ECU research sheds light on origin of type 2 diabetes

GREENVILLE, N.C. —   A discovery made by East Carolina University researchers could change the way people understand and treat conditions leading to type 2 diabetes. 

The study, according to Darrell Neufer, research contributor and professor in ECU’s Department of Exercise and Sport Science and the Department of Physiology, provides evidence that insulin resistance – a precondition that leads to diabetes – is caused by a disruption in the cell’s metabolic balance. 

“We have found that the elevated production of hydrogen peroxide is a primary event that leads to insulin resistance in muscle,” he said. 

To explain, Neufer compared the inner workings of a cell to an engine. Every cell has engines – or mitochondria – that are responsible for breaking down food to provide the energy consumed by the cell. However, when too much food is in the cell relative to need, the engine releases hydrogen peroxide. This signals to the cell that it is out-of-balance and leads to insulin resistance. 

The researchers showed that by either blocking the production or preventing the release of hydrogen peroxide from the mitochondria, they were able to prevent the development of insulin resistance in rodents fed a high-fat diet. They also showed that after five days of a high-fat diet, lean, college-aged men experienced a dramatic increase in the production of mitochondrial hydrogen peroxide.

“Our hypothesis is that insulin resistance may not be a chronic disease state, but a state that the cell moves into because of the nutritional overload it is under,” Neufer said. “If you relieve the overload by reducing caloric intake or by increasing physical activity, the insulin resistance will quickly reverse.” 

Ethan Anderson, lead author on the paper and research associate in ECU’s Department of Cardiovascular Sciences, said, “This paper represents somewhat of a paradigm shift in the way that the etiology of insulin resistance is viewed. We hope that it prompts rigorous follow-on studies to provide more information as to how mitochondrial hydrogen peroxide is connected to insulin signaling in skeletal muscle.”

In their study, the researchers also implemented a new molecule, an antioxidant that targets the mitochondria, which may lead to new treatments for insulin resistance and other types of metabolic disease. Anderson is currently exploring ways this molecule can be used to study human cardiovascular disease and as a potential therapy for patients recovering from cardiac surgery to alleviate post-operative complications. 

“Cardiac disease, stroke, cancer – all of these things and more could be potential targets for this molecule. There is the possibility for its use in numerous applications in both basic research and medicine,” he said. 

A paper based on the research, “Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance,” will appear in the March issue of the Journal of Clinical Investigation. An online version of the article is available now: http://www.jci.org/articles/view/37048 . 

Contributions were made by researchers from ECU’s Metabolic Institute for the Study of Diabetes and Obesity and other ECU departments, the Department of Molecular Physiology and Biophysics at Vanderbilt University, the Department of Pathology at University of Washington and the Department of Pharmacology at Weill Medical College of Cornell University.