Utilising the therapeutic potential of xenin and related molecules for diabetes and obesity

Abstract

The diminished incretin effect is a pathological characteristic of type 2 diabetes mellitus (T2DM), caused by reduced secretion of glucagon-like-peptide-1 (GLP-1) and blunted biological actions of glucose-dependent insulinotropic polypeptide (GIP). Presently, clinically approved GLP-1 analogues, targeting the GLP-1 arm of the incretin axis, help to overcome the diminished GLP-1 secretion. However, currently there is no clinically approved therapeutic agent to potentiate the biological actions of GIP. Furthermore, established pharmacological agents currently fail to replicate the benefits of bariatric surgery, which along with increasing prevalence increases both health and socio-economic burdens. Likewise, due to the multifactorial characteristics, current monotherapies fail to elicit persistent effective management. Therefore, novel, more-effective treatment paradigms are required to address these unmet needs. The gut hormone xenin has been reported to potentiate biological actions of GIP, with truncated analogues of xenin displaying more potent antidiabetic effects. This thesis characterised the GIP-potentiating effects of xenin-based therapies, along with their therapeutic applicability for diabetes and/or obesity. This included xenin-8-Gln, as part of a hybrid agent- (DAla2)GIP/xenin-8-Gln, multiple novel xenin hexapeptides, as well as TNP-470, an angiogenesis inhibitor shown to increase xenin concentrations. Importantly, in all therapies assessed, there was clear augmentation of GIP action, resulting in enhanced metabolic effects. (DAla2)GIP/xenin-8-Gln administered in combination with exendin-4 demonstrated metabolic benefits that were persistent in nature, which is highly favourable in such a progressive disease. Further characterisation of truncated xenin peptides showed that ψ-xenin-6 was the most potent truncated hexapeptide assessed, with GIP-potentiating and satiety effects shown, along with biological effects evident up to 8 hours. Furthermore, repeated administration of ψ-xenin-6 in combination with sitagliptin further augmented the efficacy of sitagliptin, with effects more prominent and rapid with combined modulation. Additionally, beneficial efficacy of sitagliptin was augmented through combined administration with TNP-470, displaying improvements in glucose tolerance, insulin sensitivity and significant anti-obesity effects. Together, these findings provide reinforcing evidence for development of novel xenin-based therapies, which act to potentiate biological actions of GIP, and the need for combinational therapeutic approaches to target multiple pathways to help alleviate hyperglycaemia in T2DM, with potential for translation to the clinic.

Date of Award	May 2020
Original language	English
Sponsors	Department of Employment and Learning, Northern Ireland
Supervisor	Nigel Irwin (Supervisor) & Victor Gault (Supervisor)