Sweet Science
Tom Buchanan's innovative ideals unravel the process of Type 2 diabetes while his research seeks to prevent disease.
The bicycle speaks with the faintest of clicking sounds, the tires uttering a rhythmic “whirr, whirr, whirr” as diabetes researcher Tom Buchanan, M.D., grasps the handlebars and pedals ever closer to the forested summit. Leaves crackle under the wheels’ rubber treads, an orchestra’s worth of sound punctuated only by the cries of a treetop songbird.
Buchanan has only his sweat, the gears, his wheels, the leaves and some loud birds to distract his mind from the 22-degree weather and the steep grade of the Angeles Crest Highway.
Except that in one moment, the idea comes to him—an idea that might help net another multi-million-dollar federal grant to better understand type 2 diabetes. Or maybe it is an idea that solves a tricky statistical puzzle that was blocking progress on a major study.
Free association has worked its magic again, and Buchanan can keep pedaling away. If anyone embodies the saying that genius is 1 percent inspiration and 99 percent perspiration, Buchanan might just be it.
Back at the Keck School of Medicine of USC, where the avid cyclist is chief of the division of endocrinology, metabolism and diabetes, he makes his research mission sound pretty simple.
Buchanan focuses on type 2 diabetes. Or rather, he studies the body processes behind type 2 diabetes—and why those can go wrong in some people.
Energy quest
Type 2 diabetes starts with the body’s quest for energy. All cells need fuel for energy and growth; the main energy source is a form of sugar called glucose. But cells cannot pick up and use glucose without insulin, a hormone made in the pancreas.
In most people, the process runs smoothly. But in others, things can go awry; cells start to ignore the insulin and then cannot easily absorb glucose. This is called insulin resistance. Or sometimes, the pancreas slows its production of insulin or eventually ceases it altogether.
Physicians issue a diagnosis of type 2 diabetes when too much unused glucose lingers in the blood, potentially causing serious complications such as vision loss, kidney disease and nerve damage. They prescribe changes in diet, exercise, and insulin-sensitizing medications, as well as insulin injections, if necessary.
Despite all that is known about type 2 diabetes, doctors and scientists still do not exactly know why type 2 diabetes happens.
That is where Buchanan’s ideas, whether born on a 4,200-foot bicycle climb or a stroll across campus, will make a difference. Buchanan hopes to home in on how cells become resistant to insulin and how the body stops producing insulin—so that diabetes may be prevented altogether.
Those ideas have come a long way in 30 years.
Back when Buchanan entered medicine, as a first-year resident at a private-practice Arizona hospital in the late 1970s, preventing type 2 diabetes was unheard of. Doctors were just trying to control complications.
He remembers attending a talk about research that focused on diabetes during pregnancy, also called gestational diabetes. “Glucose meters had just come out, and you could see that blood-sugar monitoring could make a difference in patients’ outcomes,” Buchanan says. “That was exciting.”
Spurred by his curiosity and smitten with scientific discovery, Buchanan decided to pursue a career in academic medicine and research and returned to Iowa, where he was raised, for a residency at Iowa State University.
During his studies, he met another resident whose uncle, coincidentally, was a researcher in diabetes and pregnancy at Northwestern University’s Feinberg School of Medicine. Northwestern had the top program in diabetes and pregnancy in the nation and boasted the “father” of gestational diabetes research, Norbert Freinkel, M.D., on its faculty; Buchanan applied and was accepted.
There, Freinkel took Buchanan under his wing. Taking a U-turn from his start as an internal medicine physician, Buchanan immersed himself in basic science and gained a strong background in physiology. It gave him the foundation to move on to human-based research, where he remains today.
Importantly, he also met prominent physiologist Richard Bergman, Ph.D., a Northwestern faculty member who later moved to the Keck School. Bergman’s influential “minimal model,” a metabolic test, has been adopted by researchers across the globe to study how insulin functions in humans.
In 1986, Bergman called Buchanan with an invitation to join him at USC. Buchanan has remained in Los Angeles ever since, to the delight of his colleagues.
Says Bergman: “Tom is an investigator of great character, who avoids trends and self-promotion while making important and highly recognized real progress.”
Cell performance
Buchanan’s research ideas have come not only from moments of clarity during his bike rides, but from talks with colleagues as well.
One such colleague is Siri Kjos, M.D., formerly at the Keck School and now chief of obstetrics at Harbor-UCLA Medical Center.
At LAC+USC Medical Center, Kjos had treated thousands of patients from the neighborhoods surrounding the Keck School, which have some of the highest diabetes rates in the nation. With Kjos’ rich database of patients, Buchanan and his colleagues began delving into what puts women at risk for developing diabetes during pregnancy.
The researchers knew the stress of pregnancy somehow spurred insulin resistance in these women and caused a buildup of glucose in the blood. In most women, the diabetes was temporary and glucose levels returned to normal after pregnancy.
