妊娠期糖尿病外周和内脏脂肪组织Omentin、lslet-1、Vaspin mRNA表达差异与胰岛素抵抗的研究
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摘要
背景
母亲孕期高血糖与不良妊娠结局的研究(hyperglycemia and adverse pregnancy outcomes study, HAPO)已经证明即使母亲血糖水平在诊断显性糖尿病以下范围内变化也与不良妊娠结局(如巨大儿、剖宫产率、胎儿高胰岛素血症、新生儿临床低血糖症)呈连续关系,而母亲胰岛素抵抗(insulin resistance, IR)是使胎儿暴露于宫内高血糖环境的关键因素,从而导致胎儿过度生长等不良妊娠结局。妊娠期糖尿病(gestational diabetes mellitus, GDM)妇女较糖耐量正常(normal glucose tolerance, NGT)孕妇存在更为严重的IR已是广泛共识,但形成机制尚不清楚。近年来随着对肥胖发病机制及其代谢后遗症研究的逐步深入,发现脂肪组织除了调节脂肪量和营养平衡,还是一个活跃的内分泌器官,可释放大量的脂肪细胞因子,调节包括脑、肝、骨骼肌等重要器官的代谢活动信号,认为营养、血糖、胰岛素和参与组织代谢的脂肪因子之间相互作用导致IR。在肥胖、多囊卵巢综合症和2型糖尿病等存在IR的非妊娠人群研究中已经发现,外周脂肪组织和内脏脂肪组织在某些重要脂肪因子如omentin、islet-1、vaspin的表达和分泌上存在差异,从而在血压、糖脂代谢、炎症、IR等生理活动调节中扮演了不同的角色。已报道有GDM病史的妇女其内脏脂肪含量高于NGT妇女,但在GDM妇女中,是否也与非妊娠人群一样,上述脂肪因子在外周脂肪和内脏脂肪组织表达存在差异?并且这种差异是否与孕期IR的形成有关联尚不明确。本课题拟研究GDM患者与NGT的妊娠妇女外周和内脏脂肪组织omentin、 islet-、vaspin mRNA表达差异与妊娠期糖脂代谢、胰岛素抵抗及经典脂肪细胞因子的关系,探讨身体不同部位脂肪组织的内分泌功能在GDM发生中的病理生理作用,旨在为GDM的临床干预提供重要线索。
目的
1、评价GDM患者与NGT妊娠妇女代谢状态、胰岛素分泌功能和R的程度及其对新生儿出生体重的影响。
2、比较GDM患者与NGT妊娠妇女内脏和外周脂肪omentn、islet-、vaspin mRNA表达差异,并分析上述脂肪因子表达水平与糖脂代谢的关系,探讨脂肪组织源性的特异性细胞因子表达在GDM发生机制中的作用。
3、分析研究对象内脏和外周脂肪omentin、 islet-1、vaspin mRNA表达水平与产前血清adiponectin、leptin、TNF-α、IL-6的关系,探讨脂肪细胞因子的表达和分泌对妊娠期IR的影响。
方法
1、选择2009年1月～2009年12月期间在昆明医学院第一附属医院产科仅需饮食控制、因产科指征行剖宫产术分娩的43例GDM孕妇为病例组,所有患者符合1998年WHO的GDM诊断标准。同期选择与每个病例按年龄接近(±1岁)、孕次接近(±1次)、产次相同、产前体重指数(body mass index, BMI)接近(±1.0kg/m2)、分娩孕周接近(±1周)相匹配并在我院剖宫产分娩的NGT孕妇作为本研究的对照组,其中病例组：对照组按1：1进行配对。
2、测量研究对象身高、产前体重,计算BMI和孕期增重,同时测定GDM组及NGT对照组产前血清血糖、总胆围醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇水平及胰岛素水平,以稳态模型评价胰岛素抵抗指数(insulin resistance index, HOMA-IR),以HOMA?细胞功能指数(HOMAp-cell index, HBCI)作为胰岛素分泌指标；比较GDM组与NGT组临床资料的差异,分析妊娠期母亲身体参数、R及胰岛素分泌功能与新生儿出生体重的关系。
3、于剖宫产手术中采集二组研究对象腹部皮下脂肪和内脏网膜脂肪组织,Trizol法提取RNA,逆转录合成cDNA第一链,实时定量PCR (Real-time quantitative polymerase chain reaction, RT-PCR)检测脂肪组织omentin、islet-1、 vaspin mRNA表达水平。比较身体不同部位脂肪组织omentin、islet-1、vaspin mRNA表达差异及与妊娠期各项生化代谢指标和R的关系。
4、ELISA方法测定二组研究对象产前血清adiponecti、leptin、TNF-α、IL-6水平,分析身体不同部位脂肪组织tin、islet-1、vaspin mRNA表达差异与上述四种细胞因子的关系。
结果
1、与NGT组比较,GDM组孕前BMI(23.09±3.59vs.21.26±2.89,P=0.011)、OGTT Oh(4.93±0.80vs.4.41±0.48,P=0.000)和2h血糖值(8.61±0.71vs.6.17±0.90,P=0.000)、产前空腹血糖(4.88±0.66vs.4.31±0.56,P=0.000)、空腹胰岛素(74.59±27.16vs.50.68±19.38,P=0.000)、甘油三酯(3.76±1.78vs.2.95±1.13,P=0.014)、低密度脂蛋白胆固醇(3.77±0.78vs.3.27±0.84,P=0.005)、leptin(4.57±1.03vs.4.10±0.63,P=0.012)、TNF-a(346.18±73.10vs.256.85±84.16,P=0.000)、IL-6(9.43±1.96vs.5.03±1.56,P=0.000)及HOMA-IR(1.18±0.17vs.0.96±0.18,P=0.000)显著增高；而高密度脂蛋白胆固醇(1.71±0.34vs.1.97±0.47,P=0.004、diponectin水平显著降低(362.95±115.53vs.450.33±80.31,P=0.000)；GDM组饮食控制后与NGT组的孕期增重(15.05±6.35vs.16.20±3.53,P=0.302)、HBCI(3.07±0.29vs.3.23±0.45,P=0.059)、新生儿出生体重(3433.30±491.85vs.3322.336±375.08,P=0.243)无显著性差异。
2、回归分析显示在研究对象中,母亲孕期增重(p=0.364,p=0.001)、胰岛素抵抗指数(β=0.218,p=0.034)是新生儿出生体重的独立预测因子。
3、在86例全部研究对象中,RT-PCR检测结果显示：①、内脏网膜脂肪组织的omentin mRNA表达水平较腹部皮下脂肪组织显著升高(0.636±0.157vs.0.063±0.016,P=0.000)。GDM组皮下脂肪组织(0.057±0.014vs.0.070±0.015,P=0.000)和网膜脂肪组织(0.560±0.125vs.0.713±0.150,P=0.000)的omentin mRNA表达水平较NGT组均显著降低。②、Islet-1mRNA主要在网膜脂肪组织中表达,且GDM组网膜组织的islet-1mRNA表达水平表达显著低于NGT组(0.200±0.031vs.0.268±0.049,P=0.000)；而无论是GDM组还是NGT组,皮下脂肪组织的islet-1mRNA仅微量表达或不表达(53.49%vs.65.12%,P=0.084),且二组间表达水平无显著性差异(0.035±0.027vs.0.041±0.022,p=0.402)；③、网膜脂肪组织的vaspin mRNA表达水平显著高于腹部皮下脂肪组织的表达水平(0.53±0.16vs.0.32±0.06,P=0.000)。GDM组皮下脂肪组织(0.33±0.06vs.0.30±0.05,P=0.006)和网膜脂肪组织(0.58±0.16vs.0.48±0.15,P=0.004)的vaspin mRNA表达水平显著高于NGT组。
4、在86例全部研究对象中,双变量Pearson相关分析显示腹部皮下脂肪组织omentin mRNA表达水平与母亲孕前BMI(r=-0.251,P=0.020)、OGTT2h血糖值(r=-0.375,P=0.000)、产前空腹血糖(r=-0.260,P=0.016)、空腹胰岛素(r=-0.242,P=0.025、HOMA-IR(r=-0.284,P=0.008)及IL-6(r=-0.304,P=0.004)呈显著性负相关；而网膜脂肪组织omentin mRNA表达水平与全部病例OGTT Oh(r=-0.274,P=0.011)和2h血糖值(r=-0.482,P=0.000)、产前空腹血糖(r=-0.259,P=0.016)、HOMA-IR(r=-0.236,P=0.029)以及血清leptin (r=-0.310, P=0.004)、TNF-a(r=-0.231,P=0.032)、IL-6(r=-0.279,P=0.009)水平呈显著性负相关,与母亲孕期增重(r=0.250,P=0.021)、产前血清adiponectin(r=0.361,P=0.001)水平呈显著性正相关。
5、在86例全部研究对象中,双变量Pearson相关分析显示网膜脂肪组织islet-1mRNA表达水平与母亲孕前BMI(r=-0.262,P=0.015)、OGTT Oh (r=-0.290,P=0.007)和2h血糖值(r=-0.532,P=0.000)、产前空腹血糖(r=-0.292,P=0.006)、空腹胰岛素(r=-0.310,P=0.004)、HOMA-IR(r=-0.347,P=0.001)、血清leptin(r=-0.228,P=0.035)、TNF-a(r=-0.237,P=0.028)、IL-6(r=-0.555,P=0.000)水平呈显著性负相关,与孕期增重(r=0.294,P=0.006)、血清adiponectin (r=0.244,P=0.023)水平呈显著性正相关。
