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

描述（由申请人提供）：超重/肥胖孕妇中妊娠期糖尿病（GDM）的发病率迅速上升，由于胎儿过度生长的高风险，需要制定有效的饮食策略，这使新生儿患儿童肥胖症和代谢综合征的风险增加。然而，缺乏足够的对照随机临床试验（RCT）的饮食治疗GDM导致共识小组放弃任何具体的饮食建议。如果有效的话，饮食疗法有可能避免医疗和加强胎儿监测的高成本。尽管历史上提倡低碳水化合物饮食以减少餐后葡萄糖波动，但碳水化合物通常被高脂肪所取代，这在动物和非人灵长类动物数据中已显示可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），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，提供更高复杂性的CHO（低脂肪）饮食有效地降低了餐后葡萄糖，并在6-7周后改善了空腹葡萄糖和胰岛素，新生儿中的肥胖较少。我们的总体假设是，与8周的低CHO/高脂肪饮食相比，更高复合CHO/低脂肪饮食将减弱母体餐后FFA并改善IR。改善胰岛素敏感性将通过降低底物可用性和下调胎盘营养转运蛋白来减少胎儿营养过剩，从而减少新生儿肥胖这项建议建立在我们的R21研究（出版中，附录）的基础上，这是第一个RCT，从GDM诊断的时间到怀孕的剩余时间提供所有的膳食。本RCT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）（40% CHO/45%脂肪）饮食对母体胰岛素抵抗、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：母体全身IR（Matsuda指数）和局部IR（AT脂解）;肠道微生物组（转移到新生儿）;和新生儿肝内脂肪（MRS）。新生儿肥胖的持续性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，我们将在婴儿出生后1年内跟踪这些变量。确定GDM的饮食，可以有效地改变母亲/胎儿代谢在怀孕后期，当胎儿生长加速是至关重要的，以减少短期和长期的代谢风险，在这个不断增长的母亲和婴儿的队列。研究结果可能导致GDM饮食治疗的范式转变，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diet has historically been advocated to decrease glucose excursions after meals, carbohydrate has typically been replaced by higher fat which has been shown in animal and non-human primate data to promote insulin resistance, glucose intolerance, and liver fat deposition in the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.