Fetal-Glycogen Regulation by Insulin-like Growth Factors

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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.