Funded PhD Opportunity Crosstalk between muscle and pancreas: Role of irisin in pancreatic beta-cell function and blood glucose control

This opportunity is now closed.

Subject: Biomedical Sciences

Summary

Insulin is a major regulator of whole-body-metabolism, where crosstalk between pancreatic beta-cells and other insulin-responsive tissues plays a vial role in maintenance of glucose homeostasis and health. Type 2 diabetes mellitus (T2DM) is characterized by dysfunctional insulin-secretion coupled with reduced insulin-sensitivity, each of which have far-reaching consequences. While the breakdown in crosstalk between islets of Langerhans and insulin-responsive tissues is recognized, the involvement of other tissues in metabolic crosstalk is far-from-understood. Several mediators of crosstalk have been proposed including ghrelin (arising from stomach/pancreas), leptin (arising from fat), and osteocalcin (arising from bone), each playing a role in energy homeostasis.

The muscle-derived peptide, irisin, has recently been proposed to bridge exercise with metabolic homeostasis [Bostrom et al Nature 481: 463-468; 2012], representing a new exciting biomolecule that could play a major role in crosstalk between muscle and pancreas [see Chen et al Diabetes Metab Rev 32: 51-59; 2016]. Insulin-sensitive skeletal muscle is a major site for glucose utilization, glucose disposal/storage, and so represents an important therapeutic target in T2DM. Preliminary data suggesting that administration of irisin in vivo can influence insulin sensitivity, insulin secretion and glucose homeostasis [also see Duan et al Int J Biol Macromol 84: 457-463; 2016; Xin et al Int J Obes 40: 443-451; 2016], clearly prompts further in-depth studies to unravel the mechanisms underlying these promising effects.

The overarching aim of this proposal is to examine the effects of the myokine irisin on pancreatic-beta cell mass, viability, and function both in vitro and in vivo (coupled with measures of other metabolic factors/endpoints in both lean and obese diabetic rodents) using a range of methods established in our laboratory. In vitro investigations will examine actions of irisin in isolated rodent islets and established rodent and human beta-cell lines (INS-1, BRIN-BD11, and 1.1B4).

These studies will examine a range of actions including effects of irisin on insulin secretion alone and in the presence of  known physiological and pharmacological secretagogues, Other in vitro studies will determine the impact of exposure to irisin, in culture, on important beta-cell parameters such as proliferation/mass/function and protection/viability. In order to examine effects of irisin in vivo it will first be necessary to determine its stability and degradation profile in plasma, this will inform dosing regimens and assist the design of stable/long-acting forms of irisin that can effectively target beta-cells. The duration and comparative actions of native irisin and stable analogues will then be examined on a range of in vivo parameters, including circulating insulin and glucose, as well as pancreatic islet size/cellular composition and beta-cell mass in both lean and obese diabetic rodents. Importantly, the effects of irisin in the absence or presence of established antidiabetic drugs will be examined, both in vitro and in vivo, giving further insights into its potential utility in a therapeutic context for T2DM. This project, conducted within Ulster’s Diabetes Research Group, will provide excellent training in a broad range of techniques and result in high impact publications.

Essential Criteria

  • Upper Second Class Honours (2:1) Degree from a UK institution (or overseas award deemed equivalent via UK NARIC)
  • 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
  • Research project completion within taught Masters degree or MRES
  • Experience using research methods or other approaches relevant to the subject domain
  • Work experience relevant to the proposed project
  • Publications - peer-reviewed
  • Experience of presentation of research findings

Funding

    Vice Chancellors Research Scholarships (VCRS)

    The scholarships will cover tuition fees and a maintenance award of £14,777 per annum for three years (subject to satisfactory academic performance). Applications are invited from UK, European Union and overseas students.

Other information

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Key Dates

Submission Deadline
Monday 19 February 2018
Interview Date
6, 7 and 8 March 2018

Contact Supervisor

Professor Neville McClenaghan

Other Supervisors

Apply online

Visit https://www.ulster.ac.uk/applyonline and quote reference number #238222 when applying for this PhD opportunity