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Attacking Diabetes

Robert Ritzel, a post doc and research associate working in Peter Butler’s lab at the Keck School of Medicine of USC. The lab, based in the Division of Endocrinology, is studying the hormone IAPP, which Butler believes may be responsible for Type 2 diabetes.

All photographs by S. Peter Lopez

ONE DAY YOUR DIET IS NOT AN ISSUE. You eat pretty much what you want, when you want. Then suddenly the good times come to an abrupt end. Every little bite has to be monitored. Sweets are pretty much forbidden, and carbohydrates must be carefully measured. Meals are scheduled at regular intervals, and the food on your plate is balanced in ways you previously only read about in magazines. Such is the startling – and difficult – transition that almost 800,000 Americans grapple with every year when they are diagnosed with diabetes. But the diagnosis represents much more than a set of irksome dietary restrictions. Called a silent killer, diabetes causes 200,000 deaths annually, more than AIDS. It is the most-diagnosed disease in the country, with more new cases than prostrate, breast, colon and lung cancers combined.

And diabetes is on the rise: it afflicts 16 million Americans today, a six-fold increase over a few decades ago. The most common diabetes, called Type 2, used to strike primarily after age 45: now it’s showing up in teens and 20-year-olds.

“It’s a horrendous public health crisis,” says Richard Bergman, chairman of physiology and biophysics in the Keck School of Medicine of USC.

At USC, the sense of urgency has never been greater. Nor has the sense of hope. Last year the school unveiled its new USC Diabetes Research Center, capitalizing on more than two decades of research into both Type 1 diabetes (an autoimmune disease) and Type 2 diabetes (a metabolic disease). The start-up center’s staff of 60 already includes 30 world-class investigators. At its first colloquium, held in April 2000, the center rolled out 18 presentations of major diabetes research now underway at USC.

According to Bergman, the Keck School now ranks among the nation’s top diabetes research programs. “Best of all,” says the center’s founding director with a smile, “our people are relatively young. We have a strong future ahead of us.”


Richard Bergman

Bergman, who came to USC in 1980, is best known as the inventor of the “minimal model” – a computer-based metabolic test that accurately predicts who will and who won’t develop diabetes. Considered a diagnostic standard, his approach has been adopted by labs throughout the world and used in some 400 independent studies.

“There’s $100 billion a year spent on diabetes treatment or complications. Diabetes is respon-sible for most of the dialysis in this country. And as people live longer, these costs will go up exponentially.”


Gestational diabetes expert Thomas Buchanan checks on patient Socorro Rodriguez in LAC+USC Medical Center.

In 1988, the university recruited Thomas Buchanan, a professor of medicine, obstetrics and gynecology and a recognized world authority on pregnancy-related diabetes, or gestational diabetes mellitus (GDM). His research has revealed that of the women who develop this temporary condition, half will get Type 2 diabetes within five years. Buchanan pioneered a drug therapy that reduces this risk by 60 percent.

Then in 1999 the Keck School brought aboard Peter Butler. USC’s new chief of endocrinology and diabetes is an international authority on the function of pancreatic beta cells (the cells that produce insulin). Butler has shown in experiments that Type 2 diabetes is associated with build-up of a naturally occurring substance that produces sheets of plaque, which can kill beta cells. Butler’s line of research may lead to new prevention or treatment strategies for diabetes – and may also shed light on a similar plaque build-up seen in Alzheimer’s disease.

Driving the new center’s position at the forefront of diabetes research is the Keck School’s forte in translational medicine – also known as the “bench-to-bedside” approach, which strives to speed advances made at the research bench to the patient bedside.

“Traditionally in medicine, there’s sort of a firewall between lab and clinical sciences,” explains Bergman. “At USC, we have very good relationships between our basic scientists and clinical scientists – and that’s rare.”

KNOWN SINCE ANTIQUITY, “diabetes mellitus” derives from the Greek diabainein (“to pass through”) and from the Latin mellitus, (“sweetened with honey”). Before the discovery of insulin, diabetes patients didn’t live long past the disease’s onset. Untreated, the condition leads to ketosis, the accumulation of ketones (products of fat breakdown) in the blood. This is followed by acidosis (accumulation of acid in the blood), with nausea and vomiting. As the toxic products of disordered carbohydrate and fat metabolism continue to build up, the patient goes into diabetic coma, followed by death.

The prognosis improved vastly, however, in 1921 with Sir Frederick Banting’s and Charles Best’s extraction of the insulin hormone from the pancreas. Insulin shots meant doctors could prevent diabetic coma, though not the disease’s disabling complications.


