In a joint study with Eli Lilly and Company, the researchers found that treatment with a human protein called C-peptide repaired damaged blood vessels and nerves in diabetic rats. The protein, a by-product of the production of insulin, is present in non-diabetic people but scarce or absent in type I (insulin-dependent) diabetics.
The protein is exciting for the sheer novelty of its effects as well as its therapeutic potential. Its modus operandi seems to be unprecedented, suggesting that the long-accepted view of how proteins affect cell function is far from the whole story. The study is described in the July 25, 1997, issue of Science.
"Some researchers had suspected that C-peptide might have some biological action, but it was difficult to prove," says Yasuo Ido, Ph.D., a research associate of pathology at the School of Medicine and lead author of the paper. "We found that not only does it have biological effects, these effects may be extremely important for protecting the heart, nerves, and arteries."
The protein is already abundant in many pharmaceutical laboratories, Ido says. Whenever insulin is manufactured, whether in the body or in a lab, C-peptide is released as a by-product. If the protein proves to be effective for human diabetics, the by-product might one day be almost as prized as the insulin.
Type I (insulin-dependent) and type II (non-insulin-dependent) diabetes each greatly increase the risk of nerve damage and cardiovascular disease. For unknown reasons, glucose imbalances in diabetic tissues lead to widespread damage of nerve cells and cells that line blood vessels. The damaged blood vessels become leaky, allowing cholesterol to seep in and set the stage for atherosclerosis and dangerous vascular occlusions. According to the Centers for Disease Control, diabetics are two to three times more likely than other people to die of atherosclerosis or other cardiovascular complications in a given year.
Beginning in the 1970's, some researchers wondered if diabetics might be suffering from a lack of C-peptide, which is normally secreted by the pancreas in concert with insulin. In 1993, Julio Santiago, M.D., professor of medicine and pediatrics at the School of Medicine, injected human diabetics with low doses of the protein -- just enough to match normal levels -- but saw no effects.
Trying a different approach, Ido and colleagues injected diabetic rats with larger doses of synthetic human C-peptide, exceeding the levels of C-peptide that rats produce naturally. The results were dramatic: Nerve cells worked normally and vessels almost completely stopped leaking. Because relatively large doses were needed to achieve the effect, researchers suspect C-peptide therapy could also help type II (non-insulin-dependent) diabetics who already have normal levels of the protein.
"Since this protein is so effective at preventing and reversing vascular leakage, it brings up the possibility that it could prevent cardiovascular disease in both types of diabetes," says Joseph R. Williamson, M.D., professor of pathology at the School of Medicine and senior researcher of the study. Type 1 diabetics would still have to take insulin, but they might not have to be so concerned about maintaining absolutely normal glucose levels to prevent vascular and nerve damage, he says.
Despite the impressive results, the researchers faced a significant problem. "We had a hard time convincing people of our findings, because the protein obviously wasn't working in the usual way," Ido says. Most researchers assumed that C-peptide, if it did anything at all, must work by fitting into a specific receptor like a key fits into a lock. Many investigators, including Ido, searched for a receptor for C-peptide without success. "It was hard to believe that C-peptide could do anything without a receptor," he said.
Researchers eventually used a molecular trick to prove that C-peptide didn't need a receptor. They made a mirror-image of the protein by reversing each of its building-block amino acids. If the protein worked like a key, its mirror-image analog would be useless because it wouldn't fit in the lock. To their astonishment, the researchers found that the mirror image of C-peptide also prevented vascular damage.
Researchers know that C-peptide binds to cell membranes, but they can only guess how it changes the cell. Paul Schlesinger, M.D., Ph.D., an associate professor of cell biology and physiology at the School of Medicine, found that C-peptide strongly affected the flow of potassium ions through artificial membranes. Perhaps, Williamson says, C-peptide helps restore a delicate electrical and ion balance in cells that is disrupted by diabetes. Researchers need to look much closer at C-peptide -- and develop a better understanding of how diabetes damages cells -- before they can determine the function of the protein, he says.