The Effect of CFTR on Islet Development and Signalling

Abstract

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.

Date of Award	May 2020
Original language	English
Sponsors	The Cystic Fibrosis Trust
Supervisor	Catriona Kelly (Supervisor) & Neville Mc Clenaghan (Supervisor)