January 17, 2005

By Cathy Eberly

Diabetes: insidious, chronic, complex. The sixth leading cause of death in America, this condition is often implicated in mortality due to heart disease or stroke and, everywhere, it is rapidly increasing.

“New evidence shows that one in three Americans born in 2000 will develop diabetes,” said Julie Louise Gerberding, M.D., M.P.H., director of the Centers for Disease Control and Prevention.“ Together we must do more to stop this growing epidemic.”

To help physicians and their patients learn effective treatment of diabetes—and,
ultimately, to prevent its development— a vigorous research effort is underway. The University of Virginia’s Division of Endocrinology and Metabolism is home to some of the most promising diabetes researchers in the world. During the past few years, Division Chief Jerry Nadler, M.D. has recruited a number of outstanding physician scientists to join the University’s research and clinical care team. He also directs the Diabetes and Hormone Center of Excellence, which the School of Medicine created to support diabetesrelated research and patient care initiatives, and to serve as a model for all medical divisions in the U.Va. Health System.

“Coming to Virginia provided me the opportunity to build a world-class diabetes program in a medical institution with an already-strong endocrine division,” said Nadler, who transferred to U.Va. in 1999 from City of Hope Hospital in Los Angeles. “In addition to recruiting four tenure-track and several non-tenure-track researchers and providing them excellent research space, we’ve been able to secure new grants and launch clinical programs. Our center is very attractive to top-notch people.”

Those who rate the quality of medical care are also noticing. This year — yet again — U.S. News & World Report ranked U.Va.’s Division of Endocrinology and Metabolism one of the nation’s top five programs of its type. “This recognition definitely helps us to recruit and retain the finest researchers,”Nadler said. “We’ve got them studying diabetes from all angles.”

Regardless of which angle they choose, today’s researchers attempt to answer four
broad questions: What causes diabetes to develop? How can it be stopped? Why do
people succumb to its complications? How can the complications be prevented?

Nadler’s own research addresses all four. With major grant support from the National Institutes of Health, he is studying cardiovascular complications of diabetes in collaboration with several investigators at the Cardiovascular Research Center. He and his colleagues are developing gene therapies to block the action of lipoxygenase, an enzyme that oxidizes fats, forming dangerous fatty acids in blood vessels that may lead to accelerated vascular disease and insulin resistance. “We’re trying to target that enzyme or block the action of its products,” he said.

He also is developing compounds to protect precious pancreatic islet cells, which are currently the only cells capable of producing insulin. “We want to be part of a major trial to test a new medication. If it works as well as we think it does, it will enable us to prevent, and even reverse, Type 1 diabetes.”

Despite the promising nature of his work, Nadler is not the only U.Va. researcher racing to halt the progress of diabetes—and to find a cure. He is joined by talented physician scientists profiled in the following pages, among others who are at the forefront of the latest in diabetes research and state-of-the-art patient care.

Raghavendra Mirmira, M.D., Ph.D.
Assistant Professor of Clinical Internal Medicine

Aiming high can pay off, as it has with Raghavendra “Raghu” Mirmira, M.D., Ph.D., an assistant professor in the U.Va. Division of Endocrinology and Metabolism and one of its most promising young diabetes researchers. Dr. Mirmira’s recent funding application to the American Diabetes Association (ADA) so impressed its scientists that they gave him their Thomas R. Lee Career Development Award for earning the highest reviewer score this year, along with a $914,000 grant.

Mirmira could have applied for a smaller grant and engaged in a less-competitive application process. That is not his style, however. He decided, instead, to compete against 1,000 applicants for the ADA’s highest honor.

His goal is lofty indeed: Mirmira and his colleagues hope to find a new way to produce insulin in the human body. Insulin-producing beta cells occur most commonly in tiny islets across the pancreas, but account for no more than two percent of all cells found there. Beta cells are both rare and fragile; when damaged or destroyed, diabetes results.

Mirmira wants to stimulate the production of insulin by hardier types of cells from other parts of the body, but first he must fully understand beta cells. “I’m interested in identifying substances found only in beta cells and not in others,” he said. “We then determine if these substances regulate the genes responsible for insulin production to find out if they can be used to produce insulin in a different cell type.”

His research focuses on the structure of chromatin, the DNA-protein complex that gives genetic material its basic structure. Mirmira believes the structure of the chromatin found in beta cells may be what differentiates them from other cells in the pancreas. If he can find a type of cell that can adjust its chromatin structure to mimic that of the beta cell, he may be able to induce it to produce insulin.

Performing an exhaustive study of chromatin’s structure is key. Mirmira is using a technique called real-time polymerase chain reaction to track small differences in chromatin structure between cell types. The technique may help him identify and focus his efforts on cells capable of becoming insulin producers.

