Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production

α细胞来源的细胞外囊泡和母体胰岛素的产生

• 批准号: 10681939
• 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: 2023-05-08 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681939
• 关键词: Ablation; Adipocytes; Adult; Alpha Cell; Amino Acids; Beta Cell; Blood; Blood Glucose; Cell Proliferation; Cell Survival; Cells; Circulation; Communication; Compensation; Endocrine; Failure; Fetal Growth; Foundations; Future; Gene Deletion; Genetic; Gestational Diabetes; Glucagon; Glucose; Health; Hormones; Human; Impairment; Insulin; Insulin Resistance; Knowledge; Label; Lactation; Link; Mediating; Metabolic; Metabolic stress; Metabolism; MicroRNAs; Modeling; Mus; Nutrient; Organ; Pancreas; Pathologic; Physiological; Placenta; Placental Lactogen; Play; Population; Pregnancy; Pregnancy Outcome; Production; Prolactin Receptor; Proliferating; Proteins; Rattus; Receptor Signaling; Reporting; Research; Role; Series; Signal Transduction; Structure of alpha Cell of islet; design; extracellular vesicles; genetic approach; glucagon-like peptide 1; glucose tolerance; improved; insulin secretion; islet; knockout gene; lipid metabolism; miRNA expression profiling; mouse model; novel; offspring; paracrine; pregnant; programs; reconstitution; restoration; success

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.

概括 为了满足胎儿生长不断的营养需求，母体的新陈代谢要经历一系列的过程。 为了调节这些代谢适应，母体胰岛逐渐在怀孕期间进行适应。 产生明显更多的胰岛素。胰岛素产生不足会导致妊娠期糖尿病和其他疾病。 尽管研究表明，胰腺 α 细胞是胰岛中的第二主要内分泌细胞。 据报道，怀孕可能会增加α细胞质量和母体血液中的胰高血糖素浓度，有一个 关于 α 细胞在控制母体代谢适应中的作用的知识差距。 发现 α-细胞在怀孕期间母体胰岛素产生中的重要作用。 与其他代谢应激类似，我们的研究表明，细胞也分泌胰高血糖素样蛋白 1 (GLP-1)。 胰岛内 GLP-1 有助于妊娠期间 α 细胞促进的胰岛素产生。 胰岛内 GLP-1 在 α 细胞促进胰岛素分泌中的作用以及胎盘催乳素 (PL) 如何调节 α 细胞 适应妊娠，我们的初步研究观察到GLP-1在生理水平上重建 在某些小鼠模型中，胰岛素的产生有所改善，但并未完全恢复，这些结果表明， 除了 GLP-1 之外，α 细胞调节胰岛素产生过程中还涉及其他机制 几乎所有细胞都通过转移生物活性物质产生细胞外囊泡（EV）。 进入受体细胞后，EVs 充当细胞间和器官内通讯的渠道。 研究不仅鉴定了α细胞衍生的EV（α-EV），而且表明α-EV可促进胰岛素分泌。 因此，我们认为α-EVs在介导调节作用中发挥着重要作用。 胰腺α细胞对怀孕期间胰岛素产生的影响。 我们将使用带有 mGFP 标记 α- 的怀孕小鼠 细胞研究妊娠引起的 α-EV 产生的动态变化。 α-EV 中的 α 细胞特异性催乳素受体 (Prlr) 基因敲除的小鼠模型也将被确定。 用于验证 PL/PRLR 在调节 α-EV 产生和 α-细胞适应妊娠中的作用。 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 总之，该项目的成功将揭示一个新的基础。 母体代谢适应机制。