Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats.
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.
Evert
Matthias
M
Institute for Pathology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Schildhaus
Hans-Ulrich
HU
Schneider-Stock
Regine
R
Dombrowski
Frank
F
D002759:Adenoma, Bile Duct / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000276:immunology / Q000473:pathology*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000276:immunology / Q000473:pathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007124:Immunoenzyme Techniques; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects* / Q000473:pathology; D008099:Liver / Q000473:pathology / Q000601:surgery; D008297:Male; D051381:Rats; D011913:Rats, Inbred BB; D011917:Rats, Inbred Lew
D001786:Blood Glucose