Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production

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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.