肝细胞生长因子、白细胞介素-6与2型糖尿病心脏自主神经病变的关系
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摘要
目的:糖尿病心脏自主神经病变(cardiovascular autonomic neuropathy,CAN)的病理基础是微血管病变,而血管内皮损伤及功能障碍与糖尿病血管病变的发生、发展密切相关。国内外已有研究表明,肝细胞生长因子(hepatocyte growth factor,HGF)和白细胞介素-6(interleukin-6,IL-6)与血管内皮功能密切相关。本研究主要探讨HGF、IL-6与2型糖尿病CAN的关系,以及各种影响2型糖尿病CAN的因素如糖尿病病程、糖化血红蛋白、血脂、微血管并发症等与HGF、IL-6的相关性。并将心率变异性(heart rate variability,HRV)分析与蹲踞试验结果作相关分析,为糖尿病CAN的早期诊断提供理论依据。
方法:选择2007.10-2008.11在河北医科大学第二医院内分泌科住院的2型糖尿病患者60例,平均年龄(57.61±11.89)岁,所有患者行蹲踞试验检查及24小时动态心电图监测。按蹲踞试验结果SqTv、SqTs值将60例2型糖尿病患者分为三组:A组(两项指标均正常)20人,男11人,女9人,平均年龄(55.00±9.56)岁;B组(一项指标异常)21人,男10人,女11人,平均年龄(57.69±12.63)岁;C组(两项指标均异常)19人,男9人,女10人,平均年龄(56.12±12.60)岁。正常对照组(N组)30例,男16例,女14例,平均年龄(55.57±10.12)岁。对照组亦行蹲踞试验检查及24小时动态心电图监测。2型糖尿病诊断符合1999年WHO糖尿病诊断标准。血清HGF和IL-6的测定采用ELISA法,将各组一般情况、HRV分析结果、蹲踞试验结果等与血清HGF、IL-6水平进行比较,探讨HGF、IL-6与2型糖尿病心脏自主神经病变的关系。
结果:
1一般项目比较
A、B、C三组血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、纤维蛋白原(FIB)水平均较N组水平高(P<0.05),高密度脂蛋白(HDL)较N组水平低(P<0.05)。HDL、HbA1c在A、C组间存在差异(P<0.05),TC、TG、LDL、FIB在糖尿病各组间比较无统计学意义(p>0.05)。A、B、C三组间病程上两两比较有显著统计学意义(P<0.01)。
2血清HGF、IL-6水平的比较
血清HGF、IL-6水平在M组(A、B、C三组合并为M组)明显高于N组,IL-6水平A、B、C、N四组间两两比较显示均有显著统计学意义(P<0.01)。HGF水平除A、B两组间未达到统计学意义(P=0.07)外,其余组间比较差异显著(P<0.01)。
3 HRV各指标的比较
2型糖尿病M组与正常对照N组相比,HRV各指标均明显降低(P<0.01)。其中连续5min正常R-R间期标准差的均值(SDNNindex)、相邻正常R-R间期差值均方根(rMSSD)、总能谱公率(TP)、极低频功率(VLF)、高频功率(HF)及最小频域在A、B、C、N四组间有统计学差异(P<0.05)。24h相邻正常R-R间期标准差(SDNN)、连续5min正常R-R间期标准差(SDANNindex)二者在A组与N组间无明显差异(P>0.05),余两两比较有差异(P<0.01)。低频功率(LF)、24小时记录R-R间期差值大于50ms的窦性心搏占总心搏百分比(PNN50)在A、B两组间比较未达到统计学差别(P>0.05),余组间比较有统计学意义(P<0.01)。最大频域A、B、C三组间比较无统计学意义(P>0.05)。LF/HF值四组间两两比较未达到统计学意义(P>0.05)。
4蹲踞试验各指标的比较
M组SqTv值、SqTs值与N组相比,统计学差异显著(P<0.01),且二者在A、B、C、N四组间两两比较有统计学意义(P<0.05)。
5 2型糖尿病组各观测指标相关及回归分析
5.1血清HGF、IL-6均与病程、HbA1c、LDL、UAER、SqTv呈正相关,与HDL、SqTs、SDNN、SDNNindex、SDANNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈负相关。另外IL-6亦和FIB呈正相关。血清HGF、IL-6二者间亦有显著相关性(r=0.70,p<0.001)。以血清HGF为因变量,以与之相关的所有影响因素为自变量行多元逐步回归分析,结果显示:UAER(r2=0.37)、LDL(r2=0.15)进入回归方程。以血清IL-6为因变量,以与之相关的所有影响因素为自变量行多元逐步回归分析,结果显示:LDL(r2=0.16)、FIB(r2=0.11)进入回归方程。
5.2病程与SDNN、SDNNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈负相关,病程亦与SqTv、SqTs、UAER呈显著相关。
5.3 SqTv与SDNN、SDNNindex、SDANNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈负相关,与UAER、SqTs、HDL亦有相关性。SqTs与SDNN、SDNNindex、SDANNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈正相关,亦和HbA1c、FIB、UAER存在相关性。
6糖尿病各组微血管并发症的比较
60例2型糖尿病患者中合并糖尿病肾病(DN)、糖尿病视网膜病变(DR)、糖尿病周围神经病变(DPN)的分别为31例、21例、34例,卡方检验示三种并发症在A、B、C三组中的患病率有统计学差别(P<0.05)。
结论:(1)血清HGF、IL-6水平在糖尿病患者中较正常人明显升高,随CAN病变程度的加重,二者呈逐步升高趋势。伴随CAN病变程度的加重,其他微血管并发症如DN、DR、DPN的发病率亦显著升高。血清HGF、IL-6水平与病程、HbA1c、LDL、HDL、UAER、SqTv、SqTs及HRV指标存在相关性。检测糖尿病患者血清HGF、IL-6水平有助于了解CAN的发病机制,指导临床通过改善血管内皮功能从而早期防治CAN。
(2)糖尿病患者各项HRV指标均较正常人显著降低。本实验选用蹲踞试验简便、依从性好,机理与传统心血管试验相同,与HRV代表交感神经、副交感神功能的指标具有良好相关性,且经济实用,可用于对糖尿病CAN患者进行初步筛选。
Objective: The pathobiology foundation of diabetes mellitus(DM) cardiovascular autonomic neuropathy(CAN) is micrangium affection, the endothelium dysfunction and injury has a close relationship with DM complications. There is a intimate relationship between Hepatocyte growth factor(HGF), interleukin-6(IL-6) and endothelium function,which has been certified by most studies . The aim of this study is to investigate the association between HGF,IL-6 and CAN in type 2 diabetes mellitus(T2DM),and the correlation between HGF,IL-6 and various kinds of factors of CAN in T2DM. It also analyzes the association between squatting test and heart rate variability(HRV),providing clinical diagnosis evidence of CAN accordingly.
