Impact of incretin polypeptides on pancreatic islet delta-cell signalling

Summary

Incretin polypeptides are gut-derived hormones released after food intake that potently enhance insulin secretion from pancreatic islet β-cells.

The incretin effect is the foundation for blockbuster GLP-1-and GIP-based therapies (e.g., semaglutide, tirzepatide) used globally to treat type 2 diabetes and obesity.

The scientific focus has overwhelmingly been on the direct action on islet β-cells or brain. In pancreatic islet, insulin-producing β-cells closely communicate with α-cells (producing glucagon) and δ-cells (somatostatin).

Somatostatin, released from δ-cells, is a powerful inhibitor of both insulin and glucagon secretion, making it a crucial regulator of islet hormone output.

Secondly, δ-cells likely play a key role in initialising the β-cell populational response to glucose, acting via electrical cell-cell coupling.

The hypothesis of this project is that incretins directly modulate δ-cell activity and somatostatin release.

This hypothesis will be tested using a multi-level experimental approach, including state-of-the-art in vitro models, including primary mouse and (subject to availability) human pancreatic islets.

Using specific genetically-encoded fluorescent indicators of such intracellular signals as calcium, ATP, fructose 1,6-bisphosphate and hormone secretion assays, we will microimage how GLP-1, GIP and various related polypeptides alter δ-cell signalling, metabolism and somatostatin release on the acute and chronic timescales.

A battery of pharmacological tools will be utilised to dissect the exact molecular signalling pathways mediating these effects.

We anticipate redefining the canonical view of incretin action by establishing δ-cells as a key target.

Expected outcomes include:

(i) the characterisation of incretin effects on δ-cell stimulus-secretion coupling,

(ii) the identification of the specific receptor and downstream mechanisms involved, and

(iii) understanding of how δ-cell-mediated paracrine signalling fine-tunes the islet response to incretins.

This work will provide an enhanced picture of islet biology, essential for developing next-generation therapeutics, which could lead to smarter, more effective combination therapies for diabetes with greater efficacy in restoring metabolic control.

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
• 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
• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Practice-based research experience and/or dissemination
• 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

NOTE - This is a self-funded research project and applicants will be required to provide evidence of funds to support their tuition fees and living expenses.

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.