Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future

Abstract

Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010. Diabetes during pregnancy is a well known risk factor for congenital anomalies in various organ systems that contribute to neonatal mortality, including cardiovascular, gastrointestinal, genitourinary and neurological systems, among which the neural tube defects are frequently reported. Over the last two to three decades, several groups around the world have focussed on identifying the molecular cues and cellular changes resulting in altered gene expression and the morphological defects and in diabetic pregnancy. In recent years, the focus has gradually shifted to looking at pre-programmed changes and activation of epigenetic mechanisms that cause altered gene expression. While several theories such as oxidative stress, hypoxia, and apoptosis triggered due to hyperglycemic conditions have been proposed and proven for being the cause for these defects, the exact mechanism or the link between how high glucose can alter gene expression/transcriptome and activate epigenetic mechanisms is largely unknown. Although preconceptual control of diabetes, (i.e., managing glucose levels during pregnancy), and in utero therapies has been proposed as an effective solution for managing diabetes during pregnancy, the impact that a fluctuating glycemic index can have on foetal development has not been evaluated in detail. A tight glycemic control started before pregnancy has shown to reduce the incidence of congenital abnormalities in diabetic mothers. On the other hand, a tight glycemic control after organogenesis and embryogenesis have begun may prove insufficient to prevent or reverse the onset of congenital defects. The importance of determining the extent to which glycemic levels in diabetic mothers should be regulated is critical as foetal hypoglycemia has also been shown to be teratogenic. Finally, the major question remaining is if this whole issue is negligible and not worthy of investigation as the efficient management of diabetes during pregnancy is well in place in many countries.

High glucose suppresses embryonic stem cell differentiation into cardiomyocytes

“…Infants from pregestational diabetic mothers have a greater risk of structural birth defects including congenital heart defects (CHDs) than those from nondiabetic mothers [2]. CHDs are the most common congenital anomalies occurring in approximately 4 to 10 per 1000 live births [3].…”

Poor sleep during the periconceptional period increases risk for neural tube defects in offspring

“…Although the biological mechanism for the observed independent association between poor sleep and NTD is not known, we postulate that glucose related metabolic alterations may play an important role in mechanisms that contribute to the etiology of NTD. Hyperinsulinemia and diabetes during pregnancy are well known risk factors for congenital anomalies in various organ systems, including cardiovascular, gastrointestinal, genitourinary and neurological systems, among which the neural tube defects are frequently reported (Hendricks et al, ; Moore et al, ; Anderson et al, ; Sukanya et al, ). In recent years, a great deal of epidemiological evidence suggested that sleep disruption, including short sleep duration and sleep fragmentation, has emerged as a major determinant of metabolic health, and is implicated in poor glucose control, hyperglycemia, elevated insulin, and diabetes (Meisinger et al, ; Spiegel et al, ; Gangwisch et al, ; Boyko et al, ; Herring et al, ; Ladson et al, ).…”

“…No single factor explains most of the variance in the rates of NTDs; instead, many biologic, behavioral, and social factors interact. Hyperinsulinemia and diabetes have been two of the well‐known risk factors for NTDs (Hendricks et al, ; Moore et al, ; Anderson et al, ; Sukanya et al, ). Recent evidence has demonstrated that poor sleep may result in hyperglycemia and diabetes (Meisinger et al, ; Spiegel et al, ; Gangwisch et al, ; Boyko et al, ; Herring et al, ; Ladson et al, ).…”

Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype

“…Maternal diabetes is associated with increased risk of NTDs in offspring (Lupo et al, 2012; Sukanya et al, 2012). The function of NOS2 with respect to NTDs was explored in a diabetes study using mouse models (Sugimura et al, 2009).…”