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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/E1168    most recent 00436.2005v2 00436.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Päth, G. Articles by Seufert, J. Search for Related Content PubMed PubMed Citation Articles by Päth, G. Articles by Seufert, J.

Glucose-dependent expansion of pancreatic -cells by the protein p8 in vitro and in vivo

¹Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg; ²Division of Metabolism, Endocrinology, and Molecular Medicine, Department of Internal Medicine I, University of Würzburg; and ³Islet Transplantation Center, Department of Internal Medicine III, University of Giessen, Germany

Submitted 9 September 2005 ; accepted in final form 2 July 2006

p8 protein expression is known to be upregulated in the exocrine pancreas during acute pancreatitis. Own previous work revealed glucose-dependent p8 expression also in endocrine pancreatic -cells. Here we demonstrate that glucose-induced INS-1 -cell expansion is preceded by p8 protein expression. Moreover, isopropylthiogalactoside (IPTG)-induced p8 overexpression in INS-1 -cells (p8-INS-1) enhances cell proliferation and expansion in the presence of glucose only. Although -cell-related gene expression (PDX-1, proinsulin I, GLUT2, glucokinase, amylin) and function (insulin content and secretion) are slightly reduced during p8 overexpression, removal of IPTG reverses -cell function within 24 h to normal levels. In addition, insulin secretion of p8-INS-1 -cells in response to 0–25 mM glucose is not altered by preceding p8-induced -cell expansion. Adenovirally transduced p8 overexpression in primary human pancreatic islets increases proliferation, expansion, and cumulative insulin secretion in vitro. Transplantation of mock-transduced control islets under the kidney capsule of immunosuppressed streptozotocin-diabetic mice reduces blood glucose and increases human C-peptide serum concentrations to stable levels after 3 days. In contrast, transplantation of equal numbers of p8-transduced islets results in a continuous decrease of blood glucose and increase of human C-peptide beyond 3 days, indicating p8-induced expansion of transplanted human -cells in vivo. This is underlined by a doubling of insulin content in kidneys containing p8-transduced islet grafts explanted on day 9. These results establish p8 as a novel molecular mediator of glucose-induced pancreatic -cell expansion in vitro and in vivo and support the notion of existing -cell replication in the adult organism.

diabetes; islet transplantation; insulin secretion; -cell proliferation