A growing epidemic.
A spectrum of diseases.
A multidisciplinary challenge.
Type 1 diabetes results after an overactive immune system destroys insulin-producing cells in the pancreas and leads to insulin deficiency. An energy crisis ensues: Despite high circulating blood sugar levels, cells in the body cannot effectively use the sugar without insulin injections.
Genetic factors, inactivity, poor diet and weight gain can lead to metabolic imbalances and resistance to insulin action. Initially insulin levels increase to compensate. However, blood sugar levels rise as the pancreas fails to make enough insulin to overcome this resistance.
BY LEE PHILLION
If current trends continue, as many as one in three American adults could have diabetes by 2050. This growing problem — U.S. Centers for Disease Control has called it “an emerging epidemic” — is already impacting an alarming number of people nationwide.
Nearly 26 million individuals in the United States are living with diabetes — an estimate that includes roughly 7 million people who remain undiagnosed. Among those age 65 and older, almost one in four have diabetes. The cost of diabetes, now over $100 billion annually, will likely grow along with the prevalence of the disease.
It’s this looming health crisis that drives the School of Medicine’s Diabetes Research Center (DRC). Located in the Department of Medicine and now in its 36th year of National Institutes of Health (NIH) funding, the DRC is a hub for multidisciplinary collaborations, making steady progress in uncovering the mechanisms involved in diabetes and its complications.
Washington University’s DRC is one of 16 centers supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Its established and comprehensive research bases in diabetes and related areas of endocrinology and metabolism ensure that scientific investigation is evolving to meet this major public health challenge.
Insulin is also an important key to fat metabolism. Without appropriate insulin action, fats (yellow) build up in tissues and the bloodstream.
As director of the Diabetes Research Center (DRC), Jean E. Schaffer, MD, the Virginia Minnich Distinguished Professor of Medicine, has a panoramic view of research underway at Washington University aimed at understanding and finding treatments and ultimately a cure for diabetes. Schaffer spearheaded the recent competitive renewal for NIH funding that will propel the DRC forward for the next five years.
Like a pass key, the hormone insulin opens the door, enabling cells to use glucose delivered by the bloodstream. Without this key, this important fuel cannot be efficiently used and stockpiles in the blood.
The DRC’s 111 members from across the school have joined forces around intersecting areas of interest to understand the basic processes involved in diabetes and its complications and to translate discoveries into better patient care. DRC funding provides support for technical expertise in state-of-the-art core facilities, a robust pilot grant program to jump start the most exciting new ideas in diabetes research, and a vibrant enrichment program of seminars and courses that stimulates the exchange of ideas.
“Multidisciplinary research is the paradigm for the DRC,” says Schaffer. “The systemic, chronic and complex nature of diabetes requires a multidimensional approach, and our members are working across the spectrum of immunology, metabolic regulation, and the end-organ complications of diabetes.”
A brief tour of major organs affected by complications of diabetes illustrates the scope of investigations connected through the DRC. The tour begins with the most complex organ — the brain. Weighing in at just 2 percent of body mass, the brain accounts for 25 percent of body glucose utilization, and fluctuations in glucose supply to the brain can dramatically affect its function.
Tamara Hershey, PhD, professor of psychiatry, neurology and radiology, uses sophisticated in vivo brain imaging coupled with neurobehavioral measurement techniques to determine how exposure to glycemic extremes impacts brain structure and function in children and adults with type 1 diabetes.
Hershey also leads the first long-term group study of brain vulnerability in Wolfram Syndrome, a rare monogenic form of juvenile-onset, insulin-dependent diabetes that is associated with neurological complications including early blindness. This longitudinal study leverages advances in the diagnosis and molecular underpinnings of the syndrome made by the late M. Alan Permutt, MD, the former director of the DRC, and Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine.
This study of Wolfram Syndrome patients will identify biomarkers and support clinical trials of specific treatment agents and serve as proof-of-principle for more genetically and environmentally complex forms of diabetes.
Diabetes complications can include blurred vision caused by damage to the retina and bleeding within the eye fluid. A treatment performed by Rajendra S. Apte, MD, PhD, takes place under subdued red lighting, permitting his precise visualization of a few millimeters of tissue while allowing the surgical team to see within the darkened room.
Our next stop is the eye. Diabetic retinopathy, caused by changes in the blood vessels behind the retina, is seen in up to 45 percent of people diagnosed with diabetes and is a leading cause of blindness in adults.
“Eye health is directly correlated to glycemic control in diabetic patients,” says Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. “Sometimes it is the eye specialist who first diagnoses the disease from its complications in the eye.”
Apte has found that immune cells called macrophages regulate the development of damaging blood vessels in not only diabetic retinopathy, but also in age-related macular degeneration and in retinopathy of prematurity (formerly known as retrolental fibroplasia), which affects prematurely-born babies.
Apte’s research into the molecular factors that lead to macrophage changes may open new opportunities for cost-effective treatments of all of these conditions.
