Type 1 diabetes (T1D) is an autoimmune disease characterized by endocrine/exocrine pancreas inflammation, fibrosis and, ultimately, decreased organ mass. Accumulating evidence suggests that this chronic inflammation may play a pivotal role in the initiation and progression of endogenous pancreatic cell plasticity. Pancreatic duct glands (PDGs), a potential stem/progenitor cell niche, represent a distinct anatomical compartment of the pancreas, forming blind-ending outpouchings from the main pancreatic duct and its branches. PDGs become activated in response to inflammation in T1D, evidenced by a high frequency of epithelial cell replication and an increase in progenitor-like cells. We addressed the hypothesis that in T1D, perturbation of hormone and non-hormone expressing cells in the interlobular ducts (ILD) and PDGs is a consequence of inflammation. Pancreatic sections from 21 T1D (disease duration 3 - 84 y) and 22 age-matched nondiabetic (ND) donors were evaluated for replication and expression of known pancreatic endocrine hormones in ducts and PDGs. We confirmed increased duct and PDG replication in T1D (T1D vs. ND— ILD: 2.8 ± 0.9 vs. 0.7 ± 0.1%, p<0.05; PDG: 3.4 ± 1.0 vs. 1.1 ± 0.4%, p<0.05) and reduced frequency of insulin expressing cells (T1D vs. ND— ILD: 0.0 ± 0.0 vs. 0.4 ± 0.1%, p<0.001; PDGs: 0.01 ± 0.01 vs. 0.8 ± 0.3%, p<0.05). The frequency of PDG cell replication was highest in T1D donors with acute pancreatitis. No differences were found in the frequency of other endocrine cell types regardless of the presence of pancreatic inflammation. These data suggest that increased pancreatic ductal cell replication in the PDG compartment of subjects with T1D is associated with sustained autoimmunity-related inflammation. Efforts are underway to determine specificity of pancreatic ductal cell changes to islet or acinar inflammation and the identity of replicating ILD and PDG cells, to better understand the mechanisms underlying pancreatic ductal cell plasticity.


S.S. Kulkarni: None. A.E. Butler: None. M.A. Atkinson: None.

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