November 19, 2013
By David Martin
|Doug Wright, Ph.D., Patricia Kluding, Ph.D., and Mamatha Pasnoor, M.D.|
Translational medicine is the process of turning biological and epidemiological discoveries into cures and treatments. The approach has been described as taking research from the "bench to bedside."
A team at the University of Kansas Medical Center is studying peripheral neuropathy, one of the major complications of diabetes. But in this instance, discovery is moving in more than one direction. Results from a human exercise study informed the way basic scientists designed a study in mice. The "bedside to bench" approach, as it were, has helped add to the understanding of various pain syndromes.
Doug Wright, Ph.D., is a neuroscientist who researches sensory nerve disorders. A professor of anatomy and cell biology, Wright has studied diabetic peripheral neuropathy, a collection of symptoms caused by nerve damage, in rodents for 15 years.
Patricia Kluding, Ph.D., is an associate professor of physical therapy and rehabilitation science. Her interest in ankle joint mobility led her into diabetes research. High blood sugar can injure nerve fibers throughout the body, particularly in the legs and feet.
Mamatha Pasnoor, M.D., is an assistant professor of neurology and co-director of the University of Kansas Neuropathy Center. An expert in peripheral nerve disease and pain, she sees many patients suffering from diabetic neuropathy.
Wright works with mice. Kluding and Pasnoor organize human studies. Though they work with different models, each is interested in how exercise might improve diabetic peripheral neuropathy, which affects 70 percent of individuals with diabetes.
The research trio designed a pilot study to evaluate the effect of physical activity on nerve function in people who had been diagnosed with diabetic peripheral neuropathy. The study participants trained with weights and did aerobic exercises for 10 weeks under Kluding's observation. Pasnoor oversaw the participants' clinical care.
Exercise is known to help people with type 2 diabetes lose weight, control their body mass index and lower their blood sugar. But what about relief from pain? "We were worried that if you take someone who has painful feet and painful legs and ask them to exercise, the pain would get worse or they wouldn't do it," Kluding says.
In fact, the exercise helped the participants in the study. After 10 weeks, the participants reported fewer symptoms of pain. Skin biopsies showed changes in their nerve fibers that were consistent with improvements in the patients' pain.
Kluding, Wright, Pasnoor and colleagues published a paper about the 10-week study in the Journal of Diabetes and its Complications in 2012. Meanwhile, Wright incorporated some of the same ideas from the study into his lab. He worked with a graduate student, Anna Groover, on designing a similar study in mice.
Normalizing pain fibers
Researchers are able to induce prediabetes in lab mice by feeding them a high-fat diet. Wright works with a strain of mice that show pain in the way they react in behavioral tests designed to measure the sensitivity of their hind paws. "When you put animals on a high fat diet, they develop pain much like a patient with diabetic neuropathy, and they develop neurological complications associated with that," Wright says.
Some of the rodents who were fed a high-fat diet were allowed to exercise on running wheels. Like the humans in the earlier study, the mice who exercised found relief their neuropathic symptoms. By the end of the 12-week study, the active mice showed less sensitivity in their paws, and their skin and muscles were not as inflamed as the skin and muscles of the sedentary mice.
The study also shed light on the mechanisms of pain. Wright says Groover was able to show that the skin has many nerves that transmit painful sensations. In the prediabetic mice, Groover observed nerves changing their features to begin to resemble nerves that convey pain. Exercise appeared to counteract this sprouting of pain axons.
"Exercise, slowly over time, corrects that and normalizes the features of the nerves so that we have a normal number of painful and non-painful nerves," Wright says. "The concept is now being widely accepted that disease-related pain conditions like diabetes and fibromyalgia can change the landscape of the type of nerves in skin. We are the first to show that exercise may be able to correct these changes in the skin."
The study, Wright says, presents a potential shift in the way scientists think about sensory nerve disorders.
Researchers have struggled to figure out how to stimulate the growth of nerve fibers in patients with disease-related pain conditions. But controlling the behavior of existing ones may provide a better path for effective treatments.
"I think everyone assumed that if you lost fibers, we need to stimulate growth back, and that will be good," Wright says. "Well, nobody can do that yet. We're one of the first to say, 'Maybe you don't need to stimulate the growth. You just need to normalize the remaining fibers that are there, and that can help the patients tremendously.'"
A richer story
While Wright's lab was at work, Pasnoor and Kluding conducted a second study of the effect of exercise on neuropathic symptoms. This intervention, which involved different group of participants, lasted 16 weeks.
The second study was designed to more carefully measure neuropathic pain. Kluding says the participants' symptoms did not get significantly worse or better. But the 16 weeks of exercise was beneficial. In addition to seeing their fitness improve and fatigue lessen, the participants indicated that pain did not interfere with their daily lives as much as it did before the study began.
"The story is a little richer than what we were able to see in the first study," she says. "They're managing their pain. They're feeling better about the pain."
Of course, Kluding says, disappearance of the pain is the optimal result. But even an intervention as powerful as physical activity has its limits. "The pain may be past the point of correcting," she says.
The first study of exercise in people with diabetic peripheral neuropathy received a pilot grant from Frontiers: The Heartland Institute for Clinical Research. Frontiers is part of the Clinical and Translational Science Award consortium, a national group of medical research institutions funded by National Institutes of Health (NIH).
Among other things, Frontiers helps researchers like Kluding, Pasnoor and Wright to build a research program and keep it intact until the data can be collected. "That's the great thing about Frontiers," Wright says. "That program is designed to support an interdisciplinary group like us who are trying to take ideas from the bench to the bedside."
This project also received funding from a Ziegler Investigator Grant given by the Department of Neurology.
Rupali Singh, Ph.D., now an assistant professor of physical therapy at the Sage College-Troy; Stephen Jernigan, Ph.D., assistant professor of physical therapy and rehabilitative science; Kevin Farmer, Ph.D.; Jason Rucker, instructor of physical therapy and rehabilitative science; and Neena Sharma, Ph.D., assistant professor of physical therapy and rehabilitative science, are co-authors of the study that appeared in the Journal of Diabetes and Its Complications. Mazen Dimachkie, M.D., professor of neurology and co-director of the University of Kansas Neuropathy Center, was the data and safety monitor for the study. Laura Herbelin, research instructor of neurology, performed the nerve conduction studies. The work was supported in part by the National Center for Research Resources, grant No. MO1 RR 02394, and the National Center for Advancing Translational Sciences, grant No. UL1TR000001.
Groover and Wright published their study in the journal Pain. Co-authors are research assistant Janelle Ryals; post-doctoral fellow Natalie Wilson, Ph.D.; Julie Christianson, Ph.D., assistant professor of anatomy and cell biology; and Brianne Guilford, Ph.D., a newly appointed assistant professor at Southern Illinois University-Evansville. The work was supported by the Kansas Intellectual and Developmental Disabilities Research Center, grant No. P30 NICHD HD 002528; the NIH, grant No. RO1NS43314; and the Kansas Idea Network of Biomedical Research Excellence (K-INBRE) program of the National Institute of General Medical Sciences, grant No. P20 GM103418.