Cardiovascular disease is the leading cause of death in patients with type 2 diabetes, and the DRC has an impressive depth and breadth in understanding diabetic cardiovascular complications. Carlos Bernal-Mizrachi, MD, assistant professor of medicine and of cell biology and physiology, has demonstrated the importance of vitamin D deficiency in patients with type 2 diabetes.
“Low vitamin D levels nearly double these patient’s relative risk of developing cardiovascular disease,” notes Bernal-Mizrachi. His work has revealed new insights into the mechanisms that link vitamin D signaling in immune cells to cholesterol deposition and atherosclerotic plaque development in diabetes.
Bernal-Mizrachi is the principal investigator of two randomized controlled interventional trials to assess the effect of vitamin D supplementation on blood pressure and subclinical markers of cardiovascular disease in diabetes.
Systemic, chronic and complex, diabetes requires a multidisciplinary approach.
Cardiologist Sharon Cresci, MD, assistant professor of medicine and genetics, wants to understand why patients with diabetes suffer from a more aggressive form of heart disease. Lever-aging her background in cardiovascular disease, metabolism and genetics, Cresci helped design a custom microarray chip that she then used to discover the first genetic variant associated with severity of coronary artery disease in patients with type 2 diabetes. Findings such as these hold promise for more effective clinical management through genotype-based personalized treatments.
These types of clinical investigations are complemented by groundbreaking basic discoveries in the effects of diabetes on blood vessels and heart muscle in the laboratories of investigators including Clay F. Semenkovich, MD, the Herbert S. Gasser Professor and co-director of the DRC.
Moreover, the concentration of research excellence in the area of diabetic heart and vascular complications spurred the formation of the Diabetic Cardiovascular Disease Center (DCDC), one of the school’s BioMed 21 interdisciplinary research centers. Institutional resources for the DCDC, co-led by Schaffer and Daniel S. Ory, MD, professor of medicine and of cell biology and physiology, have proven instrumental for several recent successful NIH funding applications for diabetic complications research at Washington University.
NERVOUS SYSTEM Nerve damage leading to pain, loss of sensation, abnormal neuroregulation
MENTAL HEALTH Depression, emotional distress
VISION Glaucoma, cataracts, retina disorders leading to blindness
ORAL HEALTH Gum disease
GASTROINTESTINAL SYSTEM Fatty liver disease
CARDIOVASCULAR SYSTEM Heart attack, peripheral vascular disease, hypertension, stroke, heart failure
URINARY SYSTEM Urinary tract infections, kidney failure
GESTATION Pregnancy complications, fetal developmental abnormalities, health risks passed on to children
SEXUAL HEALTH Menstrual irregularities, fertility problems, hormonal imbalances, erectile dysfunction
FEET Sensory diminishment, skin changes, ulcers leading to amputation
Diabetic neuropathy is another common and devastating complication that can result in end-stage renal disease. DRC member Daniel C. Brennan, MD, professor of medicine, leads one of the most experienced kidney transplant and transplant nephrology programs in the United States.
Nationally, approximately one-third of kidney transplant patients present with diabetes. And of those who do not, up to 20 percent will develop diabetes within a year after transplant. By studying new immunosuppressants and induction agents, Brennan’s team has been able to reduce post-transplant onset of diabetes to just 5 percent within the first year after surgery and achieve a 10-fold decrease in acute rejection rates, both of which improve long-term outcomes.
“Over the last eight years, our transplant team has also steadily increased the number of kidney-pancreas transplants or pancreas transplants alone for selected patients,” says Brennan. “These provide better diabetes-related and overall quality-of-life improvements.”
Program surgeons perform around 220 kidney transplants and between 15 to 20 combined or sequential kidney-pancreas transplants annually. While the majority of patients who undergo sequential kidney-pancreas transplant have type 1 diabetes, data suggest that the procedure also confers significant benefits for some patients with type 2 diabetes.
The final stop on the complications of diabetes excursion is a visit to the laboratory of Kelle H. Moley, MD, the James P. Crane professor of obstetrics and gynecology, who is an expert in reproductive endocrinology and infertility.
Men with diabetes can suffer testicular dysfunction, impotence and decreased fertility. In women, diabetes and obesity are associated with an increased risk of reproductive complications, including fetal loss and congenital malformations.
Moley’s research has provided key insights into the consequences of early fetal exposure as well as preconception gamete exposure to high concentrations of glucose, insulin and/or fatty acids and the effects of the drug metformin on miscarriages. Her work has improved understanding of pregnancy failure among women with diabetes. Other recent work suggests that systemic insulin insufficiency and resulting decreased hypothalamic-pituitary-testes axis signaling are the key detrimental factors responsible for subfertility among diabetic men.
Daniel C. Brennan, MD, follows up with patient Padma Jampala, who underwent a successful kidney transplant in 2004.