Role of liver and visceral fat in glucose and lipid metabolism during pregnancy

描述（由申请人提供）：肥胖和胰岛素抵抗是不良母体和胎儿妊娠结局的重要风险因素。肝脏和内脏脂肪储存彼此正相关，并与全身肥胖相关。此外，两者均与非妊娠成人的胰岛素敏感性指标呈负相关。虽然有限的可用证据表明，怀孕有助于中心和内脏脂肪含量的变化，但没有发表的研究评价内脏和肝脏脂肪含量的变化，或者肝脏和内脏脂肪含量是否与妊娠进展中全身、肝脏和骨骼肌胰岛素敏感性降低相关。鉴于过量的腹部和肝脏脂肪（非酒精性脂肪肝）是严重肝病，2型糖尿病和冠状动脉疾病进展的重要风险因素，了解怀孕如何有助于内脏和肝脏脂肪储存具有重要的公共卫生意义。此外，灵长类动物的研究表明，饮食脂肪增加与胎盘功能受损有关。我们所缺乏的是转化研究，研究增加的身体，区域和异位脂肪，以及伴随的胰岛素抵抗在人类胎盘功能受损或胎儿大小的表现中起着什么作用。为了填补这些重要的知识空白，我们将检查内脏和肝脏脂肪的变化（通过磁共振成像和光谱学评估）从妊娠早期到晚期，测量全身和器官特异性胰岛素敏感性（通过胰岛素钳夹技术评估），代谢组学，以检测代谢的脂质和葡萄糖中间产物的特征改变，以及子宫胎盘灌注和胎儿人体测量（在妊娠34周时通过超声评估）。为了评价变化模型，我们将对60名（20名瘦，20名超重和20名肥胖）正常葡萄糖耐受（NGT）孕妇进行前瞻性队列研究，在妊娠12-16周和妊娠32-36周再次进行评估。为了评估这些参数在妊娠晚期NGT和妊娠期糖尿病（GDM）妇女之间的差异，我们将对30名妊娠32-36周的妇女（15名NGT，15名GDM）进行病例对照研究。本研究在以下几个方面具有创新性：1）首次前瞻性评估妊娠期内脏脂肪和肝脏脂肪与胰岛素敏感性的关系，并评估内脏脂肪和肝脏脂肪的差异 2）结合最先进的成像和钳夹方法，以了解葡萄糖和脂质代谢中的器官特异性紊乱;和3）这将是第一个将这些成像和钳夹测量与脂毒性和子宫胎盘功能的新代谢特征的测量相结合的联合收割机的研究，从而测试肥胖和胰岛素抵抗之间的重要联系，其中胎儿编程以前仅在动物模型中证明。

DESCRIPTION (provided by applicant): Obesity and insulin resistance are significant risks factors for adverse maternal and fetal pregnancy outcomes. Liver and visceral fat stores are positively correlated with each other and with whole body adiposity. Additionally, both are negatively correlated with measures of insulin sensitivity in nonpregnant adults. While limited available evidence suggests that pregnancy contributes to changes in central and visceral fat content, no published studies have evaluated change in visceral and liver fat content or whether liver and visceral fat content are associated with the decrease in whole body, hepatic, and skeletal muscle insulin sensitivity seen with advancing pregnancy. Given that excess abdominal and liver fat (nonalcoholic fatty liver disease) are significant risk factors for progression to severe liver disease, type 2 diabetes, and coronary artery disease, understanding how pregnancy contributes to visceral and liver fat stores is of substantial public health importance. Furthermore, primate studies have linked increased diet fat and impaired placental function. What we are lacking are translational studies that examine what roles increased body, regional, and ectopic fat, and accompanying insulin resistance plays in the manifestation of impaired placental function or fetal size in humans. To fill these important gaps in knowledge, we will examine changes in visceral and liver fat (assessed by magnetic resonance imaging and spectroscopy) from early to late pregnancy with measures of whole body and organ-specific insulin sensitivity (assessed by insulin clamp technique), metabolomics to detect signature alterations in lipid and glucose intermediates of metabolism, and uteroplacental perfusion and fetal anthropometrics (assessed by ultrasound at 34 weeks gestation). To evaluate change models, we will conduct a prospective cohort study of 60 (20 lean, 20 overweight, and 20 obese) normal glucose-tolerant (NGT) pregnant women assessed at 12-16 weeks gestation and again at 32-36 weeks gestation. To evaluate how these parameters differ between women with NGT and gestational diabetes (GDM) in the third trimester of pregnancy, we will perform a case-control study of 30 women (15 NGT, 15 GDM) at 32-36 weeks' gestation. This study is innovative in several ways: 1) it is the first to prospectively assess visceral and liver fat durin pregnancy concurrently with insulin sensitivity and to assess differences in visceral and liver fat stores between women with and without GDM; 2) it combines state of the art imaging and clamp methodology to understand organ-specific disturbances in glucose and lipid metabolism; and 3) it will be the first study to combine these imaging and clamp measures with measures of novel metabolic signatures of liptoxicity and uteroplacental function, thereby testing an important link between obesity and insulin resistance with programming of fetus previously only demonstrated in animal models.