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Glucose Homeostasis and Genotype-Phenotype Interplay in Cystic Fibrosis Patients With CFTR Gene F508 Mutation

¹ Department of Endocrinology and Nutrition, Université Catholique de Louvain, Cliniques Universitaires St-Luc, Brussels, Belgium
² Cystic Fibrosis Unit, Université Catholique de Louvain, Cliniques Universitaires St-Luc, Brussels, Belgium

Address correspondence and reprint requests to Prof. M. Buysschaert, Cliniques Universitaires St-Luc, Service d'Endocrinologie et Nutrition, Avenue Hippocrate 54, UCL 5474, B-1200 Brussels, Belgium. E-mail: buysschaert{at}diab.ucl.ac.be

OBJECTIVE—We sought to determine the clinical phenotype of adolescent/adult patients with cystic fibrosis, according to heterozygosity or homozygosity for cystic fibrosis transmembrane regulator (CFTR) F508 mutation, and to analyze their characteristics according to glucose tolerance status.

RESEARCH DESIGN AND METHODS—A total of 76 cystic fibrosis patients with CFTR F508 mutation (33 heterozygous and 43 homozygous) stratified according to normal glucose tolerance (NGT) (n = 51) or abnormal glucose homeostasis (AGH) (impaired fasting glucose, impaired glucose tolerance, or diabetes; n = 25) had their homeostasis model assessment (HOMA) of ß-cell function and of insulin sensitivity and hyperbolic product (ß-cell function x insulin sensitivity [B x S]) measured. Pancreatic exocrine insufficiency was inferred from pancreatine requirements. Clinical effects of insulin therapy on weight and lung function were recorded.

RESULTS—AGH was observed in 24 and 40% of heterozygous and homozygous subjects, respectively. AGH patients were older than NGT patients (mean ± SD age 29 ± 10 vs. 23 ± 8 years, P = 0.006), and their ß-cell function was lower (93 ± 49 vs. 125 ± 51%, P = 0.011). Insulin sensitivity values were comparable in NGT and AGH patients. A lower B x S product was observed in AGH, although it was nonsignificant when adjusted for error propagation. Pancreatic insufficiency was observed in 52 and 100% of heterozygous and homozygous patients (P = 0.001).

CONCLUSIONS—Pre-diabetes and diabetes represent frequent comorbidities in CFTR F508 mutation in the homozygous or heterozygous states. Impairment of insulin secretion, as shown by HOMA, is an important determinant when compared with the magnitude of compensation from insulin sensitivity. Given the high prevalence of abnormal glucose tolerance, screening for (pre-)diabetes is mandatory. Insulin supplementation in diabetic subjects with CFTR F508 mutation seems a rational therapy for consideration, although this does not preclude that therapy directed toward insulin resistance could also interact.

Abbreviations: AGH, abnormal glucose homeostasis • B x S, ß-cell function x insulin sensitivity • FEV1, forced expiratory volume over 1 s • FVC, forced vital capacity • HOMA, homeostasis model assessment • HOMA-B, HOMA of ß-cell function • HOMA-S, HOMA of insulin sensitivity • IFG, impaired fasting glucose • IGT, impaired glucose tolerance • NGT, normal glucose tolerance

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