Characterisation, biological activity and therapeutic potential of xenin and modified forms in obesity-diabetes

Abstract

Novel therapeutic approaches are required to restore normoglycaemia in type 2 diabetes mellitus (T2DM). This thesis characterised and elucidated biological activity and therapeutic applicability of xenin and modified forms in obesity-diabetes. The plasma enzymatic degradation products of xenin-25 have now been characterised, namely xenin 9-25, xenin 11-25, xenin 14-25 and xenin 18-25. Xenin-25 and enzyme resistant synthetic xenin-25[Lys13PAL] enhanced insulin secretion and potentiated GIP-induced insulin release in vitro, improved anti-hyperglycaemic and insulin-releasing activity and reduced food intake in vivo. Moreover, xenin-25[Lys13PAL] demonstrated enhanced biological activity compared to native xenin-25. Twice daily administration of xenin-25[Lys13PAL] for 14 days significantly improved metabolic control in dietary-induced diabetes. Once daily administration of xenin-25[Lys13PAL], in combination with a novel acylated GIP agonist, (D-Ala2)GIP[Lys37PAL], for 21 days did not have any additive effects. Nonetheless, (D-Ala2)GIP[Lys37PAL] treated mice exhibited significant improvements in glycaemic control and insulin sensitivity. The biological role of xenin-25 degradation fragments was also assessed. As such, xenin 9-25, xenin 11-25 and xenin 14-25 had no insulinotropic, glucose-lowering or satiety effects. Nonetheless, xenin 18-25 demonstrated in vitro insulinotropic effects, and mild glucose-lowering effects in vivo. The novel xenin 18-25 analogue, xenin 18-25[Lys20PAL], demonstrated similar biological effects, but these were not enhanced compared to xenin 18-25. In addition, the amino acid substituted xenin analogues, namely xenin-25 Gln and xenin 18-25 Gln, induced in vitro insulin secretion, reduced glycaemic excursion and enhanced insulin secretion in vivo. Furthermore, xenin-25 Gln potentiated the insulinotropic action of GIP and acutely inhibited food intake. Sub-chronic administration of xenin-25 Gln or xenin 18-25 Gln improved glucose tolerance and metabolic response to GIP in high fat mice. Collectively, this thesis has demonstrated that xenin, and modified forms, possess beneficial independent biological actions in addition to GIP additive actions, and appear to have dual therapeutic properties that merit further investigation for T2DM therapy.

Thesis is embargoed until 30th September 2015

Date of Award	Sept 2013
Original language	English
Supervisor	Nigel Irwin (Supervisor), Victor Gault (Supervisor), Victor Gault (Supervisor) & Nigel Irwin (Supervisor)