Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

Abstract

Aims/hypothesis Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. Methods Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development.Results Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. Conclusions/interpretation These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.

Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes

“…However, a significant increase in beta cell replication has been reported previously in sections from patients with severe pancreatitis, suggesting that, under these circumstances, the immune cells may elaborate a stimulus for endocrine cell proliferation [20]. One study has also (green) to demonstrate that the increased number of MCM-2+ nuclei in the type 1 diabetic vs control samples was not due to lymphocyte staining.…”

The diagnosis of insulitis in human type 1 diabetes

“…While this standard islet size was not discussed at length in the workshop, it was pointed out in subsequent discussions between the authors of this letter that the standard islet diameter, in the context of human islet transplantation, is 150 μm. Furthermore, endocrine cell numbers may be used to distinguish islets from cell clusters [16].…”

Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes

“…Six pancreas (two from each region) and one spleen paraffin block from each donor were serially sectioned and stained by hematoxylin and eosin (H&E) and immunohistochemistry. Two double immunohistochemistry stains were used to identify cell replication (Ki67) and β ‐cells (insulin) or T‐cell infiltration (CD3) and α‐cells (glucagon) according to published methods . Histopathological review was conducted with an emphasis on islet morphology, size and numbers, α ‐cell and β ‐cell composition and presence of inflammation (i.e.…”