FEATURE — Spring 2010

Clay Semenkovich, the Herbert S. Gasser Professor; professor of medicine and of cell biology and physiology; and chief of the endocrinology, metabolism, and lipid research division at the School of Medicine, focuses on trying to answer the fundamental question of why people with diabetes develop heart disease early in life. He’s driven by the notion that diabetes is first and foremost a disorder of lipid (or fat) metabolism. (Photo: Joe Angeles; Background ©Stockphoto)

DIABETES: A Formidable Foe

World-renowned researchers within the University’s diabetes community collaborate to build a comprehensive understanding of this complex and proliferating disease.

By Terri McClain

Diabetes mellitus, or simply diabetes, is a complex disease characterized by the body’s inability to regulate insulin production and control blood glucose. The Centers for Disease Control estimate that nearly 8 percent of the U.S. population (approximately 26 million people) has diabetes, with more than a million new cases diagnosed annually. Further, more than 23 percent of adults aged 60 and older have the disease. Less than 1 percent of Americans under the age of 20 have diabetes, but that number is rising alarmingly in conjunction with a steady increase in the rate of childhood obesity. Potential severe complications from diabetes include heart disease, blindness, nerve damage, and kidney failure.

Two principal types of diabetes exist: type 2, associated primarily with overweight adults and children, and type 1, an autoimmune disease once known as juvenile diabetes, which can cluster with certain other autoimmune disorders, most notably thyroid disease and celiac disease. In type 1, the death of pancreatic beta-cells—the cells in the pancreas that produce insulin—occurs suddenly and requires insulin therapy. In contrast, type 2 diabetes is a progressive disorder associated with numerous risk factors. The two main abnormalities in type 2 diabetes are that pancreatic beta-cells don’t produce sufficient insulin and that the body is resistant to the insulin produced, making the insulin less effective and allowing glucose to accumulate in the blood.

Nearly 8% of the U.S. population (approximately 26 million people) has diabetes.
More than 23% of adults aged 60 and older have the disease.
Women with gestational diabetes have a 50% risk of developing type 2 diabetes later in life.

A third type, gestational diabetes, occurs in pregnant women when the placenta produces hormones that antagonize the action of insulin, making the mother more insulin resistant. Although it usually disappears immediately after birth, women with gestational diabetes have a 50 percent risk of developing type 2 diabetes later in life.

Rare forms of diabetes have been associated with certain genetic abnormalities, and studies of these monogenic (or single gene) forms are yielding important insights into disease mechanisms that may in turn help researchers produce therapies to treat and slow the progression of the more common forms.

Diabetes and metabolic syndrome
The death of a beloved teacher from diabetes complications inspired an early passion for diabetes research in Clay Semenkovich, the Herbert S. Gasser Professor; professor of medicine and of cell biology and physiology; and chief of the endocrinology, metabolism, and lipid research division at the School of Medicine.

“She spent the last six months of her life blind, short of breath, and suffering from cardiovascular disease,” Semenkovich says. “Everything I’ve done since in medicine has focused on decreasing the suffering of people with diabetes and trying to answer the fundamental question of why people with diabetes develop heart disease early in life. The vast majority of people who have diabetes will die of heart disease, so we’re driven by the notion that diabetes is first and foremost a disorder of lipid metabolism.”

The reason, says Semenkovich, is that people with glucose disorder, regardless of whether they suffer from type 1 or type 2 diabetes, also have abnormalities in lipid (or fat) metabolism that damage blood vessels. However, the differences between type 1 diabetes, characterized by an abrupt failure of the beta-cells, and type 2 diabetes, which develops over a longer period of time with accumulating stress on the beta-cells, complicate attempts to identify common processes that may lead to both cardiovascular disease and the failure of beta-cells.

Lipid disorders, in turn, form a significant part of metabolic syndrome, a group of symptoms—including high blood pressure, high blood sugar, and excess abdominal fat—that collectively confer significant risk for coronary artery disease, diabetes, and stroke. Metabolic syndrome affects almost a quarter of all adults in the United States, as well as a growing number of adolescents.

