title: Management of endocrine disease: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues.
abstract: 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 β-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either β-cell mass reduction or β-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.
authors.affiliation: Pediatric Diabetes UnitDepartment of Pediatrics, Ramón y Cajal University Hospital, Alcalá University, Crta. Colmenar Km 9.1, 28034 Madrid, Spain raquel.barrio@salud.madrid.org.
authors.forename: Raquel
authors.initials: R
authors.lastname: Barrio
mesh_terms: D003550:Cystic Fibrosis / Q000150:complications* / Q000175:diagnosis / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D003920:Diabetes Mellitus / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy*; D042241:Early Diagnosis; D056726:Genetic Association Studies; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology; D020125:Mutation, Missense
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator