If diabetes is a gun, complications are the bullets.

While it's true that high blood sugar and low levels of insulin are the underlying causes of the disease, it is the complications -- heart and kidney disease, amputations, eye damage -- that injure and kill diabetic patients.

		Video John Watkins' struggle with diabetes

Researchers who are studying the biochemical mechanisms of these problems say they are so complicated it may take years to unravel them.

But the payoff could be enormous, and could change diabetes from a debilitating illness to one that people could live with, suffering only minimal side effects.

Doctors group diabetes complications into two major categories: microsvascular (affecting small blood vessels) and macrovascular (affecting larger ones).

Microvascular complications include nephropathy, or kidney damage; neuropathy, or nerve damage; and retinopathy, or eye damage. Macrovascular complications include heart disease, heart failure and strokes.

The complications are similar both for type 1 -- formerly known as juvenile diabetes -- patients, whose bodies don't make insulin, and type 2 -- formerly known as adult onset diabetes -- patients, whose bodies resist the effects of insulin, although some studies have suggested that type 2 patients tend to have more severe complications because they've often waited longer to get treatment.

Although heart disease is the leading killer of people with diabetes, followed by complications from amputations, those aren't the problems that affect the largest number of diabetic patients.

Kidney disease

The single biggest problem is kidney damage, according to a study earlier this year by the American Association of Clinical Endocrinologists.

Chronic kidney disease affects nearly 28 percent of diabetes patients, the study showed. That's nearly five times the rate found in the rest of the population, and involves an estimated 200,000 people in Pennsylvania.

Diabetes now accounts for 50 percent of new end-stage kidney disease cases, doctors say, making it the leading cause of people going on dialysis to cleanse their blood of toxins, and the main factor driving the kidney transplant waiting list.

Dr. Robert Stanton, a researcher at the Joslin Diabetes Center in Boston , said kidney disease is not only a major threat in its own right, but it also correlates closely with heart disease. The biochemical measurements of kidney damage, he said, are "an incredibly powerful marker for progression to cardiovascular disease," probably because blood vessels in both organs are being hit with the same kind of inflammation.

He pointed to maps prepared by the United States Renal Data System showing that in 1994, there were no areas of the United States that had more than 318 end-stage kidney cases per million population. Ten years later, whole swaths of Texas, the Southwest, Midwest and the East, including parts of Pennsylvania, had more than 358 cases per million.

Foot problems

The second leading complication is foot problems, affecting 23 percent of patients, or about 164,000 Pennsylvanians. Those complications, which range from pain or numbness to slow-healing wounds and amputation, are caused both by nerve and blood vessel damage.

Foot wounds in diabetes often start out because a patient can't feel pain, said Dr. Alejandro Gonzalez , medical director of the Joslin Center for Diabetes at the Western Pennsylvania Hospital. Three of his patients all suffered damage because of numbness: One hurt his toes because he couldn't feel that a sock was stuffed in the front of his shoe; another developed sores from two quarters that had fallen into a shoe; and a third developed a hole in his foot from a grandchild's tiny toy.

A less-recognized form of neuropathy is damage to the autonomic nervous system, which controls such functions as digestion and blood pressure changes, said Dr. Murray Gordon, chief of endocrinology at Allegheny General Hospital.

In severe cases, that can lead to a bizarre complication called beazors , or balls of fibrous, undigested food in the stomach, as well as to fainting spells when vascular pressure fails to keep blood from running to the feet when a person stands up.

Retina damage

The third most prevalent complication is retinopathy, or eye damage. That affects about 19 percent of patients, or about 135,000 people in Pennsylvania.

Retinopathy can range from leaking or hemorrhaging of blood vessels in the eye to detachment of the retina, and is the leading cause of blindness in Americans, 24 to 70 years of age.

The good news is that early treatment of blood sugar problems often can prevent eye damage, said Dr. Thomas Friberg, director of the retinal service at the UPMC Eye Center.

