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 b-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either b-cell mass reduction or b-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.

Steady-State Therapy with Azithromycin or Low-Dose Prednisolone in Paediatric Cystic Fibrosis Patients: Inflammatory Markers and Disease Progression

“…In our study, AZ-treated patients were older than those of the WAT group, so we adjusted for age and P. aeruginosa colonisation, and obtained results similar to the uncorrected ones. It has become clear in recent years that fibrosis from the autodigestion of tissue by pancreatic enzymes is not the only cause of CF-related diabetes [50] . It is well known that pancreatic β-cells undergo extensive proinsulin biosynthesis, and, therefore, face a high protein-folding burden.…”

A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis

“…A similar process in CF patients also known to start in babyhood is the destruction of the pancreas which is driven by fibrosis and noted when the disease was first recognized. This is clinically important because nearly all pancreatic insufficient CF patients develop diabetes mellitus that is disproportionately lethal to females with CF [28].…”

Impact of nutritional status on pulmonary function after lung transplantation for cystic fibrosis

“…Furthermore, about 80% of our post-transplant CF patients were diabetics (CFRD or NODAT), a proportion that is much higher than previously described in pre-transplant CF patients. 26 This underlines the importance of sufficient pancreas enzyme replacement treatment (PERT), as well as thorough diabetes screening not only prior to, but also after, LT.…”