Untersuchungen der Struktur-Wirkungsbeziehung zwischen GLP-1 und dem GLP-1 Rezeptor mit Hilfe von Site-directed Mutagenesis des GLP-1 Rezeptors und des Glukagon Rezeptors

Die Probleme, die die Therapie der Volkskrankheit Diabetes mellitus aufwerfen, sind noch lange nicht gelöst. Das Hormon GLP-1(7-36)amid ist seit Jahren ein viel untersuchter Kandidat für die Therapie des Diabetes mellitus. Es hat vilefältige positive Wirkungen auf den Glukosehaushalt und im Vergleic...

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Bibliographic Details
Main Author: Fürniß-Ihns, Anna
Contributors: Göke, R. (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2007
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The problems to treat diabetes melltius are not solved yet. The hormone GLP-1(7-36)amid is a promissing candidate for the pharmacological treatment of diabetes mellitus. It has a lot of positive qualities and very little side effects compared to other antidiabetic medications. It does not lead to hypoglycemia. But it has a very short halflife and its intestinal absorbtion rate is poor. Therefore it is important to evaluate the structure-reactivity relation of GLP-1 and its receptor to be able to develope analogas usable for therapy. For this evaluation 2 rezeptor chimera and 2 hormon chimera were constructed: [I197]-GLP-1 receptor and [K195]glucagon receptor in which the the lysin at position 197 of the GLP-1 receptor was switched with the isoleucin at position 195 of the glucagon receptor, and [Q9]-GLP-1 and [E3]-glucagon in which the glutamin acid and glutamin at position 3 of the two hormones were switched. With these chimera and the wildtyp receptors and hormones binding assays and cAMP assays were done to evaluate the structure-reactivity relation between them. These experiments showed that the carboxy-element of the glutamin acid at position 3 of GLP-1 is essentiell for GLP-1 receptor coupled cellactivation. It was demonstrated that isoleucin at positon 195 of the glucagon receptor is also important for glucagon receptor coupled cellactivation. Glutamin at position 3 of glucagon is not essentiell for intracellualar cAMP production and does not interact specifically with isoleucin at position 195 of the glucagon receptor.