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PREVENTION

IDENTIFYING THOSE AT risk means little if there is no strategy for prevention. At Childrens Hospital Los Angeles, Francine Kaufman heads part of a six-year NIH-sponsored National Diabetes Prevention Trial that aims to prevent Type 1 diabetes in the relatives of the almost 800,000 Americans with the disease. Participants with high risk get a daily insulin injection. Those with moderate risk take oral insulin, and low-risk individuals are simply followed.
“We hope that giving insulin to at-risk relatives will stop the body’s immune system from destroying insulin-producing beta cells,” says Kaufman, who is president-elect of the American Diabetes Association.
Classic Type 2 diabetes prevention advice calls for increased exercise. USC investigators are now 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,” says Buchanan. The studies also confirmed that gaining weight increases risk.
One of the hardest populations to target for prevention are youngsters. “In general, the public thinks obese kids are just chunky and will grow out of it,” says Michael Goran, associate director of the Keck School’s Institute for Prevention Research, who studies the link between childhood obesity and Type 2 diabetes. But a chunky child all too often becomes a diabetic child.

Peter Butler

Goran has shown that lack of physical activity in kids increases risk, particularly among African Americans. He’s developing a CD-ROM game that teaches healthy eating habits and promotes physical activity in children. He’s also putting together a school-based intervention program for the prevention of obesity in children, and he’s working with Bergman, Kaufman and others to identify high-risk kids. The team recently was awarded a prestigious NIH grant to study metabolic factors that predict obesity and diabetes in children.
This kind of research is urgently needed, as new cases of diabetes among juveniles have spiked 10- to 15-fold in the last 20 years. To make matters worse, in children the disease seems to move at an accelerated pace – “it comes on in two to three years, versus 20 to 30 years for adults,” Goran says.
It’s become fairly obvious why the label “juvenile-onset diabetes” no longer makes sense. “In the old days,” says Jorge Mestman, director of the USC Center for Diabetes and Metabolic Diseases, “the children identified with diabetes would normally be Type 1. Now we’re seeing Type 2 diabetes diagnosed much earlier in life than ever before, among teens and people in their 20s.” Pediatricians are warning of an emerging epidemic among teenagers.
Mestman traces the trend to rising levels of inactivity and obesity: 75 percent of patients diagnosed with Type 2 diabetes are obese. And by the government’s estimate, about 6 million American children fit in that category: classified as overweight to the point of endangering their health.
“The good news is that with the proper change in lifestyle, kids can prevent development or delay the onset of this type of diabetes,” says Mestman, who is a professor of clinical medicine, obstetrics and gynecology.
Studies have also shown that certain ethnicities – including African Americans, Native Americans and Latinos – are at increased risk for Type 2 diabetes. In all three groups the diabetes rate hovers between 11 and 12 percent, about double that of the general population, according to the American Diabetes Association. In recent years, USC researchers working with the Latino population have noted a connection between diabetes and high blood pressure. They’ve tailored therapies for the double condition and searched for explanations. Molecular studies suggest certain hereditary factors, like the body’s sensitivity to salt and resistance to the hormone insulin, play a role in increasing the dual condition in this population.

