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Glucagon receptor antagonist and GIP agonist combination for diet induced obese mice.

McShane, L, Irwin, Nigel, O'Flynn, D, Franklin, Z, Hewage, C and O'Harte, Finbarr (2016) Glucagon receptor antagonist and GIP agonist combination for diet induced obese mice. Journal of Endocrinology, 229 . pp. 319-330. [Journal article]

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URL: http://joe.endocrinology-journals.org/content/early/2016/04/20/JOE-15-0463

DOI: 10.1530/JOE-15-0463

Abstract

Ablation of glucagon receptor signalling represents a potential treatment option for type 2 diabetes (T2DM). Additionally, activation of glucose-dependent insulinotropic polypeptide (GIP) receptor signalling also holds therapeutic promise for T2DM. Therefore, the present study examined both independent and combined metabolic actions of desHis1Pro4Glu9(Lys12PAL)-glucagon (glucagon receptor antagonist) and D-Ala2GIP (GIP receptor agonist), in diet induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis1Pro4Glu9(Lys12PAL)-glucagon displayed enhanced alpha-helical content compared to native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis1Pro4Glu9(Lys12PAL)-glucagon was devoid of any insulinotropic or cAMP generating actions, and did not impede D-Ala2GIP-mediated (p<0.01 to p<0.001) effects on insulin and cAMP production. Twice daily injection of desHis1Pro4Glu9(Lys12PAL)-glucagon or D-Ala2GIP alone, and in combination, in high fat fed mice failed to affect body weight or energy intake. Circulating blood glucose levels were significantly (p<0.05 to p<0.01) decreased by all treatments regimens, with plasma and pancreatic insulin elevated (p<0.05 to p<0.001) in all mice receiving D-Ala2GIP. Interestingly, plasma glucagon concentrations were decreased (p<0.05) by sustained glucagon inhibition (day 28), but increased (p<0.05) by D-Ala2GIP therapy, with combined treatment resulting in glucagon concentration similar to saline controls. All treatments improved (p<0.01) intraperitoneal and oral glucose tolerance, and peripheral insulin sensitivity. D-Ala2GIP treated mice showed increased glucose-induced insulin secretion in response to intraperitoneal and oral glucose. Metabolic rate and ambulatory locomotor activity were increased (p<0.05 to p<0.001) in all desHis1Pro4Glu9(Lys12PAL)-glucagon treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment

Item Type:Journal article
Keywords:glucagon; glucose-dependent insulinotropic polypeptide (GIP); glucose 25 homeostasis; insulin secretion; insulin sensitivity, glucagon receptor antagonist, GIP receptor agonist, diet nduced obese diabetic mice
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 > Pharmacy & Pharmaceutical Sciences
Biomedical Sciences Research Institute > Diabetes
ID Code:34551
Deposited By: Dr Nigel Irwin
Deposited On:29 Apr 2016 09:26
Last Modified:05 Sep 2017 12:52

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