Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Metformin treatment for diabetes in pregnancy increases placental size, decreases mitochondrial respiration and alters growth signalling and steroidogenesis of mouse placenta (143944)

Dayna A Zimmerman 1 , Olivia J Holland 2 , David G Simmons 1 , James S M Cuffe 1
  1. School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
  2. School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, QLD, Australia

Background

Maternal diabetes in pregnancy impairs placental mitochondrial function, which has negative consequences for fetal growth and development (1). Metformin’s ability to improve mitochondrial function and energy‑sensing in other tissues (2) suggests it may offset the placental dysfunction caused by diabetes. This study investigated whether maternal metformin treatment in the context of glucose intolerance alters placental mitochondrial respiration and subsequent metabolic signalling.

 

Methods

Female C57BL/6J mice (n=8-13/group) were fed a low-fat (LFD) or high-fat diet (HFD) for five-weeks, then treated daily via oral gavage with metformin (300 mg/kg/day) or vehicle for two weeks. Females were time-mated with a control male and continued treatment until embryonic day 18.5, when they were humanely killed for tissue collection. Placental mitochondrial respiration was assessed using high‑resolution respirometry; AMPK phosphorylation and mitochondrial protein abundance via Western blot; and gene expression via qPCR. Placental morphology was evaluated using in situ hybridisation.

 

Results

Metformin increased placental weight in HFD-fed dams by 13% (P=0.001) with proportional enlargement of the junctional and labyrinth zones. Metformin reduced mitochondrial oxidative phosphorylation through complex I by 21% in HFD placentas (P=0.048), without reducing mitochondrial complex I protein abundance. Despite this inhibition, AMPK phosphorylation was not elevated. Metformin altered placental expression of genes regulating mitochondrial dynamics, growth signalling, and steroidogenesis. This included higher Igf2 (cellular energy and nutrient sensing) in males (P=0.013) and females (P=0.010), higher Star (steroidogenic acute regulatory protein) in HFD-exposed males (P=0.006), and lower Prl3b1 (placental lactogen; modulates nutrient supply) in females (P=0.012).

 

Conclusion

These data suggest that metformin can alter placental size, mitochondrial function, and metabolic signalling, often in a diet and sex-dependent manner. Several findings diverge from known mechanisms in non‑placental tissues, particularly the absence of AMPK phosphorylation (2), suggesting a placenta-specific response. These findings have potential consequences for fetal development, supporting further investigation into long‑term health outcomes.

  1. 1. Borengasser SJ, Faske J, Kang P, Blackburn ML, Badger TM & Shankar K. (2014). In utero exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of mitochondrial dynamics in rat placenta and offspring. Physiol Genomics 46, 841–850
  2. 2. Bridges HR, Jones AJ, Pollak MN & Hirst J. (2014). Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462, 475–487.