The generation and evaluation of novel gut derived peptides for the treatment of Type 2 diabetes and obesity

Abstract

Type 2 diabetes mellitus (T2DM) is a leading non-communicable disease with increasing health, socio-economic implications and with pharmacological agents that fail to replicate the success of bariatric surgery. This thesis aims to evaluate the therapeutic potential of customised gastrointestinal (GIT)-derived peptide hormones, namely glucose-dependent insulinotropic polypeptide (GIP), xenin and neurotensin (NT) in the hope of advancing the therapeutic repertoire. GIP has important glucoselowering endocrine and exocrine actions that become impaired in T2DM. Xenin is cosecreted with GIP and known to potentiate its biological actions. Thus, the biological and therapeutic potential of twice daily administration of a previously characterised GIP/xenin hybrid, (DAla2 )GIP/xenin-8-Gln, both alone and in combination with exendin-4 was assessed in high fat fed and db/db mouse models of T2DM. In HFF mice, treatment with (DAla2 )GIP-xenin-8-Gln in combination with exendin-4 was the most effective therapeutic strategy, although (DAla2 )GIP-xenin-8-Gln alone induced notable benefits in this model. Interestingly, in the db/db model, (DAla2 )GIP-xenin-8- Gln alone was much less efficacious than combined treatment with exendin-4, most likely linked to the disease severity and notable beta cell dysfunction. Further to this, NT has several antidiabetic actions and is known to facilitate fatty acid absorption. Xenin is structurally related to NT, with similar biological actions, thought to be partially mediated through NT receptors. Preliminary in vitro studies revealed that the novel acetyl-neurotensin(8-13)-xenin-8-Gln hybrid had antidiabetic attributes that warranted further in vivo assessment. Twice daily administration of acetylneurotensin(8-13)-xenin-8-Gln in combination with exendin-4 to HFF mice had positive glucose-lowering and insulinotropic effects with beneficial actions on lipid metabolism. Interestingly, GIP action has been linked to the exacerbation of obesity and T2DM, increasing insulin resistance and fat deposition. Thus, postulation that inhibiting GIP action could potentially halt the progression of obesity-related diabetes. However, to date there is no definitively characterised peptide-based GIP antagonist. Manipulation of the amino acid sequence, with N- and C- termini truncation, yielded Pro3 (3-30)GIP as a notable GIP receptor antagonistic that merits further testing. Overall, these data show that modified GIT peptides possess notable therapeutic efficacy with potential for translation to human T2DM and obesity.

Date of Award	Feb 2019
Original language	English
Sponsors	Department for Employment and Learning
Supervisor	Nigel Irwin (Supervisor) & Victor Gault (Supervisor)