血糖相关因素对血管内皮功能的影响及川芎嗪的干预研究
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摘要
心血管疾病(cardiovascular disease，CVD)的发生(尤其是加速发展的动脉粥样硬化)是糖尿病患者高致残率和死亡率的主要原因，血管内皮细胞功能异常是糖尿病心血管并发症发生发展的重要病理生理基础。波动性高血糖比持续性高血糖更能促进糖尿病患者慢性血管并发症的发生与发展，成为糖尿病血管并发症防治领域的研究热点之一。开展糖尿病患者血糖波动的评价分析，研究波动性高血糖对血管内皮功能的影响，并揭示其作用机制，对糖尿病及其并发症的防治具有重要意义。
本课题研究分为三部分：文献综述，临床研究和基础研究。
1文献综述：
1．1综述一：糖尿病从关注糖化血红蛋白到着眼心血管事件防治的策略转变本文通过对2型糖尿病心血管终点事件的观察，更多的临床证据表明，糖尿病的治疗目标应该以减少心血管事件为主。提出糖尿病防治从策略上发生了两个转变，即以血糖为中心转向以防治心血管事件为中心的多危险因素综合防治策略；以糖化血红蛋白检测作为血糖评价的金标准转向以血糖量、质、时程控制的全面评价策略。
1．2综述二：波动性高血糖与心血管并发症关系
本文概述2型糖尿病是冠心病的等危症，内皮功能异常是糖尿病心血管并发症发生发展的重要病理生理基础。除高血糖可导致内皮功能损伤外，波动性高血糖具有更为明显的作用，包括促进内皮细胞凋亡，诱导氧化应激，增加细胞间黏附分子合成等。对血糖波动的正确认识、评价和治疗对糖尿病合并心血管并发症的研究具有重要意义。
2临床研究：
2．1 2型糖尿病患者血糖评价参数及相关性分析
目的：探讨2型糖尿病(T2DM)患者血糖评价参数及相关性分析。方法：选取T2DM患者25例，进行七点法指端毛细血管血糖测定(三餐前(早餐前(空腹)、午餐前、晚餐前)，三餐后两小时及睡前9点)，计算血糖参数：平均血糖水平(MBG)，最大血糖波动幅度(LAGE)，血糖标准差(SDBG)，平均血糖波动幅度(MAGE)；采用离子交换高压液相法检测糖化血红蛋白(HbA_(1c))，并进行其他一般性指标检测。分析HbA_(1c)及其它血糖评价参数之间的关系，HbA_(1c)及MAGE与其它指标的关系。结果：采用单因素回归分析，HbA_(1c)与FBG、MBG、LAGE、MAGE具有相关性(P＜0．01或0．05)，与SDBG相关无统计学意义(P＞0．05)；MAGE与LAGE、SDBG、HbA_(1c)、MBG具有相关性(P＜0．01或0．05)，与FBG相关无统计学意义(P＞0．05)。多元逐步回归分析表明，HbA_(1c)和MBG具有“最优”线性关系，复相关系数R=0．707，P=0．000；MAGE和LAGE具有“最优”线性关系，R=0．953，P=0．000。应用单因素回归分析，HBA_(1c)及MAGE均与血清总胆红素(TBIL)负相关，相关系数分别为-0．520(P=0．004)和-0．373(P=0．033)。结论：不同的血糖评价参数具有对血糖反应的不同侧面，HBA_(1c)与MBG关系密切，MAGE与LAGE具有较好线性关系，对糖尿病患者应该进行包括长期血糖控制指标和血糖波动性指标的全面血糖评价。
2．2 2型糖尿病患者血管内皮功能与血糖评价相关性分析
目的：探讨T2DM患者内皮依赖的血管舒张功能与血糖评价参数的相关性分析。方法：选取T2DM患者25例，予肱动脉内皮依赖性舒张功能(EDF)超声检测，同时进行七点法指端毛细血管血糖测定，计算血糖参数：MBG，LAGE，SDBG，MAGE；采用离子交换高压液相法检测HHbA_(1c)，并进行其他一般性指标检测。分析内皮依赖的血管舒张功能与血糖评价参数的相关性，及与其它一般性指标的相关性。结果：EDF与HbA_(1c)、FBG、MBG无明显相关性(P＞0．05)；与LAGE、SDBG、MAGE具相关性(P均＜0．05)。EDF并与血清尿酸水平有相关性，相关系数为-0．355(P=0．041)。结论：内皮依赖性舒张功能与血糖波动参数明显负相关，血糖波动可能加剧内皮功能损害。糖尿病心血管防治除重视高血糖外，也应关注血糖波动对血管的损害。
3基础研究：波动性高糖对人脐静脉内皮细胞的影响及川芎嗪的干预研究
目的：观察稳定性性高糖、波动性高糖对人脐静脉内皮细胞(HUVEC)的影响以及川芎嗪的干预作用，探讨不同葡萄糖状态下对内皮损伤的机制及川芎嗪的保护作用。方法：以体外培养人脐静脉内皮细胞为研究对象，予不同条件葡萄糖浓度分3组培养：稳定性正常浓度葡萄糖组(葡萄糖：5．56 mmol／L)(正常低糖)；稳定性高浓度葡萄糖组(葡萄糖：25mmol／L)(稳定高糖)；波动性高浓度葡萄糖组(间替高糖／低糖，每24 h换液)(波动高糖)。并进行不同剂量组川芎嗪干预(高剂量组：500μmol／L，中剂量组：100μmol／L，低剂量组：20μmol／L)。细胞培养8天，进行细胞活性检测，取细胞培养上清液检测NO、ET-1、TNF-α、sICAM-1含量，细胞裂解液检测胞内NOS、SOD、MDA水平。结果：与正常低糖组相比，稳定高糖组和波动高糖组HUVEC SOD，NOS，NO生成减少(P＜0．01)，MDA，ET-1，TNF-α、sICAM-1合成增多(P＜0．01)；与稳定高糖组比较，波动高糖组SOD，NOS，NO减少更明显(P＜0．01或0．05)；MDA，ET-1，sICAM-1升高更明显(P＜0．01)；高、中剂量川芎嗪干预能够部分逆转稳定高糖、波动高糖所诱导的HUVEC SOD，NOS，NO的生成减少及MDA，ET-1，TNF-α、sICAM-1的合成增多(P＜0．01或0．05)。结论：高浓度葡萄糖能够通过增加氧化应激，炎症激活，细胞间粘附分子合成等介导内皮细胞损伤，波动性高糖则加剧这一损害；川芎嗪可部分逆转高糖对内皮细胞的影响。
Cardiovascular disease(CVD),especially accelerating the development ofatherosclerosis,is a major cause of the high disability rate and mortality in type 2diabetes mellitus(T2DM).Vascular endothelial injury plays a critical role in theoccurrence and development of diabetic cardiovascular complications disease.Theoscillating glucose can have more deleterious influences than constant high glucoseon endothelial function and diabetes chronic cardiovascular complications.The studyon glucose variability has recently become a research focus in the field of diabeticcardiovascular disease.It has an important significance to study the evaluation ofglucose variability and the effect of glucose fluctuation on endothelial dysfunction inthe control of diabetic cardiovascular disease.To investigate its mechanism and theintervention measures should be studied further.
This study is divided into three parts:review,clinical study and experimentalresearch.
