294-LB: Altered a-Cell Phenotype in Pancreata Is Associated with Increased Peri-islet Collagen Ceposition

Abstract

Cystic fibrosis (CF)-related diabetes (CFRD) affects up to 50% of adults with CF, adding to treatment burden and impacting overall wellbeing. Major changes are observed in pancreas morphology with acinar tissue replaced by fibrosis and/or fat. Islets are still present even in advanced disease and may cluster together. It is believed CFRD is caused by impaired insulin secretion and loss of β-cell mass, however, detailed pathogenesis remains unknown. We investigated post-mortem pancreatic tissue from 19 donors with CF (age range: premature-27 years) and 10 donors without CF (6-65 years). CF pattern of injury (fibrotic/lipoatrophic) was assessed by routine histology. Sirius Red/Fast Green stain was used to assess fibrosis. Artificial intelligence analysis was performed to quantify intra-islet and peri-islet collagen distribution in 16 cases (7 CF, 9 control). Triple immunofluorescence staining for insulin, glucagon, and vimentin followed by confocal microscopy was used to image up to 50 islets per donor. Glucagon and vimentin-positive (glu/vim+) α-cells were observed in both CF and non-CF pancreata (mean (range) 32 (0-90)% of islets). The presence of this altered α-cell phenotype positively correlated with age in all donors (R=0.41, p<0.05). Presence of glu/vim+ α-cells correlated with peri-islet collagen density in analysed CF and control cases (glu/vim+ islets 44 (0-82)%) (R=0.60, p<0.05). In control pancreata alone glu/vim+ cells were seen in 1-82% (mean 41%) islets and correlated positively with intra-islet collagen density (R=0.76, p<0.05). Interestingly, two CF cases with confirmed diabetes showed low prevalence of this altered phenotype (2% of islets) with 13 vs 40% fibrosis in the whole section. Our data provide further evidence for exocrine-endocrine signalling in the human pancreas and suggest that presence of vimentin-expressing α-cells may be driven by increased collagen deposition in the islet microenvironment during aging and in CFRD pathogenesis. Disclosure N. Kattner: None. S. Richardson: None. Y. Al-selwi: None. D. Tiniakos: None. J. A. Shaw: Advisory Panel; Betalin Therapeutics, Provention Bio, Inc., Consultant; Mogrify. Funding Cystic Fibrosis Trust (SRC019)