妊娠期糖尿病的相关因素研究
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摘要
娠期糖尿病(GDM)是妊娠期常见的并发症之一,可使孕产妇、胎儿产生羊水过多、妊娠期高血压疾病、巨大儿或胎儿生长受限、胎儿宫内缺氧甚至死胎等,新生儿易发生呼吸窘迫综合征、低血糖、低钙血症、低镁血症、红细胞增多症及高胆红素血症等严重的并发症,并且其子代将来患糖耐量降低,儿童期肥胖、神经心理失调等风险性也增加,虽然GDM孕妇多数产后糖代谢异常能恢复正常,但将来发生糖尿病(DM)的危险性明显增加。GDM近年来发生率逐年上升,约占全部妊娠的7%,由于种族、确诊方法及标准的不同,其发病率为1%～14%。据报道,中国目前GDM发生率为1.31%-3.75%。其持续增长的流行病学趋势已构成严重的公共卫生问题,在国内外产科界正受到越来越多的关注。
GDM的病因及发病机制目前尚不明确,多数学者认为是遗传和环境两大因素的结果。本课题将从流行病学、基因等方面对其发病进行探讨。
目的:(1)揭示本地区GDM发病的相关因素,包括危险因素和保护因素,为该病的病因研究提供线索,为该病的预防控制提供依据。(2)测定本地区人群GDM的易感基因和保护基因,为探索发病机制,制定合理的预防、治疗方案寻找依据。(3)通过测定胎盘部位APNmRNA和AdipoR1/2mRNA的相对表达量在GDM病理状态下的变化趋势,分析其与新生儿体重、新生儿PI之间的关系。(4)检测GDM患者血硒及胎盘硒水平变化,探讨妊娠妇女血硒及胎盘硒水平变化与GDM对患者胎盘组织形态学改变的作用。
方法:(1)相关因素调查,采用病例对照1∶2配比设计,选择2005年8月至2007年12月在山西医科大学第一附属医院住院分娩的山西籍孕妇经筛查符合GDM诊断标准者为病例组,在同期筛查中选择非GDM孕妇作为对照组。配比条件:年龄±2岁、籍贯均为山西籍且本地居住20年以上。依据α=0.05,β=0.1,估计平均OR值3.0,对照组因素暴露比例0.2,估计样本量:病例组72人,对照组144人,采用单因素及多因素条件logistic回归计算OR值及95%可信区间。(2)用EDTA抗凝方法收集39例GDM组和42例对照组的静脉血,用饱和酚-氯仿方法提取基因组DNA,以顺序特异引物聚合酶链反应技术(polymerise chainreaction-sequence specific primers,PCR-SSP)扩增部分HLA-DR、DQ、DA部分等位基因,依据实验室工作实际及统计分析要求,随机选取病例及对照组各送30例测序。利用SPSS统计软件,采用χ~2检验比较两组间的基因频率差别,P＜0.05认为有统计学意义。(3)收集26例GDM组和30例对照组的胎盘组织,-70℃保存。采用逆转录一聚合酶链反应(reversetranscription PCR RT—PCR)技术,检测30例正常妊娠及26例GDM两组胎盘APNmRNA和AdipoR1/2 mRNA的表达,对其进行半定量分析,研究APNmRNA和AdipoR1/2mRNA在GDM病理状态下表达水平的改变,利用SPSS统计软件,数据用均数标±准差表示,采用t检验,P＜0.05认为有统计学意义。(4) 30例GDM组和30例对照组妊娠妇女,于产前采集空腹静脉血,分娩时收集胎盘组织,采用2,3-二氨基奈(DAN)荧光法及5,5-二硫代双(二硝基苯甲酸)直接法,分别检测血硒和胎盘硒水平及全血谷胱甘肽过氧化物酶(GSH-Px)的活性,并对GDM组及对照组各10例胎盘组织进行病理学观察。利用SPSS统计软件,数据用均数标士准差表示,采用t检验,P＜0.05认为有统计学意义。
结果:(1) DM家族史(OR=3.006;95%CI1.672～5.401)、孕前体重指数(OR=2.549;95%CI1.420～4.579)、孕期增重过多(OR=1.853;95%CI1.044～3.292)、巨大儿生育史(OR=2.997;95%CI1.175～7.639)、孕期运动(OR=0.447;95%CI 0.251～0.797)、平衡饮食(OR=0.538;95%CI0.290～0.998)等因素是GDM的独立影响因素,其中有意识适当的体育锻炼、平衡饮食为保护因素,其他均为危险因素。最终进入主效应模型的因素是:DM家族史(OR=2.997;95%CI1.175～7.639)、孕前体重指数(OR=2.939;95%CI1.193～7.241)、孕期增重过多(OR=1.841;95%CI1.143～2.966)、孕期运动(OR=0.393;95%CI0.220～0.703)。(2) A:HLA-Ⅱ类基因频率在两组间有差异,与以往报道一致;B:GDM组中,HLA-DRB1~*0301(χ~2=4.855:P=0.028)、DQB1~*0201(χ~2=4.667;P=0.031)基因频率显著高于对照组(38.5%vs16.7%;28.2%vs9.5%,P＜0.05),差异有统计学意义;GDM组中,HLA-DQA1~*0103基因频率显著低于对照组(7.7%vs14.3%,P＜0.05),差异有统计学意义。(χ~2=6.740;P=0.009);而GDM组中DQA1~*0501基因频率高于对照组,但两者相比差异无统计学意义(χ~2=0.509;P=0.476)。(3) A:APNmRNA和AdipoR1/2 mRNA表达于胎盘组织;B:GDM组新生儿的出生体重(t=4.667;P=0.031)、新生儿PI(t=4.667;P=0.031),均高于对照组,有统计学意义;C:GDM组APN mRNA的表达水平显著低于对照组(0.7565±0.19 vs1.1653±0.17,P＜0.05)差异有显著的统计学意义;GDM组AdipoR1 mRNA的表达水平与对照组差异无显著的统计学意义(2.0789±0.67 vs1.9843±0.68,P＞0.05):GDM组AdipoR2 mRNA的表达水平与对照组差异具有显著的统计学意义(1.5788±0.36vs1.1883±0.25,P＜0.001);D:GDM组胎盘APN mRNA的表达水平与新生儿出生体重(r=-0.959,P＜0.001)、PI(r=-0.477,P＜0.001)呈负相关,对照组胎盘APN mRNA的表达水平与其新生儿出生体重(r=-0.775,P＜0.001)、PI(r=-0.662,P＜0.001)呈负相关。