IMPAIRED insulin secretion in cystic fibrosis-related diabetes (CFRD) is driven by reduced expression of the GLP-1 receptor (GLP-1R) in pancreatic islet cells, according to the results of a new study. The findings reveal critical disruptions in cell-specific transcriptional programs that could guide future therapies aimed at improving diabetes management in patients with cystic fibrosis (CF).
Researchers compared pancreatic tissue from individuals with CFRD to those without CF or diabetes. While levels of glucagon-like peptide-1 (GLP-1) itself remained consistent, its receptor—the GLP-1R—was significantly reduced in the islet cells of those with CFRD. Since GLP-1R plays a crucial role in enhancing insulin secretion by beta cells, this reduction may contribute directly to the impaired insulin production observed in CFRD patients.
Using advanced spatial transcriptomics, the team also identified a range of gene expression changes within alpha and beta cells in CFRD patients. Notably, they found increased expression of PCSK1, a gene encoding the enzyme that generates GLP-1, and decreased expression of PCSK1N, an inhibitor of this enzyme. These shifts suggest a compensatory mechanism within alpha cells that may not fully restore function due to the lack of GLP-1 receptor availability in beta cells.
The study emphasizes that improving GLP-1 receptor levels in beta cells could be a promising therapeutic target for managing CFRD.
Reference: Gharib SA et al. Cystic fibrosis-related diabetes is associated with reduced islet protein expression of GLP-1 receptor and perturbation of cell-specific transcriptional programs. Sci Rep. 2024;14(25689).
