1. LIMES Program Unit Chemical Biology & Medicinal Chemistry, c/o Kekulé Institut für Organische Chemie und Biochemie, University of Bonn, Gerhard-Domagk-Strae 1, 53121 Bonn, Germany
2. LIMES Program Unit Molecular Immune and Cell Biology, Laboratory of Molecular Immunology, University of Bonn, Karlrobert-Kreiten Strae 13, 53115 Bonn, Germany
3. Institut für Molekulare Immunologie, GSF-Forschungszentrum für Umwelt und Gesundheit, Marchioninistr. 25, 81377 München, Germany

Correspondence to: Michael Famulok¹ Correspondence and requests for materials should be addressed to M.F. (Email: m.famulok@uni-bonn.de).

G proteins are an important class of regulatory switches in all living systems. They are activated by guanine nucleotide exchange factors (GEFs), which facilitate the exchange of GDP for GTP^{1, 2}. This activity makes GEFs attractive targets for modulating disease-relevant G-protein-controlled signalling networks^{3, 4, 5}. GEF inhibitors are therefore of interest as tools for elucidating the function of these proteins and for therapeutic intervention; however, only one small molecule GEF inhibitor, brefeldin A (BFA), is currently available^{6, 7, 8, 9}. Here we used an aptamer displacement screen to identify SecinH3, a small molecule antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization¹⁰, integrin activation¹¹ or integrin signalling¹². The application of SecinH3 in human liver cells showed that insulin-receptor-complex-associated cytohesins are required for insulin signalling. SecinH3-treated mice show increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, cytohesin inhibition results in hepatic insulin resistance. Because insulin resistance is among the earliest pathological changes in type 2 diabetes, our results show the potential of chemical biology for dissecting the molecular pathogenesis of this disease.

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