Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice.

Recent advances in human islet transplantation have highlighted the need for expanding the pool of beta-cells available for transplantation. We have developed three transgenic models in which growth factors (hepatocyte growth factor [HGF], placental lactogen, or parathyroid hormone-related protein) have been targeted to the beta-cell using rat insulin promoter (RIP). Each displays an increase in islet size and islet number, and each displays insulin-mediated hypoglycemia. Of these three models, the RIP-HGF mouse displays the least impressive phenotype under basal conditions. In this study, we show that this mild basal phenotype is misleading and that RIP-HGF mice have a unique and salutary phenotype. Compared with normal islets, RIP-HGF islets contain more insulin per beta-cell (50 +/- 5 vs. 78 +/- 9 ng/islet equivalent [IE] in normal vs. RIP-HGF islets, P < 0.025), secrete more insulin in response to glucose in vivo (0.66 +/- 0.06 vs. 0.91 +/- 0.10 ng/ml in normal vs. RIP-HGF mice, P < 0.05) and in vitro (at 22.2 mmol/l glucose: 640 +/- 120.1 vs. 1,615 +/- 196.9 pg. microg protein(-1). 30 min(-1) in normal vs. RIP-HGF islets, P < 0.01), have two- to threefold higher GLUT2 and glucokinase steady-state mRNA levels, take up and metabolize glucose more effectively, and most importantly, function at least twice as effectively after transplantation. These findings indicate that HGF has surprisingly positive effects on beta-cell mitogenesis, glucose sensing, beta-cell markers of differentiation, and transplant survival. It appears to have a unique and unanticipated effective profile as an islet mass- and function-enhancing agent in vivo.

[1]  J F Elliott,et al.  Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. , 2001, Diabetes.

[2]  A. F. Stewart,et al.  Using β-Cell Growth Factors to Enhance Human Pancreatic Islet Transplantation* , 2001 .

[3]  G. Korbutt,et al.  Glucose-dependent insulin release from genetically engineered K cells. , 2000, Science.

[4]  B. Torbett,et al.  Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice , 2000, Nature.

[5]  B. Thorens,et al.  Glucose uptake, utilization, and signaling in GLUT2-null islets. , 2000, Diabetes.

[6]  R. Burcelin,et al.  Transgenic Reexpression of GLUT1 or GLUT2 in Pancreatic β Cells Rescues GLUT2-null Mice from Early Death and Restores Normal Glucose-stimulated Insulin Secretion* , 2000, The Journal of Biological Chemistry.

[7]  E. Ryan,et al.  Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. , 2000, The New England journal of medicine.

[8]  S. Bonner-Weir,et al.  In vitro cultivation of human islets from expanded ductal tissue. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  F. Talamantes,et al.  Targeted Expression of Placental Lactogen in the Beta Cells of Transgenic Mice Results in Beta Cell Proliferation, Islet Mass Augmentation, and Hypoglycemia* , 2000, The Journal of Biological Chemistry.

[10]  E. Rosen,et al.  The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase , 2000, Oncogene.

[11]  A. Casellas,et al.  Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes , 2000 .

[12]  D. Schatz,et al.  Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells , 2000, Nature Medicine.

[13]  J. Reig,et al.  Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. , 2000, Diabetes.

[14]  S. Riordan,et al.  Hepatocyte growth factor/scatter factor‐induced intracellular signalling , 2000, International journal of experimental pathology.

[15]  A. F. Stewart,et al.  Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia* , 2000, The Journal of Biological Chemistry.

[16]  S. Bonner-Weir,et al.  Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. , 1999, Diabetes.

[17]  E. Montanya,et al.  Mechanisms of glucose hypersensitivity in beta-cells from normoglycemic, partially pancreatectomized mice. , 1999, Diabetes.

[18]  W. Heneine,et al.  Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. , 1999, Science.

[19]  T. Nakamura,et al.  Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts. , 1999, Transplantation.

[20]  L. Nie,et al.  Role of mitogen-activated protein kinase and phosphoinositide 3-kinase in the differentiation of rat pancreatic AR42J cells induced by hepatocyte growth factor , 1999, Diabetologia.

[21]  A. F. Stewart,et al.  Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse. , 1998, Endocrinology.

[22]  P. Jones,et al.  Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells. , 1998, Endocrine reviews.

[23]  Ana D. Lopez,et al.  Phosphatidylinositol 3-Kinase Is a Negative Regulator of Cellular Differentiation , 1997, The Journal of cell biology.

[24]  C. Newgard,et al.  Engineered cell lines for insulin replacement in diabetes: current status and future prospects , 1997, Diabetologia.

[25]  R. Sorenson,et al.  Adaptation of Islets of Langerhans to Pregnancy: β-Cell Growth, Enhanced Insulin Secretion and the Role of Lactogenic Hormones , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[26]  A. Bardelli,et al.  HGF receptor associates with the anti‐apoptotic protein BAG‐1 and prevents cell death. , 1996, The EMBO journal.

[27]  S. Bonner-Weir,et al.  Vulnerability of Islets in the Immediate Posttransplantation Period: Dynamic Changes in Structure and Function , 1996, Diabetes.

[28]  H. Mashima,et al.  Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. , 1996, Endocrinology.

[29]  J. Rubin,et al.  A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic beta-cell growth. , 1996, Endocrinology.

[30]  K. Matsumoto,et al.  Emerging multipotent aspects of hepatocyte growth factor. , 1996, Journal of biochemistry.

[31]  A. F. Stewart,et al.  Overexpression of Parathyroid Hormone-related Protein in the Pancreatic Islets of Transgenic Mice Causes Islet Hyperplasia, Hyperinsulinemia, and Hypoglycemia (*) , 1996, The Journal of Biological Chemistry.

[32]  D. Pipeleers,et al.  Differences in Glucose Transporter Gene Expression between Rat Pancreatic α- and β-Cells Are Correlated to Differences in Glucose Transport but Not in Glucose Utilization (*) , 1995, The Journal of Biological Chemistry.

[33]  Ana D. Lopez,et al.  Hepatocyte Growth Factor/Scatter Factor Has Insulinotropic Activity in Human Fetal Pancreatic Cells , 1994, Diabetes.

[34]  J. H. Johnson,et al.  GLUT-2 gene transfer into insulinoma cells confers both low and high affinity glucose-stimulated insulin release. Relationship to glucokinase activity. , 1994, The Journal of biological chemistry.

[35]  M. Höhne,et al.  Insulin secretion, insulin content and glucose phosphorylation in RINm5F insulinoma cells after transfection with human GLUT2 glucose-transporter cDNA. , 1993, The Biochemical journal.

[36]  J. H. Johnson,et al.  Transfection of AtT-20ins cells with GLUT-2 but not GLUT-1 confers glucose-stimulated insulin secretion. Relationship to glucose metabolism. , 1993, The Journal of biological chemistry.

[37]  J. H. Johnson,et al.  Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus. , 1990, The New England journal of medicine.

[38]  C. Ricordi.  Methods in cell transplantation , 1995 .