PhD Study : Regulation of glucose metabolism by incretin signalling

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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

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

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 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

The Doctoral College at Ulster University

Key dates

Submission deadline
Friday 7 February 2020
12:00AM

Interview Date
9 to 20 March 2020

Preferred student start date
Mid September 2020

Applying

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Contact supervisor

Professor Peter Flatt

Other supervisors

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