Mirmira has long recognized that medical research begins at the cellular level. In fact, when he was still in high school, he set his sights on becoming both a researcher and a practicing physician. Seeking to prepare for what was considered at the time a somewhat unconventional career, he enrolled in an M.D.– Ph.D. program funded by the National Institutes of Health at the University of Chicago, where he had already completed his undergraduate chemistry degree.

Mirmira’s research experience brought him job offers from a number of topnotch
institutions, including U.Va. “I wanted to go where diabetes could be my main focus,” he said, “where I knew I could get involved in a research program from the ground up and help to shape it.”

Since arriving at the University in 2000, he has done just that. His lab currently
employs six full-time and several part-time researchers. Until about a year ago, he worked alongside them. Now he spends his days documenting research results, collaborating with colleagues across the nation, and writing academic papers. “I enjoy thinking about science, how to approach my research and how to present it,” he said, citing his undergradute liberal arts education, with its “little bit of chemistry and a lot of literature,” as good preparation for his writing responsibilities.

He also does not shy away from fundraising activities. About two years ago, he met with Okla B. “Dicky” Meade, Jr. (Commerce ’67) and wife, Elizabeth, of Richmond, to describe his work. “They were intrigued by this area of research,” he said, “even as they realized it could not promise a cure tomorrow.” The Meades pledged $250,000, over three years, to jump-start his program.

Mirmira is grateful for their gift. “The Meades’ money allowed me to take some risks, to try experiments I couldn’t have afforded otherwise, to show some independence. I may not always be able to foresee where the research is taking me, but I continue doing it because I’m interested in where it might lead me next.”

Private funding — including support from NIH and other donors — has helped Mirmira continue his research. True to his original career goal, he also sees patients in U.Va.’s endocrine and metabolism clinic, located only a few steps from his lab. There he works with people who might one day benefit from his team’s discoveries.“ It’s a challenge,” he said of his dual role, acknowledging that he’s been “paged for clinical calls while doing research.”

But he believes the roles are equally important. “I think my patients benefit from my ability to understand the implications of basic research over the long term.”

Despite a grueling schedule, Mirmira and his family—including wife, Veena, and two daughters, Priya, age seven, and Anjali, age three—have found time to enjoy Charlottesville and make it their home. “In addition to the fact that the quality of work being done here at U.Va. has opened a whole new range of possibilities for me,” he said, “this is simply a wonderful place to live.”

Anthony L. McCall, M.D., Ph.D.
James M. Moss Professor of Diabetes

Jerry Nadler at a conference to discuss the University of Virginia. He was so excited about the opportunity described by Nadler, U.Va.’s Division of Endocrinology and Metabolism chief, that he called his wife, Madelyn, at home in Oregon.

“Hold on, dear,” he said. “I think we need to go visit Virginia.”

Their visit was a success. Three years ago, McCall moved his family to Charlottesville, where he accepted the James M. Moss endowed professorship.

He describes the position as a hybrid. “It’s part research and part clinical work, with a big emphasis on education,” said McCall, who formerly directed diabetes research and co-directed an NIH stroke program project grant at the Portland Veterans Administration Medical Center and the Oregon Health Sciences University. At Virginia, his responsibilities enable him to deal with diabetes in several ways. As a researcher with an M.D. from the Medical College ofWisconsin, a Ph.D. in euroscience from MIT, and with grant support from the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, he and his colleagues are studying the importance of glucose to the brain’s proper nourishment and operation. He is using this knowledge to determine what happens when the brains of some diabetics being treated with insulin fail to recognize that their blood sugar level is too low, a condition called hypoglycemia unawareness. Patients who become hypoglycemic may suffer blackouts and other potentially life-threatening symptoms.

“Insulin therapy is one of the most powerful tools we have to fight this disease,” he said. “We don’t want its side effects to limit successful use and cause people to think it’s part of the problem.”

A hypothesis advanced by McCall’s research team suggests that glucocorticoids,
steroids that naturally occur in the human body in response to inflammation, may be partly at fault. Glucocorticoids can signal the brains of certain diabetics that all is well, when, in fact, blood sugar levels are dangerously low. By understanding how the brain recognizes and organizes its hormonal defenses against hypoglycemia, McCall hopes to reduce its risks in patients receiving insulin therapy.

He also wants to understand why achieving steady control of sugar levels is so important. “Over the years,” he said,“ I’ve observed that rising and falling sugar levels — the roller coaster of diabetes — affect patients’ moods. I want to see if there are patterns to this relationship.”

