妊娠糖尿病与婴幼儿肥胖的关联性及其分子机制研究

发布时间：2018-06-06 03:54

本文选题：妊娠糖尿病 + 婴幼儿　；参考：《浙江大学》2016年博士论文

【摘要】：研究背景及目的妊娠糖尿病(Gestational diabetes mellitus,GDM)是指妊娠过程中发生或首次发现的不同程度的糖耐量受损,是一种常见的严重危害母婴近远期健康的妊娠期合并症。近年来,GDM的发生率快速上升,GDM患者宫内高糖环境可能增加子代儿童青少年期及成年后肥胖的发生风险受到广泛关注。然而,目前有关GDM与子代肥胖发生风险的研究结论并不完全一致,且研究主要集中在儿童青少年期肥胖,尚缺乏对GDM患者子代出生后婴幼儿期生长发育的研究；在中国人群中,也尚缺乏GDM与子代肥胖相关性的研究。此外,孕期不同时点血糖水平(孕早期血糖和孕中期血糖、孕中期口服葡萄糖耐量试验(OGTT)空腹血糖和糖负荷后(1 h或2 h)血糖)对子代肥胖的影响程度是否存在差别,目前尚无这方面的研究报道。GDM影响子代肥胖的生物学机制仍不明确,但宫内高糖环境可能通过改变表观遗传学来参与子代肥胖的发生。过氧化物酶体增殖物激活受体γ(PPAR-γ)在调节代谢和脂肪形成中具有重要作用,瘦素、脂联素、脂蛋白酯酶(LPL)和脂肪细胞型脂肪酸结合蛋白(AFABP)是PPAR-γ通路上的主要肥胖相关因子；而Trim28是最新发现的肥胖“开关”基因,它们可能都在“胎儿程序化”改变过程中起着十分重要的作用。然而,目前尚无关于GDM、胎儿PPAR-γ和Trim28基因甲基化以及子代肥胖间关系的研究,也无GDM、PPAR-γ通路肥胖相关因子水平以及出生后子代肥胖间关系的研究。因此,本研究选择浙江省舟山市妇幼保健院为研究现场,采用前瞻性队列研究设计探讨GDM与婴幼儿(0、6、12、18和24个月)肥胖发生风险的关联性,并在前瞻性队列研究设计基础上采用1：1匹配设计,探讨GDM、胎儿脐带血PPAR-γ和Trim28基因甲基化以及PPAR-γ通路肥胖相关因子水平与婴幼儿(0、6、12和18个月)肥胖发生风险间的关联,阐明GDM与子代肥胖发生风险的关联性及其可能的分子机制。材料和方法本研究选择浙江省舟山市妇幼保健院为研究现场,采用前瞻性队列(2011年8月至2015年5月)研究设计,通过流行病学调查问卷收集研究对象一般社会人口学特征、生活行为方式等基本信息,从孕妇体检医疗记录中摘抄孕早期空腹血糖和糖化血红蛋白以及OGTT数据(空腹血糖、糖负荷后1 h和2 h血糖)等信息,并利用医院妇幼保健系统的孕妇妊娠合并症、并发症和产时并发症、婴幼儿身长、体重等信息,选择无其它妊娠合并症、并发症和产时并发症的单胎足月新生儿及母亲为研究对象,利用多元线性回归和Logistic回归模型探讨GDM与婴幼儿(0、6、12、18和24个月)肥胖相关指标的关联性。在已纳入上述队列研究分析的母子对中,排除孕期吸烟、饮酒、药物滥用者后,按照1：1匹配设计,以孕妇年龄、孕前BMI、分娩孕周、胎儿性别及采血季节为匹配条件,GDM组与对照组各纳入50例。于分娩时,采集每位研究对象的脐带血。采用美国SEQUENOM MassArray(?) EpiTYPER技术平台检测脐带血白细胞中PPAR-γ和Trim28基因甲基化水平,采用酶联免疫吸附法检测脐带血血浆中瘦素、脂联素、LPL和AFABP的蛋白表达水平,利用多元线性回归和Logistic回归模型探讨GDM、PPAR-γ和Trim28基因甲基化以及PPAR-γ通路肥胖相关因子水平与婴幼儿(0、6、12和18个月)肥胖发生风险间的关联。结果前瞻性队列研究共纳入1232例孕妇,其中GDM有234例,占19.0%。调整混杂因素后,GDM、孕中期OGTT空腹血糖、糖负荷后1 h和2 h血糖均与出生体重、孕周别出生体重Z-Score呈明显的正相关,且均显著增加巨大儿的发生风险(P0.05)；GDM和OGTT糖负荷后2 h血糖升高均显著增加大于胎龄儿(LGA)的发生风险(OR=1.79,95%CI:1.11-2.89；OR=2.71,95%CI:1.33-5.53),未发现孕早期空腹血糖、糖化血红蛋白与新生儿出生体重相关指标存在关联(P0.05)。此外,相对于OGTT空腹血糖异常,糖负荷后血糖异常对新生儿出生体重、孕周别出生体重Z-Score以及巨大儿发生风险影响程度更大,同时OGTT空腹血糖异常与糖负荷后血糖异常呈现明显的联合作用,两者同时异常可显著增加新生儿出生体重(β=161.4 g,P=0.0192)和孕周别出生体重Z-Score(p=0.42,P=0.0121)以及LGA(OR=3.24,95%CI:1.21-8.67)和巨大儿(OR=5.73,95%CI:2.20-14.90)的发生风险；相对于孕早期血糖异常,孕中期GDM对新生儿出生体重、孕周别出生体重Z-Score影响程度更大,同时孕早期血糖异常与GDM也呈现明显的联合作用,两者同时异常可显著增加新生儿出生体重(β=125.8 g,P=0.0010)和孕周别出生体重Z-Score(β=0.30,P=0.0013)以及LGA(OR=2.34,95%CI:1.28-4.30)和巨大儿(OR=2.53,95%CI:1.37-4.67)的发生风险。GDM与6个月婴儿的BMI(β=0.31 kg/m2,P=0.0113)和年龄别BMI Z-Score(β=-0.19,P=0.0116)呈负相关,且可降低6个月婴儿超重或肥胖的发生风险(OR=0.59,95%CI:0.33-1.04；P=0.0686)；然而,未发现孕早期血糖水平或孕中期血糖水平(包括GDM)与12、18和24个月婴幼儿体重、增重、BMI.BMI变化、年龄别体重Z-Score.年龄别BMI Z-Score以及超重或肥胖存在关联(P0.05)。1：1匹配的前瞻性队列研究中主要发现GDM以及孕中期OGTT空腹血糖与Trim28基因CpG10-11位点的甲基化水平呈明显的正相关,且该位点甲基化水平又与18个月幼儿的BMI、年龄别BMI Z-Score存在明显的正相关(P0.05)。GDM以及OGTT空腹血糖也与Trim28基因各CpG位点的平均甲基化(CpGM)水平呈正相关趋势；Trim28基因CpGM水平的升高又可增加巨大儿的发生风险(OR=1.37,95%CI：1.03-1.81),且与12、18个月婴幼儿的体重、年龄别体重Z-Score、BMI和年龄别BMI Z-Score呈正相关(P0.05)。同时,GDM与18个月幼儿的BMI(β=0.67 kg/m2,P=0.0177)和年龄别BMI Z-Score(p=0.58,P=0.0221)也呈正相关。但本研究未发现孕期血糖水平、Trim28其它CpG位点基因甲基化水平以及婴幼儿肥胖间存在关联,也未发现孕期血糖水平、PPAR-γ基因甲基化水平、PPAR-γ通路肥胖相关因子(瘦素、脂联素、LPL和AFABP)水平以及婴幼儿肥胖间存在关联(P0.05)。结论1.本研究发现GDM可增加新生儿出生体重、巨大儿和LGA的发生风险以及可能降低6个月婴儿的BMI、超重或肥胖的发生风险；OGTT空腹血糖异常与糖负荷后血糖异常、孕早期血糖异常与GDM均呈现明显的联合作用,均可显著增加新生儿出生体重、巨大儿和LGA的发生风险；未发现孕早期血糖水平或孕中期血糖水平(包括GDM)与12、18和24个月婴幼儿肥胖相关指标的关联性。提示孕妇在孕前及孕期应合理膳食,加强孕早期及孕中期血糖水平的监测,积极治疗GDM,以降低不良妊娠结局及子代肥胖的发生风险。2.我们的研究结果还提示,GDM可能通过增加Trim28基因CpG10-11位点的甲基化以及CpGM水平来引起18个月幼儿BMI的增加,但未发现孕期血糖水平、PPAR-γ基因甲基化水平、PPAR-γ通路肥胖相关因子(瘦素、脂联素、LPL和AFABP)水平以及婴幼儿肥胖间存在关联。然而,机制部分的研究结果还需大样本的流行病研究予以验证。
