Niessen
Fakultäten » Medizinische Fakultät » Endokrinologie, Diabetologie und Klinische Ernährung, Klinik für » Prof. Dr. G. A. Spinas » Niessen
Completed research project
| Title / Titel | Molecular Mechanism Causing Insulin Resistance in Diabetes Mellitus Type2 | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Summary / Zusammenfassung | Insulin is one of the major players in the regulation of glucose homeostasis. It gives rise to pleiotropic effects including the stimulation of glucose uptake in skeletal muscle and fat tissue. In response to insulin the glucose transporter of the subtype4 (Glut4) is relocated from an intracellular storage compartment to the plasma membrane where it forms glucose specific pores. However, it is still not clear how insulin receptor stimulation results in Glut4 translocation. Using the insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) as bait we have identified in a two-hybrid screen six new potential components of insulin receptor signaling. We currently study their role in various aspects of insulin signal transduction in the murine fat cell line 3T3-L1 and in other established cell systems like CHO-IR/CHO or a muscle derived cell line. In a second project we study the influence of a specific subcellular localization of different signaling components of the insulin receptor cascade. In particular, we are interested if alterations in the binding affinity of IRS proteins against the insulin receptor affect glucose homeostasis. By altering the receptor-substrate affinity we intend to modify the subcellular localization of these proteins. Interestingly, the autophosphorylation and thereby the kinase activity of the insulin receptor is strongly stimulated by co-expression of IRS-1 and IRS-2 in cells. This result shows that insulin, as extracellular ligand is not the sole mechanism for insulin receptor activation. In the same line stands the result showing that increasing the receptor-substrate enhances the receptor autophosphorylation. We now focus on the impact of altered insulin receptor-substrate interactions on glucose metabolism. |
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| Publications / Publikationen | Eck MJ, Dhe-Paganon S, Trüb T, Nolte RT, Shoelson SE: Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor., Cell. 1996; 85(5): 695-705Trüb T, Wolf G, Ottinger E, Groninga L, Lynch A, White MF, Miyazaki M, Lee J, Shoelson SE: PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities., J-Biol-Chem. 1995; 270(46): 27407-10Trüb T, Choi WE, Wolf G, Ottinger E, Chen Y, Weiss M, Shoelson SE: Specificity of the PTB domain of Shc for beta turn-forming pentapeptide motifs amino-terminal to phosphotyrosine., J-Biol-Chem. 1995; 270(31): 18205-8 | ||||||
| Keywords / Suchbegriffe | Insulin, IRS-1, IRS-2, Tyrosine, Tyrosine Kinase, Diabetes | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Forschungskredit der Universität Zürich, EU, Foundation COST |
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| Duration of Project / Projektdauer | Aug 1996 to Dec 2004 |