To find patterns, the physician turned to a mathematician. Boris Kovatchev, an
associate professor in the Department of Psychiatric Medicine, has developed a mathematical model to show how sugar levels shift, over time, in patients undergoing different insulin treatment regimens. Together with psychologist Daniel Cox of the Department of Behavioral Medicine, he is studying how patterns of sugar control can affect mood and cognition.

“For the first time, we have a way to describe these patterns formally,” said McCall, who presented the trio’s results to the American Diabetes Association and will soon present them in Europe.“ By evaluating the effects of therapies on swings in blood sugar, we’ll be in a position to help people with diabetes feel better.”

In fact, much of McCall’s efforts go to improving the quality of patient care. He has formed two clinics at U.Va., staffed by experts from a variety of fields. One, a high risk diabetes clinic, treats patients whose advanced diabetes has resulted in kidney disease. The other, a diabetes and cardiovascular clinic, provides comprehensive, coordinated care for diabetics who are at risk for developing, or have already developed, cardiovascular disease. Cardiologists, dieticians, exercise specialists, and diabetes educators join McCall in testing patients for cardiovascular risk factors, providing appropriate medical care, and helping them make important lifestyle decisions.

He also trains physicians to become true resources for their patients. “With diabetes, education and effective treatment are closely linked,” he said. “It’s important that doctors give practical advice at the point of care. We teach them how to talk to their patients about this disease.”

One of the major lessons includes teaching patients how to manage their symptoms. “I believe diabetes should be a self-treated disorder. That’s why we provide information and training and help to develop a treatment plan which the doctor and the patient implement together.”

McCall’s comprehensive approach to diabetes treatment and education has found many advocates, not only among physicians in Virginia and nationwide, but also in locations beyond U.S. shores.“ Diabetes is becoming a problem everywhere— by 2030, 366 million people worldwide are expected to have the disease— but it is especially common in areas where the lifestyle has become westernized,” he said. During the last couple of years, he and colleagues Terry Saunders and Joyce Green-Pastors have been invited to Egypt and Mexico, where they teach medical specialists to become trainers who educate non-specialist physicians about the disease. “In Mexico, we will prepare 150 trainers to educate 4,500 doctors about how to recognize patients at risk for diabetes and to treat others who already know they have it. If each of those primary care doctors educates 10 patients, that’s 45,000 more patients who will receive a better quality of care.”

According to Dr. McCall, the most important lesson physicians anywhere can teach their patients is not to deny that they have the disease. “Diabetes isn’t a character disorder and it doesn’t result from a lack of willpower, but from heredity and environment,” he said. “The fact that people have it is not their fault; with education they can often help manage it successfully and avoid complications.”

Susan E. Kirk, M.D.
Associate Professor, Internal Medicine, Obstetrics and Gynecology

hen Susan Kirk was diagnosed with Type 1 diabetes at age 15, she was already planning to
become a doctor. The idea of a research career did not occur to her until years later, when she
had completed her medical training, was pregnant with her first child, and began questioning her obstetrician.
Why, she wondered, do many women with Type 1 diabetes have a temporary worsening of eye or
kidney problems during pregnancy? Why can many diabetic women go without insulin for days, or even
weeks, after their babies are born? When she learned that there were no answers to these questions, her
curiosity was piqued—and her career as a University of Virginia researcher began. Today, Dr. Kirk is recognized
as a specialist in the effects of diabetes on pregnant women and their newborn children.
A former chief resident at the University of North Carolina, Chapel Hill, Kirk decided to remain at
U.Va. after completing an endocrinology and metabolism fellowship in 1994. “This was the very best fit
for me personally and professionally,” she said. “My research ideas involve the fields of diabetes, pregnancy,
and growth hormone metabolism. Very few people around the world are looking at this combination
of issues, and I’ve received a lot of support and mentorship from colleagues within my division to help
plan and execute my studies.”
Her research focuses on placental growth hormone (PGH), which is secreted only in women when they
are pregnant. Although the exact role of PGH remains unknown, it appears to help regulate the mother’s
metabolism so she can support a growing fetus. Kirk figures that PGH is at least partially responsible for
causing the temporary symptoms of gestational diabetes in some pregnant women. It also plays a role in
conditions such as macrosomia, which causes babies of mothers with diabetes to be born at exceptionally

