# Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $197,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10838577
- **Project number:** 5R21HD112143-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jianhua Shao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $197,500
- **Award type:** 5
- **Project period:** 2023-05-08 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838577

## Citation

> US National Institutes of Health, RePORTER application 10838577, Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production (5R21HD112143-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10838577. Licensed CC0.

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