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Effects of short-term chemical ablation of glucagon signaling by peptide-based glucagon receptor antagonists on insulin secretion and glucose homeostasis in mice

Franklin, ZJ, O'Harte, Finbarr and Irwin, Nigel (2014) Effects of short-term chemical ablation of glucagon signaling by peptide-based glucagon receptor antagonists on insulin secretion and glucose homeostasis in mice. Biological Chemistry, 395 (4). pp. 433-442. [Journal article]

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DOI: 10.1515/hsz-2013-0224

Abstract

Glucagon is a hormone with important effects on blood glucose regulation. This study hasutilized the stable glucagon receptor antagonists, desHis1Pro4Glu9-glucagon anddesHis1Pro4Glu9(Lys12PAL)-glucagon, to evaluate the effects of sustained inhibition ofglucagon receptor signalling in normal mice. Twice-daily injection of either analogue for10 days had no effect on food intake, body weight and non-fasting plasma glucoseconcentrations. However, insulin levels were significantly raised (P<0.05 to P<0.01) fromday 3 onwards in desHis1Pro4Glu9-glucagon mice. After 10 days, glucose tolerance wasimproved (P<0.05) in desHis1Pro4Glu9-glucagon treated mice. Glucose-mediated insulinsecretion and circulating cholesterol levels were significantly (P<0.05 to P<0.01) decreased inboth treatment groups. Importantly, the effects of glucagon to increase blood glucose andinsulin concentrations were still annulled on day 10. Insulin sensitivity was almost identical inall groups of mice at the end of the study. In addition, no changes in pancreatic insulin andglucagon content or islet morphology were observed in either treatment group. Finally, acuteinjection of desHis1Pro4Glu9-glucagon followed by a 24 hour fast in treatment naïve mice wasnot associated with any hypoglycaemic episodes. These data indicate that peptide-basedglucagon receptor antagonists represent safe and effective treatment options for type2 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:27973
Deposited By: Dr Nigel Irwin
Deposited On:11 Nov 2013 09:35
Last Modified:15 Apr 2014 14:01

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