两组合并后,胎盘APN mRNA的表达水平与新生儿出生体重(r=-0.915,P＜0.001)、PI(r=-0.641,P＜0.001)均呈负相关。两组AdipoR2 mRNA的表达水平与新生儿出生体重(分别为:r=-0.276,r=-0.281,P均＞0.05)、PI(分别为:r=-0.143,r=-0.155,P均＞0.05)无明显相关性。(4) A:GDM组孕妇血硒、胎盘硒及血GSH-Px活性分别为(0.0620±0.0224mg/L)、(0.4854±0.0857mg/L)、(68.20±15.91)活力单位明显低于对照组(0.0783±0.0209mg/L)、(0.5473±0.0842mg/L)、(80.36±12.68)活力单位,差异有显著统计学意义(P＜0.01)。B:孕妇血硒水平与GSH-PX活性呈显著正相关(r=0.714,P＜0.001)。C:GDM组孕妇血硒与胎盘硒含量成显著正相关(r=0.639,P＜0.001),对照组血硒与胎盘硒水平无明显相关。D:光镜下观察GDM组胎盘的病理改变主要为:绒毛水肿,干绒毛小动脉管壁增厚,管腔狭窄,合体细胞结节增多,细胞滋养叶细胞及血管合体膜形成增加;对照组未见明显上述病理改变。
结论:(1) DM家族史、孕前体重指数、孕期增重过多、巨大儿生育史、孕期运动、平衡饮食等因素是GDM的独立影响因素,其中有意识适当的体育锻炼、平衡饮食为保护因素,其他均为危险因素。(2) HLA-DRB1~*0301、DQB1~*0201基因可能为该地区GDM的易感基因:而HLA-DRA1~*0103基因可能为此地区人群的保护基因。(3) A:胎盘组织中存在APNmRNA和AdipoR1/2mRNA的表达;B:GDM组胎盘组织APNmRNA表达水平低于对照组,提示胎盘组织APN mRNA的表达同样受到GDM病理状态的影响,在GDM时AdipoR1mRNA的表达水平无明显改变,而AdipoR2mRNA表达水平显著高于对照组,提示在胎盘局部APN可能主要通过AdipoR2发挥生物学效应。C:APNmRNA的表达水平与新生儿体重与PI呈负相关性;AdipoR2mRNA的表达水平与新生儿体重与PI无明显相关性。胎盘部位APN及AdipoR与母婴代谢之间的关系有待进一步探讨;(4) A:血及胎盘组织中硒的缺乏及GSH-Px活性的下降可能与GDM的发生有关;B:硒是抗氧化物酶-谷胱甘肽过氧化物酶(GSH-Px)的活性成分,GDM患者胎盘硒水平降低,可导致胎盘GSH-Px活性下降,发生脂质过氧化反应,破坏胎盘生物膜结构,可能与GDM患者胎盘组织病理改变有关。
Gestational diabetes mellitus(GDM) is one of common complication of pregnancy. Maternal,fetal and neonatal have serious complications,the risk of decreased glucose tolerance, childhood obesity and psychological disorders of their offspring will increase significantly in the future.Though the majority glucose metabolism abnormalities of GDM patient can return to normal,in the future the risk of diabetes mellitus(DM) may increase significantly.In recent years the incidence of GDM increased year by year,accounting for about 7%of all pregnancies, using different diagnosis methods and the different standards,the incidence rate varies from 1% to 14%.According to reports,the current incidence of GDM in China is 1.31%-3.75%.The continuing growth trend in epidemiological has been a serious public health problem,all the obstetrical profession has more and more attention.
Causes and Pathogenesis of GDM is still unclear;the most specialist believe that the combination of all factors is the reason of the GDM.This topic will discuss GDM from epidemiological,genetic,and other aspects of this disease.
Objective:(1) related factors survey in Shanxi region try to reveals the risk factors of GDM.(2)To study on HLA-Ⅱgene,to measure the protection gene and susceptibility gene of GDM in Shanxi region and try to look for the basis for prevention and treatment programs.(3) To measure the expression level of APNmRNA and AdipoR1/2 mRNA in the placental site and to analyze the relationship between the level ofAPNmRNA,AdipoR1/2mRNA and birth weight and newborn PI.(4) To study the changes of Selenium concentration in blood and placenta and to explore the relationship between the Selenium concentration in blood and placenta and damage of histomorphology of the placentas in Gestational Diabetes Mellitus (GDM).
