Jan. 18, 2000 Researchers Develop Transgenic Mice That Overexpress Hepatocyte Growth Factor
PITTSBURGH, Jan. 15 -- In research that may aid in the development of new therapies for diabetes, University of Pittsburgh researchers have developed transgenic mice that overexpress a protein, hepatocyte growth factor (HGF), inside pancreatic islet cells, fostering growth of this cell population which is responsible for the sugar-regulating hormone insulin.
The transgenic mice exhibited increased beta cell proliferation, enhanced islet mass, increased total insulin production, and decreased blood sugar levels when compared to control, non-transgenic mice. These combined effects resulted in the altered mice having sustained mild low blood sugar.
The research appears in the January 15 edition of The Journal of Biological Chemistry. "This is the first time that hypoglycemia and accelerated islet growth have been demonstrated in a transgenic animal model," according to Andrew F. Stewart, M.D., professor of medicine, chief of the division of endocrinology and metabolism and senior author of the paper. "These studies demonstrate that it is possible to bioengineer pancreatic islet cells so that they proliferate at a faster than normal rate over the long term in living animals, and that doing so can lead to overproduction of insulin and thereby lead to lower blood sugar levels."
At present, the primary drug treatment for diabetes is to give drugs that increase pancreatic insulin production, or to give insulin itself. Both treatments require daily administration of oral or injectable drugs.
"This research suggests that it may some day be possible to engineer islets which can be given to patients with diabetes to allow them to simultaneously measure blood glucose and secrete the appropriate amount of insulin. We are a long way from achieving this goal at present. However, the significance of these studies is that they demonstrate the plausibility of using this approach to treat diabetes in the future," said Dr. Stewart.
Diabetes occurs when the body cannot make use of the glucose in the blood for energy because either the pancreas cannot make enough insulin or the insulin that is available is not effective. Islet cells, located in the pancreas, make and secrete hormones that help the body break down and use food. Beta cells are located in the islets and make and release insulin, which controls the level of glucose in the blood. Hypoglycemia is an indication that the level of glucose (sugar) in the blood is too low.
"Previous research has shown that the protein HGF promotes cell growth in vitro. We developed the transgenic mouse model to determine if there was a similar effect in vivo," said Adolfo Garcìa-Ocaña, Ph.D., research associate in the division of endocrinology and metabolism and principal investigator.
Among the findings were:
* Blood glucose concentrations were significantly lower in HGF mice in both non-fasting and 24-hour fasting conditions compared with the glucose concentrations in normal mice.
* Pancreatic insulin levels were two-to seven-fold higher in the HGF transgenic mice compared with the corresponding controls.
* The volume of the islet cells was increased two-to three-fold in the HGF mice compared with the normal mice.
* The pancreatic beta cell replication rate was increased by a factor of 2.5 in HGF mice compared with normal mice.
"Most importantly, to examine the possible therapeutic role of HGF in diabetes, we studied the response of HGF mice to experimental diabetes induced by the drug streptozotocin (STZ)," said Dr. Garcìa-Ocaña. "Normal mice developed diabetes with injections of STZ; in contrast, HGF mice showed an attenuated response to STZ, displaying only very mild diabetes three weeks after injection. This suggests that HGF could be useful in strategies focused on increasing islet mass and function in diabetics."
Others involved in the research are Karen K. Takane, Ph.D.; Mushtaq A. Syed, M.D.; and Rupangi C. Vasavada, Ph.D., from the University of Pittsburgh School of Medicine and William M. Philbrick, Ph.D., from the department of medicine at Yale University School of Medicine.
This research was funded by the National Institutes of Health.
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