程，在糖尿病的治疗及预防其大血管并发症中有独特的优势。
Objective To discuss the multiple facters affecting carotid arterial atheroisclerosis in type 2 diabetes mellitus and observe the therapy effect of rosiglitazone.
Methods: Collected 110 cases with type 2 diabetes and examined their arterial wall thickness and local atherosclerosis in the carotid arteries (CAs) by B-mode ultrasonography of the CAs. According to the results of B-mode ultrasonography,the 110 cases were disparted for four groups：carotid arteries normal; carotid arteries incrassation; stabilization plaque and destabilization plaque. The limosis serum insulin，proinsulin，sVCAM-1，HbA1C，TC，TG，LDL-C，HDL-C，CRP and microalbuminuria were determined. The relationship between these factors and the grade of carotid arteries arteriosclerosis was analyzed. 30 cases were choosed in plaque group and these cases were therpyed by rosiglitazone for 8 weeks.
Results: insulin,proinsulin, HbA1C，BMI，CRP and microalbuminuria were not of significant difference among four groups. The level of TC,TG,LDL-C,HDL-C and sVCAM-1were lower in normal group than those in other groups. Multiple linear regression showed that the grade of carotid arteries were correlated with age，TG，LDL-C and sVCAM-1.
Conclusion：the level of sVCAM-1 was likely to be the marker of the diabetes’ complication； rosiglitazone could decrease the level of sVCAM-1 and protect the heart and vascular in diabetes patients.
引文
徐成斌，防治糖尿病粥样硬化性心血管病的新观点，国外医学内分泌分册，2003，23卷3期：172-174。
Steiner G，Stewart D,Hosking JD，et al.Baseline characteristics of the study population in the Diabetes Arteriosclerosis Intervention Study(DAIS). Am J Cardiol，1999；84：1004-1010.
John R.Predictive value of carotid 2-Dimensional ultrasound. Am J Cardiol，2001，88(Suppl)：27E-30E.
Handa N， Matsumoto M，Maeda H，et al. Ischemic stroke events and carotid atherosclerosis. Stroke，1995，26(10):1781-1786.
Jacek N， Tage N， Christer S，et al.Potential of carotid ultrasonography in the diagnosis of coronary artery disease. Stroke，1998，29(2)：439-446.
梁旭，孙枫，罗林杰等，颈动脉粥样硬化程度与血小板活化的相关分析。四川大学学报（医学版）2003；34（1）：95-97。
李秀钧，2型糖尿病防治策略的革命——从降糖治疗到全面防治心血管危险因素。中华内科杂志 2002，41（4）：1-3。
Lekakis J P，Papamichael C M，Cimponeriu A T，et al.Atherosclerotic changes of coronary atherosclerosis. Am J Cardiol，2000，85(8):949-952.
John R.Predictive value of carotid 2-Dimensional ultrasound.Am J Cardiol，2001，88(suppl)：27E-30E.
ChanblessLE，HeissG，Folsom AR，et al.Association of CAD incidence with carotid arterial wall thickness and major risk factors :the Atherlsclerlsis Risk in communities (ARIC)study，1987-1993.Am J Epidemiol，1997，146(6):483-494.
Handa N，MastamotoM，MaedaH，et al.Ischemic stroke events and carotial atherosclersis.Stroke，1995，26(10):1781-1786.
Holesworth RJ，MccollumPI，BryceJC，et al.Symptoms stenosis and carotid plaque morphology.Is plaque morphology relevant? Eur J Vasc Endovase Surge，1995，9(1):80-85.
Khoury ZA，Schwartz RA，Gottlicb SH，et al.Relation of coronary artery disease to atherlsclersic disease in the acrta，carotial and femoral arteries evaluated by ultrasound.Am J Cardiol，1997，80(11):1429-1433.
SatokiH，Nobuyoshi H，HiroyukiI，et al.Carotid plaque and intima-media thickness assessed by B-mode ultrasonography in subjects ranging from young adults to centenarians.Stork，2001，32:830-835.
