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In situ analysis reveals that CFTR is expressed in only a small minority of β-cells in normal adult human pancreas

Lookup NU author(s): Dr Michael White, Dr Rashmi Maheshwari, Dr Scott Anderson, Dr Rolando Berlinguer Palmini, Claire Jones, Sarah Armour, Dr Yuchun Ding, Professor Natalio KrasnogorORCiD, Dr Michael Gray, Professor James Shaw

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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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Abstract

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


Publication metadata

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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Funding

Funder referenceFunder name
MR/R014132/1Medical Research Council (MRC)
SRC007

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