内脂素及肿瘤坏死因子-α与2型糖尿病大血管并发症的关系
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摘要
目的：
2型糖尿病患者的大血管病变发生率很高,大血管病变主要指主动脉、冠状动脉、脑动脉、肾动脉及外周动脉等大、中动脉的粥样硬化,临床上常见的疾病有冠心病、脑卒中和下肢动脉硬化、坏疽等,调查显示大血管病变是糖尿病患者致死、致残的最主要的原因之一,其发生机制非常复杂,研究表明其病理改变是动脉粥样硬化(atherosclerosis, AS),主要病理基础是由多因素相互协作所形成的慢性、亚临床炎症以及炎症导致的胰岛素抵抗。内脂素(Visfatin)是新近发现的一个脂肪细胞因子,具有结合并激活胰岛素受体和模拟胰岛素的作用,参与糖脂代谢。研究发现其与胰岛素抵抗、糖尿病、动脉粥样硬化、肥胖等关系密切。肿瘤坏死因子-α(TNF-α)来自多种细胞参与慢性炎症和胰岛素抵抗。本文通过检测不同组别患者的内脂素、TNF-α的水平,以探讨其与2型糖尿病及其大血管并发症的关系。
研究方法：
入选的60例2型糖尿病患者为郑州大学第一附属医院2009年01月份到2009年06月份老年病科的住院患者,均符合1999年WHO糖尿病的诊断和分型标准。根据是否合并大血管病将其分为2组(MVC：大血管病变组30例；Non-MVC:非大血管病变组30例)。大血管病变者入选必须符合以下至少一条标准：①动态心电图和超声心动图或冠脉造影确诊的临床型冠心病；②头颅CT确诊的脑梗死；③多普勒超声检查颈动脉和(或)双下肢动脉血管壁硬化斑快或血栓形成。二组均排除下列情况：各种急慢性感染；各种2型糖尿病急性并发症；视网膜病变、肾脏病变等慢性并发症；各种肿瘤；其他内分泌疾病；1月内使用胰岛素、胰岛素增敏剂、降脂药物及长期服用糖皮质激素者。正常对照组：30例,为同期来我院进行常规健康体检的正常者。所有受检者采空腹肘静脉血,采用酶联免疫吸附法测定血清内脂素、TNF-α,检测空腹血糖(FPG)、空腹胰岛素(FINS)、糖化血红蛋白(HbA1c)、血脂等指标,并计算BMI、WHR及HOMA-IR,分析2型糖尿病及其大血管病变患者血清内脂素、TNF-α的含量变化及其影响因素。
所有数据均采用SPSS17.0统计软件包处理。数据用均数±标准差(x±s)表示,各组间比较采用t检验,多组间比较用方差分析,并进行直线相关分析、多元线性逐步回归分析及Logistic回归分析,以P<0.05为差异有统计学意义。
结果：
(1)与对照组相比,2型糖尿病各组患者血清内脂素、TNF-α水平均显著升高(P<0.01,P<0.01)；与非大血管病变组(Non-MVC组)相比,大血管病变组(MVC组)血清内脂素、TNF-α水平显著升高(P<0.05,P<0.01)。
(2) Visfatin与其他指标的相关性将BMI、WHR、HbA1c、FPG、TC、HOMA-IR等指标分别与Visfatin进行简单相关分析。Visfatin与BMI、WHR、FPG、FINS、HOMA-IR、TNF-α、HbA1c、TC呈正相关(P<0.01,P<0.05)。以Visfatin为因变量,以BMI、WHR、HbA1c、FPG、FINS、TC、HOMA-IR、TNF-α为自变量行多元线性逐步回归分析,WHR、HOMA-IR、BMI、FPG进入回归方程,F=175.442,P<0.01,方程有效,说明WHR、HOMA-IR、BMI、FPG是影响Visfatin水平的因素。
(3)TNF-α与其他指标的相关性将BMI、WHR、HbA1c、FPG、TC、HOMA-IR等指标分别与TNF-α进行简单相关分析。TNF-α与BMI、HbA1c、FPG、FINS、HOMA-IR、Visfatin、WHR、TG呈正相关(P<0.01,P<0.05)。以TNF-α为因变量,以BMI、WHR、HbA1c、FPG、FINS、TG、HOMA-IR、Visfatin为自变量行多元线性逐步回归分析,HOMA-IR、HbA1c、BMI进入回归方程,F=169.728,P<0.01,方程有效,说明HOMA-IR、HbA1c、BMI是影响TNF-α水平的因素。
(4)T2DM大血管病变危险因素分析以T2DM为整体,有无大血管病变为因变量Y(有=1,无=0)。以BMI、WHR、HbA1c、FPG、FINS、TC、TG、LDL-C、HDL-C、HOMA-IR、TNF-α、Visfatin等为自变量,进行Logistic回归分析,最后Visfatin、TNF-α进入回归方程。
结论：
(1)2型糖尿病各组血清内脂素、TNF-α浓度较对照组均显著升高,提示内脂素、TNF-α参与2型糖尿病的发生、发展。(2)2型糖尿病大血管病变组血清内脂素、TNF-α浓度较非大血管病变组显著升高；且Logistic回归分析结果内脂素、TNF-α是2型糖尿病大血管并发症的重要危险因素,表明内脂素、TNF-α与2型糖尿病大血管并发症的形成有关。(3)WHR、HOMA-IR、BMI、FPG是影响Visfatin水平的因素,HOMA-IR、HbA1c、BMI是影响TNF-α水平的因素。提示糖尿病患者内脂素、TNF-α水平升高可能跟肥胖、胰岛素抵抗、糖尿病等因素有关,并且相互影响共同促进了糖尿病大血管病变的发展。
Objictive:
Type 2 diabetes mellitus have a high incidence of macro-vascular complication. Macroangiopathy refers primarily to the aorta, coronary, cerebral arteries, renal arteries and limb peripheral arteries and other large, medium artery atherosclerosis. The common clinic disease is coronary heart diaease, cerebral stroke, lower limbs arteriosclerosis and gangrene, et al. In diabetic patients, mortality and disability are mainly related to the presence of chronic macro-vascular complications. The pathogenic