A protein called MondoA has been identified by researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) as a new potential target for drugs to prevent type 2 diabetes. The chronic condition accounts for between 85 and 95 percent of all people with diabetes.
A paper published Monday in the Journal of Clinical Investigation shows that blocking a cellular glucose sensor in muscle improves insulin responsiveness. In type 2 diabetes, there is not enough insulin in the body, so blood cells are only partially unlocked and glucose builds up in the blood.
"Our new study shows that a protein called MondoA may serve as a key link between insulin resistance and accumulation of fat in muscle, which occurs in obesity-related diabetes," Daniel P. Kelly, M.D., professor and director of SBP's Center for Metabolic Origins of Disease, said. "This study is the first step towards testing MondoA-targeted drugs to prevent type 2 diabetes in pre-clinical studies."
Type 2 diabetes affects about 8 percent Americans and another 25 percent of the population is at risk because of obesity. The condition accounts for as much as 20 percent of all healthcare costs in the U.S.
Insulin resistance, in which insulin no longer causes the body's cells to take up the glucose from a meal and use it for energy, leads to type 2 diabetes. Following this, glucose continues to circulate in the blood, stimulating the pancreas to make more and more insulin, which eventually becomes so stressful that the insulin-producing cells die. This results in diabetes as the pancreas can no longer produce enough insulin to control blood glucose.
"Investigating the cellular effects of SBI-477, the best hit molecule from our screen, led us to MondoA," Kelly said while talking about the research that focused on skeletal muscle because it is the main insulin-responsive tissue in the body. "Our experiments showed that this protein regulates genes involved in synthesizing fats as well as inhibiting insulin signaling.
"Until now, it wasn't clear why people who are insulin resistant accumulate fat in their muscle," he explained. "These results show that MondoA is one mechanism that ties these phenomena together, serving as a gatekeeper for fuel burning in muscle."
Kelly also said that researchers believe that “MondoA normally responds to oversupply of glucose by inhibiting transport of glucose into cells and enhancing its conversion to fat, but persistent activation promotes insulin resistance.”