Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats.

Abstract

Islet transplantation is increasingly used as a therapy for human type 1 diabetes mellitus. In our study, we investigated the effect of the transplantation of a low number (n = 350) of pancreatic islets into the right liver part on the neighboring portal bile ducts. Male streptozotocin- diabetic Lewis or autoimmune-diabetic BB/Pfd rats (n = 1065) were subdivided into 11 experimental groups. A few days after low-number islet transplantation, cholangiocytes adjacent to the grafts showed an increase in proliferative activity. During the next 12-24 months, many peri-insular ductules progressed via tumor-like cystic lesions to large cystic cholangiomas, accompanied by a translocation of the insulin receptor into the cytoplasm and an increase in expression of insulin-related signaling proteins (Insulin-receptor-substrate-1, Raf-1, Mek-1). After 24 months, 53% of rats with low-number transplantation exhibited at least one cholangioma >10 mm, significantly outnumbering tumor development in the transplant-free left liver part and in any control group. No cholangiocarcinomas emerged. A graft cell origin of the tumors was excluded by Y chromosome in situ hybridization in cross-gender transplantations. Conclusively, low-number intrahepatic islet transplantation, most likely acting by permanent local hyperinsulinism, leads to prolonged cholangiocellular proliferation in streptozotocin- and in autoimmune-diabetic rats, resulting in the development of benign cystic cholangiomas.

• Authors: Matthias Evert, Hans-Ulrich Schildhaus, Regine Schneider-Stock, Frank Dombrowski
• Journal: Virchows Archiv : an international journal of pathology (Virchows Arch) Vol. 448 Issue 6 Pg. 776-87 (Jun 2006) ISSN: 0945-6317 [Print] Germany
• PMID: 16601979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose

Topics

• Adenoma, Bile Duct (etiology, immunology, pathology)
• Animals
• Bile Duct Neoplasms (etiology, immunology, pathology)
• Bile Ducts, Intrahepatic (immunology, pathology)
• Blood Glucose (analysis)
• Body Weight
• Cell Proliferation
• Diabetes Mellitus, Experimental (complications, immunology, pathology)
• Diabetes Mellitus, Type 1 (complications, immunology, pathology)
• Female
• Fluorescent Antibody Technique, Indirect
• Immunoenzyme Techniques
• Islets of Langerhans Transplantation (adverse effects, pathology)
• Liver (pathology, surgery)
• Male
• Rats
• Rats, Inbred BB
• Rats, Inbred Lew