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desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon: Long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity.

Irwin, Nigel, Franlin, ZJ and O'Harte, Finbarr (2013) desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon: Long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity. European Journal of Pharmacology, 709 (1-3). pp. 43-51. [Journal article]

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DOI: 10.1016/j.ejphar.2013.03.041

Abstract

Glucagon is hormone secreted from the pancreatic alpha-cells that is involved in blood glucose regulation. As such, antagonism of glucagon receptor signalling represents an exciting approach for treating diabetes. To harness these beneficial metabolic effects, two novel glucagon analogues, desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon, has been evaluated for potential glucagon receptor antagonistic properties. Both novel peptides were completely resistant to enzymatic breakdown and significantly (P<0.05 to P<0.001) inhibited glucagon-mediated elevations of cAMP production in glucagon receptor transfected cells. Similarly, desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon effectively antagonised glucagon-induced increases of insulin secretion from BRIN BD11 cells. When administered acutely to normal, high fat fed or ob/ob mice, both analogues had no significant effects on overall blood glucose or plasma insulin levels when compared to saline treated controls. However, desHis1Glu9-glucagon-[mPEG] significantly (P<0.05) annulled glucagon-induced increases in blood glucose and plasma insulin levels in normal mice and had similar non-significant tendencies in high fat and ob/ob mice. In addition, desHis1Glu9(Lys30PAL)-glucagon effectively (P<0.05 to P<0.001) antagonised glucagon-mediated elevations of blood glucose levels in high fat fed and ob/ob mice, but was less efficacious in normal mice. Further studies confirmed the significant persistent glucagon receptor antagonistic properties of both novel enzyme-resistant analogues 4h post administration in normal mice. These studies emphasise the potential of longer-acting peptide-based glucagon receptor antagonists, and particularly acylated versions, for the treatment of diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:25677
Deposited By: Dr Nigel Irwin
Deposited On:15 Apr 2013 07:41
Last Modified:01 May 2013 14:33

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