HOW SWEET IT IS
New attention to diabetes is pushing the research frontiers farther and faster than ever before.
by Monika GuttmanQuick-name the most-diagnosed disease, with more new cases than such leading cancers as prostate, breast, colon and lung combined. It annually causes more deaths in the U.S. than AIDS, affects about 8 percent of the population-the same as asthma-but costs six times as much to treat on an annual basis.
Stumped? Try diabetes, the disorder that affects the body's ability to make or use insulin, the hormone necessary to move blood sugar into the cells and thus energize the body. With too much sugar in the blood, organs, nerves and blood vessels suffer serious damage.
Today 16 million people in the U.S. have diabetes mellitus, a six-fold increase over a few decades ago.
In the past, the most common type of diabetes, Type II or adult onset diabetes, was diagnosed primarily in people over 45. These days it is showing up in 20- and 30-year-olds, and pediatricians note an emerging epidemic among teenagers. At USC-affiliated Childrens Hospital Los Angeles, 35 out of 185 of all new diabetes diagnoses are Type II. (In the past, children were likely to have insulin-dependent Type I-a more deadly autoimmune disease in which the body attacks and kills cells in the pancreas, where insulin is made. With Type I, insulin supplements are required to survive; Type II may be controlled in the early stages with diet and exercise, but patients often have to take insulin in the later stages.)
Diabetes is the leading cause of new blindness in adults, the leading cause of end-stage kidney disease, the leading cause of lower extremity amputations not related to injury and one of the major contributing factors to heart disease and stroke.
The statistics and trends have caught the attention of the Centers for Disease Control and Prevention, which recently labeled diabetes a "serious public health problem."
Congress authorized $837 million for diabetes research this year, and this means diabetes is finally catching up as a research priority, says Peter Butler, M.D., chief of the division of endocrinology and diabetes in the Keck School Department of Medicine. Beginning in 1921, when insulin was isolated and extracted, diabetes became for most a chronic condition instead of a death sentence, "Diabetes was viewed as benign. No one wrote a love story about it, and in terms of research, it wasn't top of the list," Butler says.
As attention focuses on diabetes, eyes are turning to the USC Diabetes Center, which boasts a team of 30 investigators considered to be among the best worldwide. With a "bench to bedside" approach, the USC Diabetes Center focuses on what Director Richard Bergman, Ph.D., chair of the USC Department of Physiology, calls "four pillars" of diabetes investigation: identification (who is at risk), prevention, treatment and cure.
Up to now, identifying those at risk has not been simple, says Bergman. Often it isn't until symptoms appear that patients are diagnosed. "Once diagnosed, it's essentially irreversible because by then it has been developing for 15 years or more," he says. "Ideally we would catch people early and take measures to delay or prevent diabetes altogether."
Type II diabetes accounts for 90 percent of all diabetes cases. It is understood to be caused by two defects: insulin resistance (the body doesn't utilize insulin well to metabolize sugar); and diminished pancreatic function (insulin-producing beta cells wear out and don't make enough insulin for a body that can't utilize it well in the first place). Bergman used his background in engineering to develop a computerized "minimal model" for measuring insulin resistance and pancreatic function. In a clinical test, patients are injected with glucose and a pancreas-stimulating compound, monitored in a series of lab tests over several hours and given a "disposition index" that ranks risk from lowest to highest. The test has become a standard for predicting Type II diabetes. The test is expensive and time consuming, so Bergman is simplifying the procedure to create an exam capable of use in the general population.
Easier to catch are women who develop gestational diabetes-women whose blood glucose levels rise in pregnancy. Although most return to normal blood sugar levels right after delivery, more than 50 percent will develop Type II diabetes within five years, according to studies by Thomas Buchanan, M.D., professor of medicine and obstetrics and gynecology, and his colleagues at USC. "These are women who have weak beta cells in the pancreas," says Buchanan, who directs the General Clinical Research Center at LAC+USC Medical Center. "If the cells have to work hard, like in pregnancy, they appear to wear out faster than other people's cells."
To determine whether diabetes can be prevented, Buchanan and his team gave high risk women with gestational diabetes drugs postpartum to keep the beta cells from failing. Giving the women troglitazone for three to five years changed the insulin resistance of cells and reduced the load on the pancreas. "We were able to cut the incidence of diabetes by 60 percent," notes Buchanan. Because troglitazone was recently taken off the market by the Food and Drug Administration, Buchanan and his team have switched to two similar drugs, continuing with these patients to see if the rate of diabetes remains low. Buchanan is expanding his research to determine if siblings of those with gestational diabetes are also at higher risk.
Genetics research is another important frontier for identifying those at risk. Although risk factors include obesity and inadequate exercise, diabetes is not simply the result of a slothful lifestyle. Genetic markers for Type II diabetes have been identified, so relatives of people with Type II diabetes can be screened for risk.
"Today diabetes is viewed as a combination - of genetics that evolved over thousands of years where not much food was available, and (a relatively new) environment where there is a lot of food and not much physical activity," he says.
Genetic research at USC and elsewhere is proving there is no single "diabetes gene," but rather a number of markers, including at least three on chromosome 20 that work in concert to set the stage for diabetes. "This has been a very frustrating avenue, because if there are too many markers, genetics may not be useful for identification purposes," says Bergman, who predicts that in five years researchers will have a better notion of which genes affect diabetes. On the other hand, says Buchanan, genetics research has revealed "new proteins and pathways that were not previously thought to have anything to do with glucose metabolism. These could lead to new interventions."
