# Investigating the Downstream Mechanisms Contributing to Beta Cell Failure in Offspring Exposed to Maternal Obesity

> **NIH NIH K08** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $153,905

## Abstract

Project Summary/Abstract
Annually, over one million newborns are born to obese mothers in the US and suffer a higher risk of
developing type 2 diabetes at a younger age. The development of type 2 diabetes (T2D) in the
offspring of obese mothers is secondary to a combination of insulin resistance, increased adiposity,
increased inflammation, and decreased β cell function. Using preclinical models of maternal obesity,
we and others have shown that male offspring are more likely to develop islet insulin secretory
dysfunction compared to female offspring. However, the underlying molecular processes remain
unclear. Our preliminary data also showed that the sex-differences in glucose intolerance and islet
dysfunction correlated with differential expression of Regenerating islet derived protein 3-Gamma
(Reg3g). Reg3g is a ligand to Exostosin-Like Glycosyltransferase 3 (EXTL3) that initiates heparan
sulfate glycosaminoglycan (HSG) polymerization. Specifically, we found that female offspring
exposed to maternal obesity exhibited higher islet Reg3g HSG, and were protected from glucose
intolerance and islet dysfunction. The protection was diminished in Reg3g haploinsufficient female
offspring. In contrast, male offspring born to obese dams had unchanged islet Reg3g and HSG, and
exhibited significantly worse glucose tolerance and a decrease in ex-vivo insulin secretion. Finally,
treatment with recombinant Reg3g and a heparan sulfate analogue improved glucose tolerance in
male offspring of obese mice. Our preliminary data also implicated ERK1/2 signaling as the
downstream pathway activated by Reg3g and HSG that maintains β cell insulin secretion. Given
these findings, we hypothesize that the upregulation of Reg3g induces HSG formation and protects
offspring of obese mice from β cell dysfunction by maintaining ERK1/2 phosphorylation. We also
hypothesize that Reg3g preserves islet insulin secretion in offspring of obese mice and in human
islets through HSG polymerization. In this proposal, we will 1) define the role of Reg3g-HSG-ERK1/2
signaling in mediating sex-differences in islet insulin secretion in the offspring of obese mice, and 2)
determine the therapeutic potential of Reg3g-mediated HSG polymerization in rescuing pancreatic
islet dysfunction in offspring of obese mice and in human islets. This research plan will inform novel
and amenable molecular pathways that regulate sex-differences in islet dysfunction in offspring of
obese mothers. This career development award also allows the principal investigator to receive
training in the state-of-the-art concepts of islet biology and laboratory skills necessary to become an
independent physician scientist.

## Key facts

- **NIH application ID:** 10907644
- **Project number:** 5K08HD109636-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Kok Lim Kua
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $153,905
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907644

## Citation

> US National Institutes of Health, RePORTER application 10907644, Investigating the Downstream Mechanisms Contributing to Beta Cell Failure in Offspring Exposed to Maternal Obesity (5K08HD109636-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907644. Licensed CC0.

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