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New
targets found for preventing Diabetes
complications
Newswise — In diabetes patients, high blood
glucose levels can end up killing certain
cells in the eyes and kidneys, which is why
diabetes is the leading cause of adult
blindness and of kidney failure. Years ago,
scientists identified one main route for
this destruction—high glucose produces
oxidative stress through the NF-kB molecular
pathway—but success has been elusive for
drugs targeting that pathway.
Researchers at Joslin Diabetes Center now
have clarified the complications story by
detecting a second, independent pathway,
which offers new targets for preventing and
treating diabetic eye disease.
“Previously it was thought that oxidants are
the major pathway, but antioxidants don’t
seem to work in clinical trials,” notes
George L. King, M.D., Joslin’s Director of
Research, head of the Dianne Hoppes Nunnally
Laboratory and senior author on the paper
reporting the discovery in Nature Medicine’s
November issue.
“That clinical observation made it clear
that we don’t know all the mechanisms
involved,” says Pedro Geraldes, Ph.D., lead
author for the paper and a postdoctoral
researcher in the King lab.
Expanding the search for what goes wrong as
glucose levels climb, Geraldes studied the
effects on retinal pericytes (supportive
tissue cells found near small blood
vessels).
Scientists had long known that the protein
PDGF, a growth factor, is essential to a
cell-survival pathway that is required to
keep these retinal cells alive. Working both
in cultured cells and diabetic animals,
Geraldes traced a molecular cascade that
ends up increasing the expression of a novel
target, the protein SHP-1, which
de-activates PDGF activity and thus triggers
cell death.
“What’s exciting is that we finally have an
explanation for why antioxidant drugs may
not work, because there’s a parallel
pathway,” says King, who is also Professor
of Medicine at Harvard Medical School.
“We’ll need an inhibitor of SHP-1 together
with antioxidants to have a realistic chance
of preventing or stopping diabetic eye
disease.”
“We think this is also applicable to
diabetic kidney disease, because we observed
a similar increase in SHP-1 in the kidneys
of diabetic animals,” King adds.
Additionally, understanding the role that
SHP-1 plays in cell survival pathways may
shed light on studies of cancer and other
diseases, he says.
In follow-up research, Joslin scientists and
their colleagues will test the mechanism in
human cells and work on potential therapies
based on targeting SHP-1.
Funding for the research came from the
National Eye Institute, the Canadian
Institutes of Health Research and the
Juvenile Diabetes Research Foundation.
Others participating in the research include
Junko Hiraoka Yamamoto, Ph.D., Motonobu
Matsumoto, Ph.D., Allen Clermont and Lloyd
P. Aiello, M.D., Ph.D., of Joslin; Michael
Leitges, Ph.D., of the University of Oslo;
Andre Marette, Ph.D., of Université Laval;
and Timothy S. Kern, Ph.D., of Case Western
Reserve University.
Activation of PKC-delta and SHP-1 by
hyperglycemia causes vascular cell apoptosis
and diabetic retinopathy, Geraldes, P. et
al, published online by Nature Medicine at 1
p.m. on November 1, 2009. DOI:
10.1038/nm.2052.
Joslin
Diabetes Center is the world’s preeminent
diabetes research and clinical care
organization. Joslin is dedicated to
ensuring people with diabetes live long,
healthy lives and offers real hope and
progress toward diabetes prevention and a
cure for the disease. Founded in 1898 by
Elliott P. Joslin, M.D., Joslin is an
independent nonprofit institution affiliated
with Harvard Medical School. For more
information about Joslin, call
1-800-JOSLIN-1 or visit
www.joslin.org.
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