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MT1-MMP expression in first trimester placental tissue is up-regulated in type 1 diabetes as a result of elevated insulin and TNF- levels

¹Department of Obstetrics and Gynecology, Medical University of Graz, Austria
²Department of Obstetrics and Gynecology, University Hospital, Petrova, Zagreb, Croatia

Objective.: In pre-gestational diabetes the placenta at term of gestation is characterized by various structural and functional changes. If 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.

Research Design and 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 hyperglycaemia and various insulin, IGF1, IGF2 and TNF- 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 up-regulated, whereas active MT1-MMP expression was only increased in late first trimester. In isolated primary trophoblasts insulin, IGF1, IGF2 and TNF- up-regulated MT1-MMP expression, whereas glucose had no effect. The insulin effect was dependent on PI3-kinase, the IGF1 effect on MAP-kinase and the IGF2 effect on both.

Conclusions.: This is the first study to reporting alterations in the first trimester placenta in type 1 diabetes. The up-regulated MT1-MMP expression in type 1 diabetes may be the result of higher maternal insulin and TNF- 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 pre-gestational diabetes.

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