Scientific reportsOct 28, 2024

Cystic fibrosis-related diabetes is linked to lower levels of GLP-1 receptor protein and changes in gene activity in insulin-producing cells

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 20, 2026

Abstract

Reduced levels in individuals with may contribute to impaired insulin secretion.

Immunohistochemistry revealed no difference in GLP-1 levels per islet area between individuals with cystic fibrosis-related diabetes (CFRD) and controls.
GLP-1 receptor levels were significantly lower in CFRD compared to non-cystic fibrosis, non-diabetic individuals.
Spatial transcriptomics identified differentially expressed genes in α- and β-cells between CFRD and control pancreas.
In CFRD, the gene encoding the enzyme that produces GLP-1 was upregulated, while the inhibitor of this enzyme was downregulated.
Gene set enrichment analysis indicated specific pathway dysregulation in α and β cells in CFRD.
The findings suggest that while GLP-1 is available, its effectiveness may be limited due to decreased receptor levels.

Simplified

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes () and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.

Key numbers

77%

Decrease in GLP-1R protein levels

Comparison of GLP-1R area per area in vs. control pancreas.

216

Differentially expressed genes in α cells

Number of differentially expressed genes in α cells between and control subjects.

272

Differentially expressed genes in β cells

Number of differentially expressed genes in β cells between and control subjects.

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Funding

Competing interests

The authors declare no competing interests.

PubMed

Cystic fibrosis-related diabetes is linked to lower levels of GLP-1 receptor protein and changes in gene activity in insulin-producing cells

Abstract

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Abstract

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Competing interests

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