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Lookup NU author(s): Dr Michael White, Dr Rashmi Maheshwari, Dr Scott Anderson, Dr Rolando Berlinguer PalminiORCiD, Claire Jones, Sarah Armour, Dr Yuchun Ding, Professor Natalio KrasnogorORCiD, Dr Michael Gray, Professor James Shaw
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2020.
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Context: Although diabetes affects 40-50% of adults with cystic fibrosis, remarkably little is known regarding the underlying mechanisms leading to impaired pancreatic β-cell insulin secretion. Efforts towards improving the functional β-cell deficit in cystic fibrosis related diabetes (CFRD) have been hampered by an incomplete understanding of whether β-cell function is intrinsically regulated by CFTR. Definitively excluding meaningful CFTR expression in human -cells in situ would contribute significantly to the understanding of CFRD pathogenesis. Objective: To determine CFTR mRNA and protein expression within β-cells in situ in the unmanipulated human pancreas of donors without any known pancreatic pathology. Design: In situ hybridisation for CFTR mRNA expression in parallel with insulin immunohistochemical staining; and immunofluorescence co-localisation of CFTR with insulin and the ductal marker, Keratin-7, were undertaken in pancreatic tissue blocks from 10 normal adult, non-obese deceased organ donors over a wide age range (23-71 years) with quantitative image analysis. Results: CFTR mRNA was detectable in 0.45 (0.17-0.83)% (mean(range)) of insulin-positive cells. CFTR protein expression was co-localised with Keratin-7. 100% of insulin-positive cells were immunonegative for CFTR. Conclusions: For the first time, in situ CFTR mRNA expression in the unmanipulated pancreas has been shown to be present in only a very small minority (<1%) of normal adult β-cells. These data signal a need to move away from studying endocrine-intrinsic mechanisms and focus on elucidation of exocrine-endocrine interactions in human cystic fibrosis
Author(s): White MG, Maheshwari RR, Anderson SJ, Berlinguer-Palmini R, Jones C, Richardson SJ, Rotti PG, Armour SL, Ding Y, Krasnogor N, Engelhardt JF, Gray MA, Morgan NG, Shaw JAM
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Endocrinology and Metabolism
Year: 2020
Volume: 105
Issue: 5
Pages: 1366-1374
Print publication date: 01/05/2020
Online publication date: 21/11/2019
Acceptance date: 15/11/2019
Date deposited: 22/11/2019
ISSN (print): 0021-972X
ISSN (electronic): 1945-7197
Publisher: Oxford University Press
URL: https://doi.org/10.1210/clinem/dgz209
DOI: 10.1210/clinem/dgz209
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