Semenkovich’s lab currently focuses on two main areas in lipid metabolism research. One is the study of how different tissues in the body produce fats that contribute to diabetes and heart disease. The second area, now extended to clinical trials, evolved from the study of a deadly rare disease called ataxia telangiectasia, characterized by faulty DNA repair.

Patrick Lustman (right), professor of psychiatry, is co-director of the University’s Center for Mind-Body Research. At the center, he collaborates with other faculty, such as Gregory Sayuk (left), assistant professor of medicine, on the interaction between mental health and medical disorders. Lustman’s research shows that depression can play a significant role in diabetes. (Photo: Joe Angeles; Background: ©iStockphoto)

“We stumbled on the possibility that it may be appropriate to treat forms of diabetes with a simple drug called chloroquine, which is used to treat malaria,” Semenkovich says. “We found that mice with this particular defect in DNA repair developed diabetes and atherosclerosis, and that you could increase the level of expression of certain proteins that protect the DNA by giving chloroquine, which has been around forever and is generically available. It’s at least a possibility that using drugs like this could be a completely novel way of decreasing the suffering of people with diabetes.”

Depression also can play a significant role in diabetes and metabolic syndrome. Studies led by Patrick Lustman, professor of psychiatry, show that not only is depression a risk factor for diabetes, but also that diabetics suffering from depression are twice as likely to develop serious complications, including heart disease. In addition, diabetics are twice as likely to suffer depression as the general population.

The hallmark symptoms of depression—fatigue, physical inactivity, weight and appetite changes, social withdrawal—all increase the risk for diabetes and poor outcomes.

Lustman is co-founder and co-director of the University’s Center for Mind-Body Research, an online resource for investigators from different disciplines interested in the interaction between psychological and medical disorders. He also is senior investigator in a five-year National Institutes of Health (NIH)–funded study of overweight people with depression who are also insulin resistant, or pre-diabetic. The study will compare outcomes in patients who receive an antidepressant and a placebo, together with diet and exercise advice, to those who also receive a diabetes drug to help manage glucose.

“It’s a very circular problem,” says Lustman, who has been trying to unravel the connections between mental health and medical disorders for more than two decades. “Depression can contribute to obesity, hyperglycemia, and insulin resistance, which in turn can interfere with the treatment of depression. The hyperglycemia that is superimposed with depression adds to the risk of developing coronary heart disease. Add obesity to the equation—it’s easy to see how gaining 10 pounds during a depression episode could adversely affect your diabetes—and the situation becomes even worse,” he says.

About 25 percent of the cases of obesity in the population are attributable to mood disorders, so that’s a very strong linkage. In people with established diabetes and difficulties with weight and weight loss, depression can further contribute to that, impairing one’s ability to respond to lifestyle interventions and worsening outcomes for all treatable problems.”

Collaborative approach
The Center for Mind-Body Research typifies the interdisciplinary approach that distinguishes research at Washington University. Spanning 19 different clinical and basic science departments, collaboration within the University’s diabetes community is vital to building a more comprehensive understanding of this complex disease.

The Diabetes Research and Training Center (DRTC), established in 1977, facilitates research in diabetes and in related areas of endocrinology and metabolism, fosters interdisciplinary collaborations, catalyzes new ideas and scientific approaches, and promotes the translation of scientific discoveries to patient treatments and public outreach initiatives. One of only five such centers in the country, the DRTC offers expertise and training, and provides support to researchers and mentoring to new investigators in diabetes-related studies through its highly successful Pilot & Feasibility Program.

One major DRTC initiative is the Washington University Diabetes Center at Barnes-Jewish Hospital, which opened in 2006. This comprehensive center offers the latest in treatment and technology, as well as access to clinical trials and research, diabetes education, and nutrition counseling.

Although not specific to diabetes research, the Institute of Clinical and Translational Sciences (ICTS) offers an extensive infrastructure for research across disciplinary and institutional boundaries. Established through an NIH grant and directed by Kenneth Polonsky, chairman of the Department of Medicine, ICTS provides expanded opportunities for community-based research studies and assistance with the administrative and regulatory requirements of clinical research.