mechanism of diabetic vascular complications is very complicated. Studies have shown that the pathological changes are atherosclerosis (atherosclerosis, As), the main pathological basis is formed by multi-factor interaction of chronic and subclinical inflammation and insulin resistance caused by inflammation. Visfatin is a newly discovered adipocytokines, It has the role of combining and activating the insulin receptor and has the role of insulin analog, It participated in glucose andlipid metabolism. The study found that visfatin is closely linked with insulin resistance, diabetes, atherosclerosis, obesity, and so on. Tumor necrosis factor-a (TNF-a) from a variety of cells involved in chronic inflammation and insulin resistance. In order to explore the relationship between the visfatin or tumor necrosis factor-a and the diabetic macro-vascular complication, the levels of visfatin or tumor of different groups were measured by ELISA.
Methods:
60 patients with T2DM (1999 WHO diagnostic standards) were selected for this study. They are from the inpatients of Geriatrics of the First Affiliated Hospital of Zhengzhou University in January 2009 to June 2009. They are in line with 1999 WHO classification and diagnosis standards of diabetes. They were divided into two groups based on the presence or absence of diabetic macro-vascular complications (MVC) (Diabetic macro-vascular complications are 30 case and Non-diabetic macro-vascular complications are 30). Macro-vascular complications selected must meet one of the following criteria at least:①dynamic ECG and echocardiography or coronary angiography confirmed the clinical coronary artery disease;②head CT confirmed cerebral infarction;③Artery Doppler ultrasound found carotid and (or) pairs of lower extremity arterial wall sclerosis plaques sooner or thrombosis. The 30 cases of normal control group from the healthy volunteers who come to my hospital for routine health examination at the same period. Visfatin and tumor necrosis factor-a were measured by enzyme linked immunosorbent assay (ELISA), and others markers related to macro-vascular complications were also measured. We analyzed the change tendency and influential factors of visfatin and tumor necrosis factor-a in type 2 diabetic patients with or without macro-vascular complications. All the statistical analysis were dealt with SPSS 17.0 software.
Results:
(1) Compared with normal controls, the serum levels of Visfatin and TNF-a were significantly increased (P<0.01,P<0.01); Compared with Non-MVC group, the serum levels of Visfatin and TNF-a were increased (P<0.05,P<0.01) in MVC group.
(2) By multiple stepwise regression analysis, WHR、HOMA-IR、BMIand FPG were the influential factors of Visfatin (F=175.442, P<0.01).
