糖尿病视网膜病变患者血清胎球蛋白A水平的变化及其与CRP的相关性

引用本文

周中卫, 孙明忠, 居会祥, 季禹乔, 顾娟, 季飞, 丁福万, 江冬梅. 糖尿病视网膜病变患者血清胎球蛋白A水平的变化及其与CRP的相关性. 2014, 29(10): 1034-1036[ZHOU Zhongwei, SUN Mingzhong, JU Huixiang, JI Yuqiao, GU Juan, JI Fei, DING Fuwan, JIANG Dongmei. The changes of serum alpha2-Heremans-Schmid glycoprotein level and its correlation with CRP in patients with diabetic retinopathy. Labratory Medicine, 2014, 29(10): 1034-1036] 复制到剪切板

Permissions

《检验医学》编辑部

糖尿病视网膜病变患者血清胎球蛋白A水平的变化及其与CRP的相关性

周中卫¹, 孙明忠¹, 居会祥¹, 季禹乔¹, 顾娟¹, 季飞², 丁福万³, 江冬梅³

1.东南大学医学院附属盐城医院检验科,江苏盐城 224001

2.东南大学医学院附属盐城医院眼科,江苏盐城 224001

3. 东南大学医学院附属盐城医院内分泌科,江苏盐城 224001

作者简介:周中卫,男,1975年生,硕士,主管技师,主要从事临床生化及分子生物学研究。

摘要

目的

探讨糖尿病视网膜病变(DR)患者血清胎球蛋白A(AHSG)水平的变化及其与C反应蛋白(CRP)的相关性。

方法

选取2型糖尿病(T2DM)患者115例,分为糖尿病无视网膜病变(NDR)组46例、非增生性糖尿病视网膜病变(NPDR)组37例、增生性糖尿病视网膜病变(PDR)组32例;另选取正常对照组40名。采用酶联免疫吸附试验(ELISA)测定血清AHSG与CRP水平。

结果

NDR组、NPDR组及PDR组血清AHSG及CRP水平均高于正常对照组,组间比较及组内两两比较差异均有统计学意义(P<0.05,P<0.01)。T2DM患者的血清AHSG水平与CRP呈正相关(r=0.239,P<0.05)。

结论

AHSG水平升高与DR的病情严重程度有关,其可能通过促炎性效应参与DR的发生、发展。

关键词: 糖尿病视网膜病变; 胎球蛋白A; C反应蛋白

中图分类号:R446.1 文献标志码:A 文章编号:1673-8640(2014)10-1034-03

The changes of serum alpha2-Heremans-Schmid glycoprotein level and its correlation with CRP in patients with diabetic retinopathy

ZHOU Zhongwei¹, SUN Mingzhong¹, JU Huixiang¹, JI Yuqiao¹, GU Juan¹, JI Fei², DING Fuwan³, JIANG Dongmei³

1.Department of Clinical Laboratory, Yancheng Hospital, Southeast University School of Medicine, Jiangsu Yancheng 224001, China

2. Department of Ophthalmology, Yancheng Hospital, Southeast University School of Medicine, Jiangsu Yancheng 224001, China

3. Department of Endocrinology, Yancheng Hospital, Southeast University School of Medicine, Jiangsu Yancheng 224001, China

Abstract

Objective

To investigate the changes of serum alpha2-Heremans-Schmid glycoprotein(AHSG)level and its correlation with C-reactive protein (CRP) in patients with diabetic retinopathy (DR).

Methods

Serum levels of AHSG and CRP were determined by enzyme-linked immunosorbent assay (ELISA) in 115 type 2 diabetes mellitus(T2DM) patients, and the 115 T2DM patients were classified into 3 groups, 46 patients with non-diabetic retinopathy(NDR), 37 patients with non-proliferative diabetic retinopathy (NPDR) and 32 patients with proliferative diabetic retinopathy (PDR). A total of 40 healthy controls were enrolled.

Results

The serum levels of AHSG and CRP in NDR group, NPDR group and PDR group were higher than that in healthy control group, and there was statistical significance among the groups(P<0.05,P<0.01). Serum AHSG level in T2DM patients was positively correlated with CRP (r=0.239,P<0.05).

Conclusions

The increasing of AHSG level is correlated with the severity of DR, and it may be involved in the development and pathogenesis of DR by proinflammatory effects.

