Diabetes complications: more than sugar?

Physicians have long thought that consistently high concentrations of sugar in the blood lead to the various complications of diabetes, but new studies hint at subtler causes.

Last week, scientists suggested that one complication, diabetic neuropathy, may stem in part from the problem that causes diabetes in the first place: an autoimmune attack.

In type I diabetes, a person's own antibodies destroy the pancreas cells that make insulin. This disease, which usually begins in childhood, often causes some degree of neuropathy, or nerve cell degeneration. Typically, nerve cells in the legs, feet, and hands gradually deteriorate. If neuropathy affects the heart, death may result.

Researchers at the Eastern Virginia Medical School in Norfolk report evidence that antibodies in the blood of people with diabetic neuropathy can kill nerve cells. They speculate that these antibodies trigger apoptosis, a built-in mechanism that leads to a cell's demise.

Lead researcher Gary L. Pittenger presented the work on Dec. 13 at the annual meeting of the American Society for Cell Biology in Washington, D.C.

In their study, the scientists added diluted blood serum from people with diabetic neuropathy to laboratory-grown nerve cells derived from tumors of the human nervous system. Within 4 hours, the cells began to die. Serum from diabetics without neuropathy failed to produce such an effect.

To identify the agent causing the cell death, the researchers turned to its likely target, a protein called Fas/apo-1 that can trigger apoptosis. The team tagged an antibody with dye and added it to the nerve cells. The antibody homed in on Fas/apo-1 on the cell surfaces.

When the researchers also added the diabetics' serum, however, the tagged antibodies failed to bind to the cells. This result suggests that the serum contains an antibody that competes with the tagged one, says Pittenger. "It's probably an antibody against Fas/apo-1."

The researchers now aim to isolate and identify the suspected antibody. After that, says Pittenger, they must examine diabetics with and without the antibody: "That's critical."

Pittenger admits that his hypothesis "invites controversy, because the predominant thinking is that neuropathy comes from high glucose levels." However, about 40 percent of diabetics who carefully control their sugar intake still suffer nerve degeneration, he points out.

The immune system, glucose concentrations, and other factors may all contribute to diabetic neuropathy, he notes. "In some patients, high glucose may be the dominant factor. In others, autoimmune considerations may be important."

"This is a tantalizing, if rudimentary, observation that needs more evidence," says Douglas A. Greene of the diabetes center at the University of Michigan in Ann Arbor. "Multiple mechanisms for diabetic neuropathy are becoming evident on a clinical level, however, as well as a molecular one."