Methods: 60 in-ward patients with T2DM hospitalized in the Second Hospital of Hebei Medicine University from October, 2007 to November, 2008.All patients must be examined squatting test and dynamic electrocardiogram in 24 hours,then according to the value of squatting test SqTv、SqTs divide three groups. There are 20 patients (A group) without the abnormality of the result of squatting test, 11 males and 9 females, average aged 55.00±9.56 years old; there are 21 patients (B group) with one of squatting test results abnormal, 10 males and 11 females, average aged 57.69±12.63 years old; there are 19 patients (C group) with both of squatting test results abnormal, 9 males and 10 females, average aged 56.12±12.60 years old. Normal control (N group) 30 men, 16 males and 14 females, average aged 55.57±10.12 years old. All of normal control people also examine squatting test and dynamic electrocardiogram in 24 hours. The diagnosis of T2DM accorded with the new diagnosis criteria of WHO in 1999. The determination of blood serum HGF,IL-6 is based on ELISA. Compared the differences of the common conditions, HRV index, squatting test result, HGF,IL-6 and so on in four groups and study the association between HGF,IL-6 and CAN in type 2 diabetes mellitus.
Result:
1 The comparison of common conditions
Compared with N group, TC、TG、LDL and FIB level was higher in T2DM groups(p<0.05),HDL level was lower in T2DM groups(p<0.05).There was statistics significance of HbA1c and HDL between A,C groups, but there were no differences in TC、TG、LDL、FIB among three T2DM groups (p>0.05). There were significant differences in course of DM among A, B, C groups(p<0.01).
2 The comparison of the level of blood serum HGF,IL-6
Compared with N group, the level of blood serum HGF,IL-6 was much higher in M group (to merge A、B、C groups as M group, p<0.01). There were significant differences of the level of blood serum IL-6 among A, B, C, N groups(p<0.01). Except no statistics significance of the level of blood serum HGF between A,B groups(P=0.07), there were significant differences among other groups(p<0.01).
3 The comparison of index of HRV
Compared with N group, index of HRV were lower in M group (p<0.01). There were significant differences in SDNNindex, rMSSD, TP, VLF, HF and the minimum value of frequency of HRV among A, B, C ,N groups(p<0.01). Except no statistics significance of SDNN, SDANNindex between A,N groups(p>0.05), there were statistics differences among other groups(p<0.05). There were no statistics differences in LF, PNN50 betweenA,B groups(p>0.05). There were no statistics differences in the maximum value of frequency of HRV among A, B, C groups(p>0.05). There were no statistics differences in the value of LF/HF among A, B, C,N groups(p>0.05).
4 The comparison of the result of squatting test
There were significant differences in the value of SqTv and SqTs between N group and M group (p<0.01),and the differences also existed among A, B, C,N groups(p<0.05).
5 The correlation and regression analysis of observation index in T2DM groups
5.1 The level of blood serum HGF,IL-6 was positively correlated with course of diabetes mellitus,HbA1c,LDL, SqTv and UAER,and it was negatively correlated with HDL,SqTs SDNN,SDNNindex,SDANNindex, rMSSD,PNN50,TP,VLF, LF, HF and the minimum value of frequency. There was also obvious positive correlation between the level of blood serum IL-6 and HGF.For blood serum HGF level as dependent variable, all of the influential factors as independent variable do a regression analysis,using the multiple stepwise method, UAER(r2=0.37),LDL(r2=0.15)fit into the regression equation. For blood serum IL-6 level as dependent variable,all of the influential factors as independent variable do a regression analysis, using the stepwise method, LDL(r2=0.16),FIB(r2=0.11)fit into the regression equation.
5.2 The course of diabetes mellitus was negatively correlated with SDNN, SDNNindex, rMSSD, PNN50, TP, VLF, LF,HF and the minimum value of frequency.It also had correlation with SqTv, SqTs, UAER.
