A. Garcia-ocana et al., Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia, J BIOL CHEM, 275(2), 2000, pp. 1226-1232
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 relativ
ely hypoglycemic in post-prandial and fasting states compared with their no
rmal littermates. They display inappropriate insulin production, striking o
verexpression of insulin mRNA in the islet, and a a-fold increase in the in
sulin content in islet extracts. Importantly, beta cell replication rates i
n vivo are two to three times higher in RIP-HGF mice. This increase in prol
iferation results in a 2-3-fold increase in islet mass. Moreover, the islet
number per pancreatic area was also increased by approximately 50%. Finall
y, RIP-mHGF mice show a dramatically attenuated response to the diabetogeni
c 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.