A new, independent pathway that can offer targets for preventing and treating diabetic eye disease has been discovered by scientists at Joslin Diabetes Center.
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.
In the past, 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.
"Previously it was thought that oxidants are the major pathway, but antioxidants don't seem to work in clinical trials," Nature quoted Dr. George L. King as saying.
"That clinical observation made it clear that we don't know all the mechanisms involved," says Dr. Pedro Geraldes, lead author for the paper.
Geraldes studied the effects on retinal pericytes (supportive tissue cells found near small blood vessels) in a bid to expand the search for what goes wrong as glucose levels climb.
For a long time, scientists have 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, the researchers 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. We'll need an inhibitor of SHP-1 together with antioxidants to have a realistic chance of preventing or stopping diabetic eye disease," said King.
"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," he added.
Additionally, understanding the role that SHP-1 plays in cell survival pathways may shed light on studies of cancer and other diseases, he said.
The study has been published in Nature Medicine.