Diabetic Embryopathy Susceptibility in Mice Is Associated with Differential Dependence on Glucosamine and Modulation of High Glucose-Induced Oxidative Stress.

Jin Hyuk Jung,Mary R Loeken

doi:10.3390/antiox10081156

Abstract

The high KM glucose transporter, GLUT2 (SLC2A2), is expressed by embryos and causes high rates of glucose transport during maternal hyperglycemic episodes in diabetic pregnancies and causes congenital malformations (diabetic embryopathy). GLUT2 is also a low KM transporter of the amino sugar, glucosamine (GlcN), which enters the hexosamine biosynthetic pathway (HBP) and provides substrate for glycosylation reactions. Exogenous GlcN also increases activity of the pentose phosphate pathway (PPP), which increases production of NADPH reducing equivalents. GLUT2-transported GlcN is inhibited by high glucose concentrations. Not all mouse strains are susceptible to diabetic embryopathy. The aim of this study was to test the hypothesis that susceptibility to diabetic embryopathy is related to differential dependence on exogenous GlcN for glycosylation or stimulation of the PPP. We tested this using murine embryonic stem cell (ESC) lines that were derived from embryopathy-susceptible FVB/NJ (FVB), and embryopathy-resistant C57Bl/6J (B6), embryos in the presence of low or high glucose, and in the presence or absence of GlcN. There were no significant differences in Glut2 expression, or of glucose or GlcN transport, between FVB and B6 ESC. GlcN effects on growth and incorporation into glycoproteins indicated that FVB ESC are more dependent on exogenous GlcN than are B6 ESC. GlcN stimulated PPP activity in FVB but not in B6 ESC. High glucose induced oxidative stress in FVB ESC but not in B6 ESC. These results indicate that FVB embryos are more dependent on exogenous GlcN for glycosylation, but also for stimulation of the PPP and NADPH production, than are B6 embryos, thereby rendering FVB embryos more susceptible to high glucose to induce oxidative stress.

Highlights

Maternal diabetes that is present prior to pregnancy significantly increases risk for congenital malformations, a diabetic complication known as “diabetic embryopathy”; in both human fetuses and in animal models, neural tube defectsNTDs are among the most common that occur [1,2,3,4]
Using a mouse model of diabetic pregnancy, we have shown that maternal hyperglycemia, through high rates of glucose transport into embryo cells via the high KM glucose transporter, GLUT2 (SLC2A2), is responsible for diabetes-induced NTDs [5,6]
We previously reported that C57Bl/6J (B6) embryos, unlike FVB/NJ (FVB) embryos, are resistant to NTDs induced during diabetic pregnancy, despite similar levels of maternal hyperglycemia; this is correlated with failure to inhibit expression of Pax3, which is required for neural tube closure, in B6 embryos of diabetic mothers [19]

Summary

Introduction

Maternal diabetes that is present prior to pregnancy (pregestational diabetes) significantly increases risk for congenital malformations, a diabetic complication known as “diabetic embryopathy”; in both human fetuses and in animal models, neural tube defectsNTDs are among the most common that occur [1,2,3,4]. Using a mouse model of diabetic pregnancy, we have shown that maternal hyperglycemia, through high rates of glucose transport into embryo cells via the high KM glucose transporter, GLUT2 (SLC2A2), is responsible for diabetes-induced NTDs [5,6]. Several studies using animal models have shown that maternal diabetes-induced oxidative stress is central to diabetic embryopathy [7,8,9,10,11,12]. Several studies from our lab have shown that high glucose-induced oxidative stress inhibits gene expression that is required for neural tube closure and inhibition of apoptosis, thereby causing NTDs [6,12,13,14]. Embryos express the low KM (approximately 5.5 mmol/L) glucose transporters, Antioxidants 2021, 10, 1156.

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