Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated up-regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto-placental endothelium

J Clin Endocrinol Metab. 2012 Oct;97(10):3613-21. doi: 10.1210/jc.2012-1212. Epub 2012 Aug 14.


Context: Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion.

Objective: Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis.

Design: Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors.

Results: Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, P<0.05) as a result of up-regulated expression in fpEC (2.1-fold, P=0.02). MT1-MMP blocking antibodies reduced in vitro angiogenesis up to 25% (P=0.03). Pathophysiological levels of insulin and IGF-II, but not IGF-I and glucose, stimulated MT1-MMP expression in fpEC by phosphatidylinositol 3-kinase signals relayed through the insulin, but not IGF-I, receptor.

Conclusions: GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Diabetes, Gestational / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Female
  • Fetus / metabolism*
  • Glucose / metabolism
  • Humans
  • Hyperglycemia / metabolism
  • Insulin / metabolism*
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor II / metabolism*
  • Matrix Metalloproteinase 14 / metabolism*
  • Neovascularization, Physiologic / physiology
  • Placenta / blood supply
  • Placenta / cytology
  • Placenta / metabolism*
  • Pregnancy
  • Pregnancy Trimester, Third / metabolism
  • Primary Cell Culture
  • Trophoblasts / cytology
  • Trophoblasts / metabolism
  • Up-Regulation / physiology


  • Insulin
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • MMP14 protein, human
  • Matrix Metalloproteinase 14
  • Glucose