Maternal Diabetes and Oocyte Quality

描述(申请人提供)：尽管代谢控制经过一个世纪的改善，患有胰岛素依赖型糖尿病的女性怀孕仍因自然流产和先天畸形发生率增加而复杂化。此外，与“糖尿病”条件下的胚胎培养相比，糖尿病动物模型在体内对妊娠结局的影响更严重，糖尿病在排卵之前就开始了。这些观察表明，母体糖尿病的损害发生在卵母细胞或受精卵的早期阶段，这可能代表着不可逆转的母体编程。在初步研究中，我们报道了从链脲佐菌素诱导的糖尿病小鼠获得的卵母细胞核成熟延迟，成熟受到葡萄糖代谢的密切调控。这些小鼠在体内发育成2-细胞受精卵的过程也有延迟。我们假设，母体高血糖在代谢和形态水平上都会对卵母细胞和/或早期受精卵产生不利影响。我们认为这种早期计划可能是这些患者胚胎发育的后续问题和不良妊娠结局的原因。为了验证这些假说，我们设计了以下特定目标：特定目标1.裸露或完整的小鼠卵母细胞在体内暴露于高血糖环境中，与对照卵母细胞相比，在体内成熟、成熟过程中葡萄糖的利用和代谢、成熟前和成熟过程中的形态和凋亡信号方面是否有任何异常？具体目的2。这些异常是由于不可逆的排卵前事件引起的，还是卵巢移植到非糖尿病小鼠体内逆转了这些影响？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的延迟是否在一定程度上是植入前胚胎发育异常和不良妊娠结局的原因？单细胞移植能改善胚胎发育和妊娠结局吗？如果我们的假设被证明是正确的，碳水化合物代谢异常，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，可能是导致卵子质量差的一个风险因素。这些卵母细胞的变化可能解释了这三个组以及肥胖、胰岛素抵抗患者妊娠失败发生率增加的原因。在这些患者的整个生育期内，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.