Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways

Although perinatal mortality rates have improved for pregnant diabetic wome n because of insulin therapy and tight metabolic control, infants of diabet ics still experience significantly higher rates of congenital malformations and spontaneous miscarriages compared with those of non-diabetic women(1). Our results here indicate that hyperglycemic conditions, either in vivo or in vitro, modulate the expression of an apoptosis regulatory gene as early as the pre-implantation blastocyst stage in the mouse. Apoptosis in the ma mmalian pre-implantation blastocyst is a normal process, thought to protect the early embryo by eliminating abnormal cells'. Here we demonstrate that expression of Bar, a Bcl-2-like protein, is increased at the blastocyst sta ge in the presence of high concentrations of glucose, and that these change s correlate morphologically with increased DNA fragmentation. Expression of Bar and caspase are necessary for this in vitro glucose-induced apoptotic event, and ceramide is involved in mediating this embryotoxic effect of glu cose. We also show that these apoptotic cellular changes can be prevented i n vivo by treating hyperglycemic mice with insulin before and immediately a fter conception. These findings emphasize the importance of tight glycemic control in diabetic women at the earliest stages after conception.