6、在86例全部研究对象中,双变量Pearson相关分析显示腹部皮下脂肪组织vaspin mRNA表达水平与母亲孕前BMI(r=0.594,P=0.000)和产前BMI(r=0.472,P=0.000)、OGTT0h(r=0.543,P=0.000)和2h血糖值(r=0.436,P=0.000)、产前空腹血糖(r=0.489,P=0.000)、空腹胰岛素(r=0.441,P=0.000)、HOMA-IR(r=0.514,P=0.000)、血清leptin(r=0.257,P=0.017)、IL-6(r=0.292,P=0.006)水平呈显著性正相关；而网膜脂肪组织vaspin mRNA表达水平与母亲孕前BMI(r=0.457,P=0.000)和产前BMI(r=0.296,P=0.006)、OGTT Oh(r=0.425,P=0.000)和2h(r=0.401,P=0.000)血糖值、产前空腹血糖(r=0.343,P=0.001)、空腹胰岛素(r=,0.462P=0.000)、HOMA-IR(r=0.486,P=0.000)、血清leptin(r=0.403, P=0.000、TNF-a(r=0.259, P=0.016)水平呈显著性正相关,与孕期增重(r=-0.221,P=0.041)呈显著性负相关。
7、多元线性逐步回归分析显示,皮下脂肪组织的Vaspin mRNA表达水平(β=0.543,P=0.000)是OGTT Oh血糖值的独立预测因子。而网膜脂肪组织的islet-1(p=-0.347, P=0.000)、 omentin (p=-0.304, P=0.000) mRNA水平和皮下脂肪组织的vaspin ((3=0.265, P=0.002)、 omentin (p=-0.189, P=0.021) mRNA表达水平是OGTT2h血糖值的独立预测因子。
8、多元线性逐步回归分析显示：网膜脂肪组织的omentin mRNA表达水平(p=0.361,P=0.001)与adiponectin独立相关；网膜脂肪组织的vaspin (β=0.340,P=0.001)和omentin mRNA表达水平(p=-0.209,P=0.046)与leptin独立相关；网膜脂肪组织的vaspin mRNA表达水平(p=0.259,P=0.016)与TNF-a独立相关；网膜脂肪组织的islet-1(p=-0.513, P=0.000) mRNA表达水平和皮下脂肪组织的omentin (β=-0.190, P=0.040) mRNA表达水平与IL-6独立相关。
9、为了解脂肪细胞因子对妊娠期胰岛素抵抗的影响程度,再以母亲身体参数、产前血清脂联素、瘦素、TNF-α、L-6水平以及皮下和网膜脂肪组织的omentin、 islet-1、vaspin mRNA表达水平为自变量的多元线性逐步回归分析中,只有TNF-a(β=0.350,P=0.000)、腹部皮下脂肪组织的vaspin mRNA表达水平(p=0.390,P=0.000)和leptin水平(p=0.237,P=0.008)是妊娠期HOMA-IR的独立预测因子。
结论
1、GDM患者具有显著的糖脂代谢紊乱、高胰岛素血症、胰岛素抵抗和慢性炎症状态的临床特征,母亲孕期增重和胰岛素抵抗程度是新生儿出生体重的独立预测因子。
2、脂肪细胞因子—Omentin、islet-、vaspin mRNA在内脏脂肪组织的特异性表达较皮下脂肪组织更为活跃,并且这些脂肪细胞因子的表达与妊娠期糖代谢关系更为密切,而与脂代谢关系不甚明显。内脏脂肪组织omentin、islet-1mRNA表达受损可能是GDM患者糖耐量异常的潜在诱因；而皮下脂肪和内脏脂肪组织vaspin mRNA表达的增加则可能是GDM患者应对机体胰岛素抵抗的一种代偿机制。
3、妊娠期胰岛素抵抗是一个复杂的多因素作用的结果,除了胎盘激素外,脂肪因子在胰岛素抵抗的形成中也发挥了重要的调节作用。
Background
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study has already demonstrated even if the maternal blood plasma glucose levels below the diagnosis of overt diabetes, there was also a continuous graded relationship between maternal glucose and the adverse pregnancy outcomes, including macrosomia, cesarean section rate, fetal hyperinsulinemia and clinical neonatal hypoglycemia. Maternal insulin resistance (IR) during pregnancy is the key factor that makes fetal exposure to intrauterine environment of hyperglycaemia and lead to fetal excess growth and other adverse pregnant outcomes. There is a more severe IR in women with gestational diabetes mellitus (GDM) than those with normal glucose tolerance (NGT) has been recognized for many years, but the causal mechanisms remain unclear. However, with the research to understand the pathogenesis of obesity and its metabolic sequelae advancing rapidly, adipose tissue has been found to represent an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive adipokines that signal to important metabolic organs including brain, liver, and skeletal muscle. IR involve in the interaction between nutrition, blood glucose, insulin and some important adipokines which participate in various tissue metabolism. The study in non-pregnant population such as patients with obesity, polycystic ovary syndrome and type2diabetes (T2DM) has showed that there are differences in expression and secretion in certain important factors, such as omentin, islet-1, vaspin in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), thereby playing a different role in modulating some physiological activities such as blood pressure, glucose and lipid metabolism, inflammation and IR. However, it is not clear whether there are differences in the expressions of these adipokine in GDM and whether these adipokine are associated with the formation of IR during pregnancy. This study aims to compare the expression differences of omentin, islet-1, vaspin mRNA in subcutaneous and visceral adipose tissues in pregnant women with GDM and NGT, to investigate relationship between omentin, islet-1, vaspin mRNA expressions and glucolipid metabolism, IR as well as other classic adipokines in Chinese pregnant women, and to explore the endocrine function of adipose tissue in SAT and VAT, which might play role in the pathophysiology of GDM occurs and provid clues to clinical intervention for GDM.
