Defining the differential roles of insulin and IGF-1 receptors in vivo

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Type 2 diabetes is steadly increasing worldwide and is paralleled by secondary effects like cardiovascular diseases, nephro- and retinopathy. In this disorder, a central component of the pathophysiology is insulin resistance. Here, the insulin/IGF-1 system plays a crucial role by binding of insulin and allowing to activate its signaling cascade. The insulin (IR) and IGF-1 receptor (IGF1R) are highly homologous in several functional domains and share many downstream signaling components. Although both ligands can bind to each receptor, insulin and IGF-1 have remarkably different physiological roles and effects. A number of attempts have been made to address differences in insulin and IGF-1 signaling by construction of chimeric receptors but have failed to define the unique aspect of its physiological specificities. I therefore hypothesize that the major physiological differences observed in vivo between insulin and IGF-1 relate to differences in tissue distribution and timing of expression of the receptors during pre- and post-natal life, and the nature of the different ligand receptor interactions. To this end I will create transgenic mice which express IR or IR/IGF1R chimeras in the IGF1R locus and doing the converse for IGF1R and chimeric receptors in the IR locus. Using chimeric receptors will allow for investigation of the differences between the intra- and extracellular domains of the receptors in vivo. This work will rule out the differences between IR and IGF1R signaling and will help to understand their specificities in several pathophysiological diseases.