Diabetes challenges 16 million people in the United States. Here at PItt, researchers are working on the disease from every angle
As she listened to hundreds of tiny legs scurrying across her desk, 15-year-old Donna lay blanketed in darkness, trying to stifle the sound of the bugs. She thrashed in her bed, covering her ears until she couldnt take it anymore. Bonnie! she screamed across the room to her twin sister. Kill the bugs!
What bugs? What are you talking about?
Just listen, Donna whispered, theyre everywhere.
There arent any bugs, Bonnie said, her voice quivering with fear. Youre crazy. She jumped from bed, ran outside, and pounded on the house next door, where their parents were spending the evening. Its Donna, she told them, shes lost her mind. Their father and stepmother ran home and found Donna in bed, begging them to kill the bugs. They panicked, said, Come on, Donnie, lets go for a ride, and by the time they got her in the car, she was almost comatose.
As her father drove along country roads toward the emergency room, Donna sat slumped in the back seat. Her fathers voice vibrated in the distance; consciousness crashed and faded like waves against a rocky beach. The next thing she remembers is waking up in the hospital with tubes running in and out of her body, her father staring down at her with fear in his eyes.
Hey, Donnie, he said, Ive got some bad news.
Youve got diabetes.
Donna Reeds diagnosis came as a shock, but today, most doctors would say that, given her history, it was, perhaps, only a matter of time. Her grandmother had diabetes. (Reeds twin eventually got it, too.) As with many diabetics, her symptoms came on gradually, insidiously, so no one really noticed. She urinated more than usual, but didnt think much of it. The 15-minute walk home from the bus started taking a half hour, then an hour, sometimes more. Once home, shed fall asleep without even taking her coat off. Reed had always been big (size 18 or larger), and without trying, she began dropping weight. One hundred pounds later, size 10 pants hung loose.
Sixteen million Americans have diabetes (an estimated 2,200 new cases are diagnosed each day), and a disproportionate number of those cases are in Pennsylvania. Since the University of Pittsburgh is in the heart of a community with one of the largest aging populations and an obesity epidemic, Pitt researchers have sought to remain at the forefront of diabetes research. Their work spans everything from diabetes causes and treatments to education and outreach. For every two people who are diagnosed and being treated, theres one person walking around who doesnt even know they have it, says Reeds doctor, Mary Korytkowski, director of UPMCs Center for Diabetes and Endocrinology and associate professor of medicine. People explain the symptoms away by saying theyre just tired, under stress. The less explainable symptoms, like increased urination and blurred vision, come on so slowly that few notice their progression.
Diabetes is often thought of as a blood sugar disease, but in reality, its much more. Patients with diabetes dont just have a disease of sugar, says David Kelley, director of Pitts Obesity/Nutrition Research Center and professor of medicine. They have a disease of weight management, high blood pressure, nerve problems, abnormal blood lipids, and the list goes on from there. These problems stem from a disruption of the bodys delicate balancing act for restoring glucose, the sugar that fuels everything from thinking to running.
Glucose management is busy business. Cells absorb it from the blood to stay alive, muscles keep a supply for immediate energy during exercise, and the liver creates a stock to release when you skip a meal. During the day, if you eat, say, a big plate of pasta, which is rich in carbohydrates that get broken down into glucose, you stimulate a complex system that keeps glucose levels in check. The key player is the pancreas, which produces insulin, a hormone that lowers blood sugar by telling the liver to stop producing it and cells to start consuming it. But in diabetics this system breaks down. Their blood runs rich with sugar; tissues like muscle dont get enough fuel to function, while others, like the eyes and kidneys, absorb toxic amounts. For most diabetics, life revolves around a struggle to keep glucose in balance.
Though Reed describes herself as a heavy woman, size isnt her most striking feature. Shes about 70 pounds overweight, but carries it gracefully. She has a gentle face framed with pink glasses, and short waves of brown hair naturally streaked with gray. Her left hand shows a delicate gold wedding band, and her petite fingers are dotted with countless tiny blackened holes. Thats from close to 25 years of finger sticks, she says, her soft eyes warm, her smile a bit bashful.
