Evolving Mechanistic Views and Emerging Therapeutic Strategies for Cystic Fibrosis–Related Diabetes

John C. Yoon


J Endo Soc. 2017;1(11):1386-1400. 

In This Article

Future Perspectives

An interplay of β-cell intrinsic and extrinsic factors is thought to underlie the development of CFRD. At present, it seems reasonable to postulate that a mild β-cell defect, either intrinsic or secondary to altered paracrine communication between β-cells and surrounding islet and nonislet cells, becomes increasingly exacerbated as pancreatic inflammation disrupts the local environment, which may be further compounded by gradual loss of β-cell mass from cell death or dedifferentiation. However, the relative importance of each process is still unknown. Elucidating the early events in CFRD pathogenesis is clearly key, but because it is difficult in practice to recruit large numbers of infants with cystic fibrosis or obtain pancreatic tissues, pig and ferret models may provide critical clues. Although studying the natural course of CFRD in these animals is valuable, a precise dissection of the mechanism may require experimental genetics, such as tissue-selective inactivation of the CFTR gene in β-cells, α-cells, or ductal cells using promoters selective for each cell type.[103] CRISPR-mediated genome editing in nontraditional models such as pigs and ferrets has been demonstrated,[104,105] and both genomes have been sequenced. In principle, cell type–specific CFTR inactivation in these animals can address the question of whether intrinsic β-cell disease or exocrine pancreatic disease alone can produce CFRD or perhaps both are required.

The early occurrence of insulin secretion abnormalities in humans, pigs, and ferrets does not necessarily establish a key role for an intrinsic β-cell defect because concurrent disease processes are ongoing in the exocrine pancreas and in non–β-cells in the islets, which can alter paracrine signals. The sparing of islets in cystic fibrosis pigs suggests that structural destruction of islets is not necessary and perhaps local inflammation is enough to produce functional β-cell insufficiency. In humans, moreover, overt CFRD is not typically diagnosed until years or decades after exocrine pancreatic insufficiency, implying that additional processes, some of which conceivably overlap with type 2 diabetes, must take place. Alternatively, the CFRD diagnosis may be delayed because of a compensatory response and islet remodeling early in life that produce partial recovery of β-cell function and mass. It may be possible to detect such transient glycemic crises with more studies of glycemic patterns in very young children.

The CFTR modulator therapy provides a means to assess the reversibility of insulin-secretion defects in human subjects carrying appropriate CFTR genotypes amenable to such therapy, as well as in certain animal models such as the ΔF508 pig. Because recent clinical data indicate the presence of insulin-secretory defects in young infants, it is desirable to explore the potential benefits of such therapy at the earliest feasible age, with long-term follow-up to determine efficacy in preventing or delaying CFRD.[43] Older patients with established CFRD may also show clinical improvement and even resolution of CFRD, according to case reports.[73] At clinicaltrials.gov, there is an ongoing trial with pediatric patients and a planned trial with adult patients. The pig model may have utility for correlating the islet physiology to the drug response at different stages of pancreatic disease.