title: Characterisation of structurally modified analogues of glucagon as potential glucagon receptor antagonists.
abstract: Acute in vitro and in vivo biological activities of four novel structural analogues of glucagon were tested. desHis(1)Pro(4)-glucagon, desHis(1)Pro(4)Glu(9)-glucagon, desHis(1)Pro(4)Glu(9)Lys(12)FA-glucagon and desHis(1)Pro(4)Glu(9)Lys(30)FA-glucagon were stable to DPP-4 degradation and dose-dependently inhibited glucagon-mediated cAMP production (p<0.05 to p<0.001). None stimulated insulin secretion in vitro above basal levels, but all inhibited glucagon-induced insulin secretion (p<0.01 to p<0.001). In normal mice all analogues antagonised acute glucagon-mediated elevations of blood glucose (p<0.05 to p<0.001) and blocked corresponding insulinotropic responses. In high-fat fed mice, glucagon-induced increases in plasma insulin (p<0.05 to p<0.001) and glucagon-induced hyperglycaemia were blocked (p<0.05 to p<0.01) by three analogues. In obese diabetic (ob/ob) mice only desHis(1)Pro(4)Glu(9)-glucagon effectively (p<0.05 to p<0.01) inhibited both glucagon-mediated glycaemic and insulinotropic responses. desHis(1)Pro(4)-glucagon and desHis(1)Pro(4)Glu(9)-glucagon were biologically ineffective when administered 8h prior to glucagon, whereas desHis(1)Pro(4)Glu(9)Lys(12)FA-glucagon retained efficacy (p<0.01) for up to 24h. Such peptide-derived glucagon receptor antagonists have potential for type 2 diabetes therapy.
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Co. Londonderry BT52 1SA, Northern Ireland, United Kingdom. Electronic address: fpm.oharte@ulster.ac.uk.
authors.forename: F P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Franklin
authors.forename: E P
authors.initials: EP
authors.lastname: Rafferty
authors.forename: N
authors.initials: N
authors.lastname: Irwin
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005934:Glucagon / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008820:Mice, Obese; D059748:Proteolysis; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; C000600505:glucagon, deshistidyl(1)-prolyl(4)-glutamyl(9)-; D005934:Glucagon; D000242:Cyclic AMP; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: Acylation; Diabetes; FA; Glucagon; Glucagon receptor antagonist; Peptide analogue; Therapy; fatty acid