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Title: The effect of CFTR on islet development and signalling
Author: Kelsey, Ryan
ISNI:       0000 0004 9350 6878
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2020
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Cystic Fibrosis-Related Diabetes (CFRD) is the most frequently observed extra-pulmonary co-morbidity associated with Cystic Fibrosis (CF). It is an ever-increasing burden on the CF population and is estimated to be present in up to 50% of people with CF over the age of 30. People with CFRD have a six-fold greater mortality rate compared to people with CF without diabetes, however the exact mechanism for CFRD development currently remains unclear. This thesis will aim to elucidate the role of CFTR in the development and function of pancreatic islets. A novel in vivo model of CFTR inhibition model was used in this thesis and validated against commonly used transgenic models. Short-term CFTR inhibition in C57BL6 mice was shown to cause a significant reduction in the size of pancreatic islets alongside a significant reduction in insulin secretion whilst sub-chronic CFTR inhibition lead to the development of insulin resistance consistent with other models of CFRD. Expression of islet connectivity markers Connexin 36 and E-cadherin were consistently reduced across multiple CF mouse models which may contribute to altered islet morphology and dysfunction observed in CFRD. An in vitro model was used to investigate the role of exocrine secretions on endocrine function, and whilst a number of differences in inflammatory makers were observed in the presence of different CFTR mutations, these were found to have little effect on the insulin secretory ability of beta-cells. This thesis supports a role for CFTR in the regulation of islet size and function, suggesting that therapeutic approaches using CFTR modulators may be beneficial for the restoration of islet architecture and glucose homeostasis in people with CFRD.
Supervisor: Kelly, Catriona Sponsor: Cystic Fibrosis Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cystic Fibrosis ; Diabetes ; Cystic Fibrosis-Related Diabetes ; CFRD