[Abstract]:Background and objective Gestational diabetes mellitus (GDM) refers to the varying degrees of impaired glucose tolerance occurring during pregnancy or for the first time. It is a common serious harm to maternal and infant healthy pregnancy complications. In recent years, the incidence of GDM has risen rapidly, and the high glucose environment in GDM patients may increase. The risk of childhood obesity in children and adolescents is widely concerned. However, the current research conclusions about the risk of GDM and offspring obesity are not entirely consistent, and the study is mainly focused on childhood obesity, and there is still a lack of research on the growth and development of postnatal infants in GDM patients; among Chinese people, There is also a lack of study on the correlation between GDM and offspring obesity. In addition, whether there is a difference in the influence of the blood glucose level in the early pregnancy (early pregnancy glucose and midtrimester glucose, OGTT) fasting glucose tolerance test (OGTT) and glucose load (1 h or 2 h) on the offspring obesity, there is no research report on this aspect at present,.GDM The biological mechanism that affects offspring obesity is still unclear, but the intrauterine high glucose environment may be involved in the generation of offspring obesity by changing epigenetics. Peroxisome proliferator activated receptor gamma (PPAR- gamma) plays an important role in regulating metabolism and fat formation, leptin, adiponectin, lipoprotein esterase (LPL) and fat cell fat Acid binding protein (AFABP) is a major obesity related factor in the PPAR- gamma pathway; and Trim28 is the most recently discovered obesity "switch" gene, which may play a very important role in "fetal programmed" changes. However, there is no relationship between GDM, fetal PPAR- gamma and Trim28 gene methylation and offspring obesity. There is no GDM, PPAR- gamma pathway obesity related factor and postnatal obesity relationship. Therefore, this study selected the Zhoushan maternal and child health care hospital in Zhejiang Province as the research site, using prospective cohort study to explore the association between the risk of obesity in GDM and infants (0,6,12,18 and 24 months), and in the prospective team On the basis of the study design, the 1:1 matching design was used to explore the correlation between GDM, fetal umbilical cord blood PPAR- gamma and Trim28 methylation, the association of obesity related factors in PPAR- gamma pathway and the risk of obesity in infants (0,6,12 and 18 months), and to elucidate the relationship between GDM and the risk of offspring obesity and its possible molecular mechanism. The study selected Zhoushan maternal and child health care hospital of Zhejiang Province as the research site, and used a prospective cohort (August 2011 to May 2015) to study and design, collect the basic information of the general social demography, life behavior and so on through the epidemiological survey questionnaire, and extract the fasting blood glucose in the early pregnancy from the medical records of the pregnant women. Glycosylated hemoglobin and OGTT data (fasting blood glucose, 1 h and 2 h blood sugar after sugar load), and using the maternal and