Glucose homeostasis and genotype-phenotype interplay in cystic fibrosis patients with CFTR gene deltaF508 mutation.

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) deltaF508 mutation, and to analyze their characteristics according to glucose tolerance status. RESEARCH DESIGN AND METHODS A total of 76 cystic fibrosis patients with CFTR deltaF508 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 beta-cell function and of insulin sensitivity and hyperbolic product (beta-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 beta-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 deltaF508 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 deltaF508 mutation seems a rational therapy for consideration, although this does not preclude that therapy directed toward insulin resistance could also interact.