Abstract
Cystic fibrosis-related diabetes (CFRD) is the most significant extra-pulmonary comorbidity in cystic fibrosis (CF) patients, and accelerates lung decline. In addition to the traditional view that CFRD is a consequence of fibrotic destruction of the pancreas as a whole, emerging evidence may implicate a role for cystic fibrosis transmembrane-conductance regulator (CFTR) in the regulation of insulin secretion from the pancreatic islet. Impaired first-phase insulin responses and glucose homeostasis have also been reported in CF patients. CFTR expression in both human and mouse beta cells has been confirmed, and recent studies have shown differences in endocrine pancreatic morphology from birth in CF. Recent experimental evidence suggests that functional CFTR channels are required for insulin exocytosis and the regulation of membrane potential in the pancreatic beta cell, which may account for the impairments in insulin secretion observed in many CF patients. These novel insights suggest that the pathogenesis of CFRD is more complicated than originally thought, with implications for diabetes treatment and screening in the CF population. This review summarises recent emerging evidence in support of a primary role for endocrine pancreatic dysfunction in the development of CFRD.Summary• CF is an autosomal recessive disorder caused by mutations in the CFTR gene• The vast majority of morbidity and mortality in CF results from lung disease. However CFRD is the largest extra-pulmonary co-morbidity and rapidly accelerates lung decline• Recent experimental evidence shows that functional CFTR channels are required for normal patterns of first phase insulin secretion from the pancreatic beta cell• Current clinical recommendations suggest that insulin is more effective than oral glucose-lowering drugs for the treatment of CFRD. However, the emergence of CFTR corrector and potentiator drugs may offer a personalised approach to treating diabetes in the CF population
Highlights
Cystic fibrosis (CF) is the most common autosomal recessive disorder in white people, and results from mutations in the cystic fibrosis transmembrane-conductance regulator (CFTR) gene, located on the long arm of chromosome 7 in humans [1]
These results suggest that the first-phase insulin response to glucose observed in Cystic fibrosis-related diabetes (CFRD) patients may be partly attributable to responses mediated by membrane-bound voltage-dependent channels
Given the dominant role of the insulin-secreting beta cell in diabetes pathogenesis, it is perhaps not surprising that beta cells have been the first target for preliminary investigations into the role of CFTR expression in CFRD
Summary
Cystic fibrosis (CF) is the most common autosomal recessive disorder in white people, and results from mutations in the cystic fibrosis transmembrane-conductance regulator (CFTR) gene, located on the long arm of chromosome 7 in humans [1]. Class II mutations, including F508del, result from misprocessing of CFTR in the ER, leading to an absence of functional protein at the plasma membrane. Clinical implications of CFTR mutation the airways of healthy individuals (~10% of systemic levels) results in a significant increase in bacterial proliferation [8]. Oral glucose tolerance testing of 240 CF patients with and without overt diabetes demonstrated that patients with elevated glucose at 60 min had significantly reduced pulmonary function and increased HbA1c. Patients with CFRD have reduced height and weight [1] and chronically elevated protein catabolism compared with patients with CF and no diabetes. Lung disease is the primary cause of morbidity and mortality among CF patients and results from recurrent and chronic bacterial infection. Consistent with this, impaired first-phase insulin response has been reported in the absence of functional CFTR in both animal [16, 17] and human [18] studies
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