Objective
1. To evaluate the differences of metabolic states, insulin secretion and IR in pregnant women with GDM and NGT, and to investigate their impact on neonatal birth weight.
2. To compare omentin, islet-1, vaspin mRNA expressions in SAT and VAT in Chinese pregnant women with GDM and NGT, and to analyze the relationship between omentin, islet-1, vaspin mRNA expressions in different sites and glucolipid metabolism as well as IR, which might be help for investigating the role of adipose tissue with expressing specific cytokines in the pathogenesis of GDM.
3. To analyze the relationship between omentin, islet-1, vaspin mRNA expression in different sites and serum fasting adiponectin, leptin, TNF-α, IL-6levels before delivery, and to investigate whether or not the expressions and secretions of these adipokines have effects on IR during pregnancy.
Methods
1. In this prospective study,43pregnant women with GDM undergoing only alimentary control were included in the case group, The GDM group diagnosesed according to WHO criteria was compared with the control group with normal glucose tolerance (NGT) and matched for age (±yr), gravity (±1), exact parity, body mass index (BMI±1.0kg/m2), and gestational weeks at delivery (±wk) each other. Both the GDM and NGT groups delivered by elective cesarean section for obstetric indications between January and Dec2009, in the department of O&G of the1st affiliated hospital of Kunming medical collage.
2. Their height, weight, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and fasting insulin(FINS) levels before delivery were measured, BMI and weight gain during pregnancy were calculated. Homeostasis model assessment was calculated as insulin resistance index (HOMA-IR), and insulin secretion function was evaluated by homeostasis β-cell index (HBCI). The differences of clinical data between the two groups were compared and the relationship between maternal body parameters, IR and insulin secretion function with neonatal birth weight were analyzed.
3. Abdominal subcutaneous (SAT) and visceral adipose tissues (VAT) were obtained in two groups during selective cesarean section. Total RNA was extracted by Trizol and the first strand cDNA was synthesized by reverse transcription. Real-time quantitative polymerase chain reaction (RT-PCR) was used to measure the omentin, islet-1, vaspin mRNA expressions in SAT and VAT in the two groups. The relationship between omentin, islet-1, vaspin mRNA expression in different sites of adipose tissues with maternal metabolic parameters and HOMA-IR were analyzed.
4. Serum fasting adiponectin, leptin, tumor necrosis factor alpha (TNF-a) and Interleukin-6(IL-6) levels before delivery were measured by enzyme linked immunosorbent assay (ELISA). The relationship between omentin, islet-1, vaspin mRNA expression in different sites of adipose tissues with maternal serum fasting adiponectin, leptin, TNF-a and IL-6were analyzed.
Results
1. Compared with the control group (1:1), BMI before pregnancy (23.09±3.59vs.21.26±2.89, P=0.011), OGTT Oh (4.93±0.80vs.4.41±0.48, P=0.000) and2h glucose (8.61±0.71vs.6.17±0.90, P=0.000), FPG (4.88±0.66vs.4.31±0.56, P=0.000), FINS (74.59±27.16vs.50.68±19.38, P=0.000), TG (3.76±1.78vs.2.95±1.13, P=0.014), LDL-C (3.77±0.78vs.3.27±0.84, P=0.005), leptin (4.57±1.03vs.4.10±0.63, P=0.012), TNF-a (346.18±73.10vs.256.85±84.16, P=0.000)、IL-6(9.43±1.96vs.5.03±1.56, P=0.000) levels, HOMA-IR transformed to logarithm (1.18±0.17vs.0.96±0.18, P=0.000) in GDM group were significantly higher and HDL-C(1.71±0.34vs.1.97±0.47, P=0.004), adiponectin (362.95±115.53vs.450.33±80.31, P=0.000) in GDM group were significantly lower than those in control group. Received alimentary control in GDM, there were no significant differences in weight gain (15.05±6.35vs.16.20±3.53, P=0.302), HBCI (3.07±0.29vs.3.23±0.45, P=0.059) and neonatal birth weight (3433.30±491.85vs.3322.336±375.08, P=0.243) between two groups to be found.
2. Step-wise linear regression analysis showed only maternal weight gain (β=0.364, p=0.001), HOMA-IR transformed to logarithm (β=0.218, p=0.034) were proved as independent predictors of neonatal birth weight in all cases.
