Pancreatic alpha-cells and Maternal metabolic Adaptation

摘要 在怀孕期间，母亲的新陈代谢经历了一系列的适应，以满足恒定的 胎儿室的营养需求和哺乳准备。母体代谢适应失败 导致妊娠期糖尿病(GDM)和其他并发症。胰岛的数量显著增加 正常妊娠期间大量和胰岛素的产生。胰腺α细胞为第二原代细胞 胰岛中的内分泌细胞主要通过高血糖素的内分泌作用调节葡萄糖代谢。 尽管有研究报道，怀孕可能会增加α细胞质量和母体血液中的胰高血糖素 对于α细胞在控制母体代谢适应中的作用，目前还存在一个知识空白。 我们最新的研究证实了α细胞在母体胰岛素分泌中的重要作用。 怀孕了。首先，我们使用一种可诱导的遗传方法去除了成年小鼠的α细胞。尽管没有显著的 改变空腹和随机喂养的血糖浓度，α细胞消融术改善了糖耐量 在未怀孕的小鼠身上。相比之下，血糖浓度的显著升高和胰岛素的降低 在α阴性的水坝中观察到分泌物。其次，我们用一种胰升糖素受体抗体治疗怀孕的小鼠 以确定妊娠期高血糖素在母体代谢适应中的作用。令人惊讶的是， 胰高血糖素受体拮抗剂不会改变母亲的血糖和胰岛素水平。除了胰高血糖素，α- 细胞还分泌类胰高血糖素蛋白1(GLP-1)。已知胰岛内GLP-1在 在代谢应激条件下增加葡萄糖诱导的胰岛素产生。我们的研究表明， GLP-1受体激动剂可恢复α缺失型大鼠的胰岛素生成和糖代谢。因此，我们 假设α细胞通过胰岛内在调节母体代谢适应中起重要作用 旁分泌对胰岛素产生的影响。我们将使用α细胞特有的Pcsk1基因，它指导GLP-1 生产、淘汰坝和胰高血糖素或GLP-1重组来验证这一假说。鼠标模型，带 α细胞特异性催乳素受体(PRLR)基因敲除将被用来验证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 比较妊娠小鼠和经激素处理的人胰岛分离的α细胞的基因表达谱 确定α细胞如何适应怀孕。该项目的成功将揭示一种新的潜在机制 母体新陈代谢适应能力。它将对生殖医学和生殖医学的研究产生重大影响 GDM。

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.