PhD Study : ​Mechanisms of islet adaptation in pregnancy – impact of estrogen and prolactin on pancreatic β-cell energy metabolism

Summary

Type 2 diabetes is associated with dysfunction of pancreatic islet insulin-secreting β-cells, a defect that many antidiabetic drugs aim to rectify. Linked to the excessive demand for insulin secretion under chronic ‘sedentary lifestyle’ factors, such as obesity and age, type 2 diabetes irreversibly impairs β-cell energy metabolism, rendering these cells glucose-insensitive1. The true mechanisms of the β-cell injury are difficult to study, as it manifests itself at the detectable level at a late stage of the disease. At the same time, a similar demand for excessive insulin production occurs and is successfully adapted to, under pregnancy. Well-reproducible in rodent models, this observation is also valid in humans where the inability of some mothers-to-be to increase insulin output during pregnancy triggers gestational diabetes.

Despite the therapeutic potential of pathways involved in the adaptation of β-cell metabolism to augment insulin secretion in pregnancy, little is known about the molecular mechanisms linking the elevated body weight and levels of circulating estrogen and oxytocin to glycolytic and oxidative metabolism2 as well as the timecourse of this regulation. We hypothesise that pregnancy or pregnancy-associated signals reversibly sensibilise β-cell energy metabolism to the metabolic stimulus (glucose) thereby (i) providing a more efficient coupling between glucose stimulus and insulin secretion at the cost of (ii) potential oxidative damage.

We propose to dissect these details by combining in vivo studies and advanced cellular techniques to probe islet function in animal models during pregnancy/lactation with ex vivo models of the two conditions.  The in vivo (pregnancy/lactating animals, on/off high-calorie diet) and ex vivo (isolated pancreatic islets cultured with estrogen/oxytocin or co-cultured with pre-adipocytes) models will be assayed for: Cellular energy metabolism: glucose-induced generation of fructose 1,6-bisphosphate, ATP, NAD(P)H and oxidative damage (O2, superoxide) by real-time fluorescence microscopic imaging of recombinant or trappable sensors for these analytes. Cell signalling: responses to physiological agonists (glucose, GLP-13, GIP4, somatostatin5, adrenaline6) at the level of signalling pathways (Ca2+ and cAMP). Secretory function and paracrine interactions of isolated islets in response to nutrients, hormones, neurotransmitters (as above).

Food intake, body weight, circulating insulin and glucose levels in blood of the experimental animals. Subject to progress, we will make perform in vivo microscopic observations of the dynamics of glycolytic flux during pregnancy/lactation by allotransplantation of the islets into the anterior chamber of the eye of the mice. We expect these studies to provide detailed information on the physiological reversible adaptation of islet energy metabolism to pregnancy/lactation together with elucidation of the underlying molecular mechanisms involved and respective time course.

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