Dr R Ramracheya, Prof P Rorsman
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
Diabetes mellitus is the non-communicable disease epidemic of the 21st century and it has been predicted that in the UK alone there will be over 4 million people living with the condition by 2025. Currently >10% of the healthcare budget is spent on treating diabetes, amounting to an alarming £1 million per hour. The incretin effect, which in normal health is responsible for ~80% of insulin secretion at mealtimes, is impaired in type 2 diabetes1. GLP-1 is thought to be the most important incretin hormone which regulates glycaemia, making it a successful therapy for diabetes2. However, active GLP-1 is prone to rapid degradation by a group of proteolytic enzymes called dipeptidyl peptidase-IV (DPP-IV)3. Thus, prolongation of GLP-1 activity through inhibition of DPP-IV poses an attractive therapeutic opportunity for enhancement of insulin secretion in diabetes. Interestingly, the incretin hormone peptide tyrosine tyrosine (PYY) is also degraded by DPP-IV action and PYY has recently been shown to play a vital role on restoration of diabetes following Roux-En-Y gastric bypass surgery4. PYY is secreted locally by islet cells and it can affect glucose-induced insulin secretion in both rat and human islets4. Whilst pancreatic islets express DPP-IV, its role and function on local GLP-1 or PYY system remain obscure5. Our preliminary studies have indicated a local release of GLP-1 and PYY from rat and human islets raising the strong possibility of a direct effect of DPP-IV inhibition on islet secretory function. In addition, we have observed PYY receptor localisation on mouse and human pancreatic islet cells and shown that the DPP-IV inhibitor sitagliptin can enhance glucose-induced insulin secretion in isolated islets. Moreover, to date the effect of DPP-IV blockade on glucagon release from the pancreatic alpha-cells remains unclear. This is clinically important since diabetes is a bihormonal disease with not only a reduction in insulin secretion but also a marked elevation in glucagon release6. The goals of this project are three folds: 1) to explore the effects of DPP-IV inhibition on insulin, glucagon as well as somatostatin secretion; 2) to evaluate whether these effects are mediated via changes in local GLP-1 or PYY levels in the islets and 3) establish the signalling mechanism of DPP-IV inhibition in islets. This work may ultimately serve as a novel approach for enhancing the insulin-secreting capacity of donor human islets by DPP-IV inhibition pre-treatment prior to islet transplantation7. This research should ideally be performed on human islets as it is now becoming increasingly clear that there are major and important differences between mouse and human islets8, 9,10.
Funding Notes
Funding for this project is available to basic scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2017 entry, the application deadline is 6th January 2017 at 12 noon (midday).
Please visit our website for more information on how to apply.