【作者】 王素星；

【导师】 王瑞英；

【作者基本信息】 河北医科大学 ， 内科学， 2009， 硕士

【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。更多还原

【Abstract】 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 conditionsCompared 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-6Compared 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 HRVCompared 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 testThere 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 groups5.1 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 complicationsAmong 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.更多还原