Randomized Trial of Diet in GDM: Metabolic Consequences to Mother and Offspring

描述（由申请人提供）：超重/肥胖孕妇的妊娠糖尿病（GDM）发病率迅速上升，由于胎儿过度生长的高风险，这使得新生儿患儿童肥胖和代谢综合征的风险增加，因此需要制定有效的饮食策略。然而，缺乏足够的对照随机临床试验（rct）来治疗饮食性糖尿病，导致共识小组放弃了任何特定的饮食建议。如果有效，饮食疗法有可能避免高昂的医疗费用，并加强对这一不断增长的人口的胎儿监测。虽然低碳水化合物饮食历来被提倡减少餐后葡萄糖的游离，但碳水化合物通常被高脂肪所取代，这在动物和非人类灵长类动物的数据中显示，会促进后代的胰岛素抵抗、葡萄糖耐受不良和肝脏脂肪沉积。事实上，最近的人类数据表明，高母体甘油三酯（TG）和游离脂肪酸（FFA）是对饮食控制敏感的变量，在促进胎儿过度生长和婴儿肥胖方面可能至少与葡萄糖一样重要。基于R21的初步数据显示，与传统的低CHO（高脂肪）饮食相比，提供高复合CHO（低脂肪）饮食可以有效地降低6-7周后的餐后血糖，改善空腹血糖和胰岛素，减少新生儿的肥胖。我们的总体假设是，与8周的低CHO/高脂肪饮食相比，高复合CHO/低脂肪饮食会减弱孕妇餐后FFA并改善IR。胰岛素敏感性的改善将通过降低底物利用率和下调胎盘营养转运体来减少胎儿营养过剩，从而减少新生儿肥胖（主要结局）。该建议建立在我们的R21研究的基础上（已出版，附录），这是第一个提供从GDM诊断到妊娠剩余时间所有膳食的RCT。本随机对照试验的目的是比较8周等热量高复合CHO/低脂肪饮食（60% CHO/25%脂肪）与传统低CHO（高脂肪）饮食（40% CHO/45%脂肪）对母体胰岛素抵抗、胎盘营养转运蛋白和新生儿脂肪发育的影响。我们熟练的多学科团队的创新方法包括：母体IR系统（松田指数）和局部（AT脂肪分解）；肠道微生物组（转移给新生儿）；和新生儿肝内脂肪（MRS）。新生儿肥胖的持续存在与了解这些婴儿的肥胖风险有关。由于我们的试点数据表明，婴儿微生物组和母乳成分会影响出生后的脂肪积累，我们将跟踪婴儿直到1岁，并考虑这些变量。在妊娠后期，当胎儿生长加速时，确定一种可以有效改变母体/胎儿代谢的GDM饮食对于降低这一不断增长的母婴群体的短期和长期代谢风险至关重要。该研究结果可能导致GDM饮食治疗的范式转变，并可能广泛应用于仅受肥胖影响的妊娠。

DESCRIPTION (provided by applicant): The rapidly rising incidence of gestational diabetes (GDM) in overweight/obese pregnant women demands that an effective diet strategy be developed due to the high risk of fetal overgrowth, which places the newborn at increased risk for childhood obesity and metabolic syndrome. However, the lack of adequate controlled randomized clinical trials (RCTs) for treatment of GDM with diet has resulted in consensus panels abandoning any specific diet recommendation. If effective, diet therapy has the potential to avoid the high costs of medical treatment and intensified fetal monitoring for this growing population. Although a low carbohydrate diet has historically been advocated to decrease glucose excursions after meals, carbohydrate has typically been replaced by higher fat which has been shown in animal and non-human primate data to promote insulin resistance, glucose intolerance, and liver fat deposition in the offspring. In fact, recent human data suggest that hig maternal triglycerides (TG) and free fatty acids (FFA), variables sensitive to dietary manipulation, may be at least as important as glucose in contributing to excess fetal growth and infant adiposity. Preliminary data based on an R21, show that compared to a conventional lower-CHO (higher in fat) diet, providing a higher complex CHO (lower fat) diet effectively blunts postprandial glucose and improves fasting glucose and insulin after 6-7 weeks, with less adiposity in the newborn. Our global hypothesis is that compared to 8wks of a low- CHO/higher fat diet, a higher complex CHO/lower fat diet will blunt maternal post-prandial FFA and improve IR. Improved insulin sensitivity will reduce fetal over-nutrition by decreasing substrate availabilty and down-regulating placental nutrient transporters, thereby reducing neonatal adiposity (primary outcome).This proposal builds on our R21 study (in-press, Appendix), which is the first RCT to provide all meals from the time of GDM diagnosis throughout the remainder of pregnancy. The aims of this RCT are to compare the effects of an 8-wk isocaloric higher complex CHO/lower fat diet (60% CHO/25% fat) vs. a conventional low-CHO (higher fat)(40% CHO/45% fat) diet on maternal insulin resistance, placental nutrient transporters, and neonatal fat development. Innovative approaches by our skilled multidisciplinary team include: maternal IR systemically (Matsuda Index) and locally (AT lipolysis); intestinal microbiome (transferred to the newborn); and neonatal intrahepatic fat (MRS). Persistence of neonatal adiposity is relevant to understanding obesity risk in these infants. As our pilot data suggest infant microbiome and breast milk composition impact fat accrual after birth, we will follow the infants through 1-yr of life accounting for these variables. Identifying a diet for GDM that can effectively alter maternal/fetal metabolism in late pregnancy when fetal growth accelerates is critical to reducing short- and long-term metabolic risk in this growing cohort of mothers and infants. The study results could lead to a paradigm shift for diet therapy in GDM, with potential widespread application to pregnancies affected by obesity alone.