Diabetes mellitus in early pregnancy is the most severe maternal disease that is counted for 10% of newborn infants with structural defects. With the rapid increases in the number of diabetic women in childbearing age, the
birth defect rate is projected to elevate dramatically. Thus, prevention of embryonic malformations becomes an urgent task. Animal studies have revealed an involvement of oxidative stress in diabetic
embryopathy and treatment with
antioxidants can reduce embryonic abnormalities. However, the failure of clinical trials using
free radical-scavenging
antioxidants to alleviate oxidative stress-related diseases prompts researchers to reevaluate the strategy in
birth defect prevention.
Hyperglycemia also disturbs other intracellular homeostasis, generating aberrant conditions. Perturbed folding of newly synthesized
proteins causes accumulation of unfolded and misfolded
proteins in the lumen of the endoplasmic reticulum (ER). The ER under the stress activates signaling cascades, known as unfolded protein response, to suppress cell mitosis and/or trigger apoptosis. ER stress can be ameliorated by chemical chaperones, which promote protein folding.
Hyperglycemia also stimulates the expression of
nitric oxide (
NO) synthase 2 (NOS2) to produce high levels of NO and
reactive nitrogen species and augment
protein nitrosylation and nitration, resulting in nitrosative stress. Inhibition of NOS2 using inhibitors has been demonstrated to reduce embryonic malformations in diabetic animals. Therefore, targeting ER and nitrosative stress conditions using specific agents to prevent
birth defects in diabetic pregnancies warrant further investigations. Simultaneously targeting multiple stress conditions using combined agents is a potentially effective and feasible approach.