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New Administrative Leader Takes Reins at CUMC
on the Front Lines
| Berrie Center Diabetes Care and Research: Dynamic, Committed, Compassionate The motto of the Naomi Berrie Diabetes Center, " The care until the cure," is compressed yet powerful: In one breath it tells the saga of diabetes treatment and research, is optimistic and aggressive about the future, and captures the vigi-lance needed to care for people with diabetes today. These stories chronicle just a few of the ways the center's clinicians and scientists strive to provide the care and reach for a cure. By Susan Conova |
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| Diabetes is Many Diseases Although he hopes someone proves him wrong, Berrie Center researcher Domenico Accili,professor of medicine, says the chance that one “magic pill” will in the future cure type 2 diabetes is slim. “That would be my first choice, but I don’t think it will happen.” The reason? Diabetes is probably a collection of related diseases, more like cancer than
Dr. Accili, an internationally acclaimed diabetes researcher for more than 20 years, was one of the first to find evidence for this idea. Traditionally, diabetes was thought to follow the same course in everyone: first the muscle and fat cells became resistant to insulin, and that inevitably led to the failure of the insulin-producing beta cells in the pancreas and full-blown diabetes. However, Dr. Accili’s studies found that diabetes is often avoidable after muscle and fat become insulin-resistant. Other organs and tissues – the brain, liver, the beta cells themselves – also become insulin-resistant and contribute to diabetes development. It’s likely that one of these tissues is more important than the others, but that organ may be the liver in one patient, or fat cells in another. Knowing which organ dominates will become an important consideration for clinicians in the future. “We won’t find a drug that treats every aspect of diabetes,” Dr Accili says. “New drugs may only work on the beta cells, so knowing if a patient suffers from beta cell or muscle or brain insulin resistance will be important so we can target treatment to individuals.” With any luck, one of these new drugs may spring from discoveries Dr. Accili’s research lab has made in the last 10 years. The target is the excess glucose the liver produces in diabetic patients – it’s the glut of glucose in the blood that’s largely responsible for taking 5 to 10 years off the lifespan of the average person with diabetes. Dr. Accili’s work has revealed that glucose release from the liver is largely controlled by a protein called FOXO1. When FOXO1 moves into a liver cell’s nucleus, the cell produces glucose. A drug that keeps FOXO1 out of the nucleus could potentially stop excess glucose production and prevent diabetes. Dr. Accili is now working to see if a drug based on FOXO1 can be developed, but he cautions that it could take a long time for this to happen and success is not guaranteed. “We start with good drug targets we find in mice, but after that, it’s a matter of trial and error. Even the best targets frequently founder in humans, and mediocre targets sometimes turn out to work,” Dr Accili says. “There’s really no way to make the process any faster, but we feel we may be on the right track.” Beta Cell Imaging in Beta Testing Many factors may lead to diabetes, but ultimately, whether one develops the disease comes down to just one kind of cell: the pancreatic beta cell. Once these insulin-producing cells are reduced in number, blood glucose levels become uncontroll-able, and diabetes ensues. Beta cell transplants or drugs that regenerate the cells are considered by many to be a
“Without that, we really have a hard time figuring out if treatments are working,” says Rudolph Leibel, MD, co-director of the Berrie Center. “Are beta cells being saved? Are they dying? We just don’t know.” Columbia scientists may soon be able to provide these answers with a new imaging technique based on positron emission tomography (PET). PET scans are commonly used to diagnose cancer, heart disease, and brain disorders because they can detect minute molecular changes inside the body. About two years ago, Paul Harris, PhD, and Antonella Maffei, PhD, research scientists in the Department of Medicine and the Naomi Berrie Diabetes Center, found they could tally the number of beta cells present inside the pancreas by using PET to measure the level of a molecule called VMAT2 that is localized to beta cells. Since initial testing of the technique in rodents about two years ago, the researchers have shepherded beta cell imaging past a few more milestones. The PET scans are now able to detect beta cells in people; in rats, the scans can pick up transplanted beta cells as well as natural-born cells. The latter development, if replicated in people, will be critically important in monitoring clinical trials of beta cell or embryonic stem cell transplantations. Beta cell imaging also will help scientists answer some still unknown basic questions about beta cells, such as: How many beta cells does a healthy pancreas contain? What happens to beta cells as the disease progresses? And, how many are needed to stave off diabetes onset? Says Dr. Leibel: “Imaging will revolutionize what we know about diabetes as well as the way we follow patients and develop and evaluate interventions.” The Eyes Have It They say the eyes are the window to the soul, but for people with diabetes, the eyes are even more meaningful: They are a window into their health. “One reason why the Berrie Center provides onsite ophthalmologic care is because an eye exam is an easy way to see what’s going on inside the body,” says Daniel Casper,
The other reason, of course, is to prevent blindness. After living with diabetes for 15 or 20 years or more, many people with type 1 and type 2 show some signs of eye disease. Diabetic retinal disease – retinopathy – is the most common complication among diabetes patients and is still the leading cause of blindness in working-age adults. But it doesn’t have to be that way. “People who have just been diagnosed with diabetes often fear they are going to go blind, because their mother or their uncle had diabetes and that’s what happened to them,” Dr. Casper says. “These days, if patients control their diabetes, there is little reason that should happen.” Controlling diabetes – specifically controlling the level of glucose in the bloodstream – is no easy task, and blood pressure and cholesterol must be monitored as well. Patients have to adopt a whole new way of living that revolves around numbers: Eating is turned into an exercise in carbohydrate counting, and food and exercise must be guided by glucose readings taken several times a day. Doctors measure patients’ success with results from the hemoglobin A1c test: another number. For some patients, though, such