SUMMARY | FULL STORY
MEDICINE
Explanation Advanced for Complications of Diabetes
Diabetes is a serious and costly health problem largely due to the chronic vascular complications associated with the disease, yet much of the way that it leads to renal failure, retinopathy, and accelerated atherosclerosis remains a mystery.
The nuclear magnetic resonance structure of CD59 shows a lysine close to a histidine, a motif that marks the complement regulator as a potential glycation target. Courtesy of J. Halperin
A group of researchers led by José Halperin, HMS associate professor of medicine, have proposed a solution to this biological whodunit that involves complement, an agent of the immune system.
Complement proteins circulate in the blood and when activated form a membrane attack complex (MAC), which cuts pores in cells and destroys them. However, Halperin's lab has shown that many pores are reversible, allowing large molecules out of the cell before resealing. These molecules include growth factors that induce cell proliferation, a side effect of complement activation that may explain its appearance in vascular proliferative diseases like atherosclerosis. Normal cells protect themselves from complement by expressing inhibitory proteins like CD59, preventing the MAC from forming on the cell's membrane. Halperin's group wondered if the mechanism of vascular cell proliferation in a disease could be inactivation of CD59.
Research led by José Halperin has uncovered a mechanism that may explain how the high blood glucose levels of diabetes lead to cell proliferation and vascular disease.
Diabetes seems to inflict damage through glycation, the binding of glucose in the blood to proteins on the vascular wall or other tissues. Glycation is a finicky reaction that targets only certain amino acids, preferring a lysine with a histidine nearby. Halperin's group found this lysine–histidine duo in the structure of human CD59, adjacent to the protein's active site. They found that exposure to glucose inhibited the function of CD59, but in cells with a mutated lysine or histidine, the effect disappeared.
Their evidence suggests a scenario in which glucose binds to and incapacitates CD59, unleashing the MAC in endothelial tissue and causing cells to release growth factors that lead to proliferative disease. The findings, published in the May 9 Proceedings of the National Academy of Sciences, may lead to more relevant diagnostic tests for diabetes complications, because the group detected high levels of glycated CD59 in the urine of diabetics. It may also lead to better animal models of diabetes by explaining why humans experience the complications in a combination and intensity not seen in animals—humans are the only known species with the lysineÐhistidine glycation site in CD59.
