title: Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy.
abstract: BACKGROUND
  Adenosine monophosphate-activated protein kinase (AMPK) is stimulated in embryos during diabetic pregnancy by maternal hyperglycaemia-induced embryo oxidative stress. Stimulation of AMPK disrupts embryo gene expression and causes neural tube defects. Metformin, which may be taken during early pregnancy, has been reported to stimulate AMPK activity. Thus, the benefits of improved glycaemic control could be offset by stimulated embryo AMPK activity. Here, we investigated whether metformin can stimulate AMPK activity in mouse embryos and can adversely affect embryo gene expression and neural tube defects.
  
  
  METHODS
  Pregnant nondiabetic mice were administered metformin beginning on the first day of pregnancy. Activation of maternal and embryo AMPK [phospho-AMPK α (Thr172) relative to total AMPK], expression of Pax3, a gene required for neural tube closure, and neural tube defects were studied. Mouse embryonic stem cells were used as a cell culture model of embryonic neuroepithelium to study metformin effects on AMPK and Pax3 expression.
  
  
  RESULTS
  Metformin had no effect on AMPK in embryos or maternal skeletal muscle but increased activated AMPK in maternal liver. Metformin did not inhibit Pax3 expression or increase neural tube defects. However, metformin increased activated AMPK and inhibited Pax3 expression by mouse embryonic stem cells. Mate1/Slc47a1 and Oct3/Slc22a, which encode metformin transporters, were expressed at barely detectable levels by embryos.
  
  
  CONCLUSIONS
  Although metformin can have effects associated with diabetic embryopathy in vitro, the lack of effects on mouse embryos in vivo may be due to lack of metformin transporters and indicates that the benefits of metformin on glycaemic control are not counteracted by stimulation of embryo AMPK activity and consequent embryopathy.
authors: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors: Hyung-Yul
authors: HY
authors: Lee
authors: Dan
authors: D
authors: Wei
authors: Mary R
authors: MR
authors: Loeken
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D016640:Diabetes, Gestational / Q000188:drug therapy*; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000201:enzymology*; D005260:Female; D008687:Metformin / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009436:Neural Tube Defects / Q000139:chemically induced; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000187:drug effects; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000188:drug therapy*
chemical_list: D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C068686:Pax3 protein, mouse; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMP kinase; Pax3; diabetic embryopathy; diabetic pregnancy; metformin; oral hypoglycaemics
references: Diabetes. 2001 May;50(5):921-7
references: 11334434
references: J Clin Invest. 2001 Oct;108(8):1167-74
references: 11602624
references: Diabetes Care. 2006 Feb;29(2):485-6
references: 16443923
references: Diabetes. 2002 Aug;51(8):2420-5
references: 12145153
references: Eur J Pediatr. 2009 Feb;168(2):203-6
references: 18461356
references: PLoS One. 2011;6(12):e29379
references: 22216266
references: Biochem Biophys Res Commun. 1994 Mar 15;199(2):552-63
references: 7907867
references: Diabetes Metab J. 2011 Jun;35(3):193-8
references: 21785737
references: J Clin Endocrinol Metab. 2011 Aug;96(8):2354-66
references: 21697254
references: Pharm Res. 2006 Aug;23(8):1696-701
references: 16850272
references: Nat Biotechnol. 2000 Jun;18(6):675-9
references: 10835609
references: Clin Sci (Lond). 2012 Mar;122(6):253-70
references: 22117616
references: Biol Reprod. 2013 Mar 07;88(3):55
references: 23303678
references: Gynecol Obstet Invest. 2012;73(4):304-13
references: 22516925
references: Diabetes Care. 2012 Jan;35 Suppl 1:S11-63
references: 22187469
references: Prenat Diagn. 2008 Jun;28(6):544-8
references: 18509858
references: J Clin Invest. 2010 Jul;120(7):2355-69
references: 20577053
references: J Biol Chem. 2012 Jun 8;287(24):20088-99
references: 22511782
references: Arch Int Pharmacodyn Ther. 1979 Sep;241(1):165-76
references: 526068
references: Aust N Z J Obstet Gynaecol. 2011 Apr;51(2):125-9
references: 21466513
references: Teratology. 1994 Apr;49(4):260-6
references: 8073364
references: Ann Pharmacother. 2007 Jul;41(7):1174-80
references: 17535842
references: Diabetologia. 2003 Apr;46(4):538-45
references: 12739027
references: Diabetologia. 2011 Feb;54(2):339-49
references: 20972533
references: Diabetes. 2004 Dec;53(12):3258-66
references: 15561958
references: J Clin Endocrinol Metab. 2012 May;97(5):1492-500
references: 22419702
references: Reprod Toxicol. 2013 Aug;39:17-22
references: 23562376
references: Fertil Steril. 2008 Mar;89(3):625-34
references: 17678910
references: Clin Pharmacokinet. 1996 May;30(5):359-71
references: 8743335
references: Diabet Med. 2006 Mar;23(3):318-22
references: 16492217
references: Diabetes. 1999 Dec;48(12):2454-62
references: 10580436
references: Cell Cycle. 2004 Dec;3(12):1645-50
references: 15611653
references: Diabetologia. 2012 Jan;55(1):245-54
references: 21993711
references: Acta Obstet Gynecol Scand. 2012 Jun;91(6):658-78
references: 22375613