Submitted on September 9, 2005
Accepted on July 2, 2006
Glucose-dependent expansion of pancreatic 
-cells by the protein p8 in vitro and in vivo
Guenter Paeth1, Anne Opel2, Martin Gehlen2, Veit Rothhammer2, Xinjie Niu1, Catarina Limbert2, Lars Romfeld2, Sigrun R. Huegl2, Anita Knoll2, Mathias D Brendel3, Reinhard G Bretzel3, and Jochen Seufert1*
1 Department of Internal Medicine II, University Hospital of Freiburg, Division of Endocrinology and Diabetology, Freiburg, Germany
2 Department of Internal Medicine I, University of Wurzburg, Division of Metabolism, Endocrinology and Molecular Medicine, Wurzburg, Germany
3 Department of Internal Medicine III, University of Giessen, Islet Transplantation Centre, Giessen, Germany
* To whom correspondence should be addressed. E-mail: jochen.seufert{at}uniklinik-freiburg.de.
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, IPTG-induced p8 overexpression in INS-1 -cells (p8-INS1) 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-INS1 -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.