5.3 SqTv was negatively correlated with SDNN, SDNNindex, SDANNindex, rMSSD, PNN50, TP, VLF, LF, HF and the minimum value of frequency. It also had correlation with UAER, SqTs, HDL. SqTs was positively correlated with SDNN,SDNNindex,SDANNindex, rMSSD,PNN50,TP,VLF, LF, HF and the minimum value of frequency. It also had correlation with HbA1c, Fib, UAER.
6 The comparison of micrangium complications
Among 60 patients,there were 31,21,34 patients complicating with DN,DR,DPN. The result of chi-square criterion showed there were statistics differences in the three complications among A, B and C groups(p<0.05)
Conclusion:(1)The level of blood serum HGF,IL-6 is much higher in T2DM than normal group,the more serious of the CAN is,the higher of blood serum HGF,IL-6 level is. Following the development of CAN,the diabetes mellitus micrangium complications such as DN、DR、DPN also increase. There is dependablity between blood serum HGF,IL-6 level and course of diabetes mellitus, HbA1c, LDL, HDL, UAER, SqTv, SqTs and the index of HRV. Detecting the level of blood serum HGF,IL-6 helped to comprehend the pathogenesy of CAN,give clinical guidance to prevention and cure CAN in earlier period by improving function of blood vessel endothelium.
(2)Compared with normal group, the index of HRV obviously decrease in T2DM patients. This study adopt squatting test which is convenient, well complied and have the same mechanism with orthodox heart vascellum test. It also has a good dependability with the index of HRV which represent the function of sympathetic nerve and parasympathetic nerve.It is economical and practical and can be applied to sieve the CAN patients in T2DM.
方法:选择2007.10-2008.11在河北医科大学第二医院内分泌科住院的2型糖尿病患者60例,平均年龄(57.61±11.89)岁,所有患者行蹲踞试验检查及24小时动态心电图监测。按蹲踞试验结果SqTv、SqTs值将60例2型糖尿病患者分为三组:A组(两项指标均正常)20人,男11人,女9人,平均年龄(55.00±9.56)岁;B组(一项指标异常)21人,男10人,女11人,平均年龄(57.69±12.63)岁;C组(两项指标均异常)19人,男9人,女10人,平均年龄(56.12±12.60)岁。正常对照组(N组)30例,男16例,女14例,平均年龄(55.57±10.12)岁。对照组亦行蹲踞试验检查及24小时动态心电图监测。2型糖尿病诊断符合1999年WHO糖尿病诊断标准。血清HGF和IL-6的测定采用ELISA法,将各组一般情况、HRV分析结果、蹲踞试验结果等与血清HGF、IL-6水平进行比较,探讨HGF、IL-6与2型糖尿病心脏自主神经病变的关系。
结果:
1一般项目比较
A、B、C三组血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、纤维蛋白原(FIB)水平均较N组水平高(P<0.05),高密度脂蛋白(HDL)较N组水平低(P<0.05)。HDL、HbA1c在A、C组间存在差异(P<0.05),TC、TG、LDL、FIB在糖尿病各组间比较无统计学意义(p>0.05)。A、B、C三组间病程上两两比较有显著统计学意义(P<0.01)。
2血清HGF、IL-6水平的比较
血清HGF、IL-6水平在M组(A、B、C三组合并为M组)明显高于N组,IL-6水平A、B、C、N四组间两两比较显示均有显著统计学意义(P<0.01)。HGF水平除A、B两组间未达到统计学意义(P=0.07)外,其余组间比较差异显著(P<0.01)。
3 HRV各指标的比较
2型糖尿病M组与正常对照N组相比,HRV各指标均明显降低(P<0.01)。其中连续5min正常R-R间期标准差的均值(SDNNindex)、相邻正常R-R间期差值均方根(rMSSD)、总能谱公率(TP)、极低频功率(VLF)、高频功率(HF)及最小频域在A、B、C、N四组间有统计学差异(P<0.05)。24h相邻正常R-R间期标准差(SDNN)、连续5min正常R-R间期标准差(SDANNindex)二者在A组与N组间无明显差异(P>0.05),余两两比较有差异(P<0.01)。低频功率(LF)、24小时记录R-R间期差值大于50ms的窦性心搏占总心搏百分比(PNN50)在A、B两组间比较未达到统计学差别(P>0.05),余组间比较有统计学意义(P<0.01)。最大频域A、B、C三组间比较无统计学意义(P>0.05)。LF/HF值四组间两两比较未达到统计学意义(P>0.05)。
4蹲踞试验各指标的比较
M组SqTv值、SqTs值与N组相比,统计学差异显著(P<0.01),且二者在A、B、C、N四组间两两比较有统计学意义(P<0.05)。
5 2型糖尿病组各观测指标相关及回归分析
5.1血清HGF、IL-6均与病程、HbA1c、LDL、UAER、SqTv呈正相关,与HDL、SqTs、SDNN、SDNNindex、SDANNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈负相关。另外IL-6亦和FIB呈正相关。血清HGF、IL-6二者间亦有显著相关性(r=0.70,p<0.001)。以血清HGF为因变量,以与之相关的所有影响因素为自变量行多元逐步回归分析,结果显示:UAER(r2=0.37)、LDL(r2=0.15)进入回归方程。以血清IL-6为因变量,以与之相关的所有影响因素为自变量行多元逐步回归分析,结果显示:LDL(r2=0.16)、FIB(r2=0.11)进入回归方程。
5.2病程与SDNN、SDNNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈负相关,病程亦与SqTv、SqTs、UAER呈显著相关。
5.3 SqTv与SDNN、SDNNindex、SDANNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈负相关,与UAER、SqTs、HDL亦有相关性。SqTs与SDNN、SDNNindex、SDANNindex、rMSSD、PNN50、TP、VLF、LF、HF、最小频域呈正相关,亦和HbA1c、FIB、UAER存在相关性。
6糖尿病各组微血管并发症的比较
60例2型糖尿病患者中合并糖尿病肾病(DN)、糖尿病视网膜病变(DR)、糖尿病周围神经病变(DPN)的分别为31例、21例、34例,卡方检验示三种并发症在A、B、C三组中的患病率有统计学差别(P<0.05)。
结论:(1)血清HGF、IL-6水平在糖尿病患者中较正常人明显升高,随CAN病变程度的加重,二者呈逐步升高趋势。伴随CAN病变程度的加重,其他微血管并发症如DN、DR、DPN的发病率亦显著升高。血清HGF、IL-6水平与病程、HbA1c、LDL、HDL、UAER、SqTv、SqTs及HRV指标存在相关性。检测糖尿病患者血清HGF、IL-6水平有助于了解CAN的发病机制,指导临床通过改善血管内皮功能从而早期防治CAN。
(2)糖尿病患者各项HRV指标均较正常人显著降低。本实验选用蹲踞试验简便、依从性好,机理与传统心血管试验相同,与HRV代表交感神经、副交感神功能的指标具有良好相关性,且经济实用,可用于对糖尿病CAN患者进行初步筛选。
