IGFII AND PERINATAL CARBOHYDRATE METABOLISM

胰岛素样生长因子(IGF-II)是一种与胰岛素结构同源的多肽激素，其生理功能尚不清楚。IGF-II被认为在胎儿和胎盘发育中发挥重要作用。关于IGF-II作用的最令人信服的证据来自靶向干扰IGF-II基因的转基因小鼠(基因敲除小鼠)。IGF-II基因敲除小鼠的表型是妊娠最后三分之二的胎儿和胎盘的生长迟缓。虽然它们出生时的体型大约是正常产仔的60%，但它们的比例正常，而且能生育。此外，基因敲除小鼠胎盘和胎肝糖原含量显著降低，提示IGF-II可能在胎儿碳水化合物代谢中起重要作用。这项建议的总体目标是确定IGF-II在胎儿肝脏碳水化合物代谢中的作用，并阐明这种激素可能发挥作用的一些机制。IGF-II基因敲除小鼠将用于：1)确定IGF-II是否在围产期糖原代谢中发挥重要作用；2)确定IGF-II刺激糖原合成的一些细胞内信号通路。这些研究应该澄清IGF-II与胎儿碳水化合物代谢的关系，以及它对围产期生长的影响。明确IGF-II的作用及其对胎儿生长发育的影响将有助于进一步了解巨大儿和胎儿生长迟缓的机制和可能的治疗方法。

Insulin-like growth factor (IGF-II) is a polypeptide hormone with structural homology to insulin whose physiological functions are not clearly understood. IGF-II is thought to play an important role in fetal and placental development. The most compelling evidence concerning the role of IGF-II comes from transgenic mice with targeted disruption of the IGF-II gene (knockout mice). The phenotype of the IGF-II knockout mouse is growth retardation of both fetus and placenta during the last two-thirds of gestation. Although they are born approximately 60 percent the size of their normal littermates, they are normally-proportioned and fertile. In addition, the glycogen content of the placenta and fetal liver is greatly reduced in the knockout mouse suggesting that IGF-II may play an important role in the fetal carbohydrate metabolism. The overall goal of this proposal is to define the role of IGF-II in fetal hepatic carbohydrate metabolism and to elucidate some of the mechanisms by which this hormone may be exerting its effects. The IGF-II knockout mouse will be used to: 1) Determine whether IGF-II plays an important role in perinatal glycogen metabolism, 2) Determine some of the intracellular signaling pathways by which IGF-II stimulates glycogen synthesis. These studies should clarify the relationship between IGF-II and fetal carbohydrate metabolism, and its impact on perinatal growth. Defining the role of IGF-II and its effects on fetal growth will further understanding of the mechanisms and possible treatment of macrosomia and fetal growth retardation.