3. In86cases combined GDM and NGT groups, RT-PCR showed:①.There is significantly higher levels of Omentin mRNA expression in VAT than in SAT in both groups (0.636±0.157vs.0.063±0.016, P=0.000). In pregnant women with various glycometabolism states, omentin mRNA expression in GDM in both SAT (0.057±0.014vs0.070±0.015, P=0.000) and VAT (0.560±0.125vs0.713±0.150, P=0.000) are significantly lower than those in NGT.②.Islet-1mRNA expression was mainly in VAT, and islet-1mRNA expression in VAT in GDM group was significantly lower than that in NGT (0.200±0.031vs.0.268±0.049, P=0.000). However, in SAT obtained from pregnant women with GDM and NGT, islet-1mRNA were trace or virtually absent expressions (53.49%vs.65.12%, P=0.084) and there was no difference in gene expression in two groups (0.035±0.027vs.0.041±0.022, p=0.402).③. There is significantly higher levels of vaspin mRNA expression in VAT than in SAT in both groups (0.53±0.16vs.0.32±0.06, P=0.000). Vaspin mRNA expression in GDM in both SAT (0.33±0.06vs.0.30±0.05, P=0.006) and VAT (0.58±0.16vs.0.48±0.15, P=0.004) are significantly higher than those in NGT.
4. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of omentin mRNA in SAT was found to be inversely correlated with BMI before pregnancy (r=-0.251, P=0.020), OGTT2h glucose(2hPG)(r=-0.375, P=0.000), and FPG(r=-0.260, P=0.016), FINS(r=-0.242, P=0.025), HOMA-IR(r=-0.284, P=0.008), IL-6(r=-0.304, P=0.004)before delivery, respectively. Omentin mRNA in VAT was found to be inversely correlated with OGTT Oh (r=-0.274, P=0.011) and2hPG (r=-0.482, P=0.000), FPG (r=-0.259, P=0.016), HOMA-IR(r=-0.236, P=0.029), leptin(r=-0.310, P=0.004), TNF-a(r=-0.231, P=0.032), IL-6(r=-0.279, P=0.009) before delivery, whereas positively correlated with maternal weight gain(r=0.250, P=0.021) during pregnancy and serum adiponectin(r=0.361, P=0.001) levels before delivery.
5. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of islet-1mRNA in VAT was found to be inversely correlated with BMI before pregnancy (r=-0.262, P=0.015), OGTT Oh (r=-0.290, P=0.007) and2hPG(r=-0.532, P=0.000), FPG(r=-0.292, P=0.006), FINS(r=-0.310, P=0.004), HOMA-IR(r=-0.347, P=0.001), serum leptin(r=-0.228, P=0.035), TNF-a(r=-0.237, P=0.028), and IL-6(r=-0.555, P=0.000) before delivery, respectively, whereas positively correlated with maternal weight gain(r=0.294, P=0.006) during pregnancy and serum adiponectin levels (r=0.244, P=0.023) before delivery.
6. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of vaspin mRNA in SAT was found to be positively correlated with BMI before pregnancy (r=0.594, P=0.000) and before delivery(r=0.472, P=0.000), OGTT0h(r=0.543, P=0.000) and2hPG(r=0.436, P=0.000), FPG(r=0.489, P=0.000), FINS(r=0.441, P=0.000), HOMA-IR(r=0.514, P=0.000), serum leptin (r=0.257, P=0.017), and IL-6(r=0.292, P=0.006) before delivery. Whereas the expression of vaspin mRNA in VAT was found to be positively correlated with BMI before pregnancy (r=0.457, P=0.000) and before delivery(r=0.296, P=0.006), OGTT Oh (r=0.425, P=0.000) and2hPG(r=0.401, P=0.000), FPG(r=0.343, P=0.001), FINS(r=,0.462P=0.000), HOMA-IR(r=0.486, P=0.000), serum leptin(r=0.403, P=0.000), and TNF-a(r=0.259, P=0.016) before delivery, and to be inversely correlated with maternal weight gain (r=-0.221, P=0.041) during pregnancy.
7. By multivariate step-wise linear regression analysis, vaspin mRNA expressions in SAT (β=0.543, P=0.000) were proved as independent predictors of OGTT OhPG, whereas only islet-l(β=-0.347, P=0.000), omentin(β=-0.304, P=0.000) mRNA expressions in VAT and vaspin(β=0.265, P=0.002), omentin(β=-0.189, P=0.021) mRNA expressions in SAT were proved as independent predictors of OGTT2hPG.
8. By multivariate step-wise linear regression analysis, omentin mRNA expressions in VAT (β=0.361, P=0.001) was proved as independent predictors of adiponectin; vaspin (β=0.340, P=0.001) and omentin mRNA (β=-0.209, P=0.046) expressions in VAT were proved as independent predictors of leptin; vaspin mRNA expressions in VAT(β=0.259, P=0.016) was proved as independent predictors of TNF-a; and islet-1mRNA expressions in VAT(β=-0.513, P=0.000) as well as omentin expressions in SAT were proved as independent predictors of IL-6.
9. In order to investigate how these adipokines to influence on the degree of IR during pregnancy, multivariate step-wise linear regression analysis was used, in which maternal body parameters, serum adiponectin, leptin, TNF-a, IL-6levels and omentin, islet-1, vaspin mRNA expressions in SAT and VAT levels served as independent variables. The results showed that only TNF-a (β=0.350, P=0.000), vaspin mRNA expressions in SAT (β=0.390, P=0.000) and serum leptin levels (P=0.237, P=0.008) were proved as independent predictors of HOMA-IR during pregnancy.
Conclusions
1. The glycolipid metabolic disturbance, hyperinsulinemia, insulin resistance and chronic inflammatory state were the significant clinical features of GDM. Maternal weight gain and HOMA-IR were independent predictors of neonatal birth weight.
2. Adipokines-such as omentin, islet-1, vaspin mRNA expressed specifically in visceral adipose tissue is more active than subcutaneous adipose tissue, and the expressions of these adipokines are more closely related to glucose metabolism during pregnancy, and their relationships with lipid metabolism are not significant. The impaired expressions of omentin and islet-1mRNA in VAT may be the potential motivation for glucose intolerance in GDM; and vaspin mRNA expression increased in SAT may be a compensatory mechanism responsing to insulin resistance worsen in GDM.
3. Insulin resistance during pregnancy is a complex result by multiple factors, in addition to placental hormones, adipokines also play an important regulating role in the formation of insulin resistance.
