基于流行病学的低血糖负荷膳食干预对超重孕妇母子胰岛素抵抗的影响及表观遗传机制的研究

Overweight of pregnant women increases insulin resistance and risk of adverse gestational outcomes. Recent evidence from both animal studies and human subject studies shows that adverse environmental exposure during pregnancy result in adverse influence on offsprings. The hypothesis of the current study is that the healthy intervention during pregnancy to overweight pregnant women- - low glycemic diet, may improve the insulin resistance of neonates and when they grow up to 2 years old. The effect of intervention on offspring may be associated with altering the methylation of some genes of placenta tissue. The current study adopts randomized, single blinded, congtroled intervention trial, gives low glycemic index diet intervention based on the national diet and physical activity recommendations for pregnant women to intervention group and only national recommendations to control group. Four diet consulation visits will be done,at baseline (first prenatal examination), the end of 1st trimester, 2nd trimester and 3rd trimester respectively including diet assessment and diet consulation specifically to adopting low glycemic diet. Glycemic load of diet will be calculated based on 24 hour diet recall data for each individuals at every visit to help to lowing their diet glycemic load by modifying some foods. The effect of intervention is investigated by comparing the insulin resistance levels between two groups at birth from neonates and when infants are at age 2. Additionally,we compare the genomewide methylation difference between intervention group and control group, and analyze its association with the outcome change. The trail will recruit 400 overweight pregnant women as study subjects when they receive first prenatal examination, longitudinally examine insulin resistance at birth and 2 years later, examine the methylation of placenta tissue by two-step methylation methodology. Compared with previous low glycemic index diet intervention studies , the current study has the following strengths: randomzed controled trial, the largest sample size, the longest term of intervention (about 6 months), examine both clinical and subclinical outcomes, and focus on both intervention effect and mechnism. The findings of our study will have important impact on metabolic risk factor management in maternal and children health in China.

超重孕妇可因胰岛素抵抗增加不良妊娠结局的危险。最新研究表明孕期不良环境因素暴露可影响子代健康。本研究假设为: 孕期对超重孕妇的良性干预措施- - -低血糖生成指数（GI）膳食干预，可以通过作用于胎盘组织能量代谢相关基因的甲基化使干预组孕妇及所生孩子的胰岛素抵抗改善。本研究采用随机化单盲对照干预试验设计，针对初次产检超重的孕妇，在我国孕产妇保健规范基础上实施低GI膳食的干预，观察干预对母子胰岛素抵抗和妊娠结局的改善作用，同时探讨胎盘组织能量代谢相关基因的甲基化改变，分析表型改变与甲基化改变是否有关联。本研究拟入选研究对象400名，实施干预后观察分娩时和婴儿2岁时的表型，胎盘甲基化的改变采用全基因组两步法进行测定。与既往报道相比，本研究的样本量最大、干预时间最长，观察结局纵向观察的亚临床指标和临床指标，同时研究干预效果和作用机制。本研究结果对于我国妇幼卫生的政策研究具有重要的公共卫生意义。

目的：研究孕期低血糖负荷（glycemic index，GI）膳食指导对超重孕妇母子胰岛素抵抗的影响，探讨孕期膳食GI的变化与新生儿胎盘胰岛素抵抗相关基因甲基化的关系，为我国超重孕妇代谢性危险因素的管理提供科学依据。.方法：本研究采用单盲、随机对照的试验设计。选择2012年-2015年在2家协作单位进行产检的超重孕妇为研究对象，随机分配到干预组和对照组，分别在初次产检、孕中期、孕晚期进行3次面对面膳食指导。两组研究对象均接受常规的膳食指导，在此基础上为干预组提供个体化的低GI膳食指导。分析两组孕晚期空腹胰岛素及脐血C肽水平之间的差异。分别选择膳食GI降低/增加最显著的研究对象各12名作为CASE组和CONTROL组。采用Illumina 450K甲基化芯片测定两组胎盘组织的全基因组甲基化水平，从中筛选与胰岛素作用关系密切的差异甲基化基因和位点，并通过焦磷酸测序验证。从得到验证的位点中筛选关系更为密切的位点，采用焦磷酸测序检测所有样本的甲基化水平，并分析其与膳食GI变化的关系。.结果：本研究共纳入400名研究对象。干预组孕晚期膳食GI和对照组相似(63.2±10.4 vs. 64.3±10.4)，空腹胰岛素水平[13.2(9.3,13.2)uU/mL vs. 12.4(10.5,12.4)uU/mL]及新生儿脐血C肽水平(0.9±0.7 ng/mL vs. 0.8±0.6 ng/mL)，差异均无统计学意义。与对照组相比，干预组在孕晚期摄入更多的膳食纤维(11.6±8.0 g vs. 9.0±5.6 g, P=0.006)。全基因组差异甲基化结果共提示2259个位点达到显著性水平,108个差异甲基化区域，与胰岛素抵抗密切相关的PLIN1等9个基因，位于基因调控区10 个中的7个位点通过焦磷酸测序得到验证。在所有样本中，cg05009389、cg14631053、cg17586860、cg18197392、cg20950011等5个位点呈低甲基化状态，cg10490842呈中等甲基化状态，统计学关联分析并没有发现其甲基化程度与孕期膳食GI变化的关系。.结论：与常规膳食指导相比，三次个体化的低GI膳食指导不足以使超重孕妇及其新生儿显著改善胰岛素抵抗水平。孕期膳食GI的变化与新生儿胎盘组织中胰岛素抵抗相关基因的甲基化水平的统计学关联性不显著，其关系有待进一步验证。

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