1 Review
1.1 Review 1:The changes of strategy in diabetes from focusing on glycosylatedhemoglobin to avoiding cardiovascular events.
Several recent trials have led to contradictory outcomes in relation to the issue ofglycemic control and cardiovascular complications in patients with type 2 diabetes.The major target of diabetes treatment is to reduce cardiovascular events.Only relyingon the glycosylated hemoglobin as the“gold standard”of the maintenance of tightglycaemic control should be changed.A multi-pronged approach to address the totalcardiovascular risk factors is imperative.The best practice model for glycemic goalsshould include the quantity,quality and time course of glycemic exposure.
1.2 Review 2:Fluctuating high glucose and cardiovascular complications indiabetes mellitus.
Type 2 diabetes as a“coronary heart disease equivalent”,endothelial dysfunctionplays an important role in the pathogenesis of diabetic cardiovascular complications. High glucose fluctuation induces endothelial dysfunction more obviously thanuncontrolled hyperglycemia.The main mechanisms include inducing endothelial cellapoptosis,improving oxidative stress and increasing the endothelial adhesionmolecules,etc.How to exactly recognize,evaluate and treat fluctuating high glucosemaybe possesses significance in the study of diabetic cardiovascular complications.
2 Clinical study
2.1 Study on the evaluation parameters of blood glucose and the correlationbetween them in type 2 diabetes patients.
Objective:To study the evaluation parameters of blood glucose and thecorrelation between them in type 2 diabetes patients.Methods:25 diagnosed type 2diabetic patients with stable glucose-lowering treatment were enrolled.Seven point(preprandial and 120-min postprandial for each meal and bedtime)capillary glucosewas measured with an ultrasmart glucose meter(Bayer).The following indices ofglycemic variability were calculated from 7-point-daily capillary glucose profiles:mean blood glucose(MBG),large amplitude of glycemic excursions(LAGE),SD ofblood glucose(SDBG),mean amplitude of glycemic excursions(MAGE).HbA_(1c)wasmeasured by ion-exchange high-performance liquid chromatography.The generalindexes were measured.Then statistics test and correlation regression analysis werepreceded.Results:In simple correlation analysis,HBA_(1c)and FBG、MBG、LAGE、MAGE had obvious correlations(P＜0.01 or 0.05),MAGE and LAGE、SDBG、HbA_(1c)、MBG had obvious correlations(P＜0.01 or 0.05).In multivariate analysis,theprimary predictor of HBA_(1c)was MBG(R=0.707,P=0.000);the primary predictor ofMAGE was LAGE(R=0.953,P=0.000).All other glucose variables added nothing tothe models.HbA_(1c),MAGE and the level of serum total bilirubin had obvious negativecorrelations,with the Pearson correlation coefficient of-0.520(P=0.004)and-0.373(P=0.033)respectively by linear correlation and regression analysis.Conclusions:The different evaluation parameters of blood glucose might reflect the glucose profilefrom different aspects.HBA_(1c)correlates best with MBG and MAGE correlates bestwith LAGE derived from 7-point-daily capillary glucose profiles.The wholeevaluation of blood glucose in diabetes should include both long-term glucose control index and glucose variables.
2.2 Relationship between endothelium-dependent vasodilatation and theevaluation parameters of blood glucose in type 2 diabetic patients.
