Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production

总结 为了满足胎儿生长对营养的持续需求，母体的新陈代谢经历了一系列的代谢过程。 怀孕期间的适应。为了调节这些代谢适应，母体胰岛逐渐 产生更多的胰岛素胰岛素分泌不足导致妊娠糖尿病和其他 并发症胰腺α细胞是胰岛中的第二初级内分泌细胞。虽然研究 据报道，怀孕可能会增加α-细胞质量和母体血液胰高血糖素浓度， 关于α细胞在控制母体代谢适应中的作用的知识缺口。我们最近的研究 发现了α细胞在妊娠期间母体胰岛素产生中的重要作用。除胰高血糖素外，α- 细胞还分泌胰高血糖素样蛋白1（GLP-1）。与其他代谢压力类似，我们的研究表明， 胰岛内GLP-1有助于妊娠期间α-细胞促进的胰岛素产生。为了进一步研究 胰岛内GLP-1促进α-细胞胰岛素分泌及胎盘催乳素对α-细胞的调节作用 为了适应妊娠，我们的初步研究观察到GLP-1在生理水平的重建， 在一些小鼠模型中，胰岛素的产生得到改善，但没有完全恢复。这些结果表明， 除GLP-1外，α细胞调节胰岛素产生的其他机制也参与其中， 怀孕细胞外囊泡（EV）几乎由所有细胞产生。通过转移生物活性物质 当EV进入受体细胞时，EV充当细胞间和器官内通信的通道。我们的初步 研究不仅鉴定了α-细胞衍生EV（α-EV），而且显示α-EV促进胰岛素分泌。 因此，我们推测α-EVs在介导α-EVs的调节作用中起重要作用。 胰腺α细胞对妊娠期间胰岛素产生的影响。 我们将使用带有mGFP标记的α- 研究妊娠诱导的α-EV生产动态变化。micro-RNA的差异表达谱 在a-EV中也将被确定。α细胞特异性催乳素受体（Prlr）基因敲除的小鼠模型将 进一步验证PL/PRLR在调节α-EVs产生和α-细胞妊娠适应中的作用。 我们将使用来自遗传小鼠模型的胰岛和纯化的α-EV来阐明α-EV在α-细胞中的作用， 在怀孕期间调节胰岛素分泌。总之，这个项目的成功将揭示一个新的潜在的 母体代谢适应机制。

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.