child health system of pregnant women with pregnancy complications, complications and complications, infant length, weight and other information, select no other pregnancy complications, complications and complications of single full-term newborns and mothers Study subjects, using multiple linear regression and Logistic regression model to explore the correlation between GDM and infant (0,6,12,18 and 24 months) obesity related indicators. In the mother and child, who had been included in the above cohort study, excluded from pregnancy smoking, drinking, and drug abusers, according to the 1:1 matching design, the age of pregnant women, BMI before pregnancy, pregnancy week, fetus. The sex and the blood sampling season were matched, the GDM group and the control group were included in 50 cases. The umbilical cord blood of each study was collected during childbirth. The SEQUENOM MassArray (?) EpiTYPER technology platform was used to detect the methylation level of PPAR- gamma and Trim28 gene in the umbilical cord blood white blood cells and the ELISA was used to detect the leptin in the umbilical cord blood plasma. The protein expression levels of adiponectin, LPL and AFABP, using multiple linear regression and Logistic regression models to explore the correlation between the methylation of GDM, PPAR- gamma and Trim28 genes and the levels of obesity related factors in PPAR- gamma pathway and the risk of obesity in infants (0,6,12 and 18 months). Results a prospective cohort study was included in 1232 pregnant women, of which GDM was found. 234 cases, after 19.0%. adjustment of confounding factors, GDM, OGTT fasting glucose in the middle of pregnancy, 1 h and 2 h blood glucose after sugar load were all positively correlated with birth weight and gestational birth weight Z-Score, and significantly increased the risk of macrosomia (P0.05), and the increase of 2 h blood glucose after GDM and OGTT sugar load were significantly higher than that of gestational age infants (LGA). The risk (OR=1.79,95%CI:1.11-2.89; OR=2.71,95%CI:1.33-5.53) was not found in early pregnancy with fasting blood glucose, glycated hemoglobin and newborn birth weight related indicators (P0.05). In addition, compared with OGTT abnormal fasting blood glucose, abnormal blood glucose after sugar load on newborn birth weight, gestational birth weight Z-Score and huge hair hair. There was a greater degree of impact on the risk of birth, at the same time, there was a significant combination of abnormal OGTT fasting blood glucose and abnormal glucose load. Both of them also significantly increased the birth weight of the newborn (beta =161.4 g, P=0.0192) and the birth weight Z-Score (p=0.42, P=0.0121), and LGA (OR=3.24,95%CI:1.21-8.67) and giant infants (OR=5.73,95%CI:2.20). The risk of -14.90); relative to the abnormal blood glucose in the early pregnancy, the mid trimester GDM has a greater impact on the birth weight of the newborn and the birth weight Z-Score in the gestational week, and the abnormal blood glucose in the early pregnancy also has a significant combined effect on the GDM, and both of the two can significantly increase the birth weight of newborn infants (beta =125.8 g, P=0.0010) and the birth of the gestational weeks. The risk.GDM of weight Z-Score (beta =0.30, P=0.0013) and LGA (OR=2.34,95%CI:1.28-4.30) and macrosomia (OR=2.53,95%CI:1.37-4.67) was negatively correlated with the BMI (beta =0.31 kg/m2, P=0.0113) of 6 months infants and the age BMI (beta), and reduced the risk of overweight or obesity in 6 months. 