Objective:To study the correlation of the endothelium-dependent flow-mediateddilation(EDF)and the evaluation parameters of blood glucose in type 2 diabetespatients.Methods:25 diagnosed type 2 diabetic patients were enrolled.Endothelialfunction was evaluated by flow-mediated dilation measured by ultrasound.Sevenpoint capillary glucose was simultaneously measured and the following indices ofglycemic variability were calculated from 7-point-daily capillary glucose profiles:MBG,LAGE,SDBG,MAGE.HbA_(1c)was measured by ion-exchange high-performance liquid chromatography.The general indexes were measured.Thenstatistics test and correlation regression analysis were preceded.Results:EDF andHbA_(1c),FBG,MBG showed no significant correlation(P＞0.05).There was significantnegative correlation between EDF and MAGE,LAGE,SDBG(P＜0.05).EDF wasinverse correlation(r=-0.355,P=0.041)with the level of serum uric acid.Conclusions:The correlation of EDF and the glucose variables,including MAGE,LAGE,SDBG,suggests that glucose fluctuations might aggravate vascular endothelialdysfunction.The control of cardiovascular events in diabetes should pay attention tovascular injury which induced not only hyperglycemia but also blood glucosefluctuation.
3 Experimental research:Effects of tetramethylpyrazine on human umbilicalvein endothelial cells exposed to constant or intermittent high glucose in vitro.
Objective:To explore the effects of constant or intermittent high glucose onhuman umbilical vein endothelial cells(HUVEC),and the effects oftetramethylpyrazine on HUVEC by constant or intermittent high glucose levels.Methods:HUVEC were incubated for 8 days in media containing different glucoseconcentrations:5.56 mmol/1(normal glucose),25 mmol/1(constant high glucose),or adaily alternating 5.56 or 25 mmol/1 glucose(intermittent high glucose).and exposedfor 8 days to conditions of constant or intermittent high glucose levels withtetramethylpyrazine at concentrations of 500μmol/L,100μmol/L and 20μmol/L.Cell viability was measured by MTT method and cell membrane damage was determinedby lactate dehydrogenase(LDH)leakage,Nitric oxide(NO),endothelin-l(ET-1),soluble intercellular adhesion molecule-1(sICAM-1)and tumor necrosis factor-α(TNF-α)concentrations in the cell culture supernatant were measured.The activitiesof superoxide dismutase(SOD),nitric oxide synthetase(NOS)and the contents ofmalondialdehyde(MDA)in the cell lysate were examined by enzyme method orspectrophotometry.Results:The HUVEC viability and LDH leakage were nosignificance difference in different glucose culture conditions with or withouttetramethylpyrazine.Compared with normal glucose group,the activities ofSOD,NOS and the contents of NO were remarkably decreased while the contents ofMDA,ET-1,TNF-αand sICAM-1 were significantly increased in constant highglucose and intermittent high glucose groups(P＜0.01).More interestingly,thechanges of all the detection indexes(except TNF-α)in intermittent high glucosegroups were greater than that in constant high glucose group(P＜0.05 or P＜0.01).500μmol/L,100μmol/L tetramethylpyrazine could partially reverse the changes ofconstant or intermittent high glucose on HUVEC(P＜0.05 or P＜0.01).Conclusions:Both intermittent and constant high glucose can chang the function of endothelialcells.Furthermore,intermittent high glucose can have more deleterious effects thanconstant high glucose on endothelial function,which may be related to oxidativestress,inflammatory reaction and cell adhesion molecule.Tetramethylpyrazine canpartially reverse this impairment.
本课题研究分为三部分：文献综述，临床研究和基础研究。
1文献综述：
1．1综述一：糖尿病从关注糖化血红蛋白到着眼心血管事件防治的策略转变本文通过对2型糖尿病心血管终点事件的观察，更多的临床证据表明，糖尿病的治疗目标应该以减少心血管事件为主。提出糖尿病防治从策略上发生了两个转变，即以血糖为中心转向以防治心血管事件为中心的多危险因素综合防治策略；以糖化血红蛋白检测作为血糖评价的金标准转向以血糖量、质、时程控制的全面评价策略。
1．2综述二：波动性高血糖与心血管并发症关系
本文概述2型糖尿病是冠心病的等危症，内皮功能异常是糖尿病心血管并发症发生发展的重要病理生理基础。除高血糖可导致内皮功能损伤外，波动性高血糖具有更为明显的作用，包括促进内皮细胞凋亡，诱导氧化应激，增加细胞间黏附分子合成等。对血糖波动的正确认识、评价和治疗对糖尿病合并心血管并发症的研究具有重要意义。
2临床研究：
2．1 2型糖尿病患者血糖评价参数及相关性分析