(3) By multiple stepwise regression analysis, HOMA-IR、HbA1c and BMI were the influential factors of TNF-α(F=169.728, P<0.01).
(4) The multiple stepwise logistic regression analysis was used to define the association between Visfatin, TNF-α, other related indexes and macrovascular complications. Age, Visfatin, TNF-αwere related significantly with diabetic macrovascular complications.
Conclusion:
(1) The serum levels of visfatin and TNF-αare both increased remarkably in type 2 diabetis mellitus as compared with normal control group, this indicate visfatin and tumor necrosis factor-αare related to the occurrence and development of type 2 diabetes mellitus. (2) The serum levels of visfatin and TNF-αare both increased remarkably in MVC group as compared with Non-MVC group, Also, The multiple stepwise logistic regression analysis indicates that visfatin and TNF-αare important risk factors of diabetic macrovascular complications, those indicate visfatin and tumor necrosis factor-αare related to the formation of macrovascular complications in type 2 diabetes. (3) WHR、HOMA-IR、BMI and FPG were the influential factors of visfatin, HOMA-IR、HbA1c and BMI were the influential factors of TNF-α, Those suggest that the elevated levels of visfatin, tumor necrosis factor-αin type 2 diabetes mellitus due to obesity, insulin resistance, diabetes and other factors, And they influence each other and jointly accelerate the development of diabetic angiopathies.
2型糖尿病患者的大血管病变发生率很高,大血管病变主要指主动脉、冠状动脉、脑动脉、肾动脉及外周动脉等大、中动脉的粥样硬化,临床上常见的疾病有冠心病、脑卒中和下肢动脉硬化、坏疽等,调查显示大血管病变是糖尿病患者致死、致残的最主要的原因之一,其发生机制非常复杂,研究表明其病理改变是动脉粥样硬化(atherosclerosis, AS),主要病理基础是由多因素相互协作所形成的慢性、亚临床炎症以及炎症导致的胰岛素抵抗。内脂素(Visfatin)是新近发现的一个脂肪细胞因子,具有结合并激活胰岛素受体和模拟胰岛素的作用,参与糖脂代谢。研究发现其与胰岛素抵抗、糖尿病、动脉粥样硬化、肥胖等关系密切。肿瘤坏死因子-α(TNF-α)来自多种细胞参与慢性炎症和胰岛素抵抗。本文通过检测不同组别患者的内脂素、TNF-α的水平,以探讨其与2型糖尿病及其大血管并发症的关系。
研究方法：
入选的60例2型糖尿病患者为郑州大学第一附属医院2009年01月份到2009年06月份老年病科的住院患者,均符合1999年WHO糖尿病的诊断和分型标准。根据是否合并大血管病将其分为2组(MVC：大血管病变组30例；Non-MVC:非大血管病变组30例)。大血管病变者入选必须符合以下至少一条标准：①动态心电图和超声心动图或冠脉造影确诊的临床型冠心病；②头颅CT确诊的脑梗死；③多普勒超声检查颈动脉和(或)双下肢动脉血管壁硬化斑快或血栓形成。二组均排除下列情况：各种急慢性感染；各种2型糖尿病急性并发症；视网膜病变、肾脏病变等慢性并发症；各种肿瘤；其他内分泌疾病；1月内使用胰岛素、胰岛素增敏剂、降脂药物及长期服用糖皮质激素者。正常对照组：30例,为同期来我院进行常规健康体检的正常者。所有受检者采空腹肘静脉血,采用酶联免疫吸附法测定血清内脂素、TNF-α,检测空腹血糖(FPG)、空腹胰岛素(FINS)、糖化血红蛋白(HbA1c)、血脂等指标,并计算BMI、WHR及HOMA-IR,分析2型糖尿病及其大血管病变患者血清内脂素、TNF-α的含量变化及其影响因素。
所有数据均采用SPSS17.0统计软件包处理。数据用均数±标准差(x±s)表示,各组间比较采用t检验,多组间比较用方差分析,并进行直线相关分析、多元线性逐步回归分析及Logistic回归分析,以P<0.05为差异有统计学意义。
结果：
(1)与对照组相比,2型糖尿病各组患者血清内脂素、TNF-α水平均显著升高(P<0.01,P<0.01)；与非大血管病变组(Non-MVC组)相比,大血管病变组(MVC组)血清内脂素、TNF-α水平显著升高(P<0.05,P<0.01)。
