Type 2 Diabetes (T2D) affects over 415 million people globally and is characterised by cellular stresses including: poor glucose homeostasis, dyslipidaemia, inflammation, hypoxia and ER stress. Studies in mice have shown that exposure to these stresses influences beta cell differentiation status as well as cell survival and may explain the extent of beta cell mass loss that is seen in the disease. To date, studies of altered beta cell differentiation have largely been confined to murine models. I used the EndoC-bH1 human beta cell line, along with human pancreatic tissue sections, to better characterise this mechanism in human disease. To elucidate these mechanisms, I firstly established a humanised version of cell culture techniques for the EndoC βH1 cell model and assessed the influence on cell function. Secondly, I evaluated the effects of the diabetic microenvironment on beta cell differentiation and gene expression patterns. Finally, I investigated whether a diabetomimetic microenvironment induced differences in microRNA regulation in the cells. I found that the humanised EndoC-βH1 culture techniques improved glucose sensitive insulin release in the cell model. EndoC-βH1 cells exposed to a Diabetic microenvironment showed some degree of transdifferentiation and this may be due to dysregulation of splicing factor expression. These effects may be compounded by altered microRNA regulation in response to these cell stresses. These data suggest that altered gene regulation caused by a diabetic microenvironment may alter gene regulation to produce a reversible delta-like phenotype in human beta cells.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:768576 |
| Date | January 2019 |
| Creators | Jeffery, N. |
| Contributors | Harries, L. ; Richardson, S. |
| Publisher | University of Exeter |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10871/35724 |
Page generated in 0.0019 seconds