目的：探讨2型糖尿病(T2DM)患者血糖评价参数及相关性分析。方法：选取T2DM患者25例，进行七点法指端毛细血管血糖测定(三餐前(早餐前(空腹)、午餐前、晚餐前)，三餐后两小时及睡前9点)，计算血糖参数：平均血糖水平(MBG)，最大血糖波动幅度(LAGE)，血糖标准差(SDBG)，平均血糖波动幅度(MAGE)；采用离子交换高压液相法检测糖化血红蛋白(HbA_(1c))，并进行其他一般性指标检测。分析HbA_(1c)及其它血糖评价参数之间的关系，HbA_(1c)及MAGE与其它指标的关系。结果：采用单因素回归分析，HbA_(1c)与FBG、MBG、LAGE、MAGE具有相关性(P＜0．01或0．05)，与SDBG相关无统计学意义(P＞0．05)；MAGE与LAGE、SDBG、HbA_(1c)、MBG具有相关性(P＜0．01或0．05)，与FBG相关无统计学意义(P＞0．05)。多元逐步回归分析表明，HbA_(1c)和MBG具有“最优”线性关系，复相关系数R=0．707，P=0．000；MAGE和LAGE具有“最优”线性关系，R=0．953，P=0．000。应用单因素回归分析，HBA_(1c)及MAGE均与血清总胆红素(TBIL)负相关，相关系数分别为-0．520(P=0．004)和-0．373(P=0．033)。结论：不同的血糖评价参数具有对血糖反应的不同侧面，HBA_(1c)与MBG关系密切，MAGE与LAGE具有较好线性关系，对糖尿病患者应该进行包括长期血糖控制指标和血糖波动性指标的全面血糖评价。
2．2 2型糖尿病患者血管内皮功能与血糖评价相关性分析
目的：探讨T2DM患者内皮依赖的血管舒张功能与血糖评价参数的相关性分析。方法：选取T2DM患者25例，予肱动脉内皮依赖性舒张功能(EDF)超声检测，同时进行七点法指端毛细血管血糖测定，计算血糖参数：MBG，LAGE，SDBG，MAGE；采用离子交换高压液相法检测HHbA_(1c)，并进行其他一般性指标检测。分析内皮依赖的血管舒张功能与血糖评价参数的相关性，及与其它一般性指标的相关性。结果：EDF与HbA_(1c)、FBG、MBG无明显相关性(P＞0．05)；与LAGE、SDBG、MAGE具相关性(P均＜0．05)。EDF并与血清尿酸水平有相关性，相关系数为-0．355(P=0．041)。结论：内皮依赖性舒张功能与血糖波动参数明显负相关，血糖波动可能加剧内皮功能损害。糖尿病心血管防治除重视高血糖外，也应关注血糖波动对血管的损害。
3基础研究：波动性高糖对人脐静脉内皮细胞的影响及川芎嗪的干预研究
目的：观察稳定性性高糖、波动性高糖对人脐静脉内皮细胞(HUVEC)的影响以及川芎嗪的干预作用，探讨不同葡萄糖状态下对内皮损伤的机制及川芎嗪的保护作用。方法：以体外培养人脐静脉内皮细胞为研究对象，予不同条件葡萄糖浓度分3组培养：稳定性正常浓度葡萄糖组(葡萄糖：5．56 mmol／L)(正常低糖)；稳定性高浓度葡萄糖组(葡萄糖：25mmol／L)(稳定高糖)；波动性高浓度葡萄糖组(间替高糖／低糖，每24 h换液)(波动高糖)。并进行不同剂量组川芎嗪干预(高剂量组：500μmol／L，中剂量组：100μmol／L，低剂量组：20μmol／L)。细胞培养8天，进行细胞活性检测，取细胞培养上清液检测NO、ET-1、TNF-α、sICAM-1含量，细胞裂解液检测胞内NOS、SOD、MDA水平。结果：与正常低糖组相比，稳定高糖组和波动高糖组HUVEC SOD，NOS，NO生成减少(P＜0．01)，MDA，ET-1，TNF-α、sICAM-1合成增多(P＜0．01)；与稳定高糖组比较，波动高糖组SOD，NOS，NO减少更明显(P＜0．01或0．05)；MDA，ET-1，sICAM-1升高更明显(P＜0．01)；高、中剂量川芎嗪干预能够部分逆转稳定高糖、波动高糖所诱导的HUVEC SOD，NOS，NO的生成减少及MDA，ET-1，TNF-α、sICAM-1的合成增多(P＜0．01或0．05)。结论：高浓度葡萄糖能够通过增加氧化应激，炎症激活，细胞间粘附分子合成等介导内皮细胞损伤，波动性高糖则加剧这一损害；川芎嗪可部分逆转高糖对内皮细胞的影响。
Cardiovascular disease(CVD),especially accelerating the development ofatherosclerosis,is a major cause of the high disability rate and mortality in type 2diabetes mellitus(T2DM).Vascular endothelial injury plays a critical role in theoccurrence and development of diabetic cardiovascular complications disease.Theoscillating glucose can have more deleterious influences than constant high glucoseon endothelial function and diabetes chronic cardiovascular complications.The studyon glucose variability has recently become a research focus in the field of diabeticcardiovascular disease.It has an important significance to study the evaluation ofglucose variability and the effect of glucose fluctuation on endothelial dysfunction inthe control of diabetic cardiovascular disease.To investigate its mechanism and theintervention measures should be studied further.
This study is divided into three parts:review,clinical study and experimentalresearch.
1 Review
1.1 Review 1:The changes of strategy in diabetes from focusing on glycosylatedhemoglobin to avoiding cardiovascular events.
Several recent trials have led to contradictory outcomes in relation to the issue ofglycemic control and cardiovascular complications in patients with type 2 diabetes.The major target of diabetes treatment is to reduce cardiovascular events.Only relyingon the glycosylated hemoglobin as the“gold standard”of the maintenance of tightglycaemic control should be changed.A multi-pronged approach to address the totalcardiovascular risk factors is imperative.The best practice model for glycemic goalsshould include the quantity,quality and time course of glycemic exposure.
1.2 Review 2:Fluctuating high glucose and cardiovascular complications indiabetes mellitus.
Type 2 diabetes as a“coronary heart disease equivalent”,endothelial dysfunctionplays an important role in the pathogenesis of diabetic cardiovascular complications. High glucose fluctuation induces endothelial dysfunction more obviously thanuncontrolled hyperglycemia.The main mechanisms include inducing endothelial cellapoptosis,improving oxidative stress and increasing the endothelial adhesionmolecules,etc.How to exactly recognize,evaluate and treat fluctuating high glucosemaybe possesses significance in the study of diabetic cardiovascular complications.