high birth weights. She wonders if it also
plays a role in the transient worsening eye
and kidney problems that occur, during
pregnancy, in some women with Type 1
diabetes.
“ Pregnant women with diabetes are
good models for understanding what
happens to many diabetics during their
lifetimes,” she said. “But because women
with diabetes are so focused, during pregnancy,
on the health of their baby, it is
difficult to interest them in clinical
research studies.”
So Kirk turned to animal models and
studies using tissue and cell cultures for
answers. Supported by a KO8 Junior
Faculty Award from the National
Institutes of Health, she has found that
laboratory mice specially bred to include
the gene that stimulates PGH growth
often develop kidney disease, which is
identical to that seen in many diabetics
who develop it.
Blocking the action of PGH in people
with diabetes might prevent some complications.
But Kirk urges caution. “It’s not
something we’ll want to do with pregnant
women, obviously, but it might be something
we could use with other diabetic
patients at some point in their lives. We
know that pituitary growth hormone,
which is nearly identical to PGH, is present
in humans throughout their lifetimes
and has been associated with diabetic eye
and kidney disease.”
Kirk has plenty of opportunities to
help women with diabetes. As co-director
of U.Va.’s high-risk obstetrics clinic, she
spends approximately 20 percent of her
time engaged in clinical activities, working
with women who have diabetes and who
hope to conceive, or those who are already
pregnant and have, or are at risk of developing,
gestational diabetes. “I see these
women weekly and get to know them and
their families well,” she said. “It is a very
special clinic with a real team atmosphere
from the staff and patients. I really love
spending time there.”
Monitoring the condition of pregnant
women with diabetes requires
vigilance. “More and more, primary care
physicians are referring women with diabetes
to teams of specialists for care
during their pregnancies,” Kirk said.
“ Since women who develop gestational
diabetes during pregnancy have a 20 to
50 percent higher risk of developing Type
2 diabetes later in life, this attention is
vital, even after the baby is born.”
She believes there is evidence that doctors
should begin monitoring their
patients’ conditions even before the
women conceive. “Preserving the health
of the mother by normalizing her blood
sugar level as much as possible increases
the odds that she will remain healthy during
her pregnancy, and that her baby will
be born healthy.”
Teaching doctors to work more effectively
with their patients is another of
Kirk’s responsibilities. As vice-program
director of residency in internal medicine,
she prepares the next generation of doctors
for the challenges of practice and
also aids as an administrator, which can
be challenging in the ever-evolving atmosphere
of residency education.
Kirk admits to feeling torn by these
competing responsibilities. “Teaching
may well be my greatest strength,” she
said, “but research is truly my passion.”
The next few years promise to be
important ones for fueling this passion.
“ Here at the University,” she said, “I’m
surrounded by great researchers who are
more than happy to collaborate with me,
read a draft paper, or advise on a grant
application. I’m very fortunate.”
Dr. Kirk is strongly motivated by her
“ Pregnant women with
diabetes are good models
for understanding what
happens to many
diabetics during their
lifetimes. But because
women with diabetes are
so focused, during
pregnancy, on the health
of their baby, it is difficult
to interest them in clinical
research studies.”
family, especially her two daughters, ages
13 and 7. “My family is very important
to me,” she said. “As the children of a
woman with Type 1 diabetes, my daughters
are at greater risk of developing it at
some point in their lives. I’m very aware
of this risk, and want to do all I can to
make sure they remain healthy.”

Kenneth Brayman, M.D.
Professor of Surgery

t began with a knock on his
office door. Transplant surgeon
Kenneth Brayman, M.D., answered it
to find Lori Ratliff, a University of
Virginia Health System nurse, standing
there. After living with Type 1 diabetes
for 32 years, she was tired of checking her
blood sugar level six times daily and—in
spite of her vigilance—occasionally
blacking out from the effects of hypoglycemia.
She had heard that Dr. Brayman
was seeking suitable candidates for pancreatic
islet cell transplantation and
wanted to add her name to the list.
On June 3, Ratliff got her wish when
she became the first patient in Virginia to
receive transplanted islet cells. Within
weeks, her insulin dependence was
reduced 30 to 50 percent.
The University’s health care facility is
the only one in the state currently offering
pancreatic islet cell transplantation. It
is part of Brayman’s plan to position the
U.Va. Center for Cellular Transplantation
and Therapeutics as one of the top 10
transplant centers in the country. “I knew
coming to Virginia would offer a unique
opportunity to make important advancements
in the field,” he said of his decision
to leave the University of Pennsylvania in
2002 and accept the position as U.Va.’s
center director.
The need for treatment advances is
pressing. Diabetics suffering from severe
hypoglycemia often do not know that
their blood sugar is low. Occasionally, it
plummets so rapidly that they lose consciousness.
Some patients experience
relief after receiving a transplanted pancreas
and kidneys, but the complicated
nature of the surgery has prompted diabetes
experts to search for new and less
invasive treatment methods.
Pancreatic islet cell transplantation
may be the answer. The procedure involves
isolating islet cells from donated pancreases
and injecting them—via infusion
bag—into the liver. Transplanted cells
help keep the body’s insulin level steady,
so there is less risk of low blood sugar and
a reduced need for insulin injections.
Recipients must take anti-rejection drugs
for the remainder of their lives, however.
“ It typically takes two to four weeks
for the cells to settle in and begin producing
insulin,” Brayman said. “Patients
will need to undergo a second infusion a
few months after their first. Early results
show about 80 percent of people will be
off insulin one year after their treatments.”
Not all hypoglycemics qualify for the
procedure, which insurance companies
still consider experimental. But grants are
available to fund pancreatic islet transplantation
in suitable candidates.
U.Va. is embracing the new technology,
which is receiving support from the
Islet Replacement Research Foundation
(www.isletfoundation.org) and a Buchanan
Grant from the Health System.
“ Within six months, we’ll have a facility
that enables us to isolate islet cells here
instead of elsewhere,” Brayman said.
“ With our team of surgeons, endocrinologists,
radiologists, and transplant coordinators,
we expect to perform three to
five procedures in our first year.”
Pancreatic islet cell transplantation is
a rejuvenative strategy that Dr. Brayman
believes is key to the future of diabetes
treatment. “Cellular replacement therapy,”
he said, “provides hope for patients
whose inability to regulate their blood
sugar levels has caused their lives to spin
out of control.”

