Expression and localization of cystic fibrosis transmembrane conductance regulator in the rat endocrine pancreas

Boom, Alain; Lybaert, Pascale; Pollet, J.-F.; Jacobs, Paul; Jijakli, Hassan; Golstein, Philippe; Sener, Abdullah; Malaisse, Willy; Beauwens, Renaud

doi:10.1007/s12020-007-9026-x

Cited by 65 publications

(54 citation statements)

References 32 publications

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“…CFRD results more from decreased ␤-cell function than from decreased insulin sensitivity (19). This finding supports a function for CFTR in pancreatic islets where, in rats, investigators have identified CFTR mRNA (20). In mice made diabetic by streptozotocin, those who were CFTR-null (Ϫ/Ϫ) had higher blood glucose levels than other mice; the investigators concluded that islet dysfunction is inherent to the CFTR Ϫ/Ϫ state (21).…”

Section: Risk Factorsmentioning

confidence: 72%

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

et al. 2008

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OBJECTIVE -Longer survival of patients with cystic fibrosis has increased the occurrence of cystic fibrosis-related diabetes (CFRD). In this study we documented the incidence of CFRD and evaluated the association between mutations responsible for cystic fibrosis and incident CFRD, while identifying potential risk factors.RESEARCH DESIGN AND METHODS -This was a population-based longitudinal study of 50 cystic fibrosis speciality clinics in the U.K. Subjects included 8,029 individuals aged 0 -64 years enrolled in the U.K. Cystic Fibrosis Registry during 1996 -2005. Of these, 5,196 with data and without diabetes were included in analyses of incidence, and 3,275 with complete data were included in analyses of risk factors. Diabetes was defined by physician diagnosis, oral glucose tolerance testing, or treatment with hypoglycemic drugs.RESULTS -A total of 526 individuals developed CFRD over 15,010 person-years. The annual incidence was 3.5%. The incidence was higher in female patients and in patients with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classes I and II. In a multivariate model of 377 cases of 3,275 patients, CFTR class (relative risk 1.70 [95% CI 1.16 -2.49], class I or II versus others), increasing age, female sex, worse pulmonary function, liver dysfunction, pancreatic insufficiency, and corticosteroid use were independently associated with incident diabetes.CONCLUSIONS -The incidence of CFRD is high in Britain. CFTR class I and II mutations increase the risk of diabetes independent of other risk factors including pancreatic exocrine dysfunction.

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Section: Risk Factorsmentioning

confidence: 72%

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

et al. 2008

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“…Recent data suggest there may be an intrinsic defect in b-cell function in CF. CFTR is expressed in human and mouse pancreatic a and b cells, and CFTR conductance has been measured in mouse b cells (24,25). Whether CFTR plays a role in insulin secretion is unknown.…”

Section: Original Articlementioning

confidence: 99%

Diabetes-related Mortality in Adults with Cystic Fibrosis. Role of Genotype and Sex

Lewis

Blackman

Nelson

et al. 2015

Am J Respir Crit Care Med

156

124

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Rationale: Diabetes is associated with increased mortality in cystic fibrosis. Aggressive screening and early institution of insulin treatment significantly reduced this risk over the period of 1992-2008.Objectives: To determine if progressive improvement in cystic fibrosis-related diabetes (CFRD) mortality has continued since 2008, and examine associations with CFTR genotypes linked to pancreatic insufficiency and to sex.Methods: Chart review was performed on 664 patients followed from 2008 to 2012. Measurements and Main Results:Overall mortality for patients with CFRD was 1.8 per 100 person-years, compared with 0.5 in patients with CF without diabetes (P = 0.0002); neither rate changed significantly from mortality reported for [2003][2004][2005][2006][2007][2008]. Genotype impacted both mortality and diabetes risk: adults with severe CFTR genotypes experienced greater mortality at every age older than 32 years than those with mild genotypes (P = 0.002), and the risk of developing CFRD was also greatly increased in those with severe genotypes (prevalence 60% in adult patients with severe vs. 14% in adults with mild mutations). CFRD had a direct influence on mortality because it was associated with increased risk of death within each genotype category (20 vs. 2%, P = 0.007 for mild; 12 vs. 4%, P = 0.012 for severe). There was also a sex difference in adults with severe CFTR genotypes; both mortality and CFRD prevalence were higher at every age in females than males.Conclusions: Despite substantial improvement over time, mortality for CFRD patients greater than 30 years remains higher than for patients with CF without diabetes.

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“…Impaired insulin secretion " CFTR protein is expressed in a-cells and b-cells in the rat pancreas, although its role in these cells is not well known (44). Evidence reveals a role of CFTR in glucose-induced electrical activities and insulin secretion in b-cells (45).…”

Section: B-cell-specific Dysfunctionmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

Barrio¹

2015

European Journal of Endocrinology

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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet b-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either b-cell mass reduction or b-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called 'transformational' therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shown in vitro capacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.

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Expression and localization of cystic fibrosis transmembrane conductance regulator in the rat endocrine pancreas

Cited by 65 publications

References 32 publications

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

Diabetes-related Mortality in Adults with Cystic Fibrosis. Role of Genotype and Sex

MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

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