quantities fail to adequately motivate. For them, inspiration often comes from the pictures Dr. Casper stores in a 3-ring binder. “I find pictures of the eye are particularly powerful. Most people have a hard time digesting all the medical data they’re given, especially if they are new patients,” Dr. Casper says. “When I show them pictures of healthy retinas and diseased retinas, and then their own retinas, a significant percentage of patients turn their lives around.” Opening the binder, Dr. Casper stops to explain the first images, which look like two orange orbs, each perfectly healthy. “These normal retinas belong to a person who has had type 1 diabetes for more than 20 years. It shows what’s achievable if you’re careful,” he says. The images on the next pages show eyes in progressively worse shape. First only a few tiny red flecks are visible, micro-aneurysms in the retina’s blood vessels. Then, the amount of bleeding increases, often accompanied by leakage of lipids and retinal swelling. “If immediate steps aren’t taken to gain tighter glucose control at this point, the person gets into trouble,” Dr. Casper says. In the binder’s fourth set of images, abnormal vessels have started growing in the eye. In the next set, there’s a big red blotch almost covering the entire retina. “The new vessels tend to tear and bleed, and suddenly one day, the patient can’t see because there’s a big layer of blood in the eye,” Dr. Casper says. “The blood usually goes away, but creates scarring, and as the scar contracts, it pulls the retina off the back of the eye, creating a tractional retinal detachment. That’s one of the main ways that people with diabetes lose their sight.” Vision may also be impaired by swelling in the retina, so-called macular edema. Laser treatments can often prevent the progression to detachment and blindness, but lasers destroy some tissue and may impair night and peripheral vision. It’s best to avoid such treatment through tight diabetic control, Dr. Casper says, and most patients at the Berrie Center will never need it. “Most of our patients have excellent glucose control and they get an eye exam as often as needed, once, twice or even four times a year to prevent complications from retinopathy. Eye exams can often fall by the wayside for patients who don’t have a center like ours to manage their care and provide easy ’one-stop shopping’ for all their diabetic needs.” And if somehow a patient manages to avoid Dr. Casper’s eye exams, his memory for faces is almost as good as his memory of their eyes. “I will recognize patients in the hall and remind them personally to keep their eye exams up to date. Here at the Berrie Center, they can’t get away from us.” Fighting Diabetes Where Children Spend Their Lives –In School In the 1980s more than 95 percent of children with diabetes had the type 1 form of the disease, commonly referred to as “juvenile-onset diabetes.” In the 1990s, the Berrie
Today, between 20 percent and 40 percent of all new pediatric diabetes cases are type 2. “It’s not because there has been a sudden decline in the prevalence of type 1,” Dr. Rosenbaum says. “It’s that what was formerly known as adult-onset diabetes has become a pediatric disease.” The rising tide of type 2 diabetes in children has its roots in several factors acting in concert: Calorically dense foods have become more available while lifestyles have become more sedentary. The result: A steady increase in body fatness in children which, in turn, is “unmasking” underlying genetic risks for type 2 diabetes much earlier. The increasing numbers of children and adults with type 2 diabetes, Dr. Rosenbaum says, are already beginning to confront society with staggering health care costs. “Children with type 2 diabetes accrue morbidities like heart disease, blindness, and renal failure at a faster rate than adults with diabetes,” he says. “The costs of caring for people with these conditions at age 40, not at age 60, will be crippling.” In response to the crisis Dr. Rosenbaum and a team of nutritionists and exercise physiologists designed a unique health and fitness curriculum for junior high school students. They examined how diabetes risk factors develop in children and how they might be reduced through school-based interventions. Classroom sessions focused on diabetes, nutrition, and the importance of exercise, while physical education sessions focused on aerobic exercise. “In many schools, P.E. is prejudicial against less fit students,” Dr. Rosenbaum says. “Overweight kids are picked last for teams, they play last, or they’re standing around waiting for more athletic students to finish their sit-ups. Those who need it most end up exercising least. We designed the program so all children were busy but also having fun, like choreographing their own hip-hop dance routines. “In addition, we avoided stigmatizing the overweight child by taking him or her out of school to a gym or a nutritionist. My feeling is that no one should be denied a good opportunity to improve his or her health, so we wrote this curriculum for everyone,” Dr. Rosenbaum says. In fact, everyone in the study benefited, regardless of their initial level of fitness. After three months, students in the program lost more weight, had improved sensitivity to insulin, and reduced other risk factors for type 2 diabetes. In addition, the results provided insights into how diabetes develops that would have been extremely difficult to identify in studies of adults. In an editorial that accompanied publication of the findings in the Journal of Clinical Endcrinology and Metabolism [J Clin Endocrinol Metab. 2007 Feb; 92(2): 504-8], Philip Zeitler, MD, PhD, study chair of the multicenter Treatment Options for Type 2 Diabetes in Adolescents and Youth study, wrote: “The study represents an exciting advance because the results of previous school-based interventions have been somewhat disappointing, and concern was building that such interventions may not be productive.” Dr. Rosenbaum’s program succeeded in part, he thinks, because it examined sensitive biochemical measures of the students’ health. “You can miss health benefits if you just measure body fat or BMI, because you can improve your health without losing weight,” Dr. Rosenbaum says. “It’s nice that our kids became less overweight, but it’s even better that they become healthier.” With its demonstrated success – and new funding from the Starr Foundation and AMDeC – an even more detailed version of the program is now offered in schools in New York City and Long Island. “This study shows the kind of productive cooperation possible between students, schools, boards of education, and scientists. We all learned together. This kind of intervention is inexpensive and not hard to implement,” Dr. Rosenbaum says. “Our results should provide an impetus for schools to offer more physical and health education at all grade levels.” All photos by Charles Manley. |
