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

John C. Yoon

Disclosures

J Endo Soc. 2017;1(11):1386-1400. 

In This Article

Abstract and Introduction

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.

Introduction

Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is the most common life-limiting genetic condition in people of Caucasian ancestry and affects about one in 3000 newborns in Europe, North America, and Australia.[1] The incidence is lower in other parts of the world, such as in Africa (Cape Town, South Africa, one in 12,000) and Asia (Japan, one in 350,000). More than 2000 variants of the CFTR gene have been identified to date, and close to 300 are known cystic fibrosis–causing variants.[2] On the basis of functional consequence, the mutations are broadly grouped into six classes (Table 1).[3,4] The CFTR protein acts as an anion (primarily Cl) channel that controls ion movement across the cell membrane and is regulated by cyclic adenosine monophosphate-dependent phosphorylation. In pancreatic ductal cells, the Cl secretion via CFTR is functionally coupled to a Cl-bicarbonate exchanger, producing net bicarbonate secretion, and CFTR itself may also secrete bicarbonate.[5,6] Defective CFTR function reduces the volume of pancreatic secretions, predisposing to plugging of small ducts, and increases acidity, promoting premature activation of digestive enzymes.[7] In the digestive, respiratory, and reproductive systems, dysfunction of the CFTR protein leads to inspissated secretions and obstruction of epithelium-lined ducts, eventually resulting in inflammation and tissue damage.[8] Pulmonary infections, sinus disease, exocrine and endocrine pancreatic insufficiency, hepatobiliary disease, and male infertility are commonly observed in individuals with cystic fibrosis, with respiratory failure being the primary cause of death. The median predicted survival of patients with cystic fibrosis has improved dramatically because of advances in therapeutics and nutrition, and currently stands at around 40 years.[9] If the mortality continues to decline at the current rate, the median life span of children born and diagnosed in 2010 is projected to reach >50 years. Studies of specific CFTR mutants have proved instrumental in linking the underlying molecular defects to the disease phenotypes and have aided recent developments in targeted small-molecule therapy.[10]

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