Crouse JR，Byington RP，Bond M，et al.Pravastatin，lipid and arteriosclerosis in the carotid artid artery(PLAC-2).Am J Cardiol，1995，75(7):455-459.
Salonen R，Nyyssonen K，Porkkala E，et al.Kupio arteriosclerosis prevention study：a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries.Circulation，2000，97(7):1758-1764.
Howar DR. Insulin resistance and lipid metabolism.Am J Cardiol，1999，84:28-32.
Karpe F，Faire L，Mercuri M，et al.Magnitude of alimentary lipemia is related to intima-media thickness of the common carotid artery in middle-aged men.Arteriosclerosis，1998，141:307-314.
Braschi S. Postprandial hyperlipidemia，small and dense LDL，HDL sub-fractions.Ann Med Intern，2001，152:162-168.
Otsuki M，Hashunoto K，Morimoto Y，et al.Circulating vascular cell adhesion molecule-1 (VCAM-1)in Atherosclerotic NIDDM paitent，Diabetes，1997，46:2096-2101.
Cybulsky MI，Iiyama K，Li H，et al.A major role for VCAM-1 but not ICAM-1，in early atherosclersis. J Clin Invest，2001，107:1255-1262.
顾秀峰，刘乃丰， 细胞黏附分子与急性冠脉综合症，中国微循环，2002，6卷3期：184-186。
Jaakkola K，Jalkanen S， Kaunismaki K，et al，Vascular adhesion protein-1，interdellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans.J Am Coll Cardiol，2000，7:13-23.
宋玮、王彬尧、王长谦 冠心病不同类型间斑块稳定性相关指标的比较研究。 中华心血管病杂志 2002，8，30（8）：480-483。
Law RE， Goetze S， Xi XP，et al，Expression and function of PPARgamma in rat and hman vascular smooth muscle cells，Circulation，2000，101:1311-1318.
Hsueh WA，Jackson S， Law RE.Control of vascular cell proliferation and migration by PPARgamma: a new approach to the macrovascular complications of diabetes.Diabetes Care 2001，24:392-397.
Uemura S，Matsushitia H，Li W，et al.Diabetes mellitus enchance vascular matrix metalloproteinase activity: role of oxidative stress.Circulation Research，2001，88:1291-1298.
Willa A，Hsueh L，Ronald E，et al. PPAR and atherlsclerosis effects on cell growth and movement， Arteriosclerosis， Thrombosis， and Vascular Biology. 2001;21:1891.
Jones NP，Mather R，Owen S， et al.Long term efficacy of rosiglitazone as monotherapy or in combination with metformin. Diabetologia 2000，43(suppl):192A .
Fuchtenbusch M，Standl E&Schatz H. Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2diabetes mellitus.Experimental and Clinical Eneocrine and Diabetes 2000，108：151-183.
Steiner G，Stewart D,Hosking JD，et al.Baseline characteristics of the study population in the Diabetes Arteriosclerosis Intervention Study(DAIS). Am J Cardiol，1999；84：1004-1010.
John R.Predictive value of carotid 2-Dimensional ultrasound. Am J Cardiol，2001，88(Suppl)：27E-30E.
Handa N， Matsumoto M，Maeda H，et al. Ischemic stroke events and carotid atherosclerosis. Stroke，1995，26(10):1781-1786.
Jacek N， Tage N， Christer S，et al.Potential of carotid ultrasonography in the diagnosis of coronary artery disease. Stroke，1998，29(2)：439-446.
梁旭，孙枫，罗林杰等，颈动脉粥样硬化程度与血小板活化的相关分析。四川大学学报（医学版）2003；34（1）：95-97。
李秀钧，2型糖尿病防治策略的革命——从降糖治疗到全面防治心血管危险因素。中华内科杂志 2002，41（4）：1-3。
Lekakis J P，Papamichael C M，Cimponeriu A T，et al.Atherosclerotic changes of coronary atherosclerosis. Am J Cardiol，2000，85(8):949-952.