Keyword: Diabetic retinopathy; Alpha2-Heremans-Schmid glycoprotein; C-reactive protein

Show Figures

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病最常见的微血管并发症之一,随着糖尿病成为一种世界范围内的流行病,DR的发病率呈逐年增加趋势。DR的具体致病机制至今尚未完全阐明。胎球蛋白A(alpha2-heremans-schmid glycoprotein, AHSG)作为一种新型的生物标志物,在糖尿病及其多种并发症中表达增高,并参与其发生、发展^{[ 1]}。但AHSG和DR的关系目前在国内、外文献中报道甚少。C反应蛋白(C reactive protein,CRP)是一种急性时相反应蛋白,是糖尿病血管并发症最重要的的预示因子及危险因子之一^{[ 2]}。本研究通过检测2型糖尿病(type 2 diabetes mellitus,T2DM)合并视网膜病变患者不同进展阶段血清AHSG水平的变化,并分析其与CRP的相关性。

材料和方法

一、研究对象

选取2013年3月至2013年12月于东南大学医学院附属盐城医院就诊的T2DM患者115例,所有患者均符合1999年世界卫生组织(WHO)制定的糖尿病诊断标准。按照1984年中华医学会眼科学会眼底病学组讨论制定的《糖尿病视网膜病变分期标准》,根据患者眼底镜检查及眼底荧光血管造影结果将T2DM患者分为糖尿病无视网膜病变(non-diabetic retinopathy,NDR)组 46 例,男25例,女21例,平均年龄(59.76±8.82)岁;非增生性糖尿病视网膜病变(non-proliferative diabetic retinopathy,NPDR)组37例,男19例,女18例,平均年龄(60.85±9.73)岁;增生性糖尿病视网膜病变(proliferative diabetic retinopathy,PDR)组 32例,男17例,女15例,平均年龄(61.29±9.52)岁。另选择我院同期健康体检者40名为正常对照组,男22名,女18名,平均年龄(60.15±8.76)岁。空腹糖耐量正常,无糖尿病家族史,双眼眼底检查正常。所有入选者均通过超声检查排除非酒精性脂肪肝(NAFLD)、排除急慢性感染、肝、肾功能不全、眼部疾病及其它内分泌系统疾病等。

二、方法

所有受试者于清晨空腹采集静脉血,取3 mL分离血清后置-70 ℃冰箱保存,另取3 mL分离血清后即行检测血清CRP水平。AHSG采用酶联免疫吸附试验(ELISA)检测,试剂盒购自捷克BioVendor公司,批内变异系数( CV)为2.7%,批间 CV为3.2%,操作过程严格按照试剂盒说明书进行,使用美国Thermo MK3型酶标仪在450 nm处读取 OD值。CRP检测采用散射比浊法,使用Beckman-coulter IMMAGE 800 特种蛋白分析仪及其配套试剂。

三、统计学方法

采用SPSS 17.0统计软件进行统计分析。正态分布的数据用{Invalid MML} ±s表示,偏态分布的数据用中位数(四分位数)表示。正态分布的数据多组间比较采用单因素方差分析,组内两两比较用SNK- q检验;偏态分布的数据多组间比较用Kruskal-Wallis H检验,组内两两比较用Nemenyi检验;用Person 相关分析, P<0.05为差异有统计学意义。

结果

一、正常对照组与NDR组、NPDR组、PDR组血清AHSG及CRP水平检测结果比较

4组间血清AHSG及CRP水平比较差异均有统计学意义( P<0.01);NDR组、NPDR组及PDR组间血清AHSG及CRP水平均比较,差异均有统计学意义( P<0.05);NPDR组高于NDR组、PDR组高于NPDR组、组内两两比较差异均有统计学意义( P<0.05),结果见表1。

表1 正常对照组与NDR组、NPDR组、PDR组血清AHSG及CRP水平检测结果比较

三、相关性分析

相关分析表明,T2DM患者血清AHSG与CRP水平呈正相关( r=0.239, P<0.05),见图1。

	Figure Option View Download New Window
	图1 T2DM患者血清AHSG与CRP水平的相关性

讨论

AHSG主要是由肝脏合成并分泌的一种多功能糖蛋白,其最初是从胎牛血清中分离获得,在人的血清或血浆中也有表达^{[ 3]}。影响AHSG表达水平的因素较多,肝脏功能严重受损时,其表达水平会明显异常,在NAFLD患者中,AHSG表达水平呈明显增高^{[ 4]}。因此,本研究所选择的病例及正常对照人群均通过超声检查排除NAFLD。AHSG与T2DM血管并发症的发生发展密切相关,在T2DM合并心血管疾病、冠状动脉疾病及外周血管疾病等并发症中表达水平明显增高,且与病变严重性呈正相关^{[ 1, 5]}。之前的相关研究发现,AHSG在T2DM合并糖尿病肾病患者中表达水平明显升高,且与蛋白尿严重程度呈正相关^{[ 6]}。本研究结果显示,AHSG表达水平在DR患者中亦明显增高,进一步表明了其与糖尿病微血管病变的相关性。本研究中,在DR的不同发展阶段,即NDR期、NPDR期及PDR期,AHSG表达水平依次增高,提示其与DR的发生、发展密切相关,可能作为评估DR病情严重程度的标志物。

