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American Journal of Pathology, Vol 152, 1025-1038, Copyright © 1998 by American Society for Investigative Pathology

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Insulinomas derived from hyperplastic intra-hepatic islet transplants

F Dombrowski, D Klingmuller and U Pfeifer
Department of Pathology, University of Bonn, Germany. dombi@mailer.meb.uni-bonn.de

Insulinomas were induced in a new animal model by transplanting a low number of isologous pancreatic islets via the portal vein into the livers of 66 streptozotocin-induced diabetic rats. In contrast to high- number islet transplantation, which restored normoglycemia in 25 control animals, the low-number islet transplantation was followed by persisting hyperglycemia for at least 13 months. Hyperplasia of islet cells developed in the transplanted islets as a consequence of hyperglycemia, which for the beta cells is not only a secretory but also a proliferative stimulus. Six of thirty-three animals between the 18th and the 24th month after islet transplantation changed from hyperglycemia to severe hypoglycemia, due to insulinomas that had developed in the liver from the transplanted islets. In contrast to other animal models, insulinoma development in this new model does not result from DNA damage by chemicals or radiation or from the expression of transgenes, but starts from apparently normal islets prepared from untreated isologous donors, which are exposed to an imbalance in glucose metabolism. The persistent proliferative stimulus and the metabolic alterations caused by the longstanding hyperglycemia seem to be the most relevant oncogenic factors in this model.

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