Jan 27, 2006 — In a finding that could help prevent some of the worst complications of diabetes, researchers at the Albert Einstein College of Medicine have uncovered a novel molecular pathway linking high blood-sugar levels to diabetic retinopathy, a serious condition that can lead to blindness.
The study’s senior author, Dr. Michael Brownlee, is the Anita and Jack Saltz Professor of Diabetes Research and director of the Juvenile Diabetes Research Foundation’s International Center for Diabetic Complications at Einstein. The study is published as the cover story in the January 27 issue of Cell.
The study focused on methylglyoxal (MG), a chemical byproduct of the high blood sugar levels (hyperglycemia) that characterize diabetes. Methylglyoxal builds up inside those cell types that experience diabetic complications. Altered levels of MG have also been implicated in cancer, malaria, kidney failure and other diseases.
Dr. Brownlee had previously shown that hyperglycemia inside cells results in overproduction of the free radical superoxide, which in turn increases levels of the glucose-derived MG. Now, working with retinal cells, he and his colleagues have mapped out the sequence of events by which high MG levels lead to retinal damage.
The researchers found that MG turns on a gene, angiopoitentin-2, that plays a key role in diabetic retinopathy. They further showed that MG switches on angiopoitentin-2 through a novel mechanism: by directly attaching to and inactivating a protein that ordinarily inhibits the gene.
Angiopoitentin-2 produces a protein that destroys small blood vessels in the retina, impairing oxygen delivery. To compensate, the retina spawns new blood vessels—and the growth of these new vessels causes intraretinal bleeding in the diabetic eye that can ultimately lead to blindness. The findings suggest new strategies for combating diabetic retinopathy.
“Based on our findings, we believe that new drugs capable of suppressing MG levels could help to treat or even prevent diabetic retinopathy,” says Dr. Brownlee. “And since abnormal MG metabolism has also been linked to kidney failure, cancer and malaria, we feel that this discovery could have widespread implications as well.”