此外,本研究结果显示,在T2DM患者的NDR期、NPDR期及PDR期,血清CRP水平依次升高,提示DR的发生、发展和炎症的相关性。CRP是非特异性炎症的敏感标志物,随着T2DM病情的不断发展,CRP水平将持续升高^{[ 7]},同时,血清CRP等炎性细胞因子是糖尿病微血管并发症发生、发展的重要标志物^{[ 8]}。有研究发现,CRP能够刺激视网膜血管内皮细胞产生氧自由基,使氧化代谢产物增多从而引起局部炎症,继而导致血管内皮细胞功能障碍或直接损伤血管内皮细胞导致视网膜的微血管病变,最终导致DR的发生^{[ 9]}。本研究还观察到,随着DR病情的不断发展,血清AHSG水平随CRP水平不断升高,两者呈正相关,提示AHSG与炎性因子的相关性。Siegel等^{[ 10]}最新研究表明,AHSG能够通过调节血管周围的脂肪细胞活性从而产生促炎性效应。此外,AHSG还能够刺激单核细胞分泌某些细胞因子从而导致某些器官和组织产生慢性炎症^{[ 11]}。因此,本研究提示AHSG在DR发生、发展中可能产生促炎性效应。

综上所述,AHSG与DR的病情严重程度有关,可作为评估DR病情严重程度的标志物,其可能通过促炎性效应参与DR的发生、发展,但其具体的生理、病理机制尚待进一步研究。

The authors have declared that no competing interests exist.

参考文献

View Option

[1]	Vörös K, Cseh K, Kalabay L. The role of fetuin-A in cardiovascular diseases[J]. Orv Hetil, 2014, 155(1): 16-23. [本文引用:2]
[2]	Mugabo Y, Li L, Renier G. The connection between C-reactive protein (CRP) and diabetic vasculopathy. Focus on preclinical findings[J]. Curr Diabetes Rev, 2010, 6(1): 27-34. [本文引用:1]
[3]	Mori K, Emoto M, Inaba M. Fetuin-A: a multifunctional protein[J]. Recent Pat Endocr Metab Immune Drug Discov, 2011, 5(2): 124-146. [本文引用:1]
[4]	Haukeland JW, Dahl TB, Yndestad A, et al. Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies[J]. Eur J Endocrinol, 2012, 166(3): 503-510. [本文引用:1] [JCR: 3.136]
[5]	Zhao ZW, Lin CG, Wu LZ, et al. Serum fetuin-A levels are associated with the presence and severity of coronary artery disease in patients with type 2 diabetes[J]. Biomarkers, 2013, 18(2): 160-164. [本文引用:1] [JCR: 1.879]
[6]	居会祥, 周中卫, 孙明忠, 等. 2型糖尿病患者血清胎球蛋白 A 水平与糖尿病肾病的相关性[J]. 中华内分泌代谢杂志, 2014, 30(7): 592-594. [本文引用:1]
[7]	el-Mesallamy H, Suwailem S, Hamdy N. Evaluation of C-reactive protein, endothelin-1, adhesion molecule(s), and lipids as inflammatory markers in type 2 diabetes mellitus patients[J]. Mediators Inflamm, 2007, 2007: 73635. [本文引用:1] [JCR: 3.882]
[8]	张庆五, 忻鼎广, 林洁, 等. 血清vWF、IL-6、CRP与糖尿病患者血管病变的相关性分析[J]. 检验医学, 2008, 23(1): 21-23. [本文引用:1]
[9]	Tomic'M, Ljubic'S, Kastelan S. The role of inflammation and endothelial dysfunction in the pathogenesis of diabetic retinopathy[J]. Coll Antropol, 2013, 37(Suppl 1): 51-57. [本文引用:1]
[10]	Siegel-Axel DI, Ullrich S, Stefan N, et al. Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells[J]. Diabetologia, 2014, 57(5): 1057-1066. [本文引用:1] [JCR: 6.487]
[11]	Hennige AM, Staiger H, Wicke C, et al. Fetuin-A induces cytokine expression and suppresses adiponectin production[J]. PLoS One, 2008, 3(3): e1765. [本文引用:1] [JCR: 3.73]

2014

0.0

... 胎球蛋白A(alpha2-heremans-schmid glycoprotein, AHSG)作为一种新型的生物标志物,在糖尿病及其多种并发症中表达增高,并参与其发生、发展^[1] ...

