In brief

Metformin impairs the development of pancreatic beta cells and their insulin secretion function in cell culture experiments.

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A closer look at metformin in maternal diabetes

25 Jan 2022

New data suggest that metformin administered to pregnant mothers may have unintended effects on the fetus, prompting the need for further assessment of the drug’s risk-benefit ratio.

When it comes to medically-managing prenatal issues, clinicians must strike a delicate balance, weighing up the risks and benefits of drugs for treating maternal health complications. While health complications may adversely impact the pregnancy and the baby, the drugs used for treating health complications may also have unintended consequences.

In many cases, it remains unclear as to whether to continue prescribing the drug or to avoid it completely. Hence, clinicians and patients must discuss the risk and benefits of using a particular drug in pregnancy.

Currently, a drug called metformin is prescribed for certain cases of adult type 2 diabetes and gestational diabetes mellitus (GDM) in expectant mothers. GDM results from a combination of insufficient insulin production by the pancreas and increased insulin resistance, causing elevated blood sugar levels. Although GDM usually resolves after pregnancy, there is a high risk of later progression to type 2 diabetes.

While metformin has no obvious detrimental effects on babies exposed to the drug during pregnancy, there is evidence of metformin crossing the placenta to the unborn fetus. However, it had yet to be seen if metformin could potentially have more subtle impacts on the developing baby and its organs like the pancreas—until now.

A team led by Adrian Teo, a Principal Investigator from A*STAR’s Institute of Molecular and Cell Biology (IMCB), and Shiao-Yng Chan, Deputy Executive Director of A*STAR’s Singapore Institute for Clinical Sciences (SICS), Associate Professor at the National University of Singapore and Senior Consultant at the National University Hospital, developed a technique for modeling the fetal pancreas using stem cells. The researchers aimed to use this platform to examine increased rates of diabetes in children born to mothers who had diabetes during their pregnancies.

First, the team used human embryonic stem cells and created specialized cell culture conditions to coax them into forming pancreatic beta-like cells—a type of cell that synthesizes and secretes glucose-regulation hormones like insulin and amylin.

The researchers then added metformin to the cell culture media to mimic the drug passing through the placenta to the fetus. Finally, RNA sequencing and other cell-based assays were used to determine the genetic and functional changes caused by metformin exposure.

“We found that metformin exposure impairs the development of human pancreatic beta cells and their insulin secretion function in vitro,” said Teo. “We also observed a dip in the expression of key pancreatic genes and abnormal cellular metabolism.” Still, it remains to be determined if the same could also occur in vivo, or within the actual biological environment of a mother’s womb.

Their study represents the first time human stem cells have been used to predict the impact of metformin exposure in fetal pancreatic tissues. However, experimental cell culture models cannot fully capture the complexity of drug dynamics in expectant mothers, as metformin may also be cleared by the mother’s kidneys, allowing variable amounts to cross the placenta. To address these limitations, Teo’s team plans to further the study in animal models of GDM.

Ironically, the actual detrimental effects of uncontrolled high glucose from the lack of anti-diabetic drug treatment may be worse than the impact of metformin itself. “A more in-depth understanding of the implications of metformin use in the management of diabetes during pregnancy is needed,” said Teo. “Meanwhile, we caution against excessive metformin dosing during pregnancy.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Singapore Institute for Clinical Sciences (SICS).

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1. Nguyen, L., Lim, L.Y., Ding, S.S.L., Amirruddin, N.S., Hoon, S. et al. Metformin perturbs pancreatic differentiation from human embryonic stem cells, Diabetes 70, 1689-1702 (2021) | article
2. Nguyen, L., Chan, S.Y., & Teo, A.K.K. Metformin from mother to unborn child–Are there unwarranted effects? EBioMedicine, 35, 394-404 (2018) | article

About the Researcher

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Adrian Teo Kee Keong

Principal Investigator

Institute of Molecular and Cell Biology
Adrian Teo Kee Keong pursued his PhD degree at the University of Cambridge, UK, and returned to Singapore in 2010, joining A*STAR’s Institute of Medical Biology (IMB) as a postdoctoral fellow. In 2011, he moved to the Joslin Diabetes Center at Harvard Medical School, US, under the Juvenile Diabetes Research Foundation fellowship and secured two Harvard Stem Cell Institute seed grants to pursue research on human pluripotent stem cells for in vitro disease modeling of diabetes. Adrian is currently a Principal Investigator at the Institute of Molecular and Cell Biology (IMCB), A*STAR; an Assistant Professor at the Yong Loo Lin School of Medicine, National University of Singapore; and an Adjunct Assistant Professor at the School of Biological Sciences, Nanyang Technological University, Singapore.

This article was made for A*STAR Research by Wildtype Media Group