There is an acute medical need for additional drug therapies which offer improved efficacy and better glycaemic control for patients with Type 2 diabetes. Here the antidiabetic potential of several novel pro glucagon-derived peptide analogues were assessed in preclinical studies. Structural modifications, which include variations of glucagon and oxyntomodulin (Oxm), were used to develop novel peptide receptor agonists. Glucagon-based analogues assessed included native glucagon, (N-Acetyl)glucagon, (D-Ser2)glucagon, glucagon-Lys30-y-glutamyl-PAL and (D-Ser2)glucagon-end exendin. Overall, the glucagon agonist with the most potential was (D-Ser2)glucagon as it was stable to DPP-4, significantly increased insulin release in vitro , produced significant beneficial changes in blood glucose and insulin concentrations in vivo in mice and inhibited acute food intake over 3 h. Modified oxyntomodulin analogues tested included (Thr2)Oxm, (Asp3)Oxm, (Aib2)Oxm, (DSer2) Oxm, (N-Acetyl)Oxm and (D-Ser2)Oxm-Lys-y-glutamyl-PAL. (Aib2)Oxm showed most benefit and was resistant to DPP-4, significantly increased insulin release in vitro, reduced blood glucose and food intake, whilst increasing insulin concentrations in vivo. Moreover, an acylated analogue (D-Ser2)Oxm-Lys-y-glutamyl-PAL displayed longerlasting biological efficacy by reducing acute blood glucose concentrations in a glucose tolerance test, 4 h after administration. Dogfish glucagon and related analogues were also assessed, including (Tyr')(D-Ala2)dogfish glucagon, (Tyr')(D-Ala2)(Glu3)human glucagon, (D-Ala2)dogfish glucagon, (D-Ala2)dogfish glucagon-Lys '2 -y-glutamyl-PAL, (D-Ala2)dogfish glucagon-Lys20-y-glutamyl-PAL and (D-Ala2)dogfish glucagon-Lys30- y-glutamyl-PAL. (D-Ala2)dogfish glucagon had the best stability profile in mouse plasma and the greatest insulinotropic activity both in vitro and in vivo, whilst reducing blood glucose and food intake in mice. The duration of biological action was enhanced with the acylated analogues, with the most promising analogue being (D-Ala2)dogfish glucagon-Lys30 -y-glutamyl-PAL. Furthermore, chronic administration of dogfish glucagon based analogues were as effective as exendin-4 over a 28 day treatment period. This thesis demonstrates that novel pro glucagon derived peptide analogues display prominent antidiabetic effects both in vitro and in vivo, and should be investigated further for Type 2 diabetic therapies
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:674964 |
| Date | January 2013 |
| Creators | Lynch, Aisling Martina |
| Publisher | Ulster University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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