adropin在胰岛素抵抗及冠心病发病中的作用研究
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摘要
第一部分adropin在冠心病发病及支架内再狭窄中的作用研究
目的：探讨adropin在冠心病(CAD)发病及支架内再狭窄(ISR)发生中的作用，分析adropin与胰岛素抵抗(IR)的相关性。
材料及方法：入选338例因胸痛、胸闷首次于我院就诊并接受冠状动脉造影的患者。分为CAD组(管腔狭窄≥50％)(n=258)和对照组(管腔狭窄＜50％)(n=80)。根据冠脉病变情况，分为单支病变组(n=84)与多支病变组(n=174)。同时入选冠状动脉支架置入术后1年内复查冠脉造影的患者176例。分为ISR组(n=18)与无ISR组(n=158)。采取空腹外周静脉血，检测adropin、空腹血糖、空腹胰岛素、高敏C反应蛋白(hsCRP)、同型半胱氨酸、血脂等指标。记录高血压史、吸烟史、糖尿病史。计算胰岛素抵抗指数(IRI)。
结果：⑴CAD组患者的空腹血糖、空腹血浆胰岛素、IRI、hsCRP、同型半胱氨酸水平，以及男性、吸烟、IRI≥2.69患者比例均显著高于对照组(P<0.05～0.01)；adropin水平显著低于对照组(P<0.05)；多支病变组患者的hsCRP、空腹血浆胰岛素、IRI均明显高于单支病变组(P<0.05)，adropin在多支病变组与单支病变组虽然无统计学差异，但在多支病变组adropin浓度明显低于单支病变组，故其对多支病变仍有一定的预测价值；ISR患者的空腹血浆胰岛素、IRI、hsCRP、平均支架置入数，以及糖尿病、裸支架比例均显著高于无ISR组(P<0.05)，adropin浓度显著低于无ISR组（P<0.05）。
⑵多因素Logistic回归分析显示：男性、高龄(≥65岁)、IRI≥2.69、hsCRP≥10mg/L、adropin≤53.74pg/ml为CAD发病独立危险因素(P＜0.05)；hsCRP≥10mg/L为冠脉多支病变的独立危险因素(P＜0.05)；裸支架的应用为ISR的独立危险因素(P＜0.05)。
⑶ROC曲线分析结果提示：adropin与hsCRP预测CAD发病的价值较高，ROC曲线下面积分别为0.724和0.641(P均＜0.01)；hsCRP对冠脉多支病变有较高的预测价值，ROC曲线下面积为0.622(P＜0.05)。
⑷相关性分析提示，adropin与IR呈明显负相关(γ=-0.302，P=0.001)；adropin与hsCRP呈明显负相关(γ=-0.206， P=0.024)；adropin与同型半胱氨酸呈明显负相关(γ=-0.274，P=0.008)。
结论：低adropin水平是CAD发病、ISR发生的危险因素。adropin与IRI、hsCRP及同型半胱氨酸呈负相关。
第二部分adropin在胰岛素抵抗大鼠模型中的作用研究
目的：分析大鼠IR模型建立过程中，血浆adropin浓度的动态变化，探讨adropin在动脉粥样硬化形成中的作用。
材料和方法：4周龄清洁级SD大鼠分为，高糖高脂饮食组(n＝40)和对照组(n＝20)，于分组后1、3、5、8、12、16、20、24周经断尾血采血，分离出血浆。检测adropin、空腹血糖、空腹胰岛素、总胆固醇、甘油三酯。葡萄糖钳夹技术GIR与HOMA-IRI评估IR模型，分析adropin与IR的关系。取两组大鼠的主动脉，染色后镜下检测病理变化。分析adropin与主动脉内膜增生和血管平滑肌细胞(VSMC)增殖内迁之间的联系。
结果：①正常血糖-高血浆胰岛素钳夹技术及HOMA模型计算显示，经过16周高糖高脂喂养，大部分大鼠能建立IR模型。且二者在评估IR模型具有很好的相关性。
②高糖高脂喂养16周后大鼠的体重、空腹血糖、空腹血浆胰岛素、IRI、总胆固醇、甘油三酯、葡萄糖输注率（GIR60-120）较正常对照组明显增加(P<0.05～0.01)；血浆adropin浓度较正常对照组明显降低(P<0.01)；
③在大鼠胰岛素抵抗模型建立的过程中，血浆adropin浓度呈先升后降趋势，约在高糖高脂喂养12周左右达峰值，之后降低。adropin浓度与高胰岛素血症及胰岛素抵抗呈负相关；
④大鼠主动脉病理检测：与对照组比较，高糖高脂饮食组主动脉内膜增生明显，平滑肌细胞内迁、紊乱；
⑤组织PCR分析显示，adropin在大鼠肝脏、脑组织、主动脉内膜、主动脉中层平滑肌均有表达(202bp)，adropin在主动脉内膜与VSMC中表达为首次发现。
结论：在IR模型建立的过程中，血浆adropin浓度呈先升高后降低趋势，与IRI呈负相关。低adropin水平与主动脉内膜增生、VSMC增殖内迁有关。
PartI Implication of adropin in coronary atherosclerotic heartdisease and in stent restenosis
Objective: To explore the role of adropin in coronary atherosclerotic heart disease(CAD) and in stent restenosis (ISR), and to evaluate the relationship of adropin and insulinresistance (IR).