Like most diabetics, Reed draws small drops of blood from her fingertips four or five times a day to test her glucose levels and determine how much insulin she needs. More often than not, she balances her glucose with four daily doses of insulin, but other times, things go awry. The problem with insulin therapy is keeping glucose levels from soaring without letting them drop too low. Sometimes, whether its because she skipped a meal or took a bit too much insulin, Reeds glucose plummets, and she gets uncontrollably sleepy. Her speech slurs, and she staggers like she polished off a bottle of vodka. If she realizes whats happening, she eats and everything is fine. If she doesnt, thats when Hercules steps in.
Reeds husband Hercules has learned to spot her glucose fluctuations. When she starts getting confused, sleepy, or her speech becomes slurred, he tells her to eat. If she refuses, which she sometimes does, he pours three ounces of orange juice and makes her drink it. They call it the old orange-juice trick, and if he can get it in her, it almost always works.
If Reeds blood sugar drops in the middle of the night, Hercules usually knows because she gives him the tap. While shes sleeping, she reaches across their king-sized bed and taps him. Just once. He wakes up, runs for the orange juice, and she drinks it. But sometimes, she doesnt tap. Her sugar drops steadily, and Reed goes into what she calls brain shock. She breaks out in a perfusive cold sweat, and eventually rolls across the bed until her body is pressed against Hercules. When he feels that shes drenched with perspiration, he bolts into action, but Reed doesnt make it easy: If she gets too hypoglycemic, she gets belligerent. And violent.
Hercules grabs any sugar he can get. Usually its orange juice, or straight sugar he keeps stashed by the bed. Reed never remembers her low blood sugar episodes, but from what Hercules tells her, she puts up quite a fight. She screams, Im okay! I dont want sugar! She flails around the bed, clenching her jaws and resisting as much as she can. (Fortunately for her, hes much stronger.) Oh, geez, Reed says, blushing and looking down at the floor, theres been sugar all over the bed, sugar packets from restaurants spread out everywhere, orange juice all over the pillowcases. Hes tried putting cake icing between my gum and lower lip, but it ends up all over the bed, too. She shakes her head and smiles.
Hes amazing, hes gone through so much with me. Hes saved my life so many times doing this stuff. If I didnt have him, I wouldnt be here today. Hes stopped her from tumbling down long flights of stairs in hypoglycemic oblivion, rescued her when she fell into their sons red metal fire truck, you name it. And they take these crises in stride, because events like these are a part of life for diabetics and their families, even those who monitor their glucose levels vigilantly.
Many people think theres only one kind of diabetes, but actually there are two: type I and type II. Both types involve problems with insulin that leave the body unable to control glucose, and both can cause debilitating, often-fatal problems. But thats where the similarities end. Type I diabetes is an autoimmune disease, which means the bodys immune system turns on itself and attacks the insulin producing cells in the pancreas. In time, people with type I diabetes stop producing insulin, which is fatal if not treated. Type II is much more common (it accounts for about 95 percent of all diabetic cases), and its cause is more complex. Its a disorder of metabolism, where the system essentially goes haywire: The liver makes too much glucose, the pancreas doesnt make enough insulin, and muscle cells dont absorb enough glucose from the blood. The result is skyrocketing blood sugar.
Reed has type I diabetes, which is known to be hereditary. The cause of type II is harder to nail down: Patients have a genetic predisposition to it, but that doesnt usually result in disease unless you combine it with risk factors, like obesity and inactivity. We live in an environment where physical activity has been engineered out of daily life, where high calorie foods are readily available and relatively inexpensive, says Kelley. This is an environment that places a huge number of people at risk for diabetes, which means people who are predisposed are more likely to get it.
In 1966, when Reeds father told her she had diabetes, he tried to console her, saying everything would be fine, but it wasnt necessary. Reed wasnt upset. Four years earlier, when her mother died, Reed had stood by the grave, looked to the sky, and prayed for God to give her something from her mothersomething no one could take away.
Now 50, Reed shakes her head and laughs when she remembers her reaction to learning she had diabetes. It sounds weird, she says, but I was happy, because my mothers mother had diabetes, so I got it through her, and its not curable, so no one could take it away. I felt like my prayers had been answered.
Her doctor gave her an orange and wouldnt let her leave until she could inject it with insulin, then practice on herself. The thought of giving injections terrifies many people, but she didnt mind. Before her mother died, Reed promised her shed become a nurse.
Giving shots just seemed like part of her training, and she caught on quickly. Since she was sure she was going to be a nurse (and she was right), she never worried about caring for herself. But not all diabetics are so sure.
