Survival in a bad neighborhood: pancreatic islets in cystic fibrosis

Abstract

In cystic fibrosis (CF), ductal plugging and acinar loss result in rapid decline of exocrine pancreatic function. This destructive process results in remodeled islets, with only a modest reduction in insulin-producing β cells. However, β-cell function is profoundly impaired, with decreased insulin release and abnormal glucose tolerance being present even in infants with CF. Ultimately, roughly half the CF subjects develop diabetes (termed CF-related diabetes (CFRD)). Importantly, CFRD increases CF morbidity and mortality via worsening catabolism and pulmonary disease. Current accepted treatment options for CFRD are aimed at insulin replacement, thereby improving glycemia as well as preventing nutritional losses and lung decline. CFRD is a unique form of diabetes with a distinct pathophysiology that is as yet incompletely understood. Recent studies highlight emerging areas of interest. First, islet inflammation and lymphocyte infiltration are common even in young children with CF and may contribute to β-cell failure. Second, controversy exists in the literature regarding the presence/importance of β-cell intrinsic functions of CFTR and its direct role in modulating insulin release. Third, loss of the CF transmembrane conductance regulator (CFTR) from pancreatic ductal epithelium, the predominant site of its synthesis, results in paracrine effects that impair insulin release. Finally, the degree of β-cell loss in CFRD does not appear sufficient to explain the deficit in insulin release. Thus, it may be possible to enhance the function of the remaining β-cells using strategies such as targeting islet inflammation or ductal CFTR deficiency to effectively treat or even prevent CFRD.

Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis

“…All SLC26A9 constructs were tested in the PANC-1 cell line, a human pancreatic adenocarcinoma cell line that is of ductal cell origin (55), but also is a surrogate for pancreatic progenitor cells, since they can be induced to differentiate into insulin-producing cells (56). A renilla construct (pRL-TK, Promega) was included to normalize for (48,49).…”

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

“…Two other types of anion channel, Ca 2+ -activated anoctamin-1 (ANO1/TMEM16A) and cAMP-activated cystic fibrosis conductance regulator (CFTR), are reported to play a role in cAMP-amplified insulin secretion in human and mouse beta cells [206]. However, the expression of CFTR in human islets remains controversial and the development of cystic fibrosis-related diabetes may be primarily mediated by indirect effects rather than beta cell dysfunction [207,208]. ANO1 and CFTR have been shown to form a signaling complex involving Epac1 and AC1 to associate closely with GPCRs in epithelial cells [209], but whether they form a complex in beta cells is unknown.…”

Cystic fibrosis related diabetes: Medical management

“…The effectiveness of potentiators/corrector treatments for cystic fibrosis related lung disease raises very interesting questions regarding their effect on the other complications of cystic fibrosis, including CFRD. The pathophysiology of CFRD is still controversial with some groups finding CFTR in the beta or alpha cells in the islet and other groups finding no proof that CFTR is present in human islets [46]. However, what is clear is that CFTR dysfunction effects beta cell function, whether directly or indirectly [46].…”

“…The pathophysiology of CFRD is still controversial with some groups finding CFTR in the beta or alpha cells in the islet and other groups finding no proof that CFTR is present in human islets [46]. However, what is clear is that CFTR dysfunction effects beta cell function, whether directly or indirectly [46]. Given this, it can be extrapolated that effectively correcting CFTR function might be able to prevent or delay the development of CFRD if done early enough or if pathologic changes are reversible.…”