04; P=0.0686); however, it was not found that early pregnancy blood glucose level or midtrimester glucose level (including GDM) and 12,18 and 24 months infant weight, weight gain, BMI.BMI change, Z-Score. age BMI Z-Score, and overweight or obesity associated (P0.05).1: 1 matching in prospective cohort study of GDM and mid pregnancy OG There was a positive correlation between TT fasting blood glucose and the level of methylation of the Trim28 gene CpG10-11 locus, and the level of methylation of the site was also positively correlated with the BMI of 18 months young children, the P0.05.GDM and the OGTT fasting blood glucose also had a positive correlation with the average methylation (CpGM) level of the CpG loci of the Trim28 gene. The increase in the CpGM level of the 28 gene could also increase the risk of the occurrence of macrosomia (OR=1.37,95%CI:1.03-1.81), as well as the weight of the infants in 12,18 months, the age other body weight Z-Score, the BMI and the age BMI Z-Score (P0.05). Meanwhile, GDM and the BMI of the 18 month children were also present. Positive correlation. However, there was no pregnancy glucose level in this study. There was a association between Trim28 other CpG locus methylation levels and infant obesity, and no pregnancy glucose levels, PPAR- gamma methylation levels, PPAR- gamma pathway obesity related factors (leptin, adiponectin, LPL and AFABP) levels and association between infant obesity (P0.05) Conclusion the 1. study found that GDM could increase the birth weight of the newborn, the risk of the occurrence of giant infants and LGA, and the risk of reducing the BMI, overweight or obesity in the 6 month infant; the abnormal OGTT fasting blood glucose and the abnormal glucose load, the abnormal blood glucose in the early pregnancy and the GDM have a clear combined effect, which can significantly increase the birth rate of the newborn. The risk of birth weight, macrosomia and LGA, and the association between the blood glucose level in the early pregnancy or the mid trimester blood glucose level (including GDM) and the obesity related indexes of 12,18 and 24 months infants. It is suggested that pregnant women should have a reasonable diet before and during pregnancy, strengthen the monitoring of blood glucose level in the early pregnancy and midtrimester, and actively treat GDM in order to reduce the bad pregnancy. The outcome and the risk of offspring obesity.2. our results also suggest that GDM may increase the BMI increase in 18 month children by increasing the methylation of the Trim28 gene CpG10-11 site and the CpGM level, but no pregnancy glucose level, the PPAR- gamma methylation level, and PPAR- gamma pathway obesity related factors (leptin, adiponectin, LPL and AFA) are not found. There is a correlation between BP level and infant obesity. However, the results of part of the mechanism need to be verified by large sample epidemiological studies.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R714.256;R723.14

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