title: Novel dual agonist peptide analogues derived from dogfish glucagon show promising in vitro insulin releasing actions and antihyperglycaemic activity in mice.
abstract: The antidiabetic potential of thirteen novel dogfish glucagon derived analogues were assessed in vitro and in acute in vivo studies. Stable peptide analogues enhanced insulin secretion from BRIN-BD11 β-cells (p < 0.001) and reduced acute glycaemic responses following intraperitoneal glucose (25 nmol/kg) in healthy NIH Swiss mice (p < 0.05-p<0.001). The in vitro insulinotropic actions of [S2a]dogfish glucagon, [S2a]dogfish glucagon-exendin-4(31-39) and [S2a]dogfish glucagon-Lys(30)-γ-glutamyl-PAL, were blocked (p < 0.05-p<0.001) by the specific GLP-1 and glucagon receptor antagonists, exendin-4(9-39) and (desHis(1)Pro(4)Glu(9))glucagon amide but not by (Pro(3))GIP, indicating lack of GIP receptor involvement. These analogues dose-dependently stimulated cAMP production in GLP-1 and glucagon (p < 0.05-p<0.001) but not GIP-receptor transfected cells. They improved acute glycaemic and insulinotropic responses in high-fat fed diabetic mice and in wild-type C57BL/6J and GIPR-KO mice (p < 0.05-p<0.001), but not GLP-1R-KO mice, confirming action on GLP-1 but not GIP receptors. Overall, dogfish glucagon analogues have potential for diabetes therapy, exerting beneficial metabolic effects via GLP-1 and glucagon receptors.
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Co. Derry, BT52 1SA, Northern Ireland, UK. Electronic address: fpm.oharte@ulster.ac.uk.
authors.forename: F P M
authors.initials: FP
authors.lastname: O'Harte
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Co. Derry, BT52 1SA, Northern Ireland, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Ng
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Co. Derry, BT52 1SA, Northern Ireland, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Lynch
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Co. Derry, BT52 1SA, Northern Ireland, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Conlon
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Co. Derry, BT52 1SA, Northern Ireland, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004284:Dogfish / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose
keywords: Acute effects; Antidiabetic and antihyperglycaemic; Diabetes; Dogfish glucagon; Dual agonist; Glucagon; Glucagon-like peptide-1 (GLP-1); Glucose dependent insulinotropic polypeptide (GIP)