Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.
Highlights
Cystic fibrosis (CF; OMIM 219700) is the most frequent autosomal recessive disease in individuals of European ancestry with approximately 1 in 3000 births [1]
The pancreas of newborn CFTR-/- pigs present with a higher proportion of activated B lymphocytes, likely producing antibodies. These results suggest that CFTR alters B lymphocyte homeostasis, promoting the accumulation of B cells, which may contribute to Cystic fibrosis-related diabetes (CFRD)
Severe CFTR mutations cause alterations in the exocrine pancreas, which attract immune cells to this tissue leading to inflammation, islet disorganization, loss of b-cell mass, and reduced insulin production
Summary
Cystic fibrosis (CF; OMIM 219700) is the most frequent autosomal recessive disease in individuals of European ancestry with approximately 1 in 3000 births [1]. Similar to other forms of DEP, CFRD is associated with pancreatic inflammation, fibrosis and fatty infiltration leading to a reduction of the number of islets and impaired insulin secretion. Multiple factors are associated with increased risk or accelerated progression to CFRD, such as age, gender, CFTR genotype, genetic modifiers, the degree of pancreatic exocrine deficiency, lung function, liver disease, inflammation, the presence of b-cell specific autoantibodies, etc.
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