On its own, glucose is a major factor for proliferation of pancreatic ␤-cells and is also an essential prerequisite for IGF-I and growth hormone-induced growth of these cells. p8 was originally identified as an emergency gene product upregulated in pancreatic acinar cells in response to acute pancreatitis. p8 was further shown to be involved in a broad range of biological functions, including cell growth, growth arrest, apoptosis, and tumor development. These in part opposite actions may be related to distinct stimuli and pathways in certain conditions and cell types. Here we demonstrate that p8 is widely expressed in human pancreatic islets in vivo and in several ␤-cell lines in vitro. Based on this observation, we tested the hypothesis that p8 production in pancreatic ␤-cells is regulated by glucose. Incubation of rat INS-1 ␤-cells with 25 mmol/l glucose resulted in a continuous increase of proliferating cell numbers. This was accompanied by a strong upregulation of p8 mRNA and protein expression, indicating that p8 is a physiological mediator of glucose-induced pancreatic ␤-cell growth. Binding of glucose-activated protein kinase C (PKC) to two PKC sites within a highly conserved region of the p8 protein may be a possible mechanism linking glucose and p8 pathways leading to proliferation. Diabetes 53 (Suppl. 1)

. Glucose-dependent expansion of pancreatic ␤-cells by the protein p8 in vitro and in vivo. Am J Physiol Endocrinol Metab 291: E1168 -E1176, 2006. First published July 18, 2006 doi:10.1152/ajpendo.00436.2005.-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 glucoseinduced 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 TO DATE, IT IS CONTROVERSIAL whether neogenesis from pancreatic precursor cells present in ducts (2) and islets of Langerhans (45) or self duplication of existing ␤-cells (12) contributes to the formation of new pancreatic ␤-cells in the adult organism. The debate highlights that mechanisms of ␤-cell homeostasis and regenerative repair are not well understood. In particular, knowledge about molecular regulation of pancreatic ␤-cell mass expansion is limited. Important examples of factors associated with ␤-cell expansion are the incretin hormone glucagon-like peptide (GLP)-1, the GLP-1 analogon exendin (Ex)-4 (28), and the cellular molecular mediator cyclin D2 (17).Here we report on ␤-cell-expanding properties of the protein p8, which is considered to be a member of the high-mobility group (HMG)-I/Y transcription factor family despite low sequence homology (14). p8 is expressed in a broad range of tissues (25, 41) and is degraded via the ubiquitin/proteasome pathw...

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