# Prevention of Placental Insufficiency Improves Beta-Cells Function

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2023 · $454,759

## Abstract

Abstract
Pancreatic islet dysfunction is a signature feature in the pathogenesis of Type 2 Diabetes and can stem from
developmental adaptations to placental insufficiency (PI) and fetal growth restriction (FGR). We have identified
significant reductions in insulin production and secretion that persist in offspring with FGR. Our efforts to elucidate
programming mechanisms in FGR islets indicate that reductions in normal, constitutive nuclear factor kappa B
(NFκB) activity negatively affects insulin secretion. Additionally, our preliminary findings associate depressed
NFκB activity with hypoxia-induced MALAT1 expression because this long intergenic non-coding (linc) RNA
binds NFκB to prevent activation. The guiding premise of this project is that low fetal oxygen and glucose
concentrations from PI cause β-cell dysfunction during development. Therefore, we plan to correct oxygen and
glucose concentrations in FGR fetuses during PI and show improvements in insulin secretion and β-cell
proliferation. Foundational experiments demonstrate that combined supplementation of oxygen and glucose to
the fetus with PI-induced FGR improves insulin secretion, but the underlying cues that cause persistent β-cell
failure are undiscovered. We hypothesize that correction of oxygen and glucose concentrations in the PI-FGR
fetus to normal, control fetal values will prevent β-cell dysfunction by enhancing β-cell proliferation and insulin
secretion through the restoration of constitutive and physiological NFκB activity. Furthermore, fetal oxygen and
glucose correction will resolve programmed deficiencies in β-cells of FGR lambs. We have adapted our fetal
sheep model of PI-FGR to test a supplemental mixture of oxygen and glucose in a controlled, in utero
environment. Preliminary experiments with five days of oxygen and glucose correction lowered norepinephrine,
increased insulin, and restored glucose-stimulated insulin secretion (GSIS) in islets, demonstrating its suitability
as a model to test whether the capacity to reverse PI ameliorates β-cell failure. In Aim 1, we will evaluate the
combined effect of oxygen and glucose correction to improve β-cell function in fetuses and neonates with PI-
induced FGR. In Aim 2, we will determine limitations in GSIS that result from lower constitutive NFκB activity due
to MALAT1 overexpression in FGR islets. By alleviating hypoxemia and providing glucose, a major nutrient for
β-cell responsiveness, we expect that insulin secretion and β-cell proliferation will increase and programming
mechanisms causing β-cell dysfunction will return to normal. Impact of these experiments will be high, as they
will provide fundamental new knowledge about the reversibility of β-cell dysfunction in fetuses with PI-induced
FGR. In addition, our experiments will define the unique roles for NFκB regulation in β-cells from FGR fetuses
that cause developmental adaptations that persistently lower insulin secretion. We also will gain new insight on
the reversib...

## Key facts

- **NIH application ID:** 10578797
- **Project number:** 5R01DK084842-11
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** SEAN W LIMESAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $454,759
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10578797

## Citation

> US National Institutes of Health, RePORTER application 10578797, Prevention of Placental Insufficiency Improves Beta-Cells Function (5R01DK084842-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10578797. Licensed CC0.

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