Combination of inhibitor and antioxidants may help prevent diabetes complications

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.