Maternal Diabetes and Oocyte Quality

描述（由申请人提供）：尽管代谢控制已经改善了世纪，但胰岛素依赖型糖尿病女性的妊娠仍因自发性流产和先天性畸形的发生率增加而变得复杂。此外，与“糖尿病”条件下的胚胎培养物相比，糖尿病动物模型在排卵前开始对妊娠结果显示出更严重的体内影响。这些观察结果表明，母亲糖尿病的侮辱发生在卵母细胞或早期受精卵阶段，这可能代表不可逆的母体编程。在初步研究中，我们报告说，核成熟延迟从链脲佐菌素诱导的糖尿病小鼠卵母细胞和成熟密切调节葡萄糖代谢。这些小鼠在体内向2细胞合子的进展也有延迟。我们假设母体高血糖在代谢和形态学水平上对卵母细胞和/或早期受精卵产生不利影响。我们认为，这种早期编程可能是负责随后的问题，胚胎发育和不良妊娠结局在这些患者。以下具体目标旨在检验这些假设：具体目标1。与对照卵母细胞相比，暴露于体内高血糖的裸露或完整小鼠卵母细胞在体内成熟、成熟期间葡萄糖利用和代谢或成熟之前和期间的形态和凋亡信号方面是否表现出任何异常？具体目标2。这些异常是由于不可逆的排卵前事件或卵巢移植到非糖尿病小鼠逆转这些影响？卵巢移植能改善胚胎发育吗？具体目标3。卵母细胞和早期受精卵阶段的延迟是否部分导致了植入前胚胎发育异常和妊娠结局不良？胚胎发育和妊娠结局是否通过单细胞移植得到改善？如果我们的假设被证明是正确的，糖代谢异常，不仅是胰岛素依赖型糖尿病患者的特征，也是胰岛素非依赖型糖尿病患者的特征，以及多囊卵巢综合征患者的特征，可能是卵母细胞质量差的危险因素。这些卵母细胞的变化可以解释所有这三组以及肥胖、胰岛素抵抗患者中妊娠失败发生率的增加。在这些患者的整个生育年龄可能需要更积极的治疗。

DESCRIPTION (provided by applicant): 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.