TREATMENT

UNTIL PREVENTION RESEARCH bears more fruit, improved treatment is the best option for those already diagnosed. In the past decade, major studies have shown that diabetes patients 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. Advances in recent years, including better monitoring and development of pumps that deliver appropriate amounts of insulin in lieu of daily injections, make normal glucose levels more attainable. On the horizon: insulin delivered by inhalation, blood glucose monitors that don’t require a skin prick, and new transplantation methods for insulin-secreting cells.
At the newly opened USC Westside Center for Diabetes on San Vicente Boulevard in Los Angeles, Keck School physicians Butler, Kaufman and Anne Peters pursue a multi-faceted treatment approach quickly incorporating the research of USC investigators into the clinical setting. Services include screening to evaluate risk and programs to prevent the onset of diabetes. For those who already have diabetes, the center offers cutting-edge treatments including insulin pump therapy, nutrition and exercise counseling and access to research trials for new medications and other therapies. “Treating diabetes is a partnership between doctor and patient, between mother and child, between husband and wife,” says Peters, the Westside Center’s director and a professor of medicine at the Keck School.
In turn, the Westside Center is linked with the Comprehensive Diabetes Center at Roybal Community Medical Center, a model program also led by Peters. The Roybal Center, linked to LAC+USC Medical Center, provides high-quality care to low-income patients in East Los Angeles. Physicians and nurses at LAC+USC Medical Center treat 32,000 diabetes patients a year, among the highest diabetes patient loads of any medical center in the country.
Peters hopes the Roybal Center will serve as a template for creating similar diabetes centers throughout Los Angeles – a significant goal because diabetes hits low-income and minority populations especially hard. “The disease is becoming epidemic among them,” she says.
Investigators at USC and elsewhere are also exploring new drugs to treat Type 2 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, Buchanan says.
Among the most significant advances in diabetes treatment are those relating to the eye, notes Rohit Varma, associate professor of ophthalmology and lead investigator of the Los Angeles Latino Eye Study, which, among other things, 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.
CURE

NO MATTER HOW ADVANCED the treatments, the biggest hope is that researchers will find a cure.
For Type 1 diabetes, the future looks bright. A vaccine is on the horizon for people at high risk for the disease. For those already diagnosed, transplant research holds great promise. Though technically not a cure, transplanting healthy pancreas tissue may seem like one to sufferers, says Bergman. It effectively eliminates the need for insulin shots. Such transplantation is not in the realm of far-off future therapies. “In the next couple of years it will be real,” Bergman predicts.

Surgeon Richard Selby with a model of the pancreas.

The prognosis for Type 2 diabetes isn’t as good. “I don’t know anybody who will tell you that’s going to be cured,” says Bergman. “We haven’t had the major breakthroughs to support such a prediction. We still haven’t found the genes responsible; we don’t know what causes the disease. It’s going to be a major health problem for at least another 10 years, and maybe more. But I predict that we will cure diabetes someday.”
In their labs, Butler and Bergman are exploring what causes diabetes and, more specifically, what causes insulin resistance and beta cell failure.
Butler is looking at deposits of a protein in the pancreas that he believes may cause Type 2 diabetes. He is also exploring why cells in the pancreas fail.
Bergman is looking at the endothelial barrier – the wall through which insulin passes from blood to tissues – in the hopes of better understanding what makes the cells insulin-resistant. He is also studying the relationship between body fat in the belly and how the pancreas compensates for fatty-acid overload.
Many scientists look to transplantation of the entire pancreas – or specifically the insulin-producing beta cells – as the best hope of a cure. At USC, surgeon Richard Selby has pioneered combination kidney-pancreas transplants for Type 1 patients who have renal failure as a consequence of the disease.
“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,” he adds, “certain neurological changes related to the diabetes are reversed.”
Since the early 1970s, when pancreas-tissue transplantation was found to cure diabetes in rats, scientists have been trying to do the same in people. Although human pancreas transplants have been performed successfully, few patients have thrived in the long run because they must continue taking powerful immuno-suppressive drugs to prevent rejection of the transplanted organ. These drugs are toxic to cells, and they also carry many undesirable side effects. New drugs may make transplants better, Bergman believes.
However, the limited availability of organs makes transplantation an impractical long-term solution for America’s 16 million
diabetes patients. Some researchers are now trying to create artificial pancreas cells that secrete insulin in response to increased blood sugar levels.

AT USC, RESEARCHER AND CLINICIANS are confident that new attention to diabetes will advance all four lines of attack – identification, prevention, treatment and cure – farther and faster than before.
“Anything we can do to reduce the impact of diabetes will have a huge benefit,” says Bergman. “Diseases with terrible symptoms that come on very quickly get a lot of attention. 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.”





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