Researchers are making progress in unraveling the complexities of diabetes complications, but they still have a long hill to climb.

For now, much of the work is confined to studying cells in the lab or experimenting with animal models of the disease.

One key finding in recent years is that much of the damage to blood vessels in diabetes is probably being caused by oxygen compounds known as "free radicals."

That damage can cause vessels in the kidneys to stop filtering toxins and creating urine. It can cause vessels in the retina of the eye to leak fluid or hemorrhage, clouding vision. And it can reduce the blood flowing to peripheral nerves, causing some deterioration.

A brand new study by Dr. Antonio Ceriello of Warwick University in the United Kingdom and colleagues at the University of Oklahoma shows how high levels of blood glucose seem to rapidly create a persistent output of these oxygen radicals.

When the glucose combines with proteins in the cellular energy-producing factories known as mitochondria, he discovered, they reset the mechanism that produces oxygen radicals so that it stays in the "high" position even after blood sugar levels are lowered.

But there is hope. Dr. Ceriello and his colleagues found that antioxidants such as vitamin C or a blood pressure medication called telmisartan were able to block the oxidative damage in some patients.

Boosting an antioxidant

Dr. Robert Stanton, of the Joslin Diabetes Center in Boston, has found in animal and lab studies that diabetes patients may suffer from the lack of a natural creator of antioxidants called NADPH.

That, in turn, seems to be driven by reduced levels of an enzyme that is critical for making NADPH, and his group is hoping to find drugs that might boost the enzyme to normal levels.

Restoring NADPH might not only lessen the oxygen damage to the lining of blood vessels, he said, but it also might produce more of a substance called nitric oxide, which helps relax blood vessels and improve blood flow.

Nitric oxide is also a key substance in the research of Dr. Mark S. Segal, a kidney scientist at the University of Florida.

Once the lining of blood vessels has been damaged, the body recruits specialized white blood cells to go to the site of the injury and repair it. In diabetic patients, however, those cells can't function properly because they are too rigid, Dr. Segal found.

When he bathed the cells in nitric oxide in the lab, however, they became flexible again, leading him to believe that restoring proper nitric oxide levels in those cells could be crucial for repairing the vascular damage.

While many of these research projects are years away from human clinical trials, one gene therapy experiment at the University of Pittsburgh hopes to start safety testing on human volunteers next year.

It isn't directed at diabetes exclusively, but it could help many of those patients, because it is aimed at blocking the severe pain that often accompanies peripheral nerve damage.

The project is headed by Dr. Joseph Glorioso III, the William S. McEllroy Professor of Biochemistry at Pitt , whose team found a way to insert genes for a natural pain killer called enkephalin into the nerve cells of rats.

Patients with chronic nerve damage often suffer excruciating pain because the nerves become hypersensitive to touch and temperature, and while opiates like morphine can dull the pain for awhile, people quickly develop a tolerance for the painkillers and need increasing doses.

But in the rats that received the genes for the natural painkiller, "the cool thing about this is that it doesn't develop tolerance in the animals, the way morphine and other systemic drugs do."

Dr. Glorioso's team also has developed a way of inserting a receptor in the nerves for a substance called glycine, raising the possibility that one day, people may be able to wear glycine-secreting patches to temporarily block pain.

The Pitt research doesn't attack the nerve damage directly, but that's exactly where Dr. Mark Yorek at the University of Iowa is focusing.

He is driven partly by the belief that nerve damage in diabetes is an underappreciated problem.

More than half of diabetes patients end up with some kind of nerve damage, Dr. Yorek said. It often starts with pain or tingling, but then leads to numbness, "which makes patients think the problem is getting better, when in fact it's getting worse."

The numbness often means the nerves are literally pulling away from the surface of the skin, which creates particular problems in the feet, not only because those nerve signals have to travel a longer way, but because "people don't look at the bottoms of their feet, which is how wounds get started. Even a simple thing like cutting toenails can be a problem."

Once an injury occurs, it can take a long time to heal because of poor blood flow and because the high blood sugar creates a "breeding ground for bacteria," he said.

Dr. Yorek and others have discovered that the very process the body uses to get rid of extra blood glucose creates a substance called sorbitol, which can attack the lining of the nerves.

Treating 'fat rats'

To investigate which drugs might reduce that damage, Dr. Yorek has done experiments with a breed of morbidly obese lab animals known as Zucker rats.

The Zucker rats, which are twice as heavy as normal rats, lack the ability to stop eating, and as a result, they develop high blood pressure, heart problems and the rat equivalent of type 2 diabetes.

Dr. Yorek's team found it could block much of the nerve damage in Zucker rats by using either a blood pressure medication known as an ACE inhibitor or a cholesterol-lowering drug called a statin, but it also discovered that those treatments and others had much less effect on reversing nerve and vessel damage in the rats if it already had occurred.

And that poses a problem for human drug trials, Dr. Yorek said. Most trials involve patients who already have complications, and because of cost, they often last less than a year.

His animal studies suggest it may be hard to get good results that way.

"Once you have neuropathy in the patients you're studying," he said, "it's already pretty advanced, and trying to improve their status in a year, I fear the outcome will be marginal."