Monogenic studies and beta-cell death
“The hardest part of research is designing an experiment so that the results are easy to interpret,” Semenkovich says. “The best and most brilliant scientists are creative to the point of being artistic, able to set up an experimental condition so that the answer becomes obvious. Doing that and controlling the variables in people is the hardest thing in the world, because people are so amazingly complex.”

M. Alan Permutt, professor of medicine and of cell biology and physiology and former director of the Diabetes Research and Training Center, has been studying the genetics of type 2 diabetes for more than 25 years. Permutt’s lab was the first to isolate a single gene for type 2 diabetes. He says, “I think we’ve made the most progress by studying monogenic, or single gene, forms of diabetes.” (Photo: Joe Angeles)

Semenkovich’s promising research on the possible treatment of diabetes with anti-malarial drugs stems from the study of a rare disease. Such narrowly focused experiments help limit variables in the study of disease mechanisms to produce unambiguous findings that often can have a broad application.

M. Alan Permutt, professor of medicine and of cell biology and physiology, has been studying the genetics of type 2 diabetes for more than 25 years. The former director and principal investigator at DRTC, Permutt now serves as associate director in charge of Pilot & Feasibility for new diabetes investigations.

“We’ve made significant contributions to understanding the genetic basis of diabetes, which are complex genetic diseases,” says Permutt, “but I think we’ve made the most progress by studying monogenic, or single gene, forms of diabetes.”

Permutt’s lab was the first to isolate a single gene for type 2 diabetes when he and his researchers discovered the role of the glucokinase gene in the early 1990s. This discovery became the model for using monogenic forms to better understand the disease.

“What we’re undertaking is very exciting,” Permutt says of his breakthrough research on Wolfram syndrome, a rare and devastating genetic disorder that causes diabetes, followed by blindness, deafness, widespread neural degeneration, and premature death. “We isolated the Wolfram gene and published that in 1998,” Permutt says. “That enabled us to create an animal model of the disease and begin to define the cellular abnormalities.”

Now he works to fund an international registry of Wolfram’s patients to build a database of clinical information and collect patient samples for studies. His lab will collaborate with other labs around the world to sequence genes, establish cell lines to study presumed mechanisms, and screen for compounds to treat what they believe is the underlying disease mechanism.

“At present there is no medical treatment to slow the progression of the disease. So what we’re doing is positioning ourselves to have the patients ready for clinical trials when the medications become available,” Permutt says. He believes it is feasible they will come up with agents to treat this disease.

“We are also working in collaboration with pediatric endocrinologists, neuroradiologists, and neuro-opthalmologists to establish a Wolfram Clinic at St. Louis Children’s Hospital. This will establish a baseline from which we can evaluate effectiveness of therapy,” he says.

Permutt believes researchers are really moving on the genetics front, though the focus on this particular monogenic form of diabetes is narrow. He also believes the basic disease mechanism is undoubtedly typical to the more common type 2 diabetes and maybe even type 1.

“Because the more common forms of diabetes are multifactorial, involving many different genes and environmental factors, scientifically, Wolfram patients are the kinds of patients to use to prove that a medication would be beneficial,” Permutt says.

“We hope to slow the progression of disease in these children—which would be wonderful in itself—but also to find that the medication could be used for more common type 2 diabetes.”

Kenneth S. Polonsky (standing), director of the Institute of Clinical and Translational Sciences, works with postdoctoral physician Kei Fujimoto. Polonsky’s lab studies monogenic forms of diabetes in hopes of discovering the processes behind beta-cell death. (Photo: Joe Angeles)

ICTS director Polonsky also studies monogenic forms of diabetes in the hope of discovering the processes behind beta-cell death.

“We focus a lot on the death of beta-cells, because ultimately we believe that’s one of the final common mechanisms,” says Polonsky, the Adolphus Busch Professor of Medicine and professor of cell biology and physiology. “If we could inhibit the death of beta-cells, we would have a big impact on diabetes. The inciting events are different in type 1 and type 2, because one is an immune reaction that leads to the death of the cells, the other is a metabolic disease. But at the molecular and biochemical level, it’s likely that the final mechanisms that kill the cells are going to be very similar.”

