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J Biol Chem, Vol. 275, Issue 2, 1226-1232, January 14, 2000
From the Hepatocyte growth factor (HGF) is produced in
pancreatic mesenchyme-derived cells and in islet cells. In
vitro, HGF increases the insulin content and proliferation of
islets. To study the role of HGF in the islet in vivo, we
have developed three lines of transgenic mice overexpressing mHGF using
the rat insulin II promoter (RIP). Each RIP-HGF transgenic line
displays clear expression of HGF mRNA and protein in the islet.
RIP-mHGF mice are relatively hypoglycemic in post-prandial and fasting
states compared with their normal littermates. They display
inappropriate insulin production, striking overexpression of insulin
mRNA in the islet, and a 2-fold increase in the insulin content in
islet extracts. Importantly, beta cell replication rates in
vivo are two to three times higher in RIP-HGF mice. This increase
in proliferation results in a 2-3-fold increase in islet mass.
Moreover, the islet number per pancreatic area was also increased by
approximately 50%. Finally, RIP-mHGF mice show a dramatically
attenuated response to the diabetogenic effects of streptozotocin. We
conclude that the overexpression of HGF in the islet increases beta
cell proliferation, islet number, beta cell mass, and total insulin
production in vivo. These combined effects result in mild
hypoglycemia and resistance to the diabetogenic effects of streptozotocin.
Hepatocyte Growth Factor Overexpression in the Islet of
Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass,
and Induces Mild Hypoglycemia*
§,,,, and
Division of Endocrinology, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and the
¶ Department of Medicine, Yale University School of Medicine,
New Haven, Connecticut 06510
*
This work was supported by National Institutes of Health
Grants DK 47168 and DK 55023, NIDCR Grant DE 12616, and Diabetes Educational Research Center Grant DK 45735.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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