母亲孕期高血糖与不良妊娠结局的研究(hyperglycemia and adverse pregnancy outcomes study, HAPO)已经证明即使母亲血糖水平在诊断显性糖尿病以下范围内变化也与不良妊娠结局(如巨大儿、剖宫产率、胎儿高胰岛素血症、新生儿临床低血糖症)呈连续关系,而母亲胰岛素抵抗(insulin resistance, IR)是使胎儿暴露于宫内高血糖环境的关键因素,从而导致胎儿过度生长等不良妊娠结局。妊娠期糖尿病(gestational diabetes mellitus, GDM)妇女较糖耐量正常(normal glucose tolerance, NGT)孕妇存在更为严重的IR已是广泛共识,但形成机制尚不清楚。近年来随着对肥胖发病机制及其代谢后遗症研究的逐步深入,发现脂肪组织除了调节脂肪量和营养平衡,还是一个活跃的内分泌器官,可释放大量的脂肪细胞因子,调节包括脑、肝、骨骼肌等重要器官的代谢活动信号,认为营养、血糖、胰岛素和参与组织代谢的脂肪因子之间相互作用导致IR。在肥胖、多囊卵巢综合症和2型糖尿病等存在IR的非妊娠人群研究中已经发现,外周脂肪组织和内脏脂肪组织在某些重要脂肪因子如omentin、islet-1、vaspin的表达和分泌上存在差异,从而在血压、糖脂代谢、炎症、IR等生理活动调节中扮演了不同的角色。已报道有GDM病史的妇女其内脏脂肪含量高于NGT妇女,但在GDM妇女中,是否也与非妊娠人群一样,上述脂肪因子在外周脂肪和内脏脂肪组织表达存在差异?并且这种差异是否与孕期IR的形成有关联尚不明确。本课题拟研究GDM患者与NGT的妊娠妇女外周和内脏脂肪组织omentin、 islet-、vaspin mRNA表达差异与妊娠期糖脂代谢、胰岛素抵抗及经典脂肪细胞因子的关系,探讨身体不同部位脂肪组织的内分泌功能在GDM发生中的病理生理作用,旨在为GDM的临床干预提供重要线索。
目的
1、评价GDM患者与NGT妊娠妇女代谢状态、胰岛素分泌功能和R的程度及其对新生儿出生体重的影响。
2、比较GDM患者与NGT妊娠妇女内脏和外周脂肪omentn、islet-、vaspin mRNA表达差异,并分析上述脂肪因子表达水平与糖脂代谢的关系,探讨脂肪组织源性的特异性细胞因子表达在GDM发生机制中的作用。
3、分析研究对象内脏和外周脂肪omentin、 islet-1、vaspin mRNA表达水平与产前血清adiponectin、leptin、TNF-α、IL-6的关系,探讨脂肪细胞因子的表达和分泌对妊娠期IR的影响。
方法
1、选择2009年1月～2009年12月期间在昆明医学院第一附属医院产科仅需饮食控制、因产科指征行剖宫产术分娩的43例GDM孕妇为病例组,所有患者符合1998年WHO的GDM诊断标准。同期选择与每个病例按年龄接近(±1岁)、孕次接近(±1次)、产次相同、产前体重指数(body mass index, BMI)接近(±1.0kg/m2)、分娩孕周接近(±1周)相匹配并在我院剖宫产分娩的NGT孕妇作为本研究的对照组,其中病例组：对照组按1：1进行配对。
2、测量研究对象身高、产前体重,计算BMI和孕期增重,同时测定GDM组及NGT对照组产前血清血糖、总胆围醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇水平及胰岛素水平,以稳态模型评价胰岛素抵抗指数(insulin resistance index, HOMA-IR),以HOMA?细胞功能指数(HOMAp-cell index, HBCI)作为胰岛素分泌指标；比较GDM组与NGT组临床资料的差异,分析妊娠期母亲身体参数、R及胰岛素分泌功能与新生儿出生体重的关系。
3、于剖宫产手术中采集二组研究对象腹部皮下脂肪和内脏网膜脂肪组织,Trizol法提取RNA,逆转录合成cDNA第一链,实时定量PCR (Real-time quantitative polymerase chain reaction, RT-PCR)检测脂肪组织omentin、islet-1、 vaspin mRNA表达水平。比较身体不同部位脂肪组织omentin、islet-1、vaspin mRNA表达差异及与妊娠期各项生化代谢指标和R的关系。
4、ELISA方法测定二组研究对象产前血清adiponecti、leptin、TNF-α、IL-6水平,分析身体不同部位脂肪组织tin、islet-1、vaspin mRNA表达差异与上述四种细胞因子的关系。
结果
1、与NGT组比较,GDM组孕前BMI(23.09±3.59vs.21.26±2.89,P=0.011)、OGTT Oh(4.93±0.80vs.4.41±0.48,P=0.000)和2h血糖值(8.61±0.71vs.6.17±0.90,P=0.000)、产前空腹血糖(4.88±0.66vs.4.31±0.56,P=0.000)、空腹胰岛素(74.59±27.16vs.50.68±19.38,P=0.000)、甘油三酯(3.76±1.78vs.2.95±1.13,P=0.014)、低密度脂蛋白胆固醇(3.77±0.78vs.3.27±0.84,P=0.005)、leptin(4.57±1.03vs.4.10±0.63,P=0.012)、TNF-a(346.18±73.10vs.256.85±84.16,P=0.000)、IL-6(9.43±1.96vs.5.03±1.56,P=0.000)及HOMA-IR(1.18±0.17vs.0.96±0.18,P=0.000)显著增高；而高密度脂蛋白胆固醇(1.71±0.34vs.1.97±0.47,P=0.004、diponectin水平显著降低(362.95±115.53vs.450.33±80.31,P=0.000)；GDM组饮食控制后与NGT组的孕期增重(15.05±6.35vs.16.20±3.53,P=0.302)、HBCI(3.07±0.29vs.3.23±0.45,P=0.059)、新生儿出生体重(3433.30±491.85vs.3322.336±375.08,P=0.243)无显著性差异。
2、回归分析显示在研究对象中,母亲孕期增重(p=0.364,p=0.001)、胰岛素抵抗指数(β=0.218,p=0.034)是新生儿出生体重的独立预测因子。
3、在86例全部研究对象中,RT-PCR检测结果显示：①、内脏网膜脂肪组织的omentin mRNA表达水平较腹部皮下脂肪组织显著升高(0.636±0.157vs.0.063±0.016,P=0.000)。GDM组皮下脂肪组织(0.057±0.014vs.0.070±0.015,P=0.000)和网膜脂肪组织(0.560±0.125vs.0.713±0.150,P=0.000)的omentin mRNA表达水平较NGT组均显著降低。②、Islet-1mRNA主要在网膜脂肪组织中表达,且GDM组网膜组织的islet-1mRNA表达水平表达显著低于NGT组(0.200±0.031vs.0.268±0.049,P=0.000)；而无论是GDM组还是NGT组,皮下脂肪组织的islet-1mRNA仅微量表达或不表达(53.49%vs.65.12%,P=0.084),且二组间表达水平无显著性差异(0.035±0.027vs.0.041±0.022,p=0.402)；③、网膜脂肪组织的vaspin mRNA表达水平显著高于腹部皮下脂肪组织的表达水平(0.53±0.16vs.0.32±0.06,P=0.000)。GDM组皮下脂肪组织(0.33±0.06vs.0.30±0.05,P=0.006)和网膜脂肪组织(0.58±0.16vs.0.48±0.15,P=0.004)的vaspin mRNA表达水平显著高于NGT组。
4、在86例全部研究对象中,双变量Pearson相关分析显示腹部皮下脂肪组织omentin mRNA表达水平与母亲孕前BMI(r=-0.251,P=0.020)、OGTT2h血糖值(r=-0.375,P=0.000)、产前空腹血糖(r=-0.260,P=0.016)、空腹胰岛素(r=-0.242,P=0.025、HOMA-IR(r=-0.284,P=0.008)及IL-6(r=-0.304,P=0.004)呈显著性负相关；而网膜脂肪组织omentin mRNA表达水平与全部病例OGTT Oh(r=-0.274,P=0.011)和2h血糖值(r=-0.482,P=0.000)、产前空腹血糖(r=-0.259,P=0.016)、HOMA-IR(r=-0.236,P=0.029)以及血清leptin (r=-0.310, P=0.004)、TNF-a(r=-0.231,P=0.032)、IL-6(r=-0.279,P=0.009)水平呈显著性负相关,与母亲孕期增重(r=0.250,P=0.021)、产前血清adiponectin(r=0.361,P=0.001)水平呈显著性正相关。
5、在86例全部研究对象中,双变量Pearson相关分析显示网膜脂肪组织islet-1mRNA表达水平与母亲孕前BMI(r=-0.262,P=0.015)、OGTT Oh (r=-0.290,P=0.007)和2h血糖值(r=-0.532,P=0.000)、产前空腹血糖(r=-0.292,P=0.006)、空腹胰岛素(r=-0.310,P=0.004)、HOMA-IR(r=-0.347,P=0.001)、血清leptin(r=-0.228,P=0.035)、TNF-a(r=-0.237,P=0.028)、IL-6(r=-0.555,P=0.000)水平呈显著性负相关,与孕期增重(r=0.294,P=0.006)、血清adiponectin (r=0.244,P=0.023)水平呈显著性正相关。