Peter Butler

This breakthrough produced an unfortunate side effect: once it was downgraded from death sentence to chronic condition, diabetes lost some of its menace. “It was viewed as benign,” says Butler. “No one wrote a Love Story about it. In terms of research, it wasn’t top of the list.”

Modern public health statistics belie that innocuous image. Diabetes is now the sixth leading cause of death by disease in the United States. In two decades the death rate due to diabetes has increased by 30 percent, while death rates for other common illnesses, such as cardiovascular disease and stroke, have fallen. 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.

“There’s $100 billion a year spent on diabetes treatment or complications,” Bergman says. “Diabetes is responsible for most of the dialysis in this country. And,” he warns, “as people live longer, these costs will go up exponentially.”

Studies indicate that the number of diabetes patients doubles every 15 years. Currently the disease afflicts about 6 percent of the population, making it as common as asthma. Such statistics and trends have caught the attention of the U.S. Centers for Disease Control and Prevention, which recently labeled diabetes a “serious public health problem.”

Congress authorized $837 million for diabetes research last year (compared to $442 million in 1999). Diabetes is finally catching up as a research priority.

IDENTIFICATION


KECK SCHOOL RESEARCHERS are guided by what Bergman calls the “four pillars” of diabetes investigation: identifying the at-risk population, preventing onset of the disease, treating those who have already developed the disease and finding a cure.

The first line of attack is the search for people whom Bergman calls “proto-diabetics” – those who don’t yet have the disease but are likely to develop it.

In the past, early identification wasn’t an option. Usually those at risk weren’t recognized until symptoms began to appear, when it was already too late. “Once diagnosed, diabetes is essentially irreversible. By then it has been developing for 15 years or more,” says Bergman. “Ideally we would catch people early and take measures to delay or prevent diabetes altogether.”

Bergman’s own research is responsible for a major breakthrough in such identification. The USC researcher spent 20 years developing his “minimal model” for measuring insulin resistance and pancreatic function.

Drawing on his background in engineering, mathematical modeling and computer science, Bergman came up with a sophisticated computer model to assess the ever-fluctuating levels of insulin and sugar in the bloodstream. In a screening test, patients are injected with glucose and a pancreas-stimulating compound, and then are monitored over several hours. Based on timed lab results, Bergman can rank an individual’s diabetes risk from lowest to highest on a “disposition index.” Though it is costly and time-consuming, the minimal model became the standard for predicting Type 2 diabetes. Bergman has since developed a simplified, less invasive version now in broad use.

As Buchanan showed first, thanks to drugs that enhance a patient’s insulin-sensitivity doctors are now able to delay the onset of the disease in those who come up “proto-diabetic” on Bergman’s test. This approach opens the possibility of real preventive treatment, which pharmaceutical companies are exploring.

Easier to identify are women with gestational diabetes. Obstetricians routinely test for glucose intolerance during regular prenatal visits because, left untreated, the condition can lead to serious pregnancy complications. After delivery blood sugar levels usually return to normal. However, more than half the women diagnosed with gestational diabetes will develop Type 2 diabetes within five years, according to studies by Buchanan and his USC colleagues.

“These are women who have weak beta cells,” says Buchanan, “If the cells have to work hard, like in pregnancy, they appear to wear out faster than other people’s cells.”

To determine whether the onset of Type 2 diabetes could be prevented, Buchanan and his team gave women with gestational diabetes an antihyperglycemic drug after delivery to keep the beta cells from failing. Three to five years of this therapy changed the insulin resistance of cells and reduced the load on the pancreas.

“We were able to cut the incidence of Type 2 diabetes among women with gestational diabetes by 60 percent,” says Buchanan, who heads the General Clinical Research Center at Los Angeles County+ USC Medical Center.

Buchanan and his team are testing new antihyperglycemic agents while continuing to follow past patients to see if the rate of Type 2 diabetes remains low. Buchanan is expanding his research to determine if siblings of those with gestational diabetes are 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 an inactive lifestyle. Genetic markers for both Type 1 and Type 2 diabetes have already been identified.

“Today diabetes is viewed as a combination of genetics that evolved over thousands of years when not much food was available, and a relatively new environment where there’s a lot of food and not much physical activity,” Buchanan says.

Researchers now believe there’s no single diabetes gene, but rather a number of them – 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 is part of a massive international effort to decipher the disease’s genetic code by studying 1,200 Finnish families.

On the other hand, Buchanan says, genetics research has revealed “new mechanisms that were not previously thought to have anything to do with blood sugar metabolism. These could lead to new interventions.”

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.

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.

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.


Surgeon Richard Selby with a model of the pancreas.

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 environmen 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.”

Attacking Diabetes

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