# Nutrient and Insulin Metabolic Actions in IUGR Fetal Liver

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $577,321

## Abstract

PROJECT SUMMARY
The goal of this proposal is to define the molecular and metabolic effects of fetal hypoxia on the development of
fetal hepatic insulin resistance and activation of fetal hepatic glucose production rate (GPR). This is important
because pregnancies complicated by placental ischemic diseases and specifically placental insufficiency
induced intrauterine growth restriction (PI-IUGR) expose the fetus to hypoxia. We have shown that the fetal liver
during PI-IUGR has increased hepatic GPR, which is resistant to suppression by insulin. While hepatic insulin
resistance and increased GPR are likely vital adaptations in the PI-IUGR fetus, these events also are early key
hallmarks of type 2 diabetes (T2DM), to which PI-IUGR offspring are more susceptible. The PI-IUGR fetus also
has limited glucose oxidation capacity and decreased hepatic oxygen consumption, suggesting decreased
mitochondrial substrate oxidation, which may re-direct carbon for GPR. Our goal is to understand the
mechanisms for the early activation of hepatic glucose production in response to fetal hypoxia. The overall
hypothesis of this proposal is that fetal hypoxia is the major driver of hepatic insulin resistance, increased hepatic
glucose production, and decreased hepatic mitochondrial oxidation in the fetus. In Aim 1, we will test the role of
fetal hypoxia on the development of hepatic insulin resistance, increased hepatic glucose production, and
decreased hepatic mitochondrial oxidation. In Aim 2, we will determine whether chronic fetal hypoxia produces
hepatic insulin resistance via increased nuclear FOXO1 and decreased AMPK activity resulting in increased
PCK1 and PDK4 expression in the fetal liver. In Aim 3, we will determine the synergistic coordination between
glucose production and mitochondrial oxidation in isolated hepatocytes. The results of our studies will allow us
to determine the specific role of fetal hypoxia in the fetal liver on the activation of hepatic GPR and development
of hepatic insulin resistance. We also will identify the molecular and metabolic pathways involved in GPR that
are regulated by hypoxia in the fetal liver. Our studies also will differentiate hypoxia from relative hypoglycemia
as a principal cause of fetal hepatic GPR. The fetal liver is one of the most severely affected organs by PI-IUGR
and the only fetal organ to demonstrate insulin resistance, a hallmark of later life T2DM. Defining fetal hypoxia
as an early driving factor and the pathophysiological adaptations induced by hypoxia may represent the key to
understanding how fetal hypoxia programs the fetal liver to produce glucose, establishing a direct risk for
developing T2DM in later life.

## Key facts

- **NIH application ID:** 9844944
- **Project number:** 5R01DK108910-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Stephanie R Wesolowski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $577,321
- **Award type:** 5
- **Project period:** 2017-01-17 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844944

## Citation

> US National Institutes of Health, RePORTER application 9844944, Nutrient and Insulin Metabolic Actions in IUGR Fetal Liver (5R01DK108910-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9844944. Licensed CC0.

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