Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production

摘要 为了满足胎儿生长对营养的持续需求，母亲的新陈代谢经历了一系列 在怀孕期间的适应。为了调节这些代谢适应，母体胰岛逐渐 产生明显更多的胰岛素。胰岛素分泌不足会导致妊娠期糖尿病和其他 并发症。胰腺α细胞是胰岛的第二初级内分泌细胞。尽管研究表明 报道称，怀孕可能会增加α细胞质量和孕妇血液中胰高血糖素的浓度，存在 关于α细胞在控制母体代谢适应中的作用的知识差距。我们最新的研究 发现了α细胞在孕期母体胰岛素分泌中的重要作用。除了胰高血糖素，α- 细胞还分泌类胰高血糖素蛋白1(GLP-1)。与其他代谢压力类似，我们的研究表明 胰岛内的GLP-1有助于α细胞在怀孕期间促进胰岛素的产生。为进一步研究其作用， α细胞胰岛内GLP-1促进胰岛素分泌及胎盘催乳素(PL)如何调节α细胞 为了适应妊娠，我们的初步研究观察到GLP-1在生理水平上的重建 改善了一些小鼠模型的胰岛素产生，但并未完全恢复。这些结果表明， 除GLP-1外，α细胞调节的胰岛素产生还涉及其他机制 怀孕了。细胞外小泡(EV)几乎由所有细胞产生。通过转移生物活性货物 进入受体细胞，EV充当细胞间和器官内沟通的通道。我们的预赛 研究不仅发现了α细胞衍生的EVS(α-EVS)，而且表明α-EV促进胰岛素的分泌。 因此，我们假设α-EVS在调节EVS的调节效应中发挥重要作用。 妊娠期间胰腺α细胞对胰岛素产生的影响。 我们将使用mGFP标记α的怀孕小鼠- 研究妊娠诱导细胞α-EVS产生的动态变化。微核糖核酸的差示图谱 在α-电动汽车也将被确定。α细胞特异性催乳素受体(PrLR)基因敲除的小鼠模型将 被用来验证PL/PRLR在调节α-EVS的产生和α细胞对妊娠的适应中的作用。 我们将使用遗传小鼠模型中的胰岛和纯化的α-EVS来阐明α-EVS在α细胞中的作用。 在怀孕期间调节胰岛素的分泌。总而言之，该项目的成功将揭示一个新的基础 母体代谢适应的机制。

SUMMARY To meet the constant nutrient demand for fetal growth, maternal metabolism goes through a series of adaptations during pregnancy. For regulating these metabolic adaptations, maternal islets progressively produce significantly more insulin. Insufficient insulin production causes gestational diabetes mellitus and other complications. The pancreatic α-cells are the second primary endocrine cells in islets. 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 discovered the essential role of α-cells in maternal insulin production during pregnancy. Besides glucagon, α- cells also secret glucagon-like protein 1 (GLP-1). Similar to other metabolic stresses, our study showed that intraislet GLP-1 contributes to α-cell-promoted insulin production during pregnancy. To further study the role of intraislet GLP-1 in α-cell-promoted insulin secretion and how placental lactogen (PL) regulates α-cell adaptation to pregnancy, our preliminary studies observed that GLP-1 reconstitution at a physiological level improved but did not completely restore insulin production in some mouse models. These results suggest that, in addition to GLP-1, additional mechanisms are involved in α-cell-regulated insulin production during pregnancy. Extracellular vesicles (EVs) are produced from almost all cells. By transferring the bioactive cargos into the recipient cells, EVs serve as a channel for intercellular and intra-organ communication. Our preliminary study not only identified α-cell-derived EVs (α-EVs), but showed that α-EVs promote insulin secretion. Therefore, we hypothesize that the α-EVs play an important role in mediating the regulatory effects of pancreatic α-cells on insulin production during pregnancy. We will use pregnant mice with mGFP-labeled α- cells to study pregnancy-induced dynamic changes in α-EVs production. The differential profiles of micro-RNA in α-EVs will also be determined. Mouse models with α cell-specific prolactin receptor (Prlr) gene knockout will be employed to verify the role of PL/PRLR in regulating α-EVs production and α-cell adaptation to pregnancy. We will use the islets and purified α-EVs from the genetic mouse models to clarify the role of α-EVs in α-cell- regulated insulin secretion during pregnancy. Together, the success of this project will reveal a new underlying mechanism of maternal metabolic adaptation.