Glucagon receptor antagonism is becoming a key target area for type 2 diabetes treatment. This thesis evaluates the potential of novel peptide-based glucagon receptor analogues for type 2 diabetes therapy. Structural modifications of the well established glucagon analogue, desHis1Glu9-glucagon, was used to develop novel glucagon analogues. All peptide analogues were resistant to DPP-4 degradation and effectively antagonised glucagon-mediated cAMP production and insulin secretion when tested in vitro. desl-lis'Glu'-glucagon had a duration of biological action of 8 h and effectively antagonised glucagon-mediated glucose and insulin release in vivo. Mid-chain acylation of desl-lis'Glu/-glucagon did not hinder acute antagonistic properties and prolonged the duration of biological action to 24 h. An additional y-glutamyl Iinker in combination with acylation resulted in similar biological activity. C-terminal acylation also effectively antagonised acute glucagon-mediated glucose production in vivo. However, a C-terminal miniPEGylated version did not exhibit antagonistic properties. In general C-terminal modifications resulted in analogues with reduced acute biological activity indicating that mid-chain acylation was more effective. Pro4 substitution for Gly" without G1u9 replacement also resulted in reduced biological efficacy in relation to antagonising glucagon-mediated actions. However, Pro4 substitution did not hinder the activity of desl-lis'Glu'i-glucagon, emphasising the important role of Glu9 in biological activity. C-terminal acylation of this Pro4 analogue reduced its acute action in animals. However, chronic administration of non-acylated and mid-chain acylated forms of this Pr04 analogue improved metabolic status in high fat fed mice. Furthermore, chronic administration of the non-acylated Pro4 analogue exhibited similar beneficial effects as exendin-4 in high fat fed mice, but additive effects of combined administration were not evident. This thesis demonstrates that peptide-based glucagon antagonists exhibit prominent anti-diabetic effects in animal models of obesity-diabetes, and illustrates the necessity to further establish peptide-based glucagon receptor antagonists for type 2 diabetes therapy
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588499 |
| Date | January 2012 |
| Creators | Franklin, Zara Jane |
| Publisher | University of Ulster |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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