Cystic fibrosis (CF) is a life-threatening genetic disease impacting multiple organ systems, with pancreatic dysfunction as a critical complication. A recent study published in eGastroenterology presents young rabbits with CF as a novel model to study CF-related pancreatic endocrine pathology, offering insights into CF-related diabetes (CFRD), affecting up to 50% of adults with CF.
CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to abnormal chloride and sodium transport across epithelial cells. While treatments like Trikafta® have improved pulmonary outcomes, pancreatic complications persist. The study, led by Dr. Jie Xu from the University of Michigan Medical School, investigates pancreatic lesions and glucose metabolism abnormalities in CF rabbits.
The CF rabbit model was developed using CRISPR/Cas9 gene-editing technology. CF rabbits exhibited pancreatic changes such as fibrosis, vacuolar degeneration, and metaplasia of mucus-secreting epithelial cells. Insulin-producing pancreatic islets were significantly smaller compared to wild-type controls, correlating with lower circulating insulin levels and compromised glucose metabolism.
Dr. Xu stated, "Our findings suggest that rabbits with CF replicate key aspects of CF pancreatic disease," positioning them as a valuable model for translational research on CFRD.
A significant outcome of the study was the identification of an indeterminate glucose tolerance (INDET) stage in young CF rabbits, a precursor to CFRD seen in humans. This stage was characterized by delayed glucose clearance and reduced insulin secretion. Female CF rabbits displayed a higher propensity for INDET-like phenotypes, mirroring sex-based differences in human CFRD prevalence.
The implications of this research extend beyond basic science. CF rabbits provide an alternative to large-animal models, such as pigs and ferrets, which are costly and require specialized care. Rabbits are cost-effective, easier to handle, and widely used in lab settings.
Dr. Xu noted, "As the CF community shifts its focus to age-related and metabolic complications, our rabbit model becomes increasingly relevant." Understanding and mitigating CFRD will be essential for enhancing patients' quality of life.
This study also emphasizes the broader significance of CF-related pancreatic pathology. While exocrine dysfunction is well-documented, endocrine dysfunction, manifested as CFRD, presents unique challenges. CFRD features characteristics of both type 1 and type 2 diabetes, necessitating innovative therapeutic strategies.
By establishing rabbits as a viable model for CFRD research, the authors aim to facilitate targeted intervention development. Early-stage therapies addressing the INDET phase could delay or prevent full-blown diabetes in CF patients.
The National Institutes of Health funded the study (grant DK134361), highlighting its importance in addressing gaps in CF research. Future directions include exploring the long-term progression of pancreatic disease in CF rabbits and evaluating the impact of CFTR modulators like Trikafta® on endocrine outcomes.
This research represents a significant advancement in CF studies. Utilizing the unique advantages of the CF rabbit model, scientists can better understand the relationship between CFTR dysfunction and pancreatic disease, which may improve outcomes for thousands of CF patients.