Our work indicates that Alx3 confers protection against oxidative stress produced by glucose in embryonic cells, thus contributing to the prevention of the teratogenic effects of hyperglycaemia during diabetic pregnancy. Glucose up-regulates the expression of Alx3, which in turn stimulates the expression of Foxo1 and the expression of genes encoding oxidative stress-scavenging enzymes as alfa defence mechanism against excess ROS generated by hyperglycaemia. This notion is consistent with the observation of activated expression of oxidative stress-scavenging genes in wild type but not in Alx3-deficient embryos developing in diabetic mothers. Although we cannot rule out the existence of epigenetic changes on the target promoters, our data strongly support the notion that Foxo1 activation in response to glucose is due to increased expression of ALX3 stimulated by glucose itself, and not to a change in the binding efficiency of this transcription factor. That is, in the presence of low concentrations of glucose, ALX3 levels are low, and therefore Foxo1 promoter occupancy at the specific binding site described in this study is low, thus leading to reduced transactivation. On the contrary, in the presence of high concentrations of glucose, ALX3 levels a high, favoring binding to the Foxo1 promoter and increasing transactivation.