High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus.

Sebastián Gutiérrez-Vega,Daniela Mennickent,Martín Alcalá,Andrea Leiva,Axel Armella,María Del Pilar Ramos,Marta Viana,Bernel Ortega-Contreras,Enrique Guzmán-Gutiérrez,Erica Castro,Marco Loyola,Ambart Covarrubias,Carlos Escudero,Marcelo Gonzalez,Frank T Spradley

doi:10.1371/journal.pone.0242743

Abstract

Gestational Diabetes Mellitus (GDM) is characterized by abnormal maternal D-glucose metabolism and altered insulin signaling. Dysregulation of thyroid hormones (TH) tri-iodethyronine (T3) and L-thyroxine (T4) Hormones had been associated with GDM, but the physiopathological meaning of these alterations is still unclear. Maternal TH cross the placenta through TH Transporters and their Deiodinases metabolize them to regulate fetal TH levels. Currently, the metabolism of TH in placentas with GDM is unknown, and there are no other studies that evaluate the fetal TH from pregnancies with GDM. Therefore, we evaluated the levels of maternal TH during pregnancy, and fetal TH at delivery, and the expression and activity of placental deiodinases from GDM pregnancies. Pregnant women were followed through pregnancy until delivery. We collected blood samples during 10–14, 24–28, and 36–40 weeks of gestation for measure Thyroid-stimulating hormone (TSH), Free T4 (FT4), Total T4 (TT4), and Total T3 (TT3) concentrations from Normal Glucose Tolerance (NGT) and GDM mothers. Moreover, we measure fetal TSH, FT4, TT4, and TT3 in total blood cord at the delivery. Also, we measured the placental expression of Deiodinases by RT-PCR, western-blotting, and immunohistochemistry. The activity of Deiodinases was estimated quantified rT3 and T3 using T4 as a substrate. Mothers with GDM showed higher levels of TT3 during all pregnancy, and an increased in TSH during second and third trimester, while lower concentrations of neonatal TT4, FT4, and TT3; and an increased TSH level in umbilical cord blood from GDM. Placentae from GDM mothers have a higher expression and activity of Deiodinase 3, but lower Deiodinase 2, than NGT mothers. In conclusion, GDM favors high levels of TT3 during all gestation in the mother, low levels in TT4, FT4 and TT3 at the delivery in neonates, and increases deiodinase 3, but reduce deiodinase 2 expression and activity in the placenta.

Highlights

Gestational Diabetes Mellitus (GDM) is defined as any degree of glucose intolerance with onset or first manifestation during pregnancy [1]
While some studies associate a decrease in maternal Free T4 (FT4) and increase in Thyroid Stimulating Hormone (TSH) with GDM, others have related an increase in maternal Total Tri-iodothyronine (TT3, Free T3 plus protein bound T3) with this pathology [6,7,8]
Our study considered the following along pregnancy of 71 women with either Normal Glucose Tolerance (NGT) or GDM pregnancies

Summary

Introduction

Gestational Diabetes Mellitus (GDM) is defined as any degree of glucose intolerance with onset or first manifestation during pregnancy [1]. A decrease in the neonatal TH from mothers with type 2 diabetes mellitus was evidenced [11], while on the other hand, the suppression of these fetal hormones was associated with maternal glucose intolerance [12]. DIO are seleno-enzymes responsible for the catabolism of specific iodine atoms of the iodothyronine molecule [15,16,17,18]. These have three subtypes: I, II, and III (DIO1, DIO2, and DIO3, respectively), which have fundamental functions in thyroid hormone regulation [18, 19]. DIO3 is highly localized in placenta, and is the enzyme responsible for converting T4 into reverse T3 (rT3, inactive form), and catalyzes the conversion of diiodothyronine (T2) from T3, decreasing the levels of T3 [23, 24]

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Results

Conclusion