Katie Larson Ode

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field’s understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23–25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.

Background The effects of elexacaftor‐tezacaftor‐ivacaftor (ETI) on body composition in people with CF (pwCF) are unknown. Methods Dual‐energy X‐ray absorptiometry fat‐free mass and fat mass adjusted for height (FMI) as well as oral glucose tolerance test derived measures of insulin secretion and sensitivity were compared before and after ETI initiation in eight pwCF. Results Patients median age: 22 years interquartile range (IQR: 16–28), 87.5% male, median time on ETI:11 months. Weight z ‐score increased from −0.52 to 0.18 ( p = 0.014); FMI increased from 4.12 to 6.29 ( p = 0.014). Insulin secretion (C pep iAUC/Gluc iAUC) increased from 8.71 to 14.21 ( p = 0.021), insulin resistance (HOMA2 IR) increased from 0.73 to 1.25 ( p = 0.014) and insulin sensitivity decreased (Matsuda) 8.88 to 5.58 ( p = 0.036). Conclusions ETI resulted in increased weight and fat mass. BMI and muscle mass did not change. Both insulin secretion and insulin resistance increased. Longer‐term metabolic consequences of ETI need further investigation.