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

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $75,684

## Abstract

Both genetic and environmental factors contribute to the development of Type 2 diabetes (T2D).
Hyperinsulinemia is commonly seen among pregnant women with prediabetes, obesity, and gestational
diabetes, and their offspring has a greater risk for developing T2D. Yet, no current study addresses the
long-term/longitudinal metabolic outcomes of the offspring when the mother is hyperinsulinemic.
Furthermore, the mechanistic link between maternal hyperinsulinemia and the programming of
metabolic disease in the offspring remains largely unknown. The dogma is that insulin does not cross
the placenta into the fetus to regulate fetal growth. However, maternal insulin can act as a growth factor
and an anabolic hormone binding to the placental insulin receptor (IR) and insulin-like growth factor 1
receptor (IGF1R) to drive critical placental function, including nutrient flux to the fetus. Thus, maternal
insulin can change placental function by altering nutrient availability to fetal metabolic tissues causing
permanent changes that predispose the offspring to T2D in adulthood. Indeed, we have compelling
preliminary data showing increased body weight and glucose intolerance in the offspring of
hyperinsulinemic dams. We identified that placental-specific IR deletion has a beneficial effect in
improving glucose tolerance in the offspring of hyperinsulinemic dams. These observations provide a
strong premise that the placenta integrates maternal hyperinsulinemia signals with placental function
(i.e., nutrient flux and placental inflammation) to the growing fetus, thereby programming the metabolic
health of the offspring. In this supplemental award, we will test the main hypothesis that the increased
body weight and glucose intolerance programming in the offspring by maternal hyperinsulinemia is
caused in part by increased placental inflammation. To test that maternal hyperinsulinemia programs
metabolic dysfunction in offspring by accelerating the proinflammatory phase of placental development
during gestation, we will perform the following two specific aims: Aim1: Investigate whether maternal
hyperinsulinemia, in the absence of hyperglycemia and obesity, is sufficient to alter immune cell
composition and potentiate placental inflammation. Aim2: Examine the metabolic health trajectory of
offspring born to dams with hyperinsulinemia to assess if placental inflammation can lead to the
predisposition of metabolic diseases. These studies are highly significant because they will define the
molecular mechanisms whereby maternal hyperinsulinemia impacts metabolic health, and they
underscore the importance of clinically controlling insulin levels during pregnancy, like glucose, to
improve pregnancy outcomes. Thus, the anticipated success of this project will have significant
implications in improving women’s reproductive health and the metabolic health of the offspring.

## Key facts

- **NIH application ID:** 10993883
- **Project number:** 3R01DK136237-02S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Emilyn Alejandro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,684
- **Award type:** 3
- **Project period:** 2023-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993883

## Citation

> US National Institutes of Health, RePORTER application 10993883, Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health (3R01DK136237-02S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10993883. Licensed CC0.

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