1374-P: In Type 2 Diabetes, the Exocrine Pancreas Has Greater Fibrosis, Fat, Metaplastic Changes, and Microangiopathy

Type 2 diabetes (T2D) is associated with increased risk of pancreatic cancer. Our knowledge of exocrine pancreas histopathology in T2D is incomplete. To determine whether T2D is associated with changes in the pancreatic exocrine compartment, we analyzed tissue sections from the pancreatic head, body, and tail of 25 T2D donors (age 51 ± yrs, duration 3.4 ± 2.6 yrs, 9/25 on insulin, BMI 35.5 ± 6.3, A1c 7.5 ± 1.5%) and 26 non-diabetic donors (ND; age 41 ± yrs, BMI 28.7 ± 5.0, A1c 5.3 ± 0.4%) using histochemistry, immunofluorescence, and CODEX multiplexed imaging with automated quantitation and manual review by two pathologists. Compared to ND, T2D pancreata were larger (113.3 ± 6.9 vs. 93.8 ± 6.7 g, p<0.05) and had more exocrine fibrosis (29.4 ± 1.6 vs. 17.3 ± 2.7% area, p<0.01) , inter- and intra-lobular fat (14.6 ± 2.0 vs. 7.6 ± 1.5% area, p<0.01) , acinar-to-ductal metaplasia (ADM; 1.4 ± 0.3 vs. 0.3 ± 0.1 positive lobules/section, p<0.01) , pancreatic intraepithelial neoplasia (PanIN; present in 40.0 vs. 14.8%, p<0.05) , and small vessel angiopathy (7.0 ± 0.5 vs. 3.6 ± 0.6 combined score, p<0.001) . In contrast, exocrine tissue from 16 donors with type 1 diabetes (T1D; age 23 ± 7 yrs, duration 11.5 ± 8.2 years, BMI 23.7 ± 5.4, A1c 9.1 ± 1.7%) had no increase in ADM, PanIN, fat or angiopathy. Though similar in severity, T2D fibrosis was predominantly intralobular, while T1D was interlobular, perivascular, and periductal. T2D tissues with greater fibrosis had more activated stellate cells compared to low fibrosis tissues (5.6 ± 1.1 vs. 1.0 ± 0.2% area, p<0.05) . Endothelial cell density, shape, and size and macrophage abundance and phenotype were similar in T2D and ND, while T cells were greater in T2D (4.1 ± 1.6 vs. 3.9 ± 1.8% of cells, p<0.05) with no change in subtype or activation. Thus, T2D is associated with marked changes in the pancreatic exocrine compartment. Whether these exocrine changes contribute to islet dysfunction or influence the risk of pancreatic cancer in T2D is unknown.