# Mechanisms by Which IUGR Leads to Diabetes

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $485,695

## Abstract

PROJECT SUMMARY
Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is linked to
the later development of type 2 diabetes (T2D). We have developed an experimental animal
model of IUGR caused by uteroplacental insufficiency that affects the development of the fetus
by permanently altering susceptible cells, such as ß-cells, and leads to the development of T2D
in adulthood. Our preliminary data suggest that the mechanism by which IUGR leads to the
development of T2D in adulthood is via a transient activation of the Th2 response in fetal islets
resulting in localized inflammation. This is associated with the production of high levels of IL-4
and IL-10 in fetal islets. Although this immune response is short- lived, it results in a permanent
reduction in islet vascularity and impaired insulin secretion. However, it is not known which
immune cells or T cell subtypes contribute to the production of these Th2 cytokines. As each of
these immune cell types have a particular role in immune regulation, it is critically important to
determine the phenotypic profile of T cell subsets. Surprisingly, blocking the action of a single
Th2 cytokine, IL-4, restores vascularity and ß-cell function permanently in IUGR adult animals.
This suggests that IL-4 orchestrates a cascade of events leading to the abnormal ß-cell
phenotype in the IUGR animal. Epigenetic mechanisms regulate Th2 cell activation both in the
fetus and adult. The Th2 cytokine locus is highly conserved and demethylated in resting normal
fetal and neonatal CD4+ cells. Thus, additional epigenetic mechanisms must underlie the
exaggerated Th2 effector function in IUGR cells. These findings lead us to hypothesize that
IUGR induced expansion of Th2-type effector cells including macrophages and eosinophils
occurs via epigenetic mechanisms resulting in permanent ß-cell dysfunction. We propose the
following aims: Specific Aim 1: To determine whether fetal IUGR immune cells are functionally
distinct from controls resulting in an amplified Th2 response. Specific Aim 2: To define the
epigenetic landscape in IUGR fetal and neonatal immune cells. Specific Aim 3: Determine the
mechanisms by which IL4 production causes ß-cell dysfunction in IUGR animals.
Through the comprehensive analyses in the in vivo model, the results of the proposed project
will build a solid standard for extrapolation of effects and mode of action to other types of
inflammatory processes that may be identified as potential inducers of obesity and related
metabolic diseases later in life.

## Key facts

- **NIH application ID:** 9983705
- **Project number:** 5R01DK114054-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rebecca A Simmons
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,695
- **Award type:** 5
- **Project period:** 2017-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983705

## Citation

> US National Institutes of Health, RePORTER application 9983705, Mechanisms by Which IUGR Leads to Diabetes (5R01DK114054-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983705. Licensed CC0.

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