6、在86例全部研究对象中,双变量Pearson相关分析显示腹部皮下脂肪组织vaspin mRNA表达水平与母亲孕前BMI(r=0.594,P=0.000)和产前BMI(r=0.472,P=0.000)、OGTT0h(r=0.543,P=0.000)和2h血糖值(r=0.436,P=0.000)、产前空腹血糖(r=0.489,P=0.000)、空腹胰岛素(r=0.441,P=0.000)、HOMA-IR(r=0.514,P=0.000)、血清leptin(r=0.257,P=0.017)、IL-6(r=0.292,P=0.006)水平呈显著性正相关；而网膜脂肪组织vaspin mRNA表达水平与母亲孕前BMI(r=0.457,P=0.000)和产前BMI(r=0.296,P=0.006)、OGTT Oh(r=0.425,P=0.000)和2h(r=0.401,P=0.000)血糖值、产前空腹血糖(r=0.343,P=0.001)、空腹胰岛素(r=,0.462P=0.000)、HOMA-IR(r=0.486,P=0.000)、血清leptin(r=0.403, P=0.000、TNF-a(r=0.259, P=0.016)水平呈显著性正相关,与孕期增重(r=-0.221,P=0.041)呈显著性负相关。
7、多元线性逐步回归分析显示,皮下脂肪组织的Vaspin mRNA表达水平(β=0.543,P=0.000)是OGTT Oh血糖值的独立预测因子。而网膜脂肪组织的islet-1(p=-0.347, P=0.000)、 omentin (p=-0.304, P=0.000) mRNA水平和皮下脂肪组织的vaspin ((3=0.265, P=0.002)、 omentin (p=-0.189, P=0.021) mRNA表达水平是OGTT2h血糖值的独立预测因子。
8、多元线性逐步回归分析显示：网膜脂肪组织的omentin mRNA表达水平(p=0.361,P=0.001)与adiponectin独立相关；网膜脂肪组织的vaspin (β=0.340,P=0.001)和omentin mRNA表达水平(p=-0.209,P=0.046)与leptin独立相关；网膜脂肪组织的vaspin mRNA表达水平(p=0.259,P=0.016)与TNF-a独立相关；网膜脂肪组织的islet-1(p=-0.513, P=0.000) mRNA表达水平和皮下脂肪组织的omentin (β=-0.190, P=0.040) mRNA表达水平与IL-6独立相关。
9、为了解脂肪细胞因子对妊娠期胰岛素抵抗的影响程度,再以母亲身体参数、产前血清脂联素、瘦素、TNF-α、L-6水平以及皮下和网膜脂肪组织的omentin、 islet-1、vaspin mRNA表达水平为自变量的多元线性逐步回归分析中,只有TNF-a(β=0.350,P=0.000)、腹部皮下脂肪组织的vaspin mRNA表达水平(p=0.390,P=0.000)和leptin水平(p=0.237,P=0.008)是妊娠期HOMA-IR的独立预测因子。
结论
1、GDM患者具有显著的糖脂代谢紊乱、高胰岛素血症、胰岛素抵抗和慢性炎症状态的临床特征,母亲孕期增重和胰岛素抵抗程度是新生儿出生体重的独立预测因子。
2、脂肪细胞因子—Omentin、islet-、vaspin mRNA在内脏脂肪组织的特异性表达较皮下脂肪组织更为活跃,并且这些脂肪细胞因子的表达与妊娠期糖代谢关系更为密切,而与脂代谢关系不甚明显。内脏脂肪组织omentin、islet-1mRNA表达受损可能是GDM患者糖耐量异常的潜在诱因；而皮下脂肪和内脏脂肪组织vaspin mRNA表达的增加则可能是GDM患者应对机体胰岛素抵抗的一种代偿机制。
3、妊娠期胰岛素抵抗是一个复杂的多因素作用的结果,除了胎盘激素外,脂肪因子在胰岛素抵抗的形成中也发挥了重要的调节作用。
Background
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study has already demonstrated even if the maternal blood plasma glucose levels below the diagnosis of overt diabetes, there was also a continuous graded relationship between maternal glucose and the adverse pregnancy outcomes, including macrosomia, cesarean section rate, fetal hyperinsulinemia and clinical neonatal hypoglycemia. Maternal insulin resistance (IR) during pregnancy is the key factor that makes fetal exposure to intrauterine environment of hyperglycaemia and lead to fetal excess growth and other adverse pregnant outcomes. There is a more severe IR in women with gestational diabetes mellitus (GDM) than those with normal glucose tolerance (NGT) has been recognized for many years, but the causal mechanisms remain unclear. However, with the research to understand the pathogenesis of obesity and its metabolic sequelae advancing rapidly, adipose tissue has been found to represent an active endocrine organ that, in addition to regulating fat mass and nutrient homeostasis, releases a large number of bioactive adipokines that signal to important metabolic organs including brain, liver, and skeletal muscle. IR involve in the interaction between nutrition, blood glucose, insulin and some important adipokines which participate in various tissue metabolism. The study in non-pregnant population such as patients with obesity, polycystic ovary syndrome and type2diabetes (T2DM) has showed that there are differences in expression and secretion in certain important factors, such as omentin, islet-1, vaspin in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), thereby playing a different role in modulating some physiological activities such as blood pressure, glucose and lipid metabolism, inflammation and IR. However, it is not clear whether there are differences in the expressions of these adipokine in GDM and whether these adipokine are associated with the formation of IR during pregnancy. This study aims to compare the expression differences of omentin, islet-1, vaspin mRNA in subcutaneous and visceral adipose tissues in pregnant women with GDM and NGT, to investigate relationship between omentin, islet-1, vaspin mRNA expressions and glucolipid metabolism, IR as well as other classic adipokines in Chinese pregnant women, and to explore the endocrine function of adipose tissue in SAT and VAT, which might play role in the pathophysiology of GDM occurs and provid clues to clinical intervention for GDM.
Objective