Methods:(1)related factors survey in Shanxi region,1:2 case-control designed,select the patient deliveried in the First Affiliated Hospital of Shanxi Medical University from August 2005 through December 2007.The pregnant women who meet the diagnostic criteria GDM are GDM group,GDM screening test negative are control group.Proportion conditions:age±2 years old,based onα= 0.05,β= 0.1,it is estimated that the average value of OR 3.0,the average ratio of 0.2 exposure factors,the estimated sample size:72 cases,the control group 144 cases,a single-factor and multi-factor conditional logistic regression was used,then calculate OR value and 95%confidence interval.(2) 81 blood samples were collected in vacutainer tubes with EDTA from pregnant women,39 with GDM and 42 without GDM.saturated phenolchloroform extraction method of genomic DNA was used;sequence-specific primers polymerase chain reaction(polymerise chain reaction-sequence specific primers and PCR-SSP) amplification of HLA-DR and DQ,DA genes,based on the actual laboratory work and requirements of statistical analysis,30 samples in GDM group and 30 samples in control group sent to sequencing.Statistical analysis was performed using SPSS statistical software,the groups were compared usingχ~2 test,the results were considered significant at P＜0.05.(3) Placental tissure collected at the time of delivery,26 with GDM and 30 without GDM,was frosen at -70C.By the RT-PCR technique to dectect the expression level of APNmRNA and AdipoR1/2mRNA in placental site,and to take semiquantitative analysis.Statistical analysis was performed using SPSS statistical software,the groups were compared using t test,Data are presented as mean±standard deviation,and results were considered significant at P＜0.05.(4) To measured the selenium concentration in blood and placenta by 2,3-diaminonapaphthalene and glutathione peroxidase(GSH-Px) activity by a 5,5'-dithionbis(2-nitrobenzoic acid) direct method in 30 patients with GDM and 30 without GDM.Blood were collected before delivery and placental tissure were collected at the time of delivery.Furthermore,the features of the placenta(10 from control group and 10 from GDM group) pathologic changes were observed microscopically.Statistical analysis was performed using SPSS statistical software,the groups were compared using t test,Data are presented as mean+standard deviation,and results were considered significant at P＜0.05.
