# Pregnancy-Specific Mechanisms Regulating Beta-Cell Proliferation and Mass

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $308,452

## Abstract

Gestational diabetes (GDM), or hyperglycemia that first manifests during pregnancy, worsens pregnancy outcomes and long-term health risks for both a mother and her offspring. As with all types of diabetes, a relative insufficiency of functional pancreatic β-cells is a fundamental defect contributing to GDM. Normally, β-cells adapt to the metabolic challenges of pregnancy by expanding β-cell mass. This expanded mass regresses in the postpartum period. Thus, pregnancy is a unique physiologic condition that occurs in a fully-developed adult and requires rapid, dynamic changes in β-cell mass. Unfortunately, the mechanisms of normal gestational β-cell adaptation and the defects underlying GDM are poorly understood. Our long-term goal is to understand the mechanisms regulating β-cell proliferation and mass during pregnancy, in order to leverage that knowledge for therapeutic expansion of β-cells in all types of diabetes. Building on our work establishing that loss of prolactin receptor (PRLR) signaling in β-cells results in GDM, we recently identified novel PRLR differentially expressed genes (PRLR-DEGs) and key transcriptional regulators of PRLR-DEG expression. The objective of this grant is to precisely define how PRLR regulates β-cell gene expression during pregnancy and the postpartum period. We propose the central hypothesis that PRLR signaling orchestrates an anticipatory transcriptional program of β-cell mass expansion during gestation and survival of adequate β-cell mass during postpartum regression. We will test this hypothesis with the following Specific Aims: (1) elucidate transcriptional mechanisms regulating PRLR-DEGs within β-cells during pregnancy. To do so, we will use ChIP-seq and ATAC-seq to examine how PRLR-DEGs are regulated in mouse and human islets during pregnancy or in response to prolactin stimulation. In Aim (2) we will define PRLR signaling-dependent and -independent β-cell subpopulations during pregnancy using single-cell RNA sequencing, lineage tracing and colocalization studies. For Aim (3) we will identify mechanisms of β-cell survival during β-cell mass regression in the early postpartum period through pulse-chase labeling and lineage tracing of β-cells that proliferated during pregnancy, as well as examine how inducible loss of PRLR specifically within the postpartum period affects β-cell mass. Together, results from these studies will reveal transcriptional mechanisms downstream of PRLR and illuminate unique aspects of gestational proliferation (Aim 1), define β-cell subpopulations spatially and temporally across pregnancy (Aim 2), and establish a new role for PRLR signaling in regulation of β-cells postpartum (Aim 3). Our research is significant because these findings would clarify mechanisms of gestational β-cell adaptation and expand our understanding of how PRLR activation regulates transcription. At a fundamental level, these studies will expand our understanding of the mechanisms regulating dynamic changes in β-c...

## Key facts

- **NIH application ID:** 10474684
- **Project number:** 7R01DK120761-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ronadip Ralph Banerjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,452
- **Award type:** 7
- **Project period:** 2020-04-07 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474684

## Citation

> US National Institutes of Health, RePORTER application 10474684, Pregnancy-Specific Mechanisms Regulating Beta-Cell Proliferation and Mass (7R01DK120761-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474684. Licensed CC0.

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