# Placental Mitochondrial Function in Gestational Diabetes

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $334,081

## Abstract

Project Summary
Obesity (BMI>30) and gestational diabetes (GDM), which are both increasing in frequency, cause more
adverse events in pregnancy, including stillbirth, development of type 2 diabetes in later life and importantly
they also program the fetus for subsequent development of obesity and diabetes. Currently these adverse
outcomes can be reduced but not prevented by treating women with GDM. As the placenta regulates
maternal metabolism, fetal growth and development, alterations in its function affects both mother and fetus.
Energy to support placental function is generated via glycolysis, β-oxidation and oxidative phosphorylation
using glucose and fatty acids as substrates. Maternal hyperglycemia and hyperlipidemia seen with obesity and
GDM alter the type/amount of substrates available to the placenta and hence may alter placental metabolism
and energy generation. Recently we found that expression of fatty acid transporters and enzymes involved in
β-oxidation of fatty acids was altered in the placenta of pregnancies with obesity in a sexually dimorphic
manner. We also demonstrated that mitochondrial respiration, expression of mitochondrial complexes and
generation of ATP are reduced in trophoblast from women with pregnancies complicated by obesity and more
so in pregnancies complicated by type A2 GDM (requiring medication) compared to lean controls. This is
associated with increased oxidative stress, metabolic inflexibility (cannot use other substrates when glycolysis
is inhibited) in obesity, and increased glycolysis with GDM. We have exciting preliminary data that the
placenta can also use glutamine for energy generation and that placental fuel dependency between glucose,
fatty acids and glutamine is altered with obesity and GDM. Mitochondria which are involved in many placental
functions, generate superoxide anion. In many pathophysiologic states, including the placenta with obesity and
GDM there is excessive superoxide generation leading to oxidative stress, which can feedback and damage
mitochondria in a vicious cycle hence targeted pharmacologic approaches to improve mitochondrial
function are being widely promoted. Recently we demonstrated differences in oxidative stress and in
antioxidant enzymes in the placenta of obese women, again in a sexually dimorphic manner and have shown
that the antioxidant melatonin or the metabolic modulator dichloroacetate (DCA) will improve mitochondrial
respiration in trophoblast from obese women. Using maternal and fetal plasma and placental tissue from 8
groups of women (prepregnancy lean or obese, with or without GDM with either a male or a female fetus (n=8
each group) we will test the hypothesis that altered metabolomic and lipid profiles and oxidative stress seen in
the placenta with obesity GDM together with altered fatty acid uptake and oxidation leads to decreased
oxidative phosphorylation and altered fuel flexibility of mitochondria supporting placental function which can be
improved/normal...

## Key facts

- **NIH application ID:** 10396015
- **Project number:** 5R01HD095610-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** LESLIE MYATT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $334,081
- **Award type:** 5
- **Project period:** 2018-09-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396015

## Citation

> US National Institutes of Health, RePORTER application 10396015, Placental Mitochondrial Function in Gestational Diabetes (5R01HD095610-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10396015. Licensed CC0.

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