Results:(1) DM family history(OR=3.006;95%CI1.672～5.401),pre-pregnancy body mass index(OR=2.549;95%CI1.420～4.579),excessive weight gain during pregnancy (OR=1.853;95%CI1.044～3.292),previous history of abnormal pregnancy(OR=2.997; 95%CI1.175～7.639),physical exercise(OR=0.447;95%CI 0.251～0.797),balanced diet (OR=0.538;95%CI0.290～0.998) are the independent impact factors,awareness of appropriate physical exercise and balanced diet are protective factors,the other is risk factors. The factors entered the main effect model are:DM family history(OR=2.997; 95%CI1.175～7.639),pre-pregnancy body mass index(OR= 2.939;95%CI1.193～7.241), excessive weight gain(OR=1.841;95%CI1.143～2.966) during pregnancy,physical exercise (OR=0.393;95%CI0.220～0.703).(2) A:Significant differences were noted between the two groups in HLA-Ⅱgene frequency,consistent with previous reports;B:HLA-DRB1 * 0301, DQB1 * 0201 gene frequency in GDM group was significant higher than that in control group(38.5%vs16.7%28.2%vs9.5%,P＜0.05);HLA-DQA1 * 0103 gene frequency in GDM group was significantly lower than that in control group(7.7%vs14.3%,P＜0.05);DQA1* 0501 gene frequency in the GDM group is higher than that in control group,but the difference was not significant(P＞0.05).(3) A:APNmRNA and AdipoR1 / 2 mRNA were expressed in placental site;B:neonatal birth weight and neonatal PI in the GDM group were higher than those in control group(P＜0.05);C:the expression level of APN mRNA in GDM group was significantly lower than that in control group(0.7565±0.19 vs 1.1653±0.17,P＜0.05),and the expression level of AdipoR1 mRNA was no significant difference between two groups (2.0789±0.67 vs 1.9843±0.68,P＞0.05);the expression level of AdipoR2 mRNA in GDM group was significantly higher than that in control group(1.5788±0.36 vs1.1883±0.25,P＜0.05);D:The expression level of APN mRNA in GDM group was negatively correlated with birth weight(r=-0.959,P＜0.001) and newborn PI(r=-0.477,P＜0.05),The expression level of APN mRNA in control group was negatively correlated with birth weight(r=-0.775,P＜0.001) and newborn PI(r=-0.662,P＜0.05),The expression level of AdipoR2 mRNA in two groups was no correlated with birth weight(r=-0.276,P＞0.05) and newborn PI(r=-0.143,P＞0.05).(4) A:The average selenium levels of matemal blood and placental tissue and the activity of GSH-Px were significant lower in GDM group(0.0620±0.0224 mg/L)(0.4854±0.8570 mg/L)(68.20±15.91 U) than that in the control group(0.0783±0.0209 mg/L)(0.5473±0.8416 mg/L)(80.36±12.68 U) (P＜0.01).B:There was a significant positive correlation between the selenium concentration and GSH-Px activity in blood(r=0.714,P＜0.001).C:There was a positive correlation between blood and placental selenium concentrations in GDM group(r=0.639,P＜0.001),there was not correlation in control group.D:Placental tissure obtained from GDM group had swelling of villi,thickening of trunk villus small artery wall,narrowing of lumen,increasing number of syncytial sprouts,proliferating cytotrophoblasts and thickening of vasculo-syncytial membrane(VSM) under light microscopy.Placental tissure from control group did not show the pathologic changes as mentioned above.
Conclusion:(1) DM family history,pre-pregnancy body mass index,excessive weight gain during pregnancy,maternal age,previous history of abnormal pregnancy,physical exercise, balanced diet are the independent impact factors,awareness of appropriate physical exercise and balanced diet are protective factors,the other is risk factors.(2) HLA-DRB1 * 0301,DQB1 * 0201 gene may be the GDM susceptibility gene in this region,HLA-DRA1 * 0103 gene may protection gene in this region.(3) A:APNmRNA and AdipoR1/2mRNA were expressed in placental site;B:the expression level of APN mRNA in GDM group was significantly lower than that in control group,and the expression level of AdipoR1 mRNA was no significant difference between two groups;the expression level of AdipoR2 mRNA in GDM group was significantly higher than that in control group;C:The expression level of APN mRNA was negatively correlated with birth weight and newborn PI;The expression level of AdipoR2 mRNA was no correlated with birth weight and newborn PI;the mechanism how placental APN and AdipoR affect on fetal metabolism need to be further explored.(4) A:The lower level of selenium and GSH-Px may contribute to the pathogenesis of GDM.B:The placental selenium deficiency may reduce placental GSH-Px activity,the antioxidative defence may have been defective,which may be associated with the damage of histomorphology of the placenta in GDM.
