# Pathways regulating adult pancreatic beta cell replication

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Project Summary/Abstract
Type 2 diabetes (T2D) disproportionately affects the Veteran population: while 9%
percent of the total US population has T2D, 25% of the Veteran population suffers from
this disease. Adult β cell mass normally increases via replication in response to insulin
resistance, but failure of β cell proliferation plus increased β cell death lead to T2D. T2D
incidence increases with age, in part due to a decreased ability of β cells to respond to
proliferative cues as they get older. Our lab identified the FoxM1 transcription factor as a
critical regulator of postnatal β cell replication and discovered that it is induced in
response to several β cell proliferative stimuli. Foxm1 expression in islets declines with
age in mice and humans, but activation of FoxM1 in older mouse β cells increases β cell
proliferation and β cell mass, while enhancing β cell function. Thus, our data
demonstrate that FoxM1 is limiting in older β cells and that activating FoxM1 can bypass
inherent brakes in β cell proliferation. Little is known about how proliferative stimuli
induce Foxm1. Our lab discovered that connective tissue growth factor (CTGF) induces
Foxm1 and adult β cell proliferation in mouse islets in vivo and ex vivo and in human
islets ex vivo. The mechanisms and signaling pathways through which CTGF has these
effects are currently unknown This study makes use of unique in vivo mouse models as
well as ex vivo studies in both mouse and human islets from different ages. In this
proposal we will identify and manipulate CTGF signaling pathways in β cells as
molecular targets for enhancing proliferation and regeneration in adult β cells. In
addition, we explore mechanisms through which FoxM1 activation enhances β cell
proliferation and survival, focusing on the antagonistic prostaglandin E receptors EP3
and EP4, which are reciprocally regulated by FoxM1 in islets. We hypothesize that
CTGF acts through integrin β1 signaling to induce Foxm1 expression and adult β cell
proliferation, and that in the setting of β cell death, CTGF function is enhanced by
macrophage-derived signals. We further hypothesize that FoxM1 activation overcomes
age-related changes in β cell proliferation in part through alterations in prostaglandin
receptor activity. In this proposal we will: 1) Identify signaling pathways through which
CTGF activates Foxm1 expression and β cell proliferation; 2) Identify macrophage-
derived factors that cooperate with CTGF to enhance β cell mass regeneration; and 3)
Determine the role of prostaglandin EP receptors in β cell proliferation and survival.
These studies are designed to identify molecular targets to enhance proliferation and
survival in older β cells with the goal of increasing functional β cell mass.

## Key facts

- **NIH application ID:** 9814698
- **Project number:** 5I01BX003744-04
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Maureen A Gannon
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814698

## Citation

> US National Institutes of Health, RePORTER application 9814698, Pathways regulating adult pancreatic beta cell replication (5I01BX003744-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9814698. Licensed CC0.

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