Protein power: Researchers trigger insulin production in diabetic mice
Filed under Research, Health on Tuesday, January 8, 2008.GAINESVILLE,
Fla. — If the human body were a stage, then proteins would rank among
the lead actors in the play we call "Life."

These large biological molecules hold many starring roles, and their
lines are dictated by information encoded in our genes. They are
production powerhouses, regulating the basic processes of living and
controlling countless functions. Many are enzymes that produce or use
energy. Others regulate genes.

Researchers are increasingly studying proteins as potential therapies
for a variety of dread diseases because they can influence cell
behavior by fueling or dampening certain molecular signals.

Now University of Florida researchers have coaxed liver and
pancreatic cells within diabetic mice into churning out insulin by
injecting the animals with a naturally occurring protein called Pdx1,
opening up a new research avenue that someday could lead to safer
treatments for type 1 diabetes. Pdx1 activates the genes controlling
the development of the pancreas cells that make and release insulin
to maintain safe levels of glucose in the body. The UF research
team's novel approach is described online in the journal Diabetes.

"Pdx1 is so special because it possesses a unique amino acid sequence
that acts as a sort of molecular passport, allowing it to pass freely
into cells, enter the nucleus and activate insulin production and
release," said lead scientist Dr. Li-Jun Yang, an associate professor
of pathology, immunology and laboratory medicine at UF's College of
Medicine.

Earlier research has shown that inserting the Pdx1 gene into liver or
pancreas cells can induce insulin production, but most gene therapy
methods use viruses to introduce a piece of genetically engineered
DNA into cells. The disadvantage of such approaches is that
researchers can never be certain the viruses are entirely harmless,
Yang said.

The idea with protein therapy is that eventually a person's own cells
could be reprogrammed to naturally produce the hormone, restoring the
body's ability to properly regulate blood sugar levels without having
to use a potentially hazardous virus to slip corrective genes into
the body or having to transplant pancreatic cells from someone else.
That could eliminate the adverse effects sometimes associated with
gene therapy and eliminate the need for lifelong suppression of the
immune system so transplanted cells are not rejected, Yang said.

"We sought to see what happens if we inject highly pure Pdx1 protein
into (the abdomens of) diabetic animals," said Yang, who is also a
founder and head of the scientific advisory board for Transgeneron
Therapeutics Inc., which seeks to develop Pdx1 as a treatment for
diabetes. UF holds a provisional patent on Pdx1 protein
therapy. "Amazingly, the treated mice did all the rest. Upon daily
injection of this protein for 10 days into diabetic animals, their
blood glucose levels became normalized within two weeks following the
first injection. We repeated the experiment six times, and we got the
reproducible result every time. What is remarkable is that the
protein also promotes regeneration of insulin-producing cells in the
pancreas, allowing the diabetic mice to become normal."

Yang said there is now reason to believe normal blood sugar levels
can be maintained for long periods, suggesting that an infrequent
Pdx1 injection might someday replace daily insulin injections. Even
more importantly, the reprogrammed and regenerated cells should make
and release insulin, automatically maintaining safe blood sugar
levels, she said.

"Right now, promoting beta cell regeneration has become such a hot
topic," she added. "The trick is to figure out how to trigger glucose-
regulated insulin-producing cells to regenerate."

Still, the approach will have to be tested in studies that assess its
safety before scientists could conduct patient trials to determine
whether it works in people, studies that are still years away.

"What's so innovative about UF's approach is the ability to normalize
blood glucose levels in diabetic mice simply by delivering Pdx1
protein in the target cells, thus effectively eliminating the side
effects associated with gene therapy," Yang said.

Dr. Joel Habener, a professor of medicine at Harvard Medical School
whose research team was one of three groups that discovered Pdx1 and
identified it as an important regulator of pancreas development, said
using viruses as vectors for gene therapy in humans can pose problems
because of the body's immune reaction to them. He heralded the UF
findings and said the idea of using a protein to correct a condition
like diabetes is appealing because it is naturally occurring, "not a
chemical compound that's been synthesized from the mind of a chemist
that's a foreign substance."

"What these findings teach is there is promise for a therapeutic
approach to the treatment of diabetes," he said. "I think one of the
really major breakthroughs here is the demonstration of principle
that the naked protein in and of itself can get into cells and cause
changes that are remarkable in a mouse model of type 1 diabetes, the
regeneration of the insulin-producing cells in the pancreas."

http://news.ufl.edu/2008/01/08/pdx1/