Diabetes and Early Development: Epigenetics, Biological Stress, and Aging.

Abstract

Pregestational diabetes, either type 1 or type 2 diabetes, induces structural birth defects including neural tube defects (NTDs) and congenital heart defects (CHDs) in human fetuses. Rodent models of type 1 and type 2 diabetic embryopathy have been established and faithfully mimic human conditions. Hyperglycemia of maternal diabetes triggers oxidative stress in the developing neuroepithelium and the embryonic heart leading to the activation of pro-apoptotic kinases and excessive cell death. Oxidative stress also activates the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. Hyperglycemia alters epigenetic landscapes by suppressing histone deacetylation, perturbing microRNA (miRNA) expression, and increasing DNA methylation. At cellular levels, besides the induction of cell apoptosis, hyperglycemia suppresses cell proliferation and induces premature senescence. Stress signaling elicited by maternal diabetes hyperglycemia disrupts cellular organelle homeostasis leading to mitochondrial dysfunction, mitochondrial dynamic alteration, and autophagy impairment. Blocking oxidative stress, kinase activation and cellular sentence ameliorates diabetic embryopathy. Deleting the mir200c gene or restoring mir322 expression abolishes maternal diabetes hyperglycemia-induced senescence and cellular stress, respectively. Both the autophagy activator trehalose and the senomorphic rapamycin can alleviate diabetic embryopathy. Thus, targeting cellular stress, miRNAs, senescence or restoring autophagy or mitochondrial fusion is a promising approach to prevent poorly controlled maternal diabetes-induced structural birth defects. In this review, we summarize the causal events in diabetic embryopathy and propose preventions for this pathological condition.