GDM的病因及发病机制目前尚不明确,多数学者认为是遗传和环境两大因素的结果。本课题将从流行病学、基因等方面对其发病进行探讨。
目的:(1)揭示本地区GDM发病的相关因素,包括危险因素和保护因素,为该病的病因研究提供线索,为该病的预防控制提供依据。(2)测定本地区人群GDM的易感基因和保护基因,为探索发病机制,制定合理的预防、治疗方案寻找依据。(3)通过测定胎盘部位APNmRNA和AdipoR1/2mRNA的相对表达量在GDM病理状态下的变化趋势,分析其与新生儿体重、新生儿PI之间的关系。(4)检测GDM患者血硒及胎盘硒水平变化,探讨妊娠妇女血硒及胎盘硒水平变化与GDM对患者胎盘组织形态学改变的作用。
方法:(1)相关因素调查,采用病例对照1∶2配比设计,选择2005年8月至2007年12月在山西医科大学第一附属医院住院分娩的山西籍孕妇经筛查符合GDM诊断标准者为病例组,在同期筛查中选择非GDM孕妇作为对照组。配比条件:年龄±2岁、籍贯均为山西籍且本地居住20年以上。依据α=0.05,β=0.1,估计平均OR值3.0,对照组因素暴露比例0.2,估计样本量:病例组72人,对照组144人,采用单因素及多因素条件logistic回归计算OR值及95%可信区间。(2)用EDTA抗凝方法收集39例GDM组和42例对照组的静脉血,用饱和酚-氯仿方法提取基因组DNA,以顺序特异引物聚合酶链反应技术(polymerise chainreaction-sequence specific primers,PCR-SSP)扩增部分HLA-DR、DQ、DA部分等位基因,依据实验室工作实际及统计分析要求,随机选取病例及对照组各送30例测序。利用SPSS统计软件,采用χ~2检验比较两组间的基因频率差别,P＜0.05认为有统计学意义。(3)收集26例GDM组和30例对照组的胎盘组织,-70℃保存。采用逆转录一聚合酶链反应(reversetranscription PCR RT—PCR)技术,检测30例正常妊娠及26例GDM两组胎盘APNmRNA和AdipoR1/2 mRNA的表达,对其进行半定量分析,研究APNmRNA和AdipoR1/2mRNA在GDM病理状态下表达水平的改变,利用SPSS统计软件,数据用均数标±准差表示,采用t检验,P＜0.05认为有统计学意义。(4) 30例GDM组和30例对照组妊娠妇女,于产前采集空腹静脉血,分娩时收集胎盘组织,采用2,3-二氨基奈(DAN)荧光法及5,5-二硫代双(二硝基苯甲酸)直接法,分别检测血硒和胎盘硒水平及全血谷胱甘肽过氧化物酶(GSH-Px)的活性,并对GDM组及对照组各10例胎盘组织进行病理学观察。利用SPSS统计软件,数据用均数标士准差表示,采用t检验,P＜0.05认为有统计学意义。
结果:(1) DM家族史(OR=3.006;95%CI1.672～5.401)、孕前体重指数(OR=2.549;95%CI1.420～4.579)、孕期增重过多(OR=1.853;95%CI1.044～3.292)、巨大儿生育史(OR=2.997;95%CI1.175～7.639)、孕期运动(OR=0.447;95%CI 0.251～0.797)、平衡饮食(OR=0.538;95%CI0.290～0.998)等因素是GDM的独立影响因素,其中有意识适当的体育锻炼、平衡饮食为保护因素,其他均为危险因素。最终进入主效应模型的因素是:DM家族史(OR=2.997;95%CI1.175～7.639)、孕前体重指数(OR=2.939;95%CI1.193～7.241)、孕期增重过多(OR=1.841;95%CI1.143～2.966)、孕期运动(OR=0.393;95%CI0.220～0.703)。(2) A:HLA-Ⅱ类基因频率在两组间有差异,与以往报道一致;B:GDM组中,HLA-DRB1~*0301(χ~2=4.855:P=0.028)、DQB1~*0201(χ~2=4.667;P=0.031)基因频率显著高于对照组(38.5%vs16.7%;28.2%vs9.5%,P＜0.05),差异有统计学意义;GDM组中,HLA-DQA1~*0103基因频率显著低于对照组(7.7%vs14.3%,P＜0.05),差异有统计学意义。(χ~2=6.740;P=0.009);而GDM组中DQA1~*0501基因频率高于对照组,但两者相比差异无统计学意义(χ~2=0.509;P=0.476)。(3) A:APNmRNA和AdipoR1/2 mRNA表达于胎盘组织;B:GDM组新生儿的出生体重(t=4.667;P=0.031)、新生儿PI(t=4.667;P=0.031),均高于对照组,有统计学意义;C:GDM组APN mRNA的表达水平显著低于对照组(0.7565±0.19 vs1.1653±0.17,P＜0.05)差异有显著的统计学意义;GDM组AdipoR1 mRNA的表达水平与对照组差异无显著的统计学意义(2.0789±0.67 vs1.9843±0.68,P＞0.05):GDM组AdipoR2 mRNA的表达水平与对照组差异具有显著的统计学意义(1.5788±0.36vs1.1883±0.25,P＜0.001);D:GDM组胎盘APN mRNA的表达水平与新生儿出生体重(r=-0.959,P＜0.001)、PI(r=-0.477,P＜0.001)呈负相关,对照组胎盘APN mRNA的表达水平与其新生儿出生体重(r=-0.775,P＜0.001)、PI(r=-0.662,P＜0.001)呈负相关。