# Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2022 · $191,250

## Abstract

PROJECT SUMMARY
Type 2 diabetes (T2D) burden rests disproportionately on ethnic minorities and economically distressed
Appalachian communities. These populations also have high rates of low birth weight (LBW), which itself is an
independent risk factor for T2D. One major cause of LBW is uteroplacental insufficiency and subsequent
intrauterine growth restriction (IUGR). We model uteroplacental insufficiency in late gestation pregnant rats by
ligating the uterine arteries. The growth-restricted offspring display diminished glucose-stimulated insulin
secretion (GSIS), reduced islet capillary density, and decreased β-cell proliferation. We recently sequenced the
IUGR islet transcriptome at 2 weeks of age, revealing increased expression of Hyaluronan Synthase 2 (Has2),
which makes the extracellular matrix glycosaminoglycan hyaluronan (HA), and Cd44, the principal HA receptor.
HA has size-dependent opposing effects on angiogenesis and inflammation, with native high molecular weight
(HMW) HA being inhibitory and its enzymatic or oxidative fragmentation to LMW-HA being activating. Previous
studies show increased HA in serum and adipose tissue of humans with T2D, and attenuating HA levels or CD44
activity improves insulin sensitivity. Studies have yet to quantify islet HA in T2D despite evidence that HA and
HA-binding proteins are normal islet components and HA levels are altered in T2D. To determine whether HA
contributes to IUGR-mediated islet dysfunction, we will determine HA abundance, size, and cell type-specific
interactions. There is a paucity of research regarding effects of HA on β-cell function. However, HA modulates
actin cytoskeleton dynamics via regulation of monomeric G-proteins in a variety of cell types, which if occurring
in β-cells, can have profound effects on GSIS. Taken together, I hypothesize that HA abundance and size
distribution are altered in IUGR islets, and HA size-specifically modulates GSIS in vitro. The goal of
Specific Aim 1 is to determine whether IUGR alters abundance, size distribution and cell type-specific binding
of HA in islets. The goal of Specific Aim 2 is to determine whether HA size-specifically alters GSIS in vitro via
modulation of monomeric G-proteins and associated actin dynamics. In a move toward an interventional
approach, we will examine whether pharmacological modulation of HA content normalizes GSIS in IUGR islets
ex vivo. Successful completion of the proposed studies will fill a key knowledge gap regarding changes in islet-
associated HA in T2D and provide strong evidence that HA negatively impacts β-cell function. These data will
provide rationale and demonstrate feasibility for my future R01 grant application investigating an etiological role
for HA in IUGR-mediated T2D.

## Key facts

- **NIH application ID:** 10436997
- **Project number:** 5R21DK127295-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Cetewayo Saif Rashid
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $191,250
- **Award type:** 5
- **Project period:** 2021-06-23 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436997

## Citation

> US National Institutes of Health, RePORTER application 10436997, Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes (5R21DK127295-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436997. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*