Materials and methods: A totle of338consecutive patients with chest pain weredivided into CAD group (stenosis≥50%)(n=258) and control group (stenosis <50%)(n=80) by coronary angiography. The CAD group were furher divided into single-vesseldisease (n=84) group and multi-vessel disease group (n=174).176cases received coronarystent implantation1year ago were divided into ISR group (n=18) and non-ISR group(n=158) by review of coronary angiography. Adropin, fasting plasma glucose, insulin,hsCRP, homocysteine levels and lipid profiles were measured, insulin resistance index (IRI)was calculated. Multivariate analysis was performed to assess risk factors for CAD,muti-vessel disease, and ISR.
Results:⑴Fasting plasma glucose, insulin, IRI, hypersensitive C reactive protein(hsCRP), homocysteine levels in CAD group were significantly higher, adropin wassignificantly lower than those in control group (P<0.05～0.01). Male, smoking, IRI≥2.69were more common in CAD group. Fasting plasma glucose, hsCRP, IRI were significantlyhigher in multi-vessel disease group than those in single-vessel diseasegroup(P<0.05).Although adropin had no significant difference between multivessel diseasegroup and single-vessel disease group, adropin still had some predictive value inmultivessel disease. Fasting plasma insulin, hsCRP, IRI, number of stent, percentage ofdiabetes and bare metal stent proportion were significantly higher in ISR group than thosein non-ISR group. But the adropin concentration was significantly lower than that in non-ISR group (P<0.05).
⑵Multivariate logistic regression analysis revealed that male, old age, hypertension,IRI≥2.69, hsCRP≥10mg/L, adropin≤53.74pg/ml were independent risk factors for CAD(P<0.05～0.01). hsCRP≥10mg/L was independent risk factor for coronary multi-vesseldisease (P<0.01);The application of bare-metal stent was independent risk factor for theISR (P <0.05).
⑶ROC curve analysis results suggest that: hsCRP and adropin could predicted CADsignificantly, and the areas under ROC curve were0.724and0.641(P<0.01). hsCRP couldpredicted multi-vessel disease, and the area under ROC curve were0.622(P<0.05)..
⑷Correlation analysis showed that adropin was negatively associated with IRI (γ=-0.302, P=0.001), hsCRP (γ=-0.206, P=0.024) and homocysteine (γ=-0.274, P=0.008).
Conclution: The lower adropin level is a risk factor for CAD and ISR. Adropin wasnegatively correlated with IRI, hsCRP and homocysteine.
