Glucagon-like peptide-1 (GLP-1) is an incertin hormone secreted postprandially from intestinal L-cells with established actions to increase glucose-dependent insulin secretion and reduce appetite [Irwin & Flatt 2015]. Similarly, neurotensin (NT), is a 13 amino acid neuropeptide secreted by pancreatic nerves and enteroendocrine cells in response to a meal, with established effects on energy balance [Khan et al. 2017]. Both peptide hormones have also been shown to possess proliferative actions on pancreatic beta-cells and augment beta-cell function [Irwin & Flatt 2015; Khan et al. 2017]. Thus, there is clear potential for additive or synergistic benefits of these two hormones in obesity-diabetes.
In full agreement with this, neurotensin has recently been revealed to synergise with the clinically approved GLP-1 analogue, liraglutide, to help reverse obesity in high fat fed mice [Ratner et al. 2019]. In a related theme, our laboratory has also recently shown clear antidiabetic synergy between other similar gut derived peptide hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and xenin [Martin et al. 2012].
These observations later lead to the development of a single GIP/xenin hybrid peptide capable of simultaneously activating both receptor pathways [Hasib et al. 2017]. Indeed, this novel GIP/xenin hybrid displayed prominent antidiabetic therapeutic potential in rodent models of diabetes [Hasib et al. 2017]. Notably, GIP is the sister incretin of GLP-1, while xenin-25 and neurotensin share considerable homology. Thus, the established GIP/xenin axis [Craig et al. 2018] may be broadly similar to the postulated GLP-1/neurotensin interaction that will be investigated within the current research project. Moreover, given that GLP-1-based treatments are already clinically approved, unlike GIP, the potential therapeutic impact of GLP-1/NT peptides is more credible.
As such, this PhD project will build on initial exciting findings with GLP-1 and neurotensin peptides, akin to previous published work on GIP and xenin from our laboratory, with the possibility of progressing to generation of a GLP-1/NT hybrid peptide that would have considerable therapeutic promise for type 2 diabetes.
Therefore, the core objectives of this PhD research project are:
Applicants should note that Laboratory bench fees of £6,000.00 per annum are required for this self-funded PhD project.
Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.
We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.
In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.
If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.
Perry RA, Craig SL, Gault VA, Flatt PR, Irwin N. A novel neurotensin/xenin fusion peptide enhances beta-cell function and exhibits antidiabetic efficacy in high-fat fed mice. Biosci Rep. 2021 Aug 27;41(8):BSR20211275.
Craig SL, Gault VA, Shiels CE, Hamscher G, Irwin N. Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control. Biochim Biophys Acta Gen Subj. 2021 Aug;1865(8):129917.
Craig SL, Gault VA, Flatt PR, Irwin N. The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin. Biochem Pharmacol. 2021 Jan;183:114355.
Hasib A, Ng MT, Gault VA, Khan D, Parthsarathy V, Flatt PR, Irwin N. An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice.Diabetologia. 2017 60(3):541-552.
Khan D, Vasu S, Moffett RC, Gault VA, Flatt PR, Irwin N. Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival. Biol Chem. 2017 399(1):79-92.
Monday 28 February 2022
Preferred student start date
mid September 2022
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