两组合并后,胎盘APN mRNA的表达水平与新生儿出生体重(r=-0.915,P＜0.001)、PI(r=-0.641,P＜0.001)均呈负相关。两组AdipoR2 mRNA的表达水平与新生儿出生体重(分别为:r=-0.276,r=-0.281,P均＞0.05)、PI(分别为:r=-0.143,r=-0.155,P均＞0.05)无明显相关性。(4) A:GDM组孕妇血硒、胎盘硒及血GSH-Px活性分别为(0.0620±0.0224mg/L)、(0.4854±0.0857mg/L)、(68.20±15.91)活力单位明显低于对照组(0.0783±0.0209mg/L)、(0.5473±0.0842mg/L)、(80.36±12.68)活力单位,差异有显著统计学意义(P＜0.01)。B:孕妇血硒水平与GSH-PX活性呈显著正相关(r=0.714,P＜0.001)。C:GDM组孕妇血硒与胎盘硒含量成显著正相关(r=0.639,P＜0.001),对照组血硒与胎盘硒水平无明显相关。D:光镜下观察GDM组胎盘的病理改变主要为:绒毛水肿,干绒毛小动脉管壁增厚,管腔狭窄,合体细胞结节增多,细胞滋养叶细胞及血管合体膜形成增加;对照组未见明显上述病理改变。
结论:(1) DM家族史、孕前体重指数、孕期增重过多、巨大儿生育史、孕期运动、平衡饮食等因素是GDM的独立影响因素,其中有意识适当的体育锻炼、平衡饮食为保护因素,其他均为危险因素。(2) HLA-DRB1~*0301、DQB1~*0201基因可能为该地区GDM的易感基因:而HLA-DRA1~*0103基因可能为此地区人群的保护基因。(3) A:胎盘组织中存在APNmRNA和AdipoR1/2mRNA的表达;B:GDM组胎盘组织APNmRNA表达水平低于对照组,提示胎盘组织APN mRNA的表达同样受到GDM病理状态的影响,在GDM时AdipoR1mRNA的表达水平无明显改变,而AdipoR2mRNA表达水平显著高于对照组,提示在胎盘局部APN可能主要通过AdipoR2发挥生物学效应。C:APNmRNA的表达水平与新生儿体重与PI呈负相关性;AdipoR2mRNA的表达水平与新生儿体重与PI无明显相关性。胎盘部位APN及AdipoR与母婴代谢之间的关系有待进一步探讨;(4) A:血及胎盘组织中硒的缺乏及GSH-Px活性的下降可能与GDM的发生有关;B:硒是抗氧化物酶-谷胱甘肽过氧化物酶(GSH-Px)的活性成分,GDM患者胎盘硒水平降低,可导致胎盘GSH-Px活性下降,发生脂质过氧化反应,破坏胎盘生物膜结构,可能与GDM患者胎盘组织病理改变有关。
Gestational diabetes mellitus(GDM) is one of common complication of pregnancy. Maternal,fetal and neonatal have serious complications,the risk of decreased glucose tolerance, childhood obesity and psychological disorders of their offspring will increase significantly in the future.Though the majority glucose metabolism abnormalities of GDM patient can return to normal,in the future the risk of diabetes mellitus(DM) may increase significantly.In recent years the incidence of GDM increased year by year,accounting for about 7%of all pregnancies, using different diagnosis methods and the different standards,the incidence rate varies from 1% to 14%.According to reports,the current incidence of GDM in China is 1.31%-3.75%.The continuing growth trend in epidemiological has been a serious public health problem,all the obstetrical profession has more and more attention.
