Investigating the relationships between fatty acid metabolism and the control of viability in human β-cells

The University of Exeter Medical School is seeking to attract PhD candidates of outstanding ability to join their exciting and rapidly expanding programme of internationally rated research.

This PhD project will assess the relationship between the metabolism of free fatty acids and the regulation of human beta-cell viability, with the aim to identify new therapeutic strategies for the treatment of diabetes.

The successful applicant will be part of the Islet Biology group at the University of Exeter medical school and will be based in state of the art laboratories (opened January 2014) within the Research, Innovation, Learning & Development Building which is jointly operated by University of Exeter and the Royal Devon & Exeter Hospital. The start date for this studentship is the 1st October 2015.

Diabetes is a growing healthcare issue. It is estimated that 347 million people worldwide have diabetes and that by 2030 diabetes will be the 7th leading cause of death. Diabetes is a chronic disease, characterised by increased blood glucose levels due to insufficient insulin secretion. Type 2 diabetes is characterised by insulin resistance, but there is also evidence for a decline in the number of insulin secreting β-cells, causing a deficiency in insulin secretion.

Understanding the mechanisms that cause β-cell dysfunction in type 2 diabetes is an important goal to promote advances in treatment. Obesity is strongly associated with type 2 diabetes and this probably reflects a rise in circulating FFAs which leads to β-cell toxicity. Among the long chain saturated fatty acids, palmitate circulates at the highest concentration in humans and this species is toxic to both human and rodent β-cells in vitro. However, recent epidemiological association studies have suggested that circulating odd chain length FFAs (C15:0 and C17:0) are associated with a decreased risk of type 2 diabetes, suggesting that these may have a positive effect on human beta-cell survival. This, however, remains to be tested directly. Strikingly, mono-unsaturated fatty acids, such as oleate (C18:1) and palmitoleate (C16:1) are well-tolerated by β-cells and can attenuate palmitate-induced toxicity. Thus, fatty acids exert very different effects depending on their chain length and configuration.

Fatty acids are important fuels for β-cells, but the extent to which saturates and unsaturates fulfil this role has previously been difficult to estimate. In this project we propose to employ a new state-of-the-art extracellular flux analyser (XFe96, Seahorse biosciences) to measure the oxidation of fatty acids in real time in the newly available clonal human β-cell line, EndoC-βH1. Our aim is to establish whether saturated and unsaturated molecules are handled differentially and to understand whether the presence of one species influences the metabolic fate of the other. Ultimately, we expect that the insights gained will provide a means to devise a strategy to reduce the toxicity of saturated FFAs in β-cells by therapeutic intervention.

The project will provide an excellent training vehicle for a PhD student, providing the opportunity to gain experience in whole cell metabolism, tissue culture, molecular biology and biochemistry in the context of diabetes.

Contact name for scientific enquiries: Dr Hannah Welters, [Email Address Removed], 01392 408258

For any other enquiries please contact: [Email Address Removed]