1753-P: Islet GLP-1R Protein Expression Is Reduced in Humans with Cystic Fibrosis–Related Diabetes

Abstract

Impaired insulin secretion underlies the development of cystic fibrosis-related diabetes (CFRD). Glucagon like peptide-1 (GLP-1) is produced in islet α cells, and potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. In CFRD, α-cell mass is increased. Despite this, we hypothesized that levels of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to deficits in insulin secretion. To address our hypothesis, paraffin-embedded pancreas sections from humans with CFRD and age-matched nondiabetic controls (from nPOD) underwent immunohistochemistry to quantify protein levels of active GLP-1 and GLP-1R (n=5-6/group). Spatial transcriptomics (NanoString) was also performed to assess differentially expressed α- and/or β-cell genes between CFRD and control pancreas (n=3/group; 15 CFRD + 9 control islets). GLP-1 immunoreactivity was unchanged between CFRD and control pancreas (0.33±0.15 vs 0.51±0.15, % GLP-1 area/pancreas area; p=0.4), however islet GLP-1R immunoreactivity was significantly reduced (4.35±1.21 vs 18.70±0.50, % GLP-1R area/islet area; p=0.004). Surprisingly, few α- or β-cell genes were differentially expressed between CFRD and control islets. However, a gene set test (ROAST) to assess transcripts involved in GLP-1 production/signaling revealed that those in α cells (GCG, PCSK1, PCSK2, DPP-4) significantly changed in mixed directions (up- or down-regulated; p=0.001). No such perturbation was seen in the β-cell gene set (INS, GLP1R, DPP-4, PLCG1, PIP4P2, ITPR3, ADCY1, ADCY6, PRKACA, RAPGEF4; p=0.4). In sum, our data suggest CFRD is not associated with altered intra-islet GLP-1 levels, however α-cell genes that modulate GLP-1 levels are dysregulated. Also, islet GLP-1R protein levels are reduced, though expression of genes downstream of GLP-1R is unchanged. Thus, interventions to restore protein levels of islet GLP-1R and/or promote intracellular signaling beyond GLP-1R may improve β-cell function in CFRD. Disclosure R. Vemireddy: None. J.J. Castillo: None. B.S. Fountaine: None. T.K. Bammler: None. J. MacDonald: None. R.L. Hull-Meichle: Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health. Employee; Veterans Administration. Research Support; Veterans Administration. S. Gharib: None. S. Zraika: None. Funding National Institutes of Health (P30DK089507, P30DK017047)