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

描述(申请人提供)：超重/肥胖孕妇的妊娠期糖尿病(GDM)发病率迅速上升，这要求制定有效的饮食策略，因为胎儿过度生长的风险很高，这会增加新生儿患儿童肥胖症和代谢综合征的风险。然而，缺乏足够的饮食治疗妊娠期糖尿病的随机对照临床试验(RCT)，导致共识小组放弃了任何具体的饮食建议。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血糖漂移，但碳水化合物通常被较高的脂肪取代，这已在动物和非人类灵长类动物的数据中显示出来，以促进后代的胰岛素抵抗、葡萄糖耐受和肝脏脂肪沉积。事实上，最近的人类数据表明，高水平的母体甘油三酯(TG)和游离脂肪酸(FFA)，这些对饮食控制敏感的变量，在导致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(脂肪含量较高)饮食相比，提供更复杂的CHO(低脂)饮食有效地钝化餐后血糖，并在6-7周后改善空腹血糖和胰岛素，新生儿肥胖率较低。我们的全球假设是，与低CHO/高脂肪饮食8周相比，更复杂的CHO/低脂肪饮食将钝化母亲餐后FFA并改善IR。胰岛素敏感性的提高将通过减少底物的可获得性和下调胎盘营养转运体来减少胎儿过度营养，从而减少新生儿肥胖症(主要结果)。这项建议建立在我们的R21研究(在媒体中，附录)的基础上，这是第一个提供从GDM诊断时到怀孕剩余时间的所有膳食的随机对照试验。这项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)和传统低CHO(高脂肪)(40%CHO/45%脂肪)饮食对母亲胰岛素抵抗、胎盘营养转运体和新生儿脂肪发育的影响。我们技术娴熟的多学科团队的创新方法包括：母体全身IR(松田指数)和局部IR(AT脂肪分解)；肠道微生物组(转移到新生儿)；以及新生儿肝内脂肪(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脂肪的积累，我们将跟踪婴儿一年的生活，考虑到这些变量。为妊娠期糖尿病确定一种饮食，当胎儿生长加速时，能够有效地改变妊娠晚期的母婴代谢，对于减少这一不断增长的母婴队列中的短期和长期代谢风险至关重要。这项研究结果可能导致妊娠期糖尿病饮食疗法的范式转变，有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diet has historically been advocated to decrease glucose excursions after meals, carbohydrate has typically been replaced by higher fat which has been shown in animal and non-human primate data to promote insulin resistance, glucose intolerance, and liver fat deposition in the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.