But they saw that many of these same women—who were mostly Latinas—went on to develop type 2 diabetes several years after pregnancy. If Buchanan, Kjos and their colleagues could study women who had experienced gestational diabetes, they might be able to intensely study the process of type 2 diabetes while it was underway—before it could be diagnosed.
The lessons learned from these women could be applied to everyone, not just women with gestational diabetes.
First, they studied which factors seemed to put the women with gestational diabetes at risk for developing future type 2 diabetes. Then Buchanan delved deeper to see what happened within the body during the process leading up to diabetes.
Evidence began to point out the culprit: beta cells.
Beta cells are cells in the pancreas that produce insulin in response to glucose from food, he explains. When the body’s cells start resisting insulin, beta cells pump out even more insulin to try to overcome the resistance. That happens day in and day out.
These beta cells work hard and hold up fine in most people. But in others, the beta cells cannot stand up to the performance pressure, Buchanan says. Over time, they fade and die. When enough of the cells fail, the body can no longer produce insulin.
“Those whose pancreatic cells can’t take it are the ones who get diabetes,” Buchanan says.
Adds Bergman: “He has demonstrated unequivocally that not only resistance to insulin itself, but a defect in the cells that secrete insulin—the beta cells of the pancreas—play a pivotal role in the development of gestational diabetes.”
And that idea gave scientists a target for prevention.
Deterring disease
Buchanan and his colleagues decided to see if they could prevent, or at least postpone, type 2 diabetes in some of their gestational diabetes patients by giving them medications that could ease beta cells’ workload. The medications did this by making the body’s cells more responsive to insulin—lowering beta cells’ need to pump out more insulin.
In studies of two similar medications called troglitazone and pioglitazone, the researchers found that women on the medications were far less likely than women in the non-medication comparison group to develop type 2 diabetes. Although troglitazone is no longer used, pioglitazone is a commonly available drug currently approved to treat existing diabetes.
“Dr. Buchanan’s landmark studies have shown that by using agents which sensitize tissues to insulin—primarily muscle and liver-—diabetes can be effectively prevented for at least five years in those at risk for the disease,” Bergman says.
From there, Buchanan has worked with researchers in a variety of disciplines to take the ideas in many different directions.
For one, he works with geneticists to try to understand why some people are more susceptible to beta-cell failure and type 2 diabetes than others—and whether that vulnerability is inherited. Through a National Institutes of Health (NIH) grant, they are looking at more than 2,000 individuals in families of Mexican-American women with gestational diabetes to try to find candidate genes that may influence beta-cell function.
He also has collaborated on FUSION, the Finland-United States Investigation of Non-insulin-dependent diabetes, another NIH-supported project that already has found variations in one particular gene that may predispose people to type 2 diabetes.
As they study the genetic basis of diabetes, Buchanan expects to find that a number of different variants account for problems in glucose regulation. “There could be several different biologic processes that all get you to the same point,” he says.
On the clinical side, he has started ACT NOW, the Actos Now for Prevention of Diabetes study, which tests whether taking pioglitazone (known by the brand name Actos) can prevent type 2 diabetes among overweight people with pre-diabetes, a condition of mildly elevated blood sugar levels also known as impaired glucose tolerance.
If the strategy proves successful in this broad group of patients, it would provide physicians with a way to keep large numbers of high-risk people from developing full-fledged type 2 diabetes.
Currently, most physicians try to lower blood sugar in patients diagnosed with type 2 diabetes. The way Buchanan sees it, “we need to focus on people at high risk for diabetes and monitor their blood sugar regularly. They need to lose fat and become active. If their hemoglobin A1c level [a test that shows blood sugar control for the previous three months] is progressively going up, then we need to start treating their insulin resistance.
“We think early intervention will make a difference.”
ACT NOW is the sort of study that Buchanan oversees regularly at the USC General Clinical Research Center, where he is program director. His interdisciplinary background makes him a perfect fit for the role, which requires supervising dozens of complicated studies that involve human subjects.
The ability to understand different disciplines and connect ideas across numerous fields within science and medicine is what makes Buchanan unique, his colleagues say; he understands basic science, the concerns of the clinical scientist and the needs of the patient.
“He represents the kind of translational scientist that has become increasingly rare as regulatory problems and funding limitations have driven many clinical investigators out of the research arena,” Bergman says. “Also, I am proud to say that many of the concepts we developed in animal research have been successfully applied in Tom’s brilliant work, making the Keck School one of the most important examples of bona fide bench-to-bedside research that is so often touted as being a major goal of the National Institutes of Health.”
Perhaps his innovation comes from a combination of his ability to free-associate, his openness to the contributions of his colleagues and a commitment to explore new ideas to their fullest—whether those ideas come while riding his bicycle 165 miles a week through the Angeles National Forest, or while relaxing at home with his young children.
Only Buchanan knows where his next ideas will come from, but one thing is certain: They will keep rolling.
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