2 Clinical study
2.1 Study on the evaluation parameters of blood glucose and the correlationbetween them in type 2 diabetes patients.
Objective:To study the evaluation parameters of blood glucose and thecorrelation between them in type 2 diabetes patients.Methods:25 diagnosed type 2diabetic patients with stable glucose-lowering treatment were enrolled.Seven point(preprandial and 120-min postprandial for each meal and bedtime)capillary glucosewas measured with an ultrasmart glucose meter(Bayer).The following indices ofglycemic variability were calculated from 7-point-daily capillary glucose profiles:mean blood glucose(MBG),large amplitude of glycemic excursions(LAGE),SD ofblood glucose(SDBG),mean amplitude of glycemic excursions(MAGE).HbA_(1c)wasmeasured by ion-exchange high-performance liquid chromatography.The generalindexes were measured.Then statistics test and correlation regression analysis werepreceded.Results:In simple correlation analysis,HBA_(1c)and FBG、MBG、LAGE、MAGE had obvious correlations(P＜0.01 or 0.05),MAGE and LAGE、SDBG、HbA_(1c)、MBG had obvious correlations(P＜0.01 or 0.05).In multivariate analysis,theprimary predictor of HBA_(1c)was MBG(R=0.707,P=0.000);the primary predictor ofMAGE was LAGE(R=0.953,P=0.000).All other glucose variables added nothing tothe models.HbA_(1c),MAGE and the level of serum total bilirubin had obvious negativecorrelations,with the Pearson correlation coefficient of-0.520(P=0.004)and-0.373(P=0.033)respectively by linear correlation and regression analysis.Conclusions:The different evaluation parameters of blood glucose might reflect the glucose profilefrom different aspects.HBA_(1c)correlates best with MBG and MAGE correlates bestwith LAGE derived from 7-point-daily capillary glucose profiles.The wholeevaluation of blood glucose in diabetes should include both long-term glucose control index and glucose variables.
2.2 Relationship between endothelium-dependent vasodilatation and theevaluation parameters of blood glucose in type 2 diabetic patients.
Objective:To study the correlation of the endothelium-dependent flow-mediateddilation(EDF)and the evaluation parameters of blood glucose in type 2 diabetespatients.Methods:25 diagnosed type 2 diabetic patients were enrolled.Endothelialfunction was evaluated by flow-mediated dilation measured by ultrasound.Sevenpoint capillary glucose was simultaneously measured and the following indices ofglycemic variability were calculated from 7-point-daily capillary glucose profiles:MBG,LAGE,SDBG,MAGE.HbA_(1c)was measured by ion-exchange high-performance liquid chromatography.The general indexes were measured.Thenstatistics test and correlation regression analysis were preceded.Results:EDF andHbA_(1c),FBG,MBG showed no significant correlation(P＞0.05).There was significantnegative correlation between EDF and MAGE,LAGE,SDBG(P＜0.05).EDF wasinverse correlation(r=-0.355,P=0.041)with the level of serum uric acid.Conclusions:The correlation of EDF and the glucose variables,including MAGE,LAGE,SDBG,suggests that glucose fluctuations might aggravate vascular endothelialdysfunction.The control of cardiovascular events in diabetes should pay attention tovascular injury which induced not only hyperglycemia but also blood glucosefluctuation.
3 Experimental research:Effects of tetramethylpyrazine on human umbilicalvein endothelial cells exposed to constant or intermittent high glucose in vitro.
Objective:To explore the effects of constant or intermittent high glucose onhuman umbilical vein endothelial cells(HUVEC),and the effects oftetramethylpyrazine on HUVEC by constant or intermittent high glucose levels.Methods:HUVEC were incubated for 8 days in media containing different glucoseconcentrations:5.56 mmol/1(normal glucose),25 mmol/1(constant high glucose),or adaily alternating 5.56 or 25 mmol/1 glucose(intermittent high glucose).and exposedfor 8 days to conditions of constant or intermittent high glucose levels withtetramethylpyrazine at concentrations of 500μmol/L,100μmol/L and 20μmol/L.Cell viability was measured by MTT method and cell membrane damage was determinedby lactate dehydrogenase(LDH)leakage,Nitric oxide(NO),endothelin-l(ET-1),soluble intercellular adhesion molecule-1(sICAM-1)and tumor necrosis factor-α(TNF-α)concentrations in the cell culture supernatant were measured.The activitiesof superoxide dismutase(SOD),nitric oxide synthetase(NOS)and the contents ofmalondialdehyde(MDA)in the cell lysate were examined by enzyme method orspectrophotometry.Results:The HUVEC viability and LDH leakage were nosignificance difference in different glucose culture conditions with or withouttetramethylpyrazine.Compared with normal glucose group,the activities ofSOD,NOS and the contents of NO were remarkably decreased while the contents ofMDA,ET-1,TNF-αand sICAM-1 were significantly increased in constant highglucose and intermittent high glucose groups(P＜0.01).More interestingly,thechanges of all the detection indexes(except TNF-α)in intermittent high glucosegroups were greater than that in constant high glucose group(P＜0.05 or P＜0.01).500μmol/L,100μmol/L tetramethylpyrazine could partially reverse the changes ofconstant or intermittent high glucose on HUVEC(P＜0.05 or P＜0.01).Conclusions:Both intermittent and constant high glucose can chang the function of endothelialcells.Furthermore,intermittent high glucose can have more deleterious effects thanconstant high glucose on endothelial function,which may be related to oxidativestress,inflammatory reaction and cell adhesion molecule.Tetramethylpyrazine canpartially reverse this impairment.
