Compensatory hyperinsulinaemia in type 2 diabetes: targeting mitochondrial cholesterol metabolism using microRNA

Ref: S2017SHLS005

Background
Diabetes affects 6% of the adult population of the UK, and consumes nearly 10% of the annual NHS budget, and the incidence of this disease is increasing dramatically: by 2025, more than 4.5 million people in the UK may be threatened by this global issue (http://www.diabetes.org.uk). Further, it is estimated that one in three adults in the UK are on the threshold of developing diabetes, a condition sometimes termed ‘prediabetes’. Failure of beta-cells in pancreatic islets to adapt to meet the increased requirement for insulin in these individuals is a primary determinant of whether an insulin-resistant individual will progress from prediabetes to full-blown type 2 diabetes mellitus (T2DM) and associated highly damaging complications.
Understanding the mechanisms by which beta cells compensate to increase insulin on demand is therefore critical in warding off T2DM for a significant proportion of the population. Our recent work suggests that the generation of nascent high-density lipoprotein (HSL), facilitated by increased mitochondrial generation of oxysterol cell signals, can sustain beta cell function and increase expression of the insulin gene (INS2), and thus may be a critical element in compensatory insulin output in prediabetic individuals.

Aims
The purpose of this study is to define the contribution of the cell signalling pathway mediated by mitochondrial generation of oxysterols, to the compensatory hyperinsulinaemia that may slow or prevent progression to T2DM in insulin-resistant individuals. This will be achieved by:
1) Investigating the oxysterol signalling pathway in human beta-cell lines, and insulin-secreting cells derived from adult human skin fibroblasts (diabetic and non-diabetic), via application to the GCU Skin Research Tissue Bank.
2) Exploring the molecular mechanisms(s) by which oxysterol signalling impacts on beta cell function, including modulation of microRNA sequences via this pathway.
3) Demonstrating the capacity of microRNA molecules, influencing cell oxysterol signalling capacity, as possible therapeutics to protect against prediabetes in models of this disease.

Specific requirements of the project:
The successful applicant will have a strong interest in exploring therapeutic strategies for the treatment of diabetes mellitus, and hold a minimum of a first degree (2:1) or above, ideally in Cell Biology, Biochemistry or Molecular Biology or combinations thereof. Experience in tissue culture, or molecular biology techniques, would be an advantage.