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Funded PhD Opportunity

Regulation of glucose metabolism by incretin signalling

Subject: Biomedical Sciences


Summary

Incretins, such as GLP-1 and GIP, enhance secretion of insulin from pancreatic β-cells by elevating cytosolic levels of cAMP. This signal is believed to impact downstream targets of cAMP, PKA and EPAC2, that, in turn, enhance late stages of insulin vesicle exocytosis. We have shown that GLP-1 can impose its effect by an alternative pathway involving the activation of PKC (1). Importantly, the incretin signalling per se does not initiate the hormone secretion (2). It relies instead on glucose stimulus, which is reflected, in the β-cell, by the elevation of glycolytic and mitochondrial fluxes, and culminates in triggering the hormone secretion by increasing the cytosolic levels of Ca2+.

At the same time, the activation of PKA canonically counteracts glycolysis and favours glycogenolysis and gluconeogenesis; in fact, this is one of the mechanisms whereby glucagon counteracts hypoglycaemia in the liver (3). Thus, incretins impose seemingly opposite effects at different stages of glucose-induced insulin secretion. The key target for cAMP signal in the glycolytic pathway is a bi-functional enzyme known as phosphofructokinase-2 (glycolytic conformation, PFK-2), which is phosphorylated by PKA to fructose-bisphosphatase-2 (‘gluconeogenetic’ conformation, FBPase2).

Of note, the expression of FBPase-2 in pancreatic islets is dramatically upregulated in mice with a ‘metabolic’ form of type 2 diabetes (4), at the level of both protein and mRNA. This upregulation may also reflect an ‘antioxidative’ adaptation of the β-cell to the chronically elevated glycolytic flux, similarly to the antioxidative effect of another protein with a FBPase-2 activity, TIGAR (5).

We hypothesise that the effect of an incretin on insulin secretion depends on its ability to

(i) induce hormone exocytosis and (ii) preserve the β-cell from the oxidative damage, upon hyperglycaemia. We propose to address the latter, less researched, phenomenon.

In particular, we will study:

1. The acute (minutes) and chronic (days) effect of incretins on energy metabolism in mouse and human pancreatic islet cells. To that end we will image various stages of glucose metabolism (ATP, mitochondrial membrane potential, NAD(P)H as well as oxygen consumption) using a palette of fluorescent sensors. To increase the statistical power of the measurements, the imaging experiments will be performed on an automated microscopic system capable of recording the signal from 100s of islets of Langerhans, simultaneously. We will screen several key incretins and other insulin-releasing gut hormones (GLP-1, GIP, CCK, oxyntomodulin) aiming to detect potential differences between them as well as differentiating between β- and α-cells.

2. Genes underlying the acute and chronic stimulatory effect of incretins on insulin secretion. To that end, we will utilise the functional labelling technology (6), FACS-sort cell populations displaying variations in the secretory response and run RNAseq on them.

3. If pharmacological targeting of FBPase2 (7) (or downstream enzymes, such as FBPase1) can affect the acute and chronic secretory response to incretins.

4. Subject to progress, we will investigate the role of diet in the incretin effect (by pre-culturing the islets in different combinations of fuels) as well as the potential of targeting PKC (instead of PKA), which we have shown happens for GLP-1 (1)?

References

(1) Shigeto, M. et al. J Clin Invest 125, 4714-4728 (2015).
(2) Komatsu, M. et al. Proceedings of the National Academy of Sciences of the United States of America 92, 10728-10732 (1995).
(3) Frayn, K.N. (John Wiley & Sons, 2009).
(4) Haythorne, E. et al. Nature communications 10, 2474 (2019).
(5) Bensaad, K. et al. Cell 126, 107-120 (2006).
(6) Tarasov, A.I. et al. Lab on a Chip 18, 2838-2848 (2018).
(7) Liu, G.-M. et al. Cancer cell international 18, 36 (2018).


Essential criteria

  • To hold, or expect to achieve by 15 August, an Upper Second Class Honours (2:1) Degree or equivalent from a UK institution (or overseas award deemed to be equivalent via UK NARIC) in a related or cognate field.
  • Sound understanding of subject area as evidenced by a comprehensive research proposal

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
  • Work experience relevant to the proposed project
  • Publications - peer-reviewed
  • Publications record appropriate to career stage
  • Experience of presentation of research findings
  • A comprehensive and articulate personal statement
  • Use of personal initiative as evidenced by record of work above that normally expected at career stage.
  • Relevant professional qualification and/or a Degree in a Health or Health related area

Funding

    The University offers the following awards to support PhD study and applications are invited from UK, EU and overseas for the following levels of support:

    Vice Chancellors Research Studentship (VCRS)

    Full award (full-time PhD fees + DfE level of maintenance grant + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees and provide the recipient with £15,000 maintenance grant 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.

    Vice-Chancellor’s Research Bursary (VCRB)

    Part award (full-time PhD fees + 50% DfE level of maintenance grant + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees and provide the recipient with £7,500 maintenance grant 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.

    Vice-Chancellor’s Research Fees Bursary (VCRFB)

    Fees only award (PhD fees + RTSG for 3 years).

    This scholarship will cover full-time PhD tuition fees 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.

    Department for the Economy (DFE)

    The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £ 15,009 per annum for three years. EU applicants will only be eligible for the fee’s component of the studentship (no maintenance award is provided). For Non-EU nationals the candidate must be "settled" in the UK. 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.

    Due consideration should be given to financing your studies; for further information on cost of living etc. please refer to: www.ulster.ac.uk/doctoralcollege/postgraduate-research/fees-and-funding/financing-your-studies


Other information


The Doctoral College at Ulster University


Reviews

Profile picture of Kieran O'Donnell

My experience has been great and the people that I have worked with have been amazing

Kieran O'Donnell - 3D printing of biological cells for tissue engineering applications

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Profile picture of Michelle Clements Clements

Completing the MRes provided me with a lot of different skills, particularly in research methods and lab skills.

Michelle Clements Clements - MRes - Life and Health Sciences

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Profile picture of William Crowe

Throughout my PhD I’ve been provided with continuous support and guidance by my supervisors and the staff at the University.I’ve also received many opportunities to further enhance my professional development in the form of teaching experience and presenting my work at conferences which will aid in my pursuit of a career in academia or industry.

William Crowe


Key dates

Submission deadline
Friday 7 February 2020

Interview Date
9 to 20 March 2020


Applying

Apply Online  


Campus

Coleraine campus

Coleraine campus
The feeling of community at our Coleraine campus makes for a warm and welcoming student experience.


Contact supervisor

Professor Peter Flatt


Other supervisors

  • Dr Andrei Tarasov - Chair/First Supervisor Prof Patrik Rorsman - Joint Supervisor

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