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

Advances in CFRD Therapeutic Strategies

A. Insulin Therapy

Currently, insulin remains the only therapy for CFRD officially recommended by the Cystic Fibrosis Foundation and American Diabetes Association.[22] There have been no conclusive data on which insulin regimen is optimal. Insulin glargine, NPH insulin, and fast-acting prandial insulin have all been reported to produce benefits.[21,24,26] Recent treatment advances for insulin therapy include the widespread availability of insulin pumps, which lessen variability of administration and increase flexibility with regard to complex meal schedules.[77] With insulin pumps, multiple insulin boluses can be given without separate injections. This can be advantageous to patients with cystic fibrosis who are often encouraged to have frequent meals and snacks throughout the day to maintain high-calorie intake and healthy weight. Insulin pump therapy can be labor-intensive, however, and can add to the treatment burden of patients with cystic fibrosis, which may limit its uptake by patients.[78]

The growing use of continuous monitoring with glucose sensors has allowed an unprecedented level of access to patient glucose data for clinical decision-making and can help reduce the occurrence of large glycemic excursions. Continuous glucose monitoring may also have a role in screening for cystic fibrosis–related diabetes.[29] Efforts to integrate the insulin pump and continuous glucose sensor in creating closed-loop systems or an "artificial pancreas" are well under way,[79–81] with the promise of ultimately yielding a fully automated glucose sensing and insulin delivery system that requires minimal patient intervention.

B. Oral Antidiabetic Drugs and Incretin Mimetics

The number of therapeutic options for treating diabetes has increased substantially in recent years, but most of them have not been formally evaluated in patients with CFRD. Because the degree of insulin resistance in CFRD is variable, insulin-sensitizing agents such as metformin or thiazolidinediones are not routinely used for treatment of CFRD. α-Glucosidase inhibitors, which prevent digestion of carbohydrates in the intestine, or sodium-glucose co-transporter 2 inhibitors, which block reabsorption of glucose in the kidney, may not be indicated in patients with cystic fibrosis, who are usually trying to increase calorie intake and gain weight. Insulin secretagogues have been used on occasion at some centers, but insufficient evidence exists to establish a clear role in CFRD management. Observational studies have found no difference between insulin and sulfonylureas in clinical outcome.[82,83] Randomized studies compared prandial insulin with repaglinide[21,84] and concluded that insulin produced a more favorable response, especially in terms of sustained improvement of body mass index.

There may be some rationale for using drugs that target the incretin axis,[85] because impaired postprandial incretin hormone secretion has been reported in patients with cystic fibrosis without CFRD.[37,62] GLP-1 and GIP-1 secretion was lower in patients with exocrine pancreatic-insufficient cystic fibrosis than in patients with pancreatic sufficiency even when they had a normal OGTT result.[37] The available incretin modulators are GLP-1 receptor agonists, which act as incretin mimetics, and dipeptidyl peptidase-4 inhibitors, which increase GLP-1 levels indirectly by interfering with its degradation. Potential drawbacks of these drugs include GLP-1 receptor agonist–mediated reduction of appetite and weight loss and some concerns over proliferative effects in the pancreas. Of note, fat malabsorption can be a major contributor to postprandial hyperglycemia because digestion of fat serves to slow down gastric emptying and absorption of carbohydrates. Treatment of exocrine pancreatic insufficiency with pancreatic enzyme supplements has the benefit of reducing postprandial hyperglycemia, slowing gastric emptying, and augmenting incretin hormone secretion.[62,86]

C. Islet/Pancreas Transplantation and Stem Cell–Derived β-Cell Replacement Therapy

For patients with CFRD and end-stage lung disease, pancreatic islet transplantation after lung transplantation and combined lung and islet transplantation have been suggested as options.[87,88] Combined lung-pancreas transplantation is also possible but carries a higher risk of complications than lung-islet transplantation.[89] Total pancreatectomy and islet autotransplantation have been performed in some patients with chronic painful pancreatitis, including those with pancreatic-sufficient cystic fibrosis,[90] but a similar strategy has not been attempted in CFRD, largely because of lower numbers of viable islets. An innovative approach to overcome the limited supply of donor cells is to implant islet progenitor cells or β-cells that are differentiated in culture from human embryonic stem cell lines.[91] The implanted cells are encapsulated in semipermeable barrier material, obviating the need for immunosuppression. One such system has entered phase 1/2 clinical trials in patients with type 1 diabetes.

D. CFTR Modulator Therapy

Ivacaftor and lumacaftor are recently approved small-molecule drugs that target the defective CFTR proteins associated with specific genotype classes.[10] Ivacaftor is a potentiator that enhances CFTR channel activity and is effective for mutant proteins with abnormal channel gating (class III mutations) or conductance (class IV mutations). Lumacaftor is a corrector that facilitates CFTR protein folding and maturation and primarily targets patients with class II mutations such as ΔF508. Small pilot studies and case reports have demonstrated that ivacaftor therapy ameliorated impaired insulin secretion in patients with cystic fibrosis who carry common gating mutations, in some cases resulting in resolution of CFRD.[65,71–73] Longer-term studies involving larger numbers of patients are needed to confirm the proposed benefit of these drugs in treating CFRD. Agents that promote the read-through of premature termination codons have the potential for suppressing certain class I mutations. Structural modification of aminoglycoside antibiotics, which display such read-through activity at sufficiently high concentrations, is being carried out to reduce the cytotoxicity that currently prevents routine use for this purpose.[92] Ataluren, an unrelated small molecule approved in Europe to treat nonsense mutations in the dystrophin gene, has not shown efficacy in cystic fibrosis in recent phase 3 trials.[93]

E. Gene Replacement and DNA/RNA Editing Therapy

Because cystic fibrosis is a monogenic, autosomal recessive disorder, direct replacement or repair of the CFTR gene offers a potentially curative strategy.[94] For treatment of pulmonary disease, aerosolized administration of viral or nonviral vectors has been used to deliver the wild-type CFTR gene to the airways; although no CFTR gene therapy has received regulatory approval thus far, some encouraging results have been reported from clinical trials.[95] Systemic administration of pancreas-tropic serotypes of viral vectors, such as adeno-associated virus serotype 8, can in principle target pancreatic disease in cystic fibrosis, and if desired, a tissue-selective promoter can be used to drive transgene expression with viral or nonviral vectors.[96] Genome editing technologies such as CRISPR (clustered regularly interspaced short palindromic repeats), TALENs (transcription activator-like effector nucleases), and ZFNs (zinc finger nucleases) now permit the site-specific correction of CFTR gene mutations at their endogenous chromosomal loci for restoration of function. Culture studies have demonstrated successful repair of a mutant CFTR gene in this fashion.[97,98]In vivoβ-cell–targeted gene editing systems are under development and may someday achieve sufficient efficacy and safety to attempt human trials.[99] RNA editing strategies are another possible alternative. RNA oligonucleotides have been used to rescue deleted segments of CFTR messenger RNA in cultured ΔF508 cells.[100] Delivery of the whole CFTR messenger RNA is also being investigated as an option and has the appeal of being transient, less disruptive to the cell, and easily produced in large quantities.[101,102]