Abstract
Glucagon is a hormone with important effects on blood glucose regulation. This study has utilized the stable glucagon receptor antagonists, desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys12PAL)-glucagon, to evaluate the effects of sustained inhibition of glucagon receptor signalling in normal mice. Twice-daily injection of either analogue for 10 days had no effect on food intake, body weight and non-fasting plasma glucose concentrations. However, insulin levels were significantly raised (p<0.05 to p<0.01) from day 3 onwards in desHis1Pro4Glu9-glucagon mice. After 10 days, glucose tolerance was improved (p<0.05) in desHis1Pro4Glu9-glucagon treated mice. Glucose-mediated insulin secretion and circulating cholesterol levels were significantly (p<0.05 to p<0.01) decreased in both treatment groups. Importantly, the effects of glucagon to increase blood glucose and insulin concentrations were still annulled on day 10. Insulin sensitivity was almost identical in all groups of mice at the end of the study. In addition, no changes in pancreatic insulin and glucagon content or islet morphology were observed in either treatment group. Finally, acute injection of desHis1Pro4Glu9-glucagon followed by a 24-h fast in treatment naïve mice was not associated with any hypoglycaemic episodes. These data indicate that peptide-based glucagon receptor antagonists represent safe and effective treatment options for type 2 diabetes.
Acknowledgments
These studies were supported by the Department of Education and Learning, Northern Ireland and the University of Ulster Proof of Principle/Concept Funding Programme.
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