Objective: The pathobiology foundation of diabetes mellitus(DM) cardiovascular autonomic neuropathy(CAN) is micrangium affection, the endothelium dysfunction and injury has a close relationship with DM complications. There is a intimate relationship between Hepatocyte growth factor(HGF), interleukin-6(IL-6) and endothelium function,which has been certified by most studies . The aim of this study is to investigate the association between HGF,IL-6 and CAN in type 2 diabetes mellitus(T2DM),and the correlation between HGF,IL-6 and various kinds of factors of CAN in T2DM. It also analyzes the association between squatting test and heart rate variability(HRV),providing clinical diagnosis evidence of CAN accordingly.
Methods: 60 in-ward patients with T2DM hospitalized in the Second Hospital of Hebei Medicine University from October, 2007 to November, 2008.All patients must be examined squatting test and dynamic electrocardiogram in 24 hours,then according to the value of squatting test SqTv、SqTs divide three groups. There are 20 patients (A group) without the abnormality of the result of squatting test, 11 males and 9 females, average aged 55.00±9.56 years old; there are 21 patients (B group) with one of squatting test results abnormal, 10 males and 11 females, average aged 57.69±12.63 years old; there are 19 patients (C group) with both of squatting test results abnormal, 9 males and 10 females, average aged 56.12±12.60 years old. Normal control (N group) 30 men, 16 males and 14 females, average aged 55.57±10.12 years old. All of normal control people also examine squatting test and dynamic electrocardiogram in 24 hours. The diagnosis of T2DM accorded with the new diagnosis criteria of WHO in 1999. The determination of blood serum HGF,IL-6 is based on ELISA. Compared the differences of the common conditions, HRV index, squatting test result, HGF,IL-6 and so on in four groups and study the association between HGF,IL-6 and CAN in type 2 diabetes mellitus.
Result:
1 The comparison of common conditions
Compared with N group, TC、TG、LDL and FIB level was higher in T2DM groups(p<0.05),HDL level was lower in T2DM groups(p<0.05).There was statistics significance of HbA1c and HDL between A,C groups, but there were no differences in TC、TG、LDL、FIB among three T2DM groups (p>0.05). There were significant differences in course of DM among A, B, C groups(p<0.01).
2 The comparison of the level of blood serum HGF,IL-6
Compared with N group, the level of blood serum HGF,IL-6 was much higher in M group (to merge A、B、C groups as M group, p<0.01). There were significant differences of the level of blood serum IL-6 among A, B, C, N groups(p<0.01). Except no statistics significance of the level of blood serum HGF between A,B groups(P=0.07), there were significant differences among other groups(p<0.01).
3 The comparison of index of HRV
Compared with N group, index of HRV were lower in M group (p<0.01). There were significant differences in SDNNindex, rMSSD, TP, VLF, HF and the minimum value of frequency of HRV among A, B, C ,N groups(p<0.01). Except no statistics significance of SDNN, SDANNindex between A,N groups(p>0.05), there were statistics differences among other groups(p<0.05). There were no statistics differences in LF, PNN50 betweenA,B groups(p>0.05). There were no statistics differences in the maximum value of frequency of HRV among A, B, C groups(p>0.05). There were no statistics differences in the value of LF/HF among A, B, C,N groups(p>0.05).
4 The comparison of the result of squatting test
There were significant differences in the value of SqTv and SqTs between N group and M group (p<0.01),and the differences also existed among A, B, C,N groups(p<0.05).
5 The correlation and regression analysis of observation index in T2DM groups
5.1 The level of blood serum HGF,IL-6 was positively correlated with course of diabetes mellitus,HbA1c,LDL, SqTv and UAER,and it was negatively correlated with HDL,SqTs SDNN,SDNNindex,SDANNindex, rMSSD,PNN50,TP,VLF, LF, HF and the minimum value of frequency. There was also obvious positive correlation between the level of blood serum IL-6 and HGF.For blood serum HGF level as dependent variable, all of the influential factors as independent variable do a regression analysis,using the multiple stepwise method, UAER(r2=0.37),LDL(r2=0.15)fit into the regression equation. For blood serum IL-6 level as dependent variable,all of the influential factors as independent variable do a regression analysis, using the stepwise method, LDL(r2=0.16),FIB(r2=0.11)fit into the regression equation.
