Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

We investigated the role of hepatocyte growth factor (HGF) in beta-cell growth and its complex intracellular signal transduction pathways. Cell proliferation was measured in the beta-cell line INS-1 using [3H]thymidine incorporation. Activation of mitogenic signaling proteins was assessed using co-immunoprecipitation, immunoblot analysis and specific protein activity inhibitors in proliferation assays. HGF (1 x 375 nM) increased INS-1 cell proliferation in the presence of 3-24 mM glucose up to 45-fold vs unstimulated controls. HGF exceeded the effect of glucose alone (2 x 2-fold at 3 mM glucose and 1 x 7-fold in the presence of 15 mM glucose). The HGF-induced INS-1 cell proliferation was further increased by addition of IGF-I or GH. Stimulation with HGF activated the JAK-2/STAT-5 pathway with a subsequent activation of phosphatidylinositol-3'-kinase (PI3'K). PI3'K activation was necessary for HGF- and glucose-stimulated INS-1 cell proliferation. The effect of PI3'K was mediated via 70 kDa S6 kinase and protein kinase B, which showed maximum activation in the presence of 3-6 mM glucose. Protein kinase C was essential for HGF-induced INS-1 cell proliferation. The HGF effect was also mediated at low glucose concentrations via insulin receptor substrate 4 (IRS-4) whereas other IRS proteins did not show any activation. High glucose concentrations also showed an increased IRS-4/PI3'K binding and therefore activation. In conclusion, beta-cell proliferation is mediated via complex interacting signal transduction pathways. HGF, in contrast to other growth factors, seems to be of importance particularly in the presence of low glucose concentrations and therefore takes a special role in this complex concert.

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Targeted Expression of Placental Lactogen in the Beta Cells of Transgenic Mice Results in Beta Cell Proliferation, Islet Mass Augmentation, and Hypoglycemia

Journal of Biological Chemistry ◽

10.1074/jbc.275.20.15399 ◽

2000 ◽

Vol 275 (20) ◽

pp. 15399-15406 ◽

Cited By ~ 138

Author(s):

Rupangi C. Vasavada ◽

Adolfo Garcia-Ocaña ◽

Walter S. Zawalich ◽

Robert L. Sorenson ◽

Pamela Dann ◽

...

Keyword(s):

Cell Proliferation ◽

Transgenic Mice ◽

Beta Cell ◽

Beta Cells ◽

Placental Lactogen ◽

Beta Cell Proliferation ◽

Islet Mass ◽

Targeted Expression

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On the dynamics of the human endocrine pancreas and potential consequences for the development of type 1 diabetes

Acta Diabetologica ◽

10.1007/s00592-019-01420-8 ◽

2019 ◽

Vol 57 (4) ◽

pp. 503-511 ◽

Cited By ~ 1

Author(s):

Oskar Skog ◽

Olle Korsgren

Keyword(s):

Cell Proliferation ◽

Type 1 Diabetes ◽

Beta Cell ◽

Endocrine Pancreas ◽

Blood Perfusion ◽

Beta Cell Proliferation ◽

Vascular Events ◽

Islet Neogenesis ◽

Islet Mass

Abstract Little is known about the human islet life span, and beta-cell neogenesis is generally considered rare in adults. However, based on available data on beta-cell proliferation, calculations can be made suggesting that the dynamics of the endocrine pancreas is considerable even during adulthood, with islet neogenesis and a sustained increase in size of already formed islets. Islet-associated hemorrhages, frequently observed in most mammals including humans, could account for a considerable loss of islet parenchyma balancing the constant beta-cell proliferation. Notably, in subjects with type 1 diabetes, periductal accumulation of leukocytes and fibrosis is frequently observed, findings that are likely to negatively affect islet neogenesis from endocrine progenitor cells present in the periductal area. Impaired neogenesis would disrupt the balance, result in loss of islet mass, and eventually lead to beta-cell deficiency and compromised glucose metabolism, with increased islet workload and blood perfusion of remaining islets. These changes would impose initiation of a vicious circle further increasing the frequency of vascular events and hemorrhages within remaining islets until the patient eventually loses all beta-cells and becomes c-peptide negative.

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Protective action of hepatocyte growth factor for acute liver injury caused byD-galactosamine in transgenic mice

Hepatology ◽

10.1002/hep.510260523 ◽

1997 ◽

Vol 26 (5) ◽

pp. 1241-1249 ◽

Cited By ~ 2

Author(s):

J Okano ◽

G Shiota ◽

H Kawasaki

Keyword(s):

Growth Factor ◽

Liver Injury ◽

Transgenic Mice ◽

Hepatocyte Growth Factor ◽

Acute Liver Injury ◽

Protective Action ◽

Hepatocyte Growth

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Monocyte activation state regulates monocyte-induced endothelial proliferation through Met signaling

Blood ◽

10.1182/blood-2009-02-207340 ◽

2010 ◽

Vol 115 (16) ◽

pp. 3407-3412 ◽

Cited By ~ 10

Author(s):

Shai Y. Schubert ◽

Alejandro Benarroch ◽

Juan Monter-Solans ◽

Elazer R. Edelman

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Direct Interaction ◽

Endothelial Cell Proliferation ◽

Specific Cell ◽

Mrna Levels ◽

Hepatocyte Growth

Abstract Direct interaction of unactivated primary monocytes with endothelial cells induces a mitogenic effect in subconfluent, injured endothelial monolayers through activation of endothelial Met. We now report that monocytes' contact-dependent mitogenicity is controlled by activation-mediated regulation of hepatocyte growth factor. Direct interaction of unactivated monocytes with subconfluent endothelial cells for 12 hours resulted in 9- and 120-fold increase in monocyte tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) mRNA levels and bitemporal spike in hepatocyte growth factor that closely correlates with endothelial Met and extracellular signal-related kinase (ERK) phosphorylation. Once activated, monocytes cannot induce a second wave of endothelial cell proliferation and endothelial Met phosphorylation and soluble hepatocyte growth factor levels fall off. Monocyte-induced proliferation is dose dependent and limited to the induction of a single cell cycle. Monocytes retain their ability to activate other endothelial cells for up to 8 hours after initial interaction, after which they are committed to the specific cell. There is therefore a profoundly sophisticated mode of vascular repair. Confluent endothelial cells ensure vascular quiescence, whereas subconfluence promotes vessel activation. Simultaneously, circulating monocytes stimulate endothelial cell proliferation, but lose this potential once activated. Such a system provides for the fine balance that can restore vascular and endothelial homeostasis with minimal overcompensation.

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