PhD Study : Hybrid GIP/Apelin analogues for diabetes and obesity therapy

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Summary

Diabetes mellitus affects 537 million people globally and is set to rise to 784 million by 2045 (IDF 2021). Treating diabetes (mainly disease complications) accounts for around 10% of the NHS budget (£9.8 billion). In obesity associated Type 2 diabetes, abnormal insulin secretion and poor insulin action lead to hyperglycaemia. Poor glycaemic control often results in disease complications. Therefore, drugs that can induce weight loss, as well as improve blood glucose control are much sought after. Many monotherapy drug strategies fail over time, requiring additional second/third line agents to achieve better glycaemic control. Since 2005, GLP-1 mimetics (Exenatide, Liraglutide, Dulaglutide & Semaglutide) have demonstrated improved Type 2 diabetes control when added to first line therapies such as metformin. More recently, the additional benefits of GLP-1 dual agonists (co-agonists) have been demonstrated in clinical trials with Tirzepatide (Eli Lilly, USA) (Frias et al. 2018). The present study will involve the evaluation of novel co-agonist GIP/apelin peptide analogues, which activate both the GIP and APJ receptors simultaneously, promoting synergistic beneficial metabolic effects. Apelin may also be combined with other peptides such as (Pro3)GIP.

The current research proposal aims to harness the biological action of stable co-agonist peptides incorporating both GIP and apelin-13, acting as receptor agonists at GIP and APJ receptors, respectively. We have shown that apelin-13 analogues can specifically target the pancreatic beta-cell and stimulate insulin secretion and lower hyperglycaemia when administered to diet induced obese diabetic mice and diabetic db/db mice (O’Harte et al. 2018a; 2018b). More recently, hybrid peptides which contain incretin analogues linked together with apelin-13 in one single chain peptide (unimolecular), can operate in synergy as co-agonists of incretin and APJ receptors (unpublished data).  These hybrid peptides have added stability in mouse plasma, can potently stimulate insulin secretion and can effectively reduce food intake in mice, when compared to either component peptide alone.

The present study will examine the potential of unimolecular GIP linked to apelin-13 analogues, as well as long acting acylated analogues. Thus the actions of GIP/apelin hybrid peptides on insulin secretion in cultured BRIN-BD11 cells and isolated mouse islets will be assessed in the presence and absence of specific receptor antagonists. Actions on cAMP production and intracellular Ca2+ fluxes will be examined in cultured BRIN-BD11 cells. We will assess novel acylated analogues of the lead co-agonist peptide, as these are likely to have an enhanced pharmacological profile resulting from a prolonged half-life profile avoiding kidney filtration. Hybrid peptides will be tested in vivo for insulin secretion and acute glucose lowering ability, as well as inhibition of food intake in mice. Later chronic administration studies will further validate the use of these novel acylated co-agonists by direct head-to-head comparison with a clinically proven stable acylated incretin hormone mimetic (Liraglutide). Preclinical studies will be performed in high fat fed DIO mice and genetically susceptible (db/db) diabetic mice, representing relevant models of human Type 2 obesity-related diabetes. Pancreatic tissue morphology will be examined using immunohistochemistry approaches.

Please note: Applications for more than one PhD studentships are welcome, however if you apply for more than one PhD project within Biomedical Sciences, your first application on the system will be deemed your first-choice preference and further applications will be ordered based on the sequential time of submission. If you are successfully shortlisted, you will be interviewed only on your first-choice application and ranked accordingly. Those ranked highest will be offered a PhD studentship. In the situation where you are ranked highly and your first-choice project is already allocated to someone who was ranked higher than you, you may be offered your 2nd or 3rd choice project depending on the availability of this 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
  • Publications record appropriate to career stage
  • 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

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

  • Full Award: (full-time tuition fees + £19,000 (tbc))
  • Part Award: (full-time tuition fees + £9,500)
  • Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

  • Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
  • Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
  • Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
  • Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living

Recommended reading

​Frias JP (2018) Safety of Once-weekly Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes. J Fam Pract. 67(6 suppl):S25-S34. IDF 2021 Atlas https://diabetesatlas.org/

Hasib A, Ng MT, Tanday N, Craig SL, Gault VA, Flatt PR, Irwin N. (2019) Exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice. Diabetes Metab Res Rev. 35(3):e310.

O'Harte FPM, Parthsarathy V, Flatt PR. (2020) Chronic apelin analogue administration is more effective than established incretin therapies for alleviating metabolic dysfunction in diabetic db/db mice. Mol Cell Endocrinol. 504:110695.

O'Harte FPM, Parthsarathy V, Hogg C, Flatt PR. (2018a) Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice. PLoS One. 13(8):e0202350.

O'Harte FPM, Parthsarathy V, Hogg C, Flatt PR. (2018b) Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions. Peptides. 100:219-228.

Tanday N, Irwin N, Moffett RC, Flatt PR, O'Harte FPM. (2020) Beneficial actions of a long-acting apelin analogue in diabetes are related to positive effects on islet cell turnover and transdifferentiation. Diabetes Obes Metab. 22(12):2468-2478.

The Doctoral College at Ulster University

Key dates

Submission deadline
Monday 28 February 2022
12:00AM

Interview Date
April 2022

Preferred student start date
mid September 2022

Applying

Apply Online  

Contact supervisor

Professor Finbarr O'Harte

Other supervisors