title: Diverse roles of metformin during peri-implantation development: revisiting novel molecular mechanisms underlying clinical implications.
abstract: Metformin is not only a widely used oral antidiabetic drug, which acts as an insulin sensitizer and suppressor of hepatic gluconeogenesis, but it also exhibits antitumor properties. Besides, it has been utilized in the treatment of polycystic ovary syndrome (PCOS) for infertile women with glucose intolerance and as a component of combination therapy to reduce early (first trimester) pregnancy loss or spontaneous abortion (SAB). Based on recent studies demonstrating its beneficial effects on mothers and the fetus, metformin is even recommended for later stages of pregnancy. Probing into the mechanism of action revealed that it can activate a stress modulatory pathway, none other than the AMP-activated protein kinase (AMPK) via LKB 1. It is well accepted that AMPK signaling plays a crucial role during implantation by combating stress in multiple ways. Stress factors commonly encountered during pregnancy are malnutrition, diabetes, and hypoxia, which may result in SABs or other complications. For instance, the elevated levels of insulin, which are a typical characteristic of hyperinsulinemic, obese, or PCOS patients, can impair the development of the blastocyst and the preimplantation embryo. Further, a severe hypoxic environment prompts early and untimely differentiation of the embryonic cells leading to abnormal growth and development. Therefore, the modulation of stress-related pathways could be pivotal in ameliorating such stress responses during implantation. Here we hypothesize a putative noncanonical pathway underpinning the role of metformin in high-risk pregnancies to counteract stress by recreating an in vitro replica of human implantation, engaging embryonic stem cells, trophoblast stem cells, and endometrial stromal cells in a three-dimensional scaffold.
authors.affiliation: Manipal Institute of Regenerative Medicine, Manipal University Campus , Bangalore, India .
authors.forename: Poulomi
authors.initials: P
authors.lastname: Banerjee
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Bhonde
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Pal
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000022:Abortion, Spontaneous / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010064:Embryo Implantation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007247:Infertility, Female / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases