Dataset Information

Exocrine and Endocrine Inflammation Increases Cellular Replication in the Pancreatic Duct Compartment in Type 1 Diabetes.

ABSTRACT:

Context

We recently demonstrated increased cellular proliferation in the pancreatic ductal gland (PDG) compartment of organ donors with type 1 diabetes, suggesting that PDGs may harbor progenitor cells capable of pancreatic regeneration.

Objective

We evaluated the impact of diabetes and pancreatic inflammation on PDG and interlobular duct (ILD) cellular proliferation and profiles.

Methods

Endocrine hormone expression (insulin, glucagon, somatostatin, pancreatic polypeptide) and proliferating Ki67+ cells were localized within the PDG and ILD compartments by multicolor immunohistochemistry in cross-sections from the head, body, and tail regions of pancreata from those with (n = 31) or without type 1 diabetes (n = 43). Whole-slide scanned images were analyzed using digital pathology.

Results

Type 1 diabetes donors with insulitis or histologically identified pancreatitis had increased cellular replication in the ILD and PDG compartments. Interestingly, while cellular proliferation within the pancreatic ductal tree was significantly increased in type 1 diabetes (PDG mean = 3.36%, SEM = 1.06; ILD mean = 2.78%, SEM = 0.97) vs nondiabetes(ND) subjects without pancreatic inflammation (PDG mean = 1.18%, SEM = 0.42; ILD mean = 0.74%, SEM = 0.15, P < 0.05), robust replication was also observed in ND donors with pancreatitis (PDG mean = 3.52%, SEM = 1.33; ILD mean = 2.18%, SEM = 0.54, P < 0.05). Few polyhormonal cells were present in the ILD (type 1 diabetes = 0.04 ± 0.02%; ND = 0.08 ± 0.03%, P = 0.40) or PDG compartment (type 1 diabetes = 0.02 ± 0.01%; ND = 0.08 ± 0.13%, P = 0.63).

Conclusion

These data suggest that increased pancreatic ductal cell replication is associated with sustained pancreatic inflammation; however, as replicating cells were hormone-negative, PDGs do not appear to represent a compelling endogenous source of hormone-positive endocrine cells.

SUBMITTER: Kulkarni S

PROVIDER: S-EPMC9557836 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Exocrine and Endocrine Inflammation Increases Cellular Replication in the Pancreatic Duct Compartment in Type 1 Diabetes.

Kulkarni Shweta S Posgai Amanda L AL Kusmartseva Irina I Wasserfall Clive H CH Atkinson Mark A MA Butler Alexandra E AE

Journal of the Endocrine Society 20220903 11

<h4>Context</h4>We recently demonstrated increased cellular proliferation in the pancreatic ductal gland (PDG) compartment of organ donors with type 1 diabetes, suggesting that PDGs may harbor progenitor cells capable of pancreatic regeneration.<h4>Objective</h4>We evaluated the impact of diabetes and pancreatic inflammation on PDG and interlobular duct (ILD) cellular proliferation and profiles.<h4>Methods</h4>Endocrine hormone expression (insulin, glucagon, somatostatin, pancreatic polypeptide) ...[more]

PMID: 36249412

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Project description:Extracellular adenosine triphosphate (ATP) regulates pancreatic duct function via P2Y and P2X receptors. It is well known that ATP is released from upstream pancreatic acinar cells. The ATP homeostasis in pancreatic ducts, which secrete bicarbonate-rich fluid, has not yet been examined. First, our aim was to reveal whether pancreatic duct cells release ATP locally and whether they enzymatically modify extracellular nucleotides/sides. Second, we wished to explore which physiological and pathophysiological factors may be important in these processes. Using a human pancreatic duct cell line, Capan-1, and online luminescence measurement, we detected fast ATP release in response to pH changes, bile acid, mechanical stress and hypo-osmotic stress. ATP release following hypo-osmotic stress was sensitive to drugs affecting exocytosis, pannexin-1, connexins, maxi-anion channels and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, and corresponding transcripts were expressed in duct cells. Direct stimulation of intracellular Ca(2+) and cAMP signalling and ethanol application had negligible effects on ATP release. The released ATP was sequentially dephosphorylated through ecto-nucleoside triphosphate diphosphohydrolase (NTPDase2) and ecto-5'-nucleotidase/CD73 reactions, with respective generation of adenosine diphosphate (ADP) and adenosine and their maintenance in the extracellular medium at basal levels. In addition, Capan-1 cells express counteracting adenylate kinase (AK1) and nucleoside diphosphate kinase (NDPK) enzymes (NME1, 2), which contribute to metabolism and regeneration of extracellular ATP and other nucleotides (ADP, uridine diphosphate (UDP) and uridine triphosphate (UTP)). In conclusion, we illustrate a complex regulation of extracellular purine homeostasis in a pancreatic duct cell model involving: ATP release by several mechanisms and subsequent nucleotide breakdown and ATP regeneration via counteracting nucleotide-inactivating and nucleotide-phosphorylating ecto-enzymes. We suggest that extracellular ATP homeostasis in pancreatic ducts may be important in pancreas physiology and potentially in pancreas pathophysiology.

Dataset Information

Exocrine and Endocrine Inflammation Increases Cellular Replication in the Pancreatic Duct Compartment in Type 1 Diabetes.

Context

Objective

Methods

Results

Conclusion

Publications

Exocrine and Endocrine Inflammation Increases Cellular Replication in the Pancreatic Duct Compartment in Type 1 Diabetes.

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