Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes.

• DOI: 10.2337/diabetes.49.12.2079
• Publication Date: 2007-03-06T19:04:22Z
• Authors: J C Parker; R K McPherson; K M Andrews; C B Levy; J S Dubins; J E Chin; P V Perry; B Hulin; D A Perry; T Inagaki; K A Dekker; K Tachikawa; Y Sugie; J L Treadway
• Keywords: Glucagon receptor

Peptidic glucagon antagonists have been shown to lower blood glucose levels in diabetic models (1-3), but attempts identify small molecular weight receptor-binding met with little success. Skyrin, a fungal bisanthroquinone, exhibits functional antagonism by uncoupling the receptor from adenylate cyclase activation rat liver membranes (1). We examined effects of skyrin on cells transfected human and isolated hepatocytes. The used was Talaromyces wortmanni American Type Culture Collection 10517. In hepatocytes, (30 micromol/l) inhibited glucagon-stimulated cAMP production (53%) output (IC50 56 micromol/l). There no detectable effect epinephrine or glucagon-like peptide 1 (GLP-1) stimulation these parameters, which demonstrates skyrin's selective activity. Skyrin also evaluated primary cultures Unlike cell lines, are largely unresponsive glucagon, hepatocytes exhibited glucagon-dependent for 14 days culture (EC50 10 nmol/l). (10 markedly reduced (55%) glycogenolysis (27%) inhibition specific property displayed oxyskyrin not shared other bisanthroquinones. is first nonpeptidic agent demonstrated interfere coupling independent binding receptor. data presented this study indicate that results metabolic could reduce hepatocyte hence alleviate hyperglycemia.