Utility of combined GLP-1 and neurotensin receptor signalling, and/or related hybrid peptides, for type 2 diabetes therapy


​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:

  • Fully establish GLP-1 and NT interactions at the level of the pancreatic beta-cell, including aspects of insulin secretion and related mechanisms, as well as effects on beta-cell growth and survival
  • Determine benefits of combined GLP-1 and NT administration in normal and diabetic rodents Synthesis and characterise a range of novel GLP-1/NT hybrid peptides
  • Assess the in vitro enzymatic stability as well as in vitro and in vivo biological actions of novel peptides as outlined above
  • Determine duration of in vivo biological action of hybrid peptides through assessment of pharmacodynamic and/or pharmacokinetic profiles
  • Assess the beneficial effects of novel GLP-1/NT hybrid peptides alone, and in combination with established anti-diabetic drugs, in different aetiologies of type 2 diabetes.

Applicants should note that Laboratory bench fees of £6,000.00 per annum are required for this self-funded PhD project.

Essential criteria

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.

  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • Clearly defined research proposal detailing background, research questions, aims and methodology

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

  • Completion of Masters at a level equivalent to commendation or distinction at Ulster
  • Experience using research methods or other approaches relevant to the subject domain
  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • Work experience relevant to the proposed project
  • Experience of presentation of research findings
  • A comprehensive and articulate personal statement
  • Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

Recommended reading

​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.

The Doctoral College at Ulster University

Key dates

Submission deadline
Monday 28 February 2022

Interview Date
April 2022

Preferred student start date
mid September 2022


Apply Online  

Contact supervisor

Professor Nigel Irwin

Other supervisors

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