According to Linda Siminerio, executive director of Pitts Diabetes Institute, 95 percent of diabetes care falls on the patients themselves. Its a huge burden, says Siminerio. People think, Oh, you just take your pills and your shots and youre fine. But its not that simple. To live a healthy life and minimize complications, diabetics have to monitor their glucose levels, adjust their drug dosages, keep meticulous tabs on their diet, weight, exercise, circulation (all things many people either ignore or rely on primary care physicians for). But the volume of diabetes patients and the monitoring they require are more than most physicians can manage.
For instance, we follow about 1,200 kids with diabetes here at Childrens Hospital, says Siminerio. If youve got a five-year-old, and you are planning on going to the park and being active, thats going to be a whole different blood sugar and lifestyle change than if it rains and youre sitting inside watching television. I cant talk to 1,200 people every day to make the lifestyle changes they need to make. They need to be able to independently figure out what to do.
According to Siminerio and Janice Zgibor (Public Health 99, 97, Pharmacy 84), a postdoctoral fellow in endocrinology and metabolism, the solution is education. Patients need to learn the ins and outs of their disease so they can care for themselves. But the problem is, in todays world of managed care, physicians are lucky if they get 20 minutes with each patient. It takes me an hour just to teach someone how to test their blood, says Siminerio. When youve only got 20 minutes with a patient, how do you teach them? The answer is not so simple.
What weve done historically is give didactic lectures, show slides, hand out pamphlets, and say, Now you know about your diabetes. What were learning is, that doesnt work. One-on-one education is the key, and since physicians dont often have time to do it themselves, the Diabetes Institute will soon offer traveling educators who will visit doctors offices throughout Western Pennsylvania. In a sense, says Zgibor, were teaching patients to be their own primary care provider with the guidance of a health care professional.
But patient education alone doesnt always do the trick. Many patients (even those educated about the importance of managing their diabetes) dont do what their doctors recommend. To find out why, Zgibor is examining factors that stand in the way of treatments: A lot of times, providers think they understand what patient barriers to care are. They may assume a patient stopped taking medications because she couldnt afford them, when in reality, they gave her diarrhea, but she wasnt comfortable saying so. Teenagers sometimes stop taking insulin just to see whatll happen, while some adults wont treat themselves because of financial problems. There are a lot of assumptions made about why patients dont do the right thing. What were doing is actually going out and asking the patients, What keeps you from taking care of your diabetes? What will help you take care of yourself?
Even with Reeds confidence in her ability to care for herself, she quickly learned how difficult diabetes management really is. Until about 20 years ago, there was no reliable way for her to test her glucose levels at home, so she spent her first decade as a diabetic in and out of hospitals. During her first pregnancy, she spent six months in the hospital as doctors struggled to keep her glucose under control. It wasnt until after her first son was born that Reed learned to monitor her blood levels at home. Even then, she found herself suffering from sleep apnea (a common problem for diabetics) and, eventually, heart problems.
Heart disease runs in her family, and Reeds not sure if it was her diabetes or her heredity that caused her heart attack. But according to clinical researchers like Mary Korytkowski, diabetes and heart disease go hand-in-hand.The prevalence of heart disease in diabetics is staggering: 80 percent of diabetes patients die from cardiovascular disease.
Though heart disease is the main cause of death in diabetics, its also their least understood problem. There are two-to-four-fold higher rates of heart disease in diabetics than in non-diabetics, says David Kelley. And its not clear that our current drugs for treating high glucose have had a substantial impact on the rates of heart disease. The drugs help protect patients from other problems, like blindness and kidney damage, he says, but they may not be translating into as much benefit for heart disease as clinicians and patients would want. Because of this, researchers like Korytkowski and Kelley are attacking the problem from all angles. Pitt is involved in several national trials to examine everything from the effect of weight loss and exercise on cardiovascular disease in diabetics to developing new drug therapies. Several labs throughout the University are at the front line in evaluating new treatments and understanding how they work, says Kelley. In fact, very few diabetes drugs hit the market without being tested at Pitt: If you look at all the drugs that have come out in the last four or five years, I cant think of one that did not go through human testing at Pitt. This helps patients like Reed and their doctors stay on the cutting edge, says Kelley. New therapies aside, the best way to deal with diabetes is to prevent it by avoiding risk factors, but for those who have it, education and self-management are key.