"We have many diabetics who take really good care of themselves and 20 years go by and they have no retinopathy," Dr. Friberg said. "But some people can have excellent control of their diabetes and they can still get into trouble, so I want to be careful not to blame people. Just because you get eye disease doesn't mean you've failed."

Diabetes specialists close control of blood sugar closely with drugs, exercise and diet, can stave off most of the microvascular complications.

But some patients are hit by complications despite following their doctors' orders, and that may reflect a genetic susceptibility to diabetes.

Another problem: Reducing blood sugar, by itself, doesn't appear to stave off heart disease or strokes. For those conditions, which affect 3 1/2 to 5 1/2 times as many diabetes patients as others, the best medications are the same ones used by other cardiac patients -- cholesterol-lowering statins such as Lipitor, blood pressure drugs such as Vasotec and diuretics such Hydrodiuril.

One man's battle

John Watkins, 82, a retired welder and landscaper who lives in the West End, is a good example of how a model patient can work to maintain his quality of life, but still has to live with a host of complications.

Mr. Watkins, who was diagnosed with diabetes in 1975, keeps tight control over his blood sugar, takes all his other medications and won't consume anything containing more than 2 grams of sugar.

Still, it wasn't enough. Fourteen years ago -- 18 years after his diagnosis -- he woke up from a nap to hear his wife tell him, "You don't look too well … we're going to the hospital." There he found out he needed a triple heart bypass.

Just a couple weeks after coming home from the heart operation, the little toe on his right foot "began to wither up; it looked like a prune." His doctor told him it would have to be amputated. That was followed by the big toe and the fourth toe, and soon, doctors said he might have to lose his leg.

Doctors avoided that by taking off the front of his right foot, but after undergoing that procedure, he got a staph infection that kept him in the hospital for more than six months, dropped his weight to 132 pounds and left him with a serious bedsore.

But he climbed back from all of that, and when he was 76, survived another heart bypass operation.

"I believe that if I didn't believe in God and he was the source, I wouldn't have made it through," Mr. Watkins says today. "I believe God guides the minds of the doctors."

And when his specialist, West Penn's Dr. Gonzalez, asked him recently how he was able to keep his blood glucose so low, Mr. Watkins said:

"Doc, I do what you tell me to do. There's no need for me to come to you if I'm not going to do that. He just shook his head and walked away."

The scientists who investigate diabetes complications agree with Mr. Watkins.

Patients have nothing to gain by delaying the start of treatment, especially since damage is much harder to reverse than it is to prevent. And when there is procrastination, it's not always the patient's fault, said one renowned researcher, Dr. Antonio Ceriello of Warwick University in the United Kingdom.

"There are studies showing that doctors will sometimes wait a year or more before making a change in a diabetic patient's therapy," he said.

Despite such challenges, many doctors feel they've made great progress against diabetes complications in recent years.

Most specialists today agree that treatment must be started when blood sugar levels are much lower than was once considered dangerous, Allegheny General's Dr. Gordon said.

In the early 1980s, he said, a patient wasn't considered diabetic unless his measurements on a fasting blood glucose test were 200 milligrams per deciliter of blood. Today, anything above 140 on that test triggers treatment.

Until about 10 years ago, he added, doctors treating type 2 diabetes were limited to drugs that helped the pancreas secrete more insulin. Then, the Food and Drug Administration finally approved metformin, a drug that cuts the amount of glucose manufactured in the liver, greatly improving sugar control.

He also is excited by a new Amylin Pharmaceuticals injectable drug called Byetta, which seems to have the dual effect of decreasing appetite and prompting the pancreas to secrete more insulin only after a meal.

Today, "it's much more rewarding to treat diabetes because with all these different medications we can really make an impact," he said.

As investigators delve deeper into what causes complications, they also hope that one day, they may be able to block most of the damage they cause.

"I listen to people talk about a cure for diabetes," said Joslin's Dr. Stanton, "but those of us who work with complications know that diabetes would be very annoying -- but something we could live with -- if we could control the complications."