Cystic Fibrosis–Related Diabetes Workshop: Research Priorities Spanning Disease Pathophysiology, Diagnosis, and Outcomes

**Background:** Cystic fibrosis (CF) is a recessive disorder caused by mutations in the CFTR gene, leading to progressive organ dysfunction. CF-related diabetes (CFRD) is a common complication, occurring in 20% of teens and up to half of adults with CF. CFRD is associated with increased morbidity, mortality, and patient burden, and is largely driven by insulin insufficiency. The National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop (23–25 June 2021) to define knowledge gaps and research priorities.

**Methods:** The workshop brought together researchers, clinicians, and patient representatives to review current data on CFRD mechanisms, diagnosis, and treatment. Presentations covered genetic risk factors, disease pathophysiology, model systems, screening and diagnosis, nutrition, effects of CFTR modulator therapy, and health care delivery. The report summarizes these presentations and identifies priority research areas.

**Key Results:** - **Genetic Risk Factors:** Over 2,000 CFTR variants exist. Severe genotypes (e.g., F508del homozygotes) confer a risk of developing diabetes exceeding 80% by age 50 years and approaching 100% by age 60 years. Genetic modifiers outside CFTR (e.g., SLC26A9, PRSS1, TCF7L2) also influence CFRD risk. - **Pathophysiology:** Diminished insulin secretion is the dominant cause of CFRD. Histopathologic studies show partial loss of β-cell mass, altered islet composition, and islet remodeling. CFTR expression in β-cells is debated, with studies showing <1% to 30% of β-cells expressing CFTR protein. - **Model Systems:** Small-animal models (mice, rats) do not spontaneously develop CFRD. Large-animal models (CF ferrets, pigs) develop exocrine pancreas pathology similar to humans. CF ferrets show progressive endocrine dysfunction, with glucose excursions above 200 mg/dL between 1–2 months of age, followed by glycemic recovery at ~3 months, then return of dysfunction in adulthood. - **Screening and Diagnosis:** Annual oral glucose tolerance tests (OGTT) are recommended by age 10 years, but adherence is poor. Continuous glucose monitoring (CGM) is increasingly used but requires validation. - **Nutrition:** The traditional high-calorie, high-fat CF diet may contribute to poor diet quality. HEMT use has led to weight gain and emerging overweight/obesity in some patients. - **HEMT Effects:** Small studies show short-term improvements in insulin secretion with ivacaftor. Registry data show trends toward lower CFRD rates 4–5 years after ivacaftor introduction. The PROMISE endocrine substudy is evaluating elexacaftor-tezacaftor-ivacaftor effects on glucose metabolism. - **Treatment:** Insulin is the only recommended treatment for CFRD. Noninsulin therapies (GLP-1 agonists, DPP-4 inhibitors) show promise but lack efficacy data. Diabetes technology (CGM, hybrid closed-loop pumps) is understudied in CFRD. - **Health Care Delivery:** Microvascular complications in CFRD appear less severe than in other diabetes types, but aging CF population may change this. Racial/ethnic disparities in CFRD outcomes are unexplored.

**Clinical Implications:** The workshop identified critical research priorities including: understanding how HEMT affects CFRD development and progression; developing better model systems; improving screening methods; defining optimal nutritional strategies; investigating noninsulin therapies; and addressing health disparities. As the CF population ages and HEMT use expands, understanding CFRD pathogenesis and optimizing management becomes increasingly important for improving patient outcomes.