[acb-diabetics] article

[Patricia LaFrance-Wolf]

Issue 494

New Targets Found for Preventing Diabetes Complications 

 

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.

 

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.

 

George L. King, M.D., Joslin's Director of Research, head of the Dianne
Hoppes Nunnally Laboratory and senior author on the paper stated that,
"Previously

it was thought that oxidants are the major pathway, but antioxidants don't
seem to work in clinical trials." "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. 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.

 

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 November 1, 2009. DOI: 10.1038/nm.2052.  

 

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