Research may optimize diabetes therapies and preventive treatment programs
DETROIT — Exercise is known to greatly improve the ability of tissues to respond to insulin and reduce the risk for developing type 2 diabetes, but the mechanisms that cause those health benefits are not yet clear.
A Wayne State University researcher is seeking answers by studying the effects of exercise on a process that plays a critical role in insulin signaling within skeletal muscle.
Zhengping Yi, Ph.D., associate professor of pharmaceutical sciences in the Eugene Applebaum College of Pharmacy/Health Sciences and director of the Proteomics Research Laboratory, recently received a three-year grant from the American Diabetes Association for a project titled “Effect of Exercise on Human Skeletal Muscle Tyrosine Phosphoproteome.” The award is $180,000 for the first year and up to $200,000 per year for the next two years.
Muscles require energy to help people move, and sugar taken up from circulating blood is a very important source of that energy. After a meal, blood sugar increases, and the pancreas secretes insulin, which triggers cells — mainly those of skeletal muscle — to absorb the sugar. In obese adults, muscle cells commonly do not respond well to insulin, resulting in a condition called skeletal muscle insulin resistance, a main cause of type 2 diabetes.
Yi’s project focuses on the possibility that exercise induces specific yet undiscovered cellular events within skeletal muscle that can allow insulin to work more effectively to help take up blood sugar. Specifically, he is exploring how exercise affects the process of adding and/or removing a phosphate-group (i.e., phosphorus and four oxygen molecules) to or from different proteins at specific locations on those proteins.
Such “phosphorylation” or “de-phosphorylation” events provide important signals for many important cellular processes, including muscle cell uptake of sugar in response to insulin. For example, several reduced protein tyrosine phosphorylation (pTyr) events are known to occur in the skeletal muscle of insulin-resistant individuals; it serves as an early warning sign of the potential for developing type 2 diabetes.
Proteomics, Yi’s field of expertise, is relatively new and capable of determining hundreds of proteins and their phosphorylation events simultaneously. Consequently, he said, proteomics can provide a global picture of pTyr events under various conditions.
Yi’s project is the first to examine exercise’s effects on a set of proteins known as the tyrosine phosphoproteome in the skeletal muscle of humans. Using a technique called high-performance liquid chromatography nanospray-tandem mass spectrometry (HPLC-ESI-MS/MS), he will test his hypothesis that exercise improves insulin sensitivity by increasing novel pTyr events within skeletal muscle.
The overall goal, Yi said, is to identify the molecular mechanisms responsible for the improved insulin action commonly found after exercise, and to provide novel targets for prevention and treatment of type 2 diabetes. He believes pTyr, while not the only such mechanism, plays a major role in insulin signaling in skeletal muscle cells.
“If we can find a way to reverse the reduction of pTyr early enough, it may be possible to keep people from developing more severe levels of insulin resistance and type 2 diabetes,” Yi said.
Yi’s team, which includes University of Michigan researchers led by Jeffrey F. Horowitz, Ph.D., professor of movement science and director of the Substrate Metabolism Laboratory, will compare the tyrosine phosphoproteome of skeletal muscle from obese, sedentary, insulin-resistant and obese, physically active adults. Researchers will test whether insulin-stimulated pTyr is enhanced in the physically active adults compared to sedentary ones; they also will analyze other metabolic processes.
Using the same approaches, researchers will then examine the effects of a single session of mild-intensity exercise on changes in the tyrosine phosphoproteome in skeletal muscle from obese sedentary and physically active adults. Importantly, a single session of exercise is known to profoundly improve insulin resistance for several hours, even into the next day. Many researchers believe the transient improvement after each exercise session may be the main reason why exercise is associated with improved insulin resistance (i.e., the effects of each session may be more important than adaptations associated with months or even years of exercise training).
Yi’s findings may be used to optimize therapeutic and preventive treatment programs, and to design drugs targeted at improving metabolic health. To do that, additional research is needed to identify and develop drugs that can correct the abnormalities Yi and his team will discover in the skeletal muscle tyrosine phosphoproteome of insulin-resistant participants.
Such drugs would be especially useful for people who cannot exercise; they also can be combined with exercise to improve insulin sensitivity and prevent type 2 diabetes, as well as other metabolic diseases.
Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit http://www.research.wayne.edu.