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

Abstract

Diabetes is a common and important complication of cystic fibrosis, an autosomal recessive genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cystic fibrosis–related diabetes (CFRD) is associated with profound detrimental effects on the disease course and mortality and is expected to increase in prevalence as the survival of patients with cystic fibrosis continues to improve. Despite progress in the functional characterization of CFTR molecular defects, the mechanistic basis of CFRD is not well understood, in part because of the relative inaccessibility of the pancreatic tissue and the limited availability of representative animal models. This review presents a concise overview of the current understanding of CFRD pathogenesis and provides a cutting-edge update on novel findings from human and animal studies. Potential contributions from paracrine mechanisms and β-cell compensatory mechanisms are highlighted, as well as functional β-cell and α-cell defects, incretin defects, exocrine pancreatic insufficiency, and loss of islet cell mass. State-of-the-art and emerging treatment options are explored, including advances in insulin administration, CFTR modulators, cell replacement, gene replacement, and gene editing therapies.

Diabetes of the exocrine pancreas

“…Adipokines are elevated during episodes of AP and are positively associated with the development of insulin resistance and chronic hyperglycemia . Inflammatory mediators may also contribute to insulin resistance and hyperglycemia during acute exacerbations of CF . The pro‐inflammatory cytokines (interleukin 1β, tumor necrosis factor α, and interferon γ) reduce glucose‐stimulated insulin release .…”

“…36 Inflammatory mediators may also contribute to insulin resistance and hyperglycemia during acute exacerbations of CF. 37 The pro-inflammatory cytokines (interleukin 1β, tumor necrosis factor α, and interferon γ) reduce glucose-stimulated insulin release. 5 Inflammation also increases the expression of adrenomedullin and vanin-1, and these factors may have a role in DEP due to CP and pancreatic ductal adenocarcinoma.…”

Long‐term extrapulmonary comorbidities after lung transplantation in cystic fibrosis: Update of specificities

“…Fibrosis and destruction of the pancreas lead to decreased insulin secretion, whereas chronic pulmonary infection, inflammatory factors, and use of corticosteroids lead to insulin resistance . A direct role of CFTR in the impairment of insulin secretion and beta‐cell regulation is emerging . Age and pancreatic insufficiency are important risk factors for developing CFRD, which increases from 28.6% to 49.4% after LT …”

“…13 A direct role of CFTR in the impairment of insulin secretion and beta-cell regulation is emerging. [15][16][17] Age and pancreatic insufficiency are important risk factors for developing CFRD, 13,18 which increases from 28.6% to 49.4% after LT. 18 In all underlying lung diseases leading to LT, the prevalence of diabetes increases after transplantation. 19 Patients undergoing LT receive medications that can lead to impaired glucose tolerance, especially corticosteroids and tacrolimus.…”

Traitement du diabète associé à la fibrose kystique et de ses répercussions nutritionnelles

“…En effet, la digestion normale des lipides ralentit la vidange gastrique, ce qui permet une absorption des glucides plus graduelle [2,10] . Avec la FK, on observe une vidange gastrique accélérée et une hyperglycémie postprandiale chez les patients intolérants au glucose (prédiabète et DAFK) et même chez certains patients normotolérants au glucose [10,24] . Outre la meilleure digestion des lipides, la supplémentation en enzymes pancréatiques (lipases) permet un ralentissement de la vidange gastrique et une diminution de la glycémie consécutive à une absorption progressive des glucides.…”