... AHSG与T2DM血管并发症的发生发展密切相关,在T2DM合并心血管疾病、冠状动脉疾病及外周血管疾病等并发症中表达水平明显增高,且与病变严重性呈正相关^[1,5] ...

2010

0.0

... C反应蛋白(C reactive protein,CRP)是一种急性时相反应蛋白,是糖尿病血管并发症最重要的的预示因子及危险因子之一^[2] ...

2011

0.0

... 讨论AHSG主要是由肝脏合成并分泌的一种多功能糖蛋白,其最初是从胎牛血清中分离获得,在人的血清或血浆中也有表达^[3] ...

2012

3.136

0.0

... 影响AHSG表达水平的因素较多,肝脏功能严重受损时,其表达水平会明显异常,在NAFLD患者中,AHSG表达水平呈明显增高^[4] ...

2013

1.879

0.0

2014

0.0

... 之前的相关研究发现,AHSG在T2DM合并糖尿病肾病患者中表达水平明显升高,且与蛋白尿严重程度呈正相关 ^[6] ...

2007

3.882

0.0

... CRP是非特异性炎症的敏感标志物,随着T2DM病情的不断发展,CRP水平将持续升高^[7],同时,血清CRP等炎性细胞因子是糖尿病微血管并发症发生、发展的重要标志物^[8] ...

2008

0.0

2013

0.0

... 有研究发现,CRP能够刺激视网膜血管内皮细胞产生氧自由基,使氧化代谢产物增多从而引起局部炎症,继而导致血管内皮细胞功能障碍或直接损伤血管内皮细胞导致视网膜的微血管病变,最终导致DR的发生^[9] ...

2014

6.487

0.0

Diabetologia. 2014, 57(5):1057-1066

Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells

Dorothea I. Siegel-Axel (1) (2) (3) , Susanne Ullrich (1) (2) (3) , Norbert Stefan (1) (2) (3) , Kilian Rittig (1) , Felicia Gerst (1) (2) (3) , Christian Klingler (1) , Ulrike Schmidt (1) , Birgit Schreiner (1) , Elko Randrianarisoa (1) , Hans-Eberhard Schaller (4) , Ulrich A. Stock (5) (6) , Cora Weigert (1) (2) (3) , Alfred Königsrainer (7) , Hans-Ulrich Häring (1) (2) (3)

1. Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany 2. Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Tübingen, Germany 3. German Center for Diabetes Research (DZD), Tübingen, Germany 4. Department of Plastic, Hand and Reconstructive Surgery, BG-Trauma-Center, Eberhard Karls University Tübingen, Tübingen, Germany 5. Department of Thoracic, Cardiac and Vascular Surgery, University Hospital Tübingen, Tübingen, Germany 6. Department of Thoracic, Cardiac and Thoracic Vascular Surgery, University Hospital Frankfurt, Frankfurt, Germany 7. Department of General Visceral and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany

Fetuin-A (alpha2-Heremans-Schmid glycoprotein), a liver-derived circulating glycoprotein, contributes to lipid disorders, diabetes and cardiovascular diseases. In a previous study we found that perivascular fat cells (PVFCs) have a higher angiogenic potential than other fat cell types. The aim was to examine whether fetuin-A influences PVFC and vascular cell growth and the expression and secretion of proinflammatory and angiogenic proteins, and whether TLR4 -independent pathways are involved.

... Siegel等^[10]最新研究表明,AHSG能够通过调节血管周围的脂肪细胞活性从而产生促炎性效应 ...

2008

3.73

0.0

PLoS ONE. 2008, 3(3):e1765-null

Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production

Fausto Machicao 1 ,Harald Staiger 1 ,Hans-Ulrich Häring 1 ,Corinna Wicke 2 ,Norbert Stefan 1 ,Andreas Fritsche 1 ,Anita M. Hennige 1

1 Department of Internal Medicine, Division of Endocrinology, Nephrology, Vascular Disease and Clinical Chemistry, University of Tübingen, Tübingen, Germany 2 Department of General, Visceral and Transplantation Surgery, University of Tübingen, Tübingen, Germany

Background The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. Methodology and Principal Findings Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p Conclusions and Significance We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.

... 此外,AHSG还能够刺激单核细胞分泌某些细胞因子从而导致某些器官和组织产生慢性炎症^[11] ...