Fetal-Glycogen Regulation by Insulin-like Growth Factors

描述（由申请人提供）：肝脏的主要功能之一是维持血糖水平。它是一个以糖原形式存在的葡萄糖储存库，可以根据需要动员。胰岛素是一种胰腺激素，在维持葡萄糖代谢的正常稳态中起重要作用。在成人肝脏中，胰岛素可触发多种生物反应，包括葡萄糖摄取和糖原合成。然而，目前尚不清楚胰岛素或其他激素是否在胎儿糖原合成的调节中起类似的作用。 我的实验室提供的证据表明，缺乏转录因子PDX-1（胰腺和十二指肠同源框基因-1）的小鼠，即胰岛素缺乏的小鼠，在出生前肝糖原储备没有任何改变，这表明胰岛素可能不是出生前糖原合成所必需的。 胰岛素样生长因子-II（IGF-II）可能是调节胎儿糖原合成的候选因子。 IGF-II是一种肽类激素，属于胰岛素家族，在整个胎儿期高度表达。 IGF-II缺乏的小鼠不仅出生时生长迟缓，而且在妊娠后期肝糖原储备明显低于其野生型（WT）同窝出生的小鼠。 假设IGF-II是胎肝糖原合成的主要激素调节剂，并通过胰岛素受体介导这种作用。这个建议的目的是逐步剖析胎儿肝脏碳水化合物代谢的过程，从激素调节通过细胞表面受体到细胞内信号通路。实验方法将利用不同的小鼠与基因缺失（敲除）的蛋白质，可能发挥作用，在胎儿调节糖原合成。我们的目标是：1）确认IGF-II是出生前参与肝糖原合成的激素配体; 2）确定哪种受体调节胎儿肝糖原合成; 3）阐明调节胎儿糖原合成的细胞内信号传导途径。这些实验的数据将使我们更好地了解IGF-II和胰岛素的共同功能，并可能导致对胰岛素作用的深入了解。

DESCRIPTION (provided by applicant): One of the main functions of the liver is to maintain blood glucose levels. It is a repository of glucose in the form of glycogen that can be mobilized upon demand. Insulin is a pancreatic hormone that plays an important role in maintaining normal homeostasis of glucose metabolism. In the adult liver, insulin can trigger a variety of biological responses including glucose uptake and glycogen synthesis. However, it is not clear whether insulin or other hormones play a similar in the regulation of glycogen synthesis in the fetus. My laboratory has provided evidence that mice lacking the transcription factor PDX-1 (pancreatic and duodenal homoeobox gene-1), which are insulin deficient, do not have any alterations in their hepatic glycogen stores prenatally, suggesting that insulin may not be essential for glycogen synthesis before birth. A likely candidate for the regulation of glycogen synthesis in the fetus is insulin-like growth factor-II (IGF-II). IGF-II is a peptide hormone that belongs to the insulin family that is highly expressed throughout fetal life. Mice deficient in IGF-II are not only born growth-retarded but also have significantly lower hepatic glycogen stores than their wild-type (WT) littermates during late gestation. The hypothesis is that IGF-II is the main hormonal regulator of glycogen synthesis in the fetal liver and that it mediates this effect via the insulin receptor. The goal of this proposal is to dissect step by step the process of hepatic carbohydrate metabolism in the fetus, from hormonal regulation via cell surface receptors to intracellular signaling pathways. The experimental approach will make use of different mice with genetic deletions (knockouts) of proteins that may play a role in the fetal regulation of glycogen synthesis. Our aims are: 1) To confirm that IGF-II is the hormonal ligand involved in hepatic glycogen synthesis before birth; 2) To determine which receptor(s) regulates fetal hepatic glycogen synthesis; and 3) To elucidate the intracellular signaling pathways that regulate glycogen synthesis in the fetus. Data from these experiments will provide us with a better understanding of the common functions of IGF-II and insulin and may lead to insights into insulin action.