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

Abstract

. 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...

Gene expression in diapause-destined embryos of the crustacean, Artemia franciscana

“…p8 either stimulates (Päth et al, 2006) or inhibits (Jiang et al, 2006) cell growth, the outcome depending on association with other transcription factors (Jiang et al, 2005). Moreover, p8 promotes (Carracedo et al, apoptosis, the latter via interaction with prothymosin a .…”

Loss of Sugar Detection by GLUT2 Affects Glucose Homeostasis in Mice

“…Supporting this idea, pancreatic ß-cell expansion is induced by glucose-stimulated proliferation [29]–[32], and glucose-mediated reduction of apoptosis [33], [34]. However, glucotoxicity has been linked to persistent hyperglycemia in type II diabetes as a result of impaired ß-cell proliferation [35], [36] and increased apoptosis [37].…”

p8 deficiency leads to elevated pancreatic beta cell mass but does not contribute to insulin resistance in mice fed with high-fat diet

“…It has been observed that fibroblasts isolated from p8 -/- mice showed increased cell proliferation [ 34 ], and silencing of p8 in pancreatic cell lines also results in the latter [ 35 ]. In contrast, p8 overexpression is accompanied by upregulated proliferation of beta cells; however, this was only observed in the presence of glucose [ 19 ]. Additionally, p8 overexpression results in reduced beta-cell-related gene expression, insulin content and secretion.…”

“…TNF-α) lead to upregulation of p8 [ 9 ], and glucose-dependent stimulation of p8 was observed in INS-1 insulinoma cells [ 18 ]. Overexpression of p8 in human islets leads to augmented insulin secretion, as well as cellular insulin content and improved glycemic control [ 19 ]. In contrast, p8 −/− mice show mild insulin resistance compared to wild type animals but maintained normoglycemia through increase of beta cell mass and consecutive hyperinsulinemia [ 20 ].…”