John R.Predictive value of carotid 2-Dimensional ultrasound.Am J Cardiol，2001，88(suppl)：27E-30E.
ChanblessLE，HeissG，Folsom AR，et al.Association of CAD incidence with carotid arterial wall thickness and major risk factors :the Atherlsclerlsis Risk in communities (ARIC)study，1987-1993.Am J Epidemiol，1997，146(6):483-494.
Handa N，MastamotoM，MaedaH，et al.Ischemic stroke events and carotial atherosclersis.Stroke，1995，26(10):1781-1786.
Holesworth RJ，MccollumPI，BryceJC，et al.Symptoms stenosis and carotid plaque morphology.Is plaque morphology relevant? Eur J Vasc Endovase Surge，1995，9(1):80-85.
Khoury ZA，Schwartz RA，Gottlicb SH，et al.Relation of coronary artery disease to atherlsclersic disease in the acrta，carotial and femoral arteries evaluated by ultrasound.Am J Cardiol，1997，80(11):1429-1433.
SatokiH，Nobuyoshi H，HiroyukiI，et al.Carotid plaque and intima-media thickness assessed by B-mode ultrasonography in subjects ranging from young adults to centenarians.Stork，2001，32:830-835.
Crouse JR，Byington RP，Bond M，et al.Pravastatin，lipid and arteriosclerosis in the carotid artid artery(PLAC-2).Am J Cardiol，1995，75(7):455-459.
Salonen R，Nyyssonen K，Porkkala E，et al.Kupio arteriosclerosis prevention study：a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries.Circulation，2000，97(7):1758-1764.
Howar DR. Insulin resistance and lipid metabolism.Am J Cardiol，1999，84:28-32.
Karpe F，Faire L，Mercuri M，et al.Magnitude of alimentary lipemia is related to intima-media thickness of the common carotid artery in middle-aged men.Arteriosclerosis，1998，141:307-314.
Braschi S. Postprandial hyperlipidemia，small and dense LDL，HDL sub-fractions.Ann Med Intern，2001，152:162-168.
Otsuki M，Hashunoto K，Morimoto Y，et al.Circulating vascular cell adhesion molecule-1 (VCAM-1)in Atherosclerotic NIDDM paitent，Diabetes，1997，46:2096-2101.
Cybulsky MI，Iiyama K，Li H，et al.A major role for VCAM-1 but not ICAM-1，in early atherosclersis. J Clin Invest，2001，107:1255-1262.
顾秀峰，刘乃丰， 细胞黏附分子与急性冠脉综合症，中国微循环，2002，6卷3期：184-186。
Jaakkola K，Jalkanen S， Kaunismaki K，et al，Vascular adhesion protein-1，interdellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans.J Am Coll Cardiol，2000，7:13-23.
宋玮、王彬尧、王长谦 冠心病不同类型间斑块稳定性相关指标的比较研究。 中华心血管病杂志 2002，8，30（8）：480-483。
Law RE， Goetze S， Xi XP，et al，Expression and function of PPARgamma in rat and hman vascular smooth muscle cells，Circulation，2000，101:1311-1318.
Hsueh WA，Jackson S， Law RE.Control of vascular cell proliferation and migration by PPARgamma: a new approach to the macrovascular complications of diabetes.Diabetes Care 2001，24:392-397.
Uemura S，Matsushitia H，Li W，et al.Diabetes mellitus enchance vascular matrix metalloproteinase activity: role of oxidative stress.Circulation Research，2001，88:1291-1298.
Willa A，Hsueh L，Ronald E，et al. PPAR and atherlsclerosis effects on cell growth and movement， Arteriosclerosis， Thrombosis， and Vascular Biology. 2001;21:1891.
Jones NP，Mather R，Owen S， et al.Long term efficacy of rosiglitazone as monotherapy or in combination with metformin. Diabetologia 2000，43(suppl):192A .
Fuchtenbusch M，Standl E&Schatz H. Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2diabetes mellitus.Experimental and Clinical Eneocrine and Diabetes 2000，108：151-183.