GLUCOSE HOMEOSTASIS AND GENOTYPE--PHENOTYPE INTERPLAY IN CYSTIC FIBROSIS PATIENTS WITH GENE CFTR ΔF 508 MUTATION

Abstract

Objective To determine the clinical phenotype of adolescent/adult patients with cystic fibrosis (CF), according to heterozygosity or homozygosity for CFTR ΔF508 mutation, and to analyse their characteristics according to glucose tolerance status.

Design 76 CF patients with CFTR ΔF508 mutation (33 heterozygous, 43 homozygous) stratified according to normal (NGT, n=51) or abnormal glucose homeostasis (AGH; IFG-IGT or diabetes, n=25) had their HOMA β-cell function (B), insulin sensitivity (S), and [BxS] hyperbolic product 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. AGH patients were older than NGT (29±10 vs. 23±8 years, p=0.006) and their B function was lower (93±49 vs. 125±51%, p=0.011). S values were comparable in NGT and AGH. A lower BxS product was observed in AGH, although non-significant when adjusted for error propagation. Pancreatic insufficiency was observed in 52 and 100% of hetero- and homozygous patients (p=0.001).

Conclusions Prediabetes and diabetes represent frequent co-morbidities in CFTR gene ΔF 508 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 CFTR gene ΔF 508 subjects seems a rational therapy for consideration, although this does not preclude that therapy directed toward insulin resistance could also interact.