Milagros Huerta, M.D.
Assistant Professor of Pediatrics

hile working as a pediatrician in
Texas, Dr. Milagros Huerta
treated youngsters at risk for developing
diabetes. But they were not facing Type 1
diabetes, an autoimmune disorder that traditionally
strikes children and adolescents.
These patients, many of Hispanic or
Latino descent, were on the verge of developing
Type 2 diabetes. This form of the
disease is most common in adults who are
obese and physically inactive, and whose
bodies have trouble metabolizing glucose.
Huerta was alarmed by what she saw in
her young patients. “Imagine children who
are morbidly obese at the age of four or
who have Type 2 diabetes at age eight,” she
said. “I knew we had to arrest this dangerous
trend.”
After completing a fellowship in pediatric
endocrinology at U.Va. in 2001, she
got her chance. Dr. Jerry Nadler, chief of
U.Va.’s Division of Endocrinology and
Metabolism, took her under his wing. “He
offered to serve as my research mentor and
he even funded my initial study,” she said. “I
was first and foremost a clinician, but he has
helped me grow as an investigator.”
Huerta is searching for risk markers that
can predict whether obese children will
develop diabetes and perhaps even cardiovascular
disease. “I want to figure out,” she
said, “why some overweight kids become
diabetic while others of the same weight
appear to be protected in some way.”
One possible predictor of future health
problems may be a high level of adhesion
molecules present in children’s blood
vessels. These molecules serve as markers
for atherosclerosis, a precursor to heart disease.
Huerta wonders whether medication or
intensive lifestyle changes could successfully
reverse early signs of heart disease in young
people. With grant support from the NIH’s
National Institute of Diabetes and Digestive
and Kidney Diseases, she is testing the
effects of three treatment options in groups
of children aged 10 to 18. One group takes
Metformin, a popular diabetes medication;
another participates in individual and group
sessions to help them make lifestyle changes;
and the third receives one-time advice, from
a physician, on diet and exercise, which is
the current standard for care.
Although definitive research results are
not yet available, Huerta suspects that a
combination of diet and exercise changes,
and Metformin, will yield the best results in
overweight youngsters. She is pleased that
the University has a place where children
may find it easier to change their habits.
The Children’s Fitness Clinic offers a comprehensive
medical evaluation and intensive
lifestyle modification program for overweight
children and teens. The care-giving
team includes pediatric endocrinologists
and nephrologists as well as exercise physiologists,
nutritionists, nurse practitioners,
psychologists, and pediatric surgeons. Most
patients are referred to the clinic by their
primary care physician.
As the clinic’s co-medical director, Dr.
Huerta fully understands its value—and its
limitations. “We have the resources at hand
to combat an obesity problem,” she said.
“ But the truth is, there’s no secret or
groundbreaking discovery on how to treat it
before it could possibly result in diabetes.
The answer can be as simple as healthy eating
habits and more exercise. The hardest
part is to engage families in helping their
children make changes and to provide them
assistance along the road. Any behavioral
change is difficult. It requires a lot of effort
and willpower, but the results can be truly
lifesaving.”

Eugene J. Barrett, M.D., Ph.D.
Professor of Medicine and Pediatrics; Director, Diabetes Research Center