(2) Visfatin与其他指标的相关性将BMI、WHR、HbA1c、FPG、TC、HOMA-IR等指标分别与Visfatin进行简单相关分析。Visfatin与BMI、WHR、FPG、FINS、HOMA-IR、TNF-α、HbA1c、TC呈正相关(P<0.01,P<0.05)。以Visfatin为因变量,以BMI、WHR、HbA1c、FPG、FINS、TC、HOMA-IR、TNF-α为自变量行多元线性逐步回归分析,WHR、HOMA-IR、BMI、FPG进入回归方程,F=175.442,P<0.01,方程有效,说明WHR、HOMA-IR、BMI、FPG是影响Visfatin水平的因素。
(3)TNF-α与其他指标的相关性将BMI、WHR、HbA1c、FPG、TC、HOMA-IR等指标分别与TNF-α进行简单相关分析。TNF-α与BMI、HbA1c、FPG、FINS、HOMA-IR、Visfatin、WHR、TG呈正相关(P<0.01,P<0.05)。以TNF-α为因变量,以BMI、WHR、HbA1c、FPG、FINS、TG、HOMA-IR、Visfatin为自变量行多元线性逐步回归分析,HOMA-IR、HbA1c、BMI进入回归方程,F=169.728,P<0.01,方程有效,说明HOMA-IR、HbA1c、BMI是影响TNF-α水平的因素。
(4)T2DM大血管病变危险因素分析以T2DM为整体,有无大血管病变为因变量Y(有=1,无=0)。以BMI、WHR、HbA1c、FPG、FINS、TC、TG、LDL-C、HDL-C、HOMA-IR、TNF-α、Visfatin等为自变量,进行Logistic回归分析,最后Visfatin、TNF-α进入回归方程。
结论：
(1)2型糖尿病各组血清内脂素、TNF-α浓度较对照组均显著升高,提示内脂素、TNF-α参与2型糖尿病的发生、发展。(2)2型糖尿病大血管病变组血清内脂素、TNF-α浓度较非大血管病变组显著升高；且Logistic回归分析结果内脂素、TNF-α是2型糖尿病大血管并发症的重要危险因素,表明内脂素、TNF-α与2型糖尿病大血管并发症的形成有关。(3)WHR、HOMA-IR、BMI、FPG是影响Visfatin水平的因素,HOMA-IR、HbA1c、BMI是影响TNF-α水平的因素。提示糖尿病患者内脂素、TNF-α水平升高可能跟肥胖、胰岛素抵抗、糖尿病等因素有关,并且相互影响共同促进了糖尿病大血管病变的发展。
Objictive:
Type 2 diabetes mellitus have a high incidence of macro-vascular complication. Macroangiopathy refers primarily to the aorta, coronary, cerebral arteries, renal arteries and limb peripheral arteries and other large, medium artery atherosclerosis. The common clinic disease is coronary heart diaease, cerebral stroke, lower limbs arteriosclerosis and gangrene, et al. In diabetic patients, mortality and disability are mainly related to the presence of chronic macro-vascular complications. The pathogenic mechanism of diabetic vascular complications is very complicated. Studies have shown that the pathological changes are atherosclerosis (atherosclerosis, As), the main pathological basis is formed by multi-factor interaction of chronic and subclinical inflammation and insulin resistance caused by inflammation. Visfatin is a newly discovered adipocytokines, It has the role of combining and activating the insulin receptor and has the role of insulin analog, It participated in glucose andlipid metabolism. The study found that visfatin is closely linked with insulin resistance, diabetes, atherosclerosis, obesity, and so on. Tumor necrosis factor-a (TNF-a) from a variety of cells involved in chronic inflammation and insulin resistance. In order to explore the relationship between the visfatin or tumor necrosis factor-a and the diabetic macro-vascular complication, the levels of visfatin or tumor of different groups were measured by ELISA.
