# Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health

> **NIH NIH R56** · UNIVERSITY OF MINNESOTA · 2022 · $93,000

## Abstract

Abstract
Type 2 diabetes (T2D) affects nearly 1 in 10 Americans and is the 7th leading cause of death. It is clear that both
genetic and environmental factors contribute to T2D. Epidemiological studies show robust associations between
poor fetal environment and infant growth (e.g. fetal growth-restriction or over-growth) and the eventual
development of obesity, T2D, and cardiovascular disease later in life. The strong association between birthweight
and risk of T2D is U-shaped, thus, both children born small and those born large for gestational age are at risk.
We propose that maternal insulin and placental nutrient-sensing by mTORC1 are critical regulators of the
metabolic health programming of the offspring. The placenta responds to changes in the maternal
environment and integrates maternal signals to placental function in part by growth factor receptors such as the
insulin receptor, and the nutrient-sensing protein mTOR kinase. Despite years of research, the roles for maternal
insulin and placental mTOR in the metabolic health of the offspring are untested, and we have the model
and expertise to address this gap in knowledge. The first goal of this grant is to establish a causal link between
maternal insulin and the metabolic health of the offspring. In Aim 1, we will determine the roles of placental
insulin signaling in the programming of metabolic health trajectory in the offspring using functional studies
with preclinical genetic models of pregnancy complications (gain of maternal hyperinsulinemia during pregnancy
or placenta-specific loss of insulin receptor). Second, this proposal aims to identify the mechanisms underlying
the developmental programming of peripheral insulin sensitivity by placental nutrient-sensing mTOR. In Aim 2,
we will determine mechanisms of insulin sensitivity by placental mTORC1 nutrient-sensing in the
offspring using murine models with loss or gain of mTOR signaling in the placenta. Therefore, our studies
will determine if maternal hyperinsulinemia is sufficient to drive mal programming of metabolic health in the
offspring in multiparous females. Second, we will determine if enhancing placental mTORC1 is a feasible
therapeutic strategy for preserving insulin sensitivity in the adult offspring and preventing long-term metabolic
dysfunction. Understanding the programming impact of maternal insulin on the metabolic health of the offspring
will be significant in illuminating the effects of insulin therapy on the children of women with gestational diabetes,
T1D, and T2D during pregnancy, thereby advancing clinical care. The anticipated success of this project will
have significant implications in improving women's reproductive health and pregnancy outcomes.

## Key facts

- **NIH application ID:** 10625938
- **Project number:** 1R56DK131447-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Emilyn Alejandro
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $93,000
- **Award type:** 1
- **Project period:** 2022-07-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10625938

## Citation

> US National Institutes of Health, RePORTER application 10625938, Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health (1R56DK131447-01A1). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10625938. Licensed CC0.

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