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Cystic fibrosis-related diabetes is caused by islet loss and inflammation.

ABSTRACT: Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of ? cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine ? cells did not affect ? cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of ? cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by ? cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation.

SUBMITTER: Hart NJ

PROVIDER: S-EPMC5931120 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Cystic fibrosis-related diabetes is caused by islet loss and inflammation.

Hart Nathaniel J NJ Aramandla Radhika R Poffenberger Gregory G Fayolle Cody C Thames Ariel H AH Bautista Austin A Spigelman Aliya F AF Babon Jenny Aurielle B JAB DeNicola Megan E ME Dadi Prasanna K PK Bush William S WS Balamurugan Appakalai N AN Brissova Marcela M Dai Chunhua C Prasad Nripesh N Bottino Rita R Jacobson David A DA Drumm Mitchell L ML Kent Sally C SC MacDonald Patrick E PE Powers Alvin C AC

JCI insight 20180419 8

Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of β cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine ...[more]

PMID: 29669939

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Project description:Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction.Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-β1 (transforming growth factor β1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1.Conclusions: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.

Dataset Information

Cystic fibrosis-related diabetes is caused by islet loss and inflammation.

Publications

Cystic fibrosis-related diabetes is caused by islet loss and inflammation.

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