Beta-cells, it turns out, are remarkably similar to nerve cells, which suggests that the mechanism of neuronal death in degenerative neurological diseases like ALS and Alzheimer’s probably has a lot of similarities to what happens to the beta-cell in type 2 diabetes, Polonsky says. Likewise, beta-cell death is the “opposite end of the same pathway” as the cell proliferation that causes cancer.

“In most cells there are pathways that allow the cell to divide and survive and grow, and then there are pathways that make the cells die,” he says. “And in a perfectly regulated situation, there is this match between the amount of proliferation and the amount of death, and they come into balance. And if you have too little death, then cells that shouldn’t be proliferating become cancer, and if you have too much death, then cells that should be doing well die—and you get deficiency diseases like diabetes and Alzheimer’s and certain forms of heart disease.”

Polonsky recently found that cardiologist Gerald Dorn, the Philip and Sima K. Needleman Professor of Medicine, had published data on a genetic disorder that caused death in heart cells. The same pathway is important in stimulating death in beta-cells, so Polonsky is now linking with Dorn to adapt the heart disease experiments to beta-cells.

“Whether there will be treatments that are similar, involving the same drugs, I don’t know,” Polonsky says. “But we can certainly learn from each other.”

Neil H. White, professor of pediatrics and former director of the pediatric endocrinology and metabolism division, works on both treatment and prevention of diabetes. His landmark work is the Diabetes Control and Complications Trial, which continues to track patients two decades after the project began. (Photo: Joe Angeles; Background: ©iStockphoto)

At-risk populations and treatment
Helping children with diabetes is the focus of Neil H. White, professor of pediatrics and former director of the pediatric endocrinology and metabolism division. In both his practice and his research, White’s efforts center on treatment and prevention. Among his numerous research projects over the past 25 years is the landmark Diabetes Control and Complications Trial, which continues to follow patients two decades after the project began. White also works on two NIH–funded, multicenter studies. One is Treatment Options for Type 2 Diabetes in Adolescents and Youth (TOD2AY). He is national chair of the other, the Diabetes Research in Children Network (DirecNet), which looks at new technologies and drugs in the treatment of type 1 diabetes in children and adolescents.

“Do we know what triggers type 1 diabetes? No,” says White, whose clinic serves about 1,200 diabetic kids. “But genetics plays a part. Out of four potential solutions—prevention; methodologies for prolonging the beta-cell function; beta-cell replacement therapy, either transplantation or implantation; and devices or drug technology that will better control the blood sugar—technology has the most potential at the moment. We’ve come a long way with technology. We have new insulins. We have insulin pumps and now glucose sensors. Next comes developing a glucose sensor pump where the sensor actually controls the pump independently to create a so-called artificial pancreas.”

In the case of type 2 diabetes, he says, weight management is the key issue. “Exercise burns calories, so it lowers your blood sugar. But it also improves insulin sensitivity and makes insulin work better in the body,” White says. “Kids today aren’t getting enough exercise. Almost every child with type 2 diabetes is overweight, some of them quite substantially. They derive the most benefit when we implement a multidisciplinary intervention—diet, exercise, behavior—but the best marker of success is weight loss.”

For reasons unknown, minorities are at higher risk for developing type 2 diabetes. Most of the children White sees at his clinic with type 2 diabetes are African American. In poor communities, diabetes education and awareness can be severely lacking, so the Diabetes Research and Training Center and the University’s Institute for Public Health partner with underserved, at-risk communities to translate science to practice. Health policy expert Debra Haire-Joshu, professor and associate dean for research at the George Warren Brown School of Social Work and professor in the School of Medicine, heads the DRTC’s Prevention and Control Core, which works with transdisciplinary investigators to translate research from the lab to the community.

“We help investigators move basic science findings to clinical and real-world settings,” she says. “A number of Washington University researchers pursue domestic and international diabetes research. This cutting-edge medical and behavioral research needs to reach diverse populations in ways that are culturally relevant. Washington University is leading the way in promoting transdisciplinary partnerships that pull together the pieces of the puzzle needed to promote health.”

“The message I want to get across,” says Semenkovich, “is that diabetes is a serious, complicated, but very treatable condition. We are making steady progress, developing spectacular new treatments, and much of that work is being done at Washington University.”

Terri McClain is a freelance writer based in St. Charles, Missouri.