Maternal Hyperinsulinemia and Fetal Programming

描述（由申请人提供）：胎儿/新生儿损伤可导致 成人发病疾病（肥胖症、糖尿病等）但我们对 涉及的机制。我们已经证明，新生大鼠人工 在哺乳期以高碳水化合物（HC）配方奶喂养 立即发展为高胰岛素血症，持续到成年期， 伴随着肥胖。这项建议是基于我们的观察，即HC 雌性大鼠自发地传递母体特征（慢性高胰岛素血症 和成人发病肥胖症）的后代，由于胎儿的经验， 高胰岛素血症/肥胖HG妊娠。为了阐明参与的机制， 这种母胎表型转移提出了三个具体目标： (1)调查导致以下情况的母体环境因素： 编程胎儿B细胞以在断奶后发展高胰岛素血症。是 假设荷尔蒙和代谢适应与这样的一个 妊娠导致后代高胰岛素血症的发生。 (2)研究生物化学和分子机制 慢性高胰岛素血症是HG后代成年后发生的肥胖症 女性假设HG女性的子宫内环境 在后代胰岛中编程分子和生物化学变化 促进断奶时高胰岛素血症的发生及其持续至断奶后， 成年(iii)孕妇高胰岛素血症对胎儿的影响 和新生儿胰腺个体发育的影响， 特异性生长因子（IGF、FGF等）和转录因子。我们 一种假说是H（宫内环境改变胰腺细胞 在后代中的发展，以响应特定的水平的变化， 生长因子和转录因子。实验程序包括： 新生大鼠人工饲养，双向胚胎移植，胰岛素 通过分离的胰岛放射免疫测定，半定量RT-PCR测定， 免疫组织化学和原位杂交。

DESCRIPTION (provided by applicant): Fetal/neonatal insults can lead to adult-onset diseases (obesity, diabetes, etc.) but little is known about the mechanisms involved. We have demonstrated that newborn rats artificially reared on a high carbohydrate (HC) milk formula during their suckling period immediately develop hyperinsulinemia, which persists into adulthood and is accompanied by obesity. This proposal is based on our observation that HC female rats spontaneously transmit maternal traits (chronic hyperinsulinemia and adult-onset obesity) to the progeny due to the fetal experience of a hyperinsulinemic/obese HG pregnancy. To elucidate the mechanisms involved in this maternal-fetal transfer of phenotype three specific aims are proposed: (1) Investigate the maternal environmental factor(s) responsible for programming fetal B cells to develop hyperinsulinemia after weaning. It is hypothesized that hormonal and metabolic adaptations associate with such a pregnancy are responsible for programming of hyperinsulinemia in the progeny. (2) Investigate the biochemical and molecular mechanisms responsible for chronic hyperinsulinemia an adult-onset obesity in the progeny born to HG females. The hypothesis is that the intrauterine environment of the HG female programs molecular and biochemical changes in islets of the progeny facilitating the onset of hyperinsulinemia on weaning and its persistence into adulthood. (iii) Investigate the effects of maternal hyperinsulinemia on fetal and neonatal pancreatic ontogeny as influenced by alterations in the levels of specific growth factors (IGFs, FGFs, etc.) and transcription factors. Our hypothesis is that the H( intrauterine environment alters pancreatic cellular development in the progeny in response to the change in levels of specific growth factors and transcription factors. Experimental procedures include: artificial rearing of newborn rats, reciprocal embryo transfer, insulin secretion by isolated islets radioimmunoassays, semiquantitative RT-PCR assay, immunohistochemistry and in situ hybridization.