2型糖尿病合并急性冠状动脉综合征急性期血糖变异性对血管生成素2和内质网应激变化影响的研究

Study of glycemic fluctuation impact on angiopoietin-2 and endoplasmic reticulum stress in type 2 diabetes complicated with acute phase of acute coronary syndrome

目的 探讨血糖波动对2型糖尿病急性冠状动脉综合征（ACS）患者急性期血管生成素2（angiopoietin-2,Ang-2）与内质网应激的变化及对ACS危险性的影响.方法 连续入选78例糖尿病合并ACS患者,ACS病程＜7 d.并选择78例无AGS的糖尿病患者作对照,用全球急性冠状动脉事件（GRACE）评分评估ACS患者危险度;采用动态血糖检测系统（CGMS）进行3d的血糖监测;分别用实时PCR和Western印迹法检测Ang-2、内质网应激相关基因重链结合蛋白（Bip）、肌醇需求蛋白激酶Ⅰ（IREI）、类PKR的内质网应激酶（PERK）、氧调节蛋白150（ORP150）、转录激活因子6（ATF6）、X盒结合蛋白1（XBP1）、磷酸化的真核翻译起始因子2α（p-eIF2α）和单核细胞趋化蛋白1（MCP-1）mRNA和蛋白表达变化;对2组间参数进行比较;同时将血糖波动参数与Ang-2内质网应激相关基因和MCP-1也进行相关性分析;将血糖波动参数、Ang-2和内质网应激相关基因与GRACE评分进行相关分析.结果 （1）ACS组的日平均血糖波动幅度（MA GE）、日间血糖平均绝对差（MODD）、平均餐后血糖波动幅度（MPPGE）和最大血糖波动幅度（LAGE）明显高于对照组（均P＜0.05）.（2）ACS组Ang-2、内质网相关基因Bip、IREI、PERK、ORP150、ATF6、XBP1、p-eIF2α和MCP-1 mRNA表达量与对照组比较均有统计学差异（均P＜0.05）.（3）在ACS组中,作pearson相关分析,Ang-2与MAGE、LAGE、MPPGE相关（r=0.432、0.279、0.386,均P＜0.05）,Bip与MAGE、LAGE、MPPGE相关（r=0.783、0.589、0.887,均P＜0.05）;IREI与MAGE、LAGE、MPPGE、MODD相关（r=0.567、0.783、0.569、0.823,均P＜0.05）;PERK与MAGE、MPPGE、MODD相关（r=0.687、0.902、0.709,均P＜0.05）;ORP150与MAGE、LAGE、MPPGE、MODD相关（r=0.779、0.871、0.775、0.689,均P＜0.05）;ATF6与MAGE、LAGE、MPPGE、MODD相关（r=0.873、0.675、0.893、0.884,均P＜0.05）,而XBP1与血糖波动无相关性（P＞0.05）.（4）内质网应激相关基因、MCP-1与血糖波动参数相关.（5）多元Logistic逐步回归分析血糖波动是内质网应激相关基因、Ang-2和GRACE的危险因素,LAGE、MPPGE、Bip、IREI、PERK、ORP150、ATF6是影响Ang-2的危险因素;而Ang-2、年龄、MAGE、稳态模型评估的胰岛素抵抗指数（HOMA-IR）、Bip、ATF6是影响GRACE的危险因素.（6） ACS患者射血分数水平与MAGE、LAGE均呈负相关性,多元线性回归分析显示年龄、HOMA-IR、Ang-2、和MAGE、Bip、ATF6可与射血分数建立线性回归关系.结论 血糖波动使得Ang-2升高和导致内质网应激增加,还可能与心脏收缩功能受损有关.增加了患者的危险度,并影响了2型糖尿病合并ACS患者的预后.

Objective To investigate the changes in angiopoietin 2 and endoplasmic reticulum stress,and the prognosis of acute phase of coronary syndrome （ACS） in type 2 diabetic patients with glycemic fluctuations.Methods Seventy-eight cases of consecutive diabetic patients with ACS within 7 days were enrolled.Another 78 cases of non-diabetic patients with ACS were selected as control.Risk assessment with global acute coronary events （GRACE） score in patients with ACS,dynamic blood glucose monitoring system （CGMS） for three days,realtime PCR analysis of angiopoietin-2,within the reticulum stress-related heavy chain binding protein （Bip）,inositol kinase demand Ⅰ （IREI）,endoplasmic reticulum class should PKR kinase （PERK）,oxygen-regulated protein 150 （ORP150）,activating transcription factor 6 （ATF6）,X-box binding protein 1 （XBP1）mRNA expression change,phosphorylation of eukaryotic translation initiation factor 2oα （p-eIF2α） by western blotting angiopoietin-2,parameters were compared between the two groups.Correlation analysis with GRACE score ; while angiopoietin-2 parameters and glycemic fluctuation,endoplasmic reticulum stress-related genes correlation analysis were made.Results （1） ACS group average daily blood glucose fluctuations（MAGE）,mean absolute difference daytime blood glucose （MODD）,and postprandial blood glucose fluctuation （MPPGE） and the maximum amplitude of glycemic excursions （LAGE） were significantly higher [MAGE（5.13 ± 1.19） vs （3.19 ± 0.55） mmol/L,MODD （2.59 ± 0.72） vs （1.72 ± 0.63） mmol/L; MPPGE （3.51 ± 1.01） vs （2.58 ± 0.55） mmol/L and LAGE （7.75 ± 2.39） vs （4.34 ± 0.85） mmol/L,all P＜0.05].（2）In ACS group angiopoietin-2,endoplasmic reticulum associated genes Bip,IREI,PERK,ORP150,ATF6,XBP1,and monocyte chemoattractant protein 1 （MCP-1） mRNA expression levels as compared with the control group were statistically significant（all P＜0.05） ; Angiopoietin-2,protein p-eIF2α were higher（P＜0.05）.（3） In the ACS group with pearson correlation analysis,angiopoietin-2 and MAGE,LAGE,MPPGE correlation （r =0.432,0.279,0.386,all P＜0.05）,Bip and MAGE,LAGE,MPPGE correlation（r =0.783,0.589,0.887,all P＜ 0.05） ; IREI and MAGE,LAGE,MPPGE,MODD correlation （r =0.567,0.783,0.569,0.823,all P＜0.05） ; PERK and MAGE,MPPGE,MODD correlation（r =0.687,0.902,0.709,all P＜0.05） ; ORP150 and MAGE,LAGE,MPPGE,MODD correlation（r=0.779,0.871,0.775,0.689,all P＜0.05） ; ATF6 and MAGE,LAGE,MPPGE,MODD correlation（r =0.873,0.675,0.893,0.884,all P＜0.05）,while XBP1 with no correlation with glycemic fluctuations （P＞0.05）.（4） The endoplasmic reticulum stress gene was related to MCP-1 and blood glucose fluctuation parameters.（5） Multiple Logistic regression analysis revealed that LAGE,MPPGE,Bip,IREI,PERK,ORP150,ATF6 were risk factors affecting angiopoietin-2,and angiopoietin-2,ages,MAGE,homeostasis model assessment for insulin resistance,Bip,ATF6 were risk factors affecting GRACE.（6） The ejection fractions of the ACS patients showed negative correlation with MAGE and LAGE,multiple linear regression analysis showed that age,HOMA-IR,Ang-2,and MAGE,Bip,ATF6 established the linear regression relation with ejection fraction.Conclusion Glycemic fluctuations cause angiopoietin-2 to rise and lead to increased endoplasmic reticulum stress and affect the prognosis of diabetic patients with ACS.