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.

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