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Ablation of glucagon receptor signaling by peptide-based glucagon antagonists improves glucose tolerance in high fat fed mice.

Franklin, ZJ, McShane, LM, O'Harte, Finbarr and Irwin, Nigel (2014) Ablation of glucagon receptor signaling by peptide-based glucagon antagonists improves glucose tolerance in high fat fed mice. Peptides, 60 . pp. 95-101. [Journal article]

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DOI: 10.1016/j.peptides.2014.08.002

Abstract

Modification to the structure of glucagon has provided a number of glucagon receptor antagonists with possible therapeutic application for diabetes. These novel peptide analogs include desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon. This study has evaluated the metabolic benefits of once daily administration of desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon in high fat (45%) fed mice for 15 days. Administration of desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon had no significant effect on body weight, food intake or circulating glucose concentrations during the treatment period. However, both peptides significantly (P<0.05 to P<0.01) reduced circulating plasma insulin concentrations from day 6 onwards. Oral glucose tolerance and insulin sensitivity, as assessed by exogenous insulin administration, were significantly (P<0.01 to P<0.001) improved by both desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon. These metabolic benefits were accompanied by significantly (P<0.01) increased pancreatic insulin stores. No significant differences in blood triacylglycerol or cholesterol levels were noted with desHis1Pro4Glu9-glucagon, however desHis1Pro4Glu9(Lys30PAL)-glucagon treatment significantly (P<0.01) increased HDL-cholesterol levels. Glucagon-mediated elevations of glucose and insulin were effectively (P<0.01 to P<0.001) annulled in both treatment groups on day 15. Interestingly, glucose levels during an intraperitoneal glucose tolerance test were not altered by either desHis1Pro4Glu9-glucagon or desHis1Pro4Glu9(Lys30PAL)-glucagon treatment. These data provide further evidence that glucagon antagonism could provide an effective means of treating T2DM.

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:30111
Deposited By: Dr Nigel Irwin
Deposited On:09 Sep 2014 09:59
Last Modified:09 Sep 2014 09:59

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