Lipid overload

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.

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.

Systemic, chronic and complex, diabetes requires a multidisciplinary approach.

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.