Hypoglycemia, hyperglucagonemia, and fetoplacental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance

Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E522-31. doi: 10.1152/ajpendo.00420.2011. Epub 2011 Dec 13.


Alterations in insulin signaling as well as insulin action predispose to infertility as well as adverse pregnancy outcomes; however, little is known about the role of glucagon signaling in reproduction. The glucagon receptor knockout (Gcgr(-/-)) mouse created by our laboratory was used to define the role of glucagon signaling in maintaining normal reproduction. In this mouse model, lack of glucagon signaling did not alter the hypothalamic-pituitary-ovarian axis. Pregnant Gcgr(-/-) female mice displayed persistent hypoglycemia and hyperglucagonemia. Gcgr(-/-) pregnancies were associated with decreased fetal weight, increased late-gestation fetal demise, and significant abnormalities of placentation. Gcgr(-/-) placentas contained areas of extensive mineralization, fibrinoid necrosis, narrowing of the vascular channels, and a thickened interstitium associated with trophoblast hyperplasia. Absent glucagon signaling did not alter glycogen content in Gcgr(-/-) placentas but significantly downregulated genes that control growth, adrenergic signaling, vascularization, oxidative stress, and G protein-coupled receptors. Our data suggest that, similarly to insulin, glucagon action contributes to normal female reproductive function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Fetal Death / etiology
  • Fetal Diseases / etiology*
  • Fetal Diseases / metabolism
  • Fetal Growth Retardation / etiology
  • Gene Expression Regulation, Developmental
  • Glucagon / blood
  • Glucagon / physiology*
  • Heterozygote
  • Hypoglycemia / etiology*
  • Hypoglycemia / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Ovary / drug effects
  • Ovary / physiology
  • Pituitary Gland, Anterior / metabolism
  • Pituitary Gland, Anterior / pathology
  • Placenta / metabolism
  • Placenta / pathology
  • Placenta Diseases / etiology*
  • Placenta Diseases / metabolism
  • Placenta Diseases / pathology
  • Placentation
  • Pregnancy / physiology*
  • Pregnancy Proteins / genetics
  • Pregnancy Proteins / metabolism
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / physiology*
  • Signal Transduction
  • Superovulation / drug effects


  • Pregnancy Proteins
  • Receptors, Glucagon
  • Glucagon