Abstract

BackgroundGestational diabetes mellitus (GDM) is associated with important factors that influence fetal development. Sphingolipids are known to be associated with the development of diabetes. Our objective was to examine ceramide, a key sphingolipid, hyperosmolarity, and apoptosis in placentas from GDM patients treated with insulin or diet.MethodsCeramide levels were assessed in placental tissues using immunohistochemistry. Immunoblot was performed to quantify serine palmitoyltransferase (SPT), the rate-limiting enzyme in ceramide biosynthesis, NFAT5, SMIT, AR, caspase 3 and the X-linked inhibitor of apoptosis. Trophoblast cells were treated with insulin or ceramide and assessments for mitochondrial respiration, caspase 3 and XIAP were also performed.ResultsImmunohistochemistry showed increased ceramides in the placental villous trophoblasts of the insulin-treated GDM patients. Nuclear SPT was upregulated only in the insulin-treated GDM placenta when compared to controls. Nuclear NFAT5 was also increased in the GDM placenta. Active caspase 3 was elevated in placentas from both insulin- and diet-treated GDM patients. Mitochondrial respiration was decreased in trophoblasts treated with ceramide. Active caspase was not changed while XIAP protein was increased in trophoblasts treated with ceramide.ConclusionsOur findings confirm the presence of ceramide in the human placenta of control and GDM patients. Furthermore, we conclude that ceramide is increased in the placental trophoblast during insulin treatment and that its upregulation correlates with elevated NFAT5, SMIT, increased apoptosis and decreased trophoblast mitochondrial respiration.

Highlights

  • Gestational diabetes mellitus (GDM) is associated with important factors that influence fetal development

  • Placental biopsies and paraffin embedded tissues Placental biopsies and slides from paraffin embedded placental tissues for GDM-I, GDM-D, and term controls were obtained from the Research Center for Women’s and Infant’s Health Biobank, Ontario, Canada

  • Placental ceramide levels and serine palmitoyltransferase (SPT) expression Ceramide is present in the villi of trophoblast cells [10, 11] so we investigated ceramide levels in control placentas and GDM placentas induced with either diet or

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Summary

Introduction

Gestational diabetes mellitus (GDM) is associated with important factors that influence fetal development. Sphingolipids are known to be associated with the development of diabetes. While pregnancy elicits an inherent, progressive insulin-resistant state, GDM is a state where the pregnant body has become sufficiently resistant to the glucose lowering effects of insulin that hyperglycemia develops [3]. This pathology affects up to 12% of all pregnancies and can lead to higher risk of short- and long-term maternal and fetal complications. The list of maternal and fetal complications associated with GDM is lengthy, including maternal gestational hypertension and preeclampsia, shoulder dystocia, caesarian

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