MT1-MMP expression in first-trimester placental tissue is upregulated in type 1 diabetes as a result of elevated insulin and tumor necrosis factor-alpha levels.
OBJECTIVE
In pregestational diabetes, the placenta at term of gestation is characterized by various structural and functional changes. Whether similar alterations occur in the first trimester has remained elusive. Placental development requires proper trophoblast invasion and tissue remodeling, processes involving matrix metalloproteinases (MMPs) of which the membrane-anchored members (MT-MMPs) such as MT1-MMPs are key players. Here, we hypothesize a dysregulation of placental MT1-MMP in the first trimester of type 1 diabetic pregnancies induced by the diabetic environment.


METHODS
MT1-MMP protein was measured in first-trimester placentas of healthy (n = 13) and type 1 diabetic (n = 13) women. To identify potential regulators, first-trimester trophoblasts were cultured under hyperglycemia and various insulin, IGF-I, IGF-II, and tumor necrosis factor-alpha (TNF-alpha) concentrations in presence or absence of signaling pathway inhibitors.


RESULTS
MT1-MMP was strongly expressed in first-trimester trophoblasts. In type 1 diabetes, placental pro-MT1-MMP was upregulated, whereas active MT1-MMP expression was only increased in late first trimester. In isolated primary trophoblasts, insulin, IGF-I, IGF-II, and TNF-alpha upregulated MT1-MMP expression, whereas glucose had no effect. The insulin effect was dependent on phosphatidylinositol 3-kinase, the IGF-I effect on mitogen-activated protein kinase, and the IGF-II effect on both.


CONCLUSIONS
This is the first study reporting alterations in the first-trimester placenta in type 1 diabetes. The upregulated MT1-MMP expression in type 1 diabetes may be the result of higher maternal insulin and TNF-alpha levels. We speculate that the elevated MT1-MMP will affect placental development and may thus contribute to long-term structural alterations in the placenta in pregestational diabetes.
Hiden
Ursula
U
Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria. ursula.hiden@klinikum-graz.at
Glitzner
Elisabeth
E
Ivanisevic
Marina
M
Djelmis
Josip
J
Wadsack
Christian
C
Lang
Uwe
U
Desoye
Gernot
G
D000022:Abortion, Spontaneous / Q000201:enzymology / Q000235:genetics; D018929:Cell Culture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007328:Insulin / Q000097:blood*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000201:enzymology / Q000235:genetics*; D011261:Pregnancy Trimester, First; D012016:Reference Values; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D015854:Up-Regulation
D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14