Common diabetes drug may help prevent preterm birth
Metformin, a medication routinely used by millions with type 2 diabetes, plays an unexpected role in blocking a significant cause of preterm birth, according to new research.
Fascinating results are coming from a study on mice prone to premature birth. A team of scientists at Cincinnati Children's Hospital worked along with colleagues in France and Japan to analyze mice bred to lack the p53 gene, which go on to have pregnancies that end prematurely.
Without the p53 gene, decidual cells that line the uterus in pregnancy to form the placenta, show an increase in the protein mTORC1 (mammalian target of rapamycin complex), while the protein AMPK (AMP-activated protein kinase) is reduced.
Located on chromosome 17, p53 protein binds DNA and stimulates production of the protein p21 to interact with cdk2, a cell division-stimulating protein. Without the protein complex made with the fusion of these two proteins, a cell cannot move into the next stage of cell division. The p21 protein acts like a 'stop signal' to cell division.
The study is important for two reasons. First, it details the little-understood molecular pathway leading to premature birth through disruption of decidua cells. Second, researchers demonstrated in the mice two successful methods for restoring the function of decidua cells and achieving healthy, full-term births.
"This proof-of-concept study illuminates a potential mechanism behind preterm birth. It also demonstrates possible remedies already approved for human use."
Sudhansu K. Dey PhD, director of the Division of Reproductive Sciences at Cincinnati Children's and senior author of the new study.
The team has defined how two protein changes can lead to premature cell aging in the decidua — and initiate labor. The earlier this error occurs, the higher the risk of miscarriage or premature birth.
Digging deeper, the team learned that another protein, sestrin 2, plays a critical role in coordinating a relationship between AMPK and mTORC1 signals. Levels of sestrin 2 also drop in mice missing the p53 gene.
Treating mice with metformin reversed early aging of decidua cells, causing sestrin 2 levels and AMPK activity to increase and mTORC1 signaling to decrease — and led to full-term births.
The team also reported similar, but less effective results when mice were treated with resveratrol, an anti-oxidant and anti-aging diet supplement made from grape seeds.
The latest findings continue a line of research Dey has pursued for several years. In previous work, Dey and colleagues discovered that rapamycin, an immune suppressing agent, showed promise (in mice) in preventing preterm birth. However, that medication may be risky for pregnant women.
Dey says Metformin appears to be a potentially safer alternative which works along the same molecular pathway.
Preterm birth can be caused by many factors, and it remains unclear how many preterm births are triggered by early decidual aging. But, Dey believes it could be a significant number. Advancing these mice-based findings into a treatment for would-be mothers at risk of preterm birth will require extensive research which could take years.
Currently, other investigators are studying metformin and resveratrol for their potential to act as anti-aging drugs, but no human clinical trial is investigating these medications for use as a preventatives to preterm birth.
Experts working to reduce stubbornly high premature birth rates in Cincinnati and other cities say the new findings merit further investigation - especially to establish the safety of metformin use during pregnancy.
"I think the study has interesting implications. It is the first step in a potential new intervention that would have to be carefully evaluated in human clinical trials. Metformin has been widely used, but only to a limited extent in pregnancy. Future studies will be needed."
Louis Muglia MD PhD, Director, Center for Prevention of Preterm Birth, Cincinnati Children's Hospital, Ohio, USA.
Findings are published in JCI: The Journal of Clinical Investigation.
Inflammation and oxidative stress are known risk factors for preterm birth (PTB); however, the mechanisms and pathways that influence this condition are not fully described. Previously, we showed that mTORC1 signaling is increased in mice harboring a uterine-specific deletion of transformation-related protein 53 (p53d/d mice), which exhibit premature decidual senescence that triggers spontaneous and inflammation-induced PTB. Treatment with the mTORC1 inhibitor rapamycin reduced the incidence of PTB in the p53d/d mice. Decidual senescence with heightened mTORC1 signaling is also a signature of human PTB. Here, we have identified an underlying mechanism for PTB and a potential therapeutic strategy for treating the condition. Treatment of pregnant p53d/d mice with either the antidiabetic drug metformin or the antioxidant resveratrol activated AMPK signaling and inhibited mTORC1 signaling in decidual cells. Both metformin and resveratrol protected against spontaneous and inflammation-induced PTB in p53d/d females. Using multiple approaches, we determined that p53 interacts with sestrins to coordinate an inverse relationship between AMPK and mTORC1 signaling that determines parturition timing. This signature was also observed in human decidual cells. Together, these results reveal that p53-dependent coordination of AMPK and mTORC1 signaling controls parturition timing and suggest that metformin and resveratrol have therapeutic potential to prevent PTB.
The research team at Cincinnati Children's included Wenbo Deng, PhD, Jeeyeon Cha, MD, PhD, Jia Yuan, PhD, and other colleagues led by Dey in the Division of Reproductive Sciences. Collaborators also included Yasushi Hirota, University of Tokyo, Benoit Viollet at INSERM in France, and Heather Bradshaw from Indiana University Bloomington.
About Cincinnati Children's
Cincinnati Children's, a non-profit, pediatric, academic medical center established in 1883, is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. It is one of the top three recipients of pediatric research grants from the National Institutes of Health, ranked third in the nation among all Honor Roll hospitals in U.S. News and World Report's Best Children's Hospitals, and a research and teaching affiliate of the University of Cincinnati's College of Medicine. Its patient population includes the eight-county primary service area covering parts of Ohio, Kentucky and Indiana. A destination for children with complex medical conditions, it also served patients from all 50 states and nearly 70 countries during the past year. Additional information can be found on the Cincinnati Children's website. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.
This work was supported in part by grants from the March of Dimes and the March of Dimes Prematurity Research Center Ohio Collaborative as well as NIH grants to S.K. Dey. Jeeyeon Cha was a National Research Service Awardee.
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