COLLEGE STATION – Diabetes can be a killer, but the recent findings of four Texas A&M University researchers could lead to new ways to study and fight the dreaded disease.
Diabetics not only have high blood glucose (sugar) levels, they also have elevated fatty acid levels because they have trouble metabolizing glucose and fatty acids. In the past, scientists have studied the glucose and fatty acid aspects of diabetes separately because there was nothing linking them together.
Texas A&M researchers Heather Hostetler, Huan Huang, Ann Kier, and Friedhelm Schroeder, however, were able to link the two areas of study by identifying a single molecule in the nucleus of cells that regulates the metabolism of both glucose and fatty acids. The results of their study were recently published in the Journal of Biological Chemistry.
Scientists have long known that fatty acids bind with a protein called PPAR-alpha in the nucleus of cells. PPAR-alpha is a nuclear receptor, which means it is responsible for regulating the expression of specific genes. When fatty acids bind to PPAR-alpha, certain genes are turned on or off to control the metabolism of fatty acids.
Hostetler and her colleagues recently found that glucose also binds to PPAR-alpha, which presents an opportunity for scientists to study and understand one mechanism that regulates both glucose and fatty acid metabolism.
“This provides a direct link for the first time between fat and sugar metabolism and shows they are intimately linked and share the same receptor in the nucleus,” Schroeder said. “This could be a paradigm-shifter and cause people to rethink the way they look at diabetes because we now have a central player – PPAR-alpha – that’s impacted by both glucose and fatty acids.”
Normally, a hormone called insulin signals a person’s cells to take in and metabolize glucose. In diabetics, however, either not enough insulin is being produced or the person’s insulin receptors are not working. This causes some of the body’s cells to not take in glucose properly, and glucose builds up in the bloodstream, Kier explains.
Abnormally high levels of glucose in the bloodstream can severely damage a person’s blood vessels. Also, some cells in the body do not need insulin to take in glucose, and when high levels of glucose build up in these cells, it can lead to problems such as accelerated cardiovascular disease, kidney disease, nerve damage and damage to the retina of the eye.
Research conducted by Hostetler and her colleagues suggests that PPAR-alpha normally binds with both glucose and fatty acids in a very precise balance to regulate their metabolism. To metabolize fatty acids, PPAR-alpha breaks them up into small pieces and can then either burn them or make glucose out of them to store for later use, Schroeder explains.
When the balance is thrown off as it is in diabetics, however, the group’s research suggests that the high level of glucose over-stimulates PPAR-alpha, which causes it to malfunction and turn most of the fatty acid into glucose. This causes even more glucose to build up, which makes the situation even worse.
The group’s findings could also lead to the development of new drugs to prevent or reverse the harmful side effects of diabetes, which is the sixth leading cause of death in Texas. “All at once, it’s like a whole new ballgame,” Schroeder said. “The new findings open up a whole new potential class of therapeutic agents.”
One possibility is a drug that would block glucose from binding to PPAR-alpha, which would prevent PPAR-alpha from becoming over-stimulated and producing even larger amounts of glucose, Schroeder said. So far, the group has tested 1,040 drugs and found five that were able to reverse the harmful effects of high glucose on PPAR-alpha and restore the compound to its normal function.
The group hopes its findings will bring scientists together and lead to studying diabetes in a new way. “I think our findings will stimulate a lot more research that tries to understand fatty acids and glucose together, rather than in separate worlds,” Kier said. “This basic research is important because scientists can’t really progress until they go back and understand the process and how things happen physiologically.”
Journal
Journal of Biological Chemistry