Methods:
60 patients with T2DM (1999 WHO diagnostic standards) were selected for this study. They are from the inpatients of Geriatrics of the First Affiliated Hospital of Zhengzhou University in January 2009 to June 2009. They are in line with 1999 WHO classification and diagnosis standards of diabetes. They were divided into two groups based on the presence or absence of diabetic macro-vascular complications (MVC) (Diabetic macro-vascular complications are 30 case and Non-diabetic macro-vascular complications are 30). Macro-vascular complications selected must meet one of the following criteria at least:①dynamic ECG and echocardiography or coronary angiography confirmed the clinical coronary artery disease;②head CT confirmed cerebral infarction;③Artery Doppler ultrasound found carotid and (or) pairs of lower extremity arterial wall sclerosis plaques sooner or thrombosis. The 30 cases of normal control group from the healthy volunteers who come to my hospital for routine health examination at the same period. Visfatin and tumor necrosis factor-a were measured by enzyme linked immunosorbent assay (ELISA), and others markers related to macro-vascular complications were also measured. We analyzed the change tendency and influential factors of visfatin and tumor necrosis factor-a in type 2 diabetic patients with or without macro-vascular complications. All the statistical analysis were dealt with SPSS 17.0 software.
Results:
(1) Compared with normal controls, the serum levels of Visfatin and TNF-a were significantly increased (P<0.01,P<0.01); Compared with Non-MVC group, the serum levels of Visfatin and TNF-a were increased (P<0.05,P<0.01) in MVC group.
(2) By multiple stepwise regression analysis, WHR、HOMA-IR、BMIand FPG were the influential factors of Visfatin (F=175.442, P<0.01).
(3) By multiple stepwise regression analysis, HOMA-IR、HbA1c and BMI were the influential factors of TNF-α(F=169.728, P<0.01).
(4) The multiple stepwise logistic regression analysis was used to define the association between Visfatin, TNF-α, other related indexes and macrovascular complications. Age, Visfatin, TNF-αwere related significantly with diabetic macrovascular complications.
Conclusion:
(1) The serum levels of visfatin and TNF-αare both increased remarkably in type 2 diabetis mellitus as compared with normal control group, this indicate visfatin and tumor necrosis factor-αare related to the occurrence and development of type 2 diabetes mellitus. (2) The serum levels of visfatin and TNF-αare both increased remarkably in MVC group as compared with Non-MVC group, Also, The multiple stepwise logistic regression analysis indicates that visfatin and TNF-αare important risk factors of diabetic macrovascular complications, those indicate visfatin and tumor necrosis factor-αare related to the formation of macrovascular complications in type 2 diabetes. (3) WHR、HOMA-IR、BMI and FPG were the influential factors of visfatin, HOMA-IR、HbA1c and BMI were the influential factors of TNF-α, Those suggest that the elevated levels of visfatin, tumor necrosis factor-αin type 2 diabetes mellitus due to obesity, insulin resistance, diabetes and other factors, And they influence each other and jointly accelerate the development of diabetic angiopathies.
引文
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[1]Schneider DJ, Sobel BE. Determinations of Coronary vascular disease in patients with type 2 diabetes mellitus and their therapeutic implication [J]. Clin Cardiol 1997,20(5):433～440
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[1]Schneider DJ, Sobel BE. Determinations of Coronary vascular disease in patients with type 2 diabetes mellitus and their therapeutic implication [J]. Clin Cardiol 1997,20(5):433～440
[2]Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis and accelerated atherogenesis in type 2 diabetic patients [J]. Diabetes 1993,42(1):1～7
[3]Lyon CJ, Law RE, Hsueh WA. Minireview:adiposity, inflammation, and therogenesis [J].Endocrinology,2003,144(6):2195～2200
[4]Samal B, Sun Y, Steams G, et al. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor [J]. Mol Cell Biol,1994,14(2): 1431～1437
[5]Rongvaux A, Shea RJ, MulksMH, et al. Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis [J]. Eur J Immunol,2002,32(11):3225～3234
[6]Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells [J]. J Biol Chem, 2004,279 (49):50754～50763
[7]Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin:a protein secreted by visceral fat that mimics the effects of insulin [J]. Science,2005,307:426～430
[8]Sethi JK, Vidal-Puig A. Visfatin:the missing link between intra-abdominal obesity and diabetes? [J]. Trends Mol Med,2005,11(8):344～347
[9]Ognjanovic S, Bao S, Yamamoto SY,et al.Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fatal membranes[J].J Mol Endocrinol,2001,26:107～117
[10]Ando H, Yanagihara H, Hayashi Y, et al. Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue [J]. Endocrinology, 2005,146:5631～5636
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