引文
[1]The DCCT Research Group.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med,1993,329(14):977-86.
[2]UK Prospective Diabetes Study(UKPDS)Group.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes(UKPDS 33).Lancet,1998,352(9131):837-53.
[3]Haffner SM,Lehto S,R(o|¨)nnemaa T,Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.N Engl J Med,1998,339(4):229-34.
[4]Juutilainen A,Lehto S,R(o|¨)nnemaa T,et al.Type 2 diabetes as a “coronary heart disease equivalent":an 18-year prospective population-based study in Finnish subjects.Diabetes Care,2005,28(12):2901-7.
[5]Turner RC,Millns H,Neil HA,et al.Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus:United Kingdom Prospective Diabetes Study (UKPDS:23).BMJ,1998,316(7134):823-8.
[6]Ryden L,Standi E,Bartnik M,et al.Guidelines on diabetes,pre-diabetes,and cardiovascular diseases:executive summary.The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD).Eur Heart J,2007,28(1):88-136.
[7]Gaede P,Vedel P,Larson N,et al.Multifactorial intervention in cardiovascular disease in patients with type 2 diabetes.N Engl J Med,2003,348(5):383-93.
[8]Colhoun HM,Betteridge DJ,Durrington PN,et al.Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS):multicentre randomised placebo-controlled trial.Lancet,2004,364(9435):685-696.
[9]The ADVANCE Collaborative Group.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med,2008,358(24):2560-2572.
[10]The Action to Control Cardiovacular Risk in Diabetes Study Group.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med,2008,358 (24):2545-2559.
[11]Duckworth W,Abraira C,Moritz T,et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med.2009,360(2):129-39.
[12]Bell DS,O'Keefe JH,Jellinger P.Postprandial dysmetabolism:the missing link between diabetes and cardiovascular events?.Endocr Pract,2008,14(1):112-24.
[13]Dossett LA,Cao H,Mowery NT,et al.Blood glucose variability is associated with mortality in the surgical intensive care unit.Am Surg,2008,74(8):679-85.
[14]Egi M,Bellomo R,Stachowski E,et al.Variability of blood glucose concentration and short-term mortality in critically ill patients.Anesthesiology,2006,105(2):244-52.
[15]Abbatecola AM,Rizzo MR,Barbieri M,et al.Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.Neurology,2006,67(2):235-40.
[16]Gimeno-Orna JA,Castro-Alonso FJ,Boned-Juliani B,et al.Fasting plasma glucose variability as a risk factor of retinopathy in Type 2 diabetic patients.J Diabetes Complications,2003,17(2):78-81.
[17]Monteiro Silvia.Magnitude of glycaemia variation:a new risk tool in acute coronary syndromes [R/OL].(2008-09-01)[2009-03-04].http://spo.escardio.org/eSlides/ presenter,aspx? eevtid=24& letter=M..
[18]Cryer PE,Davis SN,Shamoon H.Hypoglycemia in diabetes.Diabetes Care,2003,26(6):1902-12.
[19]Fisman EZ,Motro M,Tenenbaum A,et alls hypoglycaemia a marker for increased long-term mortality risk in patients with coronary artery disease? An 8-year follow-up.Eur J Cardiovasc Prev Rehabil,2004,11(2):135-43.
[20]Desouza C,Salazar H,Cheong B,et al.Association of hypoglycemia and cardiac ischemia:a study based on continuous monitoring.Diabetes Care,2003,26(5):1485-9.
[21]Svensson AM,McGuire DK,Abrahamsson P,et al.Association between hyperand hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events.Eur Heart J,2005,26(13):1255-61.
[22]The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med,2005,353 (25):2643-2653.
[23]Holman RR,Paul SK,Bethel MA,et al.10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med,2008,359(15):1577-89.
[1]Ryden L,Standl E,Bartnik M,et al.Guidelines on diabetes,pre-diabetes,and cardiovascular diseases:executive summary.The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology(ESC)and of the European Association for the Study of Diabetes(EASD).Eur Heart J,2007,28(1):88-136.
[2]Buse JB,Ginsberg HN,Bakris GL,et al.Primary prevention of cardiovascular diseases in people with diabetes mellitus:a scientific statement from the American Heart Association and the American Diabetes Association.Circulation,2007,115(1):114-26.
[3]Hirsch IB,Brownlee M.Should minimal blood glucose variability become the gold standard of glycemic control?.J Diabetes Complications,2005,19(3):178-81.
[4]Gao W,Qiao Q,Tuomilehto J.Post-challenge hyperglycaemia rather than fasting hyperglycaemia is an independent risk factor of cardiovascular disease events.Clin Lab,2004,50(9-10):609-15.
[5]Ceriello A,Davidson J,Hanefeld M,et al.Postprandial hyperglycaemia and cardiovascular complications of diabetes:an update.Nutr Metab Cardiovasc Dis,2006,16(7):453-6.
[6]Monnier L,Colette C,Boegner C,et al.Continuous glucose monitoring in patients with type 2 diabetes:Why? When? Whom?.Diabetes Metab,2007,33(4):247-52.
