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

基本信息

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
项目类别：
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

项目摘要

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.

修改的项目摘要/摘要部分遗传和环境因素都有助于2型糖尿病（T2D）的发展。高胰岛素血症通常在患有预测性，肥胖症和妊娠糖尿病的孕妇中出现，其后代具有更大的T2D风险。然而，当前的研究尚无探讨母亲高胰岛素血症时后代的长期/纵向代谢结果。此外，母体高胰岛素血症与后代代谢疾病的编程之间的机械联系仍然很大程度上未知。教条是胰岛素不会穿过胎盘进入胎儿以调节胎儿生长。但是，母体胰岛素可以作为生长因子和合成代谢马酮与斑点胰岛素受体（IR）和胰岛素样生长因子1受体（IGF1R）的结合，以驱动关键的位置功能，包括与胎儿的营养通量。这就是孕产妇胰岛素可以通过改变对胎儿代谢组织的养分可用性来改变占位术功能，从而导致永久变化，使后代在成年期间偏向T2D。确实，我们拥有引人注目的初步数据，显示高胰岛素大坝后代的体重和葡萄糖摄入量增加。我们确定，占地特异性的IR缺失对改善高胰岛素大坝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很强的前提，即胎盘将MATAL高胰岛素血症信号与增长的胎儿相结合，从而对后代的代谢健康进行编程。在这笔赠款中，我们将检验一个主要假设，即母体高胰岛素血症在后代中增加的体重和麸质intlerance编程是由胎儿的占位量养分通量增加引起的，胎儿对胎儿的增加，这是由IR和IGF1R的增加和IGF1R信号及其下游目标，MTOR和MTOR靶标，MTOR和GLUT4介导的。检验了这一假设，我们开发了有或没有占地IR或IGF1R缺失的母体高胰岛素血症的新创新模型，以利用并获得纵向的后代同胞中代谢和物理研究的详细机械方法。在AIM 1中，我们将使用功能研究来定义长期的代谢结果和信号传导机制，从而使用具有临床前胰岛素高胰岛素血症的临床前遗传学模型，而孕产妇高胰岛素血症调节后代的代谢健康，或者在或不具有PROCENTA特定的IR，IR/IGF1R，IR/IGF1R，IR/IGF1R，IR/IGF1R或MTOR。在AIM 2中，我们将在有或没有胎盘特异性胰岛素信号或GLUT4缺陷的后代中确定材料对材料对材料的营养通量。这些机械研究非常重要，因为它们将定义分子机制，从而使母体高胰岛素血症影响代谢健康，并且强调了妊娠期间临床控制胰岛素水平的重要性，类似于葡萄糖，以改善妊娠结局。这是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。