Metformin impairs trophoblast metabolism and differentiation in dose dependent manner

Abstract

Metformin is a widely prescribed medication whose mechanism of action in not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing risks of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 μM (near-physiologic) and 2000 μM (supra-physiologic) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance was detected between vehicle and 200 μM metformin treated cells, 2000 μM metformin impaired oxidative metabolism and increased abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 μM, but not 200 μM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-physiologic concentrations of metformin impairs trophoblast metabolism and differentiation whereas physiologic concentrations of metformin do not strongly impact these processes.

The role of the placenta-brain axis in psychoneuroimmune programming

“…Gestational diabetes causes placental immaturity, necrosis, and hyper-angiogenesis ( Jarmuzek et al, 2015 ), and is linked with offspring developmental delay ( Sun et al, 2022 ) and cognitive dysfunction ( Ahmed et al, 2023 ; Van Dam et al, 2018 ), among other neurodevelopmental outcomes ( Shao et al, 2021 ) revealed by clinical studies. The gestational diabetes medication metformin is also linked to placental metabolic and differentiation phenotypes ( Nashif et al, 2023 ) as well as child neurodevelopmental abnormalities ( Deussen et al, 2023 ; Yuen et al, 2021 ). These impacts may be due in part to methylation changes; maternal plasma glucose is associated with serotonin transporter gene ( SLC6A4 ) methylation in placenta, which may be risk factor for later serotonin dysregulation and neurodevelopmental diagnoses, as discussed below (section 3.1 ) ( Song et al, 2022 ).…”

Drug repositioning in thyroid cancer treatment: the intriguing case of anti-diabetic drugs

“…Indeed, several studies have demonstrated that metformin promotes osteogenic, neuronal, myogenic, and adipogenic differentiation with varying results (Zhan et al, 2020;Ould-Brahim et al, 2018;Dadwal et al, 2015;Ahn and Cho, 2017;Fatt et al, 2015;Smieszek et al, 2018). Metformin induces cell proliferation at low concentrations' but it has anti-tumor activity at higher concentrations and can inhibit the proliferation of cancer cells (Nashif et al, 2023). At present, research is limited to in vitro and experimental animal models, however it can be hypothesized that the contradictory effects of metformin might be dependent upon specific cell types and/or dose differences.…”