1451-P: Peri-Islet Fibrosis in Cystic Fibrosis Is Associated with Altered Alpha-Cell Phenotype

Cystic fibrosis (CF) is caused by CF transmembrane conductance regulator mutations leading to impaired epithelial cell anion transport and thickened pancreatic exocrine secretions. CF-related diabetes commonly ensues through impact of pancreatic exocrine pathology on islet cell mass and function although specific mechanisms remain unclear. Paraffin-embedded blocks obtained post mortem from pancreatic body in 9 donors with CF (6 (67%) male; age: 0-27 years) were studied. Following haematoxylin and eosin staining, CF changes were scored as early, advanced or end-stage and islet microenvironment was evaluated for presence of surrounding fibrosis and adipocyte replacement. Four donors were categorised as ‘early’ pathology with 0 (1) % (median (IQR)) of islets surrounded by uninterrupted fibrosis and 0 (0) % by adipocyte replacement; 1 donor was categorised as ‘advanced’ with 100% fibrosis, 0% adipocyte replacement; and 4 donors were categorised as ‘end-stage’ with 65 (46) % fibrosis, 12 (32) % adipocyte replacement. Presence of glucagon/vimentin co-expressing cells was demonstrated by immunofluorescence staining / confocal microscopy in 1 (25%) donor with ‘early’ CF pathology and in all with more advanced exocrine changes. All islets with altered alpha-cell phenotype had peri-islet fibrosis. In pancreata with <50% fibrosis (11±17% (mean±SD) ; n=6) altered alpha-cell phenotype was seen in 11±14% of islets vs. pancreata with >50% fibrosis (93±7%; n=3) with altered alpha-cell phenotype in 65±10% islets (p<0.001) . Analysis of a chronic pancreatitis resection with incrementally increasing fibrosis from head to tail showed parallel increase in islet proportion with altered alpha-cell phenotype (head: 28%; body: 80%; tail: 78%) . We have demonstrated that peri-islet fibrosis is associated with aberrant islet glucagon/vimentin co-expression providing further evidence for exocrine-endocrine signalling in human pancreatic pathology.