Reed sits in a bustling café, her red turtleneck casting a rosy glow on her face. She reaches nonchalantly into her purse for a black leather wallet filled with syringes, lancets, and a tiny digital glucose monitor. I tell you what, she says as she takes a small needle and stabs it into her fingertip. Learning how to do your blood sugars is the best thing that can happen to a diabetic. She squeezes her finger, but nothing comes out. She stabs again, this time a bit harder, and a pearl of blood swells from the hole. If you dont learn how to test yourself, youll end up dead or in a coma, she says, squeezing the blood onto the glucose monitor. People say, Eeeeewwww, Id rather die than do that to myself. I say, no. If you were going to die, youd do it. Reed rubs her fingertips, which are callused like leather. I cant even feel it, she says. But shed do it even if it hurt because shes seen what happens to diabetics who dont take charge of their disease.
When I was in high school, she remembers, there was one other diabetic in my graduating class. He died not long after we graduated, because he did all the wrong things. He drank, refused to take his insulin. He did everything a diabetics not supposed to do. Then she shakes her head. Not long after her bug hallucination episode, a doctor told Reed shed die before her 20th birthday because her diabetes was so out of control. He didnt think Id live to be 20, she says with an I-sure-showed-them chuckle. I would love to see that doctor now.
Diabetes and Heart Disease
For decades, clinicians and researchers specializing in diabetes have focused on lowering glucose levels to help prevent blindness and kidney disease and theyve had great success. But heart disease, the number-one killer of diabetics, remains their least understood problem. Cardiovascular disease is the major unsolved clinical issue for diabetics, says Pitt endocrinologist David Kelley. Its critical because it occurs far more often than other problems, and it has a disastrous impact. Because of this, several diabetes researchers at Pitt are working to help find optimal treatment and prevention methods.
Epidemiology professor Catherine Detre, Mary Korytkowski, director of the University of Pittsburgh Center for Diabetes and Endocrinology, and other researchers have made Pitt the vanguard site for a large nationwide study for patients who already have heart disease. The Bypass Angioplasty Revascularization Initiative for people with type II diabetes (otherwise known as BARI-IID) is the first trial to look solely at heart disease among diabetics. BARI-IID has many arms, one of which will investigate whether diabetics with cardiovascular disease are better off having bypass surgery or angioplasty in combination with intensive medical treatment, or if they do better with medication alone. And when it comes to medication, theres a plethora of pharmaceutical choices for type II diabetes: Some increase the bodys insulin production, others increase sensitivity to insulin. BARI-IID will also investigate what medications are more effective for managing diabetics while protecting them from heart disease.
In addition to BARI-IID, David Kelley and other Pitt researchers are looking at preventing heart disease in a large long-term study. Over the next decade, they will examine the effect of weight loss and exercise on death from cardiovascular disease among diabetics. RS
Hope for Type I
Patients with type II diabetes have many treatment options; those with type I have no choice. Their immune systems have destroyed their islet cells (the bodys insulin producers) so their only hope lies in daily insulin injections, which is a far from desirable treatment. The regulation you can obtain with insulin injections is gross in comparison to physiological regulation from islets, says Massimo Trucco, professor of pediatrics and pathology at Pitt. Insulin is the only thing we have, but its far from being a good solution to the problem. Because of this, he and several colleagues hope to answer a vexing question: Is it possible to transplant insulin producing cells?
Recently, a group of researchers in Canada transplanted islets into a handful of adult diabetics. With the help of intensive immunosuppression to prevent transplant rejection, these patients now rely solely on their new cells for insulin. But this method has serious problems, especially for children, the patients Trucco hopes to help.
Much of the problem with islet cell transplantation lies in the drugs required to keep the body from rejecting the transplant. These drugs are no picnic, says Trucco, Theyre very toxic, and they can kill the liver and kidneys [the filters of the body] very quickly. For adults with late-stage diabetes, immunosuppression may be worth the risks, but for children, whose immune systems are still developing, the risk is too great. But Trucco may have found a way around this.
Everyones bone marrow contains stem cells, which (if grown in the right environment) can become anything from nerve to liver cells. According to Trucco, this should be true for insulin-producing cells, and hes hoping to prove it. If he succeeds, it may be possible to transplant islet cells grown from a patients bone marrow. This would eliminate immunosuppression; the transplanted cells would come from the patients own body, so the immune system wont attack them as foreign. RS