Research: Life in the Balance

Steps Forward in Diabetes and Metabolism

By Dale Short

John Corbett searches for the complex causes behind the rise of diabetes around the world. Environmental factors—including viral infections—may provide some answers.

Hear Corbett discuss the connections between diabetes research and clinical care at UAB:

Metabolism may be the ultimate quiet power source. Dependent on an intricate, delicate balance of chemicals and enzymes, it’s a process that happens constantly and automatically in our bodies, generally drawing little notice unless something goes wrong.

Diseases such as diabetes emerge when that balance is disrupted. And the seesaw seems to be swinging wildly at present; national health leaders say that diabetes has risen to epidemic levels, particularly in areas of Alabama. But UAB’s diabetes and metabolism specialists are pushing back hard, spearheading efforts to understand the environmental, genetic, and biochemical factors that could play key roles in the disease and its successful treatment.

Diabetes has been reported since ancient times, but in recent years, the rate of diabetes cases throughout the world has been steeply increasing for reasons that are not fully understood. Diabetes will someday affect one out of three people born in the year 2000, according to an estimate from the Centers for Disease Control and Prevention.

At the same time, genetics and other new technologies are opening completely new avenues of research into the disease and the metabolic balancing act. “We’ve really started to attack a number of interesting issues,” says John A. Corbett, Ph.D., director of the new UAB Comprehensive Diabetes Center, which unites scientists and clinicians from disciplines throughout UAB to conduct advanced research and develop innovative therapies. “The potential is in place to have some extraordinary things happen in the next five or six years.”

He hopes that one of those extraordinary things will be a clearer picture of why the world is seeing an increasing occurrence of diabetes. Corbett explains that genetics and environment both appear to play a role in type 1 diabetes, the most serious form, in which the body fails to produce insulin. “Identical twins with all the genetic risk factors only develop diabetes about 40 percent of the time, which tells us that it’s not just genetics. Anything that augments the immune system is considered an environmental factor that may drive diabetes; a viral infection is one possibility people have discussed.”

Corbett has been researching the viral connection for about 12 years, and he believes that “a viral etiology for the disease is quite possible—not in all patients, but viral infection may trigger it in a number of patients who are predisposed.” He looks forward to the findings of a worldwide study known as TEDDY—The Environmental Determinants of Diabetes in the Young—which is meticulously tracking the medical history of children who are genetically predisposed to the disease, from birth through adulthood, in hopes of shedding light on why some develop it and others don’t.

“They’ll be aggressively charting every viral and bacterial infection for about 5,000 kids,” Corbett says. “Personally, what I think we’ll find is that there’s not one virus or bacterial infection that drives the disease, if you’re predisposed, but that it’s a process. Multiple viruses could do it. It’s not the actual virus that drives the initiation, but the infection itself and the cellular response to it.”

Not everyone in the field shares Corbett’s perspective. “You’ll find scientists who say there’s no way viral infections can cause type 1 diabetes. I’ve pulled out statistics that absolutely suggest it could be viral, but there are other stats that say the opposite,” he explains. “So it’s like most things in life—it could be either, or it could be a lot of both. With some people, it could be completely genetic, as when the [insulin-producing] beta cells don’t grow right because of defects in the transcription factor.”

Resistance Fighter
The phenomenon known as “insulin resistance” is a main focus of Timothy Garvey, M.D., chair of the Department of Nutrition Sciences and principal investigator of UAB’s new Diabetes Research and Training Center (DRTC). One of only six centers of its kind in the country, the DRTC is being established with a $6.3-million, five-year grant from the National Institutes of Health to decrease diabetes-related morbidity and mortality, enhance quality of life for patients, and provide an environment for student training and faculty development in diabetes research.

Timothy Garvey and his colleagues have identified genes and biochemical pathways that could provide a road map for the development of new drugs against diabetes.

Garvey says that even in cases where the body produces some insulin, as in type 2 diabetes, muscle tissue is somehow unable to respond to the insulin correctly, causing elevated glucose levels to remain in the bloodstream. His research team—including colleague Yuchang Fu, Ph.D., assistant professor of nutrition sciences—recently identified two genes that may play a part in that process. Known as NR4A1 and NR4A3, the genes appear to boost insulin sensitivity in muscle tissue, helping with proper glucose uptake and keeping glucose at a healthy level. Garvey and Fu found that the genes are underexpressed in animal models with diabetes, contributing to the problem of resistance.