1. To evaluate the differences of metabolic states, insulin secretion and IR in pregnant women with GDM and NGT, and to investigate their impact on neonatal birth weight.
2. To compare omentin, islet-1, vaspin mRNA expressions in SAT and VAT in Chinese pregnant women with GDM and NGT, and to analyze the relationship between omentin, islet-1, vaspin mRNA expressions in different sites and glucolipid metabolism as well as IR, which might be help for investigating the role of adipose tissue with expressing specific cytokines in the pathogenesis of GDM.
3. To analyze the relationship between omentin, islet-1, vaspin mRNA expression in different sites and serum fasting adiponectin, leptin, TNF-α, IL-6levels before delivery, and to investigate whether or not the expressions and secretions of these adipokines have effects on IR during pregnancy.
Methods
1. In this prospective study,43pregnant women with GDM undergoing only alimentary control were included in the case group, The GDM group diagnosesed according to WHO criteria was compared with the control group with normal glucose tolerance (NGT) and matched for age (±yr), gravity (±1), exact parity, body mass index (BMI±1.0kg/m2), and gestational weeks at delivery (±wk) each other. Both the GDM and NGT groups delivered by elective cesarean section for obstetric indications between January and Dec2009, in the department of O&G of the1st affiliated hospital of Kunming medical collage.
2. Their height, weight, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and fasting insulin(FINS) levels before delivery were measured, BMI and weight gain during pregnancy were calculated. Homeostasis model assessment was calculated as insulin resistance index (HOMA-IR), and insulin secretion function was evaluated by homeostasis β-cell index (HBCI). The differences of clinical data between the two groups were compared and the relationship between maternal body parameters, IR and insulin secretion function with neonatal birth weight were analyzed.
3. Abdominal subcutaneous (SAT) and visceral adipose tissues (VAT) were obtained in two groups during selective cesarean section. Total RNA was extracted by Trizol and the first strand cDNA was synthesized by reverse transcription. Real-time quantitative polymerase chain reaction (RT-PCR) was used to measure the omentin, islet-1, vaspin mRNA expressions in SAT and VAT in the two groups. The relationship between omentin, islet-1, vaspin mRNA expression in different sites of adipose tissues with maternal metabolic parameters and HOMA-IR were analyzed.
4. Serum fasting adiponectin, leptin, tumor necrosis factor alpha (TNF-a) and Interleukin-6(IL-6) levels before delivery were measured by enzyme linked immunosorbent assay (ELISA). The relationship between omentin, islet-1, vaspin mRNA expression in different sites of adipose tissues with maternal serum fasting adiponectin, leptin, TNF-a and IL-6were analyzed.
Results
1. Compared with the control group (1:1), BMI before pregnancy (23.09±3.59vs.21.26±2.89, P=0.011), OGTT Oh (4.93±0.80vs.4.41±0.48, P=0.000) and2h glucose (8.61±0.71vs.6.17±0.90, P=0.000), FPG (4.88±0.66vs.4.31±0.56, P=0.000), FINS (74.59±27.16vs.50.68±19.38, P=0.000), TG (3.76±1.78vs.2.95±1.13, P=0.014), LDL-C (3.77±0.78vs.3.27±0.84, P=0.005), leptin (4.57±1.03vs.4.10±0.63, P=0.012), TNF-a (346.18±73.10vs.256.85±84.16, P=0.000)、IL-6(9.43±1.96vs.5.03±1.56, P=0.000) levels, HOMA-IR transformed to logarithm (1.18±0.17vs.0.96±0.18, P=0.000) in GDM group were significantly higher and HDL-C(1.71±0.34vs.1.97±0.47, P=0.004), adiponectin (362.95±115.53vs.450.33±80.31, P=0.000) in GDM group were significantly lower than those in control group. Received alimentary control in GDM, there were no significant differences in weight gain (15.05±6.35vs.16.20±3.53, P=0.302), HBCI (3.07±0.29vs.3.23±0.45, P=0.059) and neonatal birth weight (3433.30±491.85vs.3322.336±375.08, P=0.243) between two groups to be found.
2. Step-wise linear regression analysis showed only maternal weight gain (β=0.364, p=0.001), HOMA-IR transformed to logarithm (β=0.218, p=0.034) were proved as independent predictors of neonatal birth weight in all cases.