PartⅡ Implication of adropin in insulin resistance
Objective: To explore the dynamic change of plasma adropin concentration with IRprocess, and to find out the function of adropin in AS.
Methods: Four weeks old SD rats were divided into high-fat diet group (n=40) andcontrol group (n=20). Blood samples were collected by cutting tail at1st,3rd,5th,8th,12th,16th,20th,24th week. Adropin, fasting plasma glucose, insulin, totle cholesterol,triglycerides were measured. The Euglycemic hyperinsulinemic clamp technique GIR andHOMA-IR were used to identify rat insulin resistance model. Taking the rat’s aorta andstained endoscopic to detect pathological changes. Analyzing the relationgship betweenadropin and aortic intimal hyperplasia and vascular smooth muscle cells (VSMC)proliferation and internal migration.
Results:
⑴Euglycemic hyperinsulinemic clamp technique and the HOMA–IR model showthat most of the rats were able to become IR model after16weeks of high sugar high fatfeeding. The2assessment methods for IR has a good correlation.
⑵After16weeks by high sugar high fat feeding, the body weight,fasting plasmaglucose, insulin, IRI, total cholesterol, triglycerides, glucose infusion rate (GIR60-120) of rats increased significantly compared with the control group (P<0.05~0.01), and theadropin concentration was significantly lower in high sugar high fat group than that innormal control group (P <0.01).
⑶With the establishment of rat IR model, the plasma adropin concentrationincreased first and then decreased, and reached the peak at about12weeks, the adropinconcentration negatively correlated with hyperinsulinemia and insulin resistance.
⑷Rat aortic pathology detection showed intima proliferate obviously with themigration and disorder of smooth muscle cell in high sugar high fat group.
⑸Organization PCR analysis showed that adropin expressed in rat livers, brain,aortic intima, aortic medial smooth muscle (VSMC)(202bp). It was the first time to findadropin expressing in aortic intima and VSMC.
Conclution: With the establishment of rat IR model, the the plasma adropinconcentration elevated first and then decreased, and had a negative correlation with the IRI.The low adropin level may be related to vascular intima hyperplasia and VSMCproliferation and migration.
目的：探讨adropin在冠心病(CAD)发病及支架内再狭窄(ISR)发生中的作用，分析adropin与胰岛素抵抗(IR)的相关性。
材料及方法：入选338例因胸痛、胸闷首次于我院就诊并接受冠状动脉造影的患者。分为CAD组(管腔狭窄≥50％)(n=258)和对照组(管腔狭窄＜50％)(n=80)。根据冠脉病变情况，分为单支病变组(n=84)与多支病变组(n=174)。同时入选冠状动脉支架置入术后1年内复查冠脉造影的患者176例。分为ISR组(n=18)与无ISR组(n=158)。采取空腹外周静脉血，检测adropin、空腹血糖、空腹胰岛素、高敏C反应蛋白(hsCRP)、同型半胱氨酸、血脂等指标。记录高血压史、吸烟史、糖尿病史。计算胰岛素抵抗指数(IRI)。
