Cystic fibrosis (CF) is a life-threatening genetic disease affecting multiple organ systems, with pancreatic dysfunction representing a critical and often overlooked complication. A groundbreaking study published in eGastroenterology presents young rabbits with cystic fibrosis as a new and accessible model to study cystic fibrosis-related pancreatic endocrine pathology. This model provides an unprecedented opportunity to deepen our understanding of cystic fibrosis-related diabetes (CFRD), a disease that affects up to 50% of adults with cystic fibrosis.
CF is caused by mutations in the transmembrane conductance regulator (CFTR) gene, leading to abnormal transport of chloride and sodium across epithelial cells. Although advances such as Trikafta® have significantly improved pulmonary outcomes, pancreatic complications, particularly endocrine dysfunction, continue to challenge patients’ quality of life. The present study, led by Dr. Jie Xu and colleagues, explores the spontaneous development of pancreatic lesions and glucose metabolism abnormalities in CF rabbits, providing new insights into the pathophysiology of the disease.
The team developed their CF rabbit model using CRISPR/Cas9 gene editing technology. Rabbits with CF showed characteristic pancreatic changes, including fibrosis, vacuolar degeneration, and metaplasia of mucus-secreting epithelial cells. The size of insulin-producing pancreatic islets in these animals was significantly smaller than in wild-type controls, correlating with lower circulating insulin levels and compromised glucose metabolism.
Our results suggest that rabbits with CF reproduce key aspects of CF pancreatic disease. This positions them as a valuable model for translational research into CFRD and associated conditions. »
Mr. Jie Xu, corresponding author and researcher at the University of Michigan School of Medicine
A key finding of the study was the identification of an indeterminate glucose tolerance stage (INDET) in young rabbits with cystic fibrosis, a precursor to CFRD seen in human patients. This stage included a delay in glucose clearance and reduced insulin secretion, paralleling early signs of diabetes progression in humans. Interestingly, CF rabbits were more prone to INDET-like phenotypes, reflecting the sex-based differences observed in the prevalence of CFRD in humans.
The implications of this work extend well beyond basic research. Rabbits with cystic fibrosis provide an alternative to existing large animal models, such as pigs and ferrets, which are expensive and/or require specialized care. In contrast, rabbits are cost-effective, easier to handle, and widely used in the laboratory, making them accessible to a wider range of researchers.
-“As the CF community focuses on age-related and metabolic complications, our rabbit model becomes increasingly relevant,” explained Dr. Xu. “As life expectancy improves with CFTR modulators, understanding and mitigating CFRD will be key to improving patients’ quality of life.” »
The study also highlights the broader importance of pancreatic pathology linked to cystic fibrosis. While exocrine dysfunction and pancreatic insufficiency are well documented in CF, endocrine dysfunction, manifested by CFRD, presents unique challenges. CFRD combines features of type 1 and type 2 diabetes, with insulin deficiency and resistance contributing to its progression. Current treatments primarily focus on symptom management, highlighting the urgent need for innovative therapeutic strategies.
By making the rabbit a viable model for CFRD research, the authors aim to facilitate the development of targeted interventions. Early-stage therapies, such as those addressing the INDET phase, could significantly delay or prevent the onset of full-blown diabetes in CF patients. Additionally, this model allows the evaluation of emerging treatments, including those designed to modulate pancreatic inflammation, fibrosis, and insulin production.
Funding for the study from the National Institutes of Health (grant DK134361) highlights its importance in filling critical 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.
In conclusion, this work represents a significant advance in cystic fibrosis research. By leveraging the unique advantages of the CF rabbit model, scientists can better understand the complex interplay between CFTR dysfunction and pancreatic disease. This knowledge promises to improve outcomes for thousands of patients with cystic fibrosis and its complications.
