Defining the differential roles of insulin and IGF-1 receptors in vivo
Final Report Abstract
The pancreatic derived hormone insulin is primarily responsible to maintain glucose homeostasis and the major signaling pathway altered in diabetes. While type I diabetes (insulin dependent) is characterized by the lack of insulin, type II diabetes (non-insulin dependent) is characterized by insulin resistance, a state where the body can not react to insulin´s ability to lower blood glucose. The hormone IGF-1 (insulin-like growth factor) is mainly synthesized in the liver and responsible for childhood growth and anabolic action. Increased expression of IGF-1 is associated with increased risk for various kinds of cancer. Although IGF-1 and insulin have distinct effects on body physiology, they share similar signaling pathways and so far almost no intrinsic differences have been found in vitro between these pathways. To understand the specific differences between these crucial signaling pathways, we generated insulin knock-in mice, where insulin is expressed under the control of IGF-1 promoter and vice versa to understand the differences between these pathways in vivo. In addition, we established brown pre-adipocytes expressing no receptor, the insulin receptor, the IGF-1 receptor or chimeric receptors (IR/IGF-1R and IGF-1R/IR) to investigate intrinsic signaling differences. We showed that receptors containing the IGF-1R tyrosine kinase domain have a longer half-life than IR tyrosine kinase domain-harbouring receptors. Furthermore, we show that IR signaling increases mitochondrial function compared to IGF-1R, while IGF-1R increases cell growth and is more potent in differentiating brown pre-adipocytes into mature adipocytes. These data show that IGF-1R exhibit increased mitogenic potential than IR signaling while IR signaling is more important for mitochondrial function. Our new generated mouse models will help to decipher the specific signaling pathways in vivo. By understanding the specificities of these pathways, new potential therapeutic interventions could be discovered for the treatment of diabetes and/or cancer.
