\ua9 The Author(s) 2025. Aims/hypothesis: The role of intra-pancreatic lipid and collagen in type 2 diabetes pathogenesis remains unclear. We sought to examine this in pancreases from organ donors with and without diabetes. Methods: Tissue biopsies from 36 adult donor pancreases with/without type 2 diabetes were collected from 16 anatomically defined regions, with H&E, Sirius Red Fast Green and chromogranin A immunohistochemical staining and quantification performed. Intracellular lipid droplet area was quantified using transmission electron microscopy in acinar, islet endocrine, beta and alpha cells identified through ultrastructural morphology. Results: Increasing adipocyte proportional area was associated with increasing pancreas donor BMI (r=0.385, p=0.021), decreased acinar area (r=−0.762, p<0.001) and increased endocrine mass (r=0.749, p<0.001). Fibrosis was not associated with BMI, acinar area or endocrine mass. Type 2 diabetes was associated with decreased islet circularity and reduced beta:alpha cell ratio but endocrine mass was not affected. Adipocyte and fibrosis proportional areas were highest in donors with diabetes but not associated with each other. Pancreases with high fat and those with high fibrosis (>40% proportional area) appeared to form two separate subgroups. All donors with insulin-treated diabetes had a high collagen proportional area. Fibrosis but not adipocytosis was associated with decreased beta:alpha cell ratio. There was an inverse relationship between pancreatic adipocytosis and intra-acinar cell lipid content (r=−0.490, p=0.003), with the lowest levels seen in type 2 diabetes. Beta cell lipid content was associated with BMI but not type 2 diabetes. Conclusions/interpretation: Systematic human pancreatic analysis revealed two separate type 2 diabetes phenotypes: fatty, associated with central obesity; and fibrotic, associated with reduced beta cell mass without central obesity. This suggests distinct underlying pathogenic mechanisms and has potential for developing personalised disease-modifying therapeutics