Causes and Pathogenesis of GDM is still unclear;the most specialist believe that the combination of all factors is the reason of the GDM.This topic will discuss GDM from epidemiological,genetic,and other aspects of this disease.
Objective:(1) related factors survey in Shanxi region try to reveals the risk factors of GDM.(2)To study on HLA-Ⅱgene,to measure the protection gene and susceptibility gene of GDM in Shanxi region and try to look for the basis for prevention and treatment programs.(3) To measure the expression level of APNmRNA and AdipoR1/2 mRNA in the placental site and to analyze the relationship between the level ofAPNmRNA,AdipoR1/2mRNA and birth weight and newborn PI.(4) To study the changes of Selenium concentration in blood and placenta and to explore the relationship between the Selenium concentration in blood and placenta and damage of histomorphology of the placentas in Gestational Diabetes Mellitus (GDM).
Methods:(1)related factors survey in Shanxi region,1:2 case-control designed,select the patient deliveried in the First Affiliated Hospital of Shanxi Medical University from August 2005 through December 2007.The pregnant women who meet the diagnostic criteria GDM are GDM group,GDM screening test negative are control group.Proportion conditions:age±2 years old,based onα= 0.05,β= 0.1,it is estimated that the average value of OR 3.0,the average ratio of 0.2 exposure factors,the estimated sample size:72 cases,the control group 144 cases,a single-factor and multi-factor conditional logistic regression was used,then calculate OR value and 95%confidence interval.(2) 81 blood samples were collected in vacutainer tubes with EDTA from pregnant women,39 with GDM and 42 without GDM.saturated phenolchloroform extraction method of genomic DNA was used;sequence-specific primers polymerase chain reaction(polymerise chain reaction-sequence specific primers and PCR-SSP) amplification of HLA-DR and DQ,DA genes,based on the actual laboratory work and requirements of statistical analysis,30 samples in GDM group and 30 samples in control group sent to sequencing.Statistical analysis was performed using SPSS statistical software,the groups were compared usingχ~2 test,the results were considered significant at P＜0.05.(3) Placental tissure collected at the time of delivery,26 with GDM and 30 without GDM,was frosen at -70C.By the RT-PCR technique to dectect the expression level of APNmRNA and AdipoR1/2mRNA in placental site,and to take semiquantitative analysis.Statistical analysis was performed using SPSS statistical software,the groups were compared using t test,Data are presented as mean±standard deviation,and results were considered significant at P＜0.05.(4) To measured the selenium concentration in blood and placenta by 2,3-diaminonapaphthalene and glutathione peroxidase(GSH-Px) activity by a 5,5'-dithionbis(2-nitrobenzoic acid) direct method in 30 patients with GDM and 30 without GDM.Blood were collected before delivery and placental tissure were collected at the time of delivery.Furthermore,the features of the placenta(10 from control group and 10 from GDM group) pathologic changes were observed microscopically.Statistical analysis was performed using SPSS statistical software,the groups were compared using t test,Data are presented as mean+standard deviation,and results were considered significant at P＜0.05.
