The potential of novel glucagon receptor antagonists alone and in combination with other peptides for the treatment of diabetes

• Main Author: McShane, Laura Majella
• Published: Ulster University 2013
• Subjects: 616.4
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.652015

The ever increasing prevalence of diabetes mellitus worldwide warrants the need for new and effective treatment options. Although decades of research have primarily focused on insulin deficiency as the underlying defect in this disorder, a new wave of exploration in recent years has underpinned the role of hyperglucagonaemia as the key driving force behind hepatic glucose production and exacerbated hyperglycaemia in these patients. In an effort to antagonise glucagon signalling and investigate the potential benefits of glucagon ablation therapy, novel glucagon derived peptide antagonists were assessed. The structurally modified glucagon analogues; desHis1Pro4 glucagon, desHis1Pro4Glu9 glucagon, desHis1Pro4Glu9Lys12 (glut-PAL)glucagon and desHis1Pro4Glu9Lys30 (glut-PAL)glucagon were all found to be highly resistant to enzymatic degradation by mouse plasma, and each peptide successfully inhibited glucagon mediated insulin release and cAMP production in vitro. Chronic treatment with desHis1Pro4Glu9 glucagon and desHis1Pro4Glu9Lys30 (glut-PAL)glucagon significantly reduced glucagon mediated glucose excursion in vivo whilst enhancing the glucose lowering effects of exogenous insulin in high-fat fed dietary induced diabetic mice. desHis1Pro4Glu9Lys12 (glut-PAL)glucagon was found to be as effective as the stable GIP analogue D-Ala2GIP, at improving glucose tolerance and insulin sensitivity in vivo. Furthermore desHis1Pro4Glu9Lys12 (glut-PAL)glucagon therapy produced a significant increase in energy expenditure and locomotor activity with a concomitant decrease in body fat mass. Chronic administration of desHis1Pro4Glu9 glucagon and desHis1Pro4Glu9Lys12 (glut-PAL)glucagon to STZ induced diabetic mice resulted in significantly improved insulin sensitivity and glucose tolerance. Furthermore desHis1Pro4Glu9Lys12 (glut-PAL)glucagon protected against STZ mediated β-cell destruction as evidenced by residual pancreatic insulin content at termination of the study. The most striking finding was that the beneficial effects on glucose tolerance in different models of diabetes achieved by these glucagon receptor antagonists GRA’s consistently occurred without a concomitant rise in plasma insulin suggesting that glucagon ablation therapy alone is sufficient to improve glycaemic control, in the absence of insulin signalling. This thesis demonstrates that glucagon antagonism is an effective therapeutic approach for the treatment of diabetes mellitus and these analogues should be investigated further as a viable treatment option.