Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health

胎盘胰岛素信号传导和 mTOR 营养感应编程对后代代谢健康的影响

• 批准号: 10679756
• 负责人: Emilyn Alejandro
• 金额: $ 54万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679756
• 关键词: Address; Adult; Amino Acid Transporter; Amino Acids; Beta Cell; Binding; Cell membrane; Cell physiology; Childhood; Circulation; Clinical; Clinical Management; Data; Development; Environmental Risk Factor; FRAP1 gene; Fetal Development; Fetal Growth; Fetus; GLUT 4 protein; Genetic; Genetic Models; Gestational Diabetes; Glucose; Glucose Intolerance; Glucose Transporter; Grant; Growth Factor; Health; Hormones; Hyperinsulinism; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Knowledge; Leucine; Life; Link; Longitudinal cohort; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obesity; Outcome; Patients; Phosphotransferases; Physiological; Placenta; Pre-Clinical Model; Prediabetes syndrome; Pregnancy; Pregnancy Outcome; Pregnant Women; Process; Radiolabeled; Receptor Signaling; Reproductive Health; Risk; Role; SLC2A1 gene; Signal Transduction; Structure of beta Cell of islet; Testing; Tissues; Weight Gain; Woman; Work; detection of nutrient; experience; fetal; glucose tolerance; improved; in utero; in vivo; innovation; insulin secretion; insulin signaling; mTOR protein; offspring; parous; pre-clinical; prevent; receptor; success; trafficking

Modified Project Summary/Abstract Section Both genetic and environmental factors contribute to the development of Type 2 diabetes (T2D). Hyperinsulinemia is commonly seen among pregnant women with prediabetes, obesity, and gestational diabetes, and their offspring has a greater risk for developing T2D. Yet, no current study addresses the long-term/longitudinal metabolic outcomes of the offspring when the mother is hyperinsulinemic. Furthermore, the mechanistic link between maternal hyperinsulinemia and the programming of metabolic disease in the offspring remains largely unknown. The dogma is that insulin does not cross the placenta into the fetus to regulate fetal growth. However, maternal insulin can act as a growth factor and an anabolic hormone binding to the placental insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) to drive critical placental function, including nutrient flux to the fetus. Thus, maternal insulin can change placental function by altering nutrient availability to fetal metabolic tissues causing permanent changes that predispose the offspring to T2D in adulthood. Indeed, we have compelling preliminary data showing increased body weight and glucose intolerance in the offspring of hyperinsulinemic dams. We identified that placental-specific IR deletion has a beneficial effect in improving glucose tolerance in the offspring of hyperinsulinemic dams. These observations provide a strong premise that the placenta integrates maternal hyperinsulinemia signals with placental nutrient flux to the growing fetus, thereby programming the metabolic health of the offspring. In this grant, we will test the main hypothesis that the increased body weight and glucose intolerance programming in the offspring by maternal hyperinsulinemia is caused by increased placental nutrient flux to the fetus, which is mediated by increased IR and IGF1R signaling and their downstream targets, mTOR and GLUT4, in the placenta. To test this hypothesis, we developed new innovative models of maternal hyperinsulinemia with or without placental IR or IGF1R deletion, to leverage and obtain a detailed in vivo mechanistic approach of metabolic and physiological studies in a longitudinal cohort of offspring. In Aim 1, we will define long-term metabolic outcomes and signaling mechanisms whereby maternal hyperinsulinemia regulates metabolic health of the offspring using functional studies with preclinical genetic models of maternal hyperinsulinemia during pregnancy with or without placenta-specific loss of IR, IGF1R, IR/IGF1R compound or mTOR. In Aim 2, we will determine maternal-to-fetal nutrient flux in the offspring with or without placenta-specific insulin-signaling or GLUT4 deficiencies. These mechanistic studies are highly significant because they will define the molecular mechanisms whereby maternal hyperinsulinemia impacts metabolic health, and they underscore the importance of clinically controlling insulin levels during pregnancy, similar to glucose, to improve pregnancy outcomes. Thus, the anticipated success of this project will have significant implications in improving women’s reproductive health and the metabolic health of the offspring.

修改后的项目摘要/摘要部分 遗传和环境因素都会导致 2 型糖尿病 (T2D) 的发生。高胰岛素血症常见于患有糖尿病前期、肥胖和妊娠糖尿病的孕妇，其后代患 T2D 的风险更大。然而，目前还没有研究探讨当母亲患有高胰岛素血症时后代的长期/纵向代谢结果。此外，母亲高胰岛素血症与后代代谢性疾病之间的机制联系在很大程度上仍不清楚。教条是胰岛素不会穿过胎盘进入胎儿来调节胎儿生长。然而，母体胰岛素可以作为生长因子和合成代谢激素，与胎盘胰岛素受体 (IR) 和胰岛素样生长因子 1 受体 (IGF1R) 结合，以驱动关键的胎盘功能，包括向胎儿输送营养物质。因此，母体胰岛素可以通过改变胎儿代谢组织的营养可用性来改变胎盘功能，从而导致永久性变化，使后代在成年后易患 T2D。事实上，我们有令人信服的初步数据显示高胰岛素母鼠的后代体重增加和葡萄糖不耐症。我们发现胎盘特异性 IR 缺失对于改善高胰岛素血症母鼠后代的葡萄糖耐量具有有益作用。这些观察结果提供了一个强有力的前提，即胎盘将母体高胰岛素血症信号与胎盘营养流整合到生长中的胎儿，从而对后代的代谢健康进行编程。在这笔资助中，我们将检验主要假设，即母体高胰岛素血症导致后代体重增加和葡萄糖不耐症编程是由胎盘营养流向胎儿的增加引起的，这是由胎盘中 IR 和 IGF1R 信号及其下游靶点 mTOR 和 GLUT4 增加介导的。为了检验这一假设，我们开发了带有或不带有胎盘 IR 或 IGF1R 缺失的母体高胰岛素血症的新创新模型，以利用并获得纵向后代队列中代谢和生理研究的详细体内机制方法。在目标 1 中，我们将通过妊娠期母体高胰岛素血症的临床前遗传模型的功能研究（伴或不伴胎盘特异性 IR、IGF1R、IR/IGF1R 化合物或 mTOR 损失）来定义长期代谢结果和信号机制，从而母体高胰岛素血症调节后代的代谢健康。在目标 2 中，我们将确定有或没有胎盘特异性胰岛素信号或 GLUT4 缺陷的后代的母体到胎儿的营养通量。这些机制研究非常重要，因为它们将定义孕产妇高胰岛素血症影响代谢健康的分子机制，并且它们强调了在怀孕期间临床控制胰岛素水平（类似于葡萄糖）以改善妊娠结局的重要性。因此，该项目的预期成功将对改善妇女的生殖健康和后代的代谢健康产生重大影响。