Targeted incretin related peptide multi-agonist drugs for their improved potential in diabetes management

Summary

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by disrupted glucose homeostasis, resulting from progressive pancreatic β‑cell dysfunction and declining tissue insulin sensitivity (Galicia‑Garcia et al., 2020). Obesity is a major contributing factor, as chronic nutrient excess induces metabolic stress in peripheral tissues, driving insulin resistance (Allocca et al., 2025). Although β‑cells initially compensate through increased insulin secretion, prolonged demand leads to β‑cell exhaustion, impaired insulin release, persistent hyperglycaemia and broader metabolic disturbances.

Over the past two decades, incretin‑based therapeutics that mimic endogenous glucose‑dependent insulin secretagogues have transformed T2DM management. These include GLP‑1 receptor agonists (GLP-1RA’s) such as exenatide and liraglutide and, to a lesser extent GIP-RA’s. Incretin therapies improve glycaemic control by enhancing insulin secretion and reducing appetite resulting in weight loss (Zhou et al., 2023; Yao et al., 2024). More recently, dual agonists such as tirzepatide have generated considerable interest for treating both diabetes and obesity (Nauck et al., 2026). Despite their success, current treatments suffer from patient non-compliance, or they fail to fully correct for insulin resistance, or residual cardiometabolic risk.

Research at Ulster University and elsewhere has highlighted the therapeutic potential of APJ receptor agonists, which improve insulin sensitivity, glucose utilisation and confer cardiometabolic protection (Parthsarathy et al., 2017). Chronic administration of stable apelin analogues in mice has demonstrated improvements in glycaemia, HbA_1c, lipid profiles and pancreatic insulin content (O’Harte et al., 2020). Emerging evidence shows that GLP‑1R/APJR co‑agonists produce greater reductions in body weight and improved glycaemic control in preclinical models versus monotherapies (O’Harte et al., 2023). Similarly, GIPR/APJR co‑agonists provide β‑cell protection and metabolic benefits, suggesting synergistic potential. This project will investigate a multi‑agonist strategy by testing combinations of peptide analogues for synergistic antidiabetic actions and determining plasma stability, offering novel insights into metabolic regulation and improved management of chronic metabolic disease.

Objectives of the research:

Research Hypothesis – Multi-agonist activation of receptors will lead to improved antidiabetic potential of peptide therapeutics.

The key aims of this proposed project are:

1. To determine the efficacy of peptide combinations including multi-agonists on receptor mediated insulinotropic responses in cultured pancreatic BRIN-BD11 cells.
2. To determine the stability and degradation pattern of peptide analogues in mouse plasma using HPLC and MS approaches.

Methods to be used:

Peptides (≥95% purity) will be synthesised by a commercial supplier and further characterized by reversed phase HPLC. Molecular weight and structural integrity will be confirmed by matrix-assisted laser desorption ionisation time-of-flight (MALDI-ToF) mass spectrometry.

The clonal β-cell line BRIN-BD11 will be cultured in RPMI-1640 medium supplemented with foetal bovine serum and antibiotics at 37°C with 5% CO₂ (Ali et al., 2024). Insulin secretory responses will be assessed using static incubations in Krebs–Ringer bicarbonate buffer supplemented with 0.1% (w/v) BSA. Cells will be exposed to test peptides alone and in combination in the presence of low and high glucose (in presence/absence of specific receptor antagonists) with supernatants collected and stored at −20°C prior to insulin quantification by radioimmunoassay (Ali et al., 2024).

Peptide stability will be assessed following incubation (0-24 h) of peptides in mouse plasma and separation by RP-HPLC with intact and degraded peptides identified by MALDI-ToF MS.

Skills required of applicant:

The student will need to be highly motivated to undertake research and be prepared to work in an active laboratory setting. Training in tissue culture, insulin RIA, peptide analysis by RP-HPLC and MALDI-ToF MS will be provided. Data will be analysed using GraphPad Prism 8.0 software.

AccessNI clearance required

Please note, the successful candidate will be required to obtain AccessNI clearance prior to registration due to the nature of the 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.

• Experience using research methods or other approaches relevant to the subject domain
• Sound understanding of subject area as evidenced by a comprehensive research proposal
• A comprehensive and articulate personal statement

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.

• First Class Honours (1st) Degree
• Experience using research methods or other approaches relevant to the subject domain
• Work experience relevant to the proposed project
• Publications record appropriate to career stage
• Experience of presentation of research findings

Equal Opportunities

The University is an equal opportunities employer and welcomes applicants from all sections of the community, particularly from those with disabilities.

Appointment will be made on merit.

Funding and eligibility

This opportunity is open to all applicants.

The tuition fee for international and EU (excluding ROI) candidates is £19,040 for 2026/27.

Studentship funding is available to UK and ROI applicants, as follows:

• MRes studentships will be available to top ranked candidates to cover tuition fees and a Research Training Support Grant of £900.
• All applicants to the project will be considered automatically for an MRes studentship.
• Applicants who do not receive a studentship but meet admission requirements may be offered admission on a self-funded basis.
• Applicants who already hold an MRes or a doctoral degree or who have been registered on a programme of research leading to the award of an MRes or doctoral degree are NOT eligible to apply for funding.
• Applicants who hold or who are registered on a taught Master’s degree are eligible to apply.