5.2 The course of diabetes mellitus was negatively correlated with SDNN, SDNNindex, rMSSD, PNN50, TP, VLF, LF,HF and the minimum value of frequency.It also had correlation with SqTv, SqTs, UAER.
5.3 SqTv was negatively correlated with SDNN, SDNNindex, SDANNindex, rMSSD, PNN50, TP, VLF, LF, HF and the minimum value of frequency. It also had correlation with UAER, SqTs, HDL. SqTs was positively correlated with SDNN,SDNNindex,SDANNindex, rMSSD,PNN50,TP,VLF, LF, HF and the minimum value of frequency. It also had correlation with HbA1c, Fib, UAER.
6 The comparison of micrangium complications
Among 60 patients,there were 31,21,34 patients complicating with DN,DR,DPN. The result of chi-square criterion showed there were statistics differences in the three complications among A, B and C groups(p<0.05)
Conclusion:(1)The level of blood serum HGF,IL-6 is much higher in T2DM than normal group,the more serious of the CAN is,the higher of blood serum HGF,IL-6 level is. Following the development of CAN,the diabetes mellitus micrangium complications such as DN、DR、DPN also increase. There is dependablity between blood serum HGF,IL-6 level and course of diabetes mellitus, HbA1c, LDL, HDL, UAER, SqTv, SqTs and the index of HRV. Detecting the level of blood serum HGF,IL-6 helped to comprehend the pathogenesy of CAN,give clinical guidance to prevention and cure CAN in earlier period by improving function of blood vessel endothelium.
(2)Compared with normal group, the index of HRV obviously decrease in T2DM patients. This study adopt squatting test which is convenient, well complied and have the same mechanism with orthodox heart vascellum test. It also has a good dependability with the index of HRV which represent the function of sympathetic nerve and parasympathetic nerve.It is economical and practical and can be applied to sieve the CAN patients in T2DM.
引文
1许樟荣.糖尿病心血管自主神经病变.国外医学内分泌学分册,2004,24(2):84-86
2黄莹,周丽诺,胡仁明.糖尿病心血管自主神经病变检查方法的研究进展.国际内分泌代谢杂志,2007,27(1):50-53
3 Wassmann S ,Stumpf M,Strehlow K, et al. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res ,2004 ,94 (4) :534-541
4陈灏珠主编.内科学(第六版).北京:人民卫生出版社,2001:843
5 Marek Malik. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation ,1996 ,93(5) :1043-1065
6 Hoeldtke RD, Bryner KD, McNeill DR, et al. Nitrosative stress,uric acid, and peripheral nerve function in early type 1 diabetes . Diabetes, 2002, 51 (9) : 2817-2825
7 Vinik AI, Erbas T, Park TS, et al. Dermal neurovascular dysfunction in type 2 diabetes. Diabetes Care, 2001, 24 ( 8) : 1468-1475
8 Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic neuropathy. Diabetes Care, 2003, 26 (5) : 1553-1579
9 Maser RE, Mitchell BD, Vinik AI, et al.The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care,2003, 26 ( 6) : 1895-1901
10张宝慧.心脏康复研究的最新进展.中国临床康复,2003,7(1):4-5
11 Braune HJ , Geisendorfer U. Measurement of heart rate variations: influencing factors, normal values and diagnostic impact on diabetic autonomic neuropathy. Diabetes Research ,1995 ,29 (3) :179
12 Wang X, Zhou Y, Kim HP, et al. Hepatocyte growth factor protects against hypoxia /reoxygenation-induced apoptosis in endothelial cells. J Biol Chem, 2004, 279(7):5237-5243
13 Koyama J , Yokouchi K, Fukushima N , et al . Neurotrophic effect of hepatocyte growth factor on neonatal facial motor neurons.Neurol Res,2003,25(7):701-707
14于晓华,张锦,周一军.2型糖尿病合并大血管病变患者肝细胞生长因子水平观察.中国综合临床,2006,22(2):140-142
15 Haug C , Schmid-Kotsas A , Zorn U , et al. Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release. Am J Physiol Heart Circ Physiol,2000,279(6):2865-2871
16 Santini V,Ciampittiello G,Gigli F,et al . QTc and autonomic neuropathy in diabetes: Effects of acute hyperglycaemia and n-3 PUFA. Nutr Metab Cardiovasc Dis, 2007, 17(10), 712-718
17 Sheng WH, Chiang BL, Chang SC, et al. Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome. J FormosMed Assoc,2005,104(10):715-723
18 Wolfa M, Wolf D ,Rumpold H,et al . The kinase inhibitor imatinib mesylate inhibits TNF-{ alpha} production in vitro and prevents TNF-dependent acute hepatic inflammation . Proc Natl Acad Sci USA , 2005 ,102(38) :13622 - 13627
19 Mavridis G,Souliou E,Diza E, et al . Inflammatory cytokines in insulin-treated patients with type 2 diabetes. Nutr Metab Cardiovasc Dis,2008,18(7):471-476
20 Rabingovitch A. An up date on cytokmes in the pathogenesis of insulin independent diabetes mellitus. Diabetes Metab Rev , 1998 , (14): 129-134
21 Libra M,Signorelli SS,Bevelacqua Y ,et al . Analysis of G(-174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease.J Clin Pathol, 2006,59(2):211-215
22 Mastej K,Adamiec R . Neutrophil surface expression of CD11b and CD62L in diabetic microangiopathy. Acta Diabetol,2008,45(3):183-190
23张丽,陆颖理,王国兴等.TNF-α、IL-6与糖尿病神经病变的相关性及PGE1疗效的观察.全科医学临床与教育,2006,4(1):32-34
24 Marfella R,Giuqliano D,di Maro G ,et al.The squatting test: a useful tool to assess both parasympathetic and sympathetic involvement of the cardiovascular autonomic neuropathy in diabetes.Diabetes,1994,43(4):607-612
25荆春燕,叶山东.蹲踞试验对糖尿病心血管自主神经病变的诊断价值.新医学,2000,31(7):402-403
26杜登圣,宋月英,张子生等.糖尿病心脏自主神经病变检查的新方法—蹲踞试验.当代医师杂志,1998,3(4):9-11
27袁凤山,赵锦,张锦等.糖尿病患者心脏自主神经病变的电生理评估.中国临床康复,2004,8(24):5034-5036
28 Gonzalez Clemente JM,Vilardell C,Broch M, et al . Lower heart rate variability is associated with higher plasma concentrations of IL-6 in type 1 diabetes. European Journal of Endocrinology, 2007,157(1) :31–38
29郭继鸿,张海澄主编.动态心电图最新进展.北京:北京大学医学出版社, 2005: 86-119.