[7]Cersosimo E,DeFronzo RA.Insulin resistance and endothelial dysfunction:the road map to cardiovascular diseases.Diabetes Metab Res Rev,2006,22(6):423-36.
[8]Kim JA,Montagnani M,Koh KK,et al.Reciprocal relationships between insulin resistance and endothelial dysfunction:molecular and pathophysiological mechanisms.Circulation,2006,18;113(15):1888-904.
[9]Monnier L,Mas E,Ginet C,et al.Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.JAMA,2006,295(14):1681-7.
[10]Otsuka A,Azuma K,Iesaki T,et al.Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta.Diabetologia,2005,48(12):2667-74.
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[14]Piconi L,Quagliaro L,Da Ros R,et al.Intermittent high glucose enhances ICAM-1,VCAM-1,E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture:the role of poly(ADP-ribose) polymerase.J Thromb Haemost,2004,2(8):1453-9.
[15]Piconi L,Quagliaro L,Assaloni R,et al.Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction.Diabetes Metab Res Rev,2006,22(3):198-203.
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[1]The DCCT Research Group.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med,1993,329(14):977-86.
[2]UK Prospective Diabetes Study(UKPDS)Group.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes(UKPDS 33).Lancet,1998,352(9131):837-53.
[3]Kilpatrick ES,Rigby AS,Atkin SL.A_(1c) variability and the risk of microvascular complications in type 1 diabetes:data from the Diabetes Control and Complications Trial.Diabetes Care,2008,31(11):2198-202.
[4]Hirsch IB,Brownlee M.Should minimal blood glucose variability become the gold standard of glycemic control?.J Diabetes Complications,2005,19(3):178-81.
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[6]Egi M,Bellomo R,Stachowski E,et al.Variability of blood glucose concentration and short-term mortality in critically ill patients.Anesthesiology,2006,105 (2):244-52.
[7]Monnier L,Colette C.Glycemic variability:should we and can we prevent it?.Diabetes Care.2008,31 (Suppl2):S 150-4.
[8]Ceriello A,Esposito K,Piconi L,et al.Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.Diabetes,2008,57(5):1349-54.
[9]周健,贾伟平．血糖稳定性的意义及临床评估．中华医学杂志,2006,86(30)：2154-57．
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[1]Su Y,Liu XM,Sun YM,et al.Endothelial dysfunction in impaired fasting glycemia,impaired glucose tolerance,and type 2 diabetes mellitus.Am J Cardiol,2008,102(4):497-8.
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[10]Ceriello A,Esposito K,Piconi L,et al.Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.Diabetes,2008,57(5):1349-54.
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[1]Guerci B,Kearney-Schwartz A,B(o|¨)hme P,et al.Endothelial dysfunction and type 2 diabetes.Partl:physiology and methods for exploring the endothelial function.Diabetes Metab,2001,27(4 Pt 1):425-34.
[2]Monnier L,Colette C.Glycemic variability:should we and can we prevent it?Diabetes Care.2008,31(Suppl2):S 150-4.
[3]王韻，周新，汪炳华，等．川芎嗪对花生四烯酸诱导血管内皮细胞凋亡的保护作用．中草药，2004，35(2)：177-180．
[4]Lee WS,Yang HY,Kao PF,et al.Tetramethylpyrazine downregulates angiotensin Ⅱ-induced endothelin-1 gene expression in vascular endothelial cells.Clin Exp Pharmacol Physiol.2005,32(10):845-50.
[5]Jaffe EA,Nachman RL,Becker CG,et al.Culture of human endothelial cells derived from umbilical veins.Identification by morphologic and immunologic criteria.J Clin Invest,1973,52(11):2745-56.
[6]Potenza MA,Gagliardi S,Nacci C,et al.Endothelial dysfunctioni diabetes:from mechanisms to therapeuti targets.Curr Med Chem.2009; 16(1):94-112.
[7]Kilpatrick ES,Rigby AS,Atkin SL.A_(1C)variability and the risk of microvascular complications in type 1 diabetes:data from the Diabetes Control and Complications Trial.Diabetes Care,2008,31(11 ):2198-202.
[8]Hirsch IB,Brownlee M.Should minimal blood glucose variability become the gold standard of glycemic control?.J Diabetes Complications,2005,19(3):178-81.
[9]Ceriello A,Esposito K,Piconi L,et al.Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients.Diabetes,2008,57(5):1349-54.
[10]Quagliaro L,Piconi L,Assaloni R,et al.Intermittent high glucose enhances ICAM-1,VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture:the distinct role of protein kinase C and mitochondrial superoxide production.Atherosclerosis,2005,183(2):259-67.
[11]Piconi L,Quagliaro L,Da Ros R,et al.Intermittent high glucose enhances ICAM-1,VCAM-1,E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture:the role of poly(ADP-ribose)polymerase.J Thromb Haemost,2004,2(8):1453-9.
[12]Piconi L,Quagliaro L,Assaloni R,et al.Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction.Diabetes Metab Res Rev,2006,22(3):198-203.
[13]胡国芬，王建平．川芎嗪的药理作用及临床应用进展[J]．中国药物与临床，2006，6(10)：773-774．
[14]林杰，徐力辛，杨德业，等．川芎嗪对内皮祖细胞的功能影响[J]．浙江中医药大学学报，2008,32(5)：598-600．
[15]吴红金，吕俊萍，马增春，等．川芎嗪对培养人脐静脉内皮细胞基因表达谱的影响．中国实验方剂学杂志,2005，11(3)：40-43．
[2]UK Prospective Diabetes Study(UKPDS)Group.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes(UKPDS 33).Lancet,1998,352(9131):837-53.
