IGFII AND PERINATAL CARBOHYDRATE METABOLISM

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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.