Kellogg Team Will Study Eye Complications of Diabetes under New Grant

Research signals greater understanding of the mechanisms contributing to complications of type 1 diabetes

Steven Abcouwer, Ph.D., David Antonetti, Ph.D., and Thomas Gardner, M.D., M.S., are studying the eye complications of diabetes.

Researchers and clinicians across the University of Michigan Health System have been awarded a $3.5 million multi-disciplinary grant from the National Institute of Diabetes and Digestive and Kidney Disease.

Under the grant, the U-M team will study the underlying mechanisms of the debilitating complications of type 1 diabetes affecting the retina, peripheral nerve, and kidney.

Kellogg retinal specialist and Taubman Scholar Thomas W. Gardner, M.D., is one of three key researchers who will focus on the eye-related complications component of the study. Dr. Gardner is joined by Steven F. Abcouwer, Ph.D., Research Associate Professor, and David A. Antonetti, Ph.D., Professor of Ophthalmology and Visual Sciences, who has also been awarded a Jules and Doris Stein Professorship from Research to Prevent Blindness. Together, the team brings enormous expertise in the study of diabetic retinopathy (DR), a complication that causes damage to blood vessels inside the eye and, in severe cases, leads to blindness.

A leading cause of health care expenditures in the U.S., type 1 diabetes affects nearly 25.8 million Americans, while its complications cause poor quality of life and, in some cases, even death. In type 1 diabetes, the body's immune system destroys the pancreatic beta cells responsible for making insulin, a hormone the body needs to convert food into energy.

In addition to DR, two equally serious complications play havoc on the well-being of those suffering with the disease. Diabetic peripheral neuropathy causes nerve damage in the legs and feet, while diabetic nephropathy causes kidney disease and, in many cases, leads to kidney failure.

While metabolic pathways have been widely studied in tissues prone to diabetic complications, little attention has been given to responses that may disrupt the metabolism of glucose, lipids, and amino acids in a tissue-specific manner—also called metabolic reprogramming.

The Kellogg team will measure the metabolites from glucose and lipid metabolism in the eyes of individuals with DR, and in the diabetic mouse model. The information gained will help to determine how these metabolites might be modified to improve the health of the retina. "This knowledge may help us develop new drugs, or suggest that existing drugs or even diet modification are effective therapies," says Dr. Gardner. "The studies may also reveal that not all persons with diabetic retinopathy have the same problem. So, we may identify personal profiles to more specific treatment."

The new grant marks the first time researchers will look at all of the complications of type 1 diabetes in a comprehensive way. "Taken together, this work is some of the first to suggest that an important set of metabolic pathways may contribute to complications of type 1diabetes," says Dr. Gardner. "And, if we can understand those pathways, we can design interventions to prevent development and progression of these complications."

Dr. Gardner with his patient, Robert Gilmore, who sees patients as the beneficiaries of research underway at Kellogg.

Millions of individuals with type 1 diabetes stand to gain from the research made possible by this grant. Among them is a patient of Dr. Gardner's who asks about research advances at nearly every visit. Robert Gilmore, of Brooklyn, Michigan, has suffered from type 1 diabetes for over 45 years—along with debilitating complications which have caused vision loss in his right eye and nerve damage in his hands, feet, and legs. "I was on a downward spiral before coming to the Kellogg Eye Center," says Mr. Gilmore. "My vision was 20/100 in my right eye. And, I was told time and time again that my sight would continue to deteriorate."

Today, Mr. Gilmore's vision is an astounding 20/60 in his right eye. "The thought of losing your sight is very unsettling, and very personal," says Mr. Gilmore. "Patients with diabetes stand to benefit a great deal from the research underway at Kellogg."

Dr. Frank Brosius

Leading the kidney-related complications component of the research is nephrologist Frank C. Brosius, M.D., one of the study's principal investigators. "With type 1 diabetes, there appears to be a significant increase in the metabolism of glucose in the kidney. But, in the eye and nerve cells, there is actually a reduction in the metabolism of glucose," says Dr. Brosius. "This tells us that the metabolic changes in the eye, kidney, and peripheral nerve may not be the same. The presumption has been that these changes are simlar, but most of our preliminary data suggest differently." The Brosius team will examine the increase in metabolism to find out why it leads to specific downstream damage to the kidney.

Dr. Eva Feldman

Eva L. Feldman, M.D., Ph.D., Russell N. DeJong Professor of Neurology, will lead the peripheral nerve-related complications component of the research. "We will establish for the first time how the nervous system turns sugars and fats into energy in patients with diabetes," says Dr. Feldman. "Understanding this process will allow us to develop mechanismspecific therapies to target ways to increase energy output in the nervous system. We believe this will prevent the most common complication of diabetes—the injury to the nerves in the feet and hands—known as diabetic neuropathy."

Drs. Gardner, Antonetti, and Abcouwer, now in their second year at Kellogg, were initially attracted by the University's depth of expertise in diabetes research. "It took a critical mass of laboratory, clinical, and technical knowledge across the U-M Health System to get to this place," says Dr. Gardner. "We have a really tremendous team of people here."