30罗昭林,陈禹,钟抗美,等.冠心病室性心动过速患者的心率变异性分析.临床心电学杂志,2005,14(1):371
31 Moran A , Palmas W, Field L , et al . Cardiovascular autonomic neuropathy is associated with microalbuminuria in older patients with type 2 diabetes. Diabetes Care , 2004 ,27(4) : 972-977
32 Kempler P ,Tesfaye S ,Chaturvedi N ,et al . Autonomic neuropathy is associated with increased cardiovascular risk factors :the EURODIAB IDDM Complications Study. Diabet Med,2002,19(11):900-906
1 Manganini M, Maier JA. Transforming growth factor beta- inhibition of hepatocyte growth factor-induced endothelial proliferation and migration.Oncogene, 2000,19(1):124-133
2 Schaeper U,Gehring NH,Fuchs KP,et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J Cell Biol, 2000, 149(7): 1419-1432
3 Gong R, Rifai A,Dworkin LD. Activation of PI3K-Akt- GSK3 beta pathway mediates hepatocyte growth factor inhibition of RANTES expression in renal tubular epithelial cells.Biochem Biophys Res Commun, 2005, 330(1): 27-33
4 Lipschutz JH,Li S,Arisco A. Extracellular signal-regulated kinases 1/2 control claudin-2 expression in Madin-Darby canine kidney strain I and II cells.J Biol Chem, 2005, 280(5): 3780-3788
5 Jeschke MG, Herndon DN. Effect of growth factors as therapeutic drugs on hepatic metabolism during the systemic inflammatory response syndrome.Curr Drug Metab, 2004, 5(5): 399-413
6 Yoshimura S,Morishita R, Hayashi K,et al.Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model.Hypertension, 2002; 39 (5) : 1028- 1034
7陈紫榕主编.病毒性肝炎.北京:人民卫生出版社,2002 , 416-421
8 Wang X,Zhou Y,Kim HP. Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells. J Biol Chem, 2004, 279 (7) : 5237 - 5243
9 Nakagami H,Morishita R, Yamamoto K,et al. Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells.Diabetes, 2001,50(6):1472 - 1481
10 Antoku K,Maser RS,Scully WJ Jr,et al.Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein.Biochem Biophys Res Commun, 2001, 286 (5):1003 - 1010
11 Nakagami H ,Morishita R ,Yamamoto K,et al. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane.Diabetes ,2002 ,51(8):2604-2611
12 Taniyama Y,Morishita R ,Hiraoka K,et al.Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model : Molecular Mechanisms of Delayed Angiogenesis in Diabetes. Circulation ,2001 ,104 (19) :2344-2350
13郑超,文格波,曹仁贤,等.糖基化终末产物对人脐静脉内皮细胞凋亡及其受体表达的影响.中华内分泌代谢杂志, 2003, 19 (2) : 115 - 118
14 Miyata T,Wada Y,Cai Z, et al. Implication of an increased oxidative stress in the formation of advanced glycosylationend products in patients with endstage renal failure. Kidey Int,1997, 51 (4) : 1170– 1181
15付四海,黄久仪.糖基化终末产物与血管疾病.国外医学生理、病理科学与临床分册,2004,24(4):361-362
16 Jakus V,Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications.Physiol Res,2004,53(2):131 - 142
17 Gopalkrishnapillai B, Nadanathangam V, Karmakar N, et al. Evaluation of autofluorescent property of hemoglobin- advanced glycation end product as a long-term glycemic index of diabetes. Diabetes, 2003, 52 (4) : 1041 - 1046
18周一军,张锦,王佳贺.肝细胞生长因子对糖基化终产物诱导人脐静脉内皮细胞凋亡的抑制作用.中国组织化学与细胞化学杂志,2006,15(4):380-385
19 Hiratsuka A, Adachi H, Fujiura Y, et al. Strong as sociation between serum hepatocyte growth factor and metabolic syndrome. J Clin Endocrinol Metab. 2005,90(5):2927-2931
20 Capell WH,DeSouza CA,Poirier P, et al. Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia. Arterioscler Thromb Vasc Biol,2003,23(2):307-313
21 Okada M, Hojo Y, Ikeda U, et al. Interaction between monocytes and vascular smooth muscle cells induces expression of hepatocyte growth factor. J Hypertens, 2000,18(12):1825-1831
22 Wang M, Crisostomo PR, Herring C,et al. Humanprogenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. Am J Phys iol Regul Integr Comp Phys iol ,2006,291(4):R880-884
23 Nishimura M, Ushiyama M, Ohtsuka K, et al.Serum hepatocyte growth factor as a possible indicator of vascular lesions. J Clin Endocrinol Metab ,1999, 84(7): 247-248
