Despite a century of improvements in metabolic control, pregnancies in women with insulin-dependent diabetes are complicated by increased rates of spontaneous miscarriages and congenital malformations. In addition, animal models of diabetes show more serious in vivo effects on pregnancy outcome with diabetes starting prior to ovulation as compared to embryo culture in """"""""diabetic"""""""" conditions. These observations suggest that the insult of maternal diabetes is occurring at the oocyte or early zygote stage and that this may represent irreversible maternal programming. In preliminary studies, we report that nuclear maturation is delayed in oocytes obtained from streptozotocin-induced diabetic mice and maturation is closely regulated by glucose metabolism. These mice also have a delay in the in vivo progression to a 2-cell zygote. We hypothesize that maternal hyperglycemia adversely affects the oocyte and/or early zygote at both a metabolic and morphologic level. We suggest this early programming may be responsible for subsequent problems in embryo development and for the adverse pregnancy outcomes in these patients. The following specific aims are designed to test these hypotheses:
Specific Aim 1. Do denuded or intact murine oocytes exposed to hyperglycemia in vivo demonstrate any abnormalities compared to control oocytes with regard to in vivo maturation, glucose utilization and metabolism during maturation, or morphology and apoptotic signaling before and during maturation? Specific Aim 2. Are these abnormalities due to an irreversible preovulatory event or does ovarian transplantation into a nondiabetic mouse reverse these effects? Is embryo development improved with ovarian transplantation? Specific Aim 3. Are the delays at both the oocyte and early zygote stage responsible, in part, for the abnormalities in pre-implantation embryo development and poor pregnancy outcome? Is embryo development and pregnancy outcome improved with 1-cell transfer? If our hypothesis proves correct, abnormal carbohydrate metabolism, characteristic of not only insulin-dependent but also insulin-independent diabetics, as well as patients with Polycystic Ovary Syndrome, may be a risk factor for poor oocyte quality. These oocyte changes may explain the increased incidence of pregnancy failure in all three of these groups as well as obese, insulin resistant patients. Treatment that is more aggressive may be indicated for these patients throughout their reproductive years may be indicated.
