Scientists Say a Protein May Aid Diabetics
In what could be one of the most important discoveries in diabetes research since the isolation of insulin 75 years ago, scientists have found that a small protein commonly thought to be a useless byproduct of insulin production actually can protect against diabetic complications in animals.
Researchers from Washington University in St. Louis and Eli Lilly & Company report today in the journal Science that administering the protein, called C-peptide, to diabetic rats led to the repair of damaged blood vessels and nerves, an unprecedented achievement.
If confirmed, the discovery could lead to major changes in the treatment of human patients, with C-peptide being added to diabetics’ regular doses of insulin.
“The notion that you could add a particular compound [to a diabetic’s regimen] and prevent important vascular and nerve complications would be a giant step forward” in therapy, said Dr. Robert Goldstein, vice president for research of the Juvenile Diabetes Foundation.
“If it could be developed into something that would do no more than shut down the painful aspects of diabetes, that would make it one of the major advances of the century,” added Dr. Gerald Bernstein, president-elect of the American Diabetes Assn. “It’s extraordinarily exciting.”
Researchers cautioned, however, that results had been obtained so far only in a handful of animals that were given an artificially produced form of diabetes. More testing and research will be necessary before scientists understand precisely what is happening.
Nonetheless, results in rodents have generally foreshadowed those in humans, and “the stage is set to pursue clinical studies,” concluded Dr. Joseph R. Williamson of Washington University, the senior author of the research.
Diabetes is caused by the body’s inability to produce enough insulin to regulate the storage and use of sugars in the blood. About 1 million Americans with Type 1 diabetes require insulin injections two to four times per day because their bodies produce no insulin at all. Another 15 million Americans with Type 2 diabetes produce below-normal levels of insulin and are typically treated with diet and drugs that stimulate its production.
Many complications are associated with diabetes. Cardiovascular disease is two to four times more common among diabetics than among the general population and the risk of stroke is 2 1/2 times higher. Diabetic retinopathy caused by leakage of blood vessels in the eyes is the leading cause of blindness among adults.
Damage to the nerves, called peripheral neuropathy, produces sensations ranging from tingling to intense pain and often leads to the amputation of limbs, especially the legs.
The new study hints that at least some of these complications may result from the diabetic’s lack of C-peptide.
Biologists have long puzzled over the possible biological role of C-peptide, which is produced during the body’s synthesis of insulin. Although many scientists have assumed that it must have some biological activity, no one had previously found what it was.
The current study was stimulated when Dr. John Warren of the Karolinska Institutet in Stockholm reported to Lilly--the world’s largest manufacturer of insulin--that he had observed some small improvements in human patients given C-peptide along with insulin.
Skeptical, Lilly commissioned Dr. Julio Santiago of Washington University to repeat the studies. Santiago did not observe the reported effects in humans when he used C-peptide levels approximating those found in healthy individuals, but the Lilly scientists wondered if larger amounts might work better.
Williamson and pathologist Yasuo Ido had been working with an animal model in which insulin-producing cells of the pancreas are destroyed with a chemical. The animals develop diabetes and, over a period of months, show the complications found in humans, such as damaged nerves and leaky blood vessels.
The researchers first gave high levels of C-peptide along with insulin to newly diabetic rats. “To our surprise, and the surprise of the people at Lilly, C-peptide was dramatically effective,” Williamson said. The C-peptide injections prevented the complications that arose in animals given only insulin.
They then went one step further and administered high levels of C-peptide, along with insulin, to diabetic rats that had already developed complications. The team found that blood vessels in the treated animals stopped leaking and nerves began functioning properly.
But their biggest surprise came when they began trying to find the mechanism for C-peptide’s activity. All previously known peptides in humans have been shown to work through receptors, large molecules that the three-dimensional peptide fits into like a key in a lock. Other researchers had reluctantly concluded that C-peptide had no biological activity because no one, including Ido, had been able to find a C-peptide receptor.
“We had a difficult time convincing people of our findings,” Williamson said. “It was hard to believe that C-peptide could do anything without a receptor.”
But Williamson got a clue from a recently discovered class of peptide antibiotics that also do not require a receptor. Instead, the antibiotics insert themselves into the membranes of bacteria, triggering a chemical imbalance that kills them. Several experiments reported in today’s Science paper convinced the team that C-peptide is doing the same thing, but in a way that keeps cells healthy rather than killing them.
Because C-peptide is a naturally occurring substance that has already been used to treat a small number of humans, Williamson said, it should be relatively easy to obtain Food and Drug Administration permission to conduct a clinical trial. Although tests must be done to determine possible side effects of high doses, the biggest question in his mind, he said, is “Who will pay for the tests?”
A Lilly spokesman said Thursday that the company has not decided whether to sponsor such studies.
If C-peptide is found to be useful in preventing side effects, it could substantially change diabetes treatment, Williamson said. Current thinking is that the side effects are produced by wide swings in the concentration of sugars in the blood. The state-of-the-art treatment, called “tight control,” requires giving multiple insulin injections throughout the day to minimize such swings.
Tight control has been proved effective, but is very difficult for many people to achieve. With C-peptide, Williamson said, Type 1 diabetics would still have to take insulin, but would not have to be so concerned about maintaining absolutely normal sugar levels to prevent vascular and nerve damage.
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New Research
1) To manufacture insulin, the body first produces a larger protein called proinsulin.
2) One end of proinsulin is cut off by an enzyme, yielding insulin and C-peptide, which was previously thought to have no biological function.
3) Results in rats suggest, however, that the C-peptide forms channels in the membranes of many cells to alter the flow of sodium and potassium ions into and out of the cell.
Source: Science