3. In86cases combined GDM and NGT groups, RT-PCR showed:①.There is significantly higher levels of Omentin mRNA expression in VAT than in SAT in both groups (0.636±0.157vs.0.063±0.016, P=0.000). In pregnant women with various glycometabolism states, omentin mRNA expression in GDM in both SAT (0.057±0.014vs0.070±0.015, P=0.000) and VAT (0.560±0.125vs0.713±0.150, P=0.000) are significantly lower than those in NGT.②.Islet-1mRNA expression was mainly in VAT, and islet-1mRNA expression in VAT in GDM group was significantly lower than that in NGT (0.200±0.031vs.0.268±0.049, P=0.000). However, in SAT obtained from pregnant women with GDM and NGT, islet-1mRNA were trace or virtually absent expressions (53.49%vs.65.12%, P=0.084) and there was no difference in gene expression in two groups (0.035±0.027vs.0.041±0.022, p=0.402).③. There is significantly higher levels of vaspin mRNA expression in VAT than in SAT in both groups (0.53±0.16vs.0.32±0.06, P=0.000). Vaspin mRNA expression in GDM in both SAT (0.33±0.06vs.0.30±0.05, P=0.006) and VAT (0.58±0.16vs.0.48±0.15, P=0.004) are significantly higher than those in NGT.
4. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of omentin mRNA in SAT was found to be inversely correlated with BMI before pregnancy (r=-0.251, P=0.020), OGTT2h glucose(2hPG)(r=-0.375, P=0.000), and FPG(r=-0.260, P=0.016), FINS(r=-0.242, P=0.025), HOMA-IR(r=-0.284, P=0.008), IL-6(r=-0.304, P=0.004)before delivery, respectively. Omentin mRNA in VAT was found to be inversely correlated with OGTT Oh (r=-0.274, P=0.011) and2hPG (r=-0.482, P=0.000), FPG (r=-0.259, P=0.016), HOMA-IR(r=-0.236, P=0.029), leptin(r=-0.310, P=0.004), TNF-a(r=-0.231, P=0.032), IL-6(r=-0.279, P=0.009) before delivery, whereas positively correlated with maternal weight gain(r=0.250, P=0.021) during pregnancy and serum adiponectin(r=0.361, P=0.001) levels before delivery.
5. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of islet-1mRNA in VAT was found to be inversely correlated with BMI before pregnancy (r=-0.262, P=0.015), OGTT Oh (r=-0.290, P=0.007) and2hPG(r=-0.532, P=0.000), FPG(r=-0.292, P=0.006), FINS(r=-0.310, P=0.004), HOMA-IR(r=-0.347, P=0.001), serum leptin(r=-0.228, P=0.035), TNF-a(r=-0.237, P=0.028), and IL-6(r=-0.555, P=0.000) before delivery, respectively, whereas positively correlated with maternal weight gain(r=0.294, P=0.006) during pregnancy and serum adiponectin levels (r=0.244, P=0.023) before delivery.
6. In86cases combined GDM and NGT cases, by bivariate Pearson correlation analysis the expression of vaspin mRNA in SAT was found to be positively correlated with BMI before pregnancy (r=0.594, P=0.000) and before delivery(r=0.472, P=0.000), OGTT0h(r=0.543, P=0.000) and2hPG(r=0.436, P=0.000), FPG(r=0.489, P=0.000), FINS(r=0.441, P=0.000), HOMA-IR(r=0.514, P=0.000), serum leptin (r=0.257, P=0.017), and IL-6(r=0.292, P=0.006) before delivery. Whereas the expression of vaspin mRNA in VAT was found to be positively correlated with BMI before pregnancy (r=0.457, P=0.000) and before delivery(r=0.296, P=0.006), OGTT Oh (r=0.425, P=0.000) and2hPG(r=0.401, P=0.000), FPG(r=0.343, P=0.001), FINS(r=,0.462P=0.000), HOMA-IR(r=0.486, P=0.000), serum leptin(r=0.403, P=0.000), and TNF-a(r=0.259, P=0.016) before delivery, and to be inversely correlated with maternal weight gain (r=-0.221, P=0.041) during pregnancy.
7. By multivariate step-wise linear regression analysis, vaspin mRNA expressions in SAT (β=0.543, P=0.000) were proved as independent predictors of OGTT OhPG, whereas only islet-l(β=-0.347, P=0.000), omentin(β=-0.304, P=0.000) mRNA expressions in VAT and vaspin(β=0.265, P=0.002), omentin(β=-0.189, P=0.021) mRNA expressions in SAT were proved as independent predictors of OGTT2hPG.
8. By multivariate step-wise linear regression analysis, omentin mRNA expressions in VAT (β=0.361, P=0.001) was proved as independent predictors of adiponectin; vaspin (β=0.340, P=0.001) and omentin mRNA (β=-0.209, P=0.046) expressions in VAT were proved as independent predictors of leptin; vaspin mRNA expressions in VAT(β=0.259, P=0.016) was proved as independent predictors of TNF-a; and islet-1mRNA expressions in VAT(β=-0.513, P=0.000) as well as omentin expressions in SAT were proved as independent predictors of IL-6.
9. In order to investigate how these adipokines to influence on the degree of IR during pregnancy, multivariate step-wise linear regression analysis was used, in which maternal body parameters, serum adiponectin, leptin, TNF-a, IL-6levels and omentin, islet-1, vaspin mRNA expressions in SAT and VAT levels served as independent variables. The results showed that only TNF-a (β=0.350, P=0.000), vaspin mRNA expressions in SAT (β=0.390, P=0.000) and serum leptin levels (P=0.237, P=0.008) were proved as independent predictors of HOMA-IR during pregnancy.
Conclusions
1. The glycolipid metabolic disturbance, hyperinsulinemia, insulin resistance and chronic inflammatory state were the significant clinical features of GDM. Maternal weight gain and HOMA-IR were independent predictors of neonatal birth weight.
2. Adipokines-such as omentin, islet-1, vaspin mRNA expressed specifically in visceral adipose tissue is more active than subcutaneous adipose tissue, and the expressions of these adipokines are more closely related to glucose metabolism during pregnancy, and their relationships with lipid metabolism are not significant. The impaired expressions of omentin and islet-1mRNA in VAT may be the potential motivation for glucose intolerance in GDM; and vaspin mRNA expression increased in SAT may be a compensatory mechanism responsing to insulin resistance worsen in GDM.
3. Insulin resistance during pregnancy is a complex result by multiple factors, in addition to placental hormones, adipokines also play an important regulating role in the formation of insulin resistance.
引文
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