24 Haug C , Schmid-Kotsas A , Zorn U , et al. Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release. Am J Physiol,2000,279(6): H2865-2871
25 Taniyama Y, Morishita R,Aoki M, et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease.Gene Ther, 2001,8(3):181-189
26 Morishita R,Aoki M,Hashiya N,et al.Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial.Hypertension,2004,44(2):203-206
2黄莹,周丽诺,胡仁明.糖尿病心血管自主神经病变检查方法的研究进展.国际内分泌代谢杂志,2007,27(1):50-53
3 Wassmann S ,Stumpf M,Strehlow K, et al. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res ,2004 ,94 (4) :534-541
4陈灏珠主编.内科学(第六版).北京:人民卫生出版社,2001:843
5 Marek Malik. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation ,1996 ,93(5) :1043-1065
6 Hoeldtke RD, Bryner KD, McNeill DR, et al. Nitrosative stress,uric acid, and peripheral nerve function in early type 1 diabetes . Diabetes, 2002, 51 (9) : 2817-2825
7 Vinik AI, Erbas T, Park TS, et al. Dermal neurovascular dysfunction in type 2 diabetes. Diabetes Care, 2001, 24 ( 8) : 1468-1475
8 Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic neuropathy. Diabetes Care, 2003, 26 (5) : 1553-1579
9 Maser RE, Mitchell BD, Vinik AI, et al.The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care,2003, 26 ( 6) : 1895-1901
10张宝慧.心脏康复研究的最新进展.中国临床康复,2003,7(1):4-5
11 Braune HJ , Geisendorfer U. Measurement of heart rate variations: influencing factors, normal values and diagnostic impact on diabetic autonomic neuropathy. Diabetes Research ,1995 ,29 (3) :179
12 Wang X, Zhou Y, Kim HP, et al. Hepatocyte growth factor protects against hypoxia /reoxygenation-induced apoptosis in endothelial cells. J Biol Chem, 2004, 279(7):5237-5243
13 Koyama J , Yokouchi K, Fukushima N , et al . Neurotrophic effect of hepatocyte growth factor on neonatal facial motor neurons.Neurol Res,2003,25(7):701-707
14于晓华,张锦,周一军.2型糖尿病合并大血管病变患者肝细胞生长因子水平观察.中国综合临床,2006,22(2):140-142
15 Haug C , Schmid-Kotsas A , Zorn U , et al. Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release. Am J Physiol Heart Circ Physiol,2000,279(6):2865-2871
16 Santini V,Ciampittiello G,Gigli F,et al . QTc and autonomic neuropathy in diabetes: Effects of acute hyperglycaemia and n-3 PUFA. Nutr Metab Cardiovasc Dis, 2007, 17(10), 712-718
17 Sheng WH, Chiang BL, Chang SC, et al. Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome. J FormosMed Assoc,2005,104(10):715-723
18 Wolfa M, Wolf D ,Rumpold H,et al . The kinase inhibitor imatinib mesylate inhibits TNF-{ alpha} production in vitro and prevents TNF-dependent acute hepatic inflammation . Proc Natl Acad Sci USA , 2005 ,102(38) :13622 - 13627
19 Mavridis G,Souliou E,Diza E, et al . Inflammatory cytokines in insulin-treated patients with type 2 diabetes. Nutr Metab Cardiovasc Dis,2008,18(7):471-476
20 Rabingovitch A. An up date on cytokmes in the pathogenesis of insulin independent diabetes mellitus. Diabetes Metab Rev , 1998 , (14): 129-134
21 Libra M,Signorelli SS,Bevelacqua Y ,et al . Analysis of G(-174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease.J Clin Pathol, 2006,59(2):211-215
22 Mastej K,Adamiec R . Neutrophil surface expression of CD11b and CD62L in diabetic microangiopathy. Acta Diabetol,2008,45(3):183-190
23张丽,陆颖理,王国兴等.TNF-α、IL-6与糖尿病神经病变的相关性及PGE1疗效的观察.全科医学临床与教育,2006,4(1):32-34
24 Marfella R,Giuqliano D,di Maro G ,et al.The squatting test: a useful tool to assess both parasympathetic and sympathetic involvement of the cardiovascular autonomic neuropathy in diabetes.Diabetes,1994,43(4):607-612
25荆春燕,叶山东.蹲踞试验对糖尿病心血管自主神经病变的诊断价值.新医学,2000,31(7):402-403
26杜登圣,宋月英,张子生等.糖尿病心脏自主神经病变检查的新方法—蹲踞试验.当代医师杂志,1998,3(4):9-11
27袁凤山,赵锦,张锦等.糖尿病患者心脏自主神经病变的电生理评估.中国临床康复,2004,8(24):5034-5036
28 Gonzalez Clemente JM,Vilardell C,Broch M, et al . Lower heart rate variability is associated with higher plasma concentrations of IL-6 in type 1 diabetes. European Journal of Endocrinology, 2007,157(1) :31–38
29郭继鸿,张海澄主编.动态心电图最新进展.北京:北京大学医学出版社, 2005: 86-119.