[3]Haffner SM,Lehto S,R(o|¨)nnemaa T,Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.N Engl J Med,1998,339(4):229-34.
[4]Juutilainen A,Lehto S,R(o|¨)nnemaa T,et al.Type 2 diabetes as a “coronary heart disease equivalent":an 18-year prospective population-based study in Finnish subjects.Diabetes Care,2005,28(12):2901-7.
[5]Turner RC,Millns H,Neil HA,et al.Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus:United Kingdom Prospective Diabetes Study (UKPDS:23).BMJ,1998,316(7134):823-8.
[6]Ryden L,Standi E,Bartnik M,et al.Guidelines on diabetes,pre-diabetes,and cardiovascular diseases:executive summary.The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD).Eur Heart J,2007,28(1):88-136.
[7]Gaede P,Vedel P,Larson N,et al.Multifactorial intervention in cardiovascular disease in patients with type 2 diabetes.N Engl J Med,2003,348(5):383-93.
[8]Colhoun HM,Betteridge DJ,Durrington PN,et al.Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS):multicentre randomised placebo-controlled trial.Lancet,2004,364(9435):685-696.
[9]The ADVANCE Collaborative Group.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med,2008,358(24):2560-2572.
[10]The Action to Control Cardiovacular Risk in Diabetes Study Group.Effects of intensive glucose lowering in type 2 diabetes.N Engl J Med,2008,358 (24):2545-2559.
[11]Duckworth W,Abraira C,Moritz T,et al.Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med.2009,360(2):129-39.
[12]Bell DS,O'Keefe JH,Jellinger P.Postprandial dysmetabolism:the missing link between diabetes and cardiovascular events?.Endocr Pract,2008,14(1):112-24.
[13]Dossett LA,Cao H,Mowery NT,et al.Blood glucose variability is associated with mortality in the surgical intensive care unit.Am Surg,2008,74(8):679-85.
[14]Egi M,Bellomo R,Stachowski E,et al.Variability of blood glucose concentration and short-term mortality in critically ill patients.Anesthesiology,2006,105(2):244-52.
[15]Abbatecola AM,Rizzo MR,Barbieri M,et al.Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.Neurology,2006,67(2):235-40.
[16]Gimeno-Orna JA,Castro-Alonso FJ,Boned-Juliani B,et al.Fasting plasma glucose variability as a risk factor of retinopathy in Type 2 diabetic patients.J Diabetes Complications,2003,17(2):78-81.
[17]Monteiro Silvia.Magnitude of glycaemia variation:a new risk tool in acute coronary syndromes [R/OL].(2008-09-01)[2009-03-04].http://spo.escardio.org/eSlides/ presenter,aspx? eevtid=24& letter=M..
[18]Cryer PE,Davis SN,Shamoon H.Hypoglycemia in diabetes.Diabetes Care,2003,26(6):1902-12.
[19]Fisman EZ,Motro M,Tenenbaum A,et alls hypoglycaemia a marker for increased long-term mortality risk in patients with coronary artery disease? An 8-year follow-up.Eur J Cardiovasc Prev Rehabil,2004,11(2):135-43.
[20]Desouza C,Salazar H,Cheong B,et al.Association of hypoglycemia and cardiac ischemia:a study based on continuous monitoring.Diabetes Care,2003,26(5):1485-9.
[21]Svensson AM,McGuire DK,Abrahamsson P,et al.Association between hyperand hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events.Eur Heart J,2005,26(13):1255-61.
[22]The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group.Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.N Engl J Med,2005,353 (25):2643-2653.
[23]Holman RR,Paul SK,Bethel MA,et al.10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med,2008,359(15):1577-89.
[1]Ryden L,Standl E,Bartnik M,et al.Guidelines on diabetes,pre-diabetes,and cardiovascular diseases:executive summary.The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology(ESC)and of the European Association for the Study of Diabetes(EASD).Eur Heart J,2007,28(1):88-136.
[2]Buse JB,Ginsberg HN,Bakris GL,et al.Primary prevention of cardiovascular diseases in people with diabetes mellitus:a scientific statement from the American Heart Association and the American Diabetes Association.Circulation,2007,115(1):114-26.
[3]Hirsch IB,Brownlee M.Should minimal blood glucose variability become the gold standard of glycemic control?.J Diabetes Complications,2005,19(3):178-81.
[4]Gao W,Qiao Q,Tuomilehto J.Post-challenge hyperglycaemia rather than fasting hyperglycaemia is an independent risk factor of cardiovascular disease events.Clin Lab,2004,50(9-10):609-15.
[5]Ceriello A,Davidson J,Hanefeld M,et al.Postprandial hyperglycaemia and cardiovascular complications of diabetes:an update.Nutr Metab Cardiovasc Dis,2006,16(7):453-6.
[6]Monnier L,Colette C,Boegner C,et al.Continuous glucose monitoring in patients with type 2 diabetes:Why? When? Whom?.Diabetes Metab,2007,33(4):247-52.
[7]Cersosimo E,DeFronzo RA.Insulin resistance and endothelial dysfunction:the road map to cardiovascular diseases.Diabetes Metab Res Rev,2006,22(6):423-36.
[8]Kim JA,Montagnani M,Koh KK,et al.Reciprocal relationships between insulin resistance and endothelial dysfunction:molecular and pathophysiological mechanisms.Circulation,2006,18;113(15):1888-904.
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