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Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues modified at the N-terminus

Lynch, AM, Patahk, P, Flatt, YE, Gault, Victor, O'Harte, Finbarr, Irwin, Nigel and Flatt, Peter (2014) Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues modified at the N-terminus. European Journal of Pharmacology, 743 . pp. 69-78. [Journal article]

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DOI: 10.1016/j.ejphar.2014.09.018

Abstract

Oxyntomodulin (Oxm) possesses beneficial biological actions for the potential treatment of obesity-diabetes. However, rapid inactivation by dipeptidyl peptidase-4 (DPP-4) results in a short half-life, hindering therapeutic applicability. In the present study, six Oxm analogues namely, (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were synthesised and tested for DPP-4 stability and biological activity. Native Oxm, (Thr2)Oxm and (Asp3)Oxm were rapidly degraded by DPP-4, while (Aib2)Oxm, (d-Ser2)Oxm, (N-acetyl)Oxm and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL were resistant to degradation. All peptides stimulated cAMP production (P<0.01 to P<0.001) in GLP-1-R, but not in GIP-R, transfected cells. In glucagon-R transfected cells, all peptides except (N-acetyl)Oxm and (Thr2)Oxm evoked significant cAMP generation. Similarly, all analogues, except (N-acetyl)Oxm, exhibited prominent (P<0.05 to P<0.001) insulinotropic activity in BRIN BD11 cells. When administered in conjunction with glucose to normal mice only native Oxm, (Aib2)Oxm and (d-Ser2)Oxm significantly (P<0.05 to P<0.01) increased overall plasma insulin levels. The corresponding glycaemic excursion was significantly (P<0.05 to P<0.001) lowered by all Oxm peptides, barring (N-acetyl)Oxm. Further investigations revealed persistent glucose-lowering and insulin-releasing actions of (d-Ser2)Oxm-Lys-γ-glutamyl-PAL. Studies in GIP- and GLP-1-receptor KO mice with (Aib2)Oxm, (d-Ser2)Oxm, and (d-Ser2)Oxm-Lys-γ-glutamyl-PAL highlighted the importance of GLP-1 receptor signalling for the beneficial glucose homoeostatic actions of these analogues. All peptides, except (N-acetyl)Oxm, possessed significant appetite suppressive effects in mice. These data highlight the significant therapeutic promise of enzymatically stable Oxm-based peptides, particularly with position 2 modifications, for the treatment of obesity-diabetes.

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:30457
Deposited By: Dr Nigel Irwin
Deposited On:29 Oct 2014 19:40
Last Modified:29 Oct 2014 19:40

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