New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects

Abstract

Maternal diabetes is a significant risk factor for structural birth defects, including congenital heart defects and neural tube defects (NTDs). With the rising prevalence of type 2 diabetes and obesity in women of childbearing age, diabetes-induced birth defects have become an increasingly significant public health problem. Maternal diabetes in vivo and high glucose in vitro induce yolk sac injuries by damaging the morphology of cells and altering the dynamics of organelles. The yolk sac vascular system is the first system to develop during embryogenesis, therefore, it is the most sensitive to hyperglycemia. The consequences of yolk sac injuries include impairment of nutrient transportation due to vasculopathy. Although the functional relationship between yolk sac vasculopathy and structural birth defects has not yet been established, a recent study reveals that the quality of yolk sac vasculature is inversely related to embryonic malformation rates. Studies in animal models have uncovered key molecular intermediates of diabetic yolk sac vasculopathy, including hypoxia-inducible factor-1α (HIF-1α), apoptosis signal-regulating kinase 1 (ASK1) and its inhibitor thioredoxin-1 (Trx), c-Jun-N-terminal kinases (JNK), nitric oxide (NO) and nitric oxide synthase (NOS). Yolk sac vasculopathy is also associated with abnormalities in arachidonic acid and myo-inositol. Dietary supplementation with fatty acids that restore lipid levels in the yolk sac lead to reduction in diabetes-induced malformations. Although the role of the human yolk in embryogenesis is less extensive than in rodents, nevertheless, human embryonic vasculogenesis is negatively affected by maternal diabetes. Mechanistic studies have identified potential therapeutic targets for future intervention against yolk sac vasculopathy, birth defects, and other complications associated with diabetic pregnancies.

Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis

“…55,56 Therefore, therapeutics that can prevent diabetes-induced birth defects are needed. Antioxidants are effective in preventing adverse pregnancy outcomes associated with maternal diabetes in animal models 8–10,12–15,17,20–22,36,37 ; however, their effects on human pregnancies are controversial. 57,58 Our previous studies revealed that a group of natural compounds with antioxidant and signaling modulating properties reduces birth defects in animal diabetic pregnancies.…”

“…Because oxidative stress, ER stress, and apoptosis are causal events in T1DM embryopathy, our results suggest that T1DM and T2DM may share similar molecular mechanisms to cause birth defects. Based on our work to identify possible therapeutic inhibitors of the signaling pathways involved inT1DM embryopathy, 8–10,12–15,17,20–22,33,36,37 it is possible that the same interventions could successfully reduce birth defects induced by T2DM.…”

The green tea polyphenol EGCG alleviates maternal diabetes–induced neural tube defects by inhibiting DNA hypermethylation

“…14 There are approximately 5 times more neural tube defects in offspring from diabetic mothers than in those from nondiabetic mothers, despite modern preconception care. 15 Studies from our group 1,5,6,16–25 and others 26 have demonstrated that maternal diabetes induces cellular stress, including oxidative stress and endoplasmic reticulum stress, and that those cellular stresses cause apoptosis in the embryonic neural tissue, leading to neural tube defect formation. Recently several studies have suggested that altered DNA methylation disrupts the folate metabolic pathway and causes neural tube defects.…”

“…Although strict glycemic control by lifestyle and pharmacological treatment can decrease the incidence of hyperglycemia-induced embryonic malformations in pregnancies affected by preexisting maternal diabetes, 1–3,6,7 euglycemia is difficult to achieve and maintain, and even transient exposure to high glucose could lead to abnormal embryonic development. 1–3,11–13 Thus, diabetes-induced birth defects are significant public health problems, and there is an urgent need for new therapeutic approaches against diabetic embryopathy.…”

Glukosestoffwechsel und assistierte Reproduktion

“…Adipositas und erhöhten Werten des C-reaktiven Proteins gebracht werden, vor allem aber mit einem nicht diagnostizierten und unbehandelten früh einsetzenden Gestationsdiabetes mellitus (FREGDM). Im Zusammenhang mit Hyperglykämien werden Vaskulogenesestörungen ab dem Zeitpunkt der Implantation und sterile inflammatorische Veränderungen in der Plazenta als Ursache einer Präeklamp-sie in einer fortgeschrittenen Schwangerschaft diskutiert [11,20].…”