# FoxO1 in Gestational Diabetes

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $380,382

## Abstract

Abstract:
Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without
previously diagnosed diabetes. GDM affects up to 10% of all pregnancies, imposing a significant adverse
effect on the health of both mother and fetus. To date, the underlying mechanism of GDM remains elusive.
Pregnancy is commonly associated with insulin resistance in the mother, a physiological response that serves
to spare blood glucose supplies for the fetus. To overcome insulin resistance, pancreatic β-cells of pregnant
mothers release more insulin into the blood. Such an adaptive response, termed “β-cell compensation”, is
essential for maintaining normal blood glucose metabolism in pregnancies. In at-risk pregnant women, β-cells
fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. Nonetheless,
how β-cells compensate for maternal insulin resistance during pregnancy and what causes β-cell failure in
GDM are poorly understood. To decipher the mechanism of β-cell compensation for pregnancy, we determined
gestational regulation of β-cell mass and function by FoxO1 - a key transcription factor that integrates insulin
signaling and nutritional cues to cell metabolism, survival, proliferation and differentiation. We found that β-cell
FoxO1 expression is markedly upregulated, coinciding with the physiological induction of β-cell compensation
in mice during pregnancy. Furthermore, we showed that β-cell FoxO1 deficiency predisposes pregnant female
mice to GDM, as evidenced by the induction of impaired glucose tolerance, elevated blood glucose levels and
reduced glucose-stimulated insulin secretion during pregnancy. These new data underscore the importance of
FoxO1 in governing the adaptive changes of β-cell mass and function in response to pregnancy, spurring the
hypothesis that FoxO1 deregulation may be the missing link between maternal insulin resistance and β-cell
decompensation in GDM. To address this hypothesis, we will use rigorous in vivo and ex vivo studies to
characterize the role of FoxO1 in integrating gestational hormonal signaling to adaptive changes in β-cell mass
and function during pregnancy. We will determine the mechanism by which FoxO1 augments β-cell
compensation for maternal insulin resistance in female mice. Furthermore, we will determine the mechanism of
how β-cell FoxO1 deficiency causes β-cell decompensation, contributing to the development of GDM.
Accomplishing this project will deepen our understanding of gestational β-cell compensation for maternal
insulin resistance, providing new mechanistic insights into β-cell decompensation and GDM.

## Key facts

- **NIH application ID:** 10843834
- **Project number:** 5R01DK125001-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** HENGJIANG HENRY DONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,382
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843834

## Citation

> US National Institutes of Health, RePORTER application 10843834, FoxO1 in Gestational Diabetes (5R01DK125001-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10843834. Licensed CC0.

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