30罗昭林,陈禹,钟抗美,等.冠心病室性心动过速患者的心率变异性分析.临床心电学杂志,2005,14(1):371
31 Moran A , Palmas W, Field L , et al . Cardiovascular autonomic neuropathy is associated with microalbuminuria in older patients with type 2 diabetes. Diabetes Care , 2004 ,27(4) : 972-977
32 Kempler P ,Tesfaye S ,Chaturvedi N ,et al . Autonomic neuropathy is associated with increased cardiovascular risk factors :the EURODIAB IDDM Complications Study. Diabet Med,2002,19(11):900-906
1 Manganini M, Maier JA. Transforming growth factor beta- inhibition of hepatocyte growth factor-induced endothelial proliferation and migration.Oncogene, 2000,19(1):124-133
2 Schaeper U,Gehring NH,Fuchs KP,et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J Cell Biol, 2000, 149(7): 1419-1432
3 Gong R, Rifai A,Dworkin LD. Activation of PI3K-Akt- GSK3 beta pathway mediates hepatocyte growth factor inhibition of RANTES expression in renal tubular epithelial cells.Biochem Biophys Res Commun, 2005, 330(1): 27-33
4 Lipschutz JH,Li S,Arisco A. Extracellular signal-regulated kinases 1/2 control claudin-2 expression in Madin-Darby canine kidney strain I and II cells.J Biol Chem, 2005, 280(5): 3780-3788
5 Jeschke MG, Herndon DN. Effect of growth factors as therapeutic drugs on hepatic metabolism during the systemic inflammatory response syndrome.Curr Drug Metab, 2004, 5(5): 399-413
6 Yoshimura S,Morishita R, Hayashi K,et al.Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model.Hypertension, 2002; 39 (5) : 1028- 1034
7陈紫榕主编.病毒性肝炎.北京:人民卫生出版社,2002 , 416-421
8 Wang X,Zhou Y,Kim HP. Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells. J Biol Chem, 2004, 279 (7) : 5237 - 5243
9 Nakagami H,Morishita R, Yamamoto K,et al. Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells.Diabetes, 2001,50(6):1472 - 1481
10 Antoku K,Maser RS,Scully WJ Jr,et al.Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein.Biochem Biophys Res Commun, 2001, 286 (5):1003 - 1010
11 Nakagami H ,Morishita R ,Yamamoto K,et al. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane.Diabetes ,2002 ,51(8):2604-2611
12 Taniyama Y,Morishita R ,Hiraoka K,et al.Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model : Molecular Mechanisms of Delayed Angiogenesis in Diabetes. Circulation ,2001 ,104 (19) :2344-2350
13郑超,文格波,曹仁贤,等.糖基化终末产物对人脐静脉内皮细胞凋亡及其受体表达的影响.中华内分泌代谢杂志, 2003, 19 (2) : 115 - 118
14 Miyata T,Wada Y,Cai Z, et al. Implication of an increased oxidative stress in the formation of advanced glycosylationend products in patients with endstage renal failure. Kidey Int,1997, 51 (4) : 1170– 1181
15付四海,黄久仪.糖基化终末产物与血管疾病.国外医学生理、病理科学与临床分册,2004,24(4):361-362
16 Jakus V,Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications.Physiol Res,2004,53(2):131 - 142
17 Gopalkrishnapillai B, Nadanathangam V, Karmakar N, et al. Evaluation of autofluorescent property of hemoglobin- advanced glycation end product as a long-term glycemic index of diabetes. Diabetes, 2003, 52 (4) : 1041 - 1046
18周一军,张锦,王佳贺.肝细胞生长因子对糖基化终产物诱导人脐静脉内皮细胞凋亡的抑制作用.中国组织化学与细胞化学杂志,2006,15(4):380-385
19 Hiratsuka A, Adachi H, Fujiura Y, et al. Strong as sociation between serum hepatocyte growth factor and metabolic syndrome. J Clin Endocrinol Metab. 2005,90(5):2927-2931
20 Capell WH,DeSouza CA,Poirier P, et al. Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia. Arterioscler Thromb Vasc Biol,2003,23(2):307-313
21 Okada M, Hojo Y, Ikeda U, et al. Interaction between monocytes and vascular smooth muscle cells induces expression of hepatocyte growth factor. J Hypertens, 2000,18(12):1825-1831
22 Wang M, Crisostomo PR, Herring C,et al. Humanprogenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. Am J Phys iol Regul Integr Comp Phys iol ,2006,291(4):R880-884
23 Nishimura M, Ushiyama M, Ohtsuka K, et al.Serum hepatocyte growth factor as a possible indicator of vascular lesions. J Clin Endocrinol Metab ,1999, 84(7): 247-248
24 Haug C , Schmid-Kotsas A , Zorn U , et al. Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release. Am J Physiol,2000,279(6): H2865-2871
25 Taniyama Y, Morishita R,Aoki M, et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease.Gene Ther, 2001,8(3):181-189
26 Morishita R,Aoki M,Hashiya N,et al.Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial.Hypertension,2004,44(2):203-206