Because identifying high-risk groups is essential to prevent the onset of diabetes, some of the most exciting developments involve prevention. At Childrens Hospital Los Angeles, Francine Kaufman, M.D., heads part of a six-year National Diabetes Prevention Trial sponsored by the National Institutes of Health. The goal is to prevent Type I diabetes in the relatives of the almost 800,000 people in the U.S. who have insulin-dependent diabetes. Those with high risk either start on an insulin injection every day or are simply observed. Moderate risk participants either take oral insulin or are followed. Low risk individuals are simply followed.
"We hope that by giving insulin (to at-risk relatives), it will stop the body's immune system from destroying insulin-producing beta cells," says Kaufman, who is president-elect of the American Diabetes Association. First results will be released at the end of this year.
Classic diabetes prevention advice calls for increased exercise. USC investigators are determining how much is enough. "Walking didn't have an impact in terms of preventing diabetes, but those who broke a sweat in their exercise had a much lower risk of diabetes," says Buchanan. The studies also confirmed that gaining weight increases risk.
One of the hardest populations to target for prevention are youngsters, where new cases in the last 20 years increased 10-15 fold. "In general the public thinks obese kids are just chunky and will grow out of it," notes Michael Goran, Ph.D., associate director of the Keck School's Institute for Prevention Research, who studies the link between childhood obesity and diabetes. In children, the disease "happens in a much narrower time frame-two to three years-versus 20-30 years for adults." Goran has shown that lack of physical activity in kids increases risk. He is currently developing an interactive learning game that illustrates the importance of exercise and is working with Bergman, Kaufman and others to identify and target high-risk kids.
Until prevention research bears additional fruit, improved treatment is the best option for those already diagnosed. In the past decade, major studies have shown that diabetics who maintain as normal a blood sugar level as possible (with intensive blood sugar monitoring, medication, weight and diet control) can delay the onset of complications like kidney failure, nerve damage and heart disease. Some advances in recent years make normal glucose levels more attainable, including better monitoring and development of pumps that deliver appropriate amounts of insulin in lieu of daily injections. On the horizon: insulin delivered by inhalation, blood glucose monitors that do not require a skin prick, and new transplantation methods for insulin-secreting cells.
Investigators at USC and elsewhere are exploring new drugs to treat Type II diabetes: some aid the beta cells in secreting insulin, others are "insulin sensitizers" that help the cells utilize insulin, some slow glucose absorption in the stomach and some decrease the glucose released by the liver, notes Buchanan.
Some of the most significant advances in diabetic treatment relates to the eye, notes Rohit Varma, M.D., M.P.H., associate professor of ophthalmology and lead investigator of the Los Angeles Latino Eye Study, which, among other vision testing, is measuring the impact of diabetes on vision in Latinos. Diabetes weakens blood vessels, which can result in diabetic retinopathy - leakage of blood and fluid and the growth of new blood vessels in the retina. Blood and fluid collects in the eye, leading to blurred vision and eventual blindness. With laser surgery, says Varma, it is possible to plug retinal leaks and prevent further leakage. Fluids dry up and vision returns to those who have lost it, he says. Laser surgery can also prevent the growth of new blood vessels and repair retinal detachment-another complication of diabetes. Varma is also investigating new surgical methods that combat the debilitating, aggressive form of glaucoma associated with diabetes that can rapidly lead to blindness.
No matter how advanced the treatments, the biggest hope is that researchers will soon find a cure. Butler and Bergman are exploring what causes diabetes and, more specifically, insulin resistance and beta cell failure. Butler is looking at deposits in the pancreatic islet cells of amyloid-ß, a protein he believes may cause Type II diabetes. He is also exploring why cells in the pancreas fail.
Bergman is looking at the endothelial barrier through which insulin passes from blood to tissues to better understand what makes the cells insulin resistant. He is also studying the relationship between body fat in the belly or viscera and how the pancreas compensates for fatty acid overload.
Most scientists look to transplantation of the entire pancreas or specifically the insulin-producing beta cells as the best hope of a cure for people with diabetes. Although some pancreas transplants have been successful, patients must take powerful drugs to prevent rejection of the transplanted organ, and there have been few successful long-term pancreas transplants.
At USC, Richard Selby, M.D., associate professor of surgery, has started what appears to be a more successful transplant approach: combination kidney/pancreas transplants for Type I diabetics who have renal failure as a consequence of the diabetes. "The tandem transplant provides the new kidney and a stable carbohydrate environment ensures that the kidney function will not be harmed by recurrent diabetes," Selby says. "Also, certain neuropathic changes related to the diabetes are reversed as well."
Since the early 1970s, when islet transplantation was found to cure diabetes in rats, scientists have been trying to transplant the cells successfully in humans. Scientists have been frustrated because the cells responded poorly to immunosuppressive drugs. New drugs may make such transplants possible, says Bergman. Researchers are also trying to create artificial islet cells that secrete insulin in response to increased sugar levels in the blood.
Bergman and others are certain that new attention to diabetes will move all four areas of research-identification, prevention, treatment and cure-farther and faster than even the past few decades. "Diseases with terrible symptoms that come on very quickly get a lot of attention," Bergman says. "People have come to realize that diabetes is also bad, except that it happens slowly over time. The push for more answers may bring new hope to those who have this disease."
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