Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo.
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 beta-cells. Here we demonstrate that glucose-induced INS-1 beta-cell expansion is preceded by p8 protein expression. Moreover, isopropylthiogalactoside (IPTG)-induced p8 overexpression in INS-1 beta-cells (p8-INS-1) enhances cell proliferation and expansion in the presence of glucose only. Although beta-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 beta-cell function within 24 h to normal levels. In addition, insulin secretion of p8-INS-1 beta-cells in response to 0-25 mM glucose is not altered by preceding p8-induced beta-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 beta-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 beta-cell expansion in vitro and in vivo and support the notion of existing beta-cell replication in the adult organism.
Päth
Günter
G
Division of Endocrinology and Diabetology, Dept. of Internal Medicine II, University Hospital of Freiburg, 79106 Freiburg, Germany.
Opel
Anne
A
Gehlen
Martin
M
Rothhammer
Veit
V
Niu
Xinjie
X
Limbert
Catarina
C
Romfeld
Lars
L
Hügl
Sigrun
S
Knoll
Anita
A
Brendel
Mathias D
MD
Bretzel
Reinhard G
RG
Seufert
Jochen
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002096:C-Peptide / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery; D005947:Glucose / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D030781:Organisms, Genetically Modified; D010179:Pancreas / Q000166:cytology / Q000187:drug effects; D014183:Transplantation, Heterologous
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D002096:C-Peptide; D005947:Glucose; D007328:Insulin; D007544:Isopropyl Thiogalactoside; D009363:Neoplasm Proteins; C491643:NUPR1 protein, human