Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study.

Cystic fibrosis related diabetes (CFRD) is characterized by progressive insulin insufficiency. It is extraordinarily prevalent in the cystic fibrosis (CF) population, occurring in 15–20% of adolescents and, eventually, more than half of adults (1). Few of the remaining patients have completely normal glucose metabolism; even those with normal fasting and 2-hour oral glucose tolerance test (OGTT) glucose levels typically have mid-OGTT glucose elevation and have defective acute insulin secretion in response to intravenous glucose (2). While CFRD does not usually develop before puberty, it has its roots in childhood and glucose intolerance is common in 6–9 year old children with CF (3). It has not been studied in younger children, but ferret models of CF demonstrate insulin secretory abnormalities in the newborn period (4), suggesting that there may be an intrinsic defect in beta-cell function in CF. CF is caused by abnormalities in the CF transmembrane conductance regulator (CFTR), an ATP-binding cassette transporter-class ion channel involved in chloride, sodium and water transport and absorption across cell membranes. CFTR defects lead to thick, viscous secretions with well-known chronic complications including obstructive lung disease associated with infection and inflammation, sinusitis, intestinal obstruction, liver disease and infertility. Pancreatic exocrine insufficiency develops as plugged ductules prevent digestive enzymes from reaching the gut; autodigestion of the pancreas by these trapped enzymes leads to fibrosis. It has long been debated whether insulin insufficiency in CF is merely a physical, “by-stander” consequence of this fibrotic destruction of the pancreatic architecture, or if CFTR defects per se impact insulin secretion (5). CFTR is expressed in human and mouse pancreatic alpha- and beta-cells (6; 7), but it is not known whether it is involved in hormone secretion. There has previously been no way to directly test this in a human model. Ivacaftor (VX-770, Kalydeco™, Vertex Pharmaceuticals, Cambridge, MA) is the first of a group of “potentiator” molecules being developed to correct the CFTR defect. CFTR is made in the endoplasmic reticulum, processed in the Golgi apparatus, and secreted in vesicles which chaperone proteins carry to the cell membrane, where it must be inserted and then must function normally. Defects leading to CF may occur at any of these steps. In patients with the G551D mutation (about 4% of the CF population), CFTR is found in the cell membrane but is dysfunctional. Ivacaftor corrects this defect by restoring channel gating, through an as-yet unidentified mechanism (8). In clinical Phase 2 and 3 trials, ivacaftor produced dramatic improvements in skin sweat chloride levels and in lung function within just 3 weeks (9; 10), and the drug has recently been approved by the FDA in children down to age 6. The initiation of ivacaftor therapy offers a unique opportunity to test the role of CFTR in human insulin secretion, potentially opening the way for novel diabetes therapies and for prevention or at least amelioration of diabetes in CF.