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Characterisation of structurally modified analogues of glucagon as potential glucagon receptor antagonists

O'Harte, Finbarr, Franklin, ZJ, Rafferty, EP and Irwin, Nigel (2013) Characterisation of structurally modified analogues of glucagon as potential glucagon receptor antagonists. Molecular and Cellular Endocrinology, 381 (1-2). pp. 26-34. [Journal article]

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DOI: 10.1016/j.mce.2013.07.014

Abstract

Acute in vitro and in vivo biological activities of four novel structural analogues of glucagon were tested. desHis1Pro4-glucagon, desHis1Pro4Glu9-glucagon, desHis1Pro4Glu9Lys12FA-glucagon and desHis1Pro4Glu9Lys30FA-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 desHis1Pro4Glu9-glucagon effectively (p<0.05 to p<0.01) inhibited both glucagon-mediated glycaemic and insulinotropic responses. desHis1Pro4-glucagon and desHis1Pro4Glu9-glucagon were biologically ineffective when administered 8 h prior to glucagon, whereas desHis1Pro4Glu9Lys12FA-glucagon retained efficacy (p<0.01) for up to 24 h. Such peptide-derived glucagon receptor antagonists have potential for type 2 diabetes therapy.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:26533
Deposited By: Dr Nigel Irwin
Deposited On:06 Aug 2013 08:14
Last Modified:15 Apr 2014 14:03

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