Mechanisms of Congenital Malformations in Pregnancies with Pre-existing Diabetes
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DIABETES AND PREGNANCY (M-F HIVERT AND CE POWE, SECTION EDITORS)
Mechanisms of Congenital Malformations in Pregnancies with Pre-existing Diabetes Mary R. Loeken 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Fetuses of diabetic mothers are at increased risk for congenital malformations. Research in recent decades using animal and embryonic stem cell models has revealed many embryonic developmental processes that are disturbed by maternal diabetes. The aim of this review is to give clinicians a better understanding of the reasons for rigorous glycemic control in early pregnancy, and to provide background to guide future research. Recent Findings Mouse models of diabetic pregnancy have revealed mechanisms for altered expression of tissue-specific genes that lead to malformations that are more common in diabetic pregnancies, such as neural tube defects (NTDs) and congenital heart defects (CHDs), and how altered gene expression causes apoptosis that leads to malformations. Embryos express the glucose transporter, GLUT2, which confers susceptibility to malformation, due to high rates of glucose uptake during maternal hyperglycemia and subsequent oxidative stress; however, the teleological function of GLUT2 for mammalian embryos may be to transport the amino sugar glucosamine (GlcN) from maternal circulation to be used as substrate for glycosylation reactions and to promote embryo cell growth. Malformations in diabetic pregnancy may be not only due to excess glucose uptake but also due to insufficient GlcN uptake. Summary Avoiding maternal hyperglycemia during early pregnancy should prevent excess glucose uptake via GLUT2 into embryo cells, and also permit sufficient GLUT2-mediated GlcN uptake. Keywords Diabetic pregnancy . Neural tube defects . Diabetic embryopathy . Hyperglycemia in pregnancy . Oxidative stress in pregnancy . Pax3
Abbreviations CNNC Cardiac neural crest cells COHDs Cardiac outflow tract defects CHDs Congenital heart defects DNMT DNA methyltransferase ESC Embryonic stem cell GlcN Glucosamine G6PD Glucose-6-PO4 dehydrogenase Gln Glutamine GSH-EE Glutathione-ethyl ester GFP Green fluorescent protein
HBSP IRES LMP NTDs 1C GSSG PPP GSH SGLT SOD
This article is part of the Topical Collection on Diabetes and Pregnancy
Introduction
* Mary R. Loeken [email protected]
Maternal diabetes existing prior to pregnancy, either type 1 or type 2, increases risk of congenital malformations, a diabetic complication referred to as “diabetic embryopathy” [1–6]. Even in recent years, congenital malformations are increased up to 5-fold in diabetic pregnancies [7–14]. Malformations
1
Section on Islet Cell and Regenerative Biology, Department of Medicine, Joslin Diabetes Center and Harvard Medical School, One Joslin Place, Boston, MA 02215, USA
Hexosamine biosynthetic pathway Internal ribosome entry site Last menstrual period Neural tube defects One carbon Oxidized glutathione Pentose phosphate pathway Reduced glutathione Sodium/glucose cotransporter Su
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