结果：⑴CAD组患者的空腹血糖、空腹血浆胰岛素、IRI、hsCRP、同型半胱氨酸水平，以及男性、吸烟、IRI≥2.69患者比例均显著高于对照组(P<0.05～0.01)；adropin水平显著低于对照组(P<0.05)；多支病变组患者的hsCRP、空腹血浆胰岛素、IRI均明显高于单支病变组(P<0.05)，adropin在多支病变组与单支病变组虽然无统计学差异，但在多支病变组adropin浓度明显低于单支病变组，故其对多支病变仍有一定的预测价值；ISR患者的空腹血浆胰岛素、IRI、hsCRP、平均支架置入数，以及糖尿病、裸支架比例均显著高于无ISR组(P<0.05)，adropin浓度显著低于无ISR组（P<0.05）。
⑵多因素Logistic回归分析显示：男性、高龄(≥65岁)、IRI≥2.69、hsCRP≥10mg/L、adropin≤53.74pg/ml为CAD发病独立危险因素(P＜0.05)；hsCRP≥10mg/L为冠脉多支病变的独立危险因素(P＜0.05)；裸支架的应用为ISR的独立危险因素(P＜0.05)。
⑶ROC曲线分析结果提示：adropin与hsCRP预测CAD发病的价值较高，ROC曲线下面积分别为0.724和0.641(P均＜0.01)；hsCRP对冠脉多支病变有较高的预测价值，ROC曲线下面积为0.622(P＜0.05)。
⑷相关性分析提示，adropin与IR呈明显负相关(γ=-0.302，P=0.001)；adropin与hsCRP呈明显负相关(γ=-0.206， P=0.024)；adropin与同型半胱氨酸呈明显负相关(γ=-0.274，P=0.008)。
结论：低adropin水平是CAD发病、ISR发生的危险因素。adropin与IRI、hsCRP及同型半胱氨酸呈负相关。
第二部分adropin在胰岛素抵抗大鼠模型中的作用研究
目的：分析大鼠IR模型建立过程中，血浆adropin浓度的动态变化，探讨adropin在动脉粥样硬化形成中的作用。
材料和方法：4周龄清洁级SD大鼠分为，高糖高脂饮食组(n＝40)和对照组(n＝20)，于分组后1、3、5、8、12、16、20、24周经断尾血采血，分离出血浆。检测adropin、空腹血糖、空腹胰岛素、总胆固醇、甘油三酯。葡萄糖钳夹技术GIR与HOMA-IRI评估IR模型，分析adropin与IR的关系。取两组大鼠的主动脉，染色后镜下检测病理变化。分析adropin与主动脉内膜增生和血管平滑肌细胞(VSMC)增殖内迁之间的联系。
结果：①正常血糖-高血浆胰岛素钳夹技术及HOMA模型计算显示，经过16周高糖高脂喂养，大部分大鼠能建立IR模型。且二者在评估IR模型具有很好的相关性。
②高糖高脂喂养16周后大鼠的体重、空腹血糖、空腹血浆胰岛素、IRI、总胆固醇、甘油三酯、葡萄糖输注率（GIR60-120）较正常对照组明显增加(P<0.05～0.01)；血浆adropin浓度较正常对照组明显降低(P<0.01)；
③在大鼠胰岛素抵抗模型建立的过程中，血浆adropin浓度呈先升后降趋势，约在高糖高脂喂养12周左右达峰值，之后降低。adropin浓度与高胰岛素血症及胰岛素抵抗呈负相关；
④大鼠主动脉病理检测：与对照组比较，高糖高脂饮食组主动脉内膜增生明显，平滑肌细胞内迁、紊乱；
⑤组织PCR分析显示，adropin在大鼠肝脏、脑组织、主动脉内膜、主动脉中层平滑肌均有表达(202bp)，adropin在主动脉内膜与VSMC中表达为首次发现。
结论：在IR模型建立的过程中，血浆adropin浓度呈先升高后降低趋势，与IRI呈负相关。低adropin水平与主动脉内膜增生、VSMC增殖内迁有关。
PartI Implication of adropin in coronary atherosclerotic heartdisease and in stent restenosis
Objective: To explore the role of adropin in coronary atherosclerotic heart disease(CAD) and in stent restenosis (ISR), and to evaluate the relationship of adropin and insulinresistance (IR).
Materials and methods: A totle of338consecutive patients with chest pain weredivided into CAD group (stenosis≥50%)(n=258) and control group (stenosis <50%)(n=80) by coronary angiography. The CAD group were furher divided into single-vesseldisease (n=84) group and multi-vessel disease group (n=174).176cases received coronarystent implantation1year ago were divided into ISR group (n=18) and non-ISR group(n=158) by review of coronary angiography. Adropin, fasting plasma glucose, insulin,hsCRP, homocysteine levels and lipid profiles were measured, insulin resistance index (IRI)was calculated. Multivariate analysis was performed to assess risk factors for CAD,muti-vessel disease, and ISR.