Results:(1) DM family history(OR=3.006;95%CI1.672～5.401),pre-pregnancy body mass index(OR=2.549;95%CI1.420～4.579),excessive weight gain during pregnancy (OR=1.853;95%CI1.044～3.292),previous history of abnormal pregnancy(OR=2.997; 95%CI1.175～7.639),physical exercise(OR=0.447;95%CI 0.251～0.797),balanced diet (OR=0.538;95%CI0.290～0.998) are the independent impact factors,awareness of appropriate physical exercise and balanced diet are protective factors,the other is risk factors. The factors entered the main effect model are:DM family history(OR=2.997; 95%CI1.175～7.639),pre-pregnancy body mass index(OR= 2.939;95%CI1.193～7.241), excessive weight gain(OR=1.841;95%CI1.143～2.966) during pregnancy,physical exercise (OR=0.393;95%CI0.220～0.703).(2) A:Significant differences were noted between the two groups in HLA-Ⅱgene frequency,consistent with previous reports;B:HLA-DRB1 * 0301, DQB1 * 0201 gene frequency in GDM group was significant higher than that in control group(38.5%vs16.7%28.2%vs9.5%,P＜0.05);HLA-DQA1 * 0103 gene frequency in GDM group was significantly lower than that in control group(7.7%vs14.3%,P＜0.05);DQA1* 0501 gene frequency in the GDM group is higher than that in control group,but the difference was not significant(P＞0.05).(3) A:APNmRNA and AdipoR1 / 2 mRNA were expressed in placental site;B:neonatal birth weight and neonatal PI in the GDM group were higher than those in control group(P＜0.05);C:the expression level of APN mRNA in GDM group was significantly lower than that in control group(0.7565±0.19 vs 1.1653±0.17,P＜0.05),and the expression level of AdipoR1 mRNA was no significant difference between two groups (2.0789±0.67 vs 1.9843±0.68,P＞0.05);the expression level of AdipoR2 mRNA in GDM group was significantly higher than that in control group(1.5788±0.36 vs1.1883±0.25,P＜0.05);D:The expression level of APN mRNA in GDM group was negatively correlated with birth weight(r=-0.959,P＜0.001) and newborn PI(r=-0.477,P＜0.05),The expression level of APN mRNA in control group was negatively correlated with birth weight(r=-0.775,P＜0.001) and newborn PI(r=-0.662,P＜0.05),The expression level of AdipoR2 mRNA in two groups was no correlated with birth weight(r=-0.276,P＞0.05) and newborn PI(r=-0.143,P＞0.05).(4) A:The average selenium levels of matemal blood and placental tissue and the activity of GSH-Px were significant lower in GDM group(0.0620±0.0224 mg/L)(0.4854±0.8570 mg/L)(68.20±15.91 U) than that in the control group(0.0783±0.0209 mg/L)(0.5473±0.8416 mg/L)(80.36±12.68 U) (P＜0.01).B:There was a significant positive correlation between the selenium concentration and GSH-Px activity in blood(r=0.714,P＜0.001).C:There was a positive correlation between blood and placental selenium concentrations in GDM group(r=0.639,P＜0.001),there was not correlation in control group.D:Placental tissure obtained from GDM group had swelling of villi,thickening of trunk villus small artery wall,narrowing of lumen,increasing number of syncytial sprouts,proliferating cytotrophoblasts and thickening of vasculo-syncytial membrane(VSM) under light microscopy.Placental tissure from control group did not show the pathologic changes as mentioned above.
Conclusion:(1) DM family history,pre-pregnancy body mass index,excessive weight gain during pregnancy,maternal age,previous history of abnormal pregnancy,physical exercise, balanced diet are the independent impact factors,awareness of appropriate physical exercise and balanced diet are protective factors,the other is risk factors.(2) HLA-DRB1 * 0301,DQB1 * 0201 gene may be the GDM susceptibility gene in this region,HLA-DRA1 * 0103 gene may protection gene in this region.(3) A:APNmRNA and AdipoR1/2mRNA were expressed in placental site;B:the expression level of APN mRNA in GDM group was significantly lower than that in control group,and the expression level of AdipoR1 mRNA was no significant difference between two groups;the expression level of AdipoR2 mRNA in GDM group was significantly higher than that in control group;C:The expression level of APN mRNA was negatively correlated with birth weight and newborn PI;The expression level of AdipoR2 mRNA was no correlated with birth weight and newborn PI;the mechanism how placental APN and AdipoR affect on fetal metabolism need to be further explored.(4) A:The lower level of selenium and GSH-Px may contribute to the pathogenesis of GDM.B:The placental selenium deficiency may reduce placental GSH-Px activity,the antioxidative defence may have been defective,which may be associated with the damage of histomorphology of the placenta in GDM.
引文
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