FoxO1 in Gestational Diabetes

FoxO1 在妊娠糖尿病中的作用

• 批准号: 10118363
• 负责人: HENGJIANG HENRY DONG
• 金额: $ 38.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10118363
• 关键词: Address; Adverse effects; Affect; Beta Cell; Blood; Blood Glucose; Cellular Metabolic Process; ChIP-seq; Complication; Cues; Data; Development; Diabetes Mellitus; Diagnosis; FOXO1A gene; Failure; Fasting; Female; Fetus; Financial compensation; 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; Pregnancy; Pregnant Women; Prolactin; Prolactin Receptor; Protein Tyrosine Kinase; Receptor Signaling; Regulation; Risk; Role; Signal Transduction; Structure of beta Cell of islet; Techniques; Third Pregnancy Trimester; 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

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.

摘要： 妊娠期糖尿病(GDM)的特征是无糖代谢异常的孕妇 之前被诊断为糖尿病。妊娠期糖尿病影响高达10%的怀孕，造成严重的不利影响 对母亲和胎儿的健康都有影响。到目前为止，GDM的潜在机制仍然难以捉摸。 怀孕通常与母亲的胰岛素抵抗有关，这是一种生理反应， 为胎儿提供充足的血糖。为克服胰岛素抵抗，孕妇胰腺β细胞 母亲会向血液中释放更多的胰岛素。这种自适应反应被称为“β-cell补偿”， 在怀孕期间维持正常的血糖代谢所必需的。在高危孕妇中，β细胞 未能补偿母亲的胰岛素抵抗，导致胰岛素不足和妊娠期糖尿病。尽管如此， β细胞如何补偿孕期母亲的胰岛素抵抗以及是什么导致β细胞衰竭 人们对GDM知之甚少。为了破译β细胞对妊娠的补偿机制，我们确定了 整合胰岛素的关键转录因子FOXO1对β细胞质量和功能的孕期调节 细胞新陈代谢、存活、增殖和分化的信号和营养线索。我们发现β-CELL Foxo1的表达明显上调，与β细胞代偿的生理诱导相一致 在怀孕期间的小鼠身上。此外，我们还发现β细胞FoxO1缺乏症易使怀孕的女性 小鼠对GDM的作用，表现为诱导糖耐量受损、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调节β细胞质量和功能随妊娠的适应性变化，刺激 FoxO1基因失控可能是母体胰岛素抵抗和β细胞之间缺失环节的假说 妊娠期糖尿病代偿失调。为了解决这一假设，我们将使用严格的体内和体外研究来 FoxO1在整合妊娠激素信号以适应β细胞团变化中的作用 以及怀孕期间的功能。我们将确定FOXO_1增强β-细胞的机制 母鼠对母体胰岛素抵抗的补偿。此外，我们还将确定其机制。 β细胞FoxO1缺乏如何导致β细胞失代偿，促进妊娠期糖尿病的发生发展。 该项目的完成将加深我们对孕期β细胞对母体代偿的理解 胰岛素抵抗，为β细胞失代偿和妊娠期糖尿病提供了新的机制见解。