Results:⑴Fasting plasma glucose, insulin, IRI, hypersensitive C reactive protein(hsCRP), homocysteine levels in CAD group were significantly higher, adropin wassignificantly lower than those in control group (P<0.05～0.01). Male, smoking, IRI≥2.69were more common in CAD group. Fasting plasma glucose, hsCRP, IRI were significantlyhigher in multi-vessel disease group than those in single-vessel diseasegroup(P<0.05).Although adropin had no significant difference between multivessel diseasegroup and single-vessel disease group, adropin still had some predictive value inmultivessel disease. Fasting plasma insulin, hsCRP, IRI, number of stent, percentage ofdiabetes and bare metal stent proportion were significantly higher in ISR group than thosein non-ISR group. But the adropin concentration was significantly lower than that in non-ISR group (P<0.05).
⑵Multivariate logistic regression analysis revealed that male, old age, hypertension,IRI≥2.69, hsCRP≥10mg/L, adropin≤53.74pg/ml were independent risk factors for CAD(P<0.05～0.01). hsCRP≥10mg/L was independent risk factor for coronary multi-vesseldisease (P<0.01);The application of bare-metal stent was independent risk factor for theISR (P <0.05).
⑶ROC curve analysis results suggest that: hsCRP and adropin could predicted CADsignificantly, and the areas under ROC curve were0.724and0.641(P<0.01). hsCRP couldpredicted multi-vessel disease, and the area under ROC curve were0.622(P<0.05)..
⑷Correlation analysis showed that adropin was negatively associated with IRI (γ=-0.302, P=0.001), hsCRP (γ=-0.206, P=0.024) and homocysteine (γ=-0.274, P=0.008).
Conclution: The lower adropin level is a risk factor for CAD and ISR. Adropin wasnegatively correlated with IRI, hsCRP and homocysteine.
PartⅡ Implication of adropin in insulin resistance
Objective: To explore the dynamic change of plasma adropin concentration with IRprocess, and to find out the function of adropin in AS.
Methods: Four weeks old SD rats were divided into high-fat diet group (n=40) andcontrol group (n=20). Blood samples were collected by cutting tail at1st,3rd,5th,8th,12th,16th,20th,24th week. Adropin, fasting plasma glucose, insulin, totle cholesterol,triglycerides were measured. The Euglycemic hyperinsulinemic clamp technique GIR andHOMA-IR were used to identify rat insulin resistance model. Taking the rat’s aorta andstained endoscopic to detect pathological changes. Analyzing the relationgship betweenadropin and aortic intimal hyperplasia and vascular smooth muscle cells (VSMC)proliferation and internal migration.
Results:
⑴Euglycemic hyperinsulinemic clamp technique and the HOMA–IR model showthat most of the rats were able to become IR model after16weeks of high sugar high fatfeeding. The2assessment methods for IR has a good correlation.
⑵After16weeks by high sugar high fat feeding, the body weight,fasting plasmaglucose, insulin, IRI, total cholesterol, triglycerides, glucose infusion rate (GIR60-120) of rats increased significantly compared with the control group (P<0.05~0.01), and theadropin concentration was significantly lower in high sugar high fat group than that innormal control group (P <0.01).
⑶With the establishment of rat IR model, the plasma adropin concentrationincreased first and then decreased, and reached the peak at about12weeks, the adropinconcentration negatively correlated with hyperinsulinemia and insulin resistance.
⑷Rat aortic pathology detection showed intima proliferate obviously with themigration and disorder of smooth muscle cell in high sugar high fat group.
⑸Organization PCR analysis showed that adropin expressed in rat livers, brain,aortic intima, aortic medial smooth muscle (VSMC)(202bp). It was the first time to findadropin expressing in aortic intima and VSMC.
Conclution: With the establishment of rat IR model, the the plasma adropinconcentration elevated first and then decreased, and had a negative correlation with the IRI.The low adropin level may be related to vascular intima hyperplasia and VSMCproliferation and migration.
引文
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