FoxO1 in Gestational Diabetes

FoxO1 在妊娠糖尿病中的作用

基本信息

批准号：
10656362
负责人：
HENGJIANG HENRY DONG
金额：
$ 39.61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656362
关键词：
Address Adverse effects Affect Beta Cell Blood Blood Glucose Cellular Metabolic Process ChIP-seq Compensation Complication Cues Data Development Diabetes Mellitus Diagnosis FOXO1A gene Failure Fasting Female Fetus Gestational Diabetes Glucose Glucose Intolerance Goals Health Hormones Hyperglycemia Impairment Insulin Insulin Resistance Knockout Mice Link Mediating Metabolic stress Modeling Mothers Mus Nuclear Nutritional Outcome Pathway interactions Phosphorylation Physiological Plasma Play Predisposition Pregnancy Pregnant Women Prolactin Prolactin Receptor Proliferating Protein Tyrosine Kinase Receptor Signaling Regulation Risk Role Signal Transduction Structure of beta Cell of islet Techniques Third Pregnancy Trimester Tyrosine Phosphorylation Weight Gain Wild Type Mouse euglycemia forkhead protein glucose metabolism hormonal signals impaired glucose tolerance in vivo insight insulin secretion insulin signaling islet maternal weight pregnant response single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing

项目摘要

Abstract: Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without previously diagnosed diabetes. GDM affects up to 10% of all pregnancies, imposing a significant adverse effect on the health of both mother and fetus. To date, the underlying mechanism of GDM remains elusive. Pregnancy is commonly associated with insulin resistance in the mother, a physiological response that serves to spare blood glucose supplies for the fetus. To overcome insulin resistance, pancreatic β-cells of pregnant mothers release more insulin into the blood. Such an adaptive response, termed “β-cell compensation”, is essential for maintaining normal blood glucose metabolism in pregnancies. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. Nonetheless, how β-cells compensate for maternal insulin resistance during pregnancy and what causes β-cell failure in GDM are poorly understood. To decipher the mechanism of β-cell compensation for pregnancy, we determined gestational regulation of β-cell mass and function by FoxO1 - a key transcription factor that integrates insulin signaling and nutritional cues to cell metabolism, survival, proliferation and differentiation. We found that β-cell FoxO1 expression is markedly upregulated, coinciding with the physiological induction of β-cell compensation in mice during pregnancy. Furthermore, we showed that β-cell FoxO1 deficiency predisposes pregnant female mice to GDM, as evidenced by the induction of impaired glucose tolerance, elevated blood glucose levels and reduced glucose-stimulated insulin secretion during pregnancy. These new data underscore the importance of FoxO1 in governing the adaptive changes of β-cell mass and function in response to pregnancy, spurring the hypothesis that FoxO1 deregulation may be the missing link between maternal insulin resistance and β-cell decompensation in GDM. To address this hypothesis, we will use rigorous in vivo and ex vivo studies to characterize the role of FoxO1 in integrating gestational hormonal signaling to adaptive changes in β-cell mass and function during pregnancy. We will determine the mechanism by which FoxO1 augments β-cell compensation for maternal insulin resistance in female mice. Furthermore, we will determine the mechanism of how β-cell FoxO1 deficiency causes β-cell decompensation, contributing to the development of GDM. Accomplishing this project will deepen our understanding of gestational β-cell compensation for maternal insulin resistance, providing new mechanistic insights into β-cell decompensation and GDM.

抽象的：妊娠糖尿病（GDM）的特征是没有先前被诊断出的糖尿病。 GDM最多影响所有怀孕的10％，施加了重要的广告对母亲和胎儿健康的影响。迄今为止，GDM的基本机制仍然难以捉摸。怀孕通常与母亲的胰岛素抵抗有关，这是一种身体反应为了避免胎儿的血糖供应。为了克服胰岛素抵抗，怀孕的胰腺β细胞母亲将更多的胰岛素释放到血液中。这种自适应反应称为“β细胞补偿”，是维持怀孕中血糖代谢的正常代谢至关重要。在高危孕妇中，β细胞无法补偿母体胰岛素抵抗，导致胰岛素功能不全和GDM。尽管如此， β细胞如何补偿怀孕期间母体胰岛素抵抗以及导致β细胞衰竭的原因 GDM知之甚少。为了破译β细胞补偿的怀孕机制，我们确定了 FOXO1对β细胞质量和功能的妊娠调节 - 整合胰岛素的关键转录因子信号传导和营养线索，以实现细胞代谢，生存，增殖和分化。我们发现β细胞 FOXO1表达明显更新，与β细胞补偿的物理诱导一致在怀孕期间的小鼠。此外，我们表明β细胞FOXO1缺乏症患者孕妇小鼠到GDM，这是诱导葡萄糖耐受性受损，血糖水平升高和怀孕期间葡萄糖刺激的胰岛素分泌减少。这些新数据强调了 FOXO1在管理β细胞质量的适应性变化和响应妊娠方面的功能，刺激了假设FOXO1放松管制可能是Mater胰岛素抵抗与β细胞之间缺失的联系 GDM中的代偿作用。为了解决这一假设，我们将使用严格的体内和实体研究来表征FOXO1在整合妊娠激素信号传导与β细胞质量自适应变化中的作用和怀孕期间的功能。我们将确定FOXO1增强β细胞的机制补偿雌性小鼠材料胰岛素抵抗。此外，我们将确定 β细胞FOXO1缺乏如何导致β细胞代偿性，有助于GDM的发展。完成该项目将加深我们对孕产妇妊娠β细胞补偿的理解胰岛素抵抗，为β细胞代偿和GDM提供新的机械见解。