Such findings present “a bunch of possibilities for drug targets,” according to Garvey. While pharmacy and biotechnology labs are making progress with therapies that boost insulin secretion, the identification of new genes and pathways is prompting them to develop drugs to improve glucose tolerance or even to prevent diabetes. “Hopefully companies can develop drugs that modify the function of molecules—either the actual gene or other genes or proteins in the biochemical pathway,” Garvey says. “If one part affects another that affects another, and so on, making cells insulin resistant, then you could develop a drug against any gene or protein along the pathway, not just one.

“Even nondiabetic individuals have a range of insulin sensitivity, and people fall along a continuum. If they’re on the insulin-resistant side, we see higher blood pressure and lipids and a bigger waist circumference—that is metabolic syndrome, an indicator of future cardiovascular disease. The cardiovascular and metabolic aspects are so integrally intertwined, particularly in overt diabetes and heart disease, that it’s important we study the connections more closely.”

A closer look at that continuum tends to blur what once were considered clear demarcations between type 1 and type 2 diabetes, Garvey says. “The term ‘diabetes’ means different things to different people, and many diseases or syndromes fall between types 1 and 2. A number of diseases cause blood sugar to be higher than normal; in minority groups such as African Americans and Hispanic Americans, these are called ‘atypical diabetes’ because adolescents present with ketoacidosis as in type 1 and then weeks or months later change to type 2, meaning they don’t need insulin injections but may be more susceptible to having ketoacidosis build up at times of high stress.

“In other people, there’s a unique condition called LADA, for latent autoimmune disease in adults. They have antibodies that help destroy insulin cells later in life. It’s somewhat like type 1, but very slowly progressive; it can look like type 2 for a long time,” Garvey explains. “It’s a confusing time right now in the literature and the clinics, because there are so many different diseases that can present the same way.”

Obesity and Genetics
A recurring theme in many of those diseases is obesity. “There are genetics involved,” says Corbett, “but I would argue that in the United States, and western civilization in general, type 2 diabetes is predominantly a disease of lifestyle. You may have genetic susceptibilities that enhance your risk, but mainly it’s lifestyle choices. As a society, the way to prevent diabetes is to exercise and keep the weight off—there’s no better treatment for type 2 than exercise and diet. The perfect answer would be exercise in a pill.”

A pill—or some type of drug to treat obesity—is the goal of many researchers, for several reasons, Garvey explains. “We know that metabolism shows a lot of improvement if we can get patients to lose even 5 to 10 percent of their weight. They handle sugar loads better, which can improve their diabetes or even put it into remission. In the last 10 years, we’ve learned an awful lot about what regulates body weight, appetite, and so on. So there are a lot of obesity drugs in development that also could be fantastic diabetes drugs.”

“Even if genes do not cause diabetes by themselves,” adds Bruce Korf, M.D., chair of UAB’s Department of Genetics, “they can modify how our bodies metabolize sugar in major ways. There have certainly been environmental circumstances in history when a gene of this type could have conveyed advantages, such as helping conserve energy in time of famine. But today, when food is abundant, the same gene leads to a tendency to store energy when one doesn’t need it, which ultimately contributes to the risk of diabetes.

“Nobody knows how many genes play a role. It’s not as simple as identifying a certain subset of genes that account for everything, because particular genes play greater or lesser roles in different populations. I think we’ll probably end up finding a few dozen genes that, together, make up the majority of the genetic contribution.”

Research Reaches Out
Meanwhile, beyond the laboratory, other teams of professionals are bringing the latest knowledge about diabetes to people who may never visit a major medical center. Supported by a five-year, $3-million National Institutes of Health grant, UAB’s Minority Health and Research Center is beginning a new Project EXPORT outreach effort to recruit and train “community health advisors” to promote diabetes prevention and control in Alabama’s Black Belt region, home to some of the nation’s highest rates of the disease.

Mona Fouad brings diabetes prevention and treatment into the homes, churches, and grocery stores of Alabama’s Black Belt, a region where diabetes rates are among the highest in the country.

Center director Mona Fouad, M.D., M.P.H., calls it a “case-manager approach,” training community volunteers to assess barriers and build communication skills. “With our state’s high incidence of diabetes, and with more cases being diagnosed at earlier ages, there’s a great need to help people reduce their risk factors by eating healthy, exercising, and losing weight. They also need to know methods for checking their blood sugar and controlling diabetes so they don’t have complications such as renal failure, vision loss, leg ulcers, and so on.”

Fouad and project director Isabel Scarinci, Ph.D., aim to replicate the success of earlier work in the Birmingham area that addressed diabetes and colorectal cancer disparities between African Americans and whites. They developed a culturally tailored curriculum for pastors and leaders that was tested by 20 volunteers in four predominantly African-American churches. Related events included health fairs, screenings, recipe contests, and cooking demonstrations.

Fouad explains that real-life solutions for diabetes are a challenge in any setting, but especially in the rural Black Belt, where some counties don’t have a practicing endocrinologist and up to a third of residents live in poverty. The key to the community-health-advisor program’s success is “a participatory approach, looking at positives instead of negatives,” she says. “One of our exercises is what we call ‘asset mapping,’ where we list all the community’s assets for dealing with the problem. Are there volunteers who can help transport patients to clinics? Can we work with local grocery stores to highlight healthy eating habits? These counties may be low in income, but they’re high in creative resources. We start by building coalitions of county physicians, ministers, schoolteachers, nurses, and council members. They’re all partners.”

These education efforts are crucial because there are so many myths about diabetes, Fouad says. “Some people think as long as they don’t have symptoms, everything is fine. Or they take a fatalistic approach, saying that their disease is meant to be. We can help change those attitudes because we’re training key people in the community who share their lifestyles and beliefs.”

Because she can build on the infrastructure of past projects, Fouad hopes to have the initial volunteers trained in about 10 months. At that point, they can start helping to identify the target population for the new program. “We have some very eager volunteers,” says Fouad. “They’ve been trained in other health conditions, and they look forward to adding diabetes to their training.”

Place and Progress
In the broader picture, Corbett says that one of goals of the Comprehensive Diabetes Center is “to begin to bridge the clinical and research aspects of our educational training programs by bringing in fellows who want to do research—whether clinical, basic science, or bench research. We have the population base and the patients; unfortunately, Alabama and Mississippi rank at the top of the national obesity charts. If we can be at the forefront of running trials for new medications, we’re also providing better care because we’re on the cutting edge of care,” he explains. “We want to be the very best in the Deep South, where it’s needed most.”

Bruce Korf investigates the myriad roles that genes may play in modifying diabetes risk. He predicts that in the next few years, researchers will have the genetic knowledge to begin understanding how the disease develops.

The outlook for that new diabetes research is bright, if not completely clear, Korf notes. “What we’ve noticed in the past year and a half is a vast increase in knowledge about various genes. The technology has undergone a revolutionary change, and it has opened the floodgates of information. Over the next five years or so, we should know most of the major players in terms of genes that modify diabetes risk. What’s not clear is what kind of light that will shed on the mechanisms of the disease—and the treatments that will result.”

One way to illustrate the current prospects, Korf says, “is to visualize the difference between a science problem and an engineering problem. Engineering is hard to do, but we know how to do it: For example, if we have the time, money, and resources, we can go to the moon. We knew how to do it in the 1960s; we just needed the resources to make it possible. By comparison,” he explains, “a science problem is one where many of the required questions—even to conceptualize how to begin the task—simply aren’t known. Abraham Lincoln couldn’t have put a man on the moon in 1865 for any amount of money, because he had no idea what technology was needed, and much of it didn’t exist.

“So right now, gene discovery in diabetes is an engineering problem,” Korf says. “When we discover the genes, we’ll have the basic know-how. It takes money and effort, but it’s feasible to do and will be done in a matter of a few years. But because we don’t know what all those genes are or how they work, we don’t know how hard a task it will be to improve treatment or develop diagnostic tests. This remains a scientific problem; it is unpredictable just how fast that information will fall into place.”