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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 291; no. 6; pp. E1168 - E1176
• Main Authors: Path, Gunter, Opel, Anne, Gehlen, Martin, Rothhammer, Veit, Niu, Xinjie, Limbert, Catarina, Romfeld, Lars, Hugl, Sigrun, Knoll, Anita, Brendel, Mathias D, Bretzel, Reinhard G, Seufert, Jochen
• Format: Journal Article
• Language: English
• Published: United States 01.12.2006
• Subjects: Adenoviridae - genetics; Animals; Basic Helix-Loop-Helix Transcription Factors - biosynthesis; Basic Helix-Loop-Helix Transcription Factors - physiology; Blood Glucose - metabolism; Blotting, Western; Body Weight - physiology; C-Peptide - metabolism; Cell Count; Cell Proliferation - drug effects; Cells, Cultured; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - surgery; Glucose - physiology; Humans; Insulin - biosynthesis; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation; Isopropyl Thiogalactoside - pharmacology; Kidney - metabolism; Mice; Mice, Inbred C57BL; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - physiology; Organisms, Genetically Modified; Pancreas - cytology; Pancreas - drug effects; Transplantation, Heterologous
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00436.2005

1 Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg; 2 Division of Metabolism, Endocrinology, and Molecular Medicine, Department of Internal Medicine I, University of Würzburg; and 3 Islet 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 Address for reprint requests and other correspondence: J. Seufert, Division of Endocrinology and Diabetology, Dept. of Internal Medicine II, Univ. Hospital of Freiburg, 79106 Freiburg, Germany (e-mail: jochen.seufert{at}uniklinik-freiburg.de )