iCASE: Regulation of insulin biosynthesis

Background and Aims: Insulin, secreted from pancreatic beta-cells, plays an essential role in the regulation of blood glucose homeostasis, and diabetes results when circulating insulin levels fall below that required to sustain normoglycaemia. Too much insulin, by contrast, leads to life-threatening hypoglycaemia. As a consequence, insulin production is tightly regulated.

Recent studies have revealed the existence of pacemaker beta-cells (hub cells), that respond more rapidly to glucose and drive oscillations in insulin secretion [1]. Surprisingly, these cells produce less insulin than the follower cells they entrain. Why hub cells produce less insulin and whether this is a cause or a consequence of their enhanced ability to respond to glucose (or their increased sensitivity to apoptosis), is unknown. It is speculated that reducing insulin production may increase ATP levels and thereby enhance insulin secretion, but this yet to be established. How beta-cell stress, such as oxidative stress or exposure to chronically elevated lipids or glucose, impairs insulin biosynthesis is also unresolved. Glucolipotoxicity also induces a state of dedifferentiation [2,3], but whether dedifferentiation reduces insulin production (or vice versa), or if these events are simply correlated, is unclear.

Thus, this project has three aims. First, to determine why hub cells produce less insulin, and whether less insulin production leads to a reduction in beta-cell ATP levels (or vice versa). Second, to determine the molecular mechanisms underlying reduced insulin biosynthesis caused by glucolipotoxicity, and its relationship to beta-cell dedifferentiation, and to proliferation. Third, to determine the extent to which impaired insulin production can be corrected by peptide hormones such as GLP-1. This will include systematically screening a library of all endogenous protein ligands and a library of previously unstudied peptides provided by Novo Nordisk, using high-throughput screening infrastructure at Novo Nordisk.

The results will provide insight into a key biological question – how is insulin production regulated, and will have important implications for studies aimed at generating insulin-secreting cells from stem cells, and for preserving donor beta-cells for transplant. Long-term benefits will include improvements in the design and development of peptides/drugs targeted at enhancing insulin secretion in diabetes.

Skills training: The student will receive training in a wide range of interdisciplinary skills, including single cell transcriptome analysis, bioinformatics, electrophysiology, molecular and cell biology, high throughput screening, data analysis and statistics. They will be expected to obtain a Home Office Licence. Training will be provided in other relevant transferable skills such as writing research papers, planning/writing a thesis and presentation skills. Opportunities to train and mentor undergraduate and vacation student projects will be provided. Numerous specialist skills training courses are also available to the student at Oxford University.

References
[1] Cell Metab 24, 389–401 (2016).
[2] Nature Commun 5, 4639 (2014)
[3] Islets 5, 233-237 (2013).