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: F P M O'Harte, Z J Franklin, E P Rafferty, N Irwin
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 381 Issue 1-2 Pg. 26-34 (Dec 05 2013) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 23891841 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Insulin
• Receptors, Glucagon
• glucagon, deshistidyl(1)-prolyl(4)-glutamyl(9)-
• Glucagon
• Cyclic AMP
• DPP4 protein, human
• Dipeptidyl Peptidase 4

Topics

• Animals
• Blood Glucose
• Cell Line
• Cyclic AMP (biosynthesis)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Dipeptidyl Peptidase 4 (chemistry)
• Drug Evaluation, Preclinical
• Glucagon (analogs & derivatives, chemistry, pharmacology)
• HEK293 Cells
• Humans
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Insulin Secretion
• Male
• Mice
• Mice, Obese
• Proteolysis
• Receptors, Glucagon (antagonists & inhibitors)