Pancreatic alpha-cells and Maternal metabolic Adaptation

胰腺α细胞和母体代谢适应

• 批准号: 10681909
• 负责人: Jianhua Shao
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681909
• 关键词: Ablation; Address; Adult; Agonist; Alpha Cell; Amino Acids; Attenuated; Beta Cell; Binding; Blood; Blood Glucose; Cell Proliferation; Cells; Compensation; Data; Endocrine; Failure; Fasting; Fc Receptor; Foundations; Future; GCG gene; Gene Expression; Genes; Gestational Diabetes; Glucagon; Glucagon Receptor; Glucose; Health; Hormones; Human; Impairment; Injections; Insulin; Insulin Resistance; Islets of Langerhans; Knock-out; Knockout Mice; Knowledge; Lactation; Left; Mediating; Metabolic; Metabolic stress; Metabolism; Mus; Nutrient; Pancreas; Pathway interactions; Placental Lactogen; Play; Pregnancy; Pregnancy Outcome; Production; Prolactin Receptor; Proprotein Convertase 2; Proteins; Rattus; Receptor Signaling; Reporting; Reproductive Medicine; Research; Role; Series; Signal Transduction; Sorting; Structure of alpha Cell of islet; antagonist; fetal; genetic approach; glucagon-like peptide 1; glucose metabolism; glucose tolerance; improved; insulin secretion; islet; knockout gene; lipid metabolism; mouse model; offspring; paracrine; pregnant; preproglucagons; proglucagon; programs; receptor; reconstitution; success; transcriptome sequencing

SUMMARY During pregnancy, maternal metabolism goes through a series of adaptations to meet the constant nutrient demand from the fetal compartment and prepare lactation. Failure of maternal metabolic adaptation causes gestational diabetes mellitus (GDM) and other complications. There is a significant increase in islet mass and insulin production during normal pregnancy. The pancreatic α-cells are the second primary endocrine cells in islets and regulate glucose metabolism mainly through the endocrine effects of glucagon. Although studies have reported that pregnancy may increase α-cell mass and maternal blood glucagon concentrations, there is a knowledge gap about the role of α-cells in controlling maternal metabolic adaptation. Our most recent study demonstrated the essential role of α-cells in maternal insulin production during pregnancy. First, we ablated α-cells in adult mice using an inducible genetic approach. Despite no significant change in fasting and randomly fed blood glucose concentrations, α-cell ablation improved glucose tolerance in non-pregnant mice. In contrast, a significant elevation of blood glucose concentrations and low insulin secretion were observed in α-null dams. Second, we treated pregnant mice with a glucagon receptor antibody during pregnancy to determine the contribution of glucagon in maternal metabolic adaptation. Surprisingly, glucagon receptor antagonism did not alter maternal blood glucose and insulin levels. Besides glucagon, α- cells also secret glucagon-like protein 1 (GLP-1). It is known that intraislet GLP-1 plays an important role in augmenting glucose-induced insulin production under metabolic stress conditions. Our study showed that GLP-1 receptor agonist restored insulin production and glucose metabolism in α-null dams. Therefore, we hypothesize that α-cells play a vital role in regulating maternal metabolic adaptation through the intraislet paracrine effects on insulin production. We will use the α cell-specific Pcsk1 gene, which directs GLP-1 production, knockout dams, and glucagon or GLP-1 reconstitution to verify this hypothesis. Mouse models with α cell-specific prolactin receptor (Prlr) gene knockout will be employed to verify the role of PL/PRLR in regulating α-cell adaptation to pregnancy and intraislet GLP-1 production. We will use the RNAseq approach to compare gene expression profiles in sorted α-cells from pregnant mice and hormone-treated human islets to determine how α-cell adapt to pregnancy. The success of this project will reveal a new underlying mechanism of maternal metabolic adaptation. It will significantly impact the research of both reproductive medicine and GDM.

概括 在怀孕期间，母亲的新陈代谢会经历一系列的适应，以满足不断变化的需要。 胎儿室的营养需求和母体代谢适应失败。 导致妊娠糖尿病（GDM）和其他并发症 胰岛显着增加。 正常妊娠期间的质量和胰岛素生成 胰腺 α 细胞是第二个主要细胞。 胰岛内分泌细胞主要通过胰高血糖素的内分泌作用调节糖代谢。 尽管有研究报道怀孕可能会增加α细胞质量和母体血糖 浓度方面，关于 α 细胞在控制母体代谢适应中的作用存在知识差距。 我们最近的研究证明了 α 细胞在母体胰岛素产生中的重要作用 首先，我们使用诱导遗传方法消除了成年小鼠的 α 细胞，尽管没有显着效果。 空腹和随机进食血糖浓度的变化，α细胞消融改善了葡萄糖耐量 相反，在非怀孕小鼠中，血糖浓度显着升高且胰岛素水平较低。 其次，我们用胰高血糖素受体抗体治疗怀孕小鼠。 令人惊讶的是，在怀孕期间确定胰高血糖素在母体代谢适应中的贡献。 除胰高血糖素外，胰高血糖素受体拮抗作用不会改变母体血糖和胰岛素水平。 细胞还分泌胰高血糖素样蛋白 1 (GLP-1)，已知胰岛内 GLP-1 在胰岛内发挥重要作用。 我们的研究表明，在代谢应激条件下增加葡萄糖诱导的胰岛素产生。 GLP-1 受体激动剂恢复了 α-null 母鼠的胰岛素产生和葡萄糖代谢。 促进 α 细胞通过胰岛内调节母体代谢适应发挥重要作用 我们将使用 α 细胞特异性 Pcsk1 基因，该基因指导 GLP-1。 生产、敲除水坝和胰高血糖素或 GLP-1 重建来验证这一假设。 α细胞特异性催乳素受体（Prlr）基因敲除将用于验证PL/PRLR在 调节 α 细胞对妊娠的适应和胰岛内 GLP-1 的产生 我们将使用 RNAseq 方法来进行。 比较来自怀孕小鼠和经激素处理的人类胰岛的分选 α 细胞的基因表达谱 确定α细胞如何适应妊娠。该项目的成功将